Essentials of Diagnosis, Treatment, and Application of Cardiac and Peripheral Vascular Diseases

Essentials of Diagnosis, Treatment, and
Application of Cardiac and Peripheral

Vascular Diseases
List of Authors:
Lv Yan, MD
Head Supervisor, Deputy Chief Physical and Associate Professor of the
First Hospital of China Medical University (Department of Cardiology)
Li Xi, MD
Lead vascular/thyroid surgeon in the First Hospital of China Medical
University and a guest lecturer at China Medical University
Fang Yi, MD
lead surgeon and lecturer in the First Hospital of China Medical
University (Ultrasound Department)
Jing Yuchen, Master of Medicine

chief of surgery and lecturer of the First Hospital of China Medical
University (Vascular/Thyroid Surgery Department)
Wang Hao
head nurses of the First Hospital of China (Neurosurgery Department)
Series Editor:
Simon Zhang
Preface:
In the past few decades, many advances have been made in the diagnosis and
management of cardiovascular diseases. "Essentials of Diagnosis, Treatment, and
Application of Cardio and Peripheral vascular Diseases" is intended to serve as a
clinical resource for healthcare professionals who evaluate and manage patients with
cardiovascular and related diseases in various forms and challenges.
The author strives to provide short, focused chapters so that busy practitioners
can quickly find the information they need when facing specific symptoms and
manifestations of coronary heart disease, hypertension, other heart diseases,
abdominal aortic aneurysms and aortic dissecting aneurysm, etc. The content covers
specific management issues in various aspects of cardiac and peripheral vascular
diseases, including: epicardial coronary artery related diseases, coronary
microcirculation disorders, arrhythmia, basic vascular surgery skills, perioperative
physical assessment and assessment, diagnosis, treatment of aneurysms, etc. The last
part of the book reviews ultrasound and postoperative care, which are also two
integral parts of the treatment of cardiac and peripheral vascular diseases. The
appendix of each chapter provides the standard reference table of this book. More
importantly, this book complements traditional textbooks by providing professional
treatments by experienced clinicians from the First Hospital of China Medical
University.
We hope you find this book as an invaluable resource, whether it is as one

part of the surgical training, during preparation for an exam, or complementing your
day-to-day clinical practice
Lv Yan
Li Xi
Fang Yi
Jing Yuchen
Wang Hao
American Harmony Medical Academic Publisher
© 2021 American Harmony Medical Academic Publisher (Zhang & Ding, LLC). All rights
reserved.
First edition 2021

First Edition July 2021
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Contents:
SECTION I: Cardiology
Chapter 1 : Epicardial Coronary Artery Related Disease 1
Chapter 2 : Coronary Microcirculation Disorders Related Diseases 14
Chapter 3：Hypertension and its Related Heart Disease 37
Chapter 4：Arrhythmia 54
Chapter 5 : Cardiomyopathy 71
Chapter 6：Heart Failure 90
Chapter 7 : Evaluation and Management of Heart Disease 108
SECTION II: Vascular Surgery
Chapter 8： Basic Techniques of Vascular Surgery Diagnosis 110
Chapter 9 ：Basic Skills of Vascular Surgery 123
Chapter 10：Endovascular Intervention Technique 138
Chapter 11 ：Physical Assessment and Evaluation During the Perioperative

Period 152
Chapter 12： Vascular Trauma 162
Chapter 13 ：Peripheral and Abdominal Aortic Aneurysms 175
Chapter 14 ：Aortic Dissecting Aneurysm 188

Chapter 15 ：Other Aneurysms 201
Chapter 16 ：Buerger's Disease (Thromboangiitis Obliterans) 215
Chapter 17 ：Mesenteric Vascular Disease 227
Chapter 18 ：Renal Artery Disease 239
SECTION III : Ultrasound

Chapter 19 ：Ultrasound 248
SECTION IV: Preoperative and Postoperative Care

Chapter 20: Preoperative and Postoperative Care of Vascular Related Diseases
264
Essentials of Diagnosis, Treatment, and Application of Cardiac and Peripheral Vascular Disease
Chapter 1 Epicardial Coronary Artery Related Disease
Lv Yan, M.D.
1. Introduction:
Atherosclerotic disease of the epicardial coronary artery has been considered the cause of
angina for more than two centuries. For more than 100 years, the sudden thrombotic occlusion of
the epicardial coronary artery has been recognized as the cause of acute myocardial infarction
(AMI). The introduction of coronary angiography in the late 1950s made it possible to visualize
the contours of the epicardial coronary artery tree in vivo. In 1970, coronary artery bypass
grafting, and percutaneous coronary intervention (PCI) were developed. These three technologies
have been continuously improved over the years and have been successfully applied to millions
of patients worldwide.
However, the epicardial artery is only part of the coronary circulation. They produce
smaller arteries and arterioles, which then supply capillaries and constitute coronary
microcirculation, which is the main part of regulating myocardial blood flow. In the past 20
years, many studies have shown that the functional and structural abnormalities of coronary
microcirculation occur under different clinical conditions. In some cases, these abnormalities
represent side-band phenomena, and in other cases, they represent important signs of risk, and
may even help discover the pathogenesis of myocardial ischemia, thus becoming therapeutic
targets.
a. Functional Anatomy of The Coronary Circulation:
The coronary artery system consists of three compartments with different

functionalities, although boundaries of each compartment may not be clearly defined
anatomically (Figure 1.1).The proximal ventricle is represented by the large epicardial coronary
artery, also called conducting vessel. They are mostly surrounded by adipose tissues, have thick
walls, three layers, are well-represented which are adventitia, media, and intima, and have
vascular feeding tubes with diameters ranging from approximately 500μm to 2-5 mm. These
arteries have capacitive function and have little resistance to coronary blood flow (CBF) (Figure
1.1 A). Their distribution is divided into three modes.
The type I branch pattern is characterized by many branches that decrease in diameter as
they approach the endocardium. The type II branch pattern is characterized by fewer proximal
branches passing through the wall to the subendocardium of the trabecula and papillary muscles.
This is an arrangement that facilitates blood flow to the subendocardium. Type III is
characterized by small proximal branches of the epicardial blood vessels, which vascularize the
subspicardium. During systole, the epicardial artery accumulates elastic energy when the blood
content increases by approximately 25%. This elastic energy is converted into blood kinetic
energy at the beginning of diastole, which helps to quickly reopen the blood vessels in the heart
muscle. Closed by the systolic squeeze. If 90% of CBF occurs during diastole, the latter function
is particularly relevant. The more distal branches of the branches of the coronary arteries have
1
intramural pathways (intramural arteries) and have a thinner wall than the epicardial branches.
They do not have vascular feeling tubes (see Figure 1.1).
The middle compartment is represented by the pre-arteriolar vessels. (Figure 1.1B)

These small arteries are approximately 100 to 500 μm in diameter and are characterized by a
measurable pressure drop along their length and are not controlled by the direct vasomotor
control of diffusible myocardial metabolites. Their specific function is to maintain the pressure at
the origin of the small arteries within a narrow range when the coronary perfusion pressure or
blood flow changes. The closer end (500 to 150μm) mainly responds to changes in flow, while
the far end (150 to 100 μm) is more sensitive to pressure changes. The distal compartment has a
diameter of less than 100 μm and is characterized by a significant drop in pressure along its path.
Arterioles are the site of metabolic regulation of blood flow because their tone is affected by the
substances produced by surrounding myocardial cells during metabolic activity.
b.Regulation of Myocardial Blood Flow:
Myocardial blood flow (MBF) is used to reflect the tissue perfusion, that is, the volume
of blood per unit of time and per unit of cardiac mass (mL/min per g). MBF should be
distinguished from CBF because CBF is used to indicate the volume of blood that flows along a
vascular bed over a time unit (mL/min).
The cardiac pump is an aerobic organ. It requires continuous perfusion of oxygenated

blood to produce Adenosine Triphosphate (APT) and APT is necessary for contraction. The role
of the coronary circulation is to provide an adequate matching between myocardial oxygen
demand and supply. In the resting state, the tension of the coronary microvasculature is high.
When myocardial oxygen consumption increases, this intrinsically high resting tone causes the
coronary circulation to increase flow (such as oxygen extraction from arterial blood is already
close to 60%-70% under baseline conditions) through rapid changes in the diameter of small
arteries, a mechanism called functional hyperemia.
The decrease in arteriolar resistance drives a series of subsequent vascular adaptions

involving all upstream coronary vessels. The initial arteriolar response is driven by the strict
cross-talk that exists between these vessels and contracting cardiomyocytes, which is basis of
metabolic vasodilatation. The integrated coronary response to changes in myocardial oxygen
consumption involves (1) metabolic vasodilation, (2) pre-arteriolar autoregulation, (3) flow-
mediated (endothelium-dependent) vasodilation, (4) extravascular tissue pressure, and (5)
neurohumoral control.
2
Figure 1.1 Source: Chronic Coronary Artery Disease A, Author: James A. De Lemos and TorbjornOmland.
2. Acute coronary syndrome (ACS)
ACS is the result of a plaque ruptures with partial or complete obstruction of the artery.
When blood clots form around the rupture area, the obstruction happens, which leads to the
3
portion of the myocardiumsuppliedby that artery quickly suffers from a shortage of oxygen, i.e.,
ischemia. Myocardial infarction may happen if the obstruction is extensive enough.
There are three subgroups of ACS including STEMI (ST-segment elevation myocardial
infarction), NSTEMI (Non-ST-Segment Elevation Myocardial Infarction),Unstable Angina and
Sudden Death. The diagnosis and treatment shall be prompt and appropriate because ACS carries
substantial and significant morbidity and mortality.
STEMI can be the results of prolonged and complete of epicardial coronary blood vessel.
It is defined based on ECG1 criteria. In contrast, severe coronary artery narrowing, transient
occlusion, or microembolization of thrombus and/or atheromatous material usually are the
attributors of NSTEMI.
Most percutaneous coronary interventions (PCI) are performed on patients with an acute
coronary syndrome (ACS). The Syndrome includes patients with acute ST elevation myocardial
infraction2 (STEMI) and the two non-ST-elevation entities, non-ST-elevation MI (NSTEMI) and
unstable angina3 (UA).
Figure 1.1(a) Source: Angina Pectoris; Web Page:https://byjus.com/biology/angina-pectoris/
a. Patients with ST-Segment Elevation Myocardial Infarction
The symptom of STEMI includes intense pain or pressure in or around the chest,
radiating to the neck, jaw, shoulder, and/or arm. In addition, sweating, breathlessness, and a
profound sense of impending doom may also be the results of STEMI.
1
ECG is the abbreviation of electrocardiogram which is a medical test that detects cardiac abnormalities by
measuring the electrical activity generated by the heart as it contracts.
2
ST elevation myocardial infarction: ST-segment elevation myocardial infarction (STEMI) is the term cardiologists
use to describe a classic heart attack. It is one type of myocardial infarction in which a part of the heart muscle
(myocardium) has died due to the obstruction of blood supply to the area.
3
Angina: a sudden intense pain in the chest
4
Sometimes, the signs can be less noticeable because of the nonspecific or generalized
symptoms such as: Pain around the shoulder blades, arm, chest, jaw, left arm, or upper abdomen;
discomfort or tightness in the neck or arm; Indigestion or heartburn; Nausea and vomiting;
Fatigue or sudden exhaustion; shortness of breath, etc.
STEMI can cause sudden death due to the ventricular fibrillation4 or acute heart failure as
the heart cannot pump enough blood to properly supply the body. The occurrence of such heart
attack may lead the muscle itself suffering substantial permanent damage and the consequence of
Chronic heart failure. It also increases the risk of dangerous cardiac arrhythmias (irregular
heartbeats).
When STEMI is diagnosed, Treatment must be conducted. First is to administering drugs

to stabilize the myocardium including statin5medications, aspirin, beta-blockers, and morphine,
etc. To prevent permanent damages occurred to the patient, the artery should be opened within
three hours of the blockage. However, most of the damages can be avoided or at least minimized
if the artery is unblocked within the first six hours of an attack. Once the acute phase of
treatment is over and the block artery is reopened, an extensive period of recovery (an exercise-
based rehabilitation program, dietary changes, and the use of anticoagulants and lipid control
medications) should be done to stabilize the heart, and to reduce the risk of another heart attack.
b. The Patient with Non-ST-Elevation Acute Coronary Syndrome
The preeminent objective for management of acute STEMI remains achievement of early
and complete reperfusion of the infarct artery. In contrast, goals for the management of patients
with NSTE-ACS include the alleviation of symptoms and stabilization of the clinical condition
to prevent further adverse outcome.
Significant understanding of NSTE-ACS pathophysiology has accumulated, yet diverse

anatomic and mechanistic factors create a heterogenous disorder enhancing the value of
informed clinical judgment.A plethora of evidence-based treatment options are available. Clearly,
PCI has an essential role in the management of NSTE-ACS. The interventional operator
encounters a variety of clinical situations and approaches as patients present to the
catheterization laboratory; this requires comprehensive knowledge of an integrated therapeutic
approach to optimize patient outcomes and mitigate risk.
The patient population with NSTE-ACS manifests a broad spectrum of risk. In the Global
Utilization of Streptokinase6 and TPA for Occluded Arteries (GUSTO-llb) trial, recurrent
ischemia at 1 year occurred more often in patients with NSTE-ACS than STEMI (35% versus
4
Fibrillation of heart muscles resulting in interference with rhythmic contractions of the ventricles and possibly
leading to cardiac arrest.
5
A medicine that lower blood cholesterol levels by inhibiting HMG-CoA reductase.
6
An enzyme produced by some strains of streptococcus that can liquefy blood clots by converting plasminogen to
plasmin; used medicinally in some cases of myocardial infarction and pulmonary embolism.
5
23%, p <0.001). Mortality was also higher in patients with NSTEMI than STEMI (11.1%
versus 9.6%, p < 0.05) (1).
The contemporary Global Registry of Acute Coronary Events (GRACE) reported 6-

month mortality of 13% for NSTEMI and 8% for UA, with 20% of both groups requiring
readmission for ischemic events.
Moreover, patients classified as “low risk” exhibited a 2.2% mortality, with a

readmission rate of 16.6% (2). Despite therapeutic progress, considerable peril remains for
recurrent adverse events. Even 15.4% of patients receiving proven treatment advances
(glycoprotein llb/llla inhibition and an invasive strategy) in the Treat Angina with Aggrastat7 and
determine cost of therapy with an Invasive or Conservative Strategy (TACTICS TIMI-18) trial
experienced a primary endpoint event of death, MI, or readmission for ACS at 6 months (3).
c. Modern Concepts of Acute Coronary Syndrome Pathophysiology
The principal pathobiology of ACS involves plaque8 disruption and the consequences.
Anatomic factors increase the vulnerability of plaques to rupture, including positive arterial
remodeling with a large lipid core and a thin fibrous cap.
The extension of knowledge regarding the atherothrombotic process of ACS is perhaps as

important as therapeutic progress. Inflammation now is recognized as central to the dynamic
transformation occurring within the coronary vasculature.
A variety of inflammatory mediators result in leukocyte (primarily monocytes)

infiltration and degradation (metalloproteinases) of the plaque fibrous cap. Interrelated
mechanisms involving inflammatory and thrombotic pathways (such as tissue factor expression
by macrophages9) lead to thrombus formation and the clinical ACS.Embolization of plaque and
thrombus leading to microvascular obstruction and myocardial necrosis is characteristics of the
ACS patients.
The focal event resulting in presentation with an ACS is a manifestation of systematic

process.Markers (CRP, Il-6, Serum amyloid A, ICAM-1) can be measured as an index off this
widespread inflammatory response. This has been confirmed anatomically in the coronary
circulation with evidence for neutrophil activation distant from the culprit lesion in patients with
UA.
7
Aggrastat: Tirofiban (INN, trade name Aggrastat) is an antiplatelet drug. It belongs to a class of antiplatelet named
glycoprotein llb/llla inhibitors. Tirofiban is the first drug candidate whose origins can be traced to a pharmacophore
based virtual screening lead.
8
A small distinct typically raised path or region resulting from local damage or deposition of material, such as a
fatty deposit on an artery wall in atherosclerosis or a site of localized damage of brain tissue in Alzheimer’s disease.
9
A large phagocytic cell found in stationary form in the tissues or as a mobile white blood cell, especially at sites of
infection.
6
Multiple complex angiographic lesions and ultrasound-identified plaque ruptures have

been revealed in non-culprit vessels after both STEMI and NSTEMI. The presence of multiple
complex plaques is associated with recurrent ischemic events.
PCI in the environment of multicentric inflammatory arterial disease and ACS influences
procedural results and long-term outcomes. Elevated preprocedural results and long-term
outcomes. Elevated preprocedural C-reactive protein levels predict early complications and
restenosis after PCI (9,10). Embolization also remains a hazard of PCI procedures and may be
interrelated to the inflammatory process.
d. PCI for Unstable Angina and Non-ST-Elevation Myocardial Infarction
PCI generates therapeutic benefits for patients with ACS by relieving angina, stabilizing
the acute event, and enhancing the overall prognosis. Considerable technological progress has
widened the application of PCI to an expanded, more complex population of patients with
improved safety and durability.
Historically, the procedural success rate of BA in NSTE-ACS is comparable to that in

patients with stable angina, but the risk off major complications has been consistently higher.
This was particularly evident in the initial National Heart, Lung, and Blood Institute (NHLBI)
PTCA Registry. The complex lesion morphology present in ACS increases the complication risk.
The large lipid core of the ACS lesion enhances the risk for thrombogenic complications.
Intracoronary thrombus amplifies the risk off abrupt closure and its consequences. Yet,
the BA procedure success rate was 96.1% for patients with NSTE-ACS in the TIMI IllB trial
(periprocedural infarction 2.7%, emergency bypass surgery 1.4%, death 0.5%). Unstable angina
has been identified as a risk factor for restenosis.
More contemporary progress in revascularization methods is exemplified by 3,192

patients in the NHLBI Dynamic registry. Although more complex patient and lesion
characteristics were present in unstable angina, procedural success without major complication
was equivalent to stable angina patients (92.3% versus 91.2%). In-hospital (0.7% versus 0.3%, p
= NS) and 1-year (4.5% versus 3.1%, p = NS) mortality was also statistically similar. This
progress also is illustrated by patients undergoing PCI at the Mayo Medical Center since 1979
(Table 33.1). Despite conducting the procedure on order and more complex patients, clinical
success improved and resulted in fewer complications and a higher event-free survival at 1 year.
3. Chronic Coronary Syndrome
Based on a classic history of angina pectoris10 or known atherosclerotic cardiovascular

disease, patients may be given the diagnosis of Chronic Coronary Syndrome. The symptom of
Stable Angina includes chest discomfort occurs predicably and reproducibly at a certain level of
exertion. It is relieved with rest or nitroglycerin.
10
Angina pectoris, or angina for short, refers to chest discomfort that occurs when myocardial oxygen demands
exceeds oxygen supply.
7
Some patients may have stable disease but not experience classic anginal symptoms. For
example, they may have atypical chest pain, dyspnea on exertion or silent ischemia especially for
patients with diabetes mellitus. These symptoms are usually brought on exertion, emotional
stress, cold, or a heavy meal and are relieved by rest or nitroglycerin within minutes. Stress
testing or an invasive evaluation of the coronary circulation can confirm such patients’ diagnosis
of CCS.
a. Revascularization Approaches
With the accumulation of scientific information and technological progress, indications

of coronary revascularization in patients with Chronic Coronary heart disease are also constantly
evolving. The benefits associated with prompt coronary revascularization have been widely
accepted in terms of reducing the cardiovascular death and non-fatal myocardial infarction (MI)
in patients with Acute Coronary Syndrome (ACS). Nevertheless, there is little clinical evidence
that patients with stable symptoms undergoing coronary revascularization have reduced hard
clinical endpoints.
Clinical data generally supports and clinicians traditionally accept that coronary
revascularization inn patients with Chronic Stable Ischemic Heart Disease (SIHD) is suitable for
patients with high risk of future cardiovascular events or with lifestyle-limiting symptoms. Both
clinical guidelines and standards for the appropriate use of coronary revascularization provide
specific recommendations for clinicians considering a revascularization strategy in patients with
SIHD.
It has been estimated that about half of the risk reduction is directly attributable to
improved medical treatment and coronary revascularization surgery. Most of the risk reductions
are related to the improvements of medical treatment, rather than coronary revascularization
surgery. In recent years, because of the increasing number of social obesity and the prevalence of
diabetes, this improvement in cardiovascular risk has been diminished.
b. Goal of the Revascularization Treatment
The main goals of treatment for patients with chronic coronary artery disease (CAD) are
to reduce symptoms, improve quality of life (QoL), and reduce the risk of death and Myocardial
Infarction (MI).Risk factor modification and optimal drug treatment are basic strategies. Despite
the use of these evidence-based medical therapies, patients often have persistent symptoms and
residual cardiovascular risks. Data from large, multinational, and longitudinal outpatient
registries estimate that one-third of patients have active symptoms, one-quarter of patients have
evidence of ischemia, and both are associated with future cardiovascular risk.
The decision to recommend coronary revascularization for SIHD patients should be

carefully considered. Discussions with patients and family members should include a transparent
discussion of all treatment options, anticipated benefits, and risks of potential complications. In
general, the discussion of initial drug treatment should be discussed with the patient. In today's
healthcare environment, it is generally believed that patients with chronic stable angina pectoris
should receive evidence-based medical treatment initially and can be optimized over time. This
8
will include medications for angina pectoris, lifestyle interventions, and treatments to reduce
future cardiovascular risks. When patients undergo cardiac catheterization and the anatomy is
suitable for percutaneous coronary intervention (PCI), the trend in the past decade has been to
perform temporary PCI Instead of postponing. Temporary PCI occurs in the United States
approximately 86% of the time.
For selective indications, postponement of PCI can consider alternative treatment

strategies, especially in the case of high-risk multivessel CAD. In addition, certain clinical
situations are more suitable for PCI, while others are more suitable for coronary artery bypass
grafting (CABG). For example, patients who are medically non-compliant or who have recently
experienced gastrointestinal bleeding associated with peptic ulcer disease may not be the best
candidates for long-term dual antiplatelet therapy but may be suitable candidates for CABG. On
the other hand, patients with high clinical comorbidities or high weakness and three-vessel CAD
with impaired left ventricular (LV) dysfunction are expected to obtain survival benefits through
CABG, but the risk may be too high and more appropriate. Referral for multivessel PCI. These
and various other issues can usually be better reviewed by the heart team approach. This requires
interrupting the nursing process to allow multidisciplinary team discussions and getting busy
practitioners willing to meet and discuss clinical cases. The method of the Heart Team,
especially in complex situations, is desirable.
4. Typical Case Study: 77-year-old Female with Chronic Coronary Artery Disease,
Upper Limb Thrombosis, ParoxysmalAtrial Fibrillation and Cardiac Arrest.
a. Medical Record and History:
A77-year-old female was admitted due to pain and swelling of the left upper limb
swelling. Before she had been admitted to hospital at the age of 73 years, due to her chest angina
on heavy excise for 8 months, and thenshe accepted a PCI and stents were placed in the left
anterior descending branch and left circumflex.
On that occasion, she reported hypertension, glucose intolerance, hypercholesterolemia,

hypertriglyceridemia, family history of sudden death, and smoking cessation at the age of 51
years.
Her physical examination proved that her heart rate was 60 bpm and her blood pressure
was 150/80 mmHg. Her heart, lungs, and abdominal examinations were normal. There was no
edema in the lower extremities and the pulse was symmetrical.
An electrocardiogram shows sinus rhythm, with the T wave inverted from V1 to V5,II III
aVF(Figure 1.2).
9
Figure 1.2 ECG. Sinus rhythm, with the T wave inverted from V1 to V5,II III aVF.
In August 2019, the patient presented with angina pectoris during moderate exercise, and
then underwent coronary angiography (August 22, 2019). The results showed: intra stent
restenosis 90% and 80% of the LAD; left circumflex artery is 90% blocked;proximal of the right
coronary artery is blocked; and left ventricular EFis preserved, and CABG was suggested(Figure
1.3)
Figure 1.3 The result of CAG Source: the First Hospital of China Medical University.
On September 15, 2019, the patient developed persistent chest pain while resting.
Laboratory examination showed: hemoglobin 12.1 g/dL; Triglycerides, 223 mg/dL; Total
cholesterol, 175 mg/dL; HDL-cholesterol, 47 mg/dL; Low-density lipoprotein cholesterol, 83
mg/dL; creatine kinase MB mass, 0.2 ng/mL; troponin, 0.064 ng/mL.
The electrocardiogram on September 15, 2019 showed sinus rhythm, diffuse ventricular
repolarization changes in V1-V6 (Figure Figure 1.4).
10
Figure 1.4 ECG. Sinus rhythm, diffuse ventricular repolarization changes.
The test on September 29, 2011: hemoglobin 10.5g/dL; creatine kinase MB mass, 13.19
ng/mL; troponin I, 1.22 ng /mL;The patient received a temporary pacemaker implantation, but
refractory shock persisted. She suffered a new cardiac arrest and noresponding to resuscitation.
She died on September 29, 2019.
b. Clinical Aspects:
The patient was a 77-year-old woman who underwent percutaneous angioplasty and stent
placement due to chest pain. She was asymptomatic for 4 years. Angina pectoris reappeared, and
after a new transdermal intervention, she died. She underwent seven coronary angiographies,
three of which underwent angioplasty and stent implantation. The fifth and seventh operations
had complications.
In the case discussed, female patients receiving therapeutic of percutaneous coronary

intervention increased the risk of pseudoaneurysm formation. Expected treatment of femoral
pseudoaneurysm assumes that the diameter of the blood vessel is less than 2 cm. The reason for
not using ultrasound-guided percutaneous injection of thrombin may be the possibility of
spontaneous thrombosis of the vascular contents11.
A study of 7472 elderly people in their eighties (average age 83) who received
percutaneous coronary intervention reported a mortality rate of 0% to 19%, and the mortality rate
for patients over 85 years old was about 5%. The predictive factors of the rate are as follows:
Cardiogenic shock (31%); Acute myocardial infarction (11%); Lower ejection fraction (35%);
11
Pinto DM, Junior JO, Fonseca BL, Moreialvar RD, Bez LG, Lopes CS. Experiênciainicial com o uso de adesivo
tissular contendotrombina para tratamento do pseudoaneurisma femoral. J Vasc Bras. 2006;5(1):30–36.
11
Renal failure (7.2%); First coronary intervention (2.7%); Patients over 85 years old (1.8%); and
diabetes (1.2%)12.
A meta-analysis of 63 studies (1852 symptomatic and asymptomatic patients diagnosed

with chronic coronary artery disease, with an average age of 56 to 65 years) supports the
optimization of drug treatment as the initial choice for patients with chronic coronary artery
disease. Recommendations for comparing four surgical possibilities (percutaneous coronary
intervention and drug therapy; stent angioplasty and traditional balloon angioplasty; stent
angioplasty and drug therapy; drug-eluting stent angioplasty and bare metal Stent angioplasty),
there is no difference in mortality, acute myocardial infarction, coronary artery bypass surgery or
new surgery within 12 months13.
In the case discussed, 4 years after coronary artery disease stratification and percutaneous
coronary intervention, the patient developed angina pectoris during moderate exercise, which
indicates that percutaneous and drug revascularization treatment strategies to control risk factors
had not been able to stop the disease progression.
The patient's sudden clinical deterioration suggests that the release of mediators causes
hypoxemia and hypotension, and the differential diagnosis of sepsis and pulmonary
thromboembolism is required. The rapid process of arrhythmia, hypotension, severe hypoxemia,
and pulseless electrical activity in cardiac arrest may be related to a massive pulmonary
embolism14. A study confirmed that 79% of patients with pulmonary embolism have evidence of
deep vein thrombosis of the lower extremities. Among genetic or acquired risk factors, advanced
age and antiphospholipid antibody syndrome increase the possibility of recurrent deep vein acute
attacks,thrombosis, and pulmonary embolism15.
The cause of death was pulmonary thromboembolism. Patients with chronic coronary
artery disease and multiple cardiovascular risk factors (such as arterial hypertension,
hypercholesterolemia, and diabetes) exhibit progressive coronary atherosclerosis. In the past ten
years, she had repeated vascular thrombosis, and the last thromboembolic event occurred in an
uncommon site (upper extremity), which indicated the need for an assessment of thrombotic
tendency. The patient developed arrhythmia, hemodynamic instability, and refractory
cardiogenic shock, and may die due to extensive pulmonary embolism.
12
Batchelor WB, Anstrom KJ, Muhlbaier LH, Grosswald R, Weintraub WS, O'Neil WW, et al. J Am Coll
Cardiol. 3. Vol. 36. National Cardiovascular Network Collaboration; 2000. Contemporary outcome trends in the
elderly undergoing percutaneous coronary interventions: results in 7,472 octogenarians; pp. 723–730.
13
Trikalinos TA, Alsheikh-Ali AA, Tatsioni A, Nallamothu BK, Kent DM. Percutaneous coronary interventions for
nonacute coronary artery disease: a quantitative twenty-year synopsis. Lancet. 2009;373(9667):911–918.
14
Angus DC, van der Poll T. Severe sepsis and septic shock. N Engl J Med. 2013;369(9):840–851.Erratum in: N
Engl J Med. 2013;369(21):2069.
15
Tapson VF. Acute pulmonary embolism. N Engl J Med. 2008;358(10):1037–1052
12
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mechanisms and clinical implications on behalf of the Working Group on Coronary Pathophysiology and
Microcirculation, Eur Heart J 36:3134–1346,2015.
3. Tune JD:Coronarycirculation.In Granger ND,GrangerJ,editors:Colloquium Series on Integrated Systems
Physiology:From Molecule to Function,San Rafael,CA,2014,Morgan and Claypool,pp 1.
4. Crea F, Lanza GA, Camici PG: Coronary Microvascular Dysfunction, Milan, 2014, Springer Verlag Italia.
5. Beyer AM, Gutterman DD: Regulation of the human coronary microcirculation, J Mol Cell Cardiol52(4):814,
2012.
6. Sato A,Terata K, Miura H, et al.: Mechanism of vasodilation to adenosine in coronary arterioles from patients
with heart disease,Am J Physiol Heart Circ Physiol288(4):H1633,2005.
7. Duncker DJ, Bache RJ: Regulation of coronary blood flow during exercise, Physiol Rev 88(3):1009, 2008.
8. LiuY,GuttermanDD:Vascular control in humans:focus on the coronary microcirculation,Basic Res
Cardiol104(3):211,2009.
9. Hein TW, Zhang C, Wang W, et al.: Heterogeneous beta2-adrenoceptor expression and dilation in coronary
arterioles across the left ventricular wall,Circulation110(17):2708,2004.
10. Heusch G, Baumgart D, Camici P, et al.: Alpha-adrenergic coronary vasoconstriction and myocardial ischemia
in humans,Circulation101(6):689,2000.
11. Feigl EO:The paradox of adrenergic coronary vasoconstriction,Circulation76(4):737,1987.
12. Heusch G: Reprint of: the paradox of alpha-adrenergic coronary vasoconstriction revisited, J Mol Cell
Cardiol52(4):832,2012.
13
Chapter 2 Coronary Microcirculation Disorders Related Diseases
Lv Yan, M.D.
1. Introduction:Neural and Biohumoral Regulation of the Microcirculation
Arterioles and arterioles are abundantly innervated by sympathetic and parasympathetic

nerve endings, which play an important role in the regulation of Coronary Blood Floor (CBF).
Under normal circumstances, in addition to the well-known b1 adrenergic receptor-mediated
chronotropic, positive inotropic and dromotropic effects, the net effect of sympathetic activation
is through the small coronary arteries mediated by b2 adrenergic receptors vasodilatation
increases CBF, and thus contributes to feedforward control without the need for false signals,
such as a decrease in oxygen partial pressure. In the isolated subepicardial arterioles of swine, b2
adrenergic receptor mRNA was nearly three times that of the subendocardial arterioles,
indicating transmural heterogeneity. Coronary blood vessels are also rich in a-adrenergic
receptors, with a1 dominating the larger blood vessels, and a2 dominates the microcirculation.
The activation of vascular a-adrenergic receptors leads to vasoconstrictionwhich competeswith
metabolic vasodilation. Sympathetic an adrenoceptor-mediated coronary vasoconstriction has
been demonstrated during adrenergic activation, such as during exercise or during thecold
pressor reflex in humans.
Based on experimental evidence, scientists have hypothesized that the beneficial effect of
this abnormal vasoconstriction is that it helps maintain blood flow to the fragile lining of the left
ventricle, but only if the heart rate, contractility, and coronary blood flow are high. However, this
hypothesis has not been confirmed by subsequent studies, which failed to prove the beneficial
effect of a-adrenergic coronary vasoconstriction on the distribution of transmural blood flow
under physiological conditions. On the other hand, a-adrenergic coronary vasoconstriction is
effective in ischemic myocardium, and some studies have proven after the administration of
alpha-adrenergic blockers, the subendocardial blood flow is improved.
The experiment of the CBF parasympathetic control has been extensively conducted on
the dogs. Vagus nerve stimulation produces general vasodilation on the Left Ventricular (LV)
wall without being affected by the changes in myocardial metabolism. The vagus response
activated during carotid baroreceptor and/or chemoreceptor stimulation depends on the species
and endothelium. Parasympathetic vasodilation is attributed to the release of acetylcholine at the
adventitia-medical boundary mediated by the muscarinic receptors M1 and M216 and subsequent
activation of endothelial Nitric Oxide mediated dilation.
16
Muscarinic m1 receptors traditionally are considered to be postsynaptic to cholinergic fibers, while m2 receptors
are largely presynaptic receptors associated with axons.
14
2. Mechanisms of Coronary Microvascular Dysfunction (CMD)
a. The Coronary Microcirculation:
Intramyocardial arterioles with a diameter of less than 500µm is the main part of
myocardial perfusion regulation and constitute the coronary microcirculation. Coronary artery
microvascular dysfunction is another mechanism of myocardial ischemia. Coronary
microcirculation dysfunction is caused by changes in the function and/or structure of small
arteries in the myocardium and increased extravascular pressure. There is no technology that can
directly observe the anatomical structure of the human coronary artery microcirculation.
b. Function Assessment of the Coronary Microcirculation:
The way of assessing indirectly Microvascular function includes the following:

measuring Coronary Artery (CBF) or Myocardial Blood Flow (MBF) and Coronary Blood Flow
Reserve (CFR) or by calculating Microvascular Resistance (IMR) index. More in detail:
• CBF is the amount of blood flowing along the vascular bed over a time unit (mL/min).
• MBF is the blood volume per unit of time per unit of cardiac mass (mL/min per g)
• CFR is the ratio of CBF or MBF achieved by drugs such as adenosine or dipyridamole to
baseline CBF or MBF during periods of near-maximum vasodilation.
• IMR is calculated as the product of distal coronary artery and the average transit time
using the combined pressure/temperature line.
• Invasive and non-invasive techniques can be used to evaluate CBF/MBF and CFR,
including intracoronary Doppler blood flow lines, transthoracic Doppler, positron
emission tomography and cardiac magnetic resonance imaging.
c. Pathogenetic Mechanisms and Clinical Classification of Coronary Microvascular

Dysfunction:
Type Clinical Settings Main Pathogenetic

Mechanisms
In the absence of Risk factors microvascular Endothelial dysfunction
myocardial disease and angina Smooth Muscle Cell17
obstructive CAD (SMC) dysfunction
Vascular remodeling
In myocardial diseases Hypertrophic Vascular remodeling SMC
cardiomyopathy dilated dysfunction Extramural
cardiomyopathy compression Luminal
Anderson-Fabry disease Obstruction
Amyloidosis
17
Smooth muscle cells (SMCs) are involuntary, non-striated muscle cells that line the insides of hollow organs such
as arteries, lungs, bladder, the digestive system, and the reproductive system.
15
Myocarditis
Aortic Stenosis
In Obstructive CAD Stable angina Acute Endothelial dysfunction
Coronary Syndrome SMC dysfunction Luminal
obstruction
Latrogenic PCI Coronary Artery Luminal Obstruction
Grafting Automatic Dysfunction
Table 2.1 CAD, Coronary artery disease; PCI, percutaneous coronary intervention; SMC, smooth muscle
cells. (From Crea F, Camici PG, Bairey Merz CN. Coronary microvascular dysfunction: an update Eur
Heart J. 2014;35(17):1101.)
d. Structural Alterations
The structural abnormalities that cause CMD have been demonstrated in patients with
hypertrophic cardiomyopathy (HCM) and arterial hypertension. In both cases, the morphological
changes are characterized by an adverse remodeling of intramural coronary arteries that lead to
thickening of the vessel wall, mainly due to smooth muscle cell hypertrophy, increased
deposition of medial collagen, and varying degrees of thickening of the intima. Remodeling the
hypertrophic vessel wall leads to an increase in the inner wall area and a relative decrease in the
vessel lumen. Although the two conditions are similar in nature, these anatomical changes are
usually more severe in HCM patients. A common and important feature in patients with arterial
hypertension and HCM is the diffuseness of microvascular remodeling, which extends to the
entire left ventricle, regardless of the distribution of ventricular hypertrophy (i.e. symmetrical
and asymmetrical), and may also involve part off the right ventricle. The functional counterpart
of these patients, the maximum MBF and CFR of the entire left ventricle are blunted. Structural
abnormalities of the coronary microcirculation have also been described in other clinical
conditions characterized by CMD, including primary microvascular angina (MVA). This
condition is defined as the appearance of angina pectoris in the absence of overt coronary artery
disease (CAD) or cardiomyopathy. However, analysis of the endocardial myocardial biopsies
obtained from these patients yielded inconsistent results, showing some unchanged, while other
findings were heterogeneous, including mid-layer hyperplasia and hypertrophy, intimal
proliferation and degeneration, and endothelial cells proliferation and thinning of capillaries.
Finally, structural changes in intramural coronary arteries have been confirmed in other
myocardial diseases, including amyloidosis and Fabry disease.
The Coronary Microcirculation:
• Intramyocardial arterioles below 500 μm in diameter that are the main site of myocardial
perfusion regulation make up the coronary microcirculation.
• Coronary microvascular dysfunction is an additional mechanism of myocardial ischemia.
• Dysfunction of the coronary microcirculation is caused by functional and/or structural
alterations of the intramyocardial arterioles as well as by increased extravascular
compression.
• No technique allows direct visualization of the anatomy of the coronary microcirculation
in vivo in humans.
16
Functional Assessment of the Coronary Microcirculation:
• Microvascular function is assessed indirectly, by measuring coronary (CBF) or

myocardial blood flow (MBF) and coronary flow reserve (CFR) or by calculating the
index of microvascular resistance (IMR).
• CBF is the volume of blood that flows along a vascular bed over a time unit (mL/min).
• MBF is the volume of blood per unit of time per unit of cardiac mass (mL/min per g).
• CFR is the ratio of CBF or MBF during near maximal vasodilation achieved by means of
drugs such as adenosine or dipyridamole to baseline CBF or MBF.
• IMR is calculated as the product of distal coronary pressure and mean transit time using a
combined pressure/temperature wire.
• Invasive and noninvasive techniques can be used to assess CBF/MBF and CFR including
intracoronary Doppler flow wires, transthoracic Doppler, positron emission tomography,
and cardiac magnetic resonance imaging.
e. Function Change
Functional CMD may be caused by a variable combination of mechanisms leading to

impaired coronary microvasculature and mechanisms leading to increased coronary
microvascular constriction. (See Figure 2.1)
i. Alterations of Endothelium-Dependent Vasodilatation
Alterations in endothelial function may impair CBF both at rest, favoring susceptibility to
constrictor stimuli, and during increased myocardial workload, as typically occurs during
exercise. Nitric Oxide (NO) production and release are the primary mechanisms of endothelium-
mediated vasodilatation, and the most vulnerable in the case of endothelial dysfunction.
Unfortunately, NO is a volatile molecule, with a very short half-life which is 56 seconds, and
thus its correspondent measurement in vivo is difficult.
The detection of abnormal endothelium-dependent coronary microvascular expansion in

the clinical setting is mainly based on the response to a stimulus that is induce endothelial cells
to release NO to exercise their vasodilatory effect, which makes the CBF blunt or reduced.
Acetylcholine in the coronary arteries stimulates muscarinic receptors, combined with Doppler
blood flow recordings in the coronary arteries, has become the most widely used stimulus in
clinical studies, although it is limited to invasive surgery. An effective alternative to the
assessment of endothelium dependent CMD is Cold Pressure Testing (CPT), which can be
combined with imaging techniques (for examples, Positron Emission Tomography [PET]) to
measure MBF in a non-invasive manner. If the endothelial function is dysfunctional, due to the
complex vasoconstriction caused by the CPT, the vasodilatation response to these stimuli will be
weakened, and it will even become vasoconstriction when the endothelial function is severely
impaired.
17
Several experimental studies have shown that impaired NO production is a cause of

endothelial dysfunction. The most common cause is the decreased activity of endothelial eNOS18,
catalyzes the synthesis of Nitric Oxide from the amino acid L-arginine, which can activate
harmful stimulation of acetylcholine/muscarinic, bradykinin, histamine receptors or increase
friction (i.e. shear stress). In some instances, the administration off NO synthase cofactor BH4
can improve or even normalize endothelial dysfunction. Thus, it is indictive that the reduction of
this cofactor may be related to the impaired endothelial-mediated expansion, at least in some
cases. Impaired endothelium-dependent vasodilation is not only due to impaired NO production,
but also possibly due to increased degradation. NO can be inactivated by many factors, with
superoxide anion •O2– playing a major role.The overproduction of Reactive Oxygen Species
(ROS) 19 reduces the bioavailability of NO by reacting directly with NO to form
peroxynitrite(•ONOO−) and altering eNOS coupling. When uncoupled, instead of releasing NO,
eNOSproduces ROS, and ROS-mediated oxidation of the eNOS cofactor BH4 is the main
mechanism responsible for eNOS uncoupling. This series of events has been confirmed in
several conditions that are associated with impaired endothelium-dependent coronary
microvascular dilatation, including diabetes, obesity, smoking, and other cardiovascular risk
factors. Therefore, under experimental and clinical conditions, the administration of antioxidants
can prevent the formation of superoxide anions including glutathione and antioxidant vitamins,
thereby improving, or even normalizing endothelium-dependent coronary microvasculature.
NO exerts its vasodilation effect by diffusing into the cytoplasm of smooth muscle cells
and activating the guanylate cyclase20 (GC) pathway by binding to the heme group of the enzyme.
In some cases, although NO production levels are normal, NO-dependent vasodilation may be
impaired. This may be due to the oxidation of the heme group of GC, which causes the enzyme
to have no reaction to NO.
Endothelial dysfunction may also reduce the activity of EDHF and prostacyclin
PGI2.PeroxynitriteInhibits prostacyclin synthase, thereby reducing the release of PGI2. This leads
to the conversion of PGI2 precursor PGH2 to synthetic thromboxane A2 (TXA2), a powerful
vasoconstrictor. The extent to which these factors are disturbed and under what circumstances
have a significant contribution to CMD in the clinical setting is still largely unknown due to the
lack of specific tests to evaluate these pathways in vivo.
18Endothelial NOS ( eNOS ), also known as nitric oxide synthase 3 ( NOS3) or constitutive NOS ( cNOS ), is an
enzyme that in humans is encoded by the NOS3 gene located in the 7q35-7q36 region of chromosome 7.
19
Reactive oxygen species (ROS) are highly reactive chemical molecules formed due to the electron receptivity of
O2. Examples of ROS include peroxides, superoxide, hydroxyl radical, singlet oxygen, and alpha-oxygen.
20
Guranylate cyclase is found in the retina (RETGC) and modulates visual phototransduction in rods and cones. It is
part of the calcium negative feedback system that is activated in response to the hyperpolarization of the
potoreceptors by light. This causes less intracellular calcim, which stimulates guanylate cyclase-activating proteins.
18
Figure 2.1 Schematic drawing of endothelium, vascular smooth muscle, and cardiomyocyte. Illustrating neurohumoral, endothelial, and
metabolic influences. α1, α1-adrenergic receptor; α2, α2-adrenergic receptor; ACh, acetylcholine; AA, arachidonic acid; ACE, angiotensin-
converting enzyme; AI, angiotensin I; AII, angiotensin II; AT1, angiotensin type 1 receptor; AT2, angiotensin type 2 receptor; ATP, adenosine
triphosphate; β2, β2-adrenergic receptor; B2, bradykinin type 2 receptor; bET-1, big endothelin-1; COX-1, cyclooxy- genase 1; CYP450,
cytochrome P450; ECE, endothelin-converting enzyme; EDHF, endothelium-derived hyperpolarizing factor; EETs, epoxyeicosatrienoic acids;
eNOS, endothelial nitric oxide synthase; ETA, endothelin type A receptor; ETB, endothelin type B receptor; ET-1, endothelin-1; 5HT, 5-
hydroxytryptamine and receptor; H1 and H2, histamine type 1 and 2 receptors; HETEs, hydroxyeicosatetraenoic acids; H2O2, hydrogen peroxide;
IP, prostacyclin receptor; KATP, ATP-sensitive K+ channel; KCa, calcium-activated K+ channel; KIR, inward rectifying K+ channel; KV,
voltage-gated K+ channel; l-arg, l-arginine; M, muscarinic receptor; NE, norepinephrine; NO, nitric oxide; NPY, neuropeptide Y; O2, oxygen;
•O2–, superoxide anion; P1, purinergic type 1 receptor; P2, purinergic type 2 receptor; PG, prostaglandins; Trp, transient receptor potential
channels; TXA2, thromboxaneA2 and receptor; VGCC, voltage-gated calcium channels; Y1, neuropeptide Y receptor. (Source from Duncker DJ,
Koller A, Merkus D, et al. Regulation of coronary blood flow in health and ischemic heart disease. Prog Cardiovasc Dis. 2015;57(5):409.)
19
ii. Alterations of Endothelium-Independent Vasodilatation
Under some experimental and clinical conditions, impaired endothelial-independent

expansion has been shown to be a cause of CMD, where CBF increases and/or microvascular
resistance decreases in response to direct arteriole/anterior arteriole vasodilators (such as
adenosine, dipyridamole, papaverine) is abnormal.
Although there is a large amount of data documenting that the coronary microcirculation
does not depend on the expansion of the endothelium, the cellular mechanisms involved are still
not fully understood. There are two main known intracellular pathways that cause smooth muscle
cells to relax. One approach is based on the activation of adenylate cyclase, leading to the
production of cAMP21, which acts by opening KATP channels and inhibiting calcium influx into
smooth muscle cells (see Figure 2.1). This pathway is mainly activated by stimulating purinergic
A2 receptors and β2 adrenergic receptors. The second intracellular pathway mentioned above
relies on the activation of GC, which leads to the production of cGMP22. The latter pathway is
mainly activated by NO released from the endothelium, as described above.
Therefore, the mechanisms leading to the impaired response of smooth muscle cells to
vasodilator stimulation may be different in different clinical settings, because they may be
related to abnormalities in one or both of specific receptors or major intracellular signaling
pathways that regulate smooth muscle cells. relaxation. For example, due to the reduced
production of cGMP, the response to prolonged vasodilation (nitrate resistance) of nitrate
administration is reduced, which may also be related to the reduced response to NO (as shown
above).
The abnormality of endothelial-independent coronary microvascular expansion may also

involve impaired opening of KATP channels23. In fact, the activation of intracellular cAMP and
cGMP leads to the opening of KATP channels, which ultimately leads to cell hyperpolarization
and the closure of voltage-dependent calcium channels (see Figure 2.1). Finally, changes in other
K+ channels, such as KCa and Kv channels, may also be the cause of damage to endothelial-
independent coronary microvasculature.
In conclusion, changes in the smooth muscle cell relaxation that does not depend on the
endothelium in the coronary microcirculation may lead to impaired vasodilation responses to
factors that mediate CBF metabolic regulation, autoregulation and reactive hyperemia, and blood
flow-mediated expansion.
21
cAMP is a neuropeptide involved in activation of trigeminocervical system leading to neurogenic inflammation
and cause migraine.
22
cGMP is a common regulator of ion channel conductance, glycogenolysis, and cellular apoptosis. It also relaxes
smooth muscle tissues. cGMP is a secondary messenger in phototransduction in the eye.
23
KATP channels exists in the sarcolemmal, mitochondrial and nuclear membranes of various tissues. Cell
metabolism regulates K (ATP) gene expression and metabolism products regulate the channel by direct interactions,
while K (ATP) controls membrane potentials and regulate cell activities including energy metabolism, apoptosis and
gene expression.
20
iii. Vasoconstriction
The enhanced vasoconstriction of coronary microcirculation may be due to increased

release of vasoconstrictor agonists (systemic or local) (see Figure 2.1) and/or increased
sensitivity of smooth muscle cells to vasoconstriction stimuli. The view that coronary
microvasculature may cause myocardial ischemia has been confirmed in experimental models
and humans. Some vasoconstrictors cause intense and selective microvascular constriction but
have little effect on the epicardial coronary arteries.
Experimental studies in dogs have provided evidence that the administration of

endothelin-1 in the left anterior descending coronary artery can cause a dose-dependent decrease
in CBF, leading to myocardial ischemia, without any significant effect on the epicardial artery. A
similar effect was observed with intracoronary injection of angiotensin II or phenylephrine. The
experimental studies conducted on rabbits have proved that the tripeptide N-formyl-l-methionin-
L-leucil-L-phenylamine injected into the coronary arteries, works by releasing leukotrienes from
activated neutrophils. These substances act on the subendocardial and subepicardial small
coronary arteries and induce transmural myocardial ischemia.
In humans, the evidence that coronary microvascular constriction leads to myocardial

ischemia comes from the objective evidence that studies have shown that intracoronary injection
of neuropeptide Y or high-dose acetylcholine can cause chest pain and myocardial ischemia in
patients with normal coronary angiography, but there is no significant change in epicardial
coronary arteries. In patients with flow-limiting stenoses, intracoronary infusion of serotonin has
been shown to cause myocardial ischemia. Evidence shows diffuse constriction of distal
branches and reduced collateral vessel filling, but the severity of the stenosis changes little. It is
known that this response to serotonin is due to stimulation of 5HT receptors24 in the endothelial
and vascular smooth muscle.
Abnormal microvascular constriction has been confirmed in patients with chest pain and
normal coronary arteries and in patients with chronic stable angina. Strong coronary
microvascular constriction is an important pathological component of microvascular occlusion
(MVO), which accounts for a large proportion of patients with ST-segment elevation myocardial
infarction (STEMI) after direct PCI.
iv. Intravascular Plugging
Intravascular Plugging caused by atherosclerotic debris and thrombotic materials usually

occur during PCI and is related to intracoronary manipulation of friable plaques, especially in
degenerated saphenous vein grafts. In these cases, microvascular blockage usually leads to
"infarctlets", which is characterized by moderately elevated biomarkers of myocardial injury,
which is associated with a worse prognosis compared to surgery without any increase in these
24
5-hydroxytryptamine receptors or 5-HT receptors, or serotonin receptors are found in the central and peripheral
nervous system. They can be divided into 7 families of G protein-coupled receptors except for 5-HT 3 receptor, a
ligand-gated ion channel, which activated an intracellular second messenger cascade to produce an excitatory or
inhibitory response.
21
biomarkers. Intravascular plugging caused by microemboli and leukocyte-platelet aggregates is

an additional mechanism of MVO in STEMI patients.
MVO is compounded by a complex interaction of ischemia/reperfusion-related events,

including endothelial dysfunction and loss of vasodilatation mechanisms, enhanced platelet
activation-mediated vasoconstriction, TXA2 and 5HT release, and inflammation.
f. Extravascular Mechanisms
i. Extramural Compression
During the cardiac cycle, the pulsatile pattern of CBF follows typical physiological
changes, which are affected by changes in intramyocardial and intracavitary pressure that occur
during systole and diastole (see Figure 2.2). Approximately 90% of CBF occurs during the
diastole, so abnormal diastole has a more significant impact on myocardial perfusion. However,
the increase in systolic intramyocardial and intracavitary pressures, such as in the case of
increased pressure overload, may have a negative impact on myocardial perfusion. The increased
microvascular compression during systole prevents the subendocardial blood vessels’tone from
restoring in diastole, thereby imparing diastolic microvascular CBF in the subendocardial layers.
Whenever the diastolic blood pressure in the cavity rises, the diastolic CBF is impaired.
This happens in the presence of primary or secondary left ventricular hypertrophy (LVH) and
diastolic dysfunction due to increased interstitial and perivascular fibrosis. When the arteriolar
driving pressure during diastole is significantly lower than the intracavitary pressure, the
diastolic impairment of CBF will be enhanced, such as patients with severe aortic stenosis,
severe coronary stenoses, prearteriolarcontriction, or only hypotension.
ii. Tissue Edema
Abnormal capillary permeability facilitates the migration of intravascular fluid to the

interstitium, leading to myocardial edema and CMD. Experimental studies have shown that
edema does not reduce CFR. However, in the setting of MVO in STEMI, edema can aggravate
the damage of CBF. Edema is the result of a combination of multiple mechanisms, including (1)
increased osmolality, which is caused by ischemicmyocardial catabolites diffusing to the
interstitial space during the ischemic phase, recalls fluid from the intravascular compartment
during reperfusion; (2) Increased permeability of blood vessels to water and protein, and
abnormal ionic transport, leading to endothelial injury during ischemia/reperfusion; and (3)
Inflammation related to reperfusion. Coronary microvascular compression is another component
that favors intravascular cell plugging by neutrophil-platelet aggregates. Finally, myocardial
edema may occur during open heart surgery. As the hydrostatic capillary pressure increases, the
venous pressure increases, mainly in the right ventricle, which may cause interstitial edema.
Clinically, T2-based and inverted recovery cardiac magnetic resonance imaging can now be used
for noninvasive assessment of myocardial edema and MVO.
22
iii. Diastolic Time
Due to the fact that CBF mainly occurs during the diastole, the duration of the diastole
plays a central role in maintaining myocardial perfusion. In a normal heart, both subendocardial
and subepicardial perfusion are maintained in a very short diastolic period, such as during
vigorous physical exercise. Conversely, when the coronary drive pressure is significantly lower
than the intraluminal pressure, the reduction in diastolic time helps to determine the critical
reduction in myocardial perfusion, as in patients with aortic stenosis.
3. Clinical Classification of Coronary Micro Vascular Dysfunction
Theclinical classification of CMD, typically involving three types:
Type1: CMD occurs without CAD and myocardial diseases;

Type2: CMD inPatients with obstructive CAD; and
Type3: CMD caused by interventions such as bypass surgery, percutaneous
revascularization, etc., is also defined as iatrogenic.
As discussed in the previous section, these types of CMD can be maintained by inherent
changes in the microvascular system (structure and/or function) and factors derived from the
environment around the microvascular system (such as increased extravascular pressure). The
importance of these mechanisms seems to vary in different clinical settings, although several of
them may coexist in the same patient. Clinically, CMD may be severe enough to cause
myocardial ischemia alone or in combination with the traditional "epicardial" mechanism (Figure
3.1).
a. Type 1 Coronary Microvascular Dysfunction (CMD occurs without CAD and

myocardial diseases)
This type represents the functional counterpart of traditional coronary risk factors and is
the cause of MVA. Type 1 CMD may not be related to the symptoms or signs of myocardial
ischemia, but it can be revealed by demonstrating a reduction in CFR. CFR damage can be
significant, but most often it is not severe enough to limit the heart’s functional capacity during
normal daily activities. The severity of CFR reduction has been shown to correlate with the
severity of potential risk factors. In addition, correcting risk factors is usually accompanied by
improvements in CFR.
i. Cigarette Smoking
There is no doubt that smoking is a recognized risk factor for cardiovascular disease.
CMD has been confirmed in asymptomatic smokers with no evidence of CAD, and the CFR was
reduced by more than 20% compared with non-smokers. Further evidence linking smoking and
CMD come from a study of twins, which showed that smoking twins have a lower CFR rate than
non-smokers. The gas phase of cigarette smoke contains large amounts of free radicals and pro-
oxidative lipophilic quinones, which can form highly reactive hydroxyperoxide radical. The
latter increases the amount of oxidized low-density lipoprotein, which in turn damages eNOS
23
and contribute endothelial dysfunction. Clinical experience has shown that intravenous injection
of antioxidant vitamin C can normalize CFR in smokers no significant effect on non-smokers.
ii. Hypercholesterolemia
The use of PET has demonstrated a reduction in CFR in asymptomatic subjects with
hypercholesterolemia and normal coronary arteries on angiography. In subjects with elevated
total cholesterol, there is a significant inverse correlation between mortality and low-density
lipoprotein cholesterol, although there is no relationship between total cholesterol and CFR. This
supports the direct pathogenic role of this subfraction in the development of CMD. There is
evidence that the reduction in CFR in patients with dyslipidemia can be improved, at least
partially, through cholesterol-lowering strategies. In addition, in patients with familial
hyperlipidemia, in addition to conventional lipid-lowering therapy, treatment with the
peroxisome proliferator-activated receptor (PPAR)-γ agonist pioglitazone can significantly
improve myocardial glucose utilization that was paralleled by an increase hyperemic MBF.
iii. Hypertension
Arterial hypertension is the main independent risk factor for adverse cardiovascular
events. Patients with hypertension have evidence of CMD, and even without obstructive CAD,
signs and symptoms that indicate myocardial ischemia may appear. The reduction of CFR in
hypertensive patients is severe, especially if accompanied by LVH. In patients with stage 1-2
hypertension and LVH, due to the reduced hyperemia response to pressure, which is negatively
correlated with systolic blood pressure, CFR appears to be transmurallyblunted. This finding
may be due to increased extravascular pressure, increased systolic/diastolic wall stress and
impaired relaxation, resulting in impaired microvascular function. However, the damage of CFR
in hypertensive patients is not necessarily related to the degree of cardiomyocyte hypertrophy. It
is closely related to the degree of arteriole remodeling and capillary rarefaction due, at least in
part, to excessive activation of the renin-angiotensin-aldosterone system. Angiotensin-converting
enzyme inhibitor treatment can improve CFR in patients with arterial hypertension. In
spontaneously hypertensive rat models, these drugs have also been shown to improve coronary
blood flow and revert small arterial remodeling.
iv. Diabetes and Insulin Resistance
Diabetes has a direct harmful effect on blood vessels, especially endothelial function,
thereby increasing the possibility of vasoconstriction and thrombosis. In fact, there is consistent
evidence that diabetic patients exhibit CMD, which may be an early marker of atherosclerosis
before CAD that is clinically obvious. The deterioration of glucose tolerance and insulin
resistance in patients with metabolic syndrome is accompanied by progressive impairment of
coronary microvascular function. In addition, in diabetic patients, coronary vasodilator
dysfunction is a strong and independent correlate of cardiac mortality and all-cause mortality.
The pressure perfusion injury of type 2 diabetic patients can be quickly restored to normal by
insulin infusion and glycemic control with glyburide and metformin or insulin-sensitized
thiazolidinedione.
24
v. Inflammation
Chronic inflammatory diseases, such as rheumatoid arthritis, systemic lupus

erythematosus and systemic sclerosis, are important risk factors for ischemic heart disease and a
source of high cardiovascular morbidity and mortality. In these patients, inflammation can impair
coronary microvascular function and promote the development of myocardial ischemia without
obstructive CAD or even other risk factors. It has been reported that patients with MVA have
elevated levels of inflammatory markers, including C-reactive protein (CRP) and interleukin-1
receptor antagonists. High CRP levels are associated with increased frequency of ischemic ECG
changes. Recently, objective evidence has linked CMD to inflammation in patients with chest
pain and normal coronary angiography without the traditional risk factors for CAD. They
demonstrated that patients with elevated CRP levels had severely reduced CFR compared to the
control group, a finding indicative of CMD.
vi. Stable Microvascular Angina
MVA is a typical clinical manifestation of type 1 CMD. Primary stable MVA is defined
as the occurrence of anginal attacks associated with effort in the absence of obstructive CAD,
myocardial disease, and any other significant cardiovascular disease. In these patients, CMD is
the cause of myocardial ischemia and chest pain. MVA is caused by a variable combination of (1)
structural abnormalities, (2) changes in endothelium-dependent and independent vasodilation, (3)
changes in endothelium-independent vasodilation, and (4) enhanced pain sensation.
b. Type 2 Coronary Microvascular Dysfunction (CMD inPatients with obstructive CAD)
This section will only focus on the role of CMD in stable CAD. In acute coronary
syndromes, CMD is involved in the pathogenesis of MVO, also known as no-reflow
phenomenon. Therefore, CMD plays an important role in both stable CAD and acute coronary
syndrome. This phenomenon occurs in a considerable proportion of STEMI patients. Although
the culprit arteries were successfully recanalized, there was evidence of slow angiographic blood
flow or MVO, and the risk of adverse cardiovascular events at follow-up was higher.
i. Pathophysiology of Coronary Microvascular Dysfunction in Stable Coronary

Artery Disease
The role of CMD in determining the severity of symptoms in patients with chronic CAD
was initially emphasized in patients with angina, complete occlusion of a single coronary artery,
and no previous MI in the early 1990s. The angina and ischemic thresholds of these patients
showed remarkable variability. Holter monitored 25 electrocardiographic signs of ischemia
threshold, and the heart rate was relatively low; in contrast, at other times of the same day,
although the heart rate was much higher, there were no signs and symptoms of ischemia.
Because these patients have no evidence of "dynamic" stenosis. More specifically, the
vasoconstriction of the stenosis further reduces the vessel lumen, thereby increasing the severity
25
Holter monitor is a type of portable heart monitor that is small electrocardiogram device worn in a pouch around
neck or waist.
25
of the stenosis. In the large epicardial arteries, the changes in angina and ischemic threshold can
only be explained by the profound dynamic changes in coronary microvascular resistance.
Consistent with this finding, subsequent studies of patients with single-vessel CAD recorded
abnormal CFR, measured with PET, in the area covered by normal coronary arteries on
angiography.
In patients with obstructive CAD, the development of myocardial ischemia during

periods of increased oxygen demand is usually attributed to insufficient increase in flow due to
CFR depletion. However, it is worth noting that the correlation between the severity of stenosis
and the CFR measured in vivo is widely dispersed, so other factors may contribute to the
development of myocardial ischemia. In patients with stable angina pectoris, the invasive
measurement of stenosis resistance and the microvascular system in response to atrial pacing
showed increased resistance in both areas. Infusion of adenosine into the coronary arteries during
pacing can reduce microvascular resistance, indicating that CFR is not completely depleted. In
CAD patients, physiologicarteriolar vasodilation during periods of increased oxygen demand is
limited by the presence of stenosis, which results in a continuous pressure drop. The internal
control mechanism of the coronary circulation maintains the driving pressure within a range high
enough to perfuse the blood vessels, but low enough to prevent capillary damage. This control
may be as powerful as the metabolic control, although in the presence of CAD, the two may
move in opposite directions. The response of the microcirculation to an excessively low
perfusion pressure may be a heterogeneous vasoconstriction, which at maintaining pressure at
the expense of excluding some vascular units.
There is evidence that PCI revascularization can improve the symptoms of angina
pectoris compared with drug therapy in the context of optimal medical treatment, although it
does not reduce the risk of death, cardiovascular death, non-fatal myocardial infarction, or
further revascularization. However, in a considerable proportion of patients, despite the
successful revascularization, the prevalence of angina pectoris at follow-up is still high. For
example, in the clinical outcome trial that uses revascularization and active drug
evaluation(COURAGE), more than 30% of patients still have angina pectoris 1 year after PCI,
and during the 5-year follow-up, the incidence of angina was not significantly different from that
of those who did not receive Patients undergoing a revascularization surgery. These findings
indicate that although revascularization can effectively eliminate coronary artery stenosis and its
hemodynamic consequences, other mechanisms, including CMD, can also cause ischemia and
angina in these patients.
In more than 1,000 patients who underwent selective measurement of Fractional Flow
Reserve (FFR) and Index of Microvascular Resistance (IMR), the scientists found no correlation
between IMR and FFR or the severity of angiographic lesions. In addition, the predictors of high
IMR were different from those of ischemic FFR. It is foreseeable that the integration of IMR into
FFR measurements may provide more insights into the relative contribution of macrovascular
and microvascular diseases to patients with ischemic heart disease.
26
Figure 2.2 In addition to the “classic” mechanisms (ie, atherosclerotic disease and vasospastic disease) that lead to myocardial ischemia, coronary microvascular
dysfunction (CMD) has emerged as a third potential mechanism. As with the other two mechanisms, CMD (alone or in combination with the other two) can lead to
transient myocardial ischemia, as in patients with coronary artery disease (CAD) or cardiomyopathy (CMP), or to severe acute ischemia, as observed in Takotsubo
syndrome. CFR, coronary flow reserve. (From Crea F, Camici PG, Bairey Merz CN. Coronary microvascular dysfunction: an update. Eur Heart J. 2014;35(17):1101.)
The use of positron emission tomography (PET) to noninvasively quantify MBF provides
clear evidence that the inclusion of CFR in the risk prediction model leads to the correct risk
reclassification of a significant proportion of patients, including a significant proportion of
patients who are at intermediate risk. CFR is a comprehensive measurement of the functions of
the large vessels and microvascular systems. Abnormal CFR provides incremental risk
stratification beyond the conventional semi-quantitative assessment (i.e. total rest and stress
score) of myocardial perfusion studies. Measurements of absolute MBF and CFR provide
information on both regional and diffuse perfusion abnormalities, the latter being typical of
manifestation of CMD.
The data provide support for this hypothesis. The study found that patients with evidence
of ST-segment depression during exercise stress testing had a lower CBF response to adenosine
after surgery, although no significant clinical or procedures were observed between patients with
positive and negative exercise stress test results difference.
In stable CAD, CMD is not only a possible explanation for the persistence of symptoms
after successful recanalization, but also a predictor of adverse outcomes. Invasive measurements
of coronary flow velocity reserve (CFVR) indicate that abnormal CFVR in the reference vessel is
associated with a significant increase in mortality during long-term follow-up. Another study
from the same group showed that during the entire 10-year follow-up period, normal FFR and
abnormal CFVR were associated with a significant increase in the incidence of major adverse
27
cardiac events, regardless of the applied FFR cutoff. These findings strongly indicate that the
outcome of these patients is determined by CMD rather than the severity of functional stenosis.
Another scientist further confirmed these findings. In a group of chronic CAD patients,
he used PET to non-invasively measure the extent and severity of coronary artery disease and
CFR at angiography. Although the correlation between these two factors is weak, their severity is
independently related to cardiovascular death and heart failure admission at 3 years follow-up
after adjustment for the clinical risk score, ejection fraction, systemic ischemia, and early
revascularization. Interestingly, the overall CFR has an impact on the effect of revascularization,
so that only patients with low CFR seem to benefit from revascularization, and only if
revascularization includes coronary artery bypass grafting (CABG), Its event rate is comparable
to patients with preserved CFR. These data raise a contradictory hypothesis that invasive
revascularization in patients with preserved CFR may contribute to increased events.
ii. Clinical Implication
For patients with long-term angina or poor response to sublingual nitrates (a common
clinical feature in MVA patients), the microvascular origin of angina in obstructive CAD patients
can be suspected. Also, patients with angina pectoris are more severe than predicted by the
severity of coronary stenoses. Finally, it may be suspected in patients with large changes,
although this change can also be explained by the presence of "dynamic" stenoses. Nevertheless,
in individual patient, it is often difficult to determine the role of CMD in causing angina.
However, it is foreseeable that despite successful coronary revascularization, up to 30%

of patients will still have persistent angina and/or stress ischemia due to persistent CMD.
Therefore, when the goal of revascularization is to control symptoms rather than improve
outcomes, it is always worth testing the best antianginal treatment, including drugs for CMD,
before a new or repeated revascularization surgery is proposed.
After myocardial revascularization, it is very important to identify those patients with

angina and induced ischemia caused by CMD rather than restenosis. In this case, the non-
invasive assessment of CFR can provide useful incremental information for the diagnosis of
CMD and further risk stratification.
The observation that thedecrease in CFR is mainly due to the gradual decrease in peak
stress MBF, indicating the main abnormality of coronary vasodilator function and strongly
supporting the existence of CMD.
c. Type 3 Coronary Microvascular Dysfunction (CMD caused by interventions)
In addition to the CMD observed in patients with chronic CAD, coronary

revascularization through PCI or CABG can cause further temporary damage to CFR in the area
covered by the successfully recanalized artery. This is probably caused by the reflex in the
coronary arteries, leading to reversible α-adrenergic receptor-mediated coronary microvascular
constriction, restricting congested blood flow, and can pass the α-adrenergic receptor
administered antagonists before surgery to prevent. This phenomenon may result in the delayed
28
improvement of exercise-induced myocardial ischemia that can be observed after the successful
PCI.
In addition to vasoconstriction, embolization of the coronary microcirculation can cause

CMD in patients receiving PCI and CABG. The material washed out of the plaque is shed
distally in the microcirculation and may cause infarction, as evidenced by the increase in necrotic
biomarkers. In a meta-analysis of more than 7,500 patients, 29% of patients found elevated
troponin after PCI, and 15% of the elevation met the criteria for MI. Patients with PCI-related MI
are at increased risk of death and re-PCI. At follow-up, any increase in troponin was associated
with a 50% increase in the risk of major cardiovascular events.
In PCI settings that occlude saphenous vein graft, mechanical prevention of distal
embolization through filters or proximal protection devices has been shown to reduce the
occurrence of the perioperative MI and major cardiac events. In terms of drug treatment, during
elective and emergency PCI, the administration of statins has been shown to reduce perioperative
infarction by half. Similar to PCI, significant increases in biomarkers measured 2 hours and 24
hours after CABG have been shown to have significant independent prognostic significance.
Surgical trauma and cardiopulmonary bypass contribute to the systemic inflammatory response,
which can be measured by circulating cytokines that promote CMD. Many factors can
exacerbate this condition, including blood contact with the bypass circuit, myocardial ischemia
during bypass, aortic cross-clamping, and reperfusion injury. In this case, statins also have a
protective effect, reducing all-cause mortality, atrial fibrillation, and stroke, but have no
beneficial effects on postoperative infarction or renal failure. The pleiotropic effects of statins
may be the putative mechanism for this CMD improvement.
4. A Typical Case Report: Progression of coronary microvascular dysfunction to heart

failure with preserved ejection fraction.
a. Background:
In women with evidence of ischemia and no obstructive coronary artery disease the
underlying mechanism is most often attributed to coronary microvascular dysfunction. Higher
rates of adverse cardiovascular events, specifically heart failure with preserved ejection fraction,
are present in women with coronary microvascular dysfunction, leading to the hypothesis that
coronary microvascular dysfunction may contribute to the progression of heart failure with
preserved ejection fraction.
b. Case Summary:
A 55-year-old woman with a previous history of chest pain and shortness of breath was
referred to our tertiary medical center and was diagnosed with coronary microvascular
dysfunction through an invasive coronary reactivity test. After 10 years of follow-up care for
coronary microvascular dysfunction, she went to the emergency room for acute heart failure and
was diagnosed with heart failure with preserved ejection fraction.Her family history was
significant for premature coronary artery disease. Her father had a history of hypertension and
had a myocardial infarction (MI) and coronary artery bypass grafting at the age of 39. Her
29
brother had a history of coronary artery disease and had a MI at the age of 40. Her occupational
history indicated that she had been working in the field of psychology and was still an employee
in the same job at the time of the hospital visit and follow-up care.
The current case report provides a concrete example that supports existing research that
suggests that coronary microvascular dysfunction may be a precursor to heart failure with
preserved ejection fraction. Further research is needed to determine causality and management.
Coronary microvascular dysfunction (CMD) is common in women with evidence of

ischemia and no obstructive coronary artery disease (INOCA). Previous studies have shown that
compared with healthy women without symptoms, these women have a higher risk of fatal and
non-fatal cardiovascular events and are more likely to bere-admitted to hospitalfor angina or
acute coronary syndrome within 180 days of normal coronary angiography. The rate of
hospitalization for heart failure among these women is also higher. It’s worth noting that
previous reports from the Women’s Ischemic Syndrome Evaluation (WISE) study show that
90% of women hospitalized with INOCA signs and symptoms for heart failure had the same left
ventricular ejection fraction (LVEF). Although the prevalence of CMD in heart failure with
preserved ejection fraction (HFpEF) is currently unknown, exercise studies have shown that
vascular stiffness, impaired exercise vasodilation, and impaired diastolic reserve may be related
to endothelial and microvascular dysfunction. This leads to the hypothesis that CMD may
contribute to the development of HFpEF. The following case highlights some preliminary
empirical evidence to support this hypothesis.
c. Diagnosis of CMD
She underwent an exercise treadmill test, and the results showed changes in ischemic
ECG and dyspnea. Her initial echocardiogram showed a LVEF of 67%, mild diastolic
dysfunction, mild left ventricular (LV) hypertrophy, no obvious valvular heart disease, and no
pulmonary hypertension. Subsequently, an invasive left heart catheterization was performed, and
the results showed that the epicardial coronary arteries were normal and there was no
angiographic evidence of atherosclerotic plaque. She continued to have fatigue symptoms and
angina-like chest pain and was subsequently referred to our hospital for further evaluation of
suspected INOCA. During her evaluation and treatment, despite the initial treatment with
atorvastatin 20 mg daily, lisinopril 20 mg daily, aspirin 81 mg daily, and sublingual nitroglycerin,
if necessary, she continued to develop stable forms Angina and exertional dyspnea. She had a
poor clinical response to sublingual nitroglycerin. Due to her persistent symptoms and abnormal
stress tests, she was referred for coronary artery responsiveness testing (CRT) to confirm the
diagnosis of CMD.
Our patient received invasive CRT. Tests have shown that the coronary blood flow
reserve (CFR) has a normal response to adenosine in the coronary arteries (CFR 3.1; normal ≥
2.5), and the endothelial function of large vessels has abnormalities in the acetylcholine in the
coronary arteries (change in coronary artery diameter-6%, contraction; Normal, dilated),
microvascular endothelial dysfunction (coronary artery blood flow change 48%; normal ≥ 50%),
and nitroglycerin non-endothelial function in coronary arteries (coronary artery diameter change
+ 0%; normal dilation) (Table 2.2). She also underwent cardiac magnetic resonance imaging
30
(CMRI), resting perfusion imaging, and adenosine stress (140 μg/kg/min), which showed
peripheral subendocardial perfusion defects during stress, and normal LV end-diastolic volume
and body surface area (EDVi) of 56.4 mL/m2, LV mass index is 42.3 g/m2, and there is no LV
hypertrophy (seotum 7.2 mm and side wall 6.0 mm). The myocardial perfusion reserve index
(MPRI) was 1.8, which is considered a borderline abnormality (Table 2.3). There is no evidence
of myocardial scarring.
Table 2.2 Results of Coronary Reactivity Testing
Coronary Microvascular Microvascular Dysfunction Macrovascular Dysfunction

Dysfunction Pathways
a b
Non-endothelial dependent Coronary flow reserve in response Change in coronary diameter in
to adenosine response to nitroglycerin
2.8 0%
(normal ≥ 2.5) (normal ≥ 20%)
c d
Endothelial dependent Change in coronary blood flow in Change in coronary diameter in
response to acetylcholine response to acetylcholine
48% − 6%
(normal ≥ 50%) (normal ≥ 5%)
a
Non-endothelial-dependent microvascular dysfunction with coronary flow reserve 2.8 (adenosine). b Non-
endothelial-dependent macrovascular dysfunction with 0% (nitroglycerin) coronary diameter change. c Endothelial-
dependent microvascular dysfunction with coronary blood flow change 48%. d Endothelial-dependent macrovascular
dysfunction with coronary diameter change − 6% in response to acetylcholine.
Table 2.3 Changes in Left Ventricular Morphology
Cardiac magnetic resonance imaging parameters Baseline 10 years later

LV EDVi (mL/m2) 56.4 69
LV ESVi (mL/m2) 20.9 23.2
LVMi (g/m2) 42.3 48.5
LV mass-to-volume ratio (g/mL) 0.75 0.7
Wall thickness
Septum (cm) 7.15 9.34
Lateral wall (cm) 6.06 7.06
Scar (g) 0 0
LVEF (%) 67 64
LGE YES YES
MRPI 1.8 1.1
EDVi end-diastolic volume indexed to body surface area, ESVi end-systolic volume indexed to body
surface area, LGE late gadolinium enhancement, LV left ventricular, LVEF left ventricular ejection
fraction, LVMi left ventricular mass indexed to body surface area, MPRI myocardial perfusion reserve
index
The diagnosis of CMD was confirmed by coronary endothelial dysfunction observed by

invasive CRT, and carvedilol and eplerenone 25 mg daily were added to her treatment regimen.
31
She received regular clinical follow-ups, and her blood pressure and blood lipid levels were well
controlled. She reported that her angina and dyspnea had improved, and that the duration and
frequency of these episodes had also decreased.
Ten years after her initial diagnosis of CMD, our patient was hospitalized with dyspnea
symptoms. She was found to have an elevated brain natriuretic peptide (BNP) level of 406
pg/mL and a normal LVEF. She underwent a computed tomography (CT) angiogram of the chest
to assess for pulmonary embolism, which was negative but showed bilateral pulmonary edema.
She was treated with intravenous furosemide for pulmonary edema and was diagnosed with
HFpEF. Subsequently, she was instructed to increase her eplerenone and was discharged.
She continued to experience worsening dyspnea on exertion, orthopea, and paroxysmal

nocturnal dyspnea. Repeated echocardiography showed normal LV systolic function, LVEF was
64%, diastolic dysfunction manifested as a decrease in lateral E'velocity (4.2 cm/s, indicating
impaired myocardial relaxation) and an increase in E/E' ratio which is 12.9 LV (suggestive of
increased LV filling pressure). She underwent coronary CT angiography, which showed no
coronary atherosclerotic plaques, and a coronary calcium score of 0. Based on clinical symptoms,
she was diagnosed with HFpEF, ejection fraction retained at 64%, elevated BNP, and evidence
of diastolic dysfunction.
The patient also underwent repetitive rest-stress CMRI to assess myocardial structure,
function, perfusion, and scar, and 13C magnetic resonance (CMR) spectroscopy. Compared with
her previous CMRI 7 years ago, the wall thickness of her LV ventricular septum and side wall
increased (Table 2.3). On CMR spectroscopy, compared with normal control women (0.43% on
average), the myocardial triglyceride content was elevated to 0.83%, indicating that myocardial
steatosis is consistent with ischemia-induced metabolic changes and the HFpEF phenotype.
Adenosine pressure for the first pass-perfusion CMRI showed once again circumferential
subendocardial hypoperfusion (Figure 2.3). Her MPRI deteriorated from 1.8 to 1.1, consistent
with severe CMD. There was no evidence of scar in late gadolinium-enhanced imaging.
32
Figure 2.3 Baseline (a, b) and 10-year follow-up (c, d) adenosine stress first-pass perfusion cardiac magnetic
resonance imaging showed evidence of circumferential subendocardial hypoperfusion at stress, consistent with
ischemia associated with coronary microvascular dysfunction. Myocardial perfusion reserve index dropped from 1.8
to 1.1 over a 10-year period, indicating worsened of ischemia.
d. Discussion
This case records a 55-year-old woman whose CMD was diagnosed as invasive CRT.
Although hypertension and dyslipidemia were well controlled, it progressed to HFpEF within a
span of 10 years. Although we and others previously assumed that CMD might contribute to the
progression to HFpEF, we are not aware of the reported cases of CMD progression to HFpEF in
the literature. Although existing cross-sectional registration studies cannot determine whether
primary CMD causes ventricular remodeling, diastolic dysfunction, and HFpEF, or whether
these findings observed in HFpEF lead to secondary CMD, the current case provides evidence. It
indicates that CMD may contribute to the development of HFpEF.
HFpEF is commonly referred to as "diastolic heart failure" and is characterized by

impaired LV relaxation and increased LV filling pressure. The diagnosis of HFpEF is
challenging. It currently accounts for about half of all heart failure cases, and its morbidity and
mortality ratessimilar to those with heart failure with reduced ejection fraction. Previous studies
have observed an increased incidence of CMD with abnormal CFR and microvascular resistance
index (IMR) in HFpEF patients after adenosine administration compared with normal reference
control individuals.
Currently, there are not enough prospective studies to confirm that CMD contributes to
progression to HFpEF, and there are no hypothetical mechanisms. Previous studies have
determined that common inflammatory markers are responsible for the progression of heart
failure. Systemic inflammation may lead to reduced nitric oxide bioavailability, growth factor-β
expression, activation of cardiac fibroblasts, and an increase in formation of type 1 collagen. In
addition, this process may lead to interstitial fibrosis, leading to high left ventricular diastolic
stiffness, which eventually develops into HFpEF. There is currently no evidence-based treatment
for CMD or HFpEF. Understanding the link between CMD and HFpEF and disease
pathophysiology may help develop prevention and treatment strategies.
e. Conclusions
The case report of this case of HFpEF and the first CMD patient meets our hypothesis
that CMD may contribute to the development of HFpEF. In individual patients, whether these are
causal, whether they are only related to similar potential risk factors, or whether they represent
the unrelated existence of two common diseases are the subject of current research. It is
necessary to further evaluate the association between CMD and HFpEF to prove our hypothesis.
The mechanism of myocardial ischemia is multifaceted, including diseases of epicardial

coronary arteries and coronary microcirculation, and in some cases these two vascular areas can
be affected at the same time. Microvascular dysfunction is caused by abnormalities in the
function and/or structure of intramural coronary arterioles and increased extravascular
33
compression. Microvascular dysfunction usually occurs in patients with normal coronary

angiography and can only be detected by measuring and detecting functional parameters of
coronary artery physiology. These include CFR and IMR, which can be obtained using invasive
or non-invasive techniques. Clinically, CMD is divided into 4 types, which can be manifested as
exercise ischemia, resting ischemia or acute coronary syndrome.
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46. Camici PG, Rimoldi OE: The clinical value of myocardial blood flow measurement, J Nucl Med 50(7):1076,
2009.
47. Van de Hoef TP, Bax M, Damman P, et al.: Impaired coronary autoregulation is associated with long-term
fatal events in patients with stable coronary artery disease,Circ Cardiovasc Intervent6(4):329, 2013.
36
Chapter 3 Hypertension and its Related Heart Disease
Lv Yan, M.D.
a. Introduction
Systemic arterial hypertension is a condition in which systemic blood pressure (BP) is

continuously elevated in a non-physiologic way. It is usually defined as a resting systolic blood
pressure (SBP) of 140 mmHg or higher, or diastolic blood pressure (DBP) of 90 mmHg or higher
or receiving antihypertensive treatment. High blood pressure afflicts a large portion of the adult
population and an increasing number of children worldwide. Many genetic, environmental, and
behavioral factors can affect the development of hypertension. On the other hand, hypertension
has been identified as one of the main risk factors for cardiovascular disease (CVD), including
heart disease, peripheral vascular disease and stroke, and kidney disease. Understanding the
basic epidemiology of hypertension is essential for effective public health and clinical work to
prevent, detect, treat, and control this common disease.
In the past 20 years, people’s awareness, treatment, and control of hypertension have
been substantially improved, but the number of hypertensive patients who know their
hypertension and receive treatment or treatment and control is still far below the optimal level.
Data from 2019 to 2020 show that 82% of hypertensive patients realize that their blood pressure
is elevated, 75% of patients are receiving antihypertensive treatment, but only 51% of patients
have blood pressure lower than 140/90 mmHg, this level is considered to be "controlled" or
atgoals. These data reflect the significant increase in treatment and control rates from
approximately 60% and 30% in 2010 to the current level of treatment and control. Nevertheless,
extrapolating these data to the current estimated 80 million individuals with hypertension, there
are still more than 38 million hypertensive patients who do not know their diagnosis, know but
have not received treatment or have been treated but uncontrolled (Figure 3.1).
Figure 3.1 Number and Percentage of Chinese People from first and secondary cities are aware of their hypertension, treated, and controlled to
goal levels.
37
International data shows that hypertension is more common in other countries, including
developed countries. Hypertension is also the main single cause of the global burden of diseases.
Figure 3.2 shows the estimated proportion of deaths due to high systolic blood pressure in
countries around the world. There are big differences between the world and the region. Chad
has the lowest rate of death due to high systolic blood pressure at 3.8%, and Georgia has the
highest rate at 40.4%.
In recent years, the scope and trend in the global burden of hypertension have become
clearer. Scientists used data from published and unpublished health screening surveys and
epidemiological studies (including 5.4 million participants) to describe the current level and
trends of SBP in adults aged 25 and over in 199 countries. In 2008, the global age standardized
average SBP was 128.1 mm Hg for men and 124.4 mm Hg for women. Researchers estimate that
between 1980 and 2008, global SBP decreased by 0.8 mm Hg per decade for men and 1.0 mm
Hg per decade in women. Over time, there are significant regional differences in SBP trends. In
Western Europe and Australasia, women’s systolic blood pressure drops by 3.5 mmHg or more
every ten years. Among high-income groups in North America, male SBP has the largest decline,
with a decrease of 2.8 mmHg every ten years. SBP increased in Oceania, East Africa, South Asia,
and Southeast Asia for both sexes while female SBP increased in West Africa. In some East and
West African countries, women have the highest SBP, with an average of 135 mmHg or higher.
The Baltic Sea and East and West African countries have the highest male SBP at 138 mm Hg or
higher. Men and women in Western Europe have the highest SBP in high-income areas. SBP is
currently the highest overall in low- and middle-income countries, causing a huge disease burden
in these countries.
An epidemiologic association between a proposed risk factor and a disease is likely to be

causal if it fulfills the following criteria: (1) Exposure to the recommended risk factors before the
onset of the disease; (2) There is a strong association between exposure and incidence of disease;
(3) The association is dose-dependent; (4) Exposure is consistently predictive of disease in a
variety of populations; (5) The correlation is independent of other risk factors; and (6) This
correlation is plausible in biology and pathology, and is supported by animal experiments and
clinical research. In addition, it is clearer that the causal relationship between a proposed risk
factor and disease may arise from clinical trials, in which interventions to change or abolish risk
factors (through behavior or treatment) are associated with reduced incidence of the disease. As
discussed later, hypertension meets all these criteria and represents an important goal for
interventions to reduce the burden of populations and individuals with CVD and kidney disease.
b. Diagnosis of abnormal blood pressure
i. Risk Factors for Hypertension
Hypertension is a complex phenotype with multiple genetic and environmental risk factors,
as well as important gene-environment interactions.Age, along with changes in the vascular
system, demographic and socioeconomic variables is the strongest risk factors for hypertension.
The prevalence of hypertension increases sharply with age: although only 8.6% of men
and 6.2% of women are affected between the ages of 20-34, 76.4% of men and 79.9% of women
38
aged 75 and over suffer from hypertension (Figure 3.2). Therefore, in elderly patients,
hypertension is by far the most common risk factor for CVD. In the United States, approximately
81% of hypertensive patients are 45 years and older, although this group only accounts for 46%
of the US population. As the population ages, the overall prevalence of hypertension in the
population will definitely increase.
From another perspective, hypertension affects more people in their lifetime than any
other characteristic or disease studied so far. The concept of "lifetime risk" for a specific disease
provides a useful indicator for measuring the absolute burden of disease and public health impact
and provides an average lifetime risk for an individual. The lifetime risk assessment considers
the risk of disease in the remaining life cycle and the competitive risk of death caused by other
causes before the occurrence of related diseases. The Framingham Heart Study (FHS), a long-
term CVD epidemiological study, shows that for men and women who do not have hypertension
at the age of 55, the remaining lifetime risk of hypertension by the age of 80 is 93% and 91%
respectively. In other words, more than 9 out of every 10 elderly people develop high blood
pressure before death. Even those who are 65 years of age or older and do not have high blood
pressure have a remaining lifetime risk of 90%.
In Western society, SBP tends to rise with advancing age. On the contrary, DBP levels
rise until individuals reach about 50 to 55 yearsold, after which there is a plateau for several
years and then steadily decline until the end of the lifespan. A variety of factors, especially those
related to changes in arterial compliance and stiffness, can lead to the development of systolic
hypertension and the decrease of DBP with age. Both phenomena can cause a significant
increase in pulse pressure (PP) after the age of 50, which is defined as SBP minus DBP.
Therefore, hypertension, especially systolic hypertension, is almost a common aging condition,
and few people can escape its development. Only in societies where salt intake is low, physical
activity levels are very high, and obesity is rare, people can avoid age-related increases in SBP.
Figure 3.2 Prevalence of hypertension among men and women aged 18 years and over, from National Health and Nutrition Examination
Surveys 2005-2008. (Data from Mozaffarian D, Benjamin EJ, Go AS, et al. Heart disease and stroke statistics----2016 update: A report from the
American Heart Association. Circulation. 2016; 133: e 38-60)
39
ii. Weight
Weight gain is one of the main contributoryfactors of increased blood pressure. According
to the recent National Health and Nutrition Examination (NHANES) survey, the prevalence of
hypertension in obese individuals with a body mass index (BMI) of 30 kg/m2 or higher,is 42.5%,
while the prevalence of hypertension in overweight individuals (25 to 29.9 kg/m2) is 27.8%,
and15.3%in individuals with a BMI of less than 25 kg/m2. Comparing NHANES 1988-1994 with
NHANES 1999-2004, scientists found that the overall prevalence of hypertension in men
increased by 13%, and the prevalence of hypertension in women increased by 24%. After
adjusting for BMI, there was no statistically significant change in male hypertension, indicating
that the increase in BMI accounted for almost all the increase in male hypertension. For women,
after adjusting for BMI, the prevalence of hypertension continued to have a relatively large
increase, indicating that part of the increase in female hypertension can be attributed to factors
other than the increase in BMI during the recent NHANES period.
Data from Framingham also shows that the higher the BMI, the risk of hypertension
increases significantly. Compared with normal-weight adult men and women, the relative risk of
hypertension after multivariate adjustment during long-term follow-up was 1.48 and 1.70 for
overweight men and women, and 2.23 and 2.63 for obese men and women, respectively.Many
studies have also proved the important effect of weight gain on blood pressure increase and
weight loss on blood pressure reduction. As mentioned above, when most adults reach around
the age of 25, theirSBP and DBP tend to increase. However, recent data suggests that these "age-
related" increases in SBP and DBP can be avoided among young people who maintain a stable
BMI during long-term follow-up. In Coronary Artery Risk Development in Young Adults
(CARDIA) study, those who maintained a stable BMI at all six examinations over 15 years had
no significant changes in SBP or DBP, while those who had a BMI increase of 2 kg/m2 or more
significant increases in BP.
The effect of weight gain on blood pressure, and the benefits of maintaining a stable
weight or losing weight can even extend to young children. A large birth cohort study of children
examined BMI at 5 and 14 years and the relationship with 14-year-old SBP and DBP. The
average systolic and diastolic blood pressures of children who were overweight at age 5 but who
had a normal BMI at age 14 were similar to those of children who had normal BMI at both time
points. In contrast, two children who are both overweight at both ages, or a child with a normal
BMI at the age of 5 but who are overweight at the age of 14, have higher systolic and diastolic
blood pressures at age 14 than children with normal BMI at both ages, even when adjusted
Potential confounding factors.
iii. Genetic Factors
Many studies have examined potential genetic susceptibilities for hypertension. Data
consistently shows that blood pressure levels are heritable. Using data from a multi-generational
FHS cohort, Levy et al estimated that heritability measured by a single check of SBP were 0.42
and the DBP was 0.39. Using data from multiple examinations, the heritability estimates for the
long-term systolic and diastolic phenotypes are 0.57 and 0.56, respectively.
40
The availability of high-throughput technologies has recently allowed genome-wide

association studies in large-pooled cohorts to assess the link between genomic recognition
regions and BP levels. A large consortium of studies tested 2.5 million genotypes and imputed
single-nucleotide polymorphisms (SNPs) across the genome to correlate with the systolic and
diastolic blood pressure levels of 34,433 subjects of European descent. The direct genotyping of
71,225 European ancestry participants and 12,889 Indian Asian ancestry were followed up. They
also conducted a computer simulation comparison in another large consortium (n = 29,136). The
team determined the association between systolic or diastolic blood pressure and common
variants in eight genomic regions near many potentially interesting genes: CYP17A1 (p =
7×10−24), CYP1A2 (p = 1×10−23), FGF5 (p = 1×10−21), SH2B3 (p = 3×10−18), MTHFR (p =
2×10−13), c10orf107 (p = 1×10−9), ZNF652 (p = 5× 10-9)) and PLCD3 (p = 1×10-8) genes. All
variants associated with persistent blood pressure are also associated with the phenotype of
dichotomous hypertension. The authors concluded that these associations between common
variants and blood pressure and hypertension can provide mechanistic insights into blood
pressure regulation and may point to new targets for interventions to prevent cardiovascular
disease.
Updates to these genome-wide association studies continue to appear and add more
cohorts and improved genotyping methods. To date, more than 60 loci (many of which are new
or unexpected genes) have been associated with blood pressure phenotypes with similarities
noted in diverse race/ethnic groups. Similarly, rare inherited genetic syndromes are associated
with hypertension, including Liddle syndrome and 11β-hydroxylase and 17α-hydroxylase
deficiency. However, because hypertension is a complex phenotype, blood pressure levels are
determined by the complex interaction of a variety of neural, renal, endocrine, cardiac and
vascular processes, as well as environmental and behavioral factors, so there is no single gene
polymorphisms can explain a small part of hypertension alone or jointly in the populationat large.
Research on rare and low-frequency genetic polymorphisms, gene-gene interactions, gene-
environment interactions, and epigenetics may lead to new insights into blood pressure
regulation and may provide potential future targets for the prevention or treatment of
hypertension.
c. The possible role of gene variants, gene-environment interactions, and epigenetics in

essential hypertension:
Considerable effort has been devoted to searching for the genetic causes of hypertension.
Although several monogenic diseases that increase renal sodium reabsorption and blood pressure
have been found, they together account for only a small percentage of human hypertension
(<1%). Additionally, research on family blood pressure patterns has inspired research on genetic
variants that lead to essential hypertension, which suggests that genetic factors may account for
30% to 50% of blood pressure variants.
Several studies have shown that the closer the genetic correlation, the greater the
similarity of BP. For identical twins (100% genetic similarity), the systolic blood pressure
correlation coefficient ranges from 0.5 to 0.8 (average 0.6), the correlation coefficient for
fraternal twins ranges from 0.19 to 0.46 (average 0.35), and non-twin siblings (genetic About
41
50% similarity) The average correlation coefficient is about 0.23. Compared with adopted
children, biological children's blood pressure values are also more correlated.
Although many studies have shown an association between genetic polymorphisms and
BP, the genetic changes that lead to essential hypertension are still elusive. Even for widely
studied polymorphisms, such as ACE insertion/deletion and angiotensinogen polymorphism,
different results have been obtained. Polymorphisms and mutations in other genes, such as
uromodulin, α-adducin, atrial natriuretic factor, insulin receptor, β2-adrenergic receptor,
calcitonin gene-related peptide, angiotensinase C, renin-binding protein, endothelin-1 precursor,
G- In some studies, protein β3 subunit is also associated with hypertension; however, all these
polymorphisms show a weak association with BP, and many early studies have not yet been
confirmed.
Large-scale genome-wide association studies (GWAS) in identifying genes that cause

hypertension concludes that hundreds of thousands of common genetic variants have been
genotyped and BP associations have been confirmed. The International Consortium for Blood
Pressure Genome-Wide Association Studies used a multistage design among 200,000 people of
European descent, identified 16 new functional genetic variants, associated with hypertension.
Six of these loci involve genes known to regulate BP, while other gene variants suggest new
ways. However, even with these heroic attempts, the genetic variation discovered only
constitutes small risk for blood pressure variation and hypertension.
Considering the complexity of the various neural, hormonal, renal, and vascular
mechanisms for short-term and long-term blood pressure regulation, that finding several variant
alleles account for the main part of blood pressure variation. The genetic variation of BP is not
only caused by Single gene mutations but also by polymorphic genetic differences, complex
interactions of multiple genes, and interactions between genetic and environmental factors,
which add complexity to the problem.
Hypertension is believed to be caused by the cumulative effect of a variety of variant

genes that increase blood pressure. It is assumed that each gene mutation has a small effect on
blood pressure, but it may produce significant high blood pressure when working together under
necessary environmental conditions. However, despite the use of complex mathematical models
to calculate gene-gene and gene-environment interactions, the possibility of nonlinear
interactions makes it difficult to quantify the precise role of genes and environment in BP
variation.
Now a new and more complicated research to find genetic contributions to hypertension
is the possibility that epigenetic modifications may change the protein products of genes through
mitosis or meiosis without changing the DNA sequence. These epigenetic changes can occur
throughout life from early embryos to old age, and some studies have shown that epigenetic
changes can be transmitted through parental gametes for several generations. However, the
contribution of epigenetic modification to human hypertension remains largely unexplored.
The key role of environmental factors in essential hypertension is supported by the

observation that hypertension and age-related blood pressure increase rarely occur among
42
hunter-gatherers living in non-industrialized societies. In addition, a comprehensive family

analysis that includes other relatives in addition to twins shows that the environment contributes
at least 30% to blood pressure variance. These observations obviously do not imply that genetic
factors are not important in hypertension. Genetic variation may be the cause of the difference in
the distribution of baseline blood pressure and normal blood pressure in the population. When
environmental factors that produce high blood pressure (for example, excessive weight gain,
high sodium intake, low potassium intake) are added to the population baseline blood pressure,
the normal frequency distribution shifts to higher blood pressure, and the curve becomes flattener
with the increase of variability in the overall population BP. However, experimental, clinical and
population studies suggest that modern sedentary lifestyles associated with excessive weight gain
play an increasingly important role in essential hypertension.
d. Primary Hypertension and Secondary Hypertension
Primary (essential) hypertension accounts for the vast majority (>90%) of human
hypertension and involves complex interactions between multiple organ systems and blood
pressure (BP) neurohormonal controllers and local tissue control systems. Although essential
hypertension is a heterogeneous disease, overweight and obesity account for 65% to 75% of the
risk of elevated blood pressure in these patients. Genetics and other factors, such as increased
dietary sodium intake, a sedentary lifestyle, and excessive alcohol consumption, can also cause
primary hypertension. The activation of neurohormonal systems such as the sympathetic nervous
system (SNS) and renin-angiotensin-aldosterone system (RAAS) also play an important role in
the pathogenesis of hypertension. Many factors that cause essential hypertension will eventually
lead to renal dysfunction, which triggers or maintains increased blood pressure.
i. Primary (Essential) Hypertension
Many long-term blood pressure controllers directly or indirectly affect kidney function. In
patients with essential hypertension, sodium balance is maintained at a higher blood pressure,
indicating that stress-induced sodium excretion has been reset. In some hypertensive patients,
this reset is associated with increased renal tubular reabsorption, while in others, renal
vasoconstriction and GFR decrease due to intrarenal, neurohormonal or immune-mediated
mechanisms. After the diagnosis of hypertension, many kidney changes are difficult to detect,
because elevated blood pressure usually brings many renal function indicators (such as GFR,
tubular reabsorption, plasma renin) back to nearly normal.
Mild primary hypertension associated with aging, obesity, atherosclerosis, high sodium
chloride intake, low potassium intake, or excessive alcohol consumption may evolve into
secondary hypertension, especially when kidney damage occurs. Therefore, in many patients
with poorly controlled hypertension for many years, the distinction between primary and
secondary hypertension is not always clear.
ii. Monogenic (Secondary) Hypertension
Single-gene hypertension should be considered as secondary hypertension because the

underlying genetic defect can be clearly identified. The genetic defects necessary and sufficient
43
for single-gene hypertension have unique characteristics that make them different from the
genetic variants of essential hypertension (Figure 3.3). There are eight different monogenic
hypertension syndromes (MHS) including Glucocorticoid remediable aldosteronism (GRA),
Gordon Syndrome, Familial Hyperaldosteronism type III, Liddle Syndrome, Syndrome of
Apparent Mineralocorticoid Excess (AME), Hypertension and Brachydactyly Syndrome
(HTNB), Autosomal Dominant Hypertension with Exacerbation in Pregnancy, and Congenital
Adrenal Hyperplasia. Three MHSs generally have elevated aldosterone levels and are listed
above the two MHSs with generally low aldosterone. The three additional MHS have special
characteristics (occurring in pregnancy, short fingers, or virilizing characteristics). There is
considerable overlap between these three groups.
In general, single-gene familial hypertension is considered rare asthe incidence in the

general population may be less than 1/5000. However, these estimates have been challenged
since the frequency of pathological mutations may be higher than previously thought and definite
proof of significance of these genes for the general population is outstanding. Although it may be
rare, genetic variantsunderlying MHS are important in two respects:
1. For the occasional patient with high blood pressure who carries a pathogenic
monogenic hypertension variant, it is important to identify the syndrome, because in
some cases, there are specific treatments that can produce spectacular therapeutic
effects, and because the recognition of the familiarity makes cascade screening
plausible. In MHS, untreated hypertension is usually very high and can be severe
withtarget organ damage occurring early in life, premature death due to the stroke has
been observed in some cases.
2. There is no doubt that the pathways and mechanisms illuminated by the defects
caused by monogenic hypertension have permitted great progress in the understanding
of the general BP pathway. Except for one monogenic hypertension gene, all genes act
either in kidney or steroid metabolism or at the mineralocorticoid receptor (Figure 3.3).
One exception is the newly discovered monogenic hypertension gene, PDE3A, a
phosphodiesterase that may mediate hypertensive effect in the vasculature. Many of
the 13 genes in which mutations can cause monogenic hypertension and these genes
are also referred to as “Lifton genes”. Although some entities have traditionally always
had low renin levels and high aldosterone levels, while others have low levels, the
levels are usually borderline or normal. Figure 3.5 summarizes the characteristics that
should prompt clinicians to suspect monogenic hypertension. Family history is
particularly important. Once a monogenic hypertension syndrome is identified, special
treatments can be provided for certain forms that permit to obtain large treatment
effects.
There are two types of genetics of hypertension: rare familial monogenic syndromes,
which should be marked as secondary hypertension when they are identified, and genomics of
essential hypertension. Elucidating the genetic mechanism of single-gene familial hypertension
is invaluable for understanding general blood pressure pathways, and it is important to identify
these entities clinically, because specific treatments can be provided in some cases. On the
contrary, the genomics of essential hypertension cannot be explained by rare single-gene
hypertension genes. In the past decade, GWAS has identified a large number of genetic variants
44
with small effect sizes, which are beginning to help better understand the pathways that lead to
essential hypertension.
e． Orthostatic Hypotension
Orthostatic hypotension (OH) is a serious medical problem; it occurs in approximately 6%

of healthy elderly people in the community, 18% to 54% of nursing home residents, and up to
60% of hospitalized elderly people. The incidence of OH increases exponentially after the age of
65, and its importance may increase as our population ages. OH is not only the cause of
disability and impaired quality of life, but it is also associated with a 2.6-fold increase in the risk
of falls and is an independent risk factor for increased mortality. The typical patients with
orthostatic hypotension are frail elderly people with multiple comorbidities and taking multiple
drugs. Hypertension is the most common comorbidity in patients with OH; it is present in
approximately 70% of patients. In contrast, about 10% of orthostatic hypotension patients were
referred to hypertension specialists. In community studies, hypertension is closely related to OH.
The coexistence of hypertension and orthostatic hypotension is a management challenge because
treatment of one condition may worsen the other. Therefore, doctors who treat patients with
hypertension must understand the pathophysiology of orthostatic hypotension, which will
ultimately guide its treatment.
i. Pathophysiology
When a normal person stands, up to 700 milliliters of blood will accumulate in the veins
of the legs and lower abdomen. The decrease in venous return causes a brief decrease in cardiac
output.
Cardiopulmonary volume receptors and arterial baroreceptors sense the decrease in

central blood volume and arterial pressure. Afferent signals from these receptors reach the
vasomotor centers in the brainstem. Efferent fibers from these centers reduce parasympathetic
output and increase sympathetic outflow. Norepinephrine is released from the postganglionic
sympathetic nerve terminals at target organs, leading to increased heart rate and cardiac
contractility, partial restoration of venous return and diastolic ventricular filling by
venoconstriction, and an increase in peripheral resistance through arteriolar vasoconstriction. As
a net effect of these adaptive mechanisms, compared with supine position, upright cardiac output
is still reduced by 10% to 20%, systolic blood pressure (SBP) is reduced by 5 to 10 mmHg,
diastolic blood pressure increases by 2 to 5 mm Hg, and mean blood pressure remains almost
unchanged, the heart rate increases 5 to 20 beats per minute.
Damage to these compensatory autonomic mechanisms leads to OH. Primary

neurodegenerative diseases of the autonomic nervous system are the cause of the most serious
cases of OH. The common pathology of these diseases is the formation of Lewy bodies in the
peripheral noradrenergic nerves in the formation of alpha-synuclein deposits (pure autonomic
failure, Parkinson's disease) or glial cytoplasmic inclusion bodies in the central autonomic nerve
pathway (Multiple systems are shrinking). However, in most patients, OH is the result of a mild
form of autonomic nerve damage (usually related to aging or diabetes) and other aggravating
factors (usually drugs).
45
ii. Clinical Consequences of Orthostatic Hypotension
OH impairs the functional status and quality of life of patients affected by it. In addition, it
is associated with a 2.6-fold increase in the risk of falls in the elderly, and this association
persists after correcting other risk factors. OH patients usually experience syncope and falls, and
surveys indicate about 24% to 31% of patients presenting to emergency department visits.
Multiple epidemiological studies have reported that OH is related to coronary artery disease,
stroke and heart failure. The presence of OH doubles the risk of chronic kidney disease. As an
independent risk factor, it is comparable with having coronary artery disease, smoking,
hypertriglyceridemia and other risk factors that have received more attention. More importantly,
in the past 20 years, cross-sectional and longitudinal epidemiological studies have identified OH
is as an independent risk factor for cardiovascular morbidity and all-cause mortality.
Therefore, orthostatic hypotension is a burden to the healthcare system in general. A recent

report shows that the total annual rate of hospitalizations related to OH is 36 per 100,000
Chinese. adults, and this rate steadily increases with age, reaching as high as 233 people out of
10,000 in those 75 years of age or older.Considering that the Chinese population is changing
rapidly, the elderly population will account for nearly 20% of the total U.S. population in the
next 20 years. Hospitalization related to OH will be a greater challenge to our health services and
the medical community.
iii. Evaluation of the Patient with Orthostatic Hypotension
OH is defined as a continuous decrease in SBP of at least 20 mmHg or a continuous

decrease of 10 mmHg in diastolic blood pressure (DBP) within 3 minutes of standing, or a head-
up tilt to at least 60 degrees. In patients with hypertension, a 30 mmHg reduction in SBP is
considered a more appropriate criterion for orthostatic hypotension, because the magnitude of the
orthostatic blood pressure drop depends on the baseline blood pressure. The typical symptoms of
OH are dizziness, dizziness, fatigue, darkened vision, and shoulder ("hanger") pain. Patients may
beasymptomatic, or it may be difficult to recognize their symptoms. Consider that, as a general
rule, symptoms should not appear when the patient is lying on their back, mainly when standing,
and should be quickly recovered by sitting or lying down. In a hot environment and if the patient
stands still, the symptoms tend to be worse. The severity of OH is also greater in the morning, so
that it is more likely to make a diagnosis of OH if the doctor measures orthographic vital signs in
the morning than in the afternoon.
The assessment and diagnosis of OH can be done at the bedside. Autonomic nerve tests
are usually limited to specialized units and help assess the presence and severity of autonomic
nerve damage (neurogenic OH). However, this is not essential. Usually only need to measure
body blood pressure and heart rate. A significant drop in orthostatic blood pressure that is not
related to an appropriate increase in heart rate indicates neurogenic OH. Another practical
alternative to professional testing is to clinically try to improve OH by eliminating factors that
can trigger or aggravate OH; any remaining OH may have important neurogenic components.
46
The list of causes of neurogenic OH is long, but most of them become apparent after a
comprehensive assessment. In principle, any disease that causes peripheral neuropathy can cause
autonomic neuropathy and neurogenic OH. In practice, diabetes (DM) is the most common
culprit. Strict blood sugar control can delay the progression of autonomic neuropathy in type 1
diabetes, but the evidence for type 2 diabetes is not clear. B12 deficiency should be ruled out
because its treatment can lead to an improvement in OH. Particular attention should be paid to
patients with subacute onset and rapid progression of severe OH, because they usually have
autoimmune or paraneoplastic syndromes; in some cases, neurogenic OH may be the main
problem leading to the diagnosis of the underlying disease.
f. Pulse Pressure and Risks for Cardiovascular Disease
Pulse pressure (PP) is defined as the systolic minus the diastolic Blood Pressure (BP). In
recent years there has been intense interest in PP as a risk factor for Coronary Vascular Disease
(CVD). However, various investigators have struggled with how best to “anchor” the PP. For
example, a patient with a BP of 120/60 has the same PP (60 mm Hg) as a patient with a BP of
150/90, although the latter patient is clearly at higher risk for adverse events. Different
investigators have anchored the PP to the DBP, the mean arterial pressure, and the systolic BP
(SBP). As discussed earlier, Franklin et al demonstrated that increasing PP was associated with
marked increases in hazard of coronary heart disease (CHD) for subjects with the same SBP.
Doctor Chae's team also found that PP was an independent predictor of heart failure(HF) in an
elderly cohort, even after adjustment for mean arterial pressure, prevalent CHD, and other HF
risk factors. In another study, Haider and colleagues observed that SBP and PP conferred similar
risk for HF. However, other studies have found that SBP confers greater risk than PP, when SBP
and PP are considered separately or as covariates in the same multivariable model. The
aforementioned Prospective Studies Collaboration, which pooled data from 61 large
epidemiologic studies and around 1,000,000 men and women, found that the best measure of BP
for prediction of CVD events was the mean of SBP and DBP, which predicted better than SBP or
DBP alone, and much better than the PP. The recommendation of JNC 7 was that clinical focus
should remain on the SBP in determining need for therapy and achieving goal BP.
Mosley and colleagues compared the predictive utility of PP and other BP measures for
diverse CVD outcomes (including hospitalizations and mortality from stroke, MI, and HF) using
long-term follow-up data from the Chicago Heart Association Detection Project in Industry.
Baseline BP measures were assessed for predictive utility for fatal and nonfatal events over 33
years. Among 36,314 participants, who were a mean age of 39 years, 43.4% were women. In
univariate analyses, hazards ratios for stroke death per one standard deviation of PP, SBP, and
DBP, respectively, were 1.49, 1.75, and 1.71. Multiple metrics all indicated better predictive
utility for SBP and DBP compared with PP. Results for CHD or HF death, and stroke, MI, or HF
hospitalization outcomes were similar. PP had weaker predictive utility at all ages, but
particularly for those younger than 50 years of age. Overall, in this large cohort study, PP had
predictive utility for CV events that was inferior to SBP or DBP. These findings tend to support
the approach of current guidelines in the use of SBP and DBP to assess risk and the need for
treatment.
47
Hypertension is also a major risk factor for renal disease. Of the estimated 93,000 cases
of incident end-stage renal disease (ESRD) diagnosed annually, it is estimated that over 25% are
because of hypertension, and more than 40% because of combination of hypertension and
diabetes(DM). However, these numbers may substantially underestimate the contribution of BP
to the increasing incidence of renal disease, because these data provide only a single diagnostic
cause, and hypertension is present in the vast majority of those with DM. African Americans
have approximately four times the risk of whites of developing ESRD, in part because of their
significantly higher prevalence of hypertension. In addition to its contribution to ESRD, elevated
BP also occurs in and exacerbates milder forms of chronic kidney disease and worsens
proteinuria.
An association between higher baseline BP levels, typically measured at a single time

point, and lower cognitive function has been well established. Nontraditional components of BP,
such as the variability in BP from visit-to-visit (so-called long- term BP variability) have also
been associated with cognitive function in older individuals. However, long-term BP variability
throughout young adulthood to middle age has only recently been examined as a potential
predictor of cognitive function in middle age. Investigators from the CARDIA study examined
BP variability in 2326 participants across eight serial examinations over 25 years and the
association with cognitive function at an average age of 50 years. Long-term BP variability over
25 years beginning in young adulthood was associated with worse psychomotor speed and verbal
memory tests in midlife, independent of cumulative exposure to BP during follow up. In a
parallel study, the investigators used data from ambulatory blood pressure monitoring performed
at an average age of 35 years and linked it to the same cognitive function testing in midlife. In
this analysis, less nocturnal SBP dipping and higher nocturnal diastolic BP levels were
associated with lower executive function in midlife, independent of multiple measures of office
BP during long-term follow up. Nocturnal BP was not associated with psychomotor speed and
verbal memory, suggesting that different aspects of BP exposure over the lifespan may affect
regions of the brain differentially.
g. Importance of Preventing the Development of Elevated Blood Pressure
As noted earlier, BP levels tend to rise from young adulthood to the end of life. Once
hypertension has been diagnosed, many effective lifestyle interventions and drug therapies can
lower blood pressure, with dramatic reduction in CVD risk. However, it has been an open
question as to whether treatment to lower BP once hypertension is diagnosed could fully reduce
risk for CVD events to the low levels observed in individuals whose blood pressure always
remained low. Liu et al69 recently used data from the Multi-Ethnic Study of Atherosclerosis
(MESA) to examine this issue. Outcomes were compared between participants without or with
antihypertensive treatment at three BP levels: less than 120/80 mm Hg, systolic BP 120 mm Hg
to 139 mm Hg or diastolic BP 80 mm Hg to 89 mm Hg, and systolic BP 140 mm Hg or higher
or diastolic BP 90 mm Hg or higher (systolic BP ≥130 or diastolic BP ≥80 mm Hg for
participants with diabetes). Among MESA participants aged 50 years or over at baseline, those
with BP lower than 120/80 mm Hg on treatment had higher left ventricular mass index,
prevalence of estimated glomerular filtration rate less than 60 mL/min per 1.73 m2, prevalence
of coronary calcium scores greater than 100, and twice the incident cardiovascular disease rate
over 9.5 years of follow up than those with BP lower than 120/80 mm Hg without treatment. At
48
higher levels of BP, those who were treated to a given BP level also tended to be at greater risk
for CVD compared with those whose BP was at the same level without treatment. The data
suggest that, based on the current approach, antihypertensive treatment that is begun after
significant BP elevation (typically to 140 mm Hg systolic) does not restore cardiovascular
disease risk to ideal levels. Emphasis should therefore be placed on primordial prevention of BP
increases to further reduce cardiovascular disease morbidity and mortality.
h. Typical Cases Analysis
i. Management of Hypertension in the Patients with Orthostatic Hypotension
When encountering hypertensive patients with orthostatic hypotension andto prevent

syncope and falls, it is tempting to ease the antihypertensive treatment. However, current
evidence shows that this method is misguided. In the study of the elderly in the community, the
incidence of OH increased from 2% to 5% when hypertension was present, but the incidence was
19% which was highest in people whose hypertension was not controlled. More importantly, the
presence of OH itself does not increase the risk of falls, while the risk of falls in elderly people
with high blood pressure and uncontrolled OH is more than twofold. This observation supports
the treatment of OH and hypertension in these patients.
The obvious question is, which antihypertensive drugs should be used in OH patients and
which should be avoided? Limited evidence from randomized controlled trials can be used as the
basis for recommendations. Antihypertensive drugs that interfere with the autonomic orthostatic
compensation mechanism will aggravate OH. Observational studies have indeed found that the
use of alpha blockers, beta blockers and central sympathetic drugs are associated with OH. There
is a similar association with the use of thiazide diuretics. No significant associations were found
between the presence of OH and the use of calcium channel blockers. The presence of OH was
reduced in patients receiving angiotensin receptor therapy in one study, increased in patients
taking angiotensin-converting enzyme (ACE) inhibitors in another study, and in the third study,
no association was found in patients taking anti-hypertensive drugs targeting the renin-
angiotensin system.
Some patients may have isolated supine hypertension. This is most common in patients
with severe primary autonomic failure, whose sitting blood pressure may be completely normal
or only slightly elevated. There is no consensus on whether to treat isolated supine hypertension.
However, supine hypertension is associated with left ventricular hypertrophy and decreased renal
function. In addition, severely affected patients may lose up to 2 kg of body weight at night. This
is caused by stress diuresis and explains why the patient’s condition is worse in the morning.
Therefore, treatment of supine hypertension can theoretically improve OH. During the day,
avoiding the supine position is the best way to treat these patients. At night, taking several
antihypertensive drugs before bedtime have been shown to reduce supine hypertension, including
nitroglycerin patch (to be removed first thing in the morning), nebivolol, losartan, and sildenafil.
Unfortunately, because they cannot reduce nighttime diuresis, or they have residual hypotensive
effects in the morning, they did not show an improvement in the next morning OH.
49
ii. Management of Orthostatic Hypotension in the Hypertensive Patient
(1) Goal of Treatment and Overall Strategy
The main goal of OH treatment is to reduce symptoms and improve the patients’
functional status and quality of life. This requires an increase in standing blood pressure. A
recent study of patients with Parkinson's disease and OH found that if the average standing blood
pressure (BP) is higher than 75 mmHg, the symptoms are not present. This may reflect the blood
pressure below that was overcome by the brain's autoregulation. Conversely, raising blood
pressure above this level provides no additional therapeutic benefit. Therefore, the goal should
not be to "normalize" the orthostatic blood pressure, but to raise it to a level sufficient to relieve
symptoms.
The ideal therapy is to selectively improve the upright blood pressure without affecting
the supine blood pressure. However, most blood pressure boosters have the opposite effect and
produce a greater increase in supine or seated BP than in standing BP. In the absence of upright
pressor selectivity, treatment should take an onset quickly and have a short duration of action to
avoid aggravating supine hypertension. Therefore, especially for hypertensive patients, it is best
to use short-acting pressure boosters only when the patient is standing and avoid using it when
the patient is lying down.
We hypothesize that reducing orthostatic hypotension will lead to the prevention of

syncope and falls, but none of the currently available treatments show this. Even more uncertain
is that treatment will prevent the increase in mortality associated with OH. It is arguable that
medications (for example, fludrocortisone or blood pressure agents) may even have a negative
impact on cardiovascular outcomes.
Current treatment recommendations are mainly based on the study of a small number of
patients with primary autonomic failure and severe OH, and randomized controlled clinical trials
have limited evidence of long-term efficacy. No study aimed to include the most common form
of OH, diabetic patients, or elderly hypertensive patients with multiple comorbidities.
(2) Remove Offending Factors
The first step in OH management is to remove any potential factors that may precipitate
or cause OH. Medications are among the common offenders. Amitriptyline is often used to treat
pain in sensory neuropathy common in patients with autonomic neuropathy and is a common
culprit. For patients with hypertension and OH, certain drugs should be avoided, such as
diuretics and alpha blockers, but do not completely give up antihypertensive treatment
simultaneously. Doctors also need to know he "hidden" antiadrenergic drugs. Tamsulosin is
usually used to treat benign prostatic hyperplasia. It is an alpha-blocker and has a preferential
selectivity for the a1A receptors in the prostate over the a1B receptors in the blood vessels.
However, this selectivity is not absolute, and tamsulosin increases the risk of orthostatic
hypotension in susceptible individuals. Trazodone is used as an antidepressant, but it is often
overlooked that it is also a potent α1 receptor blocker that can aggravate or trigger OH.
Tizanidine is marketed as a "central muscle relaxant", but pharmacologically it is an α2 agonist,
50
very similar to clonidine in chemical structure and antihypertensive properties and can also cause
orthostatic hypotension.
Congestive heart failure is a common comorbidity in patients with OH and is usually

treated with "vasodilation" β-blockers instead of having α-blocking properties (carvedilol,
labetalol) or promoting nitric oxide (nebivolol). These drugs can indeed lower blood pressure in
patients with autonomic failure, and if cardio protection is required, it seems best to use non-
vasodilatory beta blockers. Finally, erectile dysfunction is usually an early (albeit non-specific)
sign of impaired autonomic nerve function, and phosphodiesterase inhibitors used for treatment
can significantly reduce blood pressure in patients with autonomic failure.
i. Conclusions
Orthostatic hypotension is an important and common medical problem, especially in frail

elderly people with multiple comorbidities and multiple medications. OH is an independent risk
factor for falls and overall mortality. Hypertension is one of the most common comorbidities
associated with OH. The coexistence of hypertension and OH can complicate patient
management, because one treatment can worsen the other. However, there is evidence that
uncontrolled hypertension can worsen OH, so both should be managed.
The limited data available indicate that angiotensin receptor blockers and calcium
channel blockers are the antihypertensive drugs of choice for these patients. Patients with
hypertension in the supine position can be treated by simply avoiding the supine position during
the day and taking short-acting antihypertensives before going to bed. The treatment of OH in
hypertensive patients should first focus on conservative countermeasures and treatment methods
that will not worsen hypertension. First, remove drugs that can cause or aggravate OH, including
drugs that are easily overlooked (for example, tamsulosin, tizanidine, sildenafil, trazodone, and
vasodilator β-blockers). The use of abdominal adhesive and acarbose can prevent OH and
postprandial hypotension, respectively, without increasing baseline blood pressure.
Pyridstigmine can selectively improve standing blood pressure in patients with mild autonomic
dysfunction, and oral water pills can increase blood pressure sharply but briefly in patients with
severe autonomic failure. If traditional blood pressure boosters are needed, midodrine and
droxidopa can be used. The goal is to use the lowest dose that can improve symptoms and only
give it when needed, in the early morning and afternoon in most patients.
Therefore, Hypertension is the most prevalent major risk factor for all forms of CVD and
renal disease. Risk factors for development of hypertension are well-understood, and numerous
dietary and personal habits, as well as societal issues, must be addressed if we are to lower
population levels of BP and to control individual patients’ BPs, particularly SBP. Major public
health and clinical efforts are needed to improve prevention of hypertension especially through
better control of weight. Newer research understanding the genetic underpinnings of
hypertension and important gene-environment interactions may help to point the way for novel
means of prevention. Although the benefits of antihypertensive therapy are substantial, too few
patients achieve optimal BP reduction, and so do not realize the potential reductions in risk for
CVD and renal disease. More widespread treatment and control are needed, but a greater focus
51
on primordial prevention of hypertension would be a far more effective means for reducing the
population impact of elevated BP on healthy longevity.
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53
Chapter 4 Arrhythmia
Lv Yan, M.D.
a. Sinus Arrhythmia
i. Introduction:
Sinus arrhythmia is a variation of normal sinus rhythm, which is characterized by

irregular frequency, in which the R-R interval changes greater than 0.12 seconds. In addition, the
P wave is usually a single waveform, and its pattern is consistent with the atrial activation
originating from the sinus node. During breathing, intermittent activation of the vagus nerve
occurs, leading to beat-to-beat changes in the resting heart rate. If sinus arrhythmia occurs, it
usually indicates good cardiovascular health. This activity illustrates the diagnosis of sinus
arrhythmia on telemetry and reviews the role of aninterprofessional team in managing patients in
this situation. The objective of this chapter includes the following: the features of a sinus
arrhythmia, the pathophysiology of a sinus arrhythmia and the health expected in a patient with a
sinus arrhythmia.
Sinus arrhythmia is a common incidental findingon the present of EKGs. Such finding is
normal and found at a higher prevalence in younger individuals. Lack of sinus arrhythmia may
be a sign of underlying chronic disease which requires further investigation. It is rare for patients
with sinus arrhythmia to display symptoms including shortness of breath, lower extremity edema,
dyspnea on exertion, or peripheral neuropathy. The symptoms are mostly due to some underlying
cause and not sinus arrhythmia. Care should be taken to rule out other potential causes of sinus
arrhythmia. History of trauma to the head or neck via fall or another mechanism, especially in
the setting of anticoagulation use may increase suspicion for underlying intracranial hemorrhage.
Care should be taken on a review of initial EKG to rule out 3rd-degree heart block as a cause of
sinus arrhythmia. Moreover, no physical exam findings directly correlate to the diagnosis of
sinus arrhythmia.
ii. Three Main Theorized Mechanisms of Sinus Arrhythmia
Sinus arrhythmia is a common rhythm variation and seen more often in children and
young adults. Respirations lead to vagal stimuli resulting in R-R interval variations. Its presence
is an indicator of good cardiovascular health. Loss of sinus arrhythmia may indicate underlying
heart failure or structural heart disease. Three main theorized mechanisms include respiratory-
phasic, nonrespiratory-nonphasic, and nonrespiratory-ventriculophasic sinus arrhythmia.
(1) Respiratory-Phasic
Respiratory sinus arrhythmia is a common finding. It is a normal change in heart rhythm

caused by the stimulation of the vagus nerve and changes in the filling pressure of the heart
during respiration. Recently, there has been controversy regarding the underlying pathogenesis
for sinus arrhythmia. Some studies have begun to link sinus rhythm with obesity, diabetes, and
hypertension, while other studies continue to support the reduction of sinus arrhythmias when
54
these conditions exist. Some studies have shown that it may be related to heart failure and other
systemic diseases.
` A study attempted to evaluate the effect of vagal and sympathetic efferent activity on
sinus arrhythmia by administering butylbromide and atenolol. The administration of hyoscine
butylbromide can reduce sinus arrhythmia, while atenolol can reduce vagus tone, prolong the
average R-R and increase sinus arrhythmia. The study shows that mediation of sinus arrhythmia
occurs through stimulation of the vagal. During the respiratory cycle, inspiration inhibits
vagaltone and causes an increase in sinus frequency, while exhalation increases vagal tone and
causes a decrease in frequency. This concept was supported by a later study that successfully
mimicked the respiratory cycle via stimulation of baroreceptors in the carotid artery with cycles
of phased neck suction at the frequency of normal respiration. This study shows that
baroreceptor signals play an important role in the occurrence of respiratory sinus arrhythmia.
Recently, researchers evaluated the impact of diabetes mellitus on sinus arrhythmia. They found
a decrease in sinus arrhythmia in diabetic patients, which the researchers attributed to the
autonomic effects of the disease.
(2) Nonrespiratory
In non-respiratory sinus arrhythmia, the ECG will be similar to the respiratory pattern.
The difference between the two is that non-respiratory sinus arrhythmia has nothing to do with
the respiratory cycle. Although it may occur in healthy individuals, it is more common that this
type is associated with the underlying pathology. Some people have reported that this finding is
related to underlying heart disease or digitalis overdose. A case report associated this finding
with traumatic intracerebral hemorrhage, and the authors associated it with vasospasm, hypoxia,
or increased intracranial pressure.
(3) Ventriculophasic
Ventricular sinus arrhythmia, when present, usually occurs in patients with third degree
atrioventricular block. However, they prove the relevance of premature ventricular beats. The
current theoretical mechanism suggests that ventricular phase sinus arrhythmia is caused by an
increase in stroke volume due to prolonged cardiac filling time. The increased stroke volume
triggers a carotid baroreceptor response. On the ECG, this is manifested as a shortening of the
interval between the QRS26 wave and the subsequent P wave.
iii. Evaluation, Treatment and Management
Evaluation of sinus arrhythmia, asymptomatic and normal findings are usually limited.
Attention should be paid to exclude other causes of arrhythmia including atrial fibrillation, flutter,
or multifocal atrial tachycardia and electrocardiogram. The P waves will show a uniform
morphology. On the electrocardiogram, sinus rhythm is shown as a beat-to-beat change in the P-
P interval. Usually, this change is greater than 120 milliseconds: The P-P interval increases and
decreases with inhalation and exhalation.A differential diagnosis for sinus arrhythmia would
26
QRS: A pattern seen in an electrocardiogram that indicates the pulses in a heartbeat and their duration.
55
include atrial fibrillation or third-degree AV block.No required staging criteria exist for the
evaluation of sinus arrhythmia.Sinus arrhythmia is a common finding on telemetry. It is a normal
variation found in healthy young adults. Upon confirming the diagnosis of sinus arrhythmia on
EKG, there are no further recommendations regarding treatment.
b. Atrial fibrillation
i. Introduction:
Atrial fibrillation (AF) is the most common arrhythmia diagnosed in practice. A number
of large observational cohort studies have clearly found the consequences of AF, including if an
oral anticoagulant is not prescribed, it will increase the incidence of stroke and systemic
embolism, thereby increasing morbidity and mortality. With the aging of the global population,
regardless of whether there are risk factors for AF, an epidemic is expected to occur in the next
10 to 20 years. Although not all studies support this evidence, it is clear that AF is on the rise,
and a lot of health resources are used to detect and manage AF.
AF is the most common arrhythmia in clinical practice. Between 1990 and 2013,
although the global prevalence of AF declined slightly, the total number of AF cases increased.
AF is associated with an increase in morbidity and is measured in disability-adjusted life years
(DALYs). AF can also lead to an increase in the utilization of health care resources and may
have a significant impact on the global health budgets. Several long-term cohorts have been
clearly identified, and several clinical outcomes are increased in AF patients. Among other
clinical results, AF is associated with increased risk of stroke and one third of all ischemic
strokes.
ii. Primary Prevention
Primary prevention of AF is to reduce the risk of first attack by targeting changeable risk
factors. However, this approach is challenging due to the significant knowledge gaps associated
with understanding the multiple mechanisms of AF. Some models such as CHARGE-AF have
been developed to predict the risk of AF based on age, race, height, weight, blood pressure,
smoking, use of antihypertensive drugs, diabetes and history of myocardial infarction and heart
failure. There is some evidence that there is a causal relationship between body mass index (BMI)
and AF.Some intervention studies indicate that AF ablation results may be better when actively
approaching modifiable risk factors. There is an urgent need to conduct research to inform more
geographically and ethnically diverse populations of AF primary prevention efforts, and to
evaluate the effectiveness of prevention strategies aimed at reducing the global risk of AF.
56
Figure 4.1 AF stages and proposed interventions.
iii. Diagnosis
An electrocardiogram (ECG) is still required to confirm the diagnosis. A negative ECG

does not exclude the diagnosis of AF by pulse-taking since AF may be paroxysmal. For patients
with suspected AF, diagnosis should be confirmed using a single-lead rhythm strip or 12-lead
ECG documenting ≥ 30 s of AF. A 12-lead ECG can detect other abnormalities such as left
ventricular hypertrophy, ischemia, and other clinical features. At first diagnosis, AF can be
classified as one of four types: paroxysmal (self-terminating, usually within 48 hours), persistent
(lasts longer than 7 days), long-standing persistent (has lasted one year or more) or permanent
(with presence of arrhythmia and no rhythm control). Although paroxysmal AF is associated
with somewhat lesser risk of stroke and systemic embolism than non-paroxysmal AF, all types of
AF are associated with sufficiently increased risk, especially for stroke. Therefore, the detection
of even paroxysmal AF is critical and warranting oral anticoagulation therapy in most of the
those aged 65 years or above. Inexpensive smart phone-based rhythm monitoring equipment has
potential applications in develop countries, but systems for deployment and validation require
further assessment.
The existence of cardiovascular disease and other risk factors can affect the stroke risk
and prognosis of patients with atrial fibrillation and should be systematically evaluated. It should
be emphasized that primary care physicians do not make full use of many of these scores, so
there is still a large proportion of patients in the world who are not diagnosed and treated with
oral anticoagulation (OAC) therapy, and the modifiable risk factors are not well controlled.
iv. Management Recommendations:
The role of OACs for the prevention of stroke and systemic embolism in patients with AF
is clearly established and today several options are available. The main challenges are related
with the perceived threat of bleeding in contrast to the prevention of a disabling stroke.
Populations that derive the greatest benefit from OACs are the elderly that are also at higher risk
of bleeding. Nonetheless, OACs and most likely direct oral anticoagulants are the preferred
strategy. Anticoagulation for medium and highrisk non-valvular AF is identified as a
recommended policy option by the World Health Organization (WHO) in the WHO Global
Action Plan for the Prevention and Control of NCDs 2013–2020.However, warfarin remains the
most widely available anticoagulant. Aspirin, which is widely used as an antithrombotic therapy
for AF is neither effective nor safe and has very limited indications and is rarely indicated by
most guidelines. The combination of aspirin plus clopidogrel is more effective than aspirin alone
57
but less effective than warfarin and has no advantage over warfarin in terms of major bleeding.
However, this combination may be an alternative particularly in developing countries and for
patients that live in remote rural areas where proper OAC follow-up may be unrealistic.
The decision of initiating the OAC therapy to reduce risk of stroke must be weighed
against the risk of major bleeding complications associated with the therapy, especially the intra-
cerebral hemorrhage. The highest the risk of stroke estimated by most risk scores, the higher the
risk of bleeding. The monitoring of AF patients by primary health care providers also provides
an opportunity to monitor and treat combined cardiovascular diseases, especially hypertension,
heart failure, diabetes, and valve abnormalities. Also, the management of AF should include
consideration of the management of rheumatic heart disease and valvular heart disease, both of
which are common in developing countries and are largely related to the development of AF.
The ideal patient care pathway will vary among geographies and is primarily based on
health resource availability. Key recommendations for detection, diagnosis and management of
AF includes: (1) screening of individuals with known AF risk factors and opportunistic screening
of patients 65 years or older; (2) 12-lead ECG to confirm suspected AF; (3) assessment of stroke
risk; and (4) initiation of anticoagulant therapy, combined with lifestyle modification advice if
appropriate such as weight reduction and smoking cessation. Further management strategies are
clearly established and are not the focus of these recommendations.
c. Ventricular Arrhythmias
i. Introduction:
Ventricular arrhythmias involving the fascicular system may be seen in both structurally
normal and abnormal hearts. Idiopathic fascicular ventricular tachycardia represents almost 10%
to 15% of idiopathic ventricular tachycardia related to the left ventricle. Although initial studies
focused on arrhythmias related to the left posterior fascicle, it is possible for arrhythmias to arise
from any portion of the fascicular system and in both structurally normal and abnormal hearts.
Furthermore, when approaching the patient presenting with arrhythmias arising from the His-
Purkinje system, it is important to consider the unique complexities related to mapping and
ablation. In general, fascicular ventricular tachycardia in the absence of other structural heart
disease will be termed idiopathic fascicular ventricular tachycardia (IFVT).
There are three types of IFVT, (1) left posterior branch with right bundle branch block
and left axis deviation; (2) left anterior branch with right bundle branch block and right axis
deviation pattern; and(3) upper left septal branch with narrow QRS and normal electrical axis but
often have right bundle branch block. There are rare case reports of left bundle branch block
mode, V3-V4 transition IFVT, and its normal axis comes from the right bundle branch. In
addition, there are other arrhythmias related to Purkinje and branch as they are related to the
diagnosis and mapping of IFVT. However, by far, the most common form of IFVT is the
posterior branch (about 90% of cases) (Table 4.1).
58
ECG
Type of QRS Width, ms QRS QRS Circuit
Tachycardia Morphology Axis Component
Posterior <120 - 140 RBBB Left Starts in upper septum
Fascicle (most near bundle of
common) his/proximal LBBB in
verapamil-sensitive slow
zone, travels toward apex.
Posterior fascicle is the
antegrade limb
Anterior <120 - 140 RBBB RightStarts in upper septum

Fascicle near bundle of
his/proximal LBBB in
verapamil-sensitive slow
zone, travels toward
anterior fascicle exit.
Anterior fascicle is the
antegrade limb.
Upper Septal <120 RBBB or normal Normal Circuit likely to involve
Fascicle reverse path of others.
Although not fully
characterized, the reason
for the narrow QRS may
be because of near
simultaneous antegrade
activation of the left
anterior and posterior
fascicles with the septal
fascicles with the septal
fascicles serving as the
retrograde limb.
LBBB indicates left bundle branch block; and RBBB, right bundle branch block.
ii. Approach to Ablation of IFVT
Once the mechanism and the responsible fascicle is defined, it is critical to consider
ablation. One option limitations of traditional mapping techniques and particularly if there is
high suspicion of IFVT but it proves non-inducible or non-sustained is to go upstream of the
presumed critical site and simply ablate through the proximal aspect of the fascicle, thus
preventing conduction through all distal elements.However, there are 3 issues related to this: (1)
this may require more ablation than otherwise necessary; (2) if there is interlinking between
components of the more distal fascicle and Purkinje fibers, there may still exist potential for
reentry despite elimination of the conduction through more proximal elements; and (3) pro-
arrhythmia may occur because of excessive ablation. Thus, having a systematic approach to
mapping, defining the electrograms and the circuit and deciding where to ablate is critical.
59
Another commonly used ablation method is to identify the earliest pre-systolic or

diastolic bundle or Purkinje signal associated with QRS during tachycardia and ablate there,
which may be suitable for> 50% of cases. Alternatively, the earliest can be plotted the
ventricular electrogram then, in the vicinity, ablates the fascicle or Purkinje signal. There are
several limitations of these methods, including the possibility of ineffective ablation for reentry
wide isthmus points. If ablation is done upstream of the circuit, there may be other connections
to muscles or branch-Purkinje networks. In addition, distinguishing these signals can be difficult.
Although the fascicle signal can be well separated from local ventricular activation due to the
presence of a fibrous coating of insulating fibers (resulting in a reasonable isoelectric period),
there may not be a similar isoelectric period that separates Purkinje from ventricular activation.
In addition, especially when mapping during sinus rhythm, if conduction through fascicular
fibers or Purkinje fibers is slow, so that local ventricular activation occurs before these fibers
reach their targets, there may be significant signal confusion. However, one way to better
distinguish the myocardium from the fascicular/Purkinje signal is to interpolate ventricular
premature beats during tachycardia to separate the signal, although this must be repeated at each
mapping point. This will bring two benefits: (1) We can define whether the mechanism is
reentrant or automatic according to the reset characteristics; (2) Based on the signal of movement
and whether the tachycardia is reset, we can determine whether the sensory signal is for
arrhythmias and may be reasonable targets for ablation.
Ideally, if using any or all the aforementioned techniques to map the tachycardia period
and compare the signal with the signal seen during sinus rhythm to determine the part of the
fascicles most critical arrhythmia propagation, then ablation can be targeted at these most critical
parts while saving areas that may not be relevant. However, these methods need to weigh their
limitations, including the need to repeatedly induce tachycardia and a well-placed multipolar
catheter.
Several final key points need to be considered during ablation. First, given that the
fascicular and Purkinje fibers are relatively superficial, transmural lesions are typically not
necessary to achieve success. In addition, during ablation, there is potential to cause activation of
the Purkinje tissue and to induce ventricular fibrillation. Finally, premature ablation without fully
defining the circuit elements first should not be done as ablating prematurely proximally or
distally may make further analysis/acquisition of signals difficult (e.g., ablation of a secondary
exit during more distal ablation leading to a change in QRS morphology but with continued
tachycardia).
iii. Ablation Outcomes
Overall success rates for ablation of IFVT range from 70% to 90% over long-term
follow-up. Over a follow-up of almost 5 years, in those who recurred, a shorter VT cycle length
at baseline was the only predictor of recurrence, and most commonly recurrence involved the
same fascicle, although in a third involved the left upper septal fascicle. The upper septal fascicle
in IFVT has been suggested to be an orthodromic form of IFVT and ≈50% of patients presenting
with this form of IFVT will have had a previous ablation for a more common form related to the
left anterior or posterior fascicles.
60
d. Atrioventricular Junctional Tachycardia with exit block
Atrioventricular (AV) junctional tachycardia is an abnormal rhythm caused by a focus of

enhanced automaticity within or near to the bundle or AV junction. This arrhythmia is usually
described as idiopathically or postoperatively. Exit block is defined as the failure of the electrical
propagation of pulses generated by any pacemaker to the surrounding myocardium.
This results in a narrow complex tachycardia, heart rates that vary from 120–220 bpm,
and classic signs of AV dissociation. This arrhythmia often presents with normal sinus P-wave
conduction that is subsequently blocked by the ectopic junctional beat. In some instance,
conduction from the junctional focus to the atrium may be seen. P waves, if present, may arise
before, during, or after the QRS complex and classically are inverted in the inferior leads (II, III,
and aVF) and upright in aVR.
Exit block is described as type I, or Wenckebach, with a progressive delay in conduction

that is apparent by grouped beating or a decreasing P-P (atrial) or R-R (junctional or ventricular)
interval before the blocked beat; or type II, which is characterized by a blocked beat that occurs
in the absence of preliminary signs with a length that is a multiple of the basic interval. ECG
diagnosis of an exit block is based on intermittent P-P interval prolongation in multiples
(doubling, tripling, etc.) of the normal P-P interval.Historically, this arrhythmia has been
documented in the elderly population, most commonly associated with digoxin toxicity or
myocardial infarction. One case study described this arrhythmia, which occurred non-
postoperatively in the context of normal digoxin levels and exercise and was successfully
managed with propranolol.
e. Arrhythmia caused by common extracardiac factors
i. Hypertension:
The association between hypertension and arrhythmia has long been established. Blood
pressure (BP) is a strong and independent predictor of new-onset arrhythmia and appears to be
linearly related to the incidence of arrhythmia. While the increase in risk is relatively modest
[relative risk (RR): 1.2–1.5], hypertension is so common that it is the most significant
population-attributable modifiable risk factor for arrhythmia. In other words, hypertension
contributes more to AF risk than any other known individual risk factor and is estimated to be
responsible for 14% to 20% of all arrhythmia cases.
When broken down, the risk is more closely related to systolic rather than diastolic BP.
Some studies have even suggested that systolic BP in the prehypertensive range (130–139
mmHg) is associated with an increased risk adjusted hazard ratio (aHR) of 1.28 versus a systolic
BP < 120 mmHg. Moreover, while mean arterial pressure does not appear to be associated with
incident arrhythmia, an increased pulse pressure has been associated with an increased
arrhythmia risk (aHR: 1.26 per 20 mmHg).
Hypertension may induce arrhythmia through a combination of neurohormonal activation

(activation of the sympathetic nervous system and the renin–angiotensin–aldosterone system),
61
atrial structural remodeling, atrial interstitial fibrosis, and conduction disturbances, all of which
enhance the susceptibility to arrhythmia.
ii. Diabetes
Diabetes hasalso been associated with an increased risk of atrial fibrillation (1.5 times).
Although arrhythmia and diabetes have common risk factors (diabetes is related to systemic
inflammation, autonomic dysfunction, obesity, sleep apnea, coronary artery disease, and heart
failure), previous observations have shown that there is a causal relationship, namely (1) The risk
of arrhythmia is independently related to longer duration of diabetes treatment (for each year of
diabetes duration increases, the risk of arrhythmia increases by 3%); (2) The risk of arrhythmia is
independently related to poor blood glucose control, and fasting blood glucose increases with
each increase 1 mmol/L is associated with a 33% increase in the risk of arrhythmia, and every
1% and 13% increase in hemoglobin A1c (HbA1c) is associated with an increased risk of
arrhythmia and (3) diabetes control is associated with improved arrhythmia outcomes. For
example, treatment of metformin is associated with a lower incidence of arrhythmia. In addition,
the coexistence of arrhythmia and diabetes indicates a worsening prognosis, with a 1.6-to-1.7-
fold increase in all-cause mortality, cardiovascular death and heart failure.
iii. Dyslipidemia
The association between dyslipidemia and incident AF is unclear. While several

epidemiological series have suggested that the risk of AF is inversely correlated with low-density
lipoprotein level as every standard deviation increase in low-density lipoprotein cholesterol level
was associated with a 10% reduced AF risk in ARIC, others have not. A similar contentious
relationship was reported with high-density lipoprotein, which was inversely correlated with AF
risk in some but not all series.
Given their possible pleiotropic effects, 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-

CoA) reductase inhibitors (“statins”) have been studied with respect to their influence on
arrhythmia incidence. These agents have protective effects through a prolongation in action-
potential duration and the effective refractory period, an attenuation in the downregulation of L-
type calcium channel, a suppression of pulmonary vein triggers, and an attenuation in atrial
electrical and structural remodeling and atrial fibrosis.
iv. Electrolyte Disorders
All kinds of electrolyte disorders mostly affect the potential action of myocardium, thus
affecting the excitability, automaticity, and conductivity of the myocardium. Severe electrolyte
disorders lead to abnormal origin and conduction of the cardiac excitation. The most common
electrolyte disorder is abnormal of potassium. In addition, Hyperkalemia can cause ventricular
tachycardia, ventricular flutter or fibrillation, and cardiac arrest, and hypokalemia can cause
atrial tachycardia, ventricular ectopic beats, ventricular tachycardia, ventricular block, and
atrioventricular block etc. Hyper-calcium can case sinus static, sinus arrest, ventricular premature
beat and paroxysmal ventricular tachycardia. In general, arrhythmia rarely occurs in patients with
hypocalcemia.
62
f. Antiarrhythmic Drugs:
In patients who have survived a sudden cardiac arrest or experienced sustained

ventricular arrhythmias but havedeclined ICD implants, antiarrhythmic drugs could beused as an
alternative to ICDs to reduce arrhythmia burden. Among patients who receive ICDs for the
secondaryprevention of SCD, many experience recurrent ventriculararrhythmias that trigger
appropriate defibrillator shocks.Antiarrhythmic medications may reduce the need for defibrillator
shocks in these patients and therefore improvethe quality of life. In this population with
structural heartdisease, antiarrhythmic medication options are limited toamiodarone, sotalol, or
mexilitene,with amiodarone being the preferred agent due to superior efficacy and lower
proarrhythmic effects compared to sotalol. However, amiodarone’s side effects profile with long-
term use of this medication make sotalol and mexiletine acceptable alternatives in select
scenarios, despite lower efficacy. Amiodarone can raise the defibrillation threshold, whereas
sotalol may decrease it, and these effects may be important in patients with high defibrillation
thresholds. Also, the potent β-blockade effects of sotalol can limit its use in patients with
marginally or poorly compensated heart failure.
The need for adjunctive antiarrhythmic therapy in patients who have received an ICD for
the secondary prevention of SCD is not uncommon and was reported to have been used in the
ICD therapy arms in 22% of AVID patients at 2 years and 28% of CIDS patients at 5 years.The
addition of antiarrhythmic medications aims primarily to improve quality of life and reduce
shocks, but shock prevention has not been found to improve survival in a systematic review that
included 6000 ICD recipients.
In this population of patients,antiarrhythmic drugs might also be indicated for the

treatment of supraventricular arrhythmias, which could lead to inappropriate defibrillator shocks,
especially for atrial fibrillation. With modern programming, there have been reductions in the
rates of inappropriate shocks, but control of supraventricular arrhythmias might improve quality
of life for patients regardless of reduction of inappropriate shocks.
β-Blockers
Among patients with coronary disease, those with priorMI and LV dysfunction or heart
failure may derive survival benefit from β-blocker therapy, which may also include improvement
in SCD risk as a subset of modes of death.In patients with recurrent ventricular arrhythmias, β-
blockers may suppress the adrenergic drive associated with these arrhythmias. Moreover, in
many patients with heart failure, β-blocker therapy may prevent recurrent clinical heart failure
episodes, which are known to be periods of increased risk of arrhythmia recurrence. Furthermore,
β-blockers may reduce inappropriate shocks from atrial fibrillation or sinus tachycardia with
rapid ventricular rates in these patients.In patients who survived a sudden cardiac arrest but were
not enrolled in AVID, β-blocker use was associated with a survival benefit.
Patients with coronary disease should be treated with lipid-lowering agents in

concordance with the corresponding clinical guidelines. The use of lipid-lowering agents for the
purpose of reducing SCD remains controversial but available date suggest benefit. In patients
with CHD who have received an ICD in AVID, lipid-lowering therapy was found to be
63
associated with a 60% relative reduction in the probability of VT/VF recurrence. Another
observation study showed that the use of lipid-lowering drugs was associated with a reduction of
recurrences of ventricular arrhythmias in patients with coronary disease and ICD implants.
g. A typical case analysis-Atrioventricular (AV) junctional tachycardia
i. Introduction:
Atrioventricular (AV) junctional tachycardia is an abnormal rhythm that arises from a

focus of enhanced automaticity within or adjacent to the bundle or AV junction. This
dysrhythmia is often described as arising idiopathically or postoperatively.Exit block is defined
as the failed electrical propagation of an impulse, generated by any cardiac pacemaker, into the
surrounding myocardium.
Here we report the case of an otherwise healthy adolescent female who presented with a
history of vasovagal syncope. Independent of symptoms, the patient had what seemed to be
intermittent episodes of advanced, second-degree AV block. Medical evaluation identified a final
diagnosis of idiopathic AV junctional tachycardia with exit block that was successfully managed
with flecainide and eventually cured with cryoablation. This arrhythmia has not previously been
described in a pediatric patient.
ii. Fact of the case:
The patient is a 17-year-old healthy adolescent female who presented with a history of
vasovagal syncope. Independent of symptoms, the patient had what seemed to be intermittent
episodes of advanced, second-degree AV block. Medical evaluation identified a final diagnosis
of idiopathic AV junctional tachycardia with exit block that was successfully managed with
flecainide and eventually cured with cryoablation. This arrhythmia has not previously been
described in a pediatric patient.Independently, episodes of second-degree (Mobitz type I) AV
block as well as advanced, second-degree AV block with asymptomatic pauses in AV
conduction lasting up to 4.8 seconds occurred (figure 4.2).
64
Figure 4.2 Ambulatory electrocardiographic recordings showing (A) the rhythm suspected to be advanced, second-
degree atrioventricular (AV) block with post block AV conduction variability; (B) an episode of second-degree,
Mobitz type I AV block; and (C) a rhythm showing the regularity of the P-wave intervals.
The patient was admitted to the hospital telemetry unit for evaluation and management of
AV block. Workup revealed a normal physical examination, vital signs, and 15-lead
electrocardiogram (ECG). Results of a laboratory panel revealed normal serum electrolytes,
complete blood count, erythrocyte sedimentation rate, antinuclear antibody panel, Lyme
antibody panel, and streptolysin O antibodies. Transthoracic echocardiography and cardiac
magnetic resonance imaging showed normal cardiac structure and function with no evidence of
myocarditis. The patient continued to have episodes of advanced, second-degree AV block,
particularly during periods of startle (awakening by alarm clock). A treadmill stress test revealed
sinus rhythm throughout exercise and recovery, with a peak heart rate of 206 bpm but no
dysrhythmia.
Because of her conduction system’s response to startle, the patient underwent a 30-
minute head-up tilt table test to assess for increased vagal tone. Ten minutes into the tilt, the
patient developed symptoms consistent with her chief complaints of palpitations, shortness of
breath, chest tightness, dizziness along with pallor, and syncope. At that time, sinus bradycardia
(40 bpm) and a decrease in blood pressure were documented; however, no significant ectopy or
arrhythmia was noted on continuous ECG. The patient maintained normal sinus rhythm with 1:1
AV conduction throughout the tilt and during recovery.
65
The continuous frequent episodes of prolonged advanced, second-degree AV block every

day on telemetry still exist. A dose of atropine 1 mg was administered intravenously to inhibit
potential elevated vagal tone with no effect.
According to the intermittent character of the advanced, second-degree AV block and the
patient’s symptoms during tilt table test elicited during sinus rhythm, the diagnoses of AV
junctional tachycardia with exit block and concurrent vasovagal syncope were considered. To
prove this, the decision was made to initiate flecainide 130 mg/m2/day by mouth divided twice
daily, which was prescribed based on standard adult dosing. By the third dose of flecainide, the
patient’s telemetry and ECG monitoring showed normal sinus rhythm without episodes of
advanced, second-degree AV block. The patient was observed for 3 additional days without any
symptoms and was discharged home. Outpatient Holter monitoring identified no episodes of AV
junctional tachycardia over a period of 1 year. However, she was later found to be noncompliant
with the medication, and the dysrhythmia returned on subsequent Holter monitoring.
The patient was then referred for electrophysiological (EP) study. EP study showed
normal intervals at baseline (AH interval 66 ms, HV interval 41 ms) and decremental conduction
over the AV node (AV Wenckebach with rapid atrial pacing at 410 ms, AV nodal effective
refractory period 600/310 ms), with no evidence of dual AV nodal physiology. The abnormal
rhythm was not inducible during EP study.
The doctors performed a junctional modification, and the ectopic focus was empirically
identified based on previous clinical experience. It was localized anatomically by mapping the
His bundle and moving the catheter inferiorly where no further His bundle was recognized.
Three-dimensional mapping placed the lesion <5 mm from the His position. A broad cryothermal
lesion set was placed in the right inferior input of the AV node using a Medtronic Freezor AX 8-
mm tip, 9F cryoablation catheter (Medtronic CryoCath LP, Pointe-Claire, Quebec, Canada). AV
nodal conduction properties were unchanged after the lesion set as determined by incremental
atrial pacing and a single atrial extra stimulus. No complications or signs of transient heart block
occurred during the procedure. Flecainide was discontinued, and the patient was discharged to
home the next day. Follow-up over the next year showed no recurrence of AV junctional
tachycardia without flecainide on multiple ambulatory heart rhythm monitors.
iii. Discussion
AV junctional tachycardia is an abnormal rhythm that arises from a focus of enhanced

automaticity within or adjacent to the His bundle or AV junction.This results in a narrow
complex tachycardia, heart rates that vary from 120–220 bpm, and classic signs of AV
dissociation.
This arrhythmia often presents with normal sinus P-wave conduction that is subsequently
blocked by the ectopic junctional beat. In some patients, conduction from the junctional focus to
the atrium may be seen. P waves, if present, may arise before, during, or after the QRS complex
and classically are inverted in the inferior leads (II, III, and aVF) and upright in aVR.
,
66
AV junctional tachycardia can be described based on etiology (idiopathic and

postoperative) or timing (paroxysmal and nonparoxysmal). In the pediatric population, junctional
tachycardia presents in 3 forms: congenital, postoperative, or an “adult” form.Exit block is the
failed electrical propagation of an impulse, generated by any cardiac pacemaker, into the
surrounding myocardium. Exit block is described as type I, or Wenckebach, with a progressive
delay in conduction that is apparent by grouped beating or a decreasing P-P (atrial) or R-R
(junctional or ventricular) interval before the blocked beat; or type II, which is characterized by a
blocked beat that occurs in the absence of preliminary signs with a length that is a multiple of the
basic interval. ECG diagnosis of an exit block is based on intermittent P-P interval prolongation
in multiples (doubling, tripling, etc) of the normal P-P interval.
Non-postoperative AV junctional tachycardia with exit block in the pediatric population

has not been previously described. Historically, this arrhythmia has been documented in the
elderly population, most associated with digoxin toxicity or myocardial infarction. One case
study described this arrhythmia, which occurred non-postoperatively in the context of normal
digoxin levels and exercise and was successfully managed with propranolol. The case presented
here exhibited both AV junctional tachycardia with exit block and vasovagal syncope.
Evaluation for the arrhythmia included a differential diagnosis of high vagal tone, Lyme carditis,
rheumatic fever, myocarditis, lupus, and fibrosis/sclerosis of the conduction system, yet the
respective studies were negative. Because of the vague correlation of symptoms, the patient
underwent a 30-minute head up tilt test, which reproduced her presenting symptoms but with
maintenance of sinus rhythm and fully conducting all P waves, consistent with vasovagal
syncope. We worked through the preliminary diagnosis of advanced, second-degree AV block
that was suspected; however, the intermittent occurrence of the arrhythmia suggested AV
junctional tachycardia with exit block. This diagnosis is consistent with the recordings shown in
Figure 4.2, which show consistent P-wave intervals with intermittent failure to conduct a QRS
secondary to junctional extrasystoles with exit block.
Flecainide was found to effectively treat the AV junctional tachycardia with exit block.
After a year of successful treatment with flecainide, the patient started to experience recurrent
episodes of dysrhythmia secondary to noncompliance. Because cryoablation has been shown to
effectively treat non-postoperative junctional tachycardia in the pediatric population, an elective
cryoablation of the AV junction was performed, which successfully treated the dysrhythmia.
After the EP study, the patient has shown normal cardiac conduction without episodes of AV
junctional tachycardia with exit block based on multiple ambulatory heart rhythm monitors
recorded over the following year.
iv. Conclusion
Idiopathic AV junctional tachycardia with exit block is a rare arrhythmia in pediatric

patients. In this case. AV junctional tachycardia exit block was initially resolved by flecainide
and definitively treated by junctional modification with cryoablation. Symptoms of vasovagal
syncope persisted and were conservatively managed with increased intake of fluids and salt.
67
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70
Chapter 5: Cardiomyopathy
Lv Yan, M.D.
a. Inherited Cardiomyopathies
i. Introduction:
Inherited cardiomyopathies are a major cause of heart disease in all age groups. Not only
the patients but also their families can be severely burdened by these illnesses. More than 20
years ago, the first “disease gene” for hypertrophic cardiomyopathy was identified. This finding
led to the concept that hypertrophic cardiomyopathy is a disease of the sarcomere. Similar
advances in the elucidation of the genetic basis of other forms of cardiomyopathy and in other
inherited cardiovascular diseases were made.
The identification of disease genes in numerous inherited diseases has raised expectations
for new forms of treatment. Nevertheless, for some inherited cardiomyopathies, there are
realistic prospects that molecular insights will soon lead to novel treatments. This section focuses
on recent findings regarding the mechanisms underlying cardiomyopathies that will inform
clinical practice and guide the search for therapeutic targets.
ii. Classification of Inherited Cardiomyopathies
The long-standing classification of inherited cardiomyopathies according to functional

and morphologic features is crude yet clinically useful. Despite considerable heterogeneity
within the categories of hypertrophic, dilated, restrictive, arrhythmogenic right ventricular, and
other types of cardiomyopathies, these diagnostic classifications can predict major complications
and delineate treatment options for each group. Finer resolution of these categories is to identify
clinically significant subtypes. However, Molecular insightsdo not supersede the clinical
classification since different mutations within the same gene can underlie different disorders
(Figure 5.1). Mutations that affect adjacent amino acids in the β-myosin heavy chain such as
hypertrophic cardiomyopathy or dilated cardiomyopathy. All the inherited cardiomyopathies are
genetically heterogeneous; within each category there are multiple disease genes, and many
different mutations, each of which is uncommon. The degree of genetic heterogeneity varies
among the cardiomyopathies and determines the extent to which a final common pathway of
pathogenesis can be identified for each condition.
71
Figure 5.1 Clinical Categories of Inherited Cardiomyopathies and Their Genetic Basis. The clinical entities
hypertrophic cardiomyopathy and dilated cardiomyopathy share some disease genes with each other, as well as with
restrictive cardiomyopathy and left ventricular noncompaction, which are less common. Arrhythmogenic right
ventricular cardiomyopathy appears to be a genetically distinct category, although its clinical phenotype cannot
always be easily distinguished from that of dilated cardiomyopathy. AMPK denotes AMP-activated protein kinase,
GLA α-galactosidase A, LAMP2 lysosomal-associated membrane protein 2, and TMEM43 transmembrane protein
43. Classes of genes shown in red are the overwhelmingly predominant cause of disease within the respective
categories. Source of the Image: Inherited Cardiomyopathies; Hugh Watkins, MD., PhD, and so on.
(1) Hypertrophic Cardiomyopathy
Hypertrophic cardiomyopathy is an autosomal dominant disease characterized by

unexplained hypertrophy of the left ventricle (and sometimes of the right ventricle), often with
predominant involvement of the interventricular septum. Other hallmark features are myocyte
disarray and fibrosis (Figure 5.2). Hypertrophic cardiomyopathy was termed a “disease of the
sarcomere” when the first three disease genes to be identified were found to encode components
of the contractile apparatus of heart muscle.3 Mutations in nine genes encoding sarcomeric
proteins have now been convincingly shown to cause hypertrophic cardiomyopathy. Disease-
causing mutations in any one of these genes are found in up to two thirds of patients with
hypertrophic cardiomyopathy. Mutations in MYH7, encoding the β-myosin heavy chain, and
in MYBPC3, encoding cardiac myosin-binding protein C (cMyBP-C), are the most common,
each accounting for one fourth to one third of all cases of the disease; the remaining seven genes
each account for less than 1% to 5% of cases. The mutations generally cause single amino acid
substitutions in proteins that become incorporated into the sarcomere. However, about half the
reported MYBPC3 mutations are truncations; these, and some MYBPC3 missense mutations, can
result in haploinsufficiency, a condition in which the gene product of the wild-type allele cannot
compensate for the decreased product from the mutant allele.
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Analyses in vitro and in mouse models of cardiomyopathy have shown increased

contractility of mutant myofilaments due to altered myosin kinetics, increased thin-filament
calcium sensitivity, or changes in cMyBP-C–mediated regulation. These perturbations trigger
signaling pathways that induce cardiac hypertrophy and are likely to contribute to the diastolic
dysfunction in hypertrophic cardiomyopathy. The elevated sarcoplasmic calcium concentration
during diastole, as documented in mouse models of hypertrophic cardiomyopathy, is likely to
promote signaling (e.g., by means of calcineurin–nuclear factor of activated T cells [NFAT] and
calcium-calmodulin–dependent protein kinase II), the changes in calcium handling may also
confer a predisposition to arrhythmias.
Figure 5.2 Pathogenesis of Hypertrophic Cardiomyopathy In hypertrophic cardiomyopathy, mutations in

sarcomeric proteins generally increase myofilament activation and result in myocyte hypercontractility and
excessive energy use (Panel A). Alterations in myocardial energy status can also result from primary mutations
affecting myocardial energy generation (e.g., mitochondrial transfer RNA mutations). These mitochondrial defects
and mutations in the cardiac energy-sensing apparatus (e.g., AMP-activated protein kinase [AMPK]) recapitulate a
73
hypertrophic cardiomyopathy–like phenotype. Alterations in myocardial energetics and in calcium handling

combined with stimulation of signaling pathways (e.g., the Janus-associated kinase–signal transducers and activators
of transcription [JAK-STAT] signaling pathway) diminish myocyte relaxation and promote myocyte growth, with
aberrant tissue architecture (i.e., myofibrillar disarray and myocardial fibrosis) (Panel B, hematoxylin and eosin). In
patients with hypertrophic cardiomyopathy, these changes often result in gross hypertrophy, with especially
prominent septal hypertrophy (arrow) as compared with the normal heart, as shown on the cardiac magnetic
resonance images (Panel C). Source: Inherited Cardiomyopathies; Hugh Watkins, MD., PhD, and so on.
At least two mechanisms explain how sarcomeric mutations alter calcium balance. First,
mutations affecting the thin-filament regulatory proteins tropomyosin, troponin T, and troponin I
all enhance calcium sensitivity by increasing the affinity of troponin C for calcium; mutations
affecting myosin and cMyBP-C also increase this affinity through the formation of additional
cross-bridges between thick and thin filaments.
Second, sarcomeric mutations increase the energy requirements of myosin ATPase. Since
the cross-bridge cycle generates the contractile force of the myocyte and accounts for about 70%
of the cardiomyocyte's ATP consumption, contractile inefficiency could compromise the
energetics of the myocyte. The energy deficiency could reduce the activity of other ATP-
consuming processes such as ion pumps particularly, the sarcoendoplasmic reticulum
Ca2+ ATPase [SERCA].
In a randomized trial of perhexiline in patients with nonobstructive hypertrophic

cardiomyopathy and activity-limiting symptoms, the partial inhibition of fatty acid oxidation, in
the context of the oxygen limitation due to microvascular disease in hypertrophic
cardiomyopathy, improved cardiac ATP levels and diastolic function, reduced symptoms, and
increased exercise capacity. Progressive interstitial cardiac fibrosis, resulting from non–myocyte
(e.g., fibroblast)-mediated activation of transforming growth factor β signaling, is a feature of
hypertrophic cardiomyopathy. The finding that preemptive angiotensin II type 1–receptor
inhibition prevented myocardial fibrosis in a mouse model of cardiomyopathy, as well as
encouraging results from a small clinical study, supports further investigation of this approach.
(2) Dilated Cardiomyopathy
The main features of dilated cardiomyopathy are left ventricular dilatation, systolic
dysfunction, myocyte death, and myocardial fibrosis (Figure 5.3). Analysis of asymptomatic
relatives of affected patients indicates that familial disease accounts for one third to one half of
cases. More than 40 disease genes have been identified; the most common mode of inheritance is
autosomal dominant transmission. Dilated cardiomyopathy is sometimes inherited with other
phenotypes, both cardiac such as conduction disorderand noncardiac like sensorineural hearing
loss. Unlike hypertrophic cardiomyopathy, dilated cardiomyopathy is caused by mutations in
genes that encode components of a wide variety of cellular compartments and pathways,
including the nuclear envelope, contractile apparatus, the force transduction apparatus (e.g., Z-
disk and costamere), gene transcription and splicing machinery, and calcium handling (Figure
5.3).
Due to the diversity of affected cellular processes, multiple proximal factors probably
contribute to contractile dysfunction of cardiomyocytes before cell death and fibrotic repair
occur. In dilated cardiomyopathy, mutations in the genes encoding contractile proteins result in
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functional changes that are the opposite of the changes caused by mutations in the same
contractile genes that cause hypertrophic cardiomyopathy. Mutations in the β-myosin heavy
chain gene depress motor function in dilated cardiomyopathy, and mutations in genes for thin-
filament regulatory proteins reduce the calcium sensitivity of contractile regulation and the
affinity of troponin for calcium.Hence, these mutations depress the generation of force.
Several disease genes encode components of the Z-disk (e.g., Cypher/ZASP), the
structure at the boundary of each sarcomere, or the costamere (e.g., δ-sarcoglycan), the structural
complex that links the contractile apparatus to the sarcolemma and extracellular matrix. These
mutations may cause defective transmission of force, affect stretch-sensing mechanisms
involving titin, or both. The arginine-14 deletion in phospholamban (a membrane protein of
muscle cells that regulates SERCA) causes excessive inhibition of the calcium pump and thus
reduces calcium reuptake during diastole. The pathogenic effects of other mutations (e.g., those
in LMNA, encoding the lamin A and C nuclear envelope proteins) are less clear. Nevertheless,
the diverse changes in cardiomyocyte structure and function result in autophagy, a pathway of
protein and organelle degradation, and ultimately apoptosis.
The molecular complexity of dilated cardiomyopathy suggests only a limited scope for
specific disease-modifying therapies. Broad-based approaches, perhaps involving regenerative
medicine, may be needed.
(3) Arrhythmogenic Right Ventricular Cardiomyopathy
The main feature of arrhythmogenic right ventricular cardiomyopathy (ARVC) is

fibrofatty replacement of the myocardium, mainly in the right ventricle but also in the left
ventricle. This change results in the predominant clinical feature of susceptibility to ventricular
arrhythmias. The disease is familial, and typically autosomal dominant, in about half the cases.
Mutations in five genes that encode desmosomal proteins (desmoplakin, plakoglobin, plakophilin
2, desmoglein 2, and desmocollin 2) have been found in ARVC and in two related autosomal
recessive disorders, Naxos disease (ARVC accompanied by woolly hair and palmoplantar
keratoderma) and the Carvajal syndrome (which has a similar dermatologic phenotype, but in
which left ventricular involvement is predominant) (Figure 5.4). Most causative mutations are
insertions or deletions or nonsense mutations that result in premature truncation of the encoded
proteins. Two other, non-desmosomal genes have been implicated in ARVC: one for
transforming growth factor β3 (TGF-β3) and the other for transmembrane protein 43
(TMEM43).The existence of further mapped loci indicates that additional disease genes remain
to be discovered in ARVC.
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Figure 5.3. Pathogenesis of Dilated Cardiomyopathy. Dilated cardiomyopathy is the end phenotype of diverse
mutations in heterogeneous pathways ranging from components of the membrane-scaffolding apparatus (e.g.,
sarcoglycan and dystrophinopathies), sarcomeric proteins (which exhibit reduced myofilament activation, unlike the
case for hypertrophic cardiomyopathy), nuclear envelope proteins (e.g., lamin A and C), calcium-handling proteins
(e.g., phospholamban [PLN]), transcription cofactors (e.g., eyes absent homolog 4 [EYA4]), and RNA splicing (e.g.,
ribonucleic acid–binding protein [RBM20]), to the cell energy-generating machinery (Panel A). Although these
mutations are highly diverse in terms of the pathways affected, their common features are impaired contraction,
insurmountable cellular compromise with consequent cell death and fibrotic repair (Panel B, hematoxylin and eosin),
and ultimately, gross cardiac thinning and dilatation. Such biventricular dilatation and wall thinning relative to the
cavity dimension (arrows) can be detected on cardiac magnetic resonance imaging (Panel C). Source:Inherited
Cardiomyopathies; Hugh Watkins, MD., PhD, and so on.
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Desmosomes mediate intercellular attachments and anchor cytoplasmic domains of

membrane proteins to the intermediate desmin filaments of cardiomyocytes. Mutant desmosomes
may therefore compromise cell-to-cell adhesion at intercalated disks, lessening the ability of
myocytes to withstand mechanical forces during the cardiac cycle. Damage to the cell surfaces,
causing cell detachment and cell death, probably ensues. Experimental data indicating that
mutant desmosomes also cause remodeling of gap junctionsexplain how electrocardiographic
changes and ventricular arrhythmias can develop before the loss of myocytes and dysfunction of
the right ventricle become apparent (the concealed phase of disease).
However, this mechanical defect does not explain the right ventricular predominance and
the prominence of inflammation and fibrofatty change. Desmosomal proteins also modify the
Wnt/β–catenin signaling pathway, which is important for myogenesis in the heart. Increased
nuclear translocation of plakoglobin, which is caused by the reduced plakoglobin-sequestering
capacity of mutant desmosomes, appears to suppress Wnt signaling of cardiac progenitor
cells. Redistribution of plakoglobin is a central feature of ARVC and could serve as a diagnostic
test for the disease in postmortem tissue and, conceivably, in endomyocardial-biopsy
specimens. The predilection for involvement of the right ventricle in ARVC probably depends on
properties of cardiac progenitor cells in the second heart field, the embryonic source of the right
ventricle. These primitive right-ventricle precursor cells are prone to differentiate into adipocytes
(because of reduced transcription mediated by T-cell factor/lymphoid enhancer factor [Tcf/Lef]),
rendering them more susceptible to the reduced Wnt signaling. Adipogenic transcription factors,
such as peroxisome proliferator–activated receptor gamma (PPARG) (which is known to drive
TMEM43 expression), may also mediate intracellular lipid perturbations and may contribute to
the fibrofatty change (Figure 5.4).
Thus, although existing therapy for end-stage ARVC includes conventional therapy for
heart failure, genetic insights predict that the restitution of Wnt/β–catenin myocardial signaling
and modification of lipid-metabolism pathways (e.g., by PPARG modifiers) may represent more
targeted, disease-modifying therapies.
b. Acquired Hypertrophic Cardiomyopathy
i. Introduction:
Acquired hypertrophic cardiomyopathy (Acquired-HCM) is a disease that affects the

heart muscle. The term "hypertrophy" refers to the enlargement of cells, which in this case leads
to thickening of the heart muscle. The other name of this condition includes Aging-Associated
Acquired Hypertrophic Cardiomyopathy, Diabetes-Associated Acquired Hypertrophic
Cardiomyopathy, and Hypertension-Associated Acquired Hypertrophic Cardiomyopathy.
The thickening can be in the 4 chambers of the heart, or the wall that separates the
chambers. The lower left chamber of the heart (the left ventricle) may thicken, causing the inside
of the left ventricle to become smaller. This reduces the ability of the left ventricle to relax
sufficiently and hold enough blood in the chamber. As a result, the chamber is forced to exertion,
77
when pumping blood to the rest of the body. Additionally, the heart’s mitral valve can also be
affected, causing blood to leak backward through the valve.
Figure 5.4 Pathogenesis of Arrhythmogenic Right Ventricular Cardiomyopathy.Arrhythmogenic right

ventricular cardiomyopathy (ARVC) results from perturbation of one of three groups of desmosomal proteins:
transmembrane proteins (e.g., the desmosomal cadherins, desmoglein and desmocollin), proteins anchored directly
to intermediate filaments (e.g., desmoplakin), and the armadillo family of proteins (e.g., plakoglobin and
plakophilin), which bind the desmosomal cadherins to desmoplakin (Panel A). In addition to the disruption of
78
desmosomal mechanical function, which can lead to the death of myocytes under physical stress, the suppression of
canonical Wnt/β–catenin signaling by nuclear plakoglobin translocation appears to promote adipogenesis in
mesodermal precursors. Panel B shows immunofluorescence images of left ventricular myocardium from patients
with ARVC and controls without ARVC. Although both patients with ARVC and those without show a strong
junctional signal for N-cadherin, a nondesmosomal adhesion molecule, plakoglobin, is markedly reduced in patients
with ARVC whether or not the section shows typical pathological changes of fibrofatty replacement (Panel B).
These changes explain the progressive fibrofatty replacement of ventricular myocardium (Panel C, hematoxylin and
eosin), with progressive gross effects on ventricular morphology and function, classically, but not exclusively, with
right ventricular predominance (arrows), as shown on cardiac magnetic resonance imaging. Source of the Image:
Inherited Cardiomyopathies; Hugh Watkins, MD., PhD, and so on.
Most cases of hypertrophic cardiomyopathy (HCM) are genetic. However, when the
condition develops without a known genetic cause in association with, and because of another
disease/disorder, it is differentiated from the heritable type of HCM, using the prefix
“acquired.”Acquired Hypertrophic Cardiomyopathy is considered very rare; often, the disorder is
associated with the following conditions:
• Pituitary tumors causing abnormal increase in growth hormone production, leading to

acromegaly
• Neurofibromatosis, which causes tumors in the brain and spinal cord
• Lipodystrophy, a disease with abnormality in body fat storage and utilization
• Pheochromocytoma, an adrenal gland tumor that produces hormones
• Uncontrolled diabetes
• Thyroid disease
• High blood pressure
• Aging
Therefore, having any of the above-mentioned conditions places an individual at risk for
developing Acquired-HCM.
ii. The Classifications, Risk Factors and Signs and Symptoms of Acquired
Hypertrophic Cardiomyopathy.
(1) Classifications:
Acquired Hypertrophic Cardiomyopathy can be classified as obstructive or non-

obstructive. Objective Acquired Cardiomyopathy is Blood flow blockage occurs in the left
ventricle, forcing it to exertion, to pump blood to the rest of the body. It can also affect the mitral
valve of the heart and cause blood to leak backward through the valve. For Non-obstructive
Acquired Cardiomyopathy, there is no blockage to blood flow in this condition. However, the
pumping of blood becomes inefficient, when a part, or all, the left ventricle becomes thicker.
In both types, the myocardium, especially the left ventricle, thickens, causing the inner
left ventricle to become smaller. This reduces the ability of the left ventricle to fully relax and
hold enough blood.
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(2) Risk Factors for Acquired Hypertrophic Cardiomyopathy:
• Chronic high blood pressure,

• Diabetes, particularly with poor glycemic control,
• Diseases of the thyroid gland,
• Excess growth hormone in the body (causing acromegaly), owing to a tumor affecting the
pituitary gland,
• Hormonal imbalances due to tumor in adrenal glands (pheochromocytoma),
• Tumors of the brain and spinal cord (neurofibromatosis),
• A genetic disorder in body fat generation, storage, and distribution, known as
lipodystrophy, and
• Advancing age
It is important to note that having a risk factor does not mean that one will get the
condition. A risk factor increases one’s chances of getting a condition compared to an individual
without the risk factors. Some risk factors are more important than others.
(3) The Diagnosis and Treatment of Acquired Hypertrophic Cardiomyopathy:
The diagnosis of Acquired Hypertrophic Cardiomyopathy is made with the help of

information gathered from the following tests and procedures:
• A thorough physical examination and an assessment of symptoms,

• Evaluation of personal and family medical history,
• Chest X-ray to check for heart size, contour, and fluid build-up in lungs,
• Electrocardiogram (EKG) to check the heart’s electrical activity,
• Echocardiography (ECG or echo) uses sound waves to create a moving picture of the
heart
• Stress test---- places stress on the heart by making it work harder and beat faster to
determine, if the cardiac muscles can cope with the increased workload,
• Cardiac catheterization27---- check for pressure and blood flow in the heart
• Myocardial biopsy
• Additional tests for diagnosing the medical condition causing Acquired-HCM
The non-surgical treatment options for Acquired Hypertrophic Cardiomyopathy may

include Lifestyle changes, Beta blockers and calcium channel blockers, generally the first choice
of medicines to treat cardiomyopathies, to regulate heartbeatsand other prescription medications
may help in:Regulating high blood pressure levels and heart rate, maintaining normal heartbeat
rhythm, and so on.
27
chambers. It is often coupled with coronary angiography, in which a harmless dye is injected into the coronary arties and with the help of an X-
ray, blood flow through heart and blood vessels can be observed.
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The surgical treatment options for Acquired Hypertrophic Cardiomyopathy may include
Septal myectomy and implant devices such as implantable cardioverter defibrillator (ICD). In a
small percentage of the affected individuals, heart transplantation may be necessary.
c. Mixed Cardiomyopathy
There are two types of Mixed Cardiomyopathy including Dilated Cardiomyopathy and
Restrictive Cardiomyopathy.
Dilated cardiomyopathy (DCM) has a prevalence of 1:2,500 and is the leading indication
for heart transplantation. It is defined by enlargement of ventricles, normal left ventricular wall
thickness, and systolic dysfunction. Approximately 25% to 35% of cases are familial, with such
instances being primarily inherited in an autosomal dominant pattern. DCM may also result from
a host of environmental, infectious, and systemic factors. DCM can occur at any age but is most
common in patients 40 to 59 years of age. Symptoms of DCM include arrhythmias and
thromboembolic events. Electrocardiography findings vary and may include isolated T wave
changes, septal Q waves, bundle branch blocks, tachyarrhythmias, or normal results. Diagnosis is
confirmed with echocardiography. Most patients are symptomatic at the time of diagnosis, but
asymptomatic patients may be identified through screening of family members of affected
patients. Treatment is guided by current evidence-based guidelines for heart failure. ACE
inhibitors and ARBs have been shown to provide significant mortality benefit in patients with
heart failure with reduced ejection fraction. Recent evidence further supports the use of
sacubitril/valsartan [Entresto], an angiotensin receptor-neprilysin inhibitor, in place of an ACE
inhibitor.Beta blockade is also recommended in patients with heart failure with reduced ejection
fraction.
Restrictive Cardiomyopathy. Restrictive cardiomyopathy is the least common of the

major cardiomyopathies, representing 2% to 5% of cases. The restrictive category includes many
underlying etiologies and is defined by physiologic function rather than anatomy. The pattern of
impaired ventricular filling with normal systolic function is typical, resulting from increased
myocardial stiffness. Restrictive cardiomyopathy may be primary or secondary, with amyloidosis,
sarcoidosis, radiation therapy, and scleroderma included among the common causes (Table 5.1).
Restrictive cardiomyopathy may present with signs of right-sided heart failure, such as
ascites or peripheral edema. Examination may reveal elevated jugular venous pressure before the
development of pulmonary edema. Chest radiography can detect pulmonary vascular congestion
with a normal cardiac silhouette. Electrocardiography may show diffuse reduced voltage or a
prolonged PR interval, and echocardiography may reveal biatrial enlargement and diastolic
dysfunction, although left ventricular diastolic volume, wall thickness, and systolic function
typically appear normal. Specific treatment options are limited and focus on addressing the
underlying process. Symptomatic interventions include control of volume overload with diuretics
or aldosterone antagonists and evaluation for atrioventricular block, with pacemaker insertion as
indicated.
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Table 5.1 Secondary Causes of Cardiomyopathy
Autoimmune/inflammatory Infiltrativedisorders
Dermatomyositis Amyloidosis
Polyarteritis nodosa Gaucher disease
Rheumatoid arthritis Hunter syndrome
Sarcoidosis Hurler syndrome
Scleroderma
Systemic lupus erythematosus Neuromuscular and storage disorders
Glycogen storage disorders
Endocrine Muscular dystrophy (Becker, Duchenne,
Acromegaly Emery-Dreifuss, myotonic)Neurofibromatosis
Diabetes mellitus
Hyperparathyroidism Nutritional deficiencies
Hyperthyroidism Kwashiorkor L-carnitine, niacin, selenium,
Hypothyroidism thiamine, vitamin C deficiencies
Obesity
Infectious Toxic
Chagas disease Alcohol
Hepatitis C Human immunodeficiency virus Anabolic steroids
Mycobacteria Rickettsia Chemotherapeutic agents (anthracyclines,
Viral (adenovirus, Coxsackie, Epstein-Barr, cyclophosphamide, doxorubicin
parvovirus) [Adriamycin])
Chloroquine (Aralen)
Heavy metals (arsenic, cobalt, lead, mercury)
Iron excess (hemochromatosis)
Radiation Stimulants (cocaine,
methylphenidate)
d. A Typical Case Study: Apical Hypertrophic Cardiomyopathy
i. Background:
Apical hypertrophic cardiomyopathy (ApHCM) is a relatively rare form of hypertrophic

cardiomyopathy that predominantly affects the apex of the left ventricle and typically has a
nonobstructive physiology. Its variable presentation and clinical course renders ApHCM a
commonly delayed or missed diagnosis. Furthermore, since it was first described in Japan 40
years ago, there have been differing views on its clinical course, with initial studies supporting a
more benign prognosis but more recent reports suggesting a cardiovascular morbidity of 25% to
30% and mortality in 4% to 29% of cases. This case illustrates the clinical and diagnostic
challenge of ApHCM, and reviews the current literature regarding implications for treatment and
prognostic.
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ii. Case Summary:
A 53-year-old woman presented with chronic progressive chest pain. She was initially
started on treatment for acute coronary syndrome. Diagnosis ofApical hypertrophic
cardiomyopathy (ApHCM) was initially missed on echocardiography but made on subsequent
cardiac catheterization and cardiac MRI. She improved clinically with metoprolol, had a work-up
for implantable cardioverter-defibrillator placement, and was referred for genetic testing.
ApHCM is a relatively rare form of hypertrophic cardiomyopathy that predominantly

affects the apex of the left ventricle and typically has a nonobstructive physiology. Its variable
presentation and clinical course render ApHCM a commonly delayed or missed
diagnosis.Despite earlier studies suggesting a more benign clinical course of ApHCM, recent
studies report increased morbidity and mortality, which is comparable to the prognosis of other
variants of hypertrophic cardiomyopathy such as hypertrophic obstructive cardiomyopathy. Thus,
when formulating a differential diagnosis for chest pain, it is important to include structural heart
disease including apical and other variants of hypertrophic cardiomyopathy as part of that
differential, as appropriate management can prevent these devastating sequelae. Furthermore,
when screening tests such as echocardiography cannot adequately establish the diagnosis of
ApHCM, then cardiac MRI or invasive hemodynamic testing is necessary to establish or refute
the diagnosis.
iii. Fact of the case:
Over the past few months, the patient experienced substernal chest pressure, which was
initially brought on with exertion, but recently occurred more frequently and occurred with both
with activity and rest. Over the past several weeks, these episodes were accompanied by
palpitations and lightheadedness. She denied syncope, dyspnea, nausea, vomiting, and
diaphoresis. Her past medical history was notable for hypertension, recent stroke, and obesity. Of
note, she said she had occasional exertional chest discomfort as a child and was told she had
asthma. Her family history was notable for sudden cardiac death in her paternal grandfather. She
denied alcohol consumption, tobacco smoking, and illicit drug use.
On admission, the patient was afebrile, her heart rate was 81 beats per minute, respiratory
rate was 16 breaths per minute, blood pressure was 111/73 mm Hg, and oxygen saturation was
98% on room air. She was alert and oriented and in no acute distress. She had no notable jugular
venous distension. Cardiac examination revealed regular rate and rhythm and normal S1 and S2
with no murmur or extra heart sounds. Her lungs were clear to auscultation bilaterally. No
peripheral edema was noted.
The first cardiac troponin-I drawn within 15 minutes of arrival was indeterminate at 0.3
ng/mL (normal reference range <0.04 ng/mL). Electrocardiogram exhibited deep T wave
inversions in precordial leads and met criteria for left ventricular hypertrophy (Figure 5.5). Chest
radiograph showed a normal cardiac silhouette and no pulmonary congestion. Given her
progressive chest pain, indeterminate troponin, and T wave inversions, she was started on
heparin drip, metoprolol 12.5 mg twice daily, and sublingual nitroglycerin 0.4 mg for presumed
acute coronary syndrome, and continued her home aspirin, atorvastatin, and losartan. Cardiology
was consulted and recommended echocardiography. Transthoracic echocardiography
83
demonstrated preserved ejection fraction (55% to 60%), grade 2 diastolic dysfunction (mild
restrictive pattern), moderately dilated left atrium (63 ml volume), mildly elevated pulmonary
artery systolic pressure (35 mm Hg), and possible left ventricular aneurysm. Right atrial size and
pressure, and right ventricular systolic function were within normal limits. There was no
evidence of wall motion abnormalities, dynamic left ventricular outflow tract obstruction, or
valvular disease. Given the patient’s large body habitus and technically difficult images, the left
ventricular apex was not well visualized and definitive diagnosis could not be established.
Figure 5.5. Electrocardiogram on admission exhibited deep T wave inversions in precordial leads (V2–V6) and met
criteria for left ventricular hypertrophy.
To further evaluate for ischemic etiology of the patient’s chest pain, cardiac angiography
was performed. Left heart catheterization demonstrated no significant epicardial coronary artery
disease. Left ventriculogram was suggestive of a spade-like appearance (Figure 5.2); however,
the interpreting cardiologist did not comment on this until later. During admission, our patient
was noted to have several pre-syncopal episodes with non-sustained ventricular tachycardia
(NSVT), the longest run lasting 25 beats. The second and third troponins were negative at 0.02
ng/mL.
84
A B
Figure 5.6 Left ventriculogram depicts a spade-shape silhouette of the left ventricle. A: Systole B: Diastole.
Given the patient’s symptoms, deep T wave inversions on electrocardiogram,

symptomatic ventricular tachycardia episodes, family history of sudden cardiac death, and faint
spade-shape silhouette on LV gram, cardiology recommended further cardiac imaging to
evaluate for structural etiology of the patient’s chest pain and palpitations. Cardiac MRI with
gadolinium enhancement demonstrated a spade-shape configuration of the left ventricle with
apical hypertrophy (the thickest segment measuring 3 cm) and ventricular ectopy (Figure 5.6).
LV aneurysm was not seen on cardiac MRI. These findings are consistent with apical
hypertrophic cardiomyopathy.
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Figure 5.7 Cardiac MRI with gadolinium enhancement demonstrates a spade-like silhouette of the left ventricle
with focal apical hypertrophy, confirming the diagnosis of apical hypertrophic cardiomyopathy.
Hospital course was complicated by up-trending creatinine (peaked at 1.8 mg/dL)

following cardiac catheterization, which was thought to be secondary to contrast-induced
nephropathy. Nephrology was consulted and recommended supportive management. Creatinine
was 1.3 mg/dL on discharge. The patient was chest-pain free and ambulating without symptoms
prior to discharge.
Our patient was discharged on metoprolol to prevent ventricular arrhythmias and chest
pain, had a work-up for implantable cardioverter defibrillator (ICD) placement for primary
prevention of sudden cardiac death, and was referred for genetic testing. Given the genetic
predisposition of ApHCM, the patient’s family members were also encouraged to undergo
genetic testing and echocardiography screening. At 6-month follow-up, the patient remained
symptom free. Though she had not yet undergone confirmatory genetic testing, the presence of
apex-predominant LV hypertrophy with a spade-like silhouette of the LV chamber, symptomatic
ventricular arrhythmias, family history of sudden cardiac death, and her overall clinical
presentation, strongly suggested ApHCM as the etiology of her clinical presentation.
iv. Discussion
ApHCM usually has an autosomal dominant inheritance pattern, but it may also be
sporadic. Recent studies have shown that ApHCM related to gene mutations in ACTC1, TPM1,
MYBPC3 and MYH7, and research are currently underway to determine other contributory
86
genes. It is characterized by hypertrophy of left ventricular apex, deep T wave inversion on the
electrocardiogram, and the silhouette of spades in the left ventricular cavity. Phenotypic variants
of ApHCM include apex-predominant hypertrophy, mid-ventricular obstruction with cavity
obliteration, and left ventricular aneurysm.
The heterogeneity of its presentation and variability of its clinical course rendering apical
hypertrophic cardiomyopathy a commonly missed or delayed diagnosis. About 54% of patients
are symptomatic. Symptoms include chest pain, palpitations, dyspnea, lightheadedness, and
syncope. Our patient’s chronic intermittent chest discomfort may have been an early
manifestation of ApHCM. In the absence of epicardial coronary artery disease, the chest pain of
ApHCM is caused by myocardial ischemia due to narrowing of intramural small vessel coronary
arteries from the hypertrophied myocardium as well as increased myocardial oxygen demand
from myocyte hypertrophy.
As seen in this patient, ventricular arrhythmia can be induced by asymmetric left

ventricular hypertrophy, which can lead to dizziness, syncope, or sudden cardiac death. Impaired
left ventricular filling due to wall stiffness and subsequent reduction in cardiac output can lead to
diastolic heart failure. Increased atrial pressure and dilation caused by diastolic dysfunction can
lead to atrial fibrillation, which makes it susceptible to stroke.
Management of ApHCM is geared towards symptom control, genetic testing, and
prevention of adverse cardiovascular sequelae. Beta-blockers are the recommended initial
therapy in ApHCM patients to treat angina by decreasing myocardial oxygen, prevent non-
sustained ventricular arrhythmias, and to slow heart rate to improve diastolic filling. Long-term
outcomes of beta-blocker therapy in ApHCM patients are unknown and further studies are
needed. Non-dihydropyridine calcium channel blockers are second-line therapy if patients cannot
tolerate beta-blockers. Recent studies have explored the role of ACE-inhibitors and angiotensin
II receptor blockers in reducing adverse cardiac remodeling and fibrosis in ApHCM and other
variants of hypertrophic cardiomyopathy. It is important to manage co-morbidities such as
hypertension and valvular disease, which function as mechanical stressors, to prevent further
pathological ventricular hypertrophy.
Further management of ApHCM includes work-up for ICD placement for primary
prevention of sudden cardiac death in high-risk patients, genetic testing for both the patient and
first-degree family members, and electrocardiographic and echocardiographic screening of both
patients and first-degree relatives. According to the 2011 American College of
Cardiology/American Heart Association (ACC/AHA) guidelines for hypertrophic
cardiomyopathy, the recommendations for genetic screening and follow-up are similar for both
ApHCM and its counterpart hypertrophic obstructive cardiomyopathy (HOCM). First-degree
family members who test positive for the genotype but do not display the phenotype on initial
screening should undergo serial electrocardiography and echocardiography every three to four
years for adults and every 12 to 18 months for pediatric patients. Family members who are
genotype-negative do not need further follow-up.
Since ApHCM was first described in Japan 40 years ago, there have been differing views
regarding its clinical and prognostic course. ApHCM constitutes roughly 13% to 25% of all
cases of hypertrophic cardiomyopathy in Japanese patients, however it is much less often
described in non-Japanese populations; our patient was Caucasian. The data in Western
87
populations is limited, but recent studies suggest that the risk of sudden cardiac death,
myocardial ischemia, advanced heart failure, atrial fibrillation, stroke, and ventricular
arrhythmias is comparable to patients with other variants of hypertrophic cardiomyopathy such
as HOCM. Predictors of cardiovascular morbidity include female gender, age under 41 years at
presentation, left atrial enlargement, hypertension, diabetes, apical aneurysm, and New York
Heart Association (NYHA) class II or above at presentation. Studies done by the Mayo Clinic
suggest that mortality in advanced ApHCM is comparable to ischemic cardiomyopathy and
propose the role of left ventricular assist device therapy as a bridge to transplant in ApHCM
patients with advanced heart failure. Future randomized control trials are needed evaluating
outcomes and the impact of appropriate medical therapy on patients with ApHCM.
v. Conclusions
Despite earlier studies suggesting a more benign clinical course of ApHCM, recent
studies report increased morbidity and mortality, which is comparable to the prognosis of other
variants of hypertrophic cardiomyopathy such as Hypertrophic Obstructive Cardiomyopathy
(HOCM). Thus, when formulating a differential diagnosis for chest pain, it is important to
include structural heart disease including apical and other variants of hypertrophic
cardiomyopathy as part of that differential, as appropriate management can prevent these
devastating sequelae. Furthermore, when screening tests such as echocardiography cannot
adequately establish the diagnosis of ApHCM, then cardiac MRI or invasive hemodynamic
testing is necessary to establish or refute the diagnosis. The present case illustrates these points.
88
REFERENCES:
1. Luk A, Ahn E, Soor GS, Butany J. Dilated cardiomyopathy: a review. J Clin Pathol. 2009;62(3):219-225.
2. The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial. Lancet. 1999;353(9146):9-13.
3. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in
Congestive Heart Failure (MERIT-HF). Lancet. 1999;353(9169):2001-2007.
4. Kushwaha SS, Fallon JT, Fuster V. Restrictive cardiomyopathy. N Engl J Med. 1997;336(4):267-276.
5. Ryan TD, Madueme PC, Jefferies JL, et al. Utility of echocardiography in the assessment of left ventricular
diastolic function and restrictive physiology in children and young adults with restrictive cardiomyopathy: a
comparative echocardiography-catheterization study. PediatrCardiol. 2017;38(2):381-389.
6. 1. Jan MF, Todaro MC, Oreto L, Tajik AJ. Apical hypertrophic cardiomyopathy: Present status. Int J
Cardiol. 2016;222:745–59.
7. Pasternac A, Noble J, Streulens Y, et al. Pathophysiology of chest pain in patients with cardiomyopathies and
normal coronary arteries. Circulation. 1982;65(4):778–89.
8. Samak M, Fatullayev J, Sabashnikov A, et al. Cardiac hypertrophy: An introduction to molecular and cellular
basis. Med Sci Monit Basic Res. 2016;22:75–79.
9. Kitaoka H, Doi Y, Casey SA, et al. Comparison of prevalence of apical hypertrophic cardiomyopathy in Japan
and the United States. Am J Cardiol. 2003;92:1183–86.
10. Ericksson MJ, Sonnenberg B, Woo A, et al. Long-term outcome in patients with apical hypertrophic
cardiomyopathy. J Am Coll Cardiol. 2002;39(4):638–45.
11. Muthiah K, Phan J, Robson D, et al. Centrifugal continuous-flow left ventricular device in patients with
hypertrophic cardiomyopathy: A case series. ASAIO J. 2013;59:183–87.
89
Chapter 6 Heart Failure
Lv Yan, M.D.
a. Introduction
i. The Epidemiology of Heart Failure
The burden of heart failure has always had a long-term and unchangeable connection
with hypertension. Although progress has been made in the evidence-based medical treatment of
heart failure with reduced ejection fraction and the morbidity and mortality have been
significantly reduced, the residual burden of the disease is still very large.
Heart failure is considered any condition characterized by a mismatch between metabolic,

exercise, and/or cognitive needs and cardiac function. Several important phenotypes have been
clearly identified: heart failure with reduced ejection fraction (HFrEF); heart failure with
preserved ejection fraction (HFpEF); heart failure with "improved" or "boarderline" ejection
fraction. Especially for HFrEF, a cogent pathophysiology has been well established.
Neurohormonal activation may be triggered by ventricular deformation from acute or chronic
ventricular injury, causing a cascade of maladaptive biologic response typicallycharacterized by
renin-angiotensin-aldosterone and sympathetic nervous system activation. These perturbed
systems (and other neurohormonal circuits) perpetuate left ventricular dysfunction through
progressive remodeling, that is, changes in shape and size, followed by a deterioration of systolic
performance. The severity of the disease ranges from the complete absence of any symptoms of
heart failure through progressive restrictions, including symptoms at rest.
There are many causes of heart failure. Traditional putative etiologies of left ventricular
dysfunction, systolic or diastolic, include coronary artery disease, valvular heart disease, various
specific cardiomyopathies, and concomitant arrhythmias leading to tachycardia-induced left
ventricular dysfunction. Less frequent but still important causes include metabolic disturbances,
such as diabetes and thyroid disease; myocarditis; toxic conditions mostly attributed to
chemotherapeutic agents, alcohol, and illicit drugs; and human immunodeficiency virus (HIV).
There are many other notable conditions leading to heart failure and like all the foregoing
considerations, there is reasonable evidence of a true causal effect.
Hypertension is traditionally associated with heart failure, and it is relatively easy to infer
a causal relationship from experience. However, although the evidence indisputably indicates
that hypertension is a risk factor for heart failure, it is not clear that hypertension is a pathogenic
factor for heart failure. In addition, it is important to recognize the unique contribution of
hypertension to HFpEF. HFpEF is a phenotype of heart failure and is now recognized as a major
clinical syndrome in the hospital environment, accounting for more than 50% of all acute heart
failure admissions. Unlike HFrEF, which has a clear pathophysiology, the cellular and molecular
aspects of the pathophysiology of HFpEF are still elusive. The main considerations involve
fibrosis, ventricular noncompliance, hypertrophy, and ischemia; all of these are affected by
hypertension. There may not be a universal maladaptive pathway that is the root cause of this
important disease, but hypertension is consistent with coronary artery disease, obesity, diabetes,
90
and atrial fibrillation, explaining most of concomitant comorbidities associated with clinical
HFpEF.
The treatment considerations for HFrEF are clear, but not so sure for HFpEF. Due to the
lack of a clear mechanism of left ventricular dysfunction and the heterogeneity of HFpEF
patients, the management of HFpEF is hindered. There are reasonable but uncertain data
indicating the potential benefits of mineralocorticoid receptor antagonists (MCRA) and early
signals that neprilysin inhibition combined with renin-angiotensin-aldosterone blockade may be
helpful. The best guideline continues to urge people to pay special attention to the accompanying
comorbidities, including hypertension, for which evidence-based clinical practice guidelines
exist.
For HFrEF, defined treatment algorithms are available and are populated with evidence-
based therapies proven to improve outcomes. Recent American College of Cardiology
(ACC)/American Heart Association (AHA)/Heart Failure Society of America (HFSA) clinical
practice guidelines make clear the importance of both prevailing standard bearers of therapy:
angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor II blocker (ARBs),
evidence-based beta- blockers, mineralocorticoid receptor antagonists (MCRAs), hydralazine
and isosorbide dinitrate (ISDN), and implantable cardioverter defibrillator/cardiac
resynchronization therapy (ICD/CRT); and newer therapies: valsartan/sacubitril and ivabradine.
The expected outcomes of optimal therapy for HFrEF are now substantially better than historical
expectations. Yet, whether the condition of heart failure is HFrEF, HFpEF or even HF with
improved or borderline ejection fraction, it remains clear that prevention is the more preferable
intervention.
The American College of Cardiology Foundation (ACCF)/ (AHA) guideline for the
management of heart failure has adopted a stepwise progression to characterize the natural
history of heart failure. This framework organizes treatment strategies for preventing and
controlling risk factors like hypertension (stage A), treating subclinical structural and functional
changes like LV hypertrophy and mechanical dysfunction (stage B), and reducing morbidity and
mortality in symptomatic heart failure (stages C and D). This framework emphasizes the
importance of intervening early in the progression of heart failure during stages A and B before
development of symptoms.
Of all the potential strategies that may reduce the incidence of heart failure, none seems
to have a higher benefit than the treatment of hypertension. Therefore, it is necessary to conduct
a more in-depth exploration of the relationship between hypertension and heart failure.
ii. The Heart Failure Epidemic:
37 million people worldwide suffer from heart failure. In the United States,
approximately 5.7 million Americans suffer from heart failure, and the prevalence increases with
age. In addition, more than 650,000 new cases of heart failure are diagnosed each year. Although
advances in heart failure treatment have improved survival rates, approximately 50% of people
diagnosed with heart failure will die within 5 years. The economic consequences of heart failure
are also staggering. More than 1 million people are hospitalized for heart failure each year, and
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many of them have a high risk for repeat hospitalization with a 30-day readmission rate of 25%.
In 2012, the total cost of heart failure was estimated at 30.7 billion U.S. dollars. If the current
trend continues, it is predicted that by 2030, the number of patients will increase to more than 8
million, and the total cost will increase to US$70 billion.
iii. Hypertension in the Development of Heart Failure
The population-based cohort played an important role in establishing hypertension as the

main and modifiable risk factor for heart failure in the general population. The Framingham
Heart Study is the first study to describe the association between hypertension and heart failure.
During the first 16 years of follow-up in the original Framingham cohort, 75% of 142 new-onset
heart failure patients reported previous hypertension. Framingham’s follow-up analysis reported
that men with high blood pressure were twice as likely to develop heart failure compared with
men without hypertension (hazard ratio [HR] 2.07, 95% confidence interval [CI] 1.34 to 3.20)
and Three times the risk for women (HR 3.35, 95% CI 1.67 to 6.73). Coupled with the high
prevalence of hypertension in the population, hypertension explains 39% of the population
attributable fraction of heart failure in men and 59% in women. One long-term analysis also
emphasized the impact of hypertension on the risk of life-long heart failure.
Among men and women in Framingham, the lifetime risk of heart failure is about one-
fifth, but twice in individuals with blood pressures 160/200 or more mm Hg compared with those
with blood pressures less than 140/90 mm Hg.
Cohort analysis also demonstrated the unique contribution of hypertension to the risk of
heart failure in women. In the lifetime risk analysis BY Lloyd-Jones and colleagues, the risk of
heart failure in men was significantly lower for those who did not have antecedent myocardial
infarction. However, regardless of the history of myocardial infarction, women have a similar
life-long risk of heart failure. More importantly, this observation highlights the
nonatherosclerotic mechanisms by which heart failure may occur in women. An analysis
comparing the risk factors of HFpEFwithHFrEF shows that both women and systolic blood
pressure are associated with an increased probability of HFpEF relative to HFrEF (odds ratio
[OR] 2.29, 95% CI 1.35 to 3.90 and OR 1.13 per 10 mm), thus Supporting these observations Hg,
95% CI 1.04 to 1.22, respectively).
b. Hypertensive Heart Disease:
Hypertensive heart disease describes a spectrum of conditions related to hypertension that

progresses from subclinical structural, mechanical, cellular, and extracellular myocardial changes
all the way to clinical symptoms of heart failure. In this paradigm, the hemodynamic load caused
by elevated blood pressure increases left ventricular (LV) wall stress leading to a compensatory
thickening of the LV wall and an increase in LV mass. Factors like race, sex, neurohormones,
cytokines, and growth factors modulate this hypertrophic response, resulting in fibrosis,
myocardial stiffness, mechanical dysfunction, and eventually heart failure (Figure 6.1).
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Figure 6.1 Progression of hypertensive heart disease to heart failure. HTN, Hypertension; LVH, left ventricular
hypertrophy.
i. Left Ventricular Hypertrophy and Remodeling
Although LV hypertrophy can precede hypertension, it is generally considered to be the

first step in the development of hypertensive heart disease. Data from the Framingham Heart
Study first demonstrated the association between electrocardiogram (ECG)-defined LV
hypertrophy and subsequent cardiovascular events. As imaging modalities improved, direct
measurement of LV wall thickness and mass with echo-cardiogram and magnetic resonance
imaging (MRI) confirmed the direct and linear association between blood pressure and LV mass,
an association that was even stronger using longer- term ambulatory blood pressure monitoring.
Epidemiologic studies then demonstrated the association between LV mass and incident
cardiovascular disease. For example, in the Cardiovascular Health Study (CHS), higher LV mass
index on echocardiogram was associated with systolic and diastolic dysfunction and future heart
failure risk, independent of the prevalence of incident myocardial infarction.26 In MESA,
Bluemke et al used cardiac MRI to demonstrate the association between higher levels of LV
mass and incident heart failure (HR 1.4 per 10% increment, 95% CI 1.2 to 1.5), a risk that
primarily occurred in individuals with LV hypertrophy.
Although the stages of hypertensive heart disease suggests a unidirectional progression,

randomized trials like the Losartan Intervention for Endpoint Reduction in Hypertension (LIFE)
trial have demonstrated that antihypertensive agents can reduce LV mass, a finding that is also
associated with improved outcomes in post hoc analyses. In a meta-analysis of 80 trials
comparing the efficacy of different antihypertensive drug classes for reversing LV hypertrophy
in hypertensive patients, DoctorKlingbiel identified that LV mass index decreased by 13%
reduction with ARBs, 11% with calcium channel blockers, and 10% with ACE inhibitors.
ii. Systolic and Diastolic Dysfunction
Echocardiography has also played an essential role in elucidating the effects of high
blood pressure on cardiac mechanical function leading to clinical heart failure. Although the
direct link between hypertension and systolic dysfunction is often complicated by concomitant
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cardiovascular disease, analyses like those from CHS have demonstrated the direct and stepwise
relationship between LV mass and systolic dysfunction, independent of the prevalence of
incident myocardial infarction. Diastolic dysfunction, referring to abnormalities in LV relaxation
and filling, is a hallmark of hypertensive heart disease. Because the LV remodels in response to
hypertension, cardiacmyocytes hypertrophy, and fibrotic changes occur that increase LV
stiffness and alter cardiac mechanical properties. In a cross-sectional survey of residents from
Australia, diastolic dysfunction was prevalent in 34.7% of adults aged 60 to 86 years and was
independently associated with a diagnosis of hypertension (OR 1.5, 95% CI 1.2 to 2.0), an
observation that has also been reported in residents from Olmsted County, Minnesota. More
recently, Santos et al analyzed data from 4871 participants in ARIC to demonstrate that
abnormalities in LV thickness and diastolic parameters even occur in participants with
prehypertension (blood pressure of 120 to 139 mm Hg systolic and/or 80 to 89 mm Hg diastolic).
In these analyses, prehypertensive participants had higher LV mass indices and higher
rates of mild, moderate, and severe diastolic dysfunction compared with those with optimal
blood pressures (blood pressure < 120/80 mm Hg). In recent years, speckle-tracking
echocardiography, which uses computer algorithms to track pixels of imaging data, has emerged
as a novel technique to directly measure and quantify myocardial displacement, velocity, and
deformation (stretch or contraction). Abnormalities in these measures of cardiac mechanicals
have been shown to be precursors of heart failure. Choi et al demonstrated in MESA that
circumferential strain was associated with future heart failure risk in asymptomatic individuals,
even after adjusting for age, diabetes, hypertension, myocardial infarction, LV mass, and LV
ejection fraction (HR 1.15 per 1%, 95% CI 1.01 to 1.31). Blood pressure can adversely affect
myocardial strain. In CARDIA, Doctor Kishi’s team demonstrated that cumulative exposure to
nonoptimal systolic and diastolic blood pressure in young adulthood was associated with lower
longitudinal strain rate and lower early diastolic longitudinal peak strain rate, two preclinical
signs of heart failure, at 25 years of follow-up. Few participants in these analyses had blood
pressures exceeding conventional treatment thresholds at any point during follow-up,
highlighting the implications of blood pressure exposure during the lifespan and the importance
of primordial prevention, that is, the prevention of hypertension per se as a means to prevent
more overt cardiovascular disease including heart failure.
iii. Cellular and Extracellular Changes
In addition to structural and mechanical changes from hypertension, multiple studies have
revealed cellular changes that develop in the setting of hypertension and LV hypertrophy. In
animal models of pressure-hypertrophied myocardium, stress loading increased microtubule
density leading to abnormalities in cell microarchitecture that impaired myocyte contractile
function. Transverse (t)-tubules, cell structures that regulate calcium cycling for normal myocyte
contractions, have also been linked to hypertensive heart disease. In one study, Wei et al
demonstrated that thoracic aortic banding led to t-tubule remodeling early in the development of
hypertrophy. This remodeling was present before echocardiographic evidence of LV dysfunction
and worsened as heart failure progressed (Figure 6.2). These findings were also confirmed by
Shah et al in hearts from spontaneously hypertensive rats.
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In response to chronic exposure to elevated blood pressures, t-tubules became

disorganized, lead ing to impairments in intracellular calcium cycling and abnormal myocardial
strain before overt evidence of LV dysfunction on echocardiogram.42 These studies provide a
biologic underpinning for ultrastructural cellular changes that lead to abnormal myocardial
mechanicals and eventually precede clinical heart failure. Changes in the extracellular matrix
have also been shown to play an important role in the progression from hypertensive heart
disease to heart failure. Exogenous administration of deoxycorticosterone acetate, a
mineralocorticoid, has been shown in animal models of hypertension and LV-pressure
hypertrophy to increase myocardial fibrosis, oxidative stress, diastolic stiffness, and filling
pressures. Abnormalities in levels of matrix metalloproteinases (MMP) and tissue inhibitors of
MMP (TIMP) have also been implicated in the progression of hypertensive heart disease.45,46
In one study that compared patients with LV hypertrophy to controls, those with hypertension
and nor mal LV structure had normal MMP levels, whereas those with hypertension and LV
hypertrophy had an MMP/TIMP profile that favored extracellular matrix degradation and
collagen accumulation (low MMP-2 and MMP-13 levels, high MMP-9 levels, and high TIMP-1
levels). Endomyocardial biopsies have confirmed the association between adverse MMP/TIMP
levels and cardiac fibrosis and LV dilatation.
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Figure 6.2 Progressive t-tubule remodeling in rat cardiomyocytes after exposure to thoracic aortic banding pressure-
load. The images display representative t-tubule images from the left ventricles of age-matched sham-operated (A),
hypertrophic (B), early heart failure (C), and advanced heart failure (D) hearts. In hypertrophic hearts (B) there is
loss of t-tubules (green arrows) that are more widespread with early and advanced heart failure. The yellow-framed
inset is a zoom-in view of an area 40×40 μm from the associated images. Cumulative data for myocyte t-tubule
power (TTpower), a measure of t-tubule density, at each stage is summarized (E). (From Wei S, Guo A, Chen B, et
al. T-tubule remodeling during transition from hypertrophy to heart failure. Circ Res. 2010;107(4):520-531.)
c. Diagnosis of Heart Failure
i. Classification
When classifying heart failure, the most important consideration is whether the left
ventricular ejection fraction (LVEF) is retained or decreased (less than 50%). Decreased LVEF
in systolic heart failure is a powerful predictor of mortality. As many as 40% to 50% of patients
with heart failure suffer from diastolic heart failure, but the left ventricular function is preserved.
Overall, there is no difference in survival rates between diastolic heart failure and systolic heart
failure that cannot be attributed to ejection fraction. Patients with diastolic heart failure are more
likely to be female, older, and have hypertension, atrial fibrillation, and left ventricular
hypertrophy, but no history of CAD. Compared with systolic heart failure with well-validated
therapies, diastolic heart failure lacks evidence-based treatment recommendations.
Symptoms of heart failure (systolic or diastolic heart failure) may occur with the ejection
fraction preserved or decreased. The New York Heart Association classification system is the
simplest and most widely used method for measuring the severity of symptoms (Table 6.1). This
classification system is a mature predictor of mortality and can be used to diagnose and monitor
treatment response.
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Table 6.1New York Heart Association Functional Classification of Heart Failure

I No limitations of physical activity; No heart failure symptoms
II Mild limitation of physical activity; Heart failure symptoms with significant
exertion; comfortable at rest or with mild activity
III Marked limitation of physical activity; Heart failure symptoms with mild
exertion; only comfortable at rest
IV Discomfort with any activity; Heart failure symptoms occur at resst
Adapted with permission from New York Heart Association Criteria Committee. Disease of the
Heart and Blood Vessels. Nomenclature and Criteria for Diagnosis. 6th ed. Boston, Mass.:
Little, Brown; 1964:112–113.
ii. Initial Clinical Evaluation
Although no single item on the clinical history, signs, or symptoms has been proven to
have diagnostic significance, many items are helpful in assessing the possibility of heart failure.
The initial clinical evaluation aims to confirm heart failure, determine the underlying cause, and
identify comorbidities. Preliminary assessment of suspected heart failure, including medical
history, physical examination, chest radiograph, electrocardiogram, and B-type natriuretic
peptide (BNP) test. Evaluation of ischemic heart disease in patients with heart failure is
necessary, especially if angina is present, given that CAD is the most common cause of heart
failure.
Table 6.2 History and Physical Examination Findings for Heart Failure and Selected
Alternative Causes
Heart Failure Alternative Causes
Symptoms Physical examination Symptoms Physical
findings examination
findings
Abdominal Abdomen: Abdominal swelling Abdomen: distended,

Swelling hepatojugular reflux, (liver failure) hepatosplenomegaly,
ascites tender, ascites (liver
disease)
Dyspnea on Extremities: cool, Anorexia, weight loss Extremities: joint
exertion dependent edema (sarcoidosis) inflammation/warmth
(rheumatologic
disease)
Edema Heart: Chest pain (coronary Heart: irregular rate
bradycardia/tachycardia, artery disease) or rhythm
laterally displaced point (arrhythmia)
of maximal impulse, Claudication
third heart sound (atherosclerotic
(gallop or murmur) disease)
Exercise Lungs: labored Cough (pulmonary Lungs: wheezing
Intolerance breathing, rales disease) (pulmonary disease)
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Continued
Orthopnea Neck: elevated jugular Diarrhea or skin Neck:
venous pressure lesions (amyloidosis) thyromegaly/nodule
(thyroid disease)
Fatigue Skin: cyanosis, pallor Dyspnea on exertion Skin: cyanosis
(pulmonary disease, (anemia), jaundice
valvular disease) (liver failure)
Paroxysmal Edema (liver or kidney
nocturnal dyspnea failure)
Neurologic problems
(sarcoidosis)
Palpitations
(tachyarrhythmia)
Recent weight Recent fevers, viral
gain infection (endocarditis,
myocarditis, infection)
Syncope (bradycardia,
heart block)
The Laboratory Evaluation for Heart Failure and Selected Alternative Causes includes
the following:
(1) Initial Tests:B-type natriuretic peptide level, Calcium and magnesium levels (diuretics,
cause of arrhythmia), Complete blood count (anemia), Liver function (hepatic congestion,
volume overload), Renal function (renal causes), Serum electrolyte level (electrolyte
imbalance), Thyroid-stimulating hormone level (thyroid disorders) and Urinalysis (renal
causes).
(2) Other tests for alternative causes:Arterial blood gas (hypoxia, lung disease), Blood
culture (endocarditis, systemic infection), Human immunodeficiency virus
(cardiomyopathy), Lyme Serology (bradycardia/heart block), Serum ferritin level,
transferrin saturation (giant cell anemia, hemochromatosis), Thiamine levels (deficiency,
beriberi, alcoholism), Troponin and creatine kinase-MB levels (myocardial infarction,
myocardial injury).
(3) Tests for comorbid conditions, risk management: A1C level (diabetes mellitus), Lipid
Profile (hyperlipidemia).
The levels of BNP and N-terminal pro-BNP (the cleaved inactive N-terminal fragment of
the BNP precursor) can be used to assess heart failure in patients with dyspnea. BNP is secreted
by the atria and ventricles in response to stretching or increased wall tension. BNP levels
increase with age, are higher in women and blacks, and may increase in patients with renal
failure. BNP seems to have better reliability than N-terminal pro-BNP, especially in the elderly
population. Multiple systematic reviews have concluded that BNP and N-terminal pro-BNP
levels can effectively rule out the diagnosis of heart failure because of their negative predictive
value (negative likelihood ratio [LR–] = 0.1 and 0.14). The average cutoff level for heart failure
were a BNP level of 95 pg/mL (95 ng/L) or an N-terminal pro-BNP level of 642 pg/mL (642
ng/L).
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As the level of BNP increases, the specificity increases, thereby increasing the likelihood
of heart failure diagnosis. BNP level is a strong predictor of 2 to 3 months mortality and
cardiovascular events in patients with acute heart failure, especially when the BNP level is
greater than 200 pg/mL (200 ng/L) or the N-terminal BNP level is greater than 5,180 pg per
milliliter (5,180 nanograms per liter). There is limited evidence to support monitoring of the
reduction in BNP levels in acute and outpatient settings. A 30% to 50% decrease in BNP level at
discharge indicates an increase in survival and a decrease in rehospitalization. Optimal
management of outpatient goals with BNP levels below 100 pg/mL (100 ng/L) and N-terminal
pro-BNP levels below 1,700 pg/mL (1,700 ng/L) showed decompensation, hospitalization, and
death events.
iii. Chest Radiography
A chest X-ray should be performed initially to assess heart failure, because it can identify
the lung causes of dyspnea (e.g., pneumonia, pneumothorax, masses). Chest radiographs of
patients with dyspnea showing pulmonary venous congestion and interstitial edema make the
diagnosis of heart failure more likely (LR+ = 12). Other findings, such as pleural effusion or
cardiaomegaly, may slightly increase the likelihood of heart failure (LR+ = 3.2 and 3.3), but their
absence only slightly helps reduce the likelihood of heart failure (LR– = 0.33 to 0.48).
iv. Electrocardiography
An electrocardiogram (ECG) can be used to determine other causes in patients with

suspected heart failure. Changes such as left bundle branch block, left ventricular hypertrophy,
acute or previous myocardial infarction, or atrial fibrillation can be identified, and further
investigation may be required through echocardiography, stress testing, or cardiology
consultation. The normal findings (or slight abnormalities) of the ECG make the possibility of
systolic heart failure slightly lower (LR-- = 0.27). The presence of other findings such as atrial
fibrillation, new T wave changes, or any abnormality has little effect on the diagnostic
probability of heart failure (LR+ = 2.2 to 3.8).
v. Clinical Decision Making
An electrocardiogram (ECG) can be used to determine other causes in patients with

suspected heart failure. It can identify changes such as left bundle branch block, left ventricular
hypertrophy, acute or previous myocardial infarction, or atrial fibrillation, and may require
further examination by echocardiography, stress test, or cardiology consultation. The normal
findings (or slight abnormalities) of the ECG make the possibility of systolic heart failure
slightly lower (LR-- = 0.27). Other findings such as atrial fibrillation, new T wave changes, or
the presence of any abnormalities have little effect on the diagnostic probability of heart failure
(LR+ = 2.2 to 3.8).
Below is Framingham Diagnostic Criteria for Heart Failure: Heart failure is

diagnosed when two major criteria or one major and two minor criteria are met.
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(1) Major Criteria: Acute pulmonary edema, Cardiac hypertrophy, Hepatojugular reflex,
Neck vein distension, Paroxysmal nocturnal dyspnea or orthopedic, Rales, Third heart
sound gallop.
(2) Minor Criteria:Ankle edema, Difficulty breathing when tired, Hepatomegaly,
Nocturnal cough, Pleural effusion, Tachycardia (> 120 beats/min).
d. Medication Used to Treat Heart Failure
i. Overview of Medications used to Treat Patients with Heart Failure and Reduced
Ejection Fraction.
Medication Class Examples How Medicine Works for

Heart Failure
Angiotensin-converting Captopril (Capoten®) Improve heart pump function over
enzyme inhibitor (ACE-I) Lisinopril (Zestril®, Prinivil®) time. Opens (dilates) blood vessels to
Enalapril (Vasotec®), Ramipril help the heart pump more blood to the
(Altace®) rest of your body. Controls blood
pressure and reduces risk of heart
attack. Keeps stress hormones from
making your heart failure worse.
Angiotensin Receptor Blocker Candesartan (Atacand®) Improve heart pump function over
(ARB) Valsartan (Diovan®) time. Opens (dilates) blood vessels to
Losartan (Cozaar®) help the heart pump more blood to the
rest of your body.
ARB + Niprilysin Inhibitor Sacubitril-valsartan (Entresto®) This medication is used instead of an
ACE I or ARB. The affects are
similar, but this medication may offer
other benefits
Beta-blocker Carvedilol (Coreg®, Coreg Improve heart pump function over
CR®), Metoprolol succinate (Toprol time. Controls blood pressure, reduces
XL®), Bisoprolol (Zebeta) risk of heart attack, keeps our heart
rhythm normal. Keeps stress
hormones from making heart failure
worse.
Diuretics (Water pills) Furosemide (Lasix®) Helps kidneys remove extra fluid,
Torsemide (Demadex®) which helps heart pump more easily,
Bumetanide (Bumex®) breathe more easily, and decrease or
Metolazone (Zaroxolyn®) remove swelling in feet, legs, and
Hydrochlorothiazide (HCTZ, abdomen.
Hyrdodiuril®)
Aldosterone Antagonist (also Spironolactone (Aldactone®) Keeps stress hormones from making
called a mineralocorticoid Eplerenone (Inspra®) heart failure worse. Increases the
receptor antagonist) amount of potassium in blood.
Isosorbide Dinitrate & Isosorbide (Isordil®) plus Combination of medications opens
Hydralazine Hydralazine (Apresoline®) or (dilates) the blood vessels to help
Isosorbide & Hydralazine (BiDil®) heart pump more blood to the rest of
the body.
Digoxin Digoxin Lanoxin®, Digitek®, Slows your heart rate, especially if the
Digox®, Cardoxin patient has atrial fibrillation with heart
100
failure. May be used when symptoms

of heart failure continue after taking
other medications.
Ivabradine Corlanor® Slows heart rate. Used if the patient
has a normal sinus heart rhythm but
fast heart rate and symptoms of heart
failure.
Sodium-dependent glucose Dapagliflozin® Inhibition of renal reabsorption of
transporters 2Inhibitor Empagliflozin® glucose
Table 6.3
ii. Angiotensin Converting-enzyme inhibitors (ACE-Is)
(1) Action:
• Dilates (widen) blood vessels to improve the amount of blood the heart pumps to the
body.
• Blocks effects of harmful stress hormones produced by the body that worsen heart
failure.
• Controls high blood pressure and reduces the risk of a heart attack.
• With time, helps the heart muscle pump more effectively, even in patients without
high blood pressure.
(2) Side Effects:

• Low blood pressure
• Dizziness. Take separately from other medications that cause dizziness. Get up more
slowly from lying or seated position.
• Kidney problems. Tested by blood tests; check how often to get tested.
• Elevation of Serum potassium. Tested by blood tests; check how often to get tested.
• Dry, hacking cough.
• Swelling in lips or throat.
• Birth defects/fetal death.
iii. Angiotensin Receptor Blockers (ARBs)
(1) Action: Similar actions to an ACE inhibitor; Recommended for people intolerant to
an ACE inhibitor.
(2) Side Effects:

• Low blood pressure. Check your blood pressure at home.
• Mask symptoms of low blood sugar in diabetic patients. Diabetic patients must
carefully monitor blood sugar levels.
• Slow heart rate.
• Tiredness or exercise intolerance. May take about 10-12 weeks for the heart to adjust
to effects of a beta-blocker, but symptoms improve with time.
• Dizziness. Take separately from other medications that cause dizziness. Get up more
slowly from lying or seated position.
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• ↑ Shortness of breath or edema (swelling). May take about 10-12 weeks for the heart
to adjust to effects of a beta-blocker, but symptoms improve with time. May occur in
patients with asthma.
• Erectile dysfunction (men).
iv. Aldosterone Antagonists
(1) Action:
• Block effects of harmful stress hormones produced by the body that worsen heart
failure.
• Increases potassium level in the blood.
(2) Side Effects:

• Elevate of serum potassium.
• Breast enlargement or tenderness (men) and menstrual period changes (women). It
occurs less often with eplerenone.
• Kidney problems.
v. Sodium-dependent glucose transporters 2Inhibitor
(1) Action:
• Reduce fasting blood glucose and HbA1c, protect islets β Cell function, weight loss.
• Blood pressure control, cardiovascular disease risk reduction
(2) Side Effects:

• Fungal infection of reproductive system
• urinary system infection
• insufficient capacity
• ketoacidosis
e. Application of Non-pharmacological Treatment
Approaches to the management of heart failure can be both non-pharmacological and

pharmacological; each approach complements the other. The non-pharmacological measures for
the management of heart failure includes the following:
• Compliance---provide careful advice on disease, treatment, and self-help strategies

• Diet---to ensure adequate general nutrition and reduce weight in obese patients
• Salt---patients are advised to avoid high-salt foods and do not add salt (especially
severe congestive heart failure)
• Fluids---Urging patients with overload and severe congestive heart failure to limit
fluid intake
• Alcohol---moderate drinking is recommended (to abstain from alcohol in patients
with alcohol-related cardiomyopathy)
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• Smoking---avoid smoking (adverse effects on coronary heart disease, adverse

hemodynamic effects)
• Exercise---regular exercise should be encouraged
• Vaccination---patients should consider influenza and pneumococcal vaccines
Urging patients to change their lifestyles is important for the management of chronic
heart failure. However, social activities should be encouraged, and care should be taken to ensure
that patients avoid social isolation. If possible, patients should continue their normal work and
adjust where appropriate to accommodate the reduced physical strength.
i. Contraceptive Advice:
Contraceptive advice should be provided to women of reproductive potential, especially

those with advanced heart failure (Class III-IV in the New York Heart Association classification).
Among these patients, maternal morbidity and mortality during pregnancy and childbirthrisk is
high. Current hormonal contraceptive methods are much safer than in the past: low-dose estrogen
and third-generation progesterone derivatives are associated with a relatively low risk of
thromboembolism. The intrauterine device is a suitable method of contraception.Although
considering the risk of infection and the risks associated with oral anticoagulants, these may be a
problem for patients with primary valvular disease
ii. Smoking and Alcohol Control:
Patients with heart failure should be strongly discouraged from smoking. In addition to
the clear adverse effects on coronary artery disease (which is the root cause of many patients),
smoking also has an adverse effect on hemodynamics in patients with congestive heart failure.
For example, smoking tends to reduce cardiac output, especially in patients with a history of
myocardial infarction.
Other adverse hemodynamic effects include increases in heart rate and systemic blood
pressure (double product), as well as mild increases in pulmonary artery pressure, ventricular
filling pressure, and total systemic and pulmonary vascular resistance.
Peripheral vasoconstriction may cause a slight decrease in the observed stroke volume, so
smoking increases oxygen demand and reduces myocardial oxygen supply due to shortened
diastolic filling time (increased heart rate) and increased carboxyhemoglobin concentration.
In general, considering the myocardial inhibitory properties of alcohol, drinking should

be limited to a moderate level. In addition to the direct toxic effects of alcohol on the
myocardium, heavy drinking can also cause arrhythmias (especially atrial fibrillation) and high
blood pressure and may lead to important changes in fluid balance. If you continue to drink
alcohol, the prognosis of alcoholic cardiomyopathy is very poor, and it is recommended to
abstain from alcohol. Abstinence can lead to significant improvements, and echocardiographic
studies have shown significant clinical benefits and improvements in left ventricular function.
Resuming alcohol consumption may subsequently lead to acute or worsening heart failure.
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iii. Diet and Nutrition
Although controlled trials only provide limited information on diet and nutritional
measures, these measures are as important in heart failure as in any other chronic disease to
ensure adequate and proper nutritional balance. Malnutrition may cause cardiac cachexia, but
malnutrition is not limited to patients with significant weight loss and muscle atrophy.
Patients with chronic heart failure are at increased risk of malnutrition due to (a) poor
appetite leading to reduced intake, which may be related to medications (such as aspirin,
digoxin), metabolic disorders (such as hyponatremia or renal failure) or liver congestion; (b)
malabsorption, especially in patients with severe heart failure; and (c) increased nutritional
requirements and the basal metabolic rate of patients with congestive heart failure increased up
to 20%. These factors may result in a net catabolic state of reduced lean muscle mass, leading to
increased symptoms and decreased exercise capacity. In fact, cardiac cachexia is an independent
risk factor for death in patients with chronic heart failure. Therefore, for those patients who
appear to be nutritionally poor, a formal nutritional assessment should be considered.
Weight loss in obese patients should be encouraged as excess body mass increases
cardiac workload during exercise. Weight reduction in obese patients to within 10% of the
optimal body weight should be encouraged.
iv. Exercise Training and Rehabilitation
Exercise training has been shown to be beneficial for patients with heart failure: patients
show improvement in symptoms, increased well-being, and functional capacity. However,
exercise will not lead to a significant improvement in heart function.
All patients with heart failure should be encouraged to participate in a supervised simple
exercise program. Although bed rest ("armchair therapy") may be suitable for patients with acute
heart failure, patients with chronic heart failure should be encouraged to exercise regularly. In
fact, long-term immobility may lead to lower limb muscle mass loss and systemic physical
disorders, leading to further reduction in exercise capacity and a tendency to thromboembolism.
De-adaptation itself may be harmful. Peripheral changes and central abnormalities cause
vasoconstriction, further deterioration of left ventricular function, and further decline in
functional capacity.
More importantly, regular exercise may slow down or stop this process, have a beneficial
effect on autonomic nerve function, reduce sympathetic nerve activity and enhanced vagal tone,
thereby reversing some of the adverse consequences of heart failure. Large prospective clinical
trials will determine whether these beneficial effects can improve the prognosis of patients with
chronic heart failure and reduce the incidence of sudden death.
Therefore, regular exercise should be promoted for patients because it is possible to

improve exercise tolerance and quality of life without harmful effects on left ventricular function.
Cardiac rehabilitation services are beneficial to this group, and patients should be encouraged to
develop their own routine exercise plans, including walking, cycling, and swimming.
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Nevertheless, patients should understand their limits and avoid excessive fatigue or difficulty
breathing. In the first instance, a structured walking plan will be the easiest to adopt.
f. Clinical Case Studies in Heart Failure
i. Case 1 History:
A 53-year-old man suffered from inferior and anterior myocardial infarction. Although
diuretic therapy was added, his fatigue and edema gradually increased. He received furosemide
80 mg 3 times daily, captopril 50 mg 3 times daily, aspirin 150 mg once daily, isosorbide
mononitrate SR 60 mg once daily, and amlodipine 10 mg daily One treatment.
On examination, he had dependent edema in the middle of his thigh and subtle crepitus at
the base. He had 105 resting tachycardia min-1 in sinus rhythm. Mitral and tricuspid valve
regurgitation was obvious, and supine blood pressure was as low as 95/48 mmHg. Laboratory
tests showed a decrease in serum sodium (125 mmol l-1) and impaired renal function (urea 12.8
mmol l-1; creatinine 189 μmol l-1). The chest radiograph showed mild interstitial edema, right
pleural effusion, and obvious cardiac hypertrophy. The 24-hour ECG showed repetitive but non-
sustained ventricular tachycardia (4 10-20 beats, heart rate >150 min-1) and multifocal ventricular
ectopic (>15000 abnormal beats/24 hours). Repeated echocardiography showed poor left
ventricular contractility, overall damage, significant dilation (LVEDD 750 mm), and functional
mitral regurgitation. The radionuclide scintigraphy showed a left ventricular ejection fraction of
11%.
ii. Comments:
The prospect of improving symptom control depends on optimizing current treatment

methods. Multi-drug therapy involves the risk of patient confusion and afailure of compliance.
This is an overlooked area in the care of patients with heart failure, but it is well known that it is
related to the poor clinical outcomes of patients with heart disease. Most decompensated patients
require hospitalization for evaluation and observation, although community-based care is
increasingly being studied to reduce costs (see below).
Isolated dependent edema maybe drugs related. Although amlodipine, unlike some
calcium antagonists, does not seem to cause heart failure to worsen, some patients may
experience significant edema. Unless there is active myocardial ischemia and there are no other
treatment options, discontinuation should be considered.
iii. Case 2 history
A 74-year-old female patient was admitted to the hospital because of dyspnea, orthopedic
breathing, and ankle edema that had gradually worsened in the past 3 weeks. Her GP prescribed
oral coamoxiclav and coamilofruse. She suffers from dyspepsia and her condition has worsened
in recent weeks. The general practitioner noticed a new murmur.
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She has no fever but is short of breath (25 times, min-1); low-volume pulses. The blood
pressure in the sitting position is 110/70 mmHg. The apex beat is located in the anterior axillary
line, and a parasternal lift is obvious. A pansystolic murmur can be heard, and end-inspiratory
crackles can be heard throughout the lung field. There was sacral edema.
ECG confirmed sinus tachycardia (110 beats min-1), anterolateral Q wave was a previous
infarction, and chest X-ray confirmed cardiac hypertrophy and interstitial edema. Routine
chemistry shows Na+ 128 mmol l-1; K+ 5.8 mmol l-1; urea 9 mmol l-1; creatinine 155 mmol l-1. The
creatine kinase series is not significant. The echocardiogram showed dilation of the heart (left
ventricular enddiastolic distension (LVEDD) 650 mm), hypokinesia of the anterior and septum,
and apical dilatation, consistent with a previous anterior infarction. The posterior wall was
contracting vigorously. The highvelocity jet of mitral regurgitation (4.7 ms-1) was noted, but the
left atrium was normal in size.
iv. Comments:
This is a common clinical manifestation of progressive systolic dysfunction after

unheralded myocardial infarction. Treatments and general management steps should be
considered for all such patients. Although the clinical identification or classification of the
severity of heart failure is unreliable in stable patients, recent studies have shown that in acute
heart failure clinical diagnosis is much safer. Any ECG abnormalities in patients with dyspnea
are supporting evidence of cardiogenic dyspnea. A normal ECG usually prompts another
diagnosis. Radiology of cardiac hypertrophy also supports the diagnosis of heart failure. For
more subtle radiological signs, this is not the case, even in the hands of experienced radiologists,
the clinical environment may significantly affect interpretation. Radiological cardiomegaly most
often represents significant ventricular dilatation or hypertrophy (provided that pericardial fluid
is not suspected). This combined with abnormal electrocardiogram, almost ruled out non-cardiac
causes of dyspnea.
Echocardiography can provide a clear diagnosis. Although the lack of quantitative images
is a common practical problem, it may not be important for clinical management.
106
REFERENCES:
1. Remes J, Miettinen H, Reunanen A, Pyorala K. Validity of diagnosis of heart failure in primary health care. Eur
Heart J. 1991;12:315–321.
2. Gillespie ND, McNeill GP, Pringle TH, Ogston S, Struthers AD, Pringle SD. Cross sectional study of
contribution of clinical assessment and simple cardiac investigations to diagnosis of left ventricular systolic
dysfunction in patients admitted with acute dyspnoea. Br Med J. 1997;314:936–940.
3. Davie AP, Francis CM, Love MP, et al. Value of the electrocardiogram in identifying heart failure due to left
ventricular systolic dysfunction. Br Med J. 1996;312:222–224.
4. Dargie HJ, McMurray JVV. Diagnosis and management of heart failure. Br Med J. 1994;308:321–328.
5. Badgett RG, Mulrow CD, Otto PM, Ramirez G. How well can the chest radiograph diagnose left ventricular
dysfunction? J Gen Int Med. 1996;11:625–634.
6. Choy AM, Darbar D, Lang CC, et al. Detection of left ventricular dysfunction after myocardial infarction:
comparison of clinical, echocardiographic and neurohormonal methods. Br Heart J. 1994;72:16–22.
7. 30. Rich MW, Vinson JM, Sperry JC, et al. Prevention of readmission in elderly patients with congestive heart
failure: results of a prospective randomized pilot study. J Gen Int Med. 1993;8:585–590.
8. 31. Monane M, Bohn R, Gurwitz JH, Glynn RJ. Noncompliance with congestive heart failure therapy in the
elderly. Arch Int Med. 1994;154:433–437.
9. 32. Packer M, O’Connor CM, Ghali JK, et al. Effect of amlodipine on morbidity and mortality in severe chronic
heart failure. N Engl J Med. 1996;335:1107–1114.
10. 33. The Multicenter Diltiazem Postinfarction Trial Research Group. The effect of diltiazem on mortality and re-
infarction after myocardial infarction. N Engl J Med. 1988;319:385–395.
107
Chapter 7 Evaluation and Management of Heart Disease
Lv Yan, M.D.
In order to determine the treatment strategies of surgery and ensure the safty of surgery,
necessary physical examination should be performed to identify patients whose risk of
cardiovascular complications is high. Physicians should at this point also consider the long-term
risk of cardiovascular disease as well. In general, the risk for cardiac complications is high
among patients with a marked decrease in exercise capacity (≤4 metabolic equivalents [METs]).
The Revised Cardiac Risk Index (RCRI) is useful to assess the risk of cardiac complications
during thederioperative deriod (Table 7.1)
Table 7.1 Revised Cardiac Risk Index

Ischemic heart disease (history of myocardial infarction, positiveexercise test,
current complaint of ischemic chest pain or use ofnitrate therapy, or ECG with Q
waves)
History of heart failure
History of cerebrovascular disease (transient ischemic attack, orcerebral infarction)
Insulin therapy for diabetes
Renal dysfunction (serum creatinine >2.0 mg/dL)
High-risk type of surgery (major vascular surgery)
Number of risk Cardiovascular complications Cardiovascular death (%)
factors (%) (95% CI)
0 0.5(0.2–1.1) 0.3
1 1.3 (0.7–2.1) 0.7
2 3.6 (2.1–5.6) 1.7
≥3 9.1 (5.5–13.8) 3.6
CI, confidence interval. Lee TH, Marcantonio ER, Mangione CM, et al. Derivation and prospective validation of
a simple index for prediction of cardiac risk of major noncardiac surgery. Circulation 1999;100:1043-1049.
i. Heart Failure
The guidelines for adults are based on the manner in which patients present to physicians
and encompass the extremes of presentation from acute pump failure with shock to
asymptomatic left ventricular dysfunction. We have included patients in the latter category
because proper treatment can delay or prevent the development of heart failure. Treatment
strategies frequently depend on the etiology of the heart disease, and a major focus of these
guidelines is the diagnostic approach to determine correctable etiologies and precipitating factors.
Our approach is to discuss the diagnostic studies and treatment necessary to stabilize the status of
adult patient with acute heart failure and the evaluation and treatment of patients presenting with
chronic left ventricular dysfunction or stabilized acute heart failure.As we have already discussed
the nature, diagnosis, and treatment of Acute Heart Failure in Chapter 6. Please refer to the
Chapter for the relevant information.
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ii. Hypertension
Un controlled hypertension (systemic pressure ≥180 mmHg, and/or diastolic blood

pressure≥110 mmHg) should be controlled prior to surgery. It is also important to assess the
patient for hypertensive damage to the brain, heart, kidney, blood vessels, and ocular fundus. If
pheochromocytoma is suspected, surgery should be postponed to assess for and resect the tumor
before the surgery.Anti hypertensive drugs should basically be administereduntil the day of
surgery, and be resumed after surgery without delay.
iii. Ischemic Heart Disease
Acute coronary syndrome, and stable angina with evidence of ischemia at an exercise
intensity of 4 metabolic equivalents (METs) should be treated before the surgery. The patient
should be considered for drug therapy and/or revascularization. The type of revascularization
procedure for this patient population should be considered similarly to those who are not going
to undergo surgery.
iv. Arrhythmia
It is recommended that patients with ventricular arrhythmia continue to take

antiarrhythmic drugs before operationand patients with persistent ventricular tachycardia should
take antiarrhythmic drugs during perioperative period. Patients with supraventricular arrhythmia
should take antiarrhythmic drugs before operation.Patiant with bradyarrhythmia, the indication
of temporary pacemaker is the same as that of permanent pacemaker.If the patient has an
implantable defibrillator but has stopped using it, it is recommended to monitor the patient's
cardiac function during operation and prepare an external defibrillator.
REFERENCES:
1. Shunei Kyo,Kazuhito Imanaka,Munetaka Masuda,et al. Guidelines for Perioperative Cardiovascular Evaluation
andManagement for Noncardiac Surgery (JCS 2014). Circ J 2017; 81: 247.
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Chapter 8 Basic Techniques of Vascular Surgery Diagnosis
Li Xi, M.D. / Jing Yuchen
The ultimate goals of preoperative medical assessment are to reduce the patient’s surgical
and anesthetic perioperative morbidity or mortality, and to return him to desirable functioning as
quickly as possible. It is imperative to realize that "perioperative" risk is multifactorial and a
function of the preoperative medical condition of the patient, the invasiveness of the surgical
procedure and the type of anesthetic administered. A history and physical examination, focusing
on risk factors for cardiac and pulmonary complications and a determination of the patient’s
functional capacity, are essential to any preoperative evaluation. Those with comorbidity should
be optimized for the procedure. The preoperative preparation involves procedures that are
implemented based on the nature of the expected operation as well as the findings of the
diagnostic workup and the preoperative evaluation.
a. Medical History Collection

The history is the most important component of the preoperative evaluation. The history
should include a past and current medical history, a surgical history, a family history, a social
history (use of tobacco, alcohol, and illegal drugs), a history of allergies, current and recent drug
therapy, unusual reactions or responses to drugs and any problems or complications associated
with previous anesthetics. A family history of adverse reactions associated with anesthesia
should also be obtained. In children, the history should also include birth history, focusing on
risk factors such as prematurity at birth, perinatal complications and congenital chromosomal or
anatomic malformations and history of recent infections, particularly upper and lower respiratory
tract infections. The history should include a complete review of systems to look for
undiagnosed disease or inadequately controlled chronic disease. Diseases of the cardiovascular
and respiratory systems are the most relevant in respect of fitness for anesthesia and surgery
The physical examination should build on the information gathered during the history. At
a minimum, a focused preanesthetic physical examination includes an assessment of the airway,
lungs, and heart, with documentation of vital signs. Unexpected abnormal findings on the
physical examination should be investigated before elective surgery.
b. Preoperative Risk Assessment
Preoperative assessment of cardiac risk is critically important in planning the care of a

patient who requires major vascular surgery. Peripheral arterial and venous diseases are assessed
by auscultation, palpation, and observation. Table 8.1 compares the assessment factors of
peripheral arterial and venous obstructive diseases in an extremity. Peripheral vascular
laboratories, which are similar to cardiac catheterization laboratory, have been established in
many health care facilities to perform noninvasive and invasive studies before and after surgical
intervention. Interventional radiologists perform many of the diagnostic tests. X-ray studies,
scans, imaging, ultrasound, and Doppler assessment reveal most pathologic conditions.
110
Table 8.1
Comparison of Peripheral Arterial and Venous Obstructive Diseases in an Extremity
Assessment of
Arterial Obstructive Disease Venous Obstructive Disease
Extremity
Color Dusky, blue, gray, mottled, pallor Red, purple, brown

distal to obstruction hemosiderin spots, brawny
Temperature Cool, cold Warm, hot
Dry, shiny, flaking skin; vessels not Moist, peeling skin

Visual and obvious Vessels may be tortuous and
palpable inflamed
characteristics Lack of hair on affected part Thickened tissue
Thick nails Hair present on affected part
Normal nails
Numbness, tingling, pain during Aching, throbbing, tightness,
Sensation exercise (intermittent claudication) feeling of heaviness; muscles
Pain at rest in severe disease feel fatigued
Increased pain when exposed tocold
Pain can be acute and severe Pain decreased by motion or
elevation of legs
Feels worse at end of day
Mobility Painful range of motion. Painful range of motion.

limited flexion and extension caused
by avascular necrosis at the tissue limited flexion and extension
level caused by congestive edema in
joints
Size Not enlarged, average for body build Swollen, edematous
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Assessment of
Arterial Obstructive Disease Venous Obstructive Disease
Extremity
Integrity of surface Peeling; infarcted; painful, deep, Stasis ulceration; open,

layer serous, oozing ulcers with defined draining, shallow ulcers
edges on or between toes with irregular borders
Pulses Weak or absent Present
Condition of digits Mottled, blackened, fragile, painful; Edematous, reddened,

can become gangrenous painful; can become
gangrenous
The ASA grading system was originally introduced as a simple description of the
patient's physical state (Table 8.2). Although it seems simple, it is still one of the few prospective
descriptions of the overall health of patients related to anesthesia and surgical risks. It is very
useful and should be suitable for all patients undergoing surgery. The increase in physical
condition is related to the increase in mortality. Emergency surgery can significantly increase the
risk, especially in ASA grade 4 and 5 patients.
Surgical complications occur frequently. One large studydocumented at least one

complication in 17% of surgical patients. Surgery-related morbidity and mortality generally fall
into one of three categories: cardiac, respiratory, and infectious complications. The overall risk
for surgery-related complications depends on individual factors and the type of surgical
procedure. For example, advanced age places a patient at increased risk for surgical morbidity
and mortality. The reason for an age-related increase in surgical complications appears to
correlate with an increased likelihood of underlying disease states in older persons. Diseases
associated with an increased risk for surgical complications include respiratory and cardiac
disease, malnutrition, and diabetes mellitus. With respect to the type of surgery, major vascular,
intraabdominal, and intrathoracic surgical procedures, as well as intracranial neurosurgical
procedures are frequently associated with increased perioperative morbidity and mortality. In
addition, urgent and emergency procedures constitute higher risk situations than elective,
nonurgent surgery and present a limited opportunity for preoperative evaluation and treatment.
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Status Disease State

ASA Class 1 No organic, physiologic, biochemical, or psychiatric disturbance
ASA Class 2 Mild to moderate systemic disturbance that may or may not be related to the
reason for surgery. Examples including heart disease that only slightly limits
physical activity, essential hypertension, diabetes mellitus, anemia, extreme
of age, morbid obesity, chronic bronchitis.
ASA Class 3 Severe systemic disturbance that may or may not be related to the reason for
surgery such as heart disease that limits activity, poorly controlled essential
hypertension, diabetes mellitus with vascular complications, chronic
pulmonary disease that limits activity, angina pectoris, history of prior
myocardial infarction
ASA Class 4 Severe systemic disturbance that is life-threatening with or without surgery
such as Congestive heart failure, persistent angina pectoris, advanced
pulmonary, renal, or hepatic dysfunction.
ASA Class 5 Moribund patient who has little chance of survival but is submitted to surgery
as a last resort (resuscitative effort). Examples: uncontrolled hemorrhage as
form a ruptured abdominal aneurysm, cerebral trauma, pulmonary embolus
ASA Class 6 A declared brain-dead patient whose organs are being removed for donor
purposes.
E An “E” is added to the status number to designate an emergency operation
Table 8.2 American Society of Anesthesiologists’ Classification of Physical Status
c. Assessing Cardiovascular Risk
The American College of Cardiology (ACC) and the American Heart Association (AHA)
issued a working group report on guidelines for perioperative cardiovascular assessment in non-
cardiac surgery. The purpose is to provide a framework for considering the cardiac risks of non-
cardiac surgery in various patient and surgical situations.Table 8.3 and Table 8.4 outlet the
factors in consideration of patients’ cardiovascular risk and functional capacity and surgery
specific risk.
Patients’ risk factors are usually subdivided into three categories: major, intermediate,
and minor. A 6-week period is necessary for the myocardium to heal after an infarction and for
the thrombosis to resolve. Patients with coronary revascularization done within the preceding 40
days should also be classified as high-risk patients. Because of sympathetic stimulation and
hypercoagulability during and after surgery, patients with major predictors have a five times
greater perioperative risk. Only vital or emergency surgical procedures should therefore be
considered for these patients. All elective operations should be postponed, and the patients
properly investigated and treated.
Intermediate-risk factors are proof of well-established but controlled coronary artery

disease. Diabetes mellitus is included in this category because it is frequently associated with
silent ischemia and represents an independent risk factor for perioperative mortality.
Minor risk factors are markers of an increased probability of coronary artery disease, but not of
an increased perioperative risk.
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Exercise tolerance is a major determinant of perioperative risk. It is usually evaluated by

the estimated energy requirement for various activities and graded in metabolic equivalents
(MET) on a scale defined by the Duke Activity Status Index. One MET represents the oxygen
consumption of a resting adult (3.5 ml/kg/min).
Major clinical predictions (makers of unstable coronary artery disease):

Myocardial infarction less than six weeks,
Unstable or severe angina (class III and class IV)
Decompensated congestive heart failure
Significant arrhythmias (e.g., causing hemodynamic instability)
Severe valvular disease (e.g., aortic, or mitral stenosis with value area less than 1.0 cm2)
Coronary Artery Bypass Graft (CABG) or Percutaneous Transluminal Coronary Angioplasty
(PTCA) less than six weeks.
Intermediate clinical predictors (markers of stable coronary artery disease):
Previous myocardial infarction more than 6 weeks and less than three months (more than
three months if complicated) based on the history or the presence of pathologic Q waves.
Mild angina (class I-II)
Silent ischemia (Holter monitoring)
Compensated congestive heart failure, ejection fraction less than 0.35
Post CABG or PTCA more than six weeks and less than three months, or more than six
years, or with anti-anginal therapy
Diabetes mellitus
Renal insufficiency
Minor clinical predictors (increased probability of coronary artery disease)
Familial history of coronary artery disease,
Age more than 70 years old
ECG abnormalities (arrhythmia, LVH, left bundle branch block)
Low functional capacity
History of stroke
Uncontrolled systemic hypertension
Hypercholesterolemia
Smoking
Post infarction more than three months, asymptomatic without treatment
Post CABG or PTCA more than three months and less than six years, and no symptoms of
angina nor anti-anginal therapy
LVH=left ventricular hypertrophy
Table 8.3 Patient-related predictors for risk of Perioperative Cardiac Complications
Surgical procedures can be stratified into three categories, according to their level of
perioperative physiological stress.
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High risk procedures (cardiac complication rate more than 5%)

Emergency surgery
Aortic and major vascular surgery
Prolonged surgical procedures with large fluid shifts or blood loss
Unstable hemodynamic situations
Intermediate risk procedures (cardiac complication rate 1% to 5%)
Abdominal or thoracic surgery
Neurosurgery
ENT procedures
Minor vascular surgery, including carotid endarterectomy
Orthopedic surgery
Prostatectomy
Low risk procedures (cardiac complication rate less than 1%)
Breast surgery
Superficial surgery
Eye surgery
Endoscopic procedures
Plastic and reconstructive surgery
Ambulatory surgery
Table 8.4 Surgery-related predictors for Risk of Perioperative Cardiac Complications
i. Previous Myocardial Infarction (MI)
It was generally accepted generally that a MI within 6 months of proposed surgery is a

contraindication to elective anesthesia and surgery. However, it appears now that the risk after a
previous infarction is related less to the age of the infarction than to the functional status of the
ventricles and to the amount of myocardium at risk from further ischemia. A small infarction
without residual angina in the context of a good functional status allows essential non-cardiac
surgery as soon as 6 weeks after the ischemic episode. On the contrary, a patient with a large
infarct, residual symptoms, and ejection fraction less than 0.35 has a high probability of a further
cardiac event, even 6 months after the infarction. It is usually suggested that the period within 6
weeks of infarction as a time of high risk for a perioperative cardiac event because it is the mean
healing time of the infarct-related lesion. The period from Six weeks to Three months is of
intermediate risk; this period is extended beyond three months in cases with complications such
as arrhythmias, ventricular dysfunction or continued medical therapy. In some cases, no benefit
can be demonstrated for delaying surgery more than 3 months after an ischemic accident
In addition,Recent data have shown that any event in the coronary circulation such as
ischemia, infarction, or revascularization induces a high-risk period of six weeks and an
intermediate-risk period of three months. A three-month minimum delay is mandatory before
performing non-cardiac surgery after myocardial infarction or revascularization. However, this
delay may be too long if an urgent surgical procedure is requested, as for instance with rapidly
spreading tumors, impending aneurysm rupture, infections requiring drainage, or bone fractures.
In these situations, it is beneficial to operate under the protection of β1-adrenergic antagonism
because it reduces the cardiac complication rate in such patients. When possible, beta-blockers
115
should be started days or weeks before elective surgery, with a target heart rate between 50 and
60 beats per minute.
ii. Management Recommendations
As of acute surgical emergencies, preoperative evaluation may have to be limited to

simple and critical tests, such as rapid assessment of cardiovascular vital signs, volume status,
hematocrit, electrolytes, renal function, urinalysis, and electrocardiogram. Until acute surgical
emergencies are resolved, only the most important tests and interventions are appropriate. A
more thorough evaluation can be done after surgery.
The decision to perform elective surgery begins with a risk assessment. Clinicians should
assess the patient’s preoperative risk factors and the risks associated with the planned surgery. It
is often helpful to estimate the percentage of risk for cardiac complicationsso that the surgeon
can make the most informed decision about whether to proceed. The decision to undergo further
examination depends on the interaction of the patient’s risk factors, the specific risks of the
procedure, and functional capabilities.
If a major risk predictor is present, nonemergency surgery should be delayed for medical
management, risk factor modification and possible coronary angiography. For patients at
intermediate clinical risk, both the exercise tolerance and the extent of the surgery are considered
about the need for further testing.
Patients with poor functional status should undergo noninvasive cardiac testing unless
low-risk surgery is planned. Patients with good or excellent functional status require noninvasive
testing only if they are having high-risk surgery. Finally, patients with minor risk predictors or
no risk predictors should have noninvasive testing if they have poor functional status and are
about to undergo high-risk surgery. More importantly, no preoperative cardiovascular testing
should be performed if the results will not change perioperative management.
The results of noninvasive testing can then be used to determine further perioperative
management. Such management may include intensified medical therapy or cardiac
catheterization, which may lead to coronary revascularization or potentially to cancellation or
delay of the elective noncardiac operation. Alternatively, results of the noninvasive test may lead
to a recommendation to proceed directly with surgery. In some patients, the risk of coronary
angioplasty or corrective cardiac surgery may approach or even exceed the risk of the proposed
noncardiac surgery. In some instances, this approach may be appropriate, however, if it also
significantly improves the patient’s long-term prognosis.
d. Assessing Pulmonary Risk
Careful medical history and physical examination are the most important parts of
preoperative lung risk assessment. The role of preoperative lung function testing is still uncertain.
There is no data to show that spirometry can identify high-risk groups that cannot be predicted
by medical history and physical examination. When it is uncertain whether there is lung damage,
spirometry may be useful. When it provides information that will change management or
improve risk stratification, it should be used selectively.
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Postoperative pulmonary complications (PPCs) such as pneumonia, atelectasis,

bronchitis, bronchospasm, hypoxemia, respiratory failure with prolonged mechanical ventilation
or exacerbation of underlying chronic lung disease, increase patient morbidity and mortality and
prolong the length of hospital stay after surgery. PPCs occur in approximately 20% to 30% of
patients undergoing major, non-thoracic surgery.
i. The risk factors for PPCs include the following:
• Procedure-related risk factors----primarily based on how close the surgery is to the

diaphragm such as the upper abdominal and thoracic surgery are the highest risk
procedures.
• Length of the Surgery (longer than three hours) and general anesthesia (epidural or spinal)
• Emergency Surgery.
• Underlying chronic pulmonary disease or symptoms of respiratory infection.
• Smoking
• Age more than sixty years
• Obesity
• Presence of obstructive sleep apnea
• Poor exercise tolerance or poor general health status.
The most significant of these risk factors is the site of surgery, with abdominal and
thoracic surgery having pulmonary complication rates ranging from 10 to 40 percent. The closer
the surgery is to the diaphragm, the higher the risk of pulmonary complications. The most
important modifiable risk factor is smoking. The relative risk of pulmonary complications among
smokers as compared with nonsmokers ranges from 1.4 to 4.3. Unfortunately, the risk declines
only after eight weeks of preoperative cessation. This interval allows the mucociliary transport
mechanism to recover, the secretions to decrease and the carbon monoxide levels in the blood to
drop.
The presence of either obstructive or restrictive pulmonary disease places the patient at
increased risk of developing perioperative respiratory complications. If significant pulmonary
disease is suspected by history or physical examination, determination of functional capacity,
response to bronchodilators and/or evaluation for the presence of carbon dioxide retention
through arterial blood gas analysis may be justified.
For elective anesthesia and surgery in a patient with a history of asthma, the asthmatic
condition should be under control and the patient should be free of wheezing, with a peak flow
greater than 80% of predicted. If necessary, the patient should receive a short course of steroids
such as 60 mg of prednisone daily or the equivalent prior to surgery to achieve this goal.If the
patient takes drugs regularly, treatment must not be discontinued. Any patient who has
previously been admitted to hospital for an asthmatic attack should be carefully assessed,
because airway reactivity persists for several weeks after an asthmatic episode.
The increased frequency of PPC in patients with chronic obstructive pulmonary disease
(COPD) may be explained by comorbidities such as cardiovascular disease rather than airway
obstruction. People with COPD may have long-term fatigued breathing muscles. Malnutrition,
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electrolyte, and endocrine disorders can cause respiratory muscle weakness and should be
corrected before surgery. COPD patients should be checked for unrecognized pulmonary heart
disease, and they should be treated before surgery if the correlation symptoms occur.
Generally, all patients with COPD / asthma who require home oxygen therapy or have
required hospitalization for respiratory problems in the past 6 months are assumed to be at
greater risk.Patients with obstructive sleep apnea (OSA) are prone to postoperative hypoxemia
quickly after emergence from general anesthesia. The sedative and respiratory depressant effects
of general anesthesia place the patient with OSA at significantly increased risk of airway
obstruction and respiratory compromise in the perioperative period. It is prudent to diagnose
OSA preoperatively so special treatments applied appropriately.
e. Diabetes Mellitus
The perioperative morbidity and mortality of diabetic patients are higher than those of
non-diabetic patients. When a diabetic needs surgery, it is important to remember that ignoring
the long-term complications of diabetes is more likely to cause harm to him or her than to control
blood sugar levels in the short term. Most people with long-term diabetes will experience
damage to one or more of their organs. Diabetes patients who require elective surgery should
carefully evaluate the symptoms and signs of peripheral vascular, cerebrovascular, and coronary
artery disease before surgery. Coexisting pathologies must be identified and carefully managed
during the perioperative period.
Diabetics have a higher incidence of death after MI than non-diabetics. Myocardial
ischemia or infarction may be clinically "silent" if the diabetic has autonomic neuropathy.
Therefore, a high index of suspicion for myocardial ischemia or infarction should be maintained
throughout the perioperative period if unexplained hypotension, dysrhythmias, hypoxemia, or
ECG changes develop. Eight to 31% of type 2 diabetics are reported to have asymptomatic
coronary artery disease on stress testing. Administration of perioperative beta-blockers should be
considered in diabetic patients with coronary artery disease to limit perioperative ischemia.
Despite prior controversy regarding the use of beta blockade in diabetics (due to concerns of
worsened glucose intolerance and masking symptoms of hypoglycemia), it is emphasized that
diabetics benefit as much or more than the non-diabetic population from post-MI beta blockade.
Adequate control of blood glucose concentration (< 180 mg/dL) must be established
preoperatively and maintained until oral feeding is resumed after operation. Oral hypoglycemic
agents are withheld the day of surgery for an agent with a short half-life and up to 48 hours
preoperatively for a long-acting agent such as chlorpropamide. A combination of glucose and
insulin is the most satisfactory method of overcoming the deleterious metabolic consequences of
starvation and surgical stress in the diabetic patient. Generally, there is no need for insulin
infusion in diabetics who are diet-controlled regardless of type of surgery, or in diabetics who are
on oral agents only and are undergoing minor surgeries.
Complications of perioperative hyperglycemia include dehydration, impaired wound
healing, leukocyte chemotaxis and functional inhibition (related to increased risk of infection),
deterioration of central nervous system and spinal cord injury under ischemic or hypoxic
conditions, and hyperosmolarity leading to hyperviscosity and thrombogenesis. Once the glucose
level overs 180 mg/dL (10 mmol/L), osmotic diuresis may occur; diabetes may cause
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dehydration and increase the risk of urinary tract infections. For a patient weighing 70 kg, 1
unit/hour of regular insulin can reduce glucose by approximately 2530 mg/dL (1.5 mmol/L).
Due to the residual effects of long-acting oral hypoglycemic drugs or insulin preparations
in addition to perioperative fasting, hypoglycemia may occur postoperatively [adult blood
glucose <50 mg/dL (2.8 mmol/L), children blood glucose <40 mg/dL (2.2 mmol/L) ]. The
recognition of hypoglycemia during the perioperative period may be delayed because anesthetics,
analgesics, sedatives, and sympathetic drugs can change the common symptoms of
hypoglycemia. In addition, diabetic patients with autonomic neuropathy have reduced adrenergic
symptoms associated with hypoglycemia. These symptoms usually begin with confusion,
irritability, fatigue, headache, and drowsiness, and may progress to seizures, focal neurologic
deficits, coma, and death.
f. Process support for risk mitigation: a case study of variability and resilience in
vascular surgery
Developing IT-based process support is seen as a promising avenue towards improving

efficiency and quality in healthcare.Such computer-based support may facilitate the flow of
patients and information, but also enable the monitoring of tasks and data during care processes
to ensure adherence to best practice and clinical guidelines.A key design decision in the
development of such systems is to the extent to which one should use the system to manage or to
reduce process variation.
Modern theory on quality postulates that quality is inversely proportional to
variation, which can be seen as a barrier to performance and quality. Variation is often
substantial in healthcare processes and is often reduced by managing variations falling outside
specified limits. However, process variation may also be an expression of flexibility reflecting
the problem-solving nature of clinical work. Resilience engineering theory suggests that process
variation related to flexibility is an integral part of how actors deal with uncertainty, variability,
and high risk, enhancing safety in unpredictable settings. The resilience engineering approach to
managing variations centers on attention to essential properties of adaptive behaviors.Hollnagel
proposes four properties that he characterizes as cornerstones of resilience: (a) the ability to
anticipate forthcoming events, (b) attentivity to critical issues, (c) the ability to respond
effectively to (unexpected) events, and (d) a willingness and readiness to gain knowledge by
learning from both positive and negative experiences.
Given these perspectives on process variations, we conducted a field study of existing
work practices in a care process for patients suffering from a pathological widening of their main
aorta—abdominal aortic aneurysm (AAA)—across one university hospital and two community
hospitals owned by one of the four Norwegian Regional Health Authorities. Our purpose was to
identify and describe the characteristics of process variability within and between the hospitals
and to explore types and sources of variations in the studied process. Based on this study, we
develop suggestions for how IT-based process support could be designed to enhance resilience in
this clinical process, that is risk mitigation.
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Discussion:
In this study, we have reported on the dimensions, types and causes of variations in the
monitoring of patients with aortic aneurysm, a clinical process that unfolds itself in collaboration
between multiple institutions and departments. Our approach was designed to provide a detailed
understanding of the characteristics of process variability, and with the purpose of elucidating
requirements for an IT-system.
We found that the care process for AAA patients was best described as systematic
analysis and mitigation of risks. Much of the observed variation was intended. Such intended
natural variety of protocols observed should not be considered a systematic threat for patient
safety, but rather as a necessary risk mitigation activity. Activities were planned while taking
into account the need for flexibility and opportunity to make last-minute adjustments, given these
were required to achieve particular clinical aims and/or to accommodate to the preferences of the
patient. However, risk analysis extended beyond that of traditional clinical problem-solving and
decision-making. Other risks were related to the reliability of the healthcare system. For instance,
having decided that a patient should be operated within, for example, 6 weeks, the surgeon could
not blindly trust that the scheduling department would schedule the patient for surgery within
this time limit. Existing IT systems had little support for mechanisms specifically tailored to
scheduling and knowledge building. Rather than being built into the schema of the healthcare
system, these mechanisms were reflected as characteristics of the actors' actions. To mitigate
risks associated with omission or postponement of planned activities, clinicians sometimes added
extra loops to the workflow such as an extra ultrasound examination or another consultation.
This behavior, which can be described as resilience behavior, compensated for the lack of more
formal mechanisms of resilience in the healthcare system, enhancing patient safety.
In our opinion, these findings should have a major influence on the design of IT systems
to be implemented in this domain. Despite that, medical technology now pervades healthcare
systems; the provision of care to the patient remains a human endeavor, strongly influenced by
the experiences, skills, and knowledge of the healthcare professional. We propose that IT-based
process support for clinical work should be designed to enhance two essential capabilities of a
resilient healthcare system. The first involves the capability of awareness, which refers to a
mental state of the actors that result from them having available information about the actual
execution and status of ongoing processes. These might be related to individual patients as well
as to the cohort of patients under surveillance. We believe that enhanced awareness resulting
from such IT support could prevent process breakdowns, reducing the risk of patient dropouts
and other safety threats.
The second is the capability to gain knowledge from experience. This capability refers to
the healthcare system's ability to enhance its knowledge and support a continuous learning
process among involved actors based on data about its processes and outcomes. Support for this
capability is particularly important for continually evolving trans-institutional care processes that
involve more than one treatment alternative. Such support could alleviate the challenge of
individual development of new surgical skills while also maintaining existing skills in standard
treatment, provide effective dissemination of data to substantiate the new procedure's
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effectiveness and reduce competency -related risks for patients. In order to support the
generation and dissemination of knowledge, the system should provide the following:
Feedback on process and outcome parameters for the patient group to all clinicians
involved. This feedback should include the same information on patients who experience
aneurysm rupture in order to learn from possiblefalse negative cases (patients wrongly excluded
from surgery). This is important because the mechanisms that lead to aneurysm rupture are still
largely unknown.Real-time process information to the local practitioners, alleviating potential
practice uncertainties for clinicians not directly involved in the EVAR activity with respect to
both the individual patient at hand and the patient group at the related meso-level.
Providing IT support for the capabilities of awareness and that of gaining knowledge
from experience will enhance actors' risk-mitigating ability by strengthening Hollnagel's
cornerstones of resilience. Moreover, our suggestions on IT design are in line with Hollnagel's
proposition of resilience as a result of a dynamic process in which qualities linked to the four
cornerstones have to be exercised continuously. The IT support could very well also lead to more
intended process variations, while limiting unintended process variations outlined. Similar to our
findings, studies of the effects of computerized clinical guidelines and decision-support systems
find that when clinicians indicate that their actions are exceptions, these deviations are often well
justified. As mentioned in the introduction, modern theory on quality emphasizes the importance
of reducing variation. We suggest that efforts to reduce variation should focus on unintended
process variation that cannot be attributed to risk mitigation in clinical problem-solving.
Unfortunately, distinguishing between unintended and intended process variation is not
necessarily a straightforward task. Further complicating work to improve quality by reducing
variability in highly complex healthcare settings, Ashby's requisite law states that there must be a
possible response for every type/source of variation impacting upon a system. There is, however,
important common ground between quality improvement and resilience theory. For instance,
both theories view continuous learning from exceptions as a source for improving safety, and
place emphasize on structures, procedures, and rules. Distinguishing between the two, resilience
thinking also stresses the importance of human performance in dealing with continually changing
work practice and draws heavily on opportunities for learning from successes.
Although increasing resilience through IT support seems necessary, the introduction of

such measures may create new challenges. If multiple types of changes occur at the same time,
the cumulative effect may produce increased risks, and even lead to major failures, which is
referred to as "functional resonance" by Hallnagel. As for the AAA care process, the
consequences of this resonance may have a negative impact on the assessment of acceptable
patient dropout rates and aneurysm rupture rates. In addition, all active participants involved may
contribute to resilience. In view of the boundary definition of the AAA monitoring and treatment
process, the expected change may be caused by factors in the care process itself (endogenous) or
factors in the environment/background (exogenous). Since our research is somewhat of a
surgeon-centered view, we generally cannot exclude that other healthcare personnel (for example,
EVAR radiologists and patients' primary care physicians) also contribute to resilience and
functional risk. When customizing IT support, it is necessary to consider the interaction and
influence with the surrounding environment and participants, that is, to enhance the flexibility of
a given functional framework aimed at improving patient safety.All in all, IT-based process
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solutions should be designed to promote clinicians' resilience in adapting to changing care

processes. For cross-organizational AAA care, such systems should support risk reduction
decisions and prevent patients from leaving the monitoring cycle. Our case is a limited sample,
from a small part of the healthcare system. This limits the universality of our findings.
Nonetheless, our approach should provide important insights into the design of process support
systems in our case, and these systems may also have wider applicability.
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Chapter 9 Basic Skills of Vascular Surgery
Jing Yuchen
a. Principles in Microvascular Anastomosis and Free Tissue Transfer
i. Introduction:
Microvascular transplantation is a reconstruction technique based on extracting tissues

from healthy areas of the body where there is excess or dispensation, and then transplanting them
to other areas lacking them, mainly after trauma, tumor surgery or chronic infection. From a
strict point of view, microsurgical transfer means that a double-vessel anastomosis of less than 3
mm is performed between the blood vessel in the transferred tissue and the blood vessel in the
recipient area. Ultra-microsurgery refers to those cases where the diameter of the anastomosis is
between 0.3 and 0.8 mm. Strictly speaking, the recipient blood vessel is the blood vessel that
receives the blood flow, and the blood donor is the blood vessel that flows the blood flow. From
a historical point of view, the complex of transplanted tissue is called a free flap.
Since its inception, reconstruction technology aims to restore the integrity, form, and
function of the body. Although plastic surgery is a medical discipline that brings together all
these technologies, it lacks anatomical limitations; therefore, it has a wide range of knowledge
through different body parts such as maxillofacial surgery, ophthalmology, and hand surgery.
For centuries, its purpose has been to limit the potential damage to patients by narrowing
reconstruction options. In this respect, a reconstruction ladder is defined, in which the initial
closure of the wound, secondary treatment or skin grafting is at the lower stage of the ladder, and
the skin flap is at the higher stage.
With the improvement of optical tools, vascular anastomosis can be performed more
easily, allowing free flap transfer, and establishing a skilled team. As tissue transplantation
becomes more dynamic and the success rate of microsurgery increases, the benefits become
more and more obvious. Facts have proven that transferring healthy tissue to the hands or head
and neck allows surgeons to achieve faster and better recovery in areas with high functional
requirements, while achieving more aesthetic results and lower morbidity. The same is true for
breast surgery, which can achieve reconstruction with a natural shape and sufficient volume; the
scar is hidden in the distance and there is no need to use a prosthesis. In lower limb osteomyelitis,
free muscle flaps become an alternative to amputation. In addition, with the emergence of
perforator flaps, the fasciocutaneous flaps can be transferred without removing the underlying
muscles, thereby further reducing the incidence of these microsurgery operations. Finally, a
modification to the reconstruction ladder is proposed, which is dominated by the simplicity of
reconstruction but pursues the best aesthetic and functional effects. Therefore, a reconstruction
elevator was used instead. In this way, microsurgical reconstruction has become a first-line
choice for many patients, and the technology has expanded to multiple centers.
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ii. Case Study: A Simple and Rapid Vascular Anastomosis for Emergency Surgery
A 22-year-old, otherwise healthy, male presented following a single gunshot wound to

the left groin. On examination, the patient was hemodynamically stable, but had no palpable
lower extremity pulses on the injured side (dorsalis pedis or posterior tibial). The ankle-brachial
index confirmed an arterial injury (<0.9). On immediate exploration, a transacted superficial left
femoral artery was identified. Following debridement of the contused ends of the vessel, as well
as moderate mobilization, a primary repair was completed using the technique described. The
patient was discharged home on post-operative day 3 with normal extremity function.
(1) Technique Explanation
As with most vascular anastomoses, a synthetic, nonabsorbable monofilament suture on

an atraumatic needle (6-0 polypropylene) was employed. Basic principles of vascular repair were
followed. These included debridement of contused or lacerated vessel, proper orientation, and an
absence of tension on the anastomosis. We did not require an autologous graft (reversed
saphenous vein).
This technique of vascular anastomosis requires a double-armed polypropylene suture

placed in a continuous fashion with perpendicular bites located 1 mm from the vessel edge and 1
mm apart. The anastomosis begins at the position opposite the operator (3 or 9 o'clock depending
on the patient side) where the first 2 bites are placed from inside to outside the vessel using both
arms of the suture (Figure 9.1). After tying these 2 sutures ends together, one end is passed from
outside to inside on the posterior aspect of the vessel (adjacent to the first knot of the proximal
end) (Figure 9.2). The posterior suture line is typically completed first, followed by the anterior
side (Figure 9.3). Prior to completing the last few bites of the anterior row, the vessel is flushed
of debris and air using sequential distal and proximal clamp releases in the standard fashion.
After reapplication of the vascular clamps, the visible lumen is flushed with heparinized saline,
and the last few bites of the anterior row are completed (Figure 9.4). To eliminate air from the
system, the distal vascular clamp is removed before the final knot is tied at the 3 or 9 o'clock
position. Restoration of pulses at the wrist after end-to-end anastomosis of the subclavian,
axillary, or brachial artery is considered excellent evidence of a satisfactory repair in the upper
extremity. With end-to-end anastomosis of the iliac, popliteal, or tibia artery after trauma,
completion arteriography is preferred to differentiate the presence of vascular spasm from distal
in situ thrombosis or distal embolization into the popliteal or shank arteries.
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Figure 9.1 Vascular Anastomosis Beginning at the Position Opposite the Operator.
Figure 9.2 Completed Posterior Wall Suture Line.
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Figure 9.3 Flushing the Vessel with Heparinized Saline.
Figure 9.4 Completed Anastomosis with Knot on Operator’s Side.Source: Loftus, I., & Hinchliffe, R. J.
(2019). Vascular and endovascular surgery.
Although techniques of vascular anastomosis after trauma are numerous in type and form,
most surgeons will default to the one associated with the greatest comfort and ease. This report
offers a rapid and reliable repair using a conceptually and operationally simple technique. Its
methodology is appropriate for all repairs, including cases mandating the insertion of vascular
conduit. We have employed this technique for the past 15 years in nearly all patients with
vascular injuries, regardless of the site and size of the vessel. This has included vessels of the
neck, torso, upper and lower extremities. There have been no obvious complications associated
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with its use. Major advantages include: (1) the operating system is always oriented towards the
surgeon, (2) the posterior row of sutures is placed as both ends are readily visualized, avoiding
the need for potentially obscuring traction stitches, and (3) flushing is easily performed prior to
completing the anterior suture row.
b. Thrombectomy
i. Introduction of Thrombectomy and its Correlative Trial Study:
Until recently, the treatment for acute ischemic stroke (AIS) had focused on intravenous
thrombolytic administration. In 2013, the publication of the Interventional Management of
Stroke (IMS III), Synthesis Expansion,“A Randomized Controlled Trial on Intra-Arterial Versus
Intravenous Thrombolysis in Acute Ischemic Stroke (SYNTHESIS Expansion)”, and
“Mechanical Retrieval and Recanalization of Stroke Clots Using Embolectomy trials” reported
no significant differences in functional outcome with endovascular therapy compared to standard
therapy (i.e., intravenous tissue plasminogen activator or tissue-type plasminogen activator [tPA])
alone. As a result, the 2013 American Heart Association (AHA)/American Stroke Association
guidelines for the early management of patients with acute ischemic stroke advised that the
“ability to improve patient outcomes has not yet been established” for thrombectomy devices.
However, severe methodological flaws in these studies resulted in a design bias against
endovascular therapy. In IMS III, 20% of patients randomized to receive endovascular treatment
had no large-vessel occlusion. Furthermore, the thrombectomy devices used in the studies were
antiquated and associated with unreliable recanalization rates. In SYNTHESIS Expansion, only
13% of patients underwent thrombectomy with a retrievable stent, which is a device that has
been shown to result in recanalization rates up to 3 times greater than earlier devices.
Previous randomized trials that involved patients with acute stroke1-6 showed that
endovascular thrombectomy had a clinical benefit when it was performed within 6 hours after the
onset of stroke symptoms and that the benefit diminished as the interval between the time that
the patient was last known to be well and thrombectomy increased. For the purposes of
determining eligibility for thrombolysis or thrombectomy, the time that the patient was last
known to be well has typically been the time of stroke onset, including among patients who wake
up with stroke symptoms or have an uncertain time of stroke onset. There is limited information
on the effect of thrombectomy that is performed more than 6 hours after the time that the patient
was last known to be well, particularly among patients with ischemic brain tissue that has not yet
undergone infarction and may be salvaged with reperfusion. Patients with brain tissue that may
be salvaged with reperfusion can be identified by the presence of a clinical deficit that is
disproportionately severe relative to the volume of infarcted tissue on imaging studies.
Results of previous nonrandomized studies have suggested that patients who have a
mismatch between the volume of brain tissue that may be salvaged, and the volume of infarcted
tissue could benefit from reperfusion of occluded proximal anterior cerebral vessels, even when
the reperfusion is performed more than 6 hours after the patient was last known to be well.
According to the trial data, we compared endovascular thrombectomy plus standard medical care
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with standard medical care alone for the treatment of patients with acute stroke who had last
been known to be well 6 to 24 hours earlier and who had a mismatch between clinical deficit and
infarct.
ii. Methods:
(1) Trial Design:
The HAWN trial was a multicenter, prospective, randomized, open-label trial with a
Bayesian adaptive–enrichment design and with blinded assessment of end points. The trial
protocol was approved by the institutional review board at each participating site. Enrolled
patients or their surrogates provided written informed consent. The trial was designed and
conducted by a steering committee, which was composed of independent academic investigators
and statisticians, in collaboration with the sponsor, and provided funding and the thrombectomy
devices for the trial and performed regulatory monitoring at each site and central database
maintenance.
Patients were eligible for inclusion in the trial if they had evidence of occlusion of the
intracranial internal carotid artery, the first segment of the middle cerebral artery, or both on
computed tomographic (CT) angiography or magnetic resonance angiography. In addition,
patients had to have a mismatch between the severity of the clinical deficit and the infarct
volume, which was defined according to the following criteria: those in Group A were 80 years
of age or older, had a score of 10 or higher on the National Institutes of Health Stroke Scale
(NIHSS; scores range from 0 to 42, with higher scores indicating a more severe deficit), and had
an infarct volume of less than 21 ml; those in Group B were younger than 80 years of age, had a
score of 10 or higher on the NIHSS, and had an infarct volume of less than 31 ml; and those in
Group C were younger than 80 years of age, had a score of 20 or higher on the NIHSS, and had
an infarct volume of 31 to less than 51 ml. Infarct volume was assessed with the use of diffusion-
weighted magnetic resonance imaging (MRI) or perfusion CT and was measured with the use of
automated software.
Other inclusion criteria were an age of 18 years or older, an interval between the time that
the patient was last known to be well and randomization of 6 to 24 hours, a pre-stroke score of 0
or 1 on the modified ranking scale (which ranges from 0 to 6, with a score of 0 indicating no
disability and higher scores indicating more severe disability), no evidence of intracranial
hemorrhage on CT or MRI, and no evidence of an infarct involving more than one third of the
territory of the middle cerebral artery on CT or MRI at baseline. Patients either did not meet the
usual criteria for treatment with intravenous alteplase because of a late presentation or received
treatment with intravenous alteplase and had persistent occlusion of the vessel at the time that
they were eligible for enrollment in the trial.
(2) Treatment
Patients were randomly assigned, in a 1:1 ratio, to thrombectomy plus standard medical
care (the thrombectomy group) or to standard medical care alone (the control group).
Randomization was performed with the use of a central, Web-based procedure, with block
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minimization processes to balance the two treatment groups and was stratified according to
mismatch criteria (Group A, Group B, or Group C), the interval between the time that the patient
was last known to be well and randomization (6 to 12 hours or >12 to 24 hours), and the
occlusion site (intracranial internal carotid artery or the first segment of the middle cerebral
artery).
The data of the trial was collected from 26 hospitals and at least 40 mechanical
thrombectomy procedures had been performed at each center annually. Enrolled patients were
admitted to stroke units or intensive care units. Patients who had not received intravenous
alteplase could receive therapy with antiplatelet agents, which could be started within 24 hours
after randomization. Standard medical care was provided in accordance with local guidelines.
Thrombectomy was performed with the use of the digital access catheter(a retrievable self-
expanding stent that is used to remove occlusive thrombi and restore blood flow). Rescue
reperfusion therapy with other devices or pharmacologic agents was not permitted. Concomitant
stenting of the cervical internal carotid artery at the time of thrombectomy was not permitted, but
carotid angioplasty was permitted if necessary to allow for intracranial access for the catheter to
deploy the retriever device.
(3) Endpoints, Statistical Analysis, Results and Efficacy Outcomes
For the coprimary end points, scores on the modified Rankin scale were obtained through
in-person, formal, structured interviews with patients and caregivers that were performed by
local certified assessors who were unaware of the treatment assignments. For the 43 patients for
whom in- person assessment was not possible, telephone interviews with patients, caregivers, or
both were performed.
The adaptive trial design allowed for a sample size ranging from 150 to 500 patients.
During interim analyses, the decision to stop or continue enrollment was based on a prespecified
calculation of the probability that thrombectomy plus standard care would be superior to
standard care alone with respect to the first primary end point. The enrichment trial design gave
us the flexibility to identify whether the benefit of the trial intervention was restricted to a
subgroup of patients with relatively small infarct volumes at baseline. The interim analyses,
which included patients with available follow- up data at the time of the analysis, were
prespecified to test for the futility, enrichment, and success of the trial.
Enrollment in the trial was stopped at 31 months, because the results of an interim
analysis met the prespecified criterion for trial discontinuation, which was a predictive
probability of superiority of thrombectomy of at least 95% for the first primary end point. This
was the first prespecified interim analysis that permitted stopping for this reason, and it was
based on the enrollment of 200 patients. Because enrichment thresholds had not been crossed,
the analysis included the full population of patients enrolled in the trial, regardless of infarct
volume.
Among the patients who underwent thrombectomy, immediate reperfusion was achieved
in 84% according to results of central laboratory assessments and in 82% according to results of
evaluations by local interventionists; the median interval between the time the patient was last
129
known to be well, and reperfusion was 13.6 hours (interquartile range, 11.3 to 18.0).
Recanalization was achieved at 24 hours in 77% of the patients in the thrombectomy group and
in 36% of the patients in the control group. For all the secondary end points, the comparisons
between the two treatment groups favored thrombectomy. In prespecified subgroup analyses, no
evidence of heterogeneity of treatment effect was detected; the relatively small sample size
limited the power of some of these analyses.
The rates of safety end points and serious adverse events — including stroke-related
death at 90 days, death from any cause at 90 days, and symptomatic intracerebral hemorrhage —
did not differ significantly between the two treatment groups (Table 3, and Table S2 in the
Supplementary Appendix). The rate of neurologic deterioration was lower in the thrombectomy
group than in the control group (14% vs. 26%; absolute difference, −12 percentage points; 95%
confidence interval, −23 to −1; P= 0.04)28.
(4) Discussion:
The trial showed that, among patients with stroke due to occlusion of the intracranial
internal carotid artery or proximal middle cerebral artery who had last been known to be well 6
to 24 hours earlier and who had a mismatch between the severity of the clinical deficit and the
infarct volume, outcomes for disability and functional independence at 90 days were better with
thrombectomy plus standard medical care than with standard medical care alone. For every 2
patients who underwent thrombectomy, 1 additional patient had a better score for disability at 90
days (as compared with the results in the control group); for every 2.8 patients who underwent
thrombectomy, 1 additional patient had functional independence at 90 days. The benefit of
thrombectomy was consistent across prespecified subgroups that were defined according to age,
stroke severity, occlusion site, time to treatment, and type of stroke onset, but the power of the
trial to assess differences between subgroups was limited.
Endovascular thrombectomy in patients with stroke is usually performed within 6 hours

after the onset of stroke. However, the rate of functional independence in the thrombectomy
group in our trial, in which patients received treatment 6 to 24 hours after stroke onset, was
similar to the rate reported in a pooled analysis of five trials of thrombectomy, in which patients
predominantly received treatment within 6 hours after stroke onset (49% and 46%,
respectively).7 In contrast, the rate of functional independence in the control group in our trial
was lower than the rate in the control group in the pooled analysis (13% vs. 26%). It is possible
that the worse outcomes in our control group were related to the lower rate of treatment with
intravenous alteplase (14% in our trial vs. 88% in the pooled analysis); patients were enrolled in
our trial after the accepted window of time in which intravenous thrombolytic therapy is
typically administered. An additional possible determinant of the worse outcomes in our control
group was a higher percentage of patients with adverse prognostic features, particularly an age of
28
For more detailed data information and scientific investigation of the trial, please see: Lindsay, E. (2018).
Thrombectomy 6 to 24 Hours after Stroke with a Mismatch between Deficit and Infarct. The Journal of
Emergency Medicine, 54(4), 583–584. https://doi.org/10.1016/j.jemermed.2018.02.029
130
80 years or older and an NIHSS29 score after stroke of 10 or higher. The rates of functional
independence that were observed in our control group are similar to those reported in prospective
observational studies that included older patients with occlusion of a proximal large vessel who
had a severe deficit and did not receive treatment with intravenous alteplase or thrombectomy.
Other recent randomized trials of thrombectomy have used enrollment criteria that are similar to
those used in our trial.
There were significant differences between the two groups in other baseline variables. In
post hoc sensitivity analyses that adjusted for these differences, the benefit of thrombectomy
remained.We also found that, among patients with acute stroke who have a mismatch between
the severity of the clinical deficit and the infarct volume, the safety profile for thrombectomy
performed 6 to 24 hours after the onset of stroke was similar to a previously observed safety
profile for thrombectomy performed within 6 hours after the onset of stroke; the rates of death
and symptomatic intracerebral hemorrhage did not differ significantly from the rates seen with
standard medical care. Because our trial restricted enrollment to patients with infarcts of a small
or medium volume, our findings may be concordant with previous reports that the extent of
tissue injury is a determinant of the risk of symptomatic intracerebral hemorrhage after
reperfusion therapy.
Based on retrospective studies, approximately one third of the patients with occlusion of
a proximal anterior cerebral vessel who present within 6 to 24 hours after the onset of stroke may
meet the imaging-based eligibility criteria that were used in this trial. Further studies are needed
to establish the prevalence of patients who would be eligible for thrombectomy among the entire
population of patients with ischemic stroke. Further studies are also needed to determine whether
late thrombectomy has a benefit when more widely available imaging techniques are used to
estimate the infarct volume at presentation, such as assessment of the extent of hypodensity on
non–contrast-enhanced CT.
(5) Conclusion:
In conclusion, we found that outcomes for disability were better with thrombectomy plus
standard medical care than with standard medical care alone among patients with acute stroke
who received treatment 6 to 24 hours after they had last been known to be well and who had a
mismatch between the severity of the clinical deficit and the infarct volume, which was assessed
with the use of diffusion-weighted MRI or perfusion CT and measured with the use of automated
software.
e. Endarterectomy
i. Introduction of Carotid Endarterectomy for Carotid Stenosis:
29
The score for each ability is a number between 0 and 4, 0 being normal functioning and 4 being completely
impaired. The patient’s NIHSS score is calculated by adding the number for each element of the scale; 42 is the
highest score possible. In the NIHSS, the higher the score, the more impaired a stroke patient is.
131
Stroke is the second leading cause of death worldwide. It is the most common cause of
death because of a neurological disorder. About 750,000 patients are diagnosed with this entity
yearly in the United States and more than 15 million around the globe, which corresponds to an
incidence of new stroke of approximately 160 per 100,000 population per year. The aim of
carotid endarterectomy is to reduce the risk of stroke and death in patients with carotid artery
disease. The benefit to society of surgeons undertaking this operation lies in the balance between
the risks of the natural history of the carotid disease and the risks of the surgical treatment.
Carotid endarterectomy is probably the vascular surgical procedure with the most scientific
evidence in its favor.
The natural history of carotid disease is quite different for patients with symptomatic and
asymptomatic carotid arterial stenoses. Symptomatic stenoses include those causing transient
ischemic attack and amaurosis fugax. Also included are patients who have had a previous
completed stroke. Asymptomatic patients may have a significant carotid stenosis found
incidentally, they may have a moderate stenosis that progresses on duplex follow-up, or finally
they may have a stenosis identified as part of a routine preoperative work-up before major
surgery such as coronary artery bypass grafting.
Patients with no significant carotid disease have a less than 2% chance of perioperative
stroke during and after coronary artery bypass, whereas patients with a unilateral occlusion have
an approximately 10% chance. However, only 40% of these strokes occur within 24 hours of
surgery and are thus likely to be preventable.
ii. Diagnostic Procedures of Carotid Stenosis:
Brain imaging with CT or MRI should be obtained in patients considered for Carotid
Endarterectomy (CEA)in order todocument infarction and rule out mass lesions. Carotid
investigation begins with ultrasoundand, if results agree with subsequent, good-quality MRA or
CT angiography (Figure 9.5),treatment can be planned, and catheter angiography avoided. An
equally acceptable approachis to proceed directly from ultrasound to catheter angiography,
which is still the gold-standard in carotid artery assessment. CEA should be considered for any
patient with carotid artery stenosis in whom surgery willimprove the natural history of the
disease to a greater degree than the corresponding medicaltreatment would.
In symptomatic good-risk patients with surgical morbidity and mortality (stroke and
death) ofless than 6%, proven indications for CEA include the following:
• One or more transient ischemic attacks (TIAs) in the preceding 6 months and carotid
artery stenosis exceeding 50%.
132
Figure 9.5 :Indication of Carotid StenosisSource: Loftus, I., & Hinchliffe, R. J. (2019). Vascular and
endovascular surgery.
In asymptomatic good-risk patients treated by surgeons with surgical mortality and

morbidityof less than 3%, the proven indication for CEA is stenosis exceeding 60%. The 2014
American Heart Association (AHA)/American Stroke Association (ASA)guidelines for the
prevention of stroke in patients with stroke or TIA contained the followingnew or updated
recommendations relevant to CEA:
• Carotid angioplasty and stenting (CAS) is indicated as an alternative to CEA

forsymptomatic patients at average or low risk for complications associated
withendovascular intervention when the diameter of the lumen of the internal carotid
arteryis reduced by >70% by noninvasive imaging or >50% by catheter-based imaging
ornoninvasive imaging with corroboration and the anticipated rate of
periproceduralstroke or death is <6% (class IIa; evidence level B)
• It is reasonable to consider patient age in choosing between CAS and CEA; forpatients
older than about 70 years, CEA may be associated with improved outcomeCAS,
particularly when the arterial anatomy does not favor endovascular intervention.For
younger patients, CAS is equivalent to CEA in terms of risk for
periproceduralcomplications and long-term risk for ipsilateral stroke (class IIa; evidence
level B)
133
• CAS and CEA in the above settings should be performed by operators with
establishedperiprocedural stroke and mortality rates of <6% for symptomatic patients
(class I;evidence level B)
• Routine, long term follow-up imaging of the extracranial carotid circulation withcarotid
duplex ultrasonography is not recommended (class III; evidence level B)
CEA is contraindicated if the patient’s general condition includes a serious illness that
willsubstantially increase perioperative risk or shorten life expectancy. It is also contraindicated
in patients who present acutely with a major stroke or in patients who experienced a
majordevastating stroke with minimal recovery or a significantly altered level of
consciousness.In a study of perioperative and long-term outcomes after CEA in hemodialysis
patients,Doctor Cooper found that the risks of CEA in asymptomatic dialysis-dependent patients
werehigh, possibly outweighing the benefits. They also found the risk to be high in
symptomaticpatients and suggested that it should be offered only to a small and carefully
selected cohortof these patients.
iii. Operative Techniques:
Carotid endarterectomy (Figure 9.6) can be performed with either regional or

generalAnesthesia. There are several monitoring techniques available to assesscerebral perfusion
during carotid cross-clamping. While monitoring cannot be consideredmandatory and no single
monitoring technique has emerged as being clearly superior, EEG isused the most. "Eversion"
endarterectomy is a variation in surgical technique, andthere is some evidence that more widely
practiced patch closure may reduce the acute risk ofoperative stroke and the longer-term risk of
recurrent stenosis.
An incision is made on the midline side of the sternocleidomastoid muscle. The incision
isbetween 5 and 10 cm in length. The internal, common, and external carotid arteries arecarefully
identified, controlled with vessel loops, and clamped. The lumen of the internalcarotid artery is
opened, and the atheromatous plaque substance removed. The artery is closedusing suture and a
patch to increase the size of the lumen. Hemostasis is achieved, and the overlying layers closed
with suture. The skin can be closed with suture which may be visibleor invisible (absorbable).
Many surgeons place a temporary shunt to ensure blood supply tothe brain during the procedure.
Once endarterectomy is performed, the surgeon is confronted with the choice of primary
closure of the carotid artery or the use of a patch material. The traditional approach is to
patchpatients believed to be at high risk of recurrence, such as women and those with small
carotidarteries. The different materials available for patching include autologous vein graft,
Dacron, ePTFE,and bovine pericardium. Surgeons may have their preference based on the
malleability orother characteristics of the material. Hence, there is not any particular type of
patch material is better than the other. A possible disadvantage ofvein patch is patch disruption,
and that of prosthetic material is infection.
134
Figure 9.6 Carotid Endarterectomy, Source: Loftus, I., & Hinchliffe, R. J. (2019). Vascular and endovascular
surgery.
Experience with this endovascular and less invasive procedure grows, and its
technologycontinues to evolve. Some experienced therapists have reported excellent results in
case seriesand several randomized trials are now underway comparing CAS to CEA. CAS is
cheaper, reduces hospital stay, avoids surgical complications and is more comfortable and
tolerable for patients.However, currently it is premature to incorporate CAS into routinepractice
replacing CEA.
For patients to benefit from revascularization, the surgeon's complication rate (30-day
strokeand death) must remain ≤ 3% for asymptomatic and ≤ 6% of symptomatic patients. Other
surgical complications include hemorrhage of the wound bed, which is potentiallylifethreatening,
as swelling of the neck due to hematoma could compress the trachea. Rarely,the hypoglossal
nerve can be damaged during surgery. This is likely to resultin fasciculations developing on the
tongue and paralysis of the affected side: on sticking it out,the patient's tongue will deviate
135
toward the affected side. Another rare but potentially seriouscomplication is hyper-perfusion
syndrome because of the sudden increase in perfusion of thevasculature distal to stenosis.
iv. Conclusions:
Contemporary literature argues that neurologically unstable patients, presenting repetitive

transient ischemic attacks or progressing stroke, should be managed by urgent (within 24 to 72
hours) carotid endarterectomy, even if the peri-operative stroke-death rate is slightly higher than
in the elective setting. Despite an inherent increased operative morbidity-mortality, urgent
carotid endarterectomy seems to us justified by the fact that waiting for the surgery may lead to
the development of a more profound stroke in these neurologically unstable patients. Their only
chance for neurological recovery (partial or complete) is in the early phase (12 to 60 hours after
the acute onset of the neurological syndrome of crescendo-TIAs or stroke-in-evolution). For
patients presenting a minor stroke, with limited brain infarction, carotid endarterectomy should
preferentially be done in a semi-urgent fashion, within two weeks.
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Chapter 10 Endovascular Intervention Technique
Li Xi, M.D.
a. Introduction :
Endovascular aneurysm repair was first described by Voldos and colleagues in 1986 and
Parodi and colleagues in 1991.The premise of EVAR is to exclude the aneurysm from the
systemic circulation using a preoperatively sized stent graft; this prevents further expansion and
risk of rupture. This minimally invasive technique has resulted in a paradigm shift in the
treatment of infrarenal Abdominal Aortic Aneurysm(AAA). Between 2000 and 2010, the use of
EVAR increased from 5% to 74% of all AAA repairs in the USA.
In contrast to open aneurysm repair, suitability for EVAR depends on both aneurysm
morphology and patient fitness. It is reported that up to 45% of patients
willhaveanAAAthatismorphologicallyunsuitable for conventional infrarenal internal
transplantation. Morphological variables that impact on suitability include length of infrarenal
aortic (>10mm), neck angulation (<60o), neck diameter (<30 mm), smooth parallel neck without
significant mural thrombus. In addition, the iliac arteries should be of a caliber wide and straight
enough to deliver a stent graft. As endografts evolve, the capability to treat more challenging
anatomy may expand (Figure 10.1).
Figure 10.1 Schematic Representation of Abdominal Acortic Aneurysm Repair Using an Acortic Stent
Graft, Courtesy of Medtronic Medical.
138
In general, there are four graft constructs for EVAR of infrarenal AAAs: straight aorto-
aortic tube endografts, bifurcated systems, aorto-monoiliacsystems and combined bifurcated
grafts with iliac branch grafts to permit perfusion and sealing in the external and iliac arteries.
All devices form their proximal seal in the infrarenal aortic neck with variation in the distal seal
zone – aorta, common iliac, external iliac or both external and internal iliac arteries. Aorto-aortic
stent grafts were the first described and have a very limited application in contemporary practice
in short localized saccular aneurysms, postoperative pseudoaneurysm and penetrating aortic
ulcers. In conventional AAA, aorto-aortic endografts have an unacceptably high incidence of
failure due to aneurysmal change in the seal zone.
Bifurcated grafts offer the most desirable solution by securing seal in vascular segments
unlikely to be affected by aneurysmal change and preserving normal anatomical flow. These
devices are suitable for around 50% of patients. The remainder of EVAR-eligible aneurysms
with more challenging anatomy require either an aorto-monoiliac or iliac branched stent graft.
The former may be indicated where there are problems of unilateral iliac access due to tortuosity
or stenoses and require occlusion of the contralateral common iliac artery with a plug and
revascularization of the limb with a femoral cross-over graft. Iliac-branched grafts may be
indicated in aneurysms that extend into the common iliac arteries and permit preservation of
blood flow into the internal iliac arteries using a bifurcated iliac component.
b. Patient assessment and EVAR technique
The patient should be formally assessed, discussed within a multidisciplinary team, and
counselled for EVAR as for conventional open surgery. Multidetector CT aortography should be
obtained to enable multiplanar reconstruction and sizing of the entire abdominal aorta and
iliofemoral segments and provide information regarding arterial access. Informed consent should
include the routine morbidity and the known EVAR-specific complications, including death,
reintervention, nephropathy, arterial injury, internal leak, and open surgical conversion. Ideally,
the theatre should be capable of endovascular and open procedures and equipped with fixed
imaging capability. Mobile C-arm equipment may be utilized if necessary but affords poorer
imaging capability and greater radiation dose exposure.
After anesthetic induction the patient is positioned, prepped, and draped. A surgical cut-
down to the femoral arteries permits catheterization of the arterial circulation. A total
percutaneous approach facilitated by the use of femoral closure devices may be performed
instead. Evidence to justify this approach is emerging with claims of non-inferiority compared to
surgical cut-down. After femoral access is achieved, a soft wire and catheter are placed into the
ascending aorta and a stiff guidewire is introduced through the catheter. Stiff guidewires are not
intended to be ‘working’ wires and it is not sensible to try to negotiate tortuous iliac vessels with
them. After systemic heparinization, the stent graft body is introduced over the stiff guidewire
and the renal arteries are imaged through a diagnostic catheter from the contralateral side. The
image intensifier should be angled to optimize the view of the renal arteries, and this typically
requires a small amount of cranio-caudal and oblique tilt.
The diagnostic catheter is left alongside the graft body as the top stents are released in
stages. Further angiographic runs may be performed to ensure accurate positioning relative to the
139
renal arteries. Modular devices require cannulation of the short leg of the main body of the
device prior to introduction of the contralateral limb. This is generally performed by a retrograde
approach from the contralateral femoral artery using angled catheters. Confirmation of successful
cannulation is needed to avoid the error of inadvertently deploying the contralateral limb
alongside rather than within the main graft. The iliac limbs are deployed close to the internal
iliac origins, which are defined using oblique projections. Substantial overlap at the modular
connections is essential to avoid late disconnections. Balloon forming with a compliant aortic
balloon can then be performed to optimize proximal and distal seal zones and junctions of the
modular graft components.
Completion angiography is performed to confirm the aneurysm has been excluded and to
ensure that here has been no encroachment by the fabric of the graft on the orifices of the
visceral or internal iliac arteries (Figure 10.2). Every effort must be made to resolve any
significant primary type I internal leak before completion of the procedure.
Figure 10.2. Completion angiogram of right iliac branched endovascular aneurysm repair showing satisfactory
exclusion of aorto-liac aneurysm and freedom from internal leaks.
140
c. EVAR-related complications and device failure
The physiological advantages of EVAR are reflected by the reduced requirement of

postoperative critical care support and incidence of significant cardiac, pulmonary, and renal
complications. However, in addition to the general causes of postoperative morbidity following
AAA repair, EVAR carries some procedure-specific complications.
i. Internal Leak (also called Endoleak)
Internal Leak is defined as the persistence of blood flow outside the lumen of an
endovascular stent graft but within an aneurysm sac or the adjacent vascular segment being
treated by the stent. The leak may be described as primary, originating at the time of EVAR, or
secondary, referring to a leak not seen at completion angiography but demonstrated on
subsequent surveillance imaging. Internal leak has been classified according to the source of
aberrant blood flow, since this characterizes the Internal leak and the potential for aneurysm
enlargement and eventual rupture (Table 10.1).This is most often seen in type I (Figure 10.3a)
and type III (Figure 10.3c) leaks that communicate directly with the aortic lumen, and
reintervention is almost always necessary in these patients.
Endoleak Type Source

I A: Proximal Graft attachment site
B: Distal
C: lilac occluder
II A: Simple (single vessel) Collateral Vessel
B: Complex (more than 2

vessels)
III A: Junctional Leak Graft failure
B: Mid-graft hole
C: Other (e.g. suture hole)

IV Graft wall porosity
V A: Without endoleak
B: With sealed endoleak Endotension
C: With type I or III leak
D: With type II leak
Table 10.1Internal Leak Classification
141
Type II internal leaks (Figure10.3b) denote continued blood flow into the aneurysmal sac
from refilling collateral vessels, typically the lumbar and inferior mesenteric arteries. The clinical
significance of type II internal leaks is contentious and there is no standard treatment protocol.
Increasingly, they are considered self-limiting, and an expectant course of management is
recommended. There is some evidence that they are associated with an increased risk of
reintervention, but not aneurysm rupture or survival. At the very least, they should be kept under
surveillance for signs of aneurysm sac enlargement.
Blood flow across intact graft fabric within 30 days of EVAR defines the type IV
endoleak (Figure 10.3d). These leaks typically seal spontaneously and may be seen more
frequently with thinner and more porous stent grafts. Type V endoleaks are not true leaks but are
defined as aneurysm sac expansion of >5 mm in the absence of a radiologically identifiable
endoleak. They are due to a phenomenon of internal pressure caused by the accumulation of a
transudate due to ultrafiltration of blood across the stent graft material.
a a
a b
142
a a
c d
Figure 10.3. Images showing type I–IV internal leaks post-EVAR. (a) Completion angiogram showing a type I
internal leak (proximal seal failure). (b) Post-EVAR contrast-enhanced CT scan showing a type II internal leak. (c)
Delayed angiogram showing a type IIIinternal leak (junctional graft failure). (d) Completion angiogram showing a
type IVinternal leak (graft porosity).
ii. Graft migration and dislocation
Successful EVAR depends on the generation of a blood-tight seal between stent graft and
healthy native vessel for AAA exclusion. Failure at any attachment site renders the endograft
insecure and prone to abnormal movement (migration) that is facilitated by systemic arterial
blood pressure. Significant device migration at the seal zones predisposes the patient to endoleak
(type I), whereas unwanted mobility of modular systems may lead to component dislocation and
potential type III endoleak.
Device migration most likely results from the combined effect of patient and device
related factors with a proximal attachment site failure most often described. In view of the
significant risk of type I internal leak associated with distal migration of the proximal stent,
remedial intervention is almost always indicated. This can usually be achieved with aortic cuff
deployment to repair the proximal seal, but occasionally stent revision is required.
iii. Kinking and occlusion
Any distortion (kinking) of the endograft used in EVAR may result in stent stenosis,
thrombosis and ultimately device (or limb) occlusion (Figure 10.4). In a review of 4613 EVAR
cases submitted to the EUROSTAR registry over an 8-year period, postoperative graft kinking
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was described in 3.7% cases.Patent, symptomatic kinked stents can usually by treated by balloon
angioplasty and adjunctive stenting, whereas occluded limbs typically require surgery.
a b
Figure 10.4. Post-EVAR imaging showing graft kinking and occlusion in the same patient. (a) Plain film
showing left iliac limb kinking. (b) Contrast-enhancing CT scan showing consequent intraluminal occlusion.
iv. Other EVAR-related complications
Wire and stent manipulation within the aorta and aneurysmal sac during positioning and
device deployment carries the risk of atheroembolization with potential for organ infarcts and
limb ischemia. Introduction of guidewires, large-bore catheters and the endograft itself risks
vessel injury such as rupture or dissection. Delayed presentations or iatrogenic arterial injury
may occur, with pseudoaneurysm formation requiring prompt repair.
d. Surveillance after EVAR
The modes of failure after aortic stent grafting are well documented. It is mandatory that
all patients be recruited onto a program of systematic postoperative surveillance with the aim of
detecting causes of late rupture. The principal concerns are internal leak, aneurysm enlargement
and migration of stents at the aortic or iliac landing zones or at the modular connections. Options
for the method of surveillance include duplex ultrasound, CT, magnetic resonance imaging (MRI)
and plain radiography.
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It has been shown that ultrasound can be used to detect graft-related (type I) internal
leaks reliably. Ultrasound is less effective for the detection of type II internal leaks, but since it is
known that type II internal leaks without increased sac diameter are not associated with a
significant risk of adverse clinical events, this may be regarded as an acceptable limitation. Plain
radiography using a standardized protocol is an effective method for the detection of device
migration. Stent fractures and separation of modular components are also relatively easy to
identify. It is comparatively inexpensive and usefully complements ultrasound scanning. Used in
combination these two methods represent an acceptable alternative to CT for surveillance.
It is generally accepted that surveillance after EVAR should be lifelong. The surveillance
intervals vary but typically include baseline imaging with CT and plain radiography at 1 month
after EVAR. Most protocols include more frequent surveillance intervals during the first 2 years,
with annual surveillance thereafter.
e. Outcomes after the patient received EVAR
There is now a good evidence base from randomized controlled trials in the UK, USA,
Netherlands, and France to support the use of EVAR in the normal infrarenal AAA population.
The UK EVAR-1 trial enrolled 1082 patients with suitable aneurysms (mean diameter 65mm)
that were considered fit enough for elective open AAA surgery and randomized them to either
EVAR or conventional open repair (OR). Early outcome analysis revealed significantly lower
30-day mortality for the EVAR group (1.7%) compared to open surgical controls (4.7%).
Medium-term study follow-up reported EVAR to be as effective as surgery in protecting from
late aneurysm-related death, although there was a significantly higher rate of graft-related
complications following EVAR (35% vs 8%). In a smaller but similarly designed study, the
Dutch DREAM trial compared outcome following EVAR and OR in 345 fit patients. A
significantly lower operative mortality rate post EVAR was confirmed (1.2 % vs 4.6%) with
reduced incidence of early severe postoperative complications. At 2-year follow-up, however,
there was no observed survival advantage after EVAR or OR.
The UK EVAR-1 trial demonstrated a clear short- term benefit for EVAR compared with
open surgery. Furthermore, EVAR was found to be associated with a shorter hospital stay.
However, this survival advantage is eroded over follow-up. By 4-year follow-up, there are no
differences in all-cause mortality between patients who had EVAR or open aneurysm repair. The
latest 15-year results of the EVAR-1 trial have generated further debate; beyond 8 years follow-
up, open-repair has a significantly lower all-cause mortality with an increased aneurysm and
cancer mortality amongst EVAR patients. Potential explanations for this finding include poor
compliance with EVAR surveillance protocols during the trial follow-up and whether internal
leaks in the trial were managed to the level of contemporary standards.
The latest 15-year results of the EVAR-1 trial show that compared with EVAR, open
repair is associated with long-term survival benefits. After 8 years of follow-up, the total
mortality and aneurysm-related mortality of the EVAR group were significantly higher than
those of the OR group (adjusted HR 1.25, 95% CI 1.00-1.56, total mortality P=0.048: and 5.82,
1.64 -20.65, P = 0.0064 for aneurysm-related mortality). After the first 6 months, the increased
aneurysm-related deaths in the EVAR group were mainly due to secondary sac rupture (13
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deaths in EVAR [7%] and 2 deaths in OR [1%]). Re-intervention occurred in both groups during
the follow-up period, including patients who were exempt from re-intervention after 2 or even 5
years. At all follow-up time points, the re-intervention rate was higher in the EVAR group. An
increase in cancer mortality was also observed in the EVAR group.
The UK EVAR-2 trial randomized 338 medically unfit patients who were anatomical
candidates for endovascular AAA repair (>55 mm) to either EVAR or 'best medical therapy'
(BMT). The early mortality in the EVAR limb was 9% and at a mean follow-up of 3.3 years
there was no difference in the all-cause aneurysm-related mortality between the groups. Many
clinicians have adopted these findings as justification not to offer EVAR in the higher-risk
population. Caution is advised against this approach to management as closer scrutiny of the
EVAR-2 results reveals some complicating issues. Firstly, there appeared to be an unacceptable
delay from randomization to treatment in the EVAR limb, so that nearly half (9 of 20) of the
aneurysm-related mortality was explained by rupture prior to planned AAA repair. Operative
(EVAR) mortality was surprisingly high (9%) and the rupture rate in the medically treated group
(9 per 100 person-years) was significantly lower than expected, raising concern about dis parate
medical management between the two groups. Clearly, though, EVAR-2 demonstrates the poor
long-term prognosis of the unfit AAA patient irrespective of treatment, with only 62–66% alive
at4 years.
The long-term follow-up of the EVAR-2 trialshows that after 8 years EVAR is associated
with much improved aneurysm-related survival (86% at 6 years vs 64% for no intervention),
although no clear difference in all-cause survival was observed (30% at 6 years vs 26%) . The
ability of EVAR to reduce aneurysm rupture (and aneurysm-related mortality) but not to improve
survival is the sting in the tail for EVAR. However, after 8 years less than 20% of the patients
remained alive, so that the long- term outcome for these patients might carry less weight than for
those enrolled in the EVAR trial 1.
Renal failure after EVAR is associated with an increased rate of mortality and its etiology
is probably multifactorial. Implicated factors include radiological contrast-associatednephropathy,
renal artery trauma, stent-induced stenosis and aortic neck thromboembolism following vessel
instrumentation and manipulation. It is rare for the renal ostia to be inadvertently covered by
graft fabric, and careful planning and deployment decrease the risk of this occurring. There was
concern that the introduction of suprarenal bare- stent fixation would lead to increased rates of
renal failure, especially in patients with pre-existing renal impairment; however, studies have
failed to demonstrate this.
A large American observational study has also shown that EVAR patients are more likely
to undergo AAA-related reinterventions during 4-year follow-up. However, these were less
likely to require inpatient hospitalization compared to reintervention following open aneurysm
repair. Among patients who underwent EVAR in the randomized trials, 20–30% required a
secondary reintervention over the following 6 years. Cost- analyses from the EVAR-1 trial have
shown EVAR to be associated with a higher cost than open repair.
These long-term results raise questions over the durability of EVAR. For most patients
EVAR still provides short-term but no long-term benefits but lifelong surveillance is necessary
146
to prevent aneurysm-related death. For the very frail patient with multiple comorbidities, if life
expectancy is adequate then EVAR after appropriate medical optimization may bring some
benefits; if life expectancy is short, EVAR is unlikely to bring any benefits.Future work
modelling the extent of any benefit in subgroups may help clarify this issue. Patient preference is
also important in terms of surgical approach. Clinical decision-making skills clearly remain of
crucial importance in the management of patients with large aneurysms.
f. The future of EVAR
There is still doubt whether the advantages of EVAR are reproducible in the case of AAA
rupture, with several groups advocating its role. Avoidance of laparotomy confers a marked
physiological advantage over open repair in an already dire situation. However, the urgency
associated with ruptured AAA repair results in little or no time being available to gather the
required morphological information prior to EVAR. This is of particular importance since these
aneurysms tend to have shorter and wider necks and are therefore more challenging for EVAR
with current devices. Furthermore, the requirement of a permanently available on-call
endovascular team with access to the appropriate facilities for EVAR is a significant obstacle in
most hospitals.
The IMPROVE trial is the largest randomized controlled trial to determine whether
endovascular repair improves the survival of all patients with ruptured AAA. This pragmatic trial
randomized patients with an in-hospital clinical diagnosis of ruptured AAA. The trial showed no
difference in mortality between EVAR and open repair patients. Similar findings were seen in
two other contemporary European randomized controlled trials. Interestingly, the study did
demonstrate shorter hospital stays, better quality of life and superior cost effectiveness for
patients treated with EVAR.
More than 50% of patients have aneurysm morphology that is unsuitable for conventional
endovascular repair.Of these, a significant proportion will have an inadequate length of normal
infrarenal aorta above the aneurysm within which to achieve a proximal seal, and account for up
to 15% of AAA. Fenestrated endovascular aneurysm repair (FEVAR) was first described in 1999
as an endoluminal solution for patients with an inadequate infrarenal aortic neck.Fabric
fenestrations of the endograft, with or without bridging stents, permit perfusion of visceral
branch vessels while achieving a secure proximal seal. Fenestrations may be one of three types:
scallops, small or large circular fenestrations. Scalloped grafts have a U-shaped defect in the
leading edge of the endografts for preserved patency of the most proximal visceral arteries. Both
other types of fenestrations reside in the body of the device fabric. The bare-metal scaffold
traverses large fenestrations, whereas small fenestrations lie between stent struts and require
secondary stenting to achieve a seal and prevent occlusion (Figure 10.5). Observational data on
the use of these devices has shown promise and these devices are now widely used in major
vascular canters globally. An Achilles heel of these devices is their bespoke nature, which
continues requiring 6 weeks to 12weekmanufacture time for each graft.
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Figure 10.5 Fenestrated stent graft used for the treatment of perirenal aortic aneurysms. Courtesy of Cook
Medical.
Data from the United Kingdom have demonstrated that FEVAR can be performed with a
high degree of technical success with good clinical outcomes(Figure 10.6a). Although mortality
rates of less than 5% were reported, the selected nature of these data and the lack of long-term
follow-up make widespread application of this technique difficult to justify at present. Concerns
about these devices include uncertainty regarding the long-term patency of stents in normal
branch vessels, the increased number of modular connections and the possibility that the
branches may kink if the aneurysm shrinks (Figure10.6b). The technology is evolving rapidly,
and ‘off-the-shelf’ fenestrated grafts will soon become readily available.
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Figure 10.6Three-fenestration stent graft with coil embolization of accessory right renal artery and satisfactory
exclusion of juxta renal abdominal aortic aneurysm. (a) Completion angiogram. (b) Reconstruction of surveillance
CT aortogram.
An alternative strategy for short-necked AAA is the use of parallel chimney grafts
alongside conventional aortic endografts. (Figure 10.7) This technique has gained application as
an off-the-shelf, less expensive alternative to custom-made fenestrated graft. Again, promising
results have been reported in observational studies and a systematic review reported a 5% 30-day
mortality.Nevertheless, concerns persist about the lack of randomized data and longer-term
follow-up. Further concerns exist around the potential for internal leaks in the gutters between
chimney and aortic grafts.
Figure 10.7 Schematic representation of chimney grafts/snorkels.
More recently, polymer technology has been utilized to develop novel solutions for
managing AAA. The first method modifies conventional aortic stent grafts to use inflatable
polymer rings to create a seal at the neck of the aneurysm. It is argued that this method avoids
the constant outward force, and potential for future dilatation, on the aortic neck that a
conventional stent graft would exert.A more innovative use of polymers is seen in the technique
of endovascular aneurysm sealing (EVAS). The procedure is similar to traditional EVAR; two
balloon expandable stents grafts with attached endobags are delivered up each iliac artery and
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deployed below the renal arteries. A biostable polyethylene glycol polymer is injected through
the catheters into the endobags to fill the aneurysm sac, sealing it off from the circulation and
holding the stent graft in place. This technique may negate the problem of short aortic necks and
type II endoleaks.For both methods, proof of durability is eagerly awaited.
150
REFERENCES:
1. Wanhainen A, Hultgren R, Linné A, et al. Outcome of the Swedish Nationwide Abdominal Aortic Aneurysm
Screening Program. Circulation 2016
2. TheUKSmallAneurysmTrialParticipants.Mortality results for randomized controlled trial of early elective
surgery or ultrasonographic surveillance for small abdominal aortic aneurysms. Lancet 1998
3. GreenhalghRM,BrownLC,KwongGP.Comparison of endovascular aneurysm repair with open repair in patients
with abdominal aortic aneurysm (EVAR trial 1), 30-day operative mortality results: randomized controlled trial.
Lancet 2004
4. Johnston KW. Non-ruptured abdominal aortic aneurysm: six-year follow up results from the
multicentreprospective Canadian aneurysm study. Canadian Society for Vascular Surgery Aneurysm Study
Group. J Vasc Surg 1994
5. The UK EVAR trial investigators. Endovascular versus open repair of abdominal aortic aneurysm. N Engl J
Med 2010;
6. The UK EVAR trial investigators. Endovascular versus open repair of abdominal aortic aneurysm in 15-years'
follow-up of the UK endovascular aneurysm repair trial 1 (EVAR trial 1): a randomized controlled trial. Lancet
2016
7. EVAR Trial participants. Endovascular aneurysm repair and outcome in patients unfit for open repair of
abdominal aortic aneurysm (EVAR-2 trial): randomized controlled trial. Lancet 2005
8. Improve Trial investigators. Endovascular or open repair strategy for ruptured abdominal aortic aneurysm: 30-
day outcomes from IMPROVE randomised trial. BMJ 2014
9. British Society for Endovascular Therapy and the Global Collaborators on Advanced Stent-Graft Techniques
for Aneurysm Repair (GLOBALSTAR) Registry. Early results of fenestrated endovascular repair of juxtarenal
aortic aneurysm in the United Kingdom. Circulation 2012
10. Young EL, Holt PJ, Poloniecki JD, et al. Meta- analysis and systematic review of the relationship between
surgeon annual caseload and mortality for elective open abdominal aortic aneurysm repairs. J Vasc Surg 2007
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Chapter 11 Physical Assessment and Evaluation During the Perioperative

Period
Jing Yuchen
a. Evaluation and Management of Heart Failure
The guidelines for adults are based on the manner which patients present to physicians
and encompass the extremes of presentation from acute pump failure with shock to
asymptomatic left ventricular dysfunction. We have included patients in the latter category
because proper treatment can delay or prevent the development of heart failure. Treatment
strategies frequently depend on the etiology of the heart disease, and a major focus of these
guidelines is the diagnostic approach to determine correctable etiologies and precipitating factors.
Our approach is to discuss the diagnostic studies and treatment necessary to stabilize the status of
adult patient with acute heart failure and the evaluation and treatment of patients presenting with
chronic left ventricular dysfunction or stabilized acute heart failure.As we have already discussed
the nature, diagnosis, and treatment of Acute Heart Failure in Chapter 6. Please refer to the
Chapter for the relevant information.
b. The Use of Lung Function Assessment for the Diagnosis and Management of Chronic
Airway Disease
i. Lung Function Testing:
Lung function testing assesses how well the lungs work. It is often used in the diagnosis
and assessment of chronic airways disease. Spirometry is a simple form of lung function test that
measures the amount and speed of air blown from the lungs. Most adults and children over 6
years of age are able to take a spirometry. It is used to measure the degree of airflow limitation
compared to predicted normal values and can also be used to assess variability of airflow
limitation, particularly by being measured before and after the patient is given a bronchodilator
(a type of medication that dilates the airways, hence increasing airflow to and from the lungs—
see Glossary). More complex lung function testing, performed in a respiratory function
laboratory, can be used to assess features such as how much air is left in the lungs, how well the
lungs exchange gases and the respiratory muscles strength.
Guidelines for asthma state that spirometry is ‘the best lung function test for diagnosing
asthma and for measuring lung function when assessing asthma control’ (NACA 2015).
Guidelines for Chronic Obstructive Pulmonary Disease (COPD) state that: ‘because COPD is
defined by demonstration of airflow limitation, which is not fully reversible, spirometry is
essential for its diagnosis’ (Abramson et al. 2016). The current inaccuracy of diagnosis of COPD
in community settings and the importance of using spirometry was demonstrated by an
Australian study in which only 58% of general practice patients being treated for COPD were
confirmed to have the diagnosis on post-bronchodilator spirometry. Australian asthma guidelines
(NACA 2015) recommend measuring lung function using spirometry when:
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• making or confirming asthma diagnosis

• assessing future risk
• the person has been experiencing worsening asthma control or a flare-up
• monitoring response after dose adjustment
• periodically reviewing asthma (every 1–2 years for most patients).
Australian COPD guidelines state that spirometry should be used to:
• make the diagnosis of COPD in patients with risk factors such as exposure to tobacco
smoke, occupational dusts and chemicals, and/or symptoms such as breathlessness,
frequent sputum production or intermittent cough, or a strong family history of COPD
• assess the severity of COPD and to predict prognosis
• assess eligibility for treatment with inhaled corticosteroids (ICS)
• assess response to treatment. International guidelines for asthma (GINA 2016) and
COPD (Global Initiative for Chronic Obstructive Lung Disease 2015) also
recommend measuring lung function when diagnosing and managing these conditions.
Spirometry, either alone or as part of a more complex lung function test, is essential part
of the diagnosis and ongoing management of chronic airway disease, because it is the best
method for measuring the restriction of expiratory airflow or the amount and speed of air blown
outlung.
The Australian Asthma Guidelines (NACA 2015) recommends spirometry to confirm the
diagnosis of asthma, preferably before the start of treatment, but if not possibly, shortly after the
start of treatment. Australia’s COPD Guidelines pointed out that spirometry is essential for the
diagnosis of COPD.
According to a trial study from Australia, the results show that in New South Wales, most
people aged 45 and over initiated on medications used in the management of chronic airways
disease do not have spirometry performed within 12 months before or after their initial
prescription. The majority (81.6%) of people from the 45 and Up Study for whom respiratory
medications were dispensed for the first time did not have an MBS claim for a lung function test
within 12 months before or after their initial dispensing. Similarly, 79.7% of people for whom
ICS-containing medications were dispensed for the first time had not had a claim for a lung
function test within 12 months before or after the first dispensing.
These medications are only subsidized in Australia for treatment of asthma or COPD. In
COPD, these medications are only subsidized for a subset of patients, as identified by
exacerbations plus a specific spirometry criterion. Thus, to be consistent with current guidelines
and medication subsidy arrangements, objective confirmation of the diagnosis of asthma or
COPD should have been obtained before, or within a reasonable time after, these medications
were commenced. Of those 45 and up participants for whom spirometry was performed, a sizable
proportion were billed by medical specialists (including 30% by thoracic specialists and 10% by
other specialists) while GPs accounted for 60% of the billing. These data indicate
thatsubstantially fewer lung function tests are being performed in primary care than might
otherwise be assumed. It is recommended that patients who are diagnosed with asthma begin
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treatment on short-acting beta-agonists (SABA), as needed, or regular treatment with an ICS

(plus SABA as needed) (NACA 2015).
It was not possible to examine lung function testing in people initiated on SABA (by
themselves or by a clinician) and who purchased this medication over the counter. Published
studies indicate that approximately 40% of people with asthma obtain their SABA over the
counter without a prescription. A 2015 survey of people aged over 16 years with asthma found
that 56% of general beneficiaries and 21% of insurance card holders obtained most of their
SABA over the counter. Among those respondents from the 45 and Up Study who reported ever
being diagnosed with asthma, there was evidence of spirometry for fewer than half in a 14-year
period. Among those with current asthma, around half had evidence of spirometry over the same
14-year period and just over one-third of these had 2 or more spirometry claims from 2001 to
2014.
As mentioned in the report:
“In Australia, the proportion of adults who report ever being diagnosed with asthma is
about double the proportion of those who have ongoing symptoms or treatment in adult
life consistent with current asthma (ACAM 2011). This may be due to remission of
asthma after childhood; to the difficulty of making a firm diagnosis of asthma in young
children; to misdiagnosis; or to inaccurate recall. This is reflected in the 45 and Up Study
participants, of whom 27,160 reported ever having been given a diagnosis of asthma, and
12,584 who reported having current asthma. This may also explain the lower proportion
of people (20.1%) reporting ever-diagnosed asthma who had a spirometry claim in a
recent 3-year period compared with those with current asthma (26.2%): clinicians are
more likely to request lung function testing in patients who are symptomatic enough to
take treatment. However, since only around one-quarter of people with current asthma
had any spirometry claims over the 3 years observed (from 2012–2014), it is evident that
spirometry is being used infrequently in this population for the ongoing management of
asthma.”
It is notable that only a small proportion of participants starting ICS-containing

medication had lung function testing within the recommended 12-month period. Although these
medications are intended for long-term use, there is evidence suggesting that they are sometimes
prescribed for people who do not appear to have chronic airways disease. Another medicine case
study approved for treatment of COPD; the PBS restriction specifies that a spirometry criterion
should be satisfied before the treatment is commenced.
These results demonstrate that, spirometry is almost certainly under-used for the purposes
of diagnosis and management of chronic airways disease. A study in the Netherlands found that
providing spirometry in primary care led to a change in diagnosis for half of all patients with
apparent respiratory disease. In a study, 31% of patients with either a recorded diagnosis and/or a
record of current pharmaceutical treatment for COPD were found to have been incorrectly
diagnosed when the diagnosis was checked by spirometry. Findings from the Australian Burden
of Obstructive Lung Disease (BOLD) study also confirmed inconsistency between spirometry
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evidence of COPD found in 7.5% of participants aged 40 years or over and a pre-existing
diagnosis of COPD (5.2%).
c. Perioperative Management of Diabetes
Diabetic patients in the vascular surgery ward usually have multiple comorbidities and
other complications related to diabetes. In addition to peripheral neuropathy and peripheral artery
disease, they may have evidence of ischemic heart disease, diabetic nephropathy, and autonomic
neuropathy, all of which will affect their outcome. These comorbidities need to be considered
and resolved-for example, patients with severe renal insufficiency may need to undergo a kidney
examination before any surgery, especially the use of contrast agents for angiography, because
this has the risk of worsening kidney function. Due to the risk of worsening renal failure and
lactic acidosis, metformin must be stopped for 48 hours before elective angiography. Coronary
artery disease and cardiac autonomic neuropathy increase the risk of intraoperative cardiac
events and should be treated before surgery.The hormonal and metabolic changes associated
with surgery create a particular problem in diabetes, and intravenous insulin infusions (with
dextrose and potassium) are usually needed for the perioperative period, unless the duration of
anesthesia is short (<45minutes) and the patient is not usually on insulin.
Diabetic patients who require surgery face special challenges in perioperative

management. Special attention must be paid to the prevention and treatment of metabolic
disorders. It is also important to be alert to the development of acute complications that can lead
to higher surgical morbidity and mortality.
i. Maintaining Glycemic Control:
Blood sugar control is maintained by the balance between insulin and the counter-
regulatory hormones glucagon, adrenaline, cortisol, and growth hormone. Insulin stimulates the
absorption and utilization of glucose by muscle and adipose tissue. It also inhibits hepatic
glucose produced by gluconeogenesis and glycogen breakdown. Insulin prevents the
development of ketosis and protein breakdown. During the perioperative period, there must be
enough insulin to prevent metabolic decompensation.
To stabilize glycemic control in patients taking insulin, frequent glucose monitoring

should be performed, with insulin dosages adjusted appropriately. Ideally, patients should
monitor blood glucose levels before meals, after meals, and at bedtime. Long-acting insulin (e.g.,
ultralente, glargine [Lantus]) can be discontinued one to two days before surgery, and glucose
levels can be stabilized with a regimen of intermediate insulin (e.g., NPH, lente) mixed with
short-acting insulin (e.g., regular, lispro [Humalog] or aspart [Novolog]) twice daily or short-
acting insulin before every meal. However, on the day before surgery, long-acting insulin can be
continued throughout the day if the patient's control is good, particularly if the patient is using
glargine. Since this newer insulin analog maintains a stable level throughout the day, more
experience with its use may demonstrate its safety as a basal insulin throughout the perioperative
period.
155
Oral agents are generally discontinued before surgery. Long-acting sulfonylureas (e.g.,
chlorpropamide) are stopped 48 to 72 hours before surgery, while short-acting sulfonylureas,
other insulin secretagogues, and metformin [Glucophage] can be withheld the night before or the
day of surgery. No recommendations exist for discontinuation of thiazolidinediones (e.g.,
rosiglitazone and pioglitazone) before surgery; their extremely long duration of action probably
indicates no rationale for stopping them at all. In patients with good metabolic control who are
undergoing relatively minor surgery, antihyperglycemic treatment may not be needed on the day
of surgery. Otherwise, insulin will generally be used.
ii. Preoperative Evaluation
Preoperative evaluation includes assessment of metabolic control and any diabetes-

associated complications, including cardiovascular disease, autonomic neuropathy, and
nephropathy, which could affect the surgical outcome. Therefore, in elective surgical procedures,
potential problems should be identified, corrected, and stabilized before surgery.
Asymptomatic cardiac ischemia occurs relatively often in patients with diabetes. The
presence of cardiovascular risk factors should prompt a thorough evaluation. At minimum,
resting electrocardiography should be performed, but a stress test is often justified if there is
suspicion for cardiovascular disease. Cardiac autonomic neuropathy may predispose patients to
perioperative hypotension, so the presence of resting tachycardia, orthostatic hypotension,
peripheral neuropathy, and loss of normal respiratory heart rate variability should be sought.
Serum creatinine levels should be measured, but they are not a sensitive indicator of early
renal dysfunction, which is usually advanced before an elevation in creatinine develops. Kidney
function can be estimated by using creatinine clearance formulas but, if a high index of suspicion
for renal impairment exists, a measured creatinine level from a 24-hour urine collection is the
best gauge of renal function. Diabetic patients with proteinuria or abnormal creatinine clearance
have a greater risk of developing acute renal failure.
iii. Perioperative Response to Surgery and Anesthesia
Surgery and anesthesia invoke a neuroendocrine stress response with release of counter-
regulatory hormones, which results in peripheral insulin resistance, increased hepatic glucose
production, impaired insulin secretion, and fat and protein breakdown, with potential
hyperglycemia and even ketosis in some cases. The degree of this response depends on the
complexity of the surgery and any postsurgical complications.
In addition to counter-regulatory hormone excess and relative insulin deficiency, fasting

and volume depletion contribute to metabolic decompensation. Diabetic ketoacidosis occurs
infrequently in patients with type 2 diabetes, but hyperglycemic hyperosmolar non-ketosis states
are well described. The latter are characterized by extreme hyperglycemia, hyperosmolarity,
volume depletion, and associated changes in mental status resulting from inadequate insulin
action, osmotic diuresis, fluid losses from surgery or overuse of diuretics, and volume under-
replacement. In patients with type 1 diabetes, diabetic ketoacidosis may develop in the absence
of severe hyperglycemia because of inadequate insulin availability during a time of increased
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demand.Hyperglycemia inhibits host defenses against infection, including many leukocyte

functions. Hyperglycemia also impairs wound healing because of its detrimental effects on
collagen formation and resulting diminished wound tensile strength.
Many patients with diabetes who require emergency surgery will not be in good
metabolic control at that time and may even have diabetic ketoacidosis. The priority is to assess
glycemic, acid-base, electrolyte, and fluid status, and correct any derangements before surgery.
This step is especially critical if acidosis or potassium abnormalities are present. Surgery should
be delayed, if possible, to stabilize metabolic status. Table 11.1 presents considerations to bear in
mind in preparing patients with diabetes for emergency surgery.
Preoperative Assessment Preoperative Treatment

Metabolic status: immediate measurement of Delay surgery if possible until metabolic
plasma glucose, pH, creatinine, BUN, control and volume status are stabilized
electrolytes
Volume status: check for orthostasis, elevated Maximize glucose, electrolyte, and acid-base
BUN and/or creatinine, urine output status:
Cardiac status: ECG
Insulin and glucose infusions
Saline infusion if volume is depleted,

depending on renal function and cardiac
status
Potassium infusion if renal function is

normal and serum potassium is normal or low
Bicarbonate infusion only in patients with

severe acidosis
Table 11.1 Minimizing the Risk of Emergency Surgery in Patients with Diabetes; BUN= Blood Urea Nitrogen;
ECG= Electrocardiographh
iv. Conclusions:
It is clear that surgical outcomes are improved in patients with diabetes who are
maintained in good metabolic control. Physicians must be cognizant of patients' preoperative
control, their relative need for insulin, and any factors that may be likely to increase insulin
requirements.
When insulin requirements are in doubt, it is better to err on the side of providing rather
than withholding insulin. The administration of adequate glucose in conjunction with the
judicious use of insulin will prevent hypoglycemia. Diabetic ketoacidosis or hyperosmolar states,
which may result from inadequate dosing of insulin, are not so easily managed. The key to
success of any perioperative management plan is frequent monitoring of glucose, electrolyte, and
fluid levels, and acid-base status. Prevention of surgical complications because of hyperglycemia
is possible with meticulous perioperative glucose management.
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d. Laboratory Evaluation of Kidney Disease:
It is well acknowledged that laboratory measurement and reporting are critical to

promoting early detection and management of chronic kidney disease (CKD). It has been fully
proven that renal impairment is closely related to coronary artery disease (CAD) and
cardiovascular mortality. In addition to common risk factors, decreased renal function also
affects the cardiovascular system through a variety of mechanisms, such as increased aldosterone
activity, increased pro-inflammatory effects, and platelet activation. These mechanisms cause the
occurrence and progression of CAD to accelerate, leading to a poor prognosis for patients with
decreased renal function. In addition to the obvious chronic kidney disease, minor damage to
renal function is also associated with an increased risk of coronary arteries. Therefore, the
different stages of renal insufficiency as biomarkers for identification and precise quantification
are essential for the risk stratification, prevention, and treatment of CAD.
i. Estimated Glomerular Filtration Rate:
The estimated glomerular filtration rate (eGFR) is the most relevant parameter for
evaluating renal function in clinical practice. In the past few decades, different equations for
estimating GFR have been developed. Today, the Chronic Kidney Disease Epidemiology
Collaboration (CKD-EPI) eGFR equation is the best validated equation for accuracy and risk
prediction, especially in individuals with normal or only mildly reduced GFR. Therefore, the
CKD-EPI equation is currently replacing other eGFR equations, such as the Cockcroft-Gault
equation or the Kidney Disease Diet Correction (MDRD) equation. Despite some limitations,
serum creatinine is still the most used kidney marker for estimating GFR.
Many large studies have shown that cardiovascular risk is related to a drop in eGFR of 60
mL/min/1.73 m2 or lower. Individuals with eGFR below 60 mL/min/1.73 m2 are defined as high
cardiovascular risk. Although these individuals are exposed to more adverse reactions due to the
use of cardiovascular drugs or iodine-containing contrast media compared with individuals with
intact renal function, the benefits of intensive CVD treatment are far greater for patients with
decreased renal function. Therefore, it is recommended to perform baseline and annual creatinine
measurements for all patients with known or suspected CAD and use eGFR to assess renal
function.
ii. Cystatin C
Due to changes in creatinine production, secretion, and extrarenal excretion that are
affected by age, gender, muscle metabolism, and renal reserve, serum creatinine measurement
has limitations, so a potentially more powerful renal marker was evaluated. Among them,
cystatin C is the best verified and most extensive kidney marker in addition to serum creatinine.
Cystatin C is produced by all nucleated cells at a relatively constant rate, is filtered in the
glomerulus, and is not reabsorbed in the renal tubules. As there are fewer changes affected by
age, gender, muscle mass, diet, or other factors, impaired cystatin C concentration can better
detect particularly mild declines in renal function. In a large group of patients with CAD who
have normal or only mildly reduced renal function, cystatin C is an effective predictor of
cardiovascular mortality beyond classic risk factors.
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In terms of GFR prediction, compared with the use of the creatinine-based III eGFR
equation, the use of cystatin C to estimate eGFR with the cystatin C-based eGFR equation has
similar accuracy. The CKD-EPI eGFR equation using the combination of serum creatinine and
cystatin C has been shown to estimate GFR more accurately than the eGFR equation based on
these markers alone. In terms of cardiovascular risk prediction, compared with the eGFR
calculated based on the serum creatinine equation, the eGFR calculated based on cystatin C or
combined with the CKD-EPI equation has a stronger correlation with cardiovascular prognosis.
HF patients and a group of CAD patients.
Measuring cystatin C in addition to serum creatinine and evaluating eGFR using the
combined CKD-EPI equation is helpful as a confirmatory test for patients whose creatinine-
based GFR is estimated to be 45 to 75 mL/min/1.73 m2 to identify, or to rule out cardiovascular
high-risk situations more accurately with reduced renal function and GFR lower than 60
mL/min/1.73 m2.This requires the most intensive treatment of cardiovascular risk factors.
iii. Treatment Options:
Chronic kidney disease is a risk factor for CAD and has a major impact on the outcome
of stable CAD and treatment decisions. There are several risk factors for patients with chronic
kidney disease that interact with the medical and diagnostic management of stable CAD and
accelerate the development of CAD. Patients with end-stage renal disease have increased
mortality from cardiovascular disease, so these patients should be monitored for possible
symptoms of CAD. In CAD patients, the risk of sudden cardiac death increased by 11% per 10
mL/10 mL, and the glomerular filtration rate was minimally decreased. Myocardial perfusion
imaging has prognostic value for patients with end-stage renal disease without CAD symptoms,
although the screening of asymptomatic patients is not currently in routine clinical use. The
examination of suspected CAD in patients with symptomatic kidney disease follows the same
pattern as in patients with normal renal function.
However, the presence of impaired renal function increases the probability of pre-
examination for reporting CAD in patients with chest pain, so noninvasive test results need to be
interpreted accordingly. In addition, in patients with advanced renal failure and dialysis patients
with reduced urine output, the use of iodine-containing contrast media should be minimized to
prevent contrast media nephropathy. Similarly, special attention should be paid to drugs that are
cleared by the kidneys, which may require dose reduction or replacement.
For CAD patients with or without renal insufficiency, the same treatment plan should be
started. Therefore, risk correction therapy should be initiated. However, compared with patients
without impaired renal function, these patients have a higher risk of mortality and complications.
Coronary artery bypass surgery is associated with higher operative mortality and greater
possibility of hemodialysis in non-hemodialysis-dependent patients after revascularization.
Existing studies have shown that it is related to percutaneous coronary intervention (PCI). In
contrast, its long-term survival rate has a trend of improvement.
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Chapter 12 Vascular Trauma
a. General Principles of Management of Vascular Injury
Fewer than 10% of patients with polytrauma have associated vascular injuries, but these
injuries can cause significant morbidity and mortality. In most European countries the majority
of vascular trauma is caused by blunt (traffic accidents) and iatrogenic injuries. In South Africa,
injuries are mostly penetrating and have also changed from predominantly stab wounds to
injuries caused by firearms. Complex vascular injuries have a high morbidity and mortality, and
a clear understanding of the pathophysiology of vascular trauma and a logical approach to the
management of those injuries are essential for a favorable outcome.
Procedures are performed under general anesthesia in a suitably equipped theatre. Blood
products should be available and arrangements for intraoperative autotransfusion should be made
where further bleeding is expected. The value of prophylactic antibiotics in vascular surgery is
established.Adequate exposure is vital for obtaining proximal and distal control of injured
vessels. This often requires inclusion of adjacent anatomical areas in the operative field, e.g.,
preparing the neck in thoracic injuries (and vice versa) and the abdomen in groin injuries. An
uninjured leg is prepared for possible vein harvesting should bypass be required. Vascular
control must be achieved proximally and distally before directly approaching the area of injury.
Bleeding may be temporarily arrested by digital compression or by endovascular means until
clamps have been applied.
In blunt and high-velocity trauma there is often extensive intimal damage, and careful
debridement of the vessel is necessary until normal-appearing intima is found (Figure 12.1a to
Figure 12.1c). Antegrade and retrograde flow should be evaluated. Arteries are cleared of
thrombus by careful passage of embolectomy catheters followed by irrigation with heparin-saline
solution. Simple laceration of the vessel wall is repaired by lateral suture, provided it does not
lead to stenosis when patch graft angioplasty is indicated. Where more than 50% of the
circumference of a vessel wall is damaged, this area should be excised followed by end-to-end
anastomosis. This requires mobilization of the proximal and distal arterial stumps to achieve
approximation without tension. It this approach fails; an interposition graft is indicated.
Autologous vein is the preferred conduit for reconstruction.
Where there is a mismatch in diameter between the vessel that needs to be repaired and
the available autologous vein, either a paneled or spiral vein graft should be used. Prosthetic
material may be used in the absence of available autologous vein or as part of a damage control
strategy. When the complex arterial repair will result in delay in revascularization, intraluminal
shunts should be used to maintain antegrade flow during repair, thereby reducing ischemic time.
Completion angiography should be performed to document a technically perfect repair and to
assess the distal arterial tree. Associated injuries are addressed once vascular repair has been
completed. Wound debridement should be performed with removal of all devitalized and
contaminated tissue. Contaminated wounds are left open, but the vascular repair must be covered
162
by soft tissue. Repeated wound inspections are performed, with delayed primary suture when the
wound is clean.
Figure 12.1a Blunt injury of the intima
Figure 12.1b Blunt injury of resected
Figure 12.1c Replaced with a venous

interposition graftSource of the Image: A Companion to specialist surgical practice----Vascular and
Endovascular Surgery, Ian Loftus and Robert J. Hinchliffe.
163
Venous injuries found during exploration for associated arterial injury should be repaired,
if the repair itself can be done simply (e.g. lateral suture repair) and only if it will not
significantly delay treatment of associated injuries or destabilize the patient's condition. Complex
venous repair or bypass should only be attempted if the patient is hemodynamically stable. All
veins, including the inferior vena cava (IVC), can be tied off in cases of hemodynamic instability.
b. Endovascular management of Vascular Trauma
The application of endovascular techniques in the injured patient has many potential
advantages. General anesthesia is not required. Surgical trauma, with further blood loss,
hypothermia, etc., as well as cross-clamping of major vessels, distal ischemia, and subsequent
reperfusion injury, is avoided. The main advantage is the option of approaching complex arterial
lesions in anatomically challenging locations from a remote site. A difficult exploration in an
injured area is avoided, with less potential damage to surrounding structures, and preventing
fresh bleeding. Intravascular technology is increasingly used in vascular trauma, but it still has
certain limitations. These techniques are usually not applicable, mainly due to time constraints,
for patients with active bleeding, unstable patients, or patients with end-organ ischemia. In
situations where there are symptoms of compression, infected wounds, or accompanying injuries
that require open exploration, endovascular techniques are contraindicated. Technical limitations
include the inability to pass the guidewire through the lesion, where thrombus in the lumen
prevents the safe passage of the guidewire due to the risk of distal embolization, or there is a
lumen difference between the proximal and distal involved segments.
Embolization therapy has become the standard treatment for managing significant
bleeding following pelvic fractures and to control bleeding due to penetrating and blunt trauma
of the liver, kidneys and spleen. Endovascular techniquesare used to manage vascular trauma in
three ways:
(1) To obtain hemostasis. Damaged vessels are embolized using a variety of substances
including hemostatic agents (gel foam), coils and balloons. Embolization therapy is
also the preferred option for treating vertebral artery lesions and lesions of non-
essential, inaccessible vessels in other regions.
(2) To obtain vascular control.Temporaryballoon occlusion of a damaged vessel at the
time of diagnostic angiography can prevent exsanguinating bleeding until surgical
control is achieved. It is especially valuable in relatively inaccessible regions and
allows limiting the extent of the exposure to obtain surgical control.This technique is
valuable in injuries in zones 1 and 3 of the neck, the abdominal aorta, proximal
subclavian and iliac arteries.
(3) For vascular repair. Covered stent grafts are used for repairing vessels in
anatomically challenging locations and to avoid major surgical exposures, e.g., the
thoracic aorta, thoracic outlet vessels, internal carotid, and vertebral arteries. This will
be discussed in more detail in the relevant sections. Covered stent grafts may also be
used as a temporary measure to allow stabilization of the patient until definitive open
repair later.
164
In-stent stenosis, graft migration, stent breakage and endoleak are well-known
complications of tent graft repair. Durability is therefore of concern in the younger population
who are the main victims of trauma. However, good long-term results have been published for
endograft repair of carotid, subclavian and thoracic aortic injuries
c. Thoracic and Abdominal Vascular Injuries
i. Thoracic Vascular Injuries:
Most thoracic vascular injuries are caused by penetrating trauma, with a mortality rate as
high as 90%. Blunt aortic injury is considered as the second most common cause of death in
trauma patients; 70–90% of patients sustaining these injuries will die before reaching a hospital
and, if left untreated, 90% will die within 4 months. The site of insertion of the ligamentum
arteriosum, just distal to the origin of the left subclavian artery, is the typical point of injury.
Deceleration or compression injury may also involve the brachiocephalic trunk, the pulmonary
veins, and the vena cava.
Patients with penetrating thoracic vascular trauma are usually hemodynamically unstable,
often with continuing hemorrhage into the pleural cavity or the mediastinum and should be taken
for urgent thoracotomy. Patients with blunt thoracic trauma may initially be hemodynamically
stable and the injury may not be immediately apparent due to the high incidence of concomitant
trauma. The following clinical findings may be associated with underlying thoracic great vessel
injury:
• Shock/hypotension,
• Difference in blood pressure or pulses between the two upper extremities,
• Difference in blood pressure between upper and lower extremities (false constriction
syndrome),
• Expanding hematoma at the thoracic outlet,
• Left flail chest,
• Subscapular murmur,
• Palpable sternal fracture,
• Palpable fracture of the thoracic spine,
• external evidence of major chest trauma,
• history indicating deceleration or compressioninjury to the chest.
Indications for urgent surgery are haemodynamic instability, increasing haemorrhage

from chest tubes and radiographic evidence of an expanding haematoma. An initial large volume
of blood drained from a chest tube (>1500mL) or ongoing haemorrhage of more than 200–300
mL/hour may indicate great vessel injury that requires thoracotomy.
The classification of thoracic aortic injuries is useful in terms of staging the extent of
injury and guiding intervention. Minimal aortic lesions, i.e., grade I (intimal flap/intramural
hematoma/thrombus <10mm) or grade II (intimal flap/intramural hematoma/thrombus >20 mm)
are managed non-operatively with close observation, whilst grade III lesions (pseudoaneurysm,
165
simple or complex but no extravasation) and grade IV lesions (active contrast extravasation) will
require intervention.
Patients selected for initial non-operative management should be closely monitored, with
systolic blood pressure kept below 120 mmHg or mean arterial pressure below 80 mmHg.
Intravenous beta-blockade, titrated to heart rate, was shown to be beneficial in patients with a
blunt aortic injury.
Endovascular stent grafting currently the preferred method for treating traumatic rupture
of the descending thoracic aorta. Mortality is significantly lower compared to open surgery
which is from 9% to 19% with a decreased risk of spinal cord ischemia, renal injury, graft, and
systemic infection. Numerous studies have indicated that the durability of thoracic stent grafts up
to 10 years with low complication and re-intervention rates.
Open surgery is reserved for unstable, hypotensive patients for injuries of the ascending
aorta and arch, and where endovascular treatment is not readily available. The basic surgical
approaches are median sternotomy, left anterolateral thoracotomy and left posterolateral
thoracotomy.
ii. Abdominal Vascular Injuries
Penetrating trauma accounts for 90–95% of abdominal vascular injuries, with a high
mortality due to the nature of these injuries as well as associated injuries to other intraabdominal
organs. It is important to consider intraabdominal injury with all penetrating injuries from the
fourth intercostal space anteriorly to the upper thighs.
The unstable patient with a possible abdominal vascular injury requires immediate
surgery. The stable patient should be investigated according to the injuries. Plain abdominal
radiography using radio-opaque markers (paperclips) placed on the entrance and exit wounds is
of value in establishing the trajectory of missiles in penetrating injuries. Digital subtraction
angiography (DSA) and Computed tomography angiography(CTA) have little, if any, role in the
diagnosis of abdominal vascular injury when the patient is unstable. CTA is the investigation of
choice in stable patients with penetrating or blunt abdominal trauma.
Abdominal vascular injuries are usually associated with hemodynamic instability or

concomitant bowel injuries requiring a laparotomy. The abdominal cavity should be entered
rapidly as tamponade. Also, Hemodynamic stability may be lost with relaxation of the abdominal
musculature at the induction of anesthesia. A generous laparotomy incision is required from
xiphisternum to suprapubic. Four-quadrant packing of the abdomen is performed immediately
and the proximal aorta is controlled at the diaphragmatic crus. Once the vascular injury is
controlled, resuscitation with blood products is started. Bowel injuries are temporarily controlled
until vascular repair is effective.
The retroperitoneum is divided into three anatomical zones for purposes of treatment.
Central retroperitoneal hematomas (zone 1) are formally explored due to the high incidence of
associated major vascular, pancreatic, or duodenal injuries, and the high morbidity and mortality
166
if these are overlooked. Flank/perinephric hematomas (zone 2) caused by penetrating injuries

should routinely be explored, whilst hematomas caused by blunt trauma can be left alone if they
are not expanding and the urography on contrast-enhanced CT scan is normal. Zone 3 injuries,
which are confined to or originate from the pelvis, are most often associated with pelvic fractures;
exploration in these cases can be hazardous and is usually avoided. Retroperitoneal hematomas
following penetrating injuries are usually explored to exclude major vascular injuries.
Different surgical exposures are used for specific injuries:
• Medial visceral rotation of the left-sided viscera (Mattox maneuver), i.e. spleen, tail of the
pancreas, left colon and kidney allows accessto the supracoeliac aorta, coeliac axis with its
branches to the left, superior mesenteric artery (SMA), inferior mesenteric artery, left renal
artery and left iliac vessels.
• The Cattell–Braasch or extended Kocher maneuver (right-sided medial visceral rotation)
allows access to infrahepatic inferior vena cava, right renal vein, portal system and right
iliac vessels.
• The infrarenal aorta and IVC are exposed by reflecting the transverse colon superiorly and
the small intestine to the right and then dividing the midline retroperitoneum.
• The iliac arteries are exposed via separate incisions lateral to the caecum and sigmoid,
respectively, avoiding injury to the ureters as they cross the common iliac arteries. The iliac
veins may be accessible only after dividing the arteries that lie anterior to them.
d. Cervical Vascular Injuries
i. Carotid Artery Injuries:
The cervical vessels are involved in 25% of patients with neck trauma. Carotid artery
injury constitutes 5–10% of all arterial injuries. The mortality for carotid injuries ranges from
10% to 31%, with permanent neurological deficit ranging from 16% to 60%.
ii. Mechanism
More than 90% of carotid artery injuries are caused by penetrating injuries. Blunt trauma
is caused by bone fragments related to mandibular, temporal bone, or cervical spine fractures
directly hitting the artery, overextension, over rotation, or contusion.
Penetrating injury may cause partial or complete transection of the vessel,

pseudoaneurysm or arteriovenous fistula (Figure 12.2). Pseudoaneurysm may have an acute or
delayed onset, with progressive enlargement causing compression of the aerodigestive tract or
brachial plexus. Blunt trauma may cause intimal flaps, intramural hematomas, dissection,
complete disruption of the arterial wall with pseudoaneurysms, arteriovenous fistulas and total
occlusion (Figure 12.3). Neurological sequelae are caused by hypoperfusion (transected or
thrombosed vessels) or embolization from thrombus, pseudoaneurysm or arteriovenous fistula.
167
Figure 12.2. Arteriovenous fistula between the carotid artery and internal jugular vein caused by gunshot wound.
Source of the Image: A Companion to specialist surgical practice----Vascular and Endovascular Surgery, Ian Loftus
and Robert J. Hinchliffe.
i. Clinical Signs
Active external bleeding, rapidly expanding cervical hematoma, absent carotid pulse and
a bruit or thrill are indicative of vascular injury. Signs that may indicate an associated vascular
injury warranting further investigation include bleeding from wounds of the neck or the pharynx,
a deficit of the superficial temporal artery pulse, ipsilateral Horner's sign, dysfunction of cranial
nerves IX–XII, a widened mediastinum, fractures of the skull base and temporal bone, and
fractures and dislocation of the cervical spine. Neurological deficit may be present, but obscured
due to concomitant head injury, shock or the use of alcohol or drugs. About 50% of patients with
established blunt injury to the carotid and vertebral arteries could initially be asymptomatic, but
43–58% of these will eventually develop neurological signs after hospital admission.
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Figure 12.3 Dissection of the common carotid artery with blunt trauma to the neck following a motor vehicle
accident.
ii. Management
Mandatory exploration of all penetrating neck injuries has been replaced by a selective
approach. Active external bleeding can be controlled in the emergency room by direct digital
compression, or a Foley catheter inflated in the wound tract to obtain balloon tamponade.
Active pulsatile hemorrhage, expanding cervical hematoma and airway compromise are
indications for urgent surgical exploration. Some low-velocity penetrating injuries may be
managed expectantly with careful observation, provided there is no active bleeding, and the
distal circulation is normal. These injuries include intimal defects, small pseudoaneurysms (<5
mm) and non-obstructive intimal flaps. Most penetrating carotid artery injuries, however, are
best managed by primary arterial repair or endovascular stent grafting.
169
Neurological deficit is only a contraindication to surgical repair in a deeply comatose

patient with a dense neurological deficit, arterial occlusion, and a huge infarct on cerebral CT.All
other patients with associated neurological deficit would benefit from arterial repair, with
improved mortality and final neurological status. Most blunt injuries of the carotid and vertebral
arteries result in intimal disruption, with dissection and/or thrombosis, and the immediate goal of
management is to restore cerebral perfusion and to prevent embolization. Systemic
anticoagulation is therefore the treatment of choice because it limits the formation, propagation
and/or embolization of the thrombus. Intravenous heparin is administered in the acute phase,
followed by oral anticoagulation for at least 3 months.
An important advantage of endovascular repair of cervical-mediastinal trauma is the

avoidance of general anesthesia and the ability to monitor neurological status during the
procedure. Endovascular therapies are used in three ways in the management of cervical vascular
trauma:
(1) Angiographic embolization. This is indicated for (a) injury to the vertebral artery in
the osseus vertebral canal and (b) persistent bleeding from external carotid artery branches (face,
oro- and nasopharynx).
(2) Temporary balloon occlusion. This is used as an adjunct to support standard open
vascular repair in neck zone 1 and 3 injuries. An occlusion balloon is placed via the femoral
artery to provide proximal endoluminal control of the injured vessel, allowing surgical exposure
in a more controlled fashion, and possibly avoiding sternotomy for proximal control.
(3) Covered stent grafts. These are indicated for penetrating wounds, arteriovenous
fistulae and pseudoaneurysms in injury to the vertebral artery in the osseus vertebral canal
surgically inaccessible regions, and persistent bleeding from external carotid artery branches in
patients where extensive surgical exploration is to be avoided due to multiple traumas, local
aggravating factors or high surgical risk due to medical comorbidities.
e. Extremity Vascular Trauma
The incidence of peripheral vascular injury depends on the degree and type of trauma,
ranging from 0.6-3.6% for isolated limb fractures to 25-30% for all penetrating limb injuries.
The risk of limb loss is greatest after blunt trauma and high-speed missile or close-range shotgun
injuries.
i. Diagnosis
CTA has proven excellent sensitivity and specificity for diagnosing extremity vascular
injury and can replace DSA as a diagnostic modality. Any extremity injury warrants a complete
physical examination of the injured extremity and distal vessels. The absence of hard signs of
vascular injury reliably excludes surgically significant arterial injury. The occurrence of delayed
thrombosis stresses the importance of regular reassessment of the peripheral circulation for at
least 24 hours after orthopedic injury. There is a role for duplex Doppler studies in patients with
soft signs of vascular injury or with proximity injuries.
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ii. General Principles of Management
(1) Restoration of perfusion to an ischemic extremity should be performed as quickly as

possible. Contemporary studies emphasize the importance of restoration of perfusion
within 3 to 4 hours to optimize neuromuscular recovery of the injured limb.Adjunctive
therapies such as hypertonic saline resuscitation, temporary intravascular shunts,
fasciotomy, limb cooling and ischemic reconditioning may reduce the severity of
ischemic injury.
(2) Non-operative observation of asymptomatic non-occlusive arterial injuries isacceptable.
These injuries can be definedas small pseudoaneurysms, intimal flaps or irregularities,
small arteriovenous fistulas, and hemodynamically insignificant narrowing of the vessels.
If the subsequent repair of these injuries is required, it can be done without significant
increase in morbidity.
(3) Extremity arterial trauma is usually addressed by conventional open surgical techniques.
Endovascular treatment usually consists of embolization of non-essential vessels after
penetrating trauma.
(4) Simple arterial repairs do better than grafts. If complex repair is required, vein grafts
appear to be the best choice. PTFE is an acceptable conduit when no vein is available and
may even be used in a contaminated field. Effort should be made to cover the graft with
soft tissue.
Figure 12.4. Temporary shunt in right superficial femoral artery, allowing distal perfusion while external fixator is
applied to the femur. Source of the Image: A Companion to specialist surgical practice----Vascular and
Endovascular Surgery, Ian Loftus and Robert J. Hinchliffe.
171
(5) Early four-compartment lower leg fasciotomy should be applied liberally. Indicationsfor
fasciotomy include: (i) ischemic time greater than 4–6 hours; (ii) signs of acute ischemia;
(iii) extensive soft-tissue injuries; (iv) combined arterial and venous injuries; (v) intra-
compartmental bleeding; and(vi) increased compartmental pressure. Measurement of
compartment pressures is an important adjunct and must be donein all compartments.
Pressures should be interpreted in the context of each individual patient because tissue
perfusion is a balance between compartment pressure and blood pressure. Acceptable
compartment pressures have been defined as absolute compartment pressures of less than
20 mmHg and at least 30 mmHg less than mean arterial pressure.
(6) Completion arteriogram should be performed after arterial repair to assess patency and
technical perfection of the repair. Although amputation rates increase with longer
ischemia times, quantifying the relationship is difficult, because amputation rates also
depend on other factors such as extent of soft-tissue damage, the capacity of collaterals,
pre-existing arterial disease and the vessels injured.
(7) In certain cases, primary amputation maybe considered. Scoring systems such as the
mangled extremity severity score (MESS) have been developed to help predict the
outcomeof limb salvage procedures. A MESS score of 7 or more has a predicted
amputation rate of 100%. Several MESS score calculators are available online. Given the
significance of amputation, delaying the procedure even bya day or two is preferred as it
allows careful examination of the limb and discussion with the patient and family.
(8) The doctor should take measures to protect against the systemic effects of reperfusion
injury and subsequent renal damage. A diuresis of atleast 2–3 mL/kg per hour is
maintained with the administration of adequate volumes of normal saline. This should be
started during the operation and is continued postoperatively for as long as the serum
myoglobin and creatine kinase remain elevated. Measures to treat hyperkalemia may be
required.
iii. Vascular Injuries to the Upper Limb
(1) Brachial Artery Injuries:
The most common injuries to the brachial artery are associated with either a
supracondylar fracture or an elbow dislocation followed by penetrating vascular trauma. Upper
extremity vascular injuries are usually not life-threatening, but significant morbidity may occur.
Return of function is often related to associated nerve injury. In the case of blunt injury, the
fracture or dislocation should be reduced. If the distal pulse returns, the patient should be treated
expectantly with regularevaluation of the circulation every two hours. If the limb remains
ischemic or even if the hand is pink with no pulses, it is mandatory to explore and repair the
arterial injury to avoid complications like an ischemic contracture. With penetrating trauma, the
injury should be repaired by open surgical repair.
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(2) Distal Arterial Injuries to the Upper extremity:
Most of the injuries to the forearm circulation are due to a penetrating mechanism. When
only one vessel in the forearm is injured, it may usually be ligated without any adverse effects. If
both the radial and ulnar arteries are injured at least one should be repaired ------ preferably the
ulnar artery as this vessel is in most cases the dominant supply to the hand. These injuries are
often accompanied by injuries to the accompanying nerve and will require repair of the nerve.
Venous injuries to the arm rarely require repair and even injuries to the brachial and axillary
veins may be ligated because the collateral venous network is extensive.
iv. Vascular Injuries to the Lower Limb
These injuries are often associated with skeletal injuries, especially posterior dislocation
of the knee, proximal tibial fractures, and supracondylar femur fractures. Immediate arterial
repair should be performed when the skeletal injury is stable and not significantly displaced.
When there is instability, severe displacement and where extreme orthopedic manipulation is
anticipated, a temporary shunt should be placed to restore blood flow while the orthopedic repair
is completed, after which definite arterial repair is performed. Patients may have significant
bleeding from extremity vascular injuries and a tourniquet should be used if the bleeding cannot
be controlled with direct pressure.
(1) Femoral Vascular Injuries
Bleeding from the femoral triangle can be difficult to control, particularly if both artery
and vein are injured. The suprainguinal region should be entered through a separate incision
above the inguinal ligament to obtain proximal control of the vessels. Effort should be made to
also repair the common femoral vein.It is common that Iatrogenic injuries (pseudoaneurysms and
arteriovenous fistula) which is secondary to attempted femoral access might occur. Primary
treatment of femoral pseudoaneurysms consists of ultrasound-guided compression and thrombin
injection.
(2) Popliteal Vascular Injury
The lower leg is almost totally dependent on the popliteal artery. Popliteal artery injury
has an amputation rate of up to 16%. The association between posterior knee dislocation and
popliteal artery disruption is well known (Figure 12.5). All patients with posterior knee
dislocations should have a complete neurovascular examination of the affected limb. Most
popliteal artery injuries present with hard signs of arterial injury. The absence of hard signs is
usually sufficient to rule out injuries to the popliteal artery. Injury to popliteal veins should be
repaired to minimize postoperative swelling and compartment syndrome and to improve the
patency of arterial repairs.
Compartment syndrome is a major risk factor for amputation following popliteal artery
injury. There is evidence that fasciotomy performed at the time of arterial repair, but before the
development of compartment syndrome (prophylactic fasciotomy) may lower amputation rates,
particularly in patients with long preoperative delays, extensive injuries, injuries of the artery and
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vein, and venous injuries treated with ligation.Single tibial vessels may be ligated if there is
documented collateral flow distally.
(3) Resuscitative Endovascular Balloon Occlusion of the Aorta (REBOA)
Temporary occlusion of the aorta with a percutaneously placed balloon has been used as
an adjunct to resuscitation and hemorrhage control in thoracic, abdominal, and pelvic
trauma.However, high quality evidence in support of this technique islacking. A recent
systematic review of REBOA concluded that the evidence is weak, with no clear reduction of
hemorrhage-associated mortality.A study from Japan found an association between the use of
REBOA and an excess mortality in patients with hemodynamically unstable torso trauma.
REFERENCES:
1. Inaba K, Aksoy H, Seamon MJ, et al. Multicentre evaluation of temporary intravascular shunt use in vascular
trauma. J Trauma
2. Hafez HM, Woolgar J, Robbs JV. Lower extremity arterial injury: results of 550 cases and review of risk factors
associated with limb loss. J Vasc Surg
3. Ian Lofftus, Robert J. Hinchliffe, A Companion to Specialist Surgical Practice----Vascular and Endovascular
Surgery.
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Chapter 13 Peripheral and Abdominal Aortic Aneurysms
Li Xi, M.D.
a. Introduction
The normal diameter of the aorta varies with age, sex and bodyweight.It decreases in size
as it leaves the thorax and enters the abdomen, tapering to its iliac bifurcation. However, the
infrarenal aorta enlarges progressively with age. An aortic aneurysm is a permanent localized
dilatation of all three layers of the vessel wall of at least a 50% increase in diameter compared to
the expected normal diameter of the aorta.If the maximum normal diameter of the aorta is 2.1cm,
aneurysmal dilatation is said to occur when the diameter exceeds 3.0 cm.
The abdominal aorta is the most affected artery and accounts for 90% of all aneurysms
which 95% originate below the level of the renal arteries. The aortic arch, thoracic aorta and
thoracoabdominal aorta are involved in approximately 10% of aneurysms. Although this
description represents a continuous spectrum,the morphology or shape of aneurysms may be
classified as saccular or fusiform. Saccular aneurysms affect only a small portion of the aortic
circumference while fusiform lesions involve the entire circumference of the vessel.
b. Epidemiology
The prevalence of abdominal aortic aneurysm (AAA) in men over 65 years is around 7–
8% which is to be six times greater in men than in women.In determining the prevalence of AAA,
the frequently asymptomatic nature of the disease is a major confounding factor. Data on
prevalence stem from four sources: autopsy surveys, routine mortality and hospital inpatient
statistics and population-screening surveys. However, screening surveys offer, potentially, the
most accurate estimate of prevalence.
The prevalence of screen-detected AAA in men in England is reported to be between 1.3

and 12.7%.This variation is accounted for by differing criteria for the definition of AAA and the
age group screened. If the criterion of aortic diameter >29 mm is used as the definition for AAA,
the prevalence in men aged 65 years within the UK screening programmer in the year of 2014 to
2015 was 1.2%.These figures are in keeping with data from other European and North American
series.Interestingly, data from autopsy- based surveys yield similar results. The prevalence of
AAA at autopsy in the UK has been reported at 2.3% in men and 1.6% in women.
Ruptured abdominal aortic aneurysm (AAA) accounts for around 10000 deaths each year
in the United Kingdom.This represents a similar number to deaths caused by gastric, esophageal,
and prostatic malignancies.Cause-specific mortality data for England and Wales and Hospital
Episodes Statistics for England have shown that AAA mortality and ruptured AAA admission
have fallen in England and Wales by around one-third, while non-ruptured AAA admission has
remained steady between 2001 and 2009.However, globally, AAA mortality has not declined
over a similar period. National differences can be explained by variations in cardiovascular risk
factors. Of these, the reduction in smoking prevalence correlates most closely with declines in
AAA mortality.Epidemiological data on peripheral aneurysm are less readily available. However,
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the association with AAA is well recognized and approximately 25% of patients with AAA have
synchronous femoral or popliteal aneurysms.It is likely that peripheral aneurysm will have
similar epidemiological trends to AAA.
c. Pathophysiology
The cause of aneurysms remains unclear. Historically, aneurysmal change was thought to
be underpinned by atherosclerosis. However, because of histological and epidemiological
differences it is now recognized that atherosclerosis is a coexistent phenomenon and the majority
of AAA which is 90 percent are thought to represent a degenerative or non-specific process.
Abdominal aortic aneurysms exhibit familial clustering. This raises the possibility of both
genetic and environmental etiological factors. Genes encoding for type III collagen, matrix
metalloproteinases and protease inhibitors and plasminogen activator inhibitors have all been
reported to play some role in AAA development or expansion.However, no specific genes have
been convincingly implicated to date and it is inferred that susceptibility to the development of
AAA is an irreversible process with multiple genetic and environmental risk factors. Genetic
influences are attributed to a few gene polymorphisms with large effects.
North American and European data suggest that there is a fourfold increase in risk of
having an AAA for the brother of a patient having an AAA.Familial abdominal aortic aneurysms
are more common when the index case is female, and rupture is said to occur at a younger age
and more often than with sporadic aneurysms.
Established independent risk factors for AAA include male gender, age, hypertension,
hyperlipidemia, and smoking. In particular, the relationship between tobacco uses and AAA
development is striking. Aneurysms are four times more prevalent amongst smokers than non-
smokers and the comparative relative risks of chronic cigarette smokers developing an AAA are
threefold greater than their risk of developing coronary artery disease. For these reasons, it is
thought that smoking is the foremost environmental risk factor for aneurysm development and
growth. Interestingly, diabetes is associated with a reduced risk.
Abdominal aortic aneurysms are characterized histologically by destruction of elastin and

collagen in the tunica media and tunica adventitia, smooth muscle cell apoptosis with thinning of
the medial wall, infiltration of lymphocytes and macrophages, and neovascularization.Four
pathological mechanisms are thought to play central roles in AAA development: proteolysis of
connective tissue, inflammation, biomechanical stress and genetic influences.
i. Proteolysis
Macrophage and aortic smooth muscle cell derived matrix metalloproteinases (MMPs)
and other proteases are secreted into the extracellular matrix and are integral to aneurysm
formation. Even though MMPs are expressed and active during normal physiological aortic
remodeling, they mediate degradation of elastin and collagen within the aortic media and internal
lamina in AAA pathogenesis.A shift in the balance between MMPs and their inhibitors moves
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away from normal remodeling activity towards pathological elastin and collagen degradation.
Factors initiating and propagating proteolysis in the aorta remain unclear.
ii. Inflammation
Transmural lymphocyte and macrophage infiltration are histological characteristics of

AAA. An inflammatory cytokine cascade released by these cells is thought to stimulate protease
activation. The chemotactic triggerwhich is responsible for this cellular migration remains
uncertain,despite the fact that it has been proposed that aortic elastin degradation products,
interstitial collagen or oxidized low-density lipoprotein, may be antigenic and chemotactic
stimuli for macrophages.
iii. Biomechanics
The aortic wall contains smooth muscle, elastin and collagen arranged in concentric
layers to withstand arterial pressure. Elastin is the principal load-bearing element in the aorta
while collagen provides tensile strength to help maintain the structural integrity of the vascular
wall.The normal aorta displays a reduction in the elastin tocollagen ratio as it passes from the
thorax into the abdomen.Thus, the abdominal aorta has less elastin and less load-bearing
potential than the aortic arch.
Matrix metalloproteinase-9 expression and activity is increased in the abdominal aorta

compared with aortic arch and thoracic aorta. Activation of these proteases is also thought to be
brought about by the disruption of normal laminar flow seen in the infrarenal aorta.Furthermore,
the attenuation of the vasa vasorum in the infrarenal aorta is proposed to contribute to relative
hypoxia of the vessel stimulating MMP activity. These factors are all thought to contribute to the
predisposition of the infrarenal aorta to develop aneurysmal change.
iv. Genetics
Although multifactorial genetic influences are involved in AAA development, the

polymorphisms responsible for aneurysm pathogenesis remain elusive. Similarly, the phenotypic
expression of these traits is uncertain. It is proposed that an abnormality of the primary structures
of elastin and collagen or a mutation, directly or indirectly, affecting protease and protease-
inhibitor activity are implicated.
d. Clinical features
About 75% of aortic aneurysms are asymptomatic and are discovered incidentally. A
small proportion will present with symptoms related to pressure on adjacent structures
(dysphagia, ureteric obstruction, cava obstruction).
A small subset of abdominal aortic aneurysm cases may present with the triad of lower
back pain, weight loss and raised erythrocyte sedimentation rate. This triad is characteristic of
inflammatory abdominal aortic aneurysm, which represents the most extreme end of the
spectrum of chronic inflammatory change seen in degenerative aneurysms, and accounts for 10%
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of all abdominal aortic aneurysms. These cases are further characterized by a thickened
aneurysm wall, retroperitoneal fibrosis that may cause obstructive uropathy and dense adhesions
to adjacent viscera. Most of the clinical symptoms due to aortic aneurysm are related to
aneurysm rupture or embolism of mural thrombus.
Aneurysm rupture is associated with an estimated overall mortality of 90% and a significant
proportion of patients will not reach hospital. Of those that present, most will have a contained
retroperitoneal hematoma causing tamponade and resulting in temporary hemodynamic stability.
The characteristic triad of abdominal or back pain, hypovolemic shock and a pulsatile abdominal
mass is present in only a few patients and the symptoms may be vague, and an abdominal mass
missed. Other symptoms and signs may include groin pain, syncope, paralysis, or flank mass. A
ruptured aneurysm should be considered in any elderly patient with unexplained hypotension and
abdominal symptoms. The diagnosis may be confused with renal colic, diverticulitis, pancreatitis,
or disease affecting the lumbar spine. A small proportion of abdominal aortic aneurysms rupture
into an adjacent structure causing a primary aortic fistula; rupture into the vena cava produces a
large arteriovenous fistula. In this case, symptoms include tachycardia, congestive heart failure,
leg swelling, abdominal thrill, abdominal bruit, renal failure and peripheral ischemia. Abdominal
aortic aneurysms may rupture into the fourth part of the duodenum and presentation may be with
a herald upper gastrointestinal bleed followed by massive hemorrhage.
Embolism: patients with embolization of thrombus from an aortic aneurysm may also present
with acute ischemia of the lower limb due to occlusion of the femoral or popliteal artery. Small
aortic aneurysms may also undergo acute occlusion due to thrombosis as the aortic lumen
becomes progressively narrowed by the accumulation of mural thrombus; these patients may
present with acute bilateral lower limb ischemia.
Screening: As most AAA are asymptomatic, most patients who suffer rupture will die, B-mode
ultrasound is a highly sensitive and specific diagnostic tool, and elective aneurysm repair is an
effective prophylaxis against rupture, population screening is appealing. A meta-analysis of four
randomized controlled trials of screening elderly men for AAA with 15-year follow-up, has
shown a significant and substantial reduction in the risk of death from AAA and the need for
emergency surgery with an associated increase in elective repair.
In England, the National Health Service AAA screening program began in 2009. It offers
all men aged 65 years an invitation for ultrasound screening. The same screening strategy is
employed in Sweden and the rest of the United Kingdom. Interestingly, both programs have
demonstrated an incremental cost-efficiency ratio of £7000 per quality-adjusted life-year
(QALY). Compared with existing screening programs for breast and cervical cancer, AAA
screening for men remains cost effective.
The Multicenter Aneurysm Screening Study (MASS) trial has provided good statistical
evidence to show that the prevalence of aneurysm-related death is reduced significantly in a
screened male population from 65 to 74 years old, with a 53% reduction in those who attended
for screening. Because other causes of death overshadow those due to ruptured AAAs, it has not
been possible to demonstrate a statistically significant overall survival advantage for the screened
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population. Nevertheless, the case for extending population-based screening for AAAs is
convincing.
Analysis of the 10-year Multicenter Aneurysm Screening Study (MASS) data shows that
the NHS AAA Screening Program (NAAASP) will prevent significant numbers of AAA ruptures
and AAA deaths. It also proves that the number of lives saved will greatly outweigh the number
of post-elective surgery deaths. The following figures use the 10-year MASS data and assume an
80% attendance for screening and a 5% post-elective surgery mortality: 240 men need to be
invited (192 scanned) to save one AAA death over 10 years and each 2080 men invited for
screening (1660 scanned) result in one extra post-elective surgery death. This means that over 10
years, for every 10000 men scanned under the NAAASP, 65 AAA ruptures will be prevented,
saving 52 lives. However, there will also be six post-elective surgery deaths involving men
whose aneurysm is detected under the screening program.
e. Diagnosis
Aortic aneurysms may not be detected by clinical examination. Calcification of the

aneurysm wall may be apparent on plain abdominal or chest radiograph, but this method lacks
sensitivity and is unsatisfactory for routine use. B-mode ultrasound is the diagnostic
investigation of choice for the detection of AAA, providing accurate assessment of the aneurysm
diameter and some indication regarding site.Computed tomography (CT) is the investigation of
choice to delineate abdominal aortic aneurysm morphology and relationship to the visceral and
renal arteries. CT or magnetic resonance imaging will detect thoracic aortic aneurysms.
f. Principles of management
The principles of management in asymptomatic abdominal aortic aneurysm are based on

an assessment of the risk of aneurysm rupture weighed against the morbidity and mortality
associated with surgical repair. The size and growth of AAA are strongly associated with the
amount and duration of smoking; smoking cessation can moderate this risk.The association
between hypertension and hypercholesterolemia and AAA suggests that medical management of
these conditions may have a benefit on aneurysm growth.
However, several drugs have been investigated in randomized controlled and non-
randomized trials including beta-blockers, ACE inhibitors, angiotensin-receptor blockers and
statins. None of these drugs has been shown to confer a benefit.Nevertheless, given the strong
association between atherosclerosis and AAA, it is recommended that aneurysm patients receive
best medical therapy to reduce the incidence of cardiovascular events.
The natural history of untreated asymptomatic AAA is one of expansion and potential
rupture. Measurement of the maximum anteroposterior diameter of the aneurysm predicts the
risk of rupture. Randomized controlled data on abdominal aortic aneurysm of <55mm diameter
has demonstrated a mean risk of rupture of 1% per year.However, there is little randomized
evidence to inform the rate of rupture in large aneurysms. A multicenter study of 198 patients
with AAA >5.5cm for whom elective repair was not planned due to medical comorbidity or
patient refusal, demonstrated a 1-year rupture risk for AAA of 5.5–5.9 cm of 9.4%, 10.2% for
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AAA of 6.0–6.9 cm and 32.5% for AAA of >7cm.Interestingly, the risk of rupture in the smallest
AAA diameter cohorts was significantly greater than that reported in randomized controlled
trials. This finding has been reported across other studies and it is likely that patients with
significant coexistent morbidity are at a higher risk of rupture than their healthier counterparts.
The projected annual rates of rupture for AAA from a meta-analysis of 13 studies are shown in
Table 13.1.However, some small aneurysms rupture and some large aneurysms do not.
Figure 13.1.Reconstructed CT aortogram of infrarenal aorto-iliac aneurysm.
AAA size (cm) Risk of Rupture Per Year (%)

< 3.0 0
3-3.9 0.4
4-4.9 1.1
5-5.9 3.3
6-6.9 9.4
7-7.9 24
Table 13.1 Annual abdominal Aortic Aneurysm Rupture Risk in relation to Size.
Patients with asymptomatic abdominal aortic aneurysm of 30mm to 54mm should be kept
under regular ultrasound surveillance to monitor growth. Current recommendations for
surveillance intervals are every three years for 30mm to 34mm, annually for 35mm to 44mm,
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and every 6 months for 45mm to 54mm.Elective repair is only recommended in asymptomatic
abdominal aortic aneurysm of more than 55mm diameter. This applies to both open and
endovascular aneurysm repair. The operative mortality associated with elective infrarenal
abdominal aortic aneurysm repair is between 1% and 6%.
Symptomatic, intact AAA or rapid expansion (>1 cm/ year) represents a relative
indication for operative repair. It is thought that symptoms of pain attributable to an aneurysm
are due to acute expansion or imminent rupture and urgent repair is recommended. Aneurysm
rupture is usually an absolute indication for surgery because without repair, mortality is almost
certain. Surgery in some patients may be futile due to comorbidity or poor preoperative clinical
condition such unconsciousness, or cardiac arrest.
The Medical Research Council-sponsored UK Small Aneurysm Trial (SAT) randomized

1090 patients with asymptomatic AAAs of 4.0–5.5 cm diameter to either initial ultrasound
surveillance (527 patients) or surgery (563 patients). In the surveillance group, 321 patients
eventually underwent surgery due to rapid expansion or growth to above the 5.5 cm threshold. In
the early surgery group, the 30-day mortality rate was 5.8%. There was no difference in survival
between the groups and the UK SAT concluded that early operative intervention for patients with
AAAs of less than 5.5 cm diameter was not indicated. The rupture rate for untreated small
aneurysms in this trial was less than 2% per annum. However, the rate was relatively higher in
females, and this suggests that elective surgery may be indicated for smaller aneurysms in this
group of patients. However, at present the data are insufficiently robust to support this
conclusion convincingly.
g. Repair of intact abdominal aortic aneurysm
There are two methods by which abdominal aortic aneurysms may be excluded –
traditional open repair and endovascular aneurysm repair (EVAR). Open surgical repair of AAA
is a durable and cost-effective procedure. Endovascular aneurysm repair is effective and safe in
selected patients, with lower short and medium-term morbidity and mortality rates than open
surgery. Patients with AAAs have a markedly reduced life expectancy in comparison with age-
and sex-matched controls. The 5-year survival of patients post open surgery varies from 62% to
72% (compared with 83–90% in age- and sex-matched populations), with most deaths due to
coronary artery disease.
i. Preoperative assessment
Patients with asymptomatic AAAs >55mm who are candidates for surgical repair require
careful risk assessment of their general health and fitness to determine their suitability for
surgery. The goals of assessment are: to identify patients in whom the balance of risk favors
surgical intervention, to reduce perioperative morbidity and mortality by identifying modifiable
comorbidity; to determine suitability for either open or endovascular repair by assessing
aneurysm anatomy; to determine patient preferences for management.
Thorough clinical assessment is necessary as it is recognized that perioperative death is

related to pre- existing physiological status companion. Most early deaths after AAA repair
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relate to cardiac events and if pre-existing cardiac disease is identified and treated prior to
surgery, survival rates can be improved.
The Medical Research Council-sponsored Small Aneurysm Trial (SAT) randomly

selected 1090 patients with asymptomatic AAAs of 4.0–5.5 cm diameter to either initial
ultrasound surveillance (527 patients) or surgery (563 patients). In the surveillance group, 321
patients eventually underwent surgery due to rapid expansion or growth to above the 5.5 cm
threshold. In the early surgery group, the 30-day mortality rate was 5.8%. There was no
difference in survival between the groups and the SAT concluded that early operative
intervention for patients with AAAs of less than 5.5 cm diameter was not indicated. The rupture
rate for untreated small aneurysms in this trial was less than 2% per annum. However, the rate
was relatively higher in females, and this suggests that elective surgery may be indicated for
smaller aneurysms in this group of patients. However, at present the data are insufficiently robust
to support this conclusion convincingly.
Another study demonstrated an in-hospital mortality rate of 4.7% with a 5-year survival
rate of 68%. The UK Small Aneurysm Trial reported a 30-day mortality rate of 5.8% and the
recent EVAR-1 trial a 30-day mortality rate of 4.7% in patients fit for surgery.
Preoperative assessment often includes:
• Full blood count

• Serum urea and electrolytes
• Liver function tests
• Pulmonary function tests
• Cardiac assessment with resting ECG and echocardiography
• Cardiopulmonary exercise testing
• Multidetector CT aortography.
Further cardiovascular assessment including exercise ECG, dobutamine-stress ECHO, or

coronary angiographymay be indicated in patients with a history or symptoms of ischemic heart
disease.In patients with significant and irreversible comorbidity, it is appropriate to continue
ultrasound surveillance until aneurysm diameter reaches a size where the risk of rupture
outweighs the increased risk of surgical mortality. It may be impossible to justify elective
operative repair regardless of size in patients with overwhelming comorbidity.
j. Open Repair
There are two methods by which abdominal aortic aneurysms may be excluded –
traditional open repair and endovascular aneurysm repair (EVAR). Open surgical repair of AAA
is a durable and cost- effective procedure. Endovascular aneurysm repair is effective and safe in
selected patients, with lower short- and medium-term morbidity and mortality rates than open
surgery. Patients with AAAs have a markedly reduced life expectancy in comparison with age-
and sex-matched controls. The 5-year survival of patients post open surgery varies from 62% to
72% (compared with 83–90% in age- and sex-matched populations), with the majority of deaths
due to coronary artery disease.
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Under general anesthesia and with perioperative broad-spectrum antibiotic and

thromboembolic (heparin [s/c]) prophylaxis, a transverse supraumbilical or midline incision is
utilized to allow a transperitoneal approach to the aorta. Alternatively, an oblique left-sided
abdominal incision may be used to achieve an extraperitoneal approach to the aorta. Epidural
analgesia may also be used to improve postoperative respiratory function. The routine use of cell
salvage for intraoperative autologous transfusion is a useful adjunct companion.
At laparotomy, the transverse colon is reflected upwards, and the small bowel reflected to
the right. Division of the posterior peritoneum exposes the aneurysm. The left renal vein is
identified and the neck of an infrarenal aneurysm will be identified. The common iliac vessels
are also identified and exposed. Care should be taken to avoid damage to the hypogastric plexus
of nerves to avoid postoperative sexual dysfunction. After which aortic and iliac clamps are
applied,a bolus of heparin is given intravenously to reduce the risk of thrombosis in situ and
perioperative cardiac injury. If the aneurysm extends into the common iliac arteries, the vessels
may be mobilized to the common iliac bifurcation and control obtained of the internal and
external iliac arteries. The aneurysm sac is opened longitudinally, and mural thrombus removed.
Back-bleeding from the lumbar, median sacral and inferior mesenteric arteries (IMA) may ensue
and over-sewing these vessels controls this. The aneurysm may be repaired using a tube (60–
70%) or bifurcated prosthetic aortic graft made from sealed or coated, knitted DacronTM. The
graft is secured proximally and distally using an inlay technique and end-to-end anastomoses
with a monofilament suture.
The lower limbs are re-perfused sequentially upon completion of the anastomoses. The
anesthetist should be warned prior to releasing the clamps of each limb because of the
hypotension caused by limb reperfusion and the sudden release of anoxic metabolites from the
lower limbs into the systemic circulation. The aneurysm sac is closed over the aortic graft to
reduce the risk of late postoperative aorta fistulation. The lower limbs and left colon should be
inspected to ensure adequate perfusion. Postoperatively patients are extubated and managed in a
high-dependency unit. Early procedure-specific complications are mainly cardiac and respiratory
in etiology although renal dysfunction, colonic ischemia, and lower limb problems due to
microembolism may also occur. The patient should be encouraged to mobilize early, and oral
intake can be re-established within 24 hours. In-hospital stay is usually 7–14 days. The 30- day
mortality rate has remained around 3–5% for the past 10 years.
Aortic aneurysmal disease extends above the renalarteries toinvolveavariablelengthofthe

thoracic aorta in 5–10% of patients. Transperitoneal suprarenal clamping may be possible for
juxta renal AAA, but more proximal aneurysms require supracoeliac clamping performed by
laparotomy with medial visceral rotation or thoracotomy and replacement with a DacronTM
aortic prosthesis as well as reimplantation of the visceral and intercostal arteries. The results of
surgery in specialist centers are good but complications such as paraplegia, organ dysfunction
and significant mortality may occur. A few centers have advocated the technique of laparoscopic
aortic surgery. There is an absence of any randomized data to support its use outside of a clinical
trial.
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h. Operative repair of ruptured abdominal aortic aneurysm
The surgical mortality associated with ruptured AAA is more than 40%. Once a ruptured
AAA is diagnosed, patients suitable for attempted repair should be transferred to the operating
theatre immediately. In general, patients should receive cautious fluid resuscitation with
permissive hypotension. Sudden overloading of the intravascular compartment together with its
associated increase in systemic blood pressure may cause expansion and rupture of a contained
retroperitoneal hematoma resulting in potential exsanguination.
In theory, the patient is prepared and draped prior to the induction of anesthesia; central
venous access can be performed after induction. Rapid sequence induction is performed together
with rapid entry into the abdomen to limiting the potential hypotensive effects of anesthesia
caused by the loss of tamponade from relaxation of the anterior abdominal wall. The neck of the
aneurysm must be identified for clamping despite the significant.
i. Case Study: Abdominal aortic aneurysm in patients affected by intermittent

claudication-----prevalence and clinical predictors
Systemic atherosclerosis represents the leading cause of morbidity and mortality in the
western countries, with increased prevalence in the elderly population. The atherosclerotic
disease may involved different part of vascular tree, in particular coronary arteries, carotid
arteries and peripheral arteries.Abdominal aortic aneurysm (AAA) is a frequent cause of death in
the elderly and its incidence has increased during last decades because of the increasing life-
expectancy and the development of easy and low-cost diagnostic tools like ultrasound. The rising
incidence of AAA and the severe prognosis in case of rupture with a mortality rate that can be as
high as 90% call for early identification and elective repair. However, opposing views have been
published on the importance of ultrasound screening for AAA and there is still debate on the
high -risk populations who need to be screened.
Lower extremity peripheral arterial disease (LE-PAD), one of the main expressions of
atherosclerosis, affects about 27 million people in Europe and the United States and is associated
with a high risk of developing fatal and non-fatal ischemic cardiovascular events. Patients
affected by LE-PAD seem to be at particularly high risk for AAA development. Accordingly, we
aimed this study at assessing the prevalence and the clinical predictors of the presence of AAA in
a homogeneous cohort of LE-PAD patients affected by intermittent claudication, the most
frequent clinical expression of LE-PAD.
(1) Methods:
We performed an abdominal ultrasound in 213 consecutive patients with documented

LE-PAD attending our outpatient complaining intermittent claudication. Using an Image Point
Hx ultrasound system (Hewlett Packard) and a 3.0 MHz transducer, we measured in each patient
both antero-posterior and transverse outer diameters at the largest portion of the infrarenal
abdominal aorta. AAA was defined by an infrarenal abdominal aorta diameter ≥ 3 cm [23].
Infrarenal abdominal aortas 2.6 to 2.9 cm were defined ecstatic.
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The diagnosis of PAD was based on the presence of an ankle brachial index (ABI) ≤ 0.90.
ABI was measured after participants had rested supine for 5 minutes. The systolic blood pressure
in both brachial arteries, and the ankle systolic blood pressure in the right and left posterior tibial
and dorsalis pedis arteries were measured using a Doppler probe. The ABI for each leg was then
determined using the higher of the two readings from either the posterior tibial or dorsalis pedis
arteries, and the higher of the two brachial readings. The lower ABI of the two legs was used for
diagnostic purposes.In each patient, clinical history and risk factors were assessed. Smokers
included current and former smokers. Hypertension was diagnosed if systolic arterial pressure
exceeded 140 mmHg and/or diastolic arterial pressure exceeded 90 mmHg, or if the patient used
antihypertensive drugs. Hypercholesterolemia was diagnosed if plasma total cholesterol
exceeded 200 mg/dL, plasma low-density lipoprotein cholesterol exceeded 130 mg/dL, or if the
patient used lipid-lowering drugs because of a history of hypercholesterolemia. Diabetes mellitus
was diagnosed if plasma fasting glucose exceeded 126 mg/ dL or if the patient used
hypoglycemic agents. A history of coronary artery disease, previous myocardial infarction, or
ischemic stroke was documented by hospital records. All patients underwent ultrasound
examination of carotid arteries.
All participants gave written informed consent to the study, which was approved by our
institutional Ethics Committee.Blood was drawn from an antecubital vein using a 19-gauge
needle in a Vacutainer system (Becton-Dickson, Franklin Lakes, NJ). Neutrophil count was
measured with the Bayer H*2 hematology analyzer (Bayer Diagnostic Division, Tarrytown,
NY).Statistical analyses were performed using SPSS 12.0 (SPSS, Inc., Chicago, IL, USA).
Variables were expressed as absolute numbers and percentage or mean ± SD, except for
neutrophil count, which was expressed as median and inter-quartile range because of their
skewed distribution. Comparisons were made by t-test for unpaired samples, χ2 test, or Mann–
Whitney U test, as appropriate. For continuous variables, receiver-operating characteristic (ROC)
curve analysis was used to identify the threshold levels that provided the best cut-off for the
prediction of the presence AAA. Correlations between continuous variables were evaluated by
Spearman analysis.All statistical tests were two-sided. For all tests, a p-value <0.05 was
considered statistically significant.
(2) Statistics:
The ultrasound was inconclusive in 3 patients (1.4%), thus 210 patients (169 males, 41
females, mean age 65.9 ± 9.8 yr) completed the study. Overall, AAA was present in 19 patients
(9.0%), with a not significant higher prevalence in men than in women (10.1% vs 4.9%, p =
0.300). Furthermore, patients with AAA were older (71.2 ± 7.0 vs 65.4 ± 9.9 years, p = 0.015) ,
were more likely to have hypertension (94.7% vs 71.2%, p = 0.027), and greater neutrophil count
(5.5 [4.5 – 6.2] vs 4.1 [3.2 – 5.5] x103/μL, p = 0.010). The prevalence progressively increased
with age (p for trend = 0.013), with a maximum of 15.8% in over 75-year-subjects. Of note, in
our population we observed a higher prevalence of carotid stenosis >50% in claudicate patients
with AAA, although not significant (47.4 vs 29.3%, p = 0.105). No relationship was found
between the ankle/brachial index and the presence of AAA. For continuous variabilities, which
are associated to the presence of AAA at univariate analysis (i.e. age and neutrophil count), ROC
curve analysis was performed to evaluate the best cut-offs to predict the presence of the disease.
The best cut-offs were ≥ 66 years for age and ≥ 5.1 x103/μL for neutrophil count. Importantly,
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the c-statistic for neutrophil count (0.73, 95% CI 0.60 – 0.86, p = 0.010) was higher than that for
age (0.67, CI 0.56 –0.78, p = 0.017) (Figure 1). In our population the prevalence of AAA in
claudicate patients with a neutrophil count ≥ 5.1 x103/μL (cut-off identified at ROC analysis)
was as high as 29.0%. Of note, Spearman analysis showed that neutrophil count and age are not
correlated (ρ = -0.123, p = 0.230).
(3) Discussion:
The present study demonstrates that prevalence of AAA in claudicate patients is much
higher than that reported in the general population, with the highest clinical predictors being
advanced age and an elevated inflammatory status.To decrease the number of deaths from
ruptured AAA, early detection by screening subjects at high risk is needed. Physical examination
is not effective in identifying the presence of an AAA, while abdominal ultrasound is an accurate
test to detect the presence of this life-threatening disease. Elderly males are those who show the
highest prevalence of the disease in the general population.
Indeed, there is evidence that screening programs involving males with> 65 years are
cost-effective. The strong association with age has been confirmed also in our population of
claudicate patients. Indeed, we observed that the prevalence of AAA dramatically increases after
65 years (optimal cut-off identified at ROC analysis being ≥ 66 years) and no AAA was found in
patients younger than 55 years of age. Thus, age cut-off to initiate screening for AAA in patients
with intermittent claudication seems to be the same than in general population. These results
might suggest that performing an abdominal ultrasound in all claudicate patients may not be
advisable. However, in our study, we found that an elevated inflammatory status, evaluated by
neutrophil count, is a powerful predictor of the presence of AAA in patients with intermittent
claudication, and that the neutrophil count did not correlate with age. Initiating the screening in
patients ≥ 65 years with intermittent claudication might consequently lead to miss some
diagnosis of AAA, and therefore in claudicate patients with an elevated inflammatory status the
ultrasound screening should be performed irrespective of age. At this regard, pathophysiological
studies are needed to evaluate whether the increased inflammation observed in our population of
intermittent claudication patients affected by AAA is a cause or a consequence of the presence of
AAA.
(4) Conclusion:
The high prevalence of AAA among patients affected by intermittent claudication makes
them a suitable target population for AAA screening. In our opinion ultrasound screening should
be considered in these patients, especially in those with an elevated neutrophil count. However,
further studies are warranted to elucidate if screening all patients with intermittent claudication
for of this life-threatening condition is cost-effective.
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1. The UK Small Aneurysm Trial Participants.Mortality results for randomised controlled trial of early elective
surgery or ultrasonographic surveillance for small abdominal aortic aneurysms. Lancet 1998.
2. Johnston KW. Non-ruptured abdominal aortic aneurysm: six-year follow up results from the
multicentreprospective Canadian aneurysm study. Canadian Society for Vascular Surgery Aneurysm Study Group. J
Vasc Surg 1994.
3. Morrow DA, Braunwald E, Bonaca MP, Ameriso SF, Dalby AJ, Fish MP, Fox KA, Lipka LJ, Liu X, Nicolau JC,
et al: Vorapaxar in the secondary prevention of atherothrombotic events. The New England journal of medicine.
2012
4. Giugliano G, Di Serafino L, Perrino C, Schiano V, Laurenzano E, Cassese S, De Laurentis M, Schiattarella GG,

Brevetti L, Sannino A, et al: Effects of successful percutaneous lower extremity revascularization on cardiovascular
outcome in patients with peripheral arterial disease. International journal of cardiology. 2012
5. Cassese S, Esposito G, Mauro C, Varbella F, Carraturo A, Montinaro A, Cirillo P, Galasso G, Rapacciuolo A,

Piscione F: MGUard versus bAre-metal stents plus manual thRombectomy in ST-elevation myocarDial infarction
pAtieNts-(GUARDIAN) trial: study design and rationale. Catheterization and cardiovascular interventions : official
journal of the Society for Cardiac Angiography & Interventions. 2012
6. Contaldi C, Losi MA, Rapacciuolo A, Prastaro M, Lombardi R, Parisi V, Parrella LS, Di Nardo C, Giamundo A,
Puglia R, et al: Percutaneous treatment of patients with heart diseases: selection, guidance and follow-up. A review.
Cardiovascular ultrasound. 2012
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Chapter 14 Aortic Dissecting Aneurysm
Li Xi, M.D.
a. Thoracic dissection and acute aortic syndrome
i. Pathology, classification, and clinical presentations
The acute aortic syndromes are a group of conditions affecting the thoracic aorta that
cause patients to present to hospital with chest pain and encompasses three main pathological
entities: aortic dissection (Figure 14.1a and Figure 14.1b), intramural hematoma (IMH;Figure
14.2) and penetrating aortic ulcers (PAUs; Figure 14.3). All three conditions may coexist, and
both IMH and penetrating ulcer may instigate a classical aortic dissection.
Figure 14.1a. Sagittal reconstruction showing the classic appearance of a type B aortic dissection.
Aortic dissection is defined as a tear in the intima of the aorta that allows blood to form a
pathological plane of cleavage between itself and the adventitia by disrupting the media. These
two new channels are referred to as the true and false lumens. Typically, the pressure within the
false lumen is higher than the true lumen, as the outflow is usually a small re-entry tear. This
leads to compression of the true lumen, which can result in malperfusion of the viscera or limbs,
or rupture of the false lumen. Such branch vessel malperfusion may be described as ‘dynamic’,
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due to a mobile dissection flap intermittently ‘shuttering’ the ostia of vessels during systole, or
static due to a relatively fixed flap (Figure 14.4).
Figure 14.2. Axial CT appearance of Intramural hematomaFigure 14.3 Axial CT appearance of penetrating aortic
ulcer
Figure 14.4. Patient with a type B thoracic aortic dissection showing compression of the true lumen causing
malperfusion of the coeliac artery and therefore visceral ischemia.
IMH is defined as clotted blood in the intramural space without an obvious intimal tear.
This is thought to result from rupture of medial vasa vasora and is often regarded as a precursor
to dissection. IMH accounts for up to 5–15% of acute aortic syndromes and has a prognosis like
classical aortic dissection.PAU results from focal ulceration of an atherosclerotic plaque into the
media and may be associated with hematoma within the aortic wall. Penetrating ulcers have a
poorer prognosis than classical dissection, with higher rates of aortic rupture, but make up only
5% of acute aortic syndrome presentations. PAU is a disease of the intima, in comparison with
dissection and IMH, which are considered to be diseases of the media.
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Aortic dissections are classified by site, chronicity, and presentation. The most crucial
classification involves the site of dissection. Under the commonly used Stanford classification,
type A dissection involves the ascending aorta whereas type B dissection originates distal to the
left subclavian artery. The DeBakey system is also used to classify site. DeBakey I dissections
extend from the ascending aorta into the descending, DeBakey II involve only the ascending
aorta and DeBakey III originate from beyond the left subclavian artery (IIIa do not extend below
the diaphragm whereas IIIb do). Dissections are termed acute when they are less than 2 weeks
after the onset of symptoms and are chronic after this period. Many now recognise a third,
subacute phase between 2 and 12 weeks which may have significance in terms of the predicted
response to endovascular treatment.In addition, dissections may be complicated or
uncomplicated. Complicated aortic dissections exhibit clinical or imaging findings such as
impending or frank rupture, malperfusion, persistent pain and refractory hypertension. A recent
expert consensus suggested a more comprehensive way of classifying dissection based on the
following: Duration of disease, Size of the aorta, Segmental Extent, Clinical complications and
Thrombus within the lumen (DSSCT).
Acute aortic syndromes often present with the sudden onset of sharp tearing or stabbing
chest pain, which radiates to the neck and back. Pain is absent in 10% of patients, and
asymptomatic presentation is more common in diabetics. Acute rupture or malperfusion may
lead to collapse and death, neurological deficits, symptomatic limb ischemia, or visceral
ischemia. Hypotension is seen in patients with rupture or critical malperfusion, but hypertension
is often present. Chronic dissection is often asymptomatic but can cause back pain or chronic
visceral ischemia. Consensus guidelines from the American Heart Association place high-risk
features into three categories.High-risk predisposing conditions include aortic instrumentation,
Marfan’s syndrome or thoracic aortic aneurysmal disease. High-risk pain features include an
abrupt onset of ripping, tearing, or stabbing pain in the chest, back, or abdomen. High-risk
features of the examination include discrepancy in limb perfusion, focal neurological signs, a
new murmur of aortic regurgitation and circulatory shock. Urgent imaging should be undertaken
if clinical suspicion of aortic dissection is sufficient based on the presence of these features.
ii. Investigation of suspected acute aortic syndrome
Axial imaging to visualize the whole aorta must be undertaken if a diagnosis of acute
aortic syndrome is suspected. Serum D-dimer levels can be raised, and concentrations above 500
ng/mL are often present in patients with acute dissection, although this has a relatively low
specificity.Multidetector computed tomography angiography (CTA) is the preferred
investigation and a meta-analysis of 1139 patients with aortic dissection found that CTA had a
sensitivity of 100%, specificity of 98% and a diagnostic odds ratio of 6.5. The disadvantages of
computed tomography angiography are the need to use potentially nephrotoxic contrast media,
exposure to ionizing radiation, and inability to assess functional aortic insufficiency. This
technique is limited due to inability to visualize the descending aorta, although aortic valve
insufficiency and pericardial tamponade can be diagnosed effectively. Transesophageal
echocardiography can visualize the entire thoracic aorta and despite the requirement for
esophageal intubation, can be performed at the bedside.
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Transesophageal echocardiography can also be an adjunct to endovascular repair due to

the ability to see devices within the aortic lumen. Magnetic resonance angiography has a high
sensitivity and specificity when used to diagnose aortic dissection. Gadolinium contrast agents
are less nephrotoxic than iodinated substances used for computed tomography angiography and
there is no associated ionizing radiation. Disadvantages include its limited use in patients with
claustrophobia or metal devices, although it can be used in those with nitinol aortic stent grafts.
Long acquisition times and limited availability reduce its usefulness in the emergency setting, for
which computed tomography angiography is ideal. The use of most current“four-dimensional”
cine MRI techniques may offer the potential for dynamic assessment of aortic dissection to
determine the nature of blood flow within the true and false lumen. This information may be
used to determine which patients are likely to benefit from earlier treatment due to an increased
risk of subsequent aortic expansion.
iii. Initial management of acute aortic dissection
Management of aortic dissection involves rapid pharmacological control of blood

pressure and left ventricular ejection velocity. The short-term goal of management is to
resuscitate the patient and arrange definitive investigations to confirm the diagnosis. Persistent
hypertension should be managed with intravenous beta-blockade via an agent such as labetalol to
reduce aortic wall shear stress in the arch. A target heart rate of 60–80 beats/minute and systolic
blood pressure of 100mmHg to 120mmHg should be reached, taking into account the patient’s
normal blood pressure. Glyceryl trinitrate should be avoided as the reduction in diastolic blood
pressure may lead to a widened pulse pressure and a reflex tachycardia, and it increases aortic
wall shear stress. Invasive cardiovascular monitoring will be required and transfer of the patient
to a level II or III environment in a sufficiently experienced cardiovascular center is mandatory.
While maintaining a low blood pressure is ideal, it is important to ensure adequate organ
perfusion by monitoring urine output, neurological status checks and checking peripheral
perfusion. Regular arterial blood–gas analysis and examination for trends in markers of tissue
perfusion may provide clues that malperfusion is developing. Type A dissection has a 1%
mortality per hour from aortic rupture, aortic regurgitation, pericardial tamponade, or coronary
ischemia and is treated by emergency surgical graft repair of the ascending aorta, with or without
aortic valve replacement.
After the acute phase, the management of type B dissections is initially medical in those
with acute uncomplicated presentations, with intervention reserved for those exhibiting signs of
complications. Intravenous agents can be replaced by oral antihypertensives, and European,
American, and Japanese guidelines advocate beta-blockers with a target blood pressure of less
than130 mmHg, with the addition of vasodilators in refractory cases.For many years this was
thought to be adequate treatment in the longer term, but recent studies have shown a high rate of
failure of medical treatment in the mid-term. Due to the fact that the open surgical repair is
highly invasive, it was the mainstay of treatment for acute complicated dissection for many years
but is associated with high levels of mortality and morbidity. With mortality rates as high as 30%
reported in multinational registry data, endovascular repair is now seen as an attractive
alternative.
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iv. Endovascular management of complicated acute type B thoracic dissection
Endovascular therapy is now the primary treatment for complicated type B thoracic
dissections due to superior perioperative results compared with open surgery. The aim of
treatment is to cover the primary entry tear with an endovascular stent-graft which depressurizes
the false lumen and allows expansion of the true lumen. In the acute phase, this reduces the
probability of aortic rupture and alleviates dynamic branch vessel occlusion by allowing
preferential perfusion of the true lumen (Figure 14.5). If there is residual static branch vessel
occlusion, this may be treated by secondary stent placement. In the longer term, this promotes
aortic remodeling, and it is defined as the restoration of normal anatomy occurring with
thrombosis and regression of the false lumen over time. Its operative technique is similar to that
described above for thoracic aneurysms. The proximal stent-graft is deployed in non-dissected
aorta, usually in Ishimaru zone 2 or 3. Graft oversizing is limited to 10% and balloon dilatation
should be avoided where possible. Some recommend avoiding stents with proximal bare stents,
although the evidence for this conflicting.
Figure 14.5. Patient with a subacute type B dissection who has undergone treatment by endovascular stent-grafting.
Figure 14.5a shows the preoperative appearance and Figure 14.5b shows complete remodeling of the false lumen
following the repair.
These measures are designed to reduce the risk of retrograde dissection, and careful
deployment of the proximal stent-graft is necessary to avoid this.A long length of aortic coverage
is generally recommended to promote remodeling, although there is limited evidence to support
this approach. A shorter length of aortic coverage may seal the primary tear but will rely on
distal aortic remodeling to reduce perfusion in the distal aorta. A longer endograft promotes a
greater degree of false lumen thrombosis by direct compression but may increase the risk of
paraplegia. A combination of a short-covered stent to seal the primary tear and a long uncovered
stent which pins back the false lumen has been described with some encouraging results. In
addition, other endovascular techniques including visceral stenting or percutaneous fenestration
may be required to treat malperfusion. The early results of TEVAR of complicated type B
dissections are significantly better than for open repair, with combined registry data suggesting a
mortality rate of 13%, a stroke rate of 6% and a paraplegia rate of 2%.
v. Early management of uncomplicated type B dissection
Given the relatively high rate of failure of medical management observed at mid-term
follow-up, it has been suggested that patients with uncomplicated acute type B dissections might
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benefit from TEVAR in preventing acute and long-term complications. The rationale is that
promoting aortic remodeling prevents the progressive degenerative changes that lead to late
aortic events. The INSTEAD-XL trial randomized 140 patients with a diagnosis of
uncomplicated type B dissection a median of 3.5weeks after diagnosis to be treated either by
TEVAR and best medical therapy (72 patients) or by best medical therapy alone (68 patients).In
the intervention group, the peri-procedural mortality and morbidity was low, with two deaths,
two serious intra-procedural technical complications and three serious neurological
complications. A total of 14 patients were crossed over from best medical therapy to the
intervention group, with five of these performed as an emergency and four requiring open repair.
Although the risk of mid-term all-cause death was similar in both groups (11.1% vs
19.3%), aortic specific mortality was lower (6.9% vs 19.3%) and later disease progression was
less frequent in the TEVAR group (27% vs 46.1%). These results in conjunction with other
registry data have prompted some to suggest that uncomplicated type B dissection should be
treated with early TEVAR in the subacute phase. The rationale for this is that the aorta has
stabilized enough to reduce the risks associated with treating acute dissection, such as retrograde
type A dissection, but still retains enough plasticity to allow remodeling of the aorta to take place.
This remains a point of controversy and there is no conclusive evidence to support this viewpoint
although many experts advocate this approach.
Careful morphological studies and long-term follow-up will be required to define which
subgroup of patients are at risk from late events and therefore may benefit from early TEVAR
for uncomplicated disease. Many risk factors such as false lumen diameter of over 22mm, entry
tear located on the lesser curve of the aortic arch and partially thrombosed false lumen have been
suggested, but at present none has been satisfactorily validated in any kind of model.
b. Treatment of chronic type B dissections
Uncomplicated chronic type B dissection is preferably managed conservatively, with

regular surveillance scanning performed on an annual basis. Most published guidelines
recommend the use of beta-blockers for blood pressure control, and findings from the
International Registry of Aortic Dissection (IRAD) support this by demonstrating a reduction in
mortality. Calcium channel blockers were also shown to reduce mortality specifically in patients
with type B dissection,although there is no consensus algorithm for management of hypertension
in patients with dissection. Despite medical management, many patients develop aortic dilatation
that may eventually require intervention.
Generally, patients are considered for surgery when the aorta measures over 5.5cm, or
when the false lumen measures over 4cm. Open surgical repair have the perceived benefit of
completely replacing the diseased segment of aorta. Therefore, it reduces the need for
reintervention in the future, but even modern series from specialized centers report high levels of
debilitating perioperative adverse events.Endovascular treatment can be performed with a
relatively low morbidity and mortality in comparison with open surgical repair and protects
against aortic-related death in the mid-term,although it remains some concerns regarding long-
term durability due to the relatively high rate of aortic reintervention rates observed in the
MOTHER registry.This is thought to be due to the tendency of the dissection flap to become
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relatively fixed and immobile, and therefore resistant to remodeling. The success of TEVAR for
chronic dissection is dependent on maximizing the chances of aortic remodeling, and there is
some evidence to suggest that certain factors relating to the repair may influence this.
A longer length of aortic coverage seems to be preferable in chronic dissections, allowing

a greater proportion of false lumen to be directly compressed as well as covering the main entry
tear and any minor fenestrations in the descending thoracic aorta. Despite this, high rates of false
lumen thrombosis were achieved in the trial where only a single stent-graft was used in 83% of
patients. There are limited data regarding which type of endovascular device is most suitable to
treating aortic dissection and how to correctly plan the endovascular repair. Most stent-graft
systems are primarily designed to treat thoracic aortic aneurysms, and their indications for use
reflect this. There is evidence to suggest that proximal and distal oversizing of endografts should
be less aggressive to avoid unnecessarily excessive radial force, which has been associated with
damage to the aortic wall and retrograde dissection.
According to existing published current definitions, the cut-off points at which a

dissection becomes chronic varies, with some using 14 days from presentation and others using
90. There is no upper limit. However, some patients who are 2 weeks from presentation with
those who presented up to 15 years previously.The trial intervention arm recruited patients at a
median of 3.5weeks after the diagnosis, meaning many would be categorized as subacute
dissections. This partially explains why a 90.6% total false lumen thrombosis at 5 years was
achieved in a group of patients with chronic dissection. Another study that treated patients at a
mean of 100 weeks post diagnosis only achieved false lumen thrombosis in 39% at a 3-year
follow up.This further supports the idea of a subacute group which may exist for up to a year in
some cases.
c. Management of intramural hematoma and penetrating aortic ulcer
Management of these conditions closely resembles that of dissection in both the acute
and chronic phase. There is a relative paucity of data to direct therapy in comparison with aortic
dissection, and the most recent consensus guidelines for management incorporated mostly
institutional series combined with expert panel opinion.Medical management of both conditions
appears safe in the early phase unless there is hemodynamic instability, persistent pain, signs of
impending rupture or progressive peri- aortic hemorrhage. Patients must then undergo
surveillance to look for increase in diameter to over 55mm or a yearly increase of more than
5mm. In both conditions, endovascular treatment is preferable to open surgery given the superior
perioperative and three-year mortality reported in existing series.
TEVAR is now considered to be the gold standard for complicated acute type B thoracic
dissections and other acute aortic syndromes. Some patients with uncomplicated disease appear
to benefit from early TEVAR although it is difficult at present to define which group this is. The
indications for treatment and best interventional approach to chronic dissection, IMH and PAU
require further study and refinement.
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d. A Case Study of Acute Aortic Dissection
i. Introduction:
The most common symptom of acute aortic dissection is acute pain in the chest or back.
Pain can occur alone, or it can be accompanied by signs of syncope, congestive heart failure, or
signs of cerebrovascular accident. Painless aortic dissection is not common, but symptoms and
only signs of congestive heart failure, cerebrovascular accident, and hypo-pulsation may occur.
A study to evaluate the factors that lead to a delay in diagnosis. Delays mainly occur in female
patients with atypical symptoms that are not sudden or do not include chest, back, or any pain.
Therefore, the atypical symptoms of aortic dissection should always be considered.
ii. Information of the Case
A 77-year-old Chinese woman came to the Vascular Surgery Clinic of the First Hospital
of China Medical University, presenting with chest pain that started the day before. She had a
medical history of hypertension and had been on medication (losartan and aspirin) for 5 years.
The day before, at about 7 PM she suddenly felt a strong chest pain of numerical rating scale
(NRS) 8-10 in the substernal area. She described the character of the pain as oppressive without
radiating pain. This excruciating pain lasted for about 10 minutes combined with a doomed
feeling, diaphoresis, and difficulty in taking deep breaths. She also felt slight faintness with
urinary incontinence. She visited a local clinic the next morning and chest pain was relieved to
NRS 3-4 after 3 tablets of sublingual nitroglycerin. When she came to our outpatient clinic, she
presented with moderate chest pain of 3/4 on the NRS. She looked acutely ill, and nothing
specific was detected in her heart and lung sounds.
Under assessment of ACS, she was immediately referred to the emergency department.
Initial vital signs at the emergency room were stable: blood pressure 108/75 mm Hg, pulse rate
82/min, respiration rate 20/min, body temperature 36.6℃, saturation 99%. Electrocardiogram
(EKG) was immediately taken which showed normal sinus rhythm with nonspecific ST deviation.
Laboratory findings were as follows: creatine kinase (CK) 129 IU/L, CK-myocardial band 3.0
IU/L, troponin I 0.03 ng/mL, C-reactive protein 0.59 mg/dL, white blood cell 8,900/µL,
hemoglobin 11.4 g/dL, D-dimer assay 13.60 ug/mL. Cardiac enzyme levels were all within
normal limits and nothing specific was found on the laboratory tests except an increase in D-
dimer. The chest radiograph showed mild mediastinal widening with no active lung lesions
(Figure A). From the data above, it was less likely that the cause of chest pain was from ACS.
Therefore, an additional imaging study was performed: computed tomography (CT) angiography
+ 3-dimensional aorta (contrast) (Figure B).
Surprisingly, the CT results showed aortic dissection type A starting from the distal
ascending aorta with its distal extent just proximal to the right main renal artery (Figure C). The
diameter of the ascending aorta was 50 mm and there was no evidence of coronary artery os
involvement. The thoracic surgery department was immediately contacted, and the patient had an
emergency operation: replacement of ascending aorta, proximal arch, and innominate artery with
Hemashield graft and open heart valvuloplasty of the aortic valve due to mild aortic regurgitation.
The patient showed postoperative atrial fibrillation, which was managed by continuous infusion
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of amiodarone. Otherwise, she recovered well from the surgery and was discharged 18 days after
the operation, with short-term follow-up at the outpatient clinic of thoracic surgery.
Figure A: Chest radiograph-mild mediastinal widening with no active lung lesions.
Figure B: Computed tomography angio + 3-dimensional heart: aortic dissection type A starting from the distal
ascending aorta.
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Figure C: Computed tomography angio + 3-dimensional heart: distal extent of dissection just proximal
to left main renal artery.
iii. Discussions:
This case reports a 77-year-old woman presenting with symptoms of chest pain that were
thought to be from ACS, but later diagnosed as acute aortic dissection type A. According to
Doctor Hagan, up to 30% of patients later found to have aortic dissection are initially suspected
of having other conditions, such as ACSs, aneurysms, pericarditis, pulmonary embolism, aortic
stenosis, or even cholecystitis. Despite recent advances in diagnostic methods, misdiagnosis
occurs in 25% to 50% of patients on initial evaluation with symptoms mimicking those of acute
myocardial infarction and other cardiovascular disorders. Acute aortic syndrome is frequently
confused with ACS, leading to delayed diagnosis and inappropriate treatment with antiplatelet,
antithrombin, and fibrinolytic therapies. Exposure to these agents is associated with
hemodynamic instability, hemorrhagic pleural and pericardial effusions, increased hemorrhagic
postoperative complications, and a trend toward increased mortality. Therefore, not only is it
important to have a clinical suspicion of aortic dissection in patients with abrupt chest pain, but
also in patients with unexplained syncope, stroke, acute onset of congestive heart failure, or
symptoms of acute ischemia of extremities or viscera.
First, it is important to assess the risk factors of aortic dissection through a

comprehensive medical history collection. Aortic dissection is more common in men (1.55:1)
and increases with age. The doctor must ask the patient about the underlying disease, such as
high blood pressure, atherosclerosis, or any pre-existing aortic aneurysm. In this case report, the
patient has a history of hypertension. Family history of aortic disease may also be a risk factor.
Iatrogenic causes of aortic dissection include cardiac catheterization, angioplasty, or cardiac
surgery. For young patients, a history of collagen diseases such as Marfan syndrome and Ehlers-
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Danlos syndrome, two-leaf aortic valve, aortic coarctation, and Turner syndrome should be
investigated.
The most common symptom of acute aortic dissection is chest pain, which accounts for
79% of type A dissections and 63% of type B dissections. The characteristics of aortic dissection
pain are usually severe, tearing, and tearing, and come on suddenly. The severity of the pain is
usually the most severe at the onset. The pain of acute aortic dissection may change its position
as the dissection expands further. In contrast, the pain associated with acute ACS starts slowly
and increases over time, and its characteristics are usually more depressing and duller. In this
case, the patient has a sudden onset of chest pain, the most severe at the time of the onset.
However, she described the characteristics of pain as oppressive, rather than sharp or tearing.
Although the characteristics of pain do not match the typical pain associated with aortic
dissection, doctors must always suspect aortic dissection because of the possibility of atypical
manifestations and the possibility of aortic dissection combined with ACS.
In addition, sublingual administration of nitroglycerin can relieve the severity of chest

pain in this case. Nitroglycerin works by relaxing smooth muscles and dilating veins, arteries,
and coronary arteries. Vein dilation can reduce preload, thereby reducing ventricular wall stress,
thereby reducing myocardial oxygen demand. Nitroglycerin can temporarily relieve chest pain
by lowering the patient's blood pressure and reducing wall stress. However, since vasodilators
may increase the force of left ventricular ejection, caution must be exercised when using
nitroglycerin alone.
Uncommonly, the reported incidence of painless dissection is 6.4% to 17%. Uncommon

symptoms include syncope, symptoms of congestive heart failure, pericardial tamponade,
weakness of the lower limbs, paraplegia, mesenteric ischemia, or peripheral ischemia. Physical
examination can provide important clues for the diagnosis of aortic dissection. The blood
pressure of the left and right arms or legs must be measured. Hypertension was found in 70% of
distal dissections and 35% of proximal dissections. Pulse examinations must be performed on
both upper and lower limbs, because less than 20% of patients suffer from missing or poor pulse
due to compression of the intimal flap or hematoma. About half of patients with proximal aortic
dissection have a diastolic murmur, indicating aortic valve insufficiency. Sometimes the murmur
may be very faint. In this case, the doctor may not recognize the murmur. Neurological
examinations used to assess neurological deficits such as loss of consciousness and ischemic
palsy are important because they can occur in up to 40% of patients with proximal aortic
dissection.
iv. Conclusion:
Despite continuous research into novel biochemical diagnostic markers such as smooth
muscle myosin heavy chain, there is still no specific blood test marker that can be used to
diagnose aortic dissection. D-dimer may be used as an exclusive method to rule out pulmonary
embolism and aortic dissection if done within 24 hours after symptom onset. An ECG must be
performed on all patients for the differential diagnosis of acute myocardial infarction of aortic
dissection. However, clinicians must always keep in mind that aortic dissection can be combined
with myocardial infarction if the dissecting membrane involves the coronary arteries. Thirty one
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percent of aortic dissection patients present with a normal ECG. Therefore, ECG cannot be used
as a diagnostic tool. The role of chest radiographs remains unclear in the diagnosis of aortic
dissection since 60-90% show abnormal results such as abnormal aortic contour, mediastinal
widening, or aortic shadow widening.
To confirm the diagnosis, imaging tests such as CT, magnetic resonance imaging (MRI),
transesophageal echocardiography (TTE), or aortic angiography must be performed. With the
improvement of CT, CT is the most used method for diagnosing aortic dissection because it has a
high degree of specificity, sensitivity, and practicality. However, CT has its limitations because it
cannot detect aortic insufficiency. MRI also has high specificity and sensitivity, but the test is
time-consuming and less usable. Therefore, MRI is usually used for subsequent imaging or
chronic dissection. TEE is usually used for patients with unstable hemodynamics because it can
be performed at the bedside or in the operating room in an emergency.
Considering the cost and radiation exposure, using imaging methods for every patient
suspected of having acute aortic syndrome is very expensive and ineffective. Therefore, the
American Heart Association has proposed guidelines with risk assessment tools that can be used
to stratify patients from low risk to high risk. According to risk groups, this guideline provides
clinicians with a framework for additional diagnostic methods based on disease probability. A
study conducted in 2011 tested the sensitivity of the above guidelines and its sensitivity was
95.7%. According to this risk score, the risk score for detection of aortic dissection in this patient
is 1 (sudden onset of chest pain). Thus, the patient will undergo aortic imaging for assessment.
This case report emphasizes the importance of clinical suspicion of aortic dissection and
discusses the important clinical presentations of aortic dissection and its diagnostic methods.
Furthermore, recent studies on aortic dissection detection risk scores have been discussed. Many
patients will visit not only the emergency room, but the out-patient clinic, presenting symptoms
of chest pain only, or any symptoms of aortic dissection. Clinicians must always be aware of
aortic dissection even though the patient presents only with chest pain that might be similar to
chest pain of ACS, and thorough history taking, and physical examination must be performed.
REFERENCES:
1. Spittell PC, Spittell JA, Jr, Joyce JW, Tajik AJ, Edwards WD, Schaff HV, et al. Clinical features and differential
diagnosis of aortic dissection: experience with 236 cases (1980 through 1990) Mayo Clin Proc. 1993
2. Hagan PG, Nienaber CA, Isselbacher EM, Bruckman D, Karavite DJ, Russman PL, et al. The International
Registry of Acute Aortic Dissection (IRAD): new insights into an old disease. JAMA. 2000
3. Erbel R, Alfonso F, Boileau C, Dirsch O, Eber B, Haverich A, et al. Diagnosis and management of aortic
dissection. Eur Heart J. 2001
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4. Harris KM, Strauss CE, Eagle KA, Hirsch AT, Isselbacher EM, Tsai TT, et al. Correlates of delayed recognition
and treatment of acute type A aortic dissection: the International Registry of Acute Aortic Dissection
(IRAD) Circulation. 2011
5. Klompas M. Does this patient have an acute thoracic aortic dissection? JAMA. 2002
6. Hansen MS, Nogareda GJ, Hutchison SJ. Frequency of and inappropriate treatment of misdiagnosis of acute
aortic dissection. Am J Cardiol. 2007
7. Meszaros I, Morocz J, Szlavi J, Schmidt J, Tornoci L, Nagy L, et al. Epidemiology and clinicopathology of aortic
dissection. Chest. 2000
8. Hasham SN, Lewin MR, Tran VT, Pannu H, Muilenburg A, Willing M, et al. Nonsyndromic genetic
predisposition to aortic dissection: a newly recognized, diagnosable, and preventable occurrence in families. Ann
Emerg Med. 2004
9. Park SW, Hutchison S, Mehta RH, Isselbacher EM, Cooper JV, Fang J, et al. Association of painless acute aortic
dissection with increased mortality. Mayo Clin Proc. 2004
10. Imamura H, Sekiguchi Y, Iwashita T, Dohgomori H, Mochizuki K, Aizawa K, et al. Painless acute aortic
dissection: diagnostic, prognostic and clinical implications. Circ J. 2011
11. Fann JI, Sarris GE, Mitchell RS, Shumway NE, Stinson EB, Oyer PE, et al. Treatment of patients with aortic
dissection presenting with peripheral vascular complications. Ann Surg. 1990
12. Hugli OW. Letter by Hugli regarding article, "Diagnosis of acute aortic dissection by D-dimer: the International
Registry of Acute Aortic Dissection Substudy on Biomarkers (IRAD-Bio) experience". Circulation. 2010
13. Kamp TJ, Goldschmidt-Clermont PJ, Brinker JA, Resar JR. Myocardial infarction, aortic dissection, and
thrombolytic therapy. Am Heart J. 1994
14. Rogers AM, Hermann LK, Booher AM, Nienaber CA, Williams DM, Kazerooni EA, et al. Sensitivity of the
aortic dissection detection risk score, a novel guideline-based tool for identification of acute aortic dissection at
initial presentation: results from the international registry of acute aortic dissection. Circulation. 2011
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Chapter 15 Other Aneurysms
Jing Yuchen
True aneurysms of the upper limb arteries are uncommon. The subclavian artery is the
most frequent site, usually caused by thoracic outlet compression. These patients may present
with distal ischemia, embolization, or acute thrombosis. False aneurysms from trauma or
infection often produce motor or sensory impairment because of brachial plexus compression. As
described later, subclavian artery aneurysms are best managed by a combined supraclavicular
and infraclavicular approach. Aneurysms of the brachiocephalic artery are rare. In the series of
Kieffer et al. the perioperative death rate was 11%, most deaths occurring in patients operated in
an emergency setting.
An aberrant right subclavian artery arising from the descending thoracic aorta is a
common anomaly. Rarely, the artery compresses the esophagus against the trachea, producing a
condition described as dysphagia. Aneurysmal degeneration, known as Kommerell's
diverticulum, may also occur. The largest experience has been reported by Kieffer et al. Because
of the possibility of rupture, resection of the aneurysmal artery with aortic prosthetic
reconstruction via a thoracic approach is recommended. As this technique carries a relatively
high postoperative mortality, hybrid procedures with aortic stent grafts are more commonly used
with success.
a. Upper arm artery aneurysms
Axillary artery aneurysms are usually caused by blunt or penetrating trauma. Degenerative
or congenital aneurysms are rare in this location. False aneurysms of the axillary artery occur
with humeral fractures and anterior dislocation of the shoulder. These aneurysms can lead to
neurological complications because of compression of the brachial plexus. Duplex scan and
arteriography allow an accurate diagnosis. The axillary artery is exposed by a deltopectoral
incision with division of the pectoralis minor. The aneurysm is resected followed by interposition
of a reversed saphenous vein graft. Stent grafts have been used for emergency control of upper
limb aneurysms but their long- term integrity is often compromised by compression between the
first rib and clavicle or by excessive arterial flexion.
b. Lower arm and hand artery aneurysms
Radial artery aneurysms are usually due to inadequate compression or infection following
removal of an intra-arterial blood pressure cannula. If the test shows good filling of the hand
from the ulnar artery, then the radial artery can simply be ligated above and below the aneurysm.
Otherwise, reconstruction using a vein graft is required.
c. Renal Artery Aneurysm
Renal artery aneurysmsare rare, and their natural history is poorly studied. The annual
growth rate is estimated to be 0.6mm a year; the rupture rate being 3–5%, with a mortality of
<10%. Treatment indications are the presence of clinical symptoms, thromboembolism,
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refractory hypertension, size >2cm, female in reproductive age, dissection, or rupture. Open,
endovascular, and robotic repair are reported with primary patency rates of 75– 100%,
reintervention rates of 0–22% and overall mortality of 1%.
d. Popliteal artery aneurysms
Popliteal aneurysms are the most common peripheral aneurysms, accounting for more than
80% of all peripheral aneurysms. The ratio of popliteal aneurysm to AAA is approximately 1:15.
Half are bilateral, the third is asymptomatic, and 40% are related to AAA.
Although rupture is rare, 50% of cases present with peripheral limb-threatening ischemia.
In common with aneurysms at all other sites, laminated thrombus develops within popliteal
aneurysms. The popliteal artery is continually subjected to flexion and extension, greatly
increasing the risk of disintegration and embolization of this thrombus. In many patients
microembolization of the peripheral circulation occurs silently prior to main vessel occlusion or
thrombosis of the popliteal aneurysm itself. For this reason, the viability of the limb may be
seriously threatened. Furthermore, compromise of the run- off circulation can impact adversely
on the outcome from emergency bypass surgery. The bigger the aneurysm, the more likely there
is to be thrombus. The presence of intraluminal thrombus is therefore a more important
indication for elective surgical intervention than the size of the aneurysm. Any thrombus
detected by ultrasound, CT or MRI constitutes an indication for elective treatment t. In the
absence of laminated thrombus, it is generally accepted that aneurysms with a diameter of 2 cm
or greater warrant consideration for elective surgical repair.
Traditionally, popliteal aneurysms are treated by proximal and distal ligation and bypass
using autologous vein undertaken via a medial approach. However, recent studies have identified
persistent flow within the popliteal aneurysm in 30% of patients treated in this way. Furthermore,
there is a significant risk of continued expansion and even rupture due to pressurization of the
sac resulting from backflow through geniculate branches. Therefore, a posterior approach and
insertion of an inlay graft is to be preferred.
An acutely thrombosed popliteal aneurysm is a clinical emergency. Preoperative or on-

table thrombolysis has been used to open up the run- off vessels and thereby facilitate bypass
surgery. There is some low-level evidence to suggest that this approach may improve the
chances of successful limb salvage.
With the evolution of flexible endografts, endovascular repair is now a viable alternative to
open surgery for the treatment of some popliteal aneurysms. Long-term follow-up suggests that
in selected patients this is a durable technique, capable of achieving excellent patency rates and
limb preservation78 (Figure 15.1a, Figure 15.1b and Figure 15.1c). Further large-scale clinical
trials are warranted to help define optimal candidates for this technique.
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Figure 15.1 Angiogram of Popliteal Aneurysm. (a) Diagnostic Angiogram (b) BallonMoulding of Popliteal Stent
Graft (c) Completion Angiogram off Popliteal Stent Graft. Source of the Image: A Companion to specialist surgical
practice----Vascular and Endovascular Surgery, Ian Loftus and Robert J. Hinchliffe.
Another important determinant of patient outcome following AAA repair is the ability and
experience of the operating surgeon. A recent meta-analysis demonstrated a significantly lower
mortality following AAA repair with higher volume surgeons and suggested a minimum
caseload of 13 open AAAs per annum for continued practice. With further analysis, this number
is likely to rise and, naturally, this has significant implications for the provision of vascular
services and would support the argument for fewer, larger, regional vascular centers linked
directly to a nationwide targeted AAA screening program.
e. Common Femoral Aneurysms
Femoral arterial aneurysms can be divided simply into true or false aneurysms. True
aneurysms relate to a distinct pathological process involving all three layers of the femoral
arterial wall. False aneurysms are due to a traumatic breach of a vessel wall with an associated
contained blood collection with flow.
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Both disease processes maybe symptomatic or asymptomatic. Symptomatic femoral

aneurysms can present as a pulsatile groin mass that may or may not be painful, leg swelling
(due to femoral vein compression and deep vein thrombosis) or features associated with chronic
ischemia attributable to aneurysm thrombosis /embolization. Rupture can occur but is rare.
Asymptomatic pathology is usually discovered incidentally on clinical examination or imaging
studies of a patient with an aneurysm elsewhere or with chronic ischemia.
i. True Femoral Aneurysms
True femoral aneurysms are the second commonest peripheral artery aneurysm after the
popliteal artery. They occur in 2–3% of patients with aortic aneurysms and tend to be a disease
of elderly men (male-to-female ratio 30:1). The condition is frequently bilateral, and a coexistent
generalized aneurysmal process may be manifest in other anatomical sites such as the aortoiliac
or popliteal arteries.
Small, asymptomatic true femoral artery aneurysms can be managed expectantly with
clinical assessment at intervals. Surgical treatment is indicated for symptoms and probably for
most aneurysms of 3.5cm or more in size. Usually, a short interposition or inlay graft tube
anastomosed proximally at the level of the inguinal ligament and distal to the common femoral
bifurcation is required. This is a relatively small operation with durable results.
ii. False Femoral Aneurysms
The common femoral artery is regularly used for catheterization of the arterial circulation
(eg angiography, cardiac catheterization, EVAR, intraaorta balloon pumps, etc.). Therefore,
iatrogenic injury leading to false aneurysm is a relatively common occurrence that complicates
approximately 1% of transfemoral interventions. The diagnosis should be suspected in any
patient with a pulsatile mass at the site of a recent arterial cannulation. Initially a duplex scan
should be obtained to both confirm the diagnosis and characterize the false aneurysm. If the
pathology is small (< 2 cm) and associated with minimal symptoms, simple observation with
rescanning may be justified, as most of these pseudoaneurysms will thrombose spontaneously
within 2–4 weeks. Other options include compression therapy (direct pressure and/or ultrasound
guided) to seal the feeding arterial jet. Thrombin injection is an effective
treatmentwithareportedsuccessrateofover95%. If these measures fail or in cases of tense swelling,
threatened skin viability or neurology, open surgical repair is indicated. Unlike non-invasive
methods, surgery has the advantage of combining both the arterial repair and field
decompression. The former is usually a primary repair of the vessel with a suture, although
formal graft reconstruction is sometimes required.
Infected femoral pseudoaneurysms are now the most common type of infected aneurysm
observed in clinical practice, largely explained by increased intravenous drug abuse in recent
years. Although the usual microorganism cultured is a Staphylococcus species, the infection may
be polymicrobial and close liaison with the microbiology team is required for appropriate
antibiotic therapy. The surgical strategy for infected femoral false aneurysms depends largely on
its cause. For non-IVDA patients, arterial excision, and reconstruction with autologous conduit
(e.g., long saphenous vein and obturator bypass) following the operative principles for infected
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aneurysms earlier outlined is preferred. In IVDA patients, arterial excision with ligation alone
(i.e., no reconstruction) is advised due to the unacceptable risk of subsequent graft infection with
continued drug abuse and likelihood of exhausted superficial veins. Ligation of the femoral
artery does not necessarily mandate amputation if only one femoral segment is involved. If the
femoral bifurcation is excised, however, the risk of limb loss is significant and reconstructive
surgery may need to be considered.
f. Hybrid visceral revascularization and endovascular repair of thoraco-abdominal

aortic aneurysms
A combination of open surgical and endovascular strategies has been suggested to reduce
surgical insult by removing the need for thoracotomy and aortic cross-clamping, whilst reducing
the duration of visceral and renal ischemia. There are fewer technical considerations than for
complex endovascular solutions as all that is required is sufficient length of proximal and distal
landing zones in non-diseased or replaced aorta. In addition, visceral vessels must be able to be
accessed for bypass from a healthy donor site, such as the iliac system. Most often a
transperitoneal retrograde visceral revascularization is used to allow an adequate distal landing
zone for placement of an endovascular stent- graft that extends from the thoracic to the distal
abdominal aorta or iliac vessels. This approach may be combined with supra-aortic debranching
to create a very proximal landing zone (Figure 15.2). A collaborative paper reporting outcomes
of 107 consecutive cases across three units described a 15% mortality and 8.4% permanent
paraplegia rate in all comers. Superficially, these results do not appear to show a significant
advantage over conventional surgery, but these patients tended to be older, have more
comorbidity, and a higher proportion of type II and III aneurysms than comparable open series.
Figure 15.2 Operative Pictures of Two patients undergoing retrograde visceral revascularization. Many different
graft configurations are possible, with varying numbers of vessels requiring revascularization. Source of the Image:
A Companion to specialist surgical practice----Vascular and Endovascular Surgery, Ian Loftus and Robert J.
Hinchliffe.
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Endovascular techniques have evolved significantly in recent years, and many doctors
would preferentially offer minimally invasive surgery as first-line therapy for patients with
thoraco-abdominal aneurysms. Open surgery is recommended for younger, fitter patients and
those with connective tissue disorders, due to proven durability in these cases. Improvements in
the delivery of FEVAR and BEVAR have rendered hybrid techniques less attractive in recent
years. Most would now recommend them only in urgent cases unsuitable for an off-the-shelf
branched device or for more extensive open surgery.
g. Thoraco-abdominal aortic aneurysms (TAAAs)
i. Classification and etiology
Thoracic aneurysms that involve the visceral segment of the abdominal aorta are
traditionally described as thoraco-abdominal aneurysms and are classified according to the extent
of the aneurysmal disease (Figure 15.3 description of the Crawford classification). The etiology
of thoraco-abdominal aneurysms differs from infrarenal aneurysms, with medial degenerative
disease and chronic dissection being particularly prevalent.As with thoracic aortic aneurysm,
connective tissue disorders are a strong risk factor for the development of TAAAs.
Figure 15.3 Crawford Classification of Thoraco-abdominal Aneurysms Source of the Image: A Companion to
specialist surgical practice----Vascular and Endovascular Surgery, Ian Loftus and Robert J. Hinchliffe.
ii. Incidence, clinical presentation, and indications for treatment
The incidence of TAAA is poorly studied but rare. Relatively more patients with TAAAs
are symptomatic than patients with other aortic aneurysms. The presence of back pain is
particularly common, and this symptom may precede aortic rupture or intramural dissection. The
rationale for treatment of TAAAs largely derives from a natural history study from Crawford and
DeNatale, who reported a series of 94 patients unsuitable for surgery.After 24 months' follow-up,
only 24% of these patients were alive, which contrasted with the 59% 5-year survival of a
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concurrent cohort of patients who underwent operative repair. Based on these results, it was
concluded that patients with significant thoraco-abdominal aneurysms should have an operative
repair unless precluded by coexistent medical conditions. The advent of fenestrated and branched
stent-graft systems has meant that many patients can now be treated by endovascular means.
Despite being minimally invasive this is a technically demanding procedure, and there is a
relatively higher risk of morbidity and mortality in comparison with ‘standard’ infrarenal EVAR.
iii. Technique of surgical repair
Before any surgery can be considered, detailed imaging of the aorta must be obtained and
examined using multiplanar reconstruction software. The physiological reserve of the patient
should be comprehensively assessed and should include cardiac stress testing. A left
thoracotomy is performed for extent of I–III aneurysmsalthough it is possible to repair some type
IV aneurysms via a totally abdominal approach.
The abdominal aorta is usually exposed by left medial visceral rotation and the
diaphragm is partially divided with a circumferential incision preferred to preserve nerve supply.
After the dissection has been completed the aneurysm is clamped at its proximal and distal
extents, and an arteriotomy made in the lateral aneurysm wall. It is important that the arteriotomy
is sited away from the visceral origins in the abdominal portion of the aneurysm. The proximal
anastomosis is performed with a completely transected aorta to prevent aorto-esophageal fistula.
If possible, the proximal anastomosis is fashioned to include adjacent intercostal or visceral
arteries, whilst any remaining intercostal arteries are directly reimplanted into the graft or
revascularized by separate jump grafts. The visceral arteries are then directly anastomosed into
elliptical openings in the graft, utilizing an inclusion technique. If possible, the coeliac, superior
mesenteric and right renal arteries are taken on one patch; anastomosing the distal graft to the
aortic bifurcation or iliac arteries completes the reconstruction.
During thoraco-abdominal aneurysm repair, prolonged visceral ischemia is the main

cause of postoperative renal dysfunction and can also contribute to multiple organ failure. To
reduce the severity of organ hypoperfusion, partial left heart bypass with a centrifugal pump may
be utilized to drain blood from the left atrium or upper pulmonary vein and return it via the
femoral artery or aorta. This facilitates renal and visceral perfusion whilst the proximal
anastomosis is fashioned if the distal aortic clamp remains proximal to the visceral
vessels.During the abdominal part of the aneurysm repair, the coeliac trunk, superior mesenteric
artery and both renal arteries can be selectively perfused with catheters that are connected to the
left heart bypass. Paraplegia may complicate thoraco-abdominal aneurysm repair in up to 20% of
cases and is increased in more proximal aneurysms, with lengthy clamp time, renal impairment,
advanced age and emergency presentations. Paraplegia results from damage to the spinal cord
due to a combination of division of spinal cord arteries, prolonged spinal cord ischemia during
aortic clamping, reperfusion injury and postoperative hypotension. Maintenance of spinal cord
blood supply may be achieved by reimplantation of patent intercostal arteries and by distal aortic
perfusion. CSF pressure increases during aortic clamping, and CSF drainage has been advocated
to reduce paraplegia.
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A functional approach to the problem of neurological deficit aims at intraoperative

monitoring of the spinal cord function. Somatosensory-evoked potentials are widely used to
detect spinal cord ischemia during aortic cross-clamping and to identify vessels critical to spinal
cord blood supply, which may then be perfused and reimplanted. An alternative approach is to
use motor-evoked potentials, which have been reported to improve paraplegia rates.This
technique involves stimulating the brain with electrical currents and monitoring the resulting
signals in peripheral muscles. If these are damped perioperatively then measures may be taken to
improve spinal perfusion.
(1) Results of surgical repair of thoraco-abdominal aneurysms
The mortality and morbidity rates following conventional repair of TAAAs are still
significant, with specialized hospitals reporting mortality rates of 5–16%, with paraplegia rates
of 4–11%.However, these excellent results are not representative of outcomes outside of these
hospitals with national/community mortality rates exceeding 20% at 30 days and 30% at 1 year.
(2) Endovascular repair of thoracoabdominal aortic aneurysms
Advances in stent-graft technology have allowed the manufacture of stent-grafts with

fenestration (FEVAR) or branches (BEVAR) to treat thoraco-abdominal aneurysm. These seal
above and below the diseased segment of aorta in a similar fashion to standard endografts but
allow visceral branch perfusion via the placement of bridging stents between the main body of
the stent-graft into the ostia of visceral vessels. Fenestrated stent- grafts are customized for each
individual patient and require a period of weeks to months from ordering to being ready to use.
Stent-graft systems with preformed branches can be used ‘off the shelf’ provided the necessary
ancillary components are available. Anatomical suitability is important, and access problems,
aortic tortuosity and target vessel morphology are some of the main reasons that patients are not
suitable for this kind of repair. Initially the application of this technology was limited, and the
number of patients receiving this kind of repair was low and confined to a small number of
super-specialized units.
The results of these procedures have improved as technology and perioperative care have
developed, and now many hospitals are beginning to offer this as first-line therapy, often except
for young patients or those with a connective tissue disease. Both Fenestrated endovascular
aortic repair (FEVAR) andBranched Endovascular Aortic Aneurysm Repair (BEVAR) require
the partial deployment of an endograft in the visceral aorta through which the fenestrations or
branches are cannulated. This is performed via access from the groin or the upper limb, and once
secure access is obtained the device can be fully deployed and the visceral stents can be
advanced into position. When these are in position the graft can be completed with a bifurcated
section if necessary and a final angiographic run obtained to check that the aneurysm has been
sealed and the visceral vessels are patent.
(3) Results of endovascular repair of TAAA
Excellent early results have been reported in selected groups of patients treated at
hospitals of excellence, although it is unclear to what extent these results are generalizable.The
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largest modern institutional series reported the results of 354 procedures with a perioperative
mortality of 3.5% to 7%.
As with open repair, paraplegia remains a serious problem and complicated up to 4% of

procedures. Long-term durability appeared to be good, with target vessel patency of 96% at mid-
term follow-up although reinterventions were reported in 19% for a variety of reasons. Longer-
term all-cause mortality remains a concern, with this series reporting 57% freedom from
mortality.
h. Thoraco-abdominal Aortic Aneurysm Treatment Case Study and Summary
(1) Early Results
In 60 cases, the debranching procedure was performed. A preventive renovisceral

debranching procedure was performed in 10 (17%) of them. Regarding the renovisceral
debranching procedure, the average operation time was 537 ± 120 min (range 305–840 min). The
average number of anastomosis sites was 8.6 ± 2.2 (range 5–14). The average amount of bleeding
was 2033 ± 1218 ml (range 500–4900 ml). Most patients required blood transfusions. The
average stay in the intensive care unit was 3.6 ± 2.8 days (range 0–16 days).
Early outcomes are summarized in Table 15.1. One patient with a true aneurysm had
paraplegia after the renovisceral debranching operation though the cause was unknown. The
patient died due to an aneurysmal rupture during hyperbaric oxygen therapy for the paraplegia.
In addition to this patient, 2 cases of an aneurysmal rupture occurred while waiting for TEVAR.
One case was rescued with emergency TEVAR, but another case resulted in death. Four cases
(7%) of anastomotic hemorrhaging were found, and embolization and open hemostasis were
performed. One (2%) patient who had CKD G4 before surgery newly started maintenance
dialysis after the renovisceral debranching operation. Although 5 (8%) patients needed transient
dialysis with continuous hemodiafiltration in the intensive care unit, everyone got off transient
dialysis. Gastrointestinal dysfunction, such as intestinal obstruction and diarrhea, was found in 6
(10%) patients. There were no respiratory complications. The total amount of visceral bypass
grafts was 223. Quadruple bypasses (celiac, SMA and bilateral renal) were performed in 48 cases
(80%). Triple bypasses (celiac, SMA and lateral renal: 4 and SMA and bilateral renal: 3) were
performed in 7 cases (12%). Double bypasses (celiac and SMA) were performed in 5 cases (8%).
Three of 223 grafts showed early occlusion, for an early graft patency rate of 98.7%. Twenty-one
(35%) patients were evaluated by contrast CT for more than 1 year. The average follow-up
period was 29.6 ± 14.2 months (range 12–60 months), in which there was no bypass late
occlusion.
There were 55 (92%) cases that completed the hybrid repair, and the waiting period until
TEVAR, excluding the cases of preventive renovisceral debranching and TEVAR performed
simultaneously, was 35.2 ± 39.3 days (range 1–185 days). The waiting period from preventing
renovisceral debranching to TEVAR was 600 ± 561 days (range 104–1665 days). Regarding
TEVAR after renovisceral debranching, the average operation time was 161 ± 82 min (range 63–
441 min), and the average stay in the intensive care unit was 1.7 ± 2.7 days (range 0–15 days).
Cerebrospinal fluid drainage was performed in 18 (30%) patients at TEVAR. Two (4%) patients
209
with a true aneurysm had spinal cord ischemia after TEVAR. One of these patients underwent
emergency TEVAR, as he went into shock 1 day after undergoing the renovisceral debranching
procedure due to an impending rupture. Paraplegia occurred as a result of performing TEVAR
under hypotension, and the patient did not recover. Another patient underwent elective TEVAR
4 years after the preventive renovisceral debranching operation. Delayed paraparesis occurred
suddenly while walking on postoperative Day 7 of TEVAR. Cerebrospinal drainage and steroid
administration were successful, and her paraparesis recovered without any after-effects. Eight
cases (15%) with a wide range of aneurysms excluded with stent graft showed a trend toward
disseminated intravascular coagulopathy. In-hospital death occurred in 3 cases (5%), including 2
cases of rupture while waiting for TEVAR and 1 myocardial infarction after hybrid TEVAR.
Variables Total (%) Less than 70 years More than 70

of age (%) years of age
(%)
Major Complications after Renovisceral Debranching
Aneurysm rupture while waiting 3 (5) 1 (5) 2 (5)
for TEVAR
Paraplegia 1 (2) 1 (5) 0
Bleeding of anastomosis site 4 (7) 1 (5) 3 (7)
Newly maintenance dialysis 1 (2) 0 1 (2)
Occlusion of reconstructed 3 (5) 0 3 (7)
renovisceral branch
Celiac trunk 2 (4) 0 2 (5)
Right renal artery 1 (2) 0 1 (2)
Respiratory dysfunction 0 0 0
Major complications after TEVAR
Paraplegia 2 (4) 0 2 (5)
DIC (bleeding tendency) 8 (15) 4 (21) 4 (10)
Hospital mortality 3 (5) 1 (5) 2 (5)
Aneurysm rupture while waiting 2 (3) 1 (5) 1 (2)
for TEVAR
Acute Myocardial Infarction 1 (2) 0 1 (2)
Table 15.1 Early Outcomes, DIC: Disseminated Intravascular Coagulopathy; TEVAR: Thoracic Endovascular
Aortic Repair.
(2) Late Results:
The mean follow-up time was 32.9 ± 26.2 months (range 2.6–116.6 months). The follow-
up completion rate was 96.7%. The size of the aneurysm was tracked using CT. Four (7%)
patients required an additional treatment. Three (5%) required an additional TEVAR. One had
Type I endoleak, 1 had Type III endoleak and the rest had aneurysmal change of the proximal
edge of stent graft. During follow up, 4 cases (7%) of Type II endoleak were recognized, and
trans arterial embolization was performed in 1 case in which enlargement of the aneurysm was
210
confirmed. The others have been followed up intensively using CT. Late mortality was observed
in 17 (28%) patients. Two (3%) patients who had not visited the hospital after the preventive
renovisceral debranching operation died due to aneurysm rupture. Others died due to pneumonia,
malignant tumor, cerebrovascular disease, and cardiovascular disease, among other causes. All
patients who died were ≥70 years of age.
The mean age of the deceased patients at the time of operation was 80 years. The all-
cause survival rate was 75.9% ± 5.6% at 2 years, 65.2% ± 7.0% at 5 years and 43.5% ± 13.4% at
8 years. Because there were many elderly patients, the long-term all-cause survival rate tended to
be low. In the patients younger than 70 years, the survival rate was 94.7% ± 5.1% at 2 years and
94.7% ± 5.1% at 5 years. One patient died of aneurysm rupture while waiting for TEVAR early
postoperatively. In the patients aged 70–80 years, the survival rate was 74.5% ± 9.9% at 2 years,
67.7% ± 11.1% at 5 years and 67.7% ± 11.1% at 8 years. In the patients ≥80 years of age, the
survival rate was 58.4% ± 11.3% at 2 years, 39.0% ± 1.9% at 5 years and 19.5% ± 11.4% at
8 years. The rate of freedom from aortic events was 92.9% ± 3.5% at 2 years, 80.5% ± 7.5% at
5 years and 72.5% ± 10.2% at 8 years. There were no aneurysm-related deaths in the long-term
among patients who completed hybrid TEVAR.
(3) Discussion:
The treatment of Thoraco-abdominal aortic aneurysms(TAAA) continues to have a high

mortality and paraplegia rate. DoctorCoselli et al. reported excellent results of 5% for 30-day
mortality, and the rate of spinal cord ischemia was 3.8%; however, in many reports, the mortality rate
of open repair exceeds 10%. Furthermore, it was reported that mortality was strongly related to
advanced age, with a 30-day mortality rate after elective open surgery exceeding 20% in patients
≥70 years of age. With the spread of endovascular treatment, many hybrid operations combining
visceral debranching with TEVAR for TAAAs have been reported. Our renovisceral debranching
procedure is associated with a long operation time because of the large number of anastomosis sites,
and surgery itself is not considered a minimally invasive modality. When the operation time is the
same for both surgical procedures, then you may be able to complete conventional open surgery.
However, from the viewpoint of not using extracorporeal circulation and not requiring thoracotomy,
it is possible for the elderly and high-risk patients who hesitate to undergo conventional open surgery
to withstand such invasive surgery. The long-term outcomes are important to extend the indications
to younger patients. If there is a low risk of retreatment due to internal leaks in the long-term period
and if the long-term patency of visceral bypass can be safely guaranteed, then this procedure might
be considered a good treatment for younger patients. However, further long-term follow-up studies
are necessary before any definitive conclusions can be made.
Graft patency of renovisceral debranching is important with this procedure. Some reports
have assessed the branch graft patency after open repair of TAAAs, reporting a 10-year patency rate
of 93–100%. It was reported the graft patency rate after renovisceral debranching. Their inflow sites
of visceral revascularization originated either from the native artery or from aortic prosthetic grafts,
and the long-term patency rate of all grafts was 86.1% at 5 years. In addition, the right renal artery is
the most likely to be occluded, and most occlusions appear within 30 days after surgery. We use the
retrograde approach from the left leg of the bifurcated graft for renovisceral debranching, and
Another report indicates that no marked differences in the patency between antegrade and retrograde
grafts. In our case, 3 of 223 grafts showed early occlusion, and the early graft patency rate was
211
98.7%. Although long-term follow-up by contrast CT is insufficient at present, no deaths due to graft
occlusion have been reported. Another issue is whether renovisceral debranching from the left leg of
the bifurcated graft can provide a sufficient blood flow to each organ. However, there is still no clear
evidence concerning the blood flow, and therefore, we use as large a bifurcated graft as possible.
Another idea for debranching surgery is to place the bypass between the abdominal aorta and femoral
artery with a 10-mm graft. Generally, the iliac arteries become thinner with age, and their properties
are worse. This bypass then becomes a good access route for subsequent TEVAR, and there is no risk
of iliac arterial injury.
The choice of simultaneous or staged TEVAR is an important issue in hybrid repair for
TAAAs. When we perform this hybrid procedure in emergency cases of rupture, it is necessary
to perform TEVAR simultaneously. However, TEVAR in haemodynamically unstable patients
increases the risk of spinal cord ischemia. Although the main advantage of staged TEVAR is a
reduced risk of spinal cord ischemia, in our study, 2 cases of spinal cord ischemia (1 with
paraplegia and 1 with paraparesis) occurred in staged TEVAR. One patient developed paraplegia
after TEVAR performed urgently under hypotension, and the other developed late paraparesis on
Day 7 after TEVAR. There were no cases of spinal cord ischemia in the 3 patients who
underwent a single-stage procedure. As previously reported, we also believe it is extremely
important for TEVAR to be performed in hemodynamically stable patients. In our facility,
TEVAR is performed by local anesthesia under sedation, so the movements of the legs are
confirmed immediately after surgery. We try to keep the mean blood pressure above 80 mmHg
during the operation. Some scientists suggested that cerebrospinal fluid drainage is not essential
in TEVAR under such circumstances. The main disadvantage of staged TEVAR is the risk of an
aneurysmal rupture while waiting for TEVAR, which we see in 5 cases. Two of them occurred
after preventive debranching surgery. Now, depending on the size of the aneurysm, we try to
perform TEVAR as soon as possible after the renovisceral debranching operation. Patients are
carefully followed up after preventive debranching surgery so as not to miss the timing of the
next TEVAR.
Since the introduction of specifically designed fenestrated, branched endografts and new
standardized endoprostheses in the endovascular field, whether hybrid repair for TAAAs is
justified is debatable. One doctor published their 10-year experience with fenestrated and
branched stent grafts for TAAAs. They reported an in-hospital mortality rate of 9% and a similar
rate of spinal cord ischemia. There were 2 deaths in relation to the aneurysms, and 24% of the
patients need reintervention during the follow-up period. Although these results are not
particularly good, the results have continually been improving due to advances in devices and
endovascular techniques. Treating TAAAs with a total endovascular technique is complicated in
procedure, and the use of commercially available devices is limited; this approach is not
common now. However, the trend over time is tending toward total endovascular treatment, and
these devices will undoubtedly evolve and be used more and more in the years to come. Hybrid
repair-combined renovisceral debranching with TEVAR may be applied temporarily until total
endovascular procedures become common. However, this hybrid repair will likely remain a
standard procedure for a while, as it can be performed in elderly and high-risk patients.
212
(4) Conclusion
Although, except for the replacement of bifurcated grafts of abdominal aortic aneurysms,
TAAA's renal visceral debranching surgery is not minimally invasive in terms of surgical
invasiveness, but elderly patients can withstand such surgical invasiveness. Although total
endovascular treatments, such as branch stent grafts, may replace this mixed TEVAR in the
future, TEVAR for renal visceral debranching used for TAAA is a problem for elderly patients,
repeated cases, and high-risk patients who are unwilling to undergo conventional open surgery is
the better choice. However, further long-term follow-up studies are needed to expand the
indications for young patients.
REFERENCES :
1. Coselli JS, Bozinovski J, LeMaire SA. Open surgical repair of 2286 thoracoabdominal aortic aneurysms. Ann
Thorac Surg 2007
2. Schepens MA, Heijmen RH, Ranschaert W, Sonker U, Morshuis WJ. Thoracoabdominal aortic aneurysm repair:
results of conventional open surgery. Eur J VascEndovasc Surg 2009
3. Rigberg DA, McGory ML, Zingmond DS, Maggard MA, Agustin M, Lawrence PF et al. . Thirty-day mortality
statistics underestimate the risk of repair of thoracoabdominal aortic aneurysms: a statewide experience. J Vasc
Surg 2006;
4. Youssef M, Neufang A, Jungmann F, Vahl CF, Dorweiler B. Patency of renal and visceral vessels after open
thoracoabdominal aortic replacement. J Vasc Surg 2015
5. Kouchoukos NT, Kulik A, Castner C. Branch graft patency after open repair of thoracoabdominal aortic
aneurysms. J Thorac Cardiovasc Surg 2017
6. Shahverdyan R, Gawenda M, Brunkwall J. Five-year patency rates of renal and visceral bypasses after
abdominal debranching for thoraco-abdominal aortic aneurysm. Eur J VascEndovasc Surg 2013
7. Kansal N, LoGerfo FW, Belfield AK, Pompeslli FB, Hamdan AD, Angle N et al. . A comparison of antegrade
and retrograde mesenteric bypass. Ann Vasc Surg 2002
8. Hughes GC, Barfield ME, Shah AA, Williams JB, Kuchibhatla M, Hanna JM et al. Staged total abdominal
debranching and thoracic endovascular aortic repair for thoracoabdominal aneurysm. J Vasc Surg 2012
9. Canaud L, Karthikesalingam A, Jackson D, Cresswell L, Cliff M, Markar SS et al. Clinical outcomes of single
versus staged hybrid repair for thoracoabdominal aortic aneurysm. J Vasc Surg 2013
10. Chiesa R, Melissano G, Marrocco-Trischitta MM, Civilini E, Setacci F. Spinal cord ischemia after elective
stent-graft repair of the thoracic aorta. J Vasc Surg 2005;
213
11. Ullery BW, Cheung AT, Fairman RM, Jackson BM, Woo EY, Bavaria J et al. . Risk factors, outcomes, and
clinical manifestations of spinal cord ischemia following thoracic endovascular aortic repair. J Vasc Surg 2011;
12. Rossi SH, Patel A, Saha S, Gwozdz A, Salter R, Gkoutzios P et al. . Neuroprotective strategies can prevent
permanent paraplegia in the majority of patients who develop spinal cord ischemia after endovascular repair of
thoracoabdominal aortic aneurysms. Eur J VascEndovasc Surg 2015
13. Bisdas T, Panuccio G, Sugimoto M, Torsello G, Austermann M. Risk factor for spinal cord ischemia after
endovascular repair of thoracoabdominal aortic aneurysms. J Vasc Surg 2015
14. Verhoeven ELG, Katsargyris A, Bekkema F, Oikonomou K, Zeebregts CJAM, Ritter W et al. . Ten-year
experience with endovascular repair of thoracoabdominal aortic aneurysms: results from 166 consecutive
patients. Eur J VascEndovasc Surg 2015;
214
Chapter 16 Buerger's Disease (Thromboangiitis Obliterans)
Li Xi, M.D.
a. Introduction
Buerger's disease is a vasculitis syndrome char acterised by segmental, non-

atherosclerotic, inflammatory thrombotic occlusions of the small and medium-sized arteries and
veins of the extremities. The lower limbs are most commonly affected. There is associated
migratory superficial thrombophlebitis. Buerger's disease usually occurs in men less than 45
years of age, although disease in women and older people is recognized. The cause is unknown,
but smoking is by the far the most important risk factor and appears to be key in pathogenesis, to
the extent that a smoking history is generally regarded as a prerequisite for diagnosis.
Periodontitis may also be a risk factor. Altered blood flow parameters, including hematocrit and
red cell rigidity, have been detected, and prothrombin gene mutation and anticardiolipin
antibodies may confer increased risk of disease.
Thrombus histology differs in acute and chronic disease. Acutely, thrombi are
inflammatory and hypercellular, comprising neutrophils, giant cells and micro abscesses. Later
they become fibrosed (‘organized thrombus’) and inflammatory cells are absent. Throughout the
disease process there is sparing of the internal elastic lamina, and this is key in differentiating
Buerger’s disease from atherosclerosis and other vasculitis.
The symptoms of Buerger's disease include intermittent claudication, usually of the foot
or leg, and rest pain indicative of critical limb ischemia. Ulceration or gangrene can follow. More
than one limb may be involved. Ischemia of the fingers may mimic Raynaud’s phenomenon.
Migratory superficial thrombophlebitis occurs in around 40% and may predate symptoms of
ischemia. This manifests as tender nodules overlying veins and is rare in the other vasculitis
apart from Behçet’s disease. Clinical examination may reveal palpable femoral and popliteal
pulses but absent pedal pulses. Allen’s test is non-specific but may suggest compromised blood
flow to the hand, which in a young smoker raises the suspicion of Buerger’s disease. Peripheral
nerve involvement is seen in up to 70% of cases.
b. Examination
A thorough and systematic approach aims to establish the site and severity of PAD and
elicit signs of atherosclerosis and its risk factors in any part of the cardiovascular system.
General inspection for peripheral stigmata of cardiovascular disease such as cigarette staining of
fingernails, scars from previous surgery, amputated limbs and toes, and xanthelasma should be
sought. Measurement of blood pressure in both arms and the inter-arm difference, palpation of
radial and brachial pulses including the rhythm, rate and volume and cardiac and pulmonary
auscultation are mandatory to assess the extent of atherosclerotic involvement.
Careful inspection of the feet for skin integrity including the interdigital web spaces and
heel pressure points, skin color and changes with elevation and dependency and temperature are
noted. Abnormal femoral and foot pulses, lower extremity bruits, unilateral cool extremities,
215
prolonged venous refill time and Buerger's test are findings highly suggestive of underlying PAD
and capillary refill test, foot discoloration, atrophic skin and hairless extremities are unhelpful in
the diagnosis of PAD.
Body mass index (BMI) should be calculated by measuring height and weight. This is a
good estimate of obesity, which may affect the patient's ability to walk. Obesity may also affect
the risk of anesthesia and the possibility of surgical complications. In some cases, weight loss
can greatly reduce the patient's symptoms.
Palpation of pulses is subjective, and is influenced by the sensitivity of the fingers, the
experience of the examiner, the obesity of the patient and the warmth of the room. This should
commence with a preliminary examination of the abdomen, assessing the aorta for the presence
of an aneurysm and palpation for other abdominal masses. The femoral artery should be palpable
in all subjects (Figure 16.1). If it is occluded, it can often be palpated as a hard cord due to
atherosclerosis. If the pulse feels weak it is often because of proximal obstruction causing
reduced femoral artery blood pressure. The popliteal pulse is more difficult to palpate,
particularly in a well-muscled or obese subject, but should always be examined to exclude an
aneurysm (Figure 16.2).
Palpation of the foot pulses should always be performed and described. It may be
difficult when the foot is swollen, or the room is cold. Presence or absence of foot pulses on
physical examination is a ‘‘week’’ and subjective sign of PAD and should always be
supplemented by objective measurements (ABPI). The absence of a single foot pulse may have
little clinical significance and, although it should be recorded, it is not an indication for more
detailed investigation. Auscultation of the neck, abdomen and groin should be performed to
assess for bruits that may suggest stenoses of the carotid, renal/ mesenteric and femoral arteries.
Figure 16.1 (left) Palpation of femoral pulse may require both hands except in the thin patients. One hand pushes
the lower abdomen out of the way and the other palpates the femoral artery/pulse.
Figure 16.2 (right) a popliteal pulse is best felt using both hands with the leg relaxed in slight flexion.
c. Exercise Challenge
Patients present occasionally with a classic history of IC, but with palpable foot pulses.
These patients may have been investigated previously for joint disease or lumbar nerve root
irritation even though their history may be 'typical' of claudication. Most often, there is proximal
216
aortoiliac disease with collaterals through the pelvis, sufficient to produce adequate or even
normal pulses at rest. In patients who complain of symptoms only on exercise, it is useful to
examine the leg following an exercise challenge. This can be done quite simply by asking the
patient to walk up and down the corridors of the outpatient clinic or on a treadmill if available.
Exercising the calf muscle by repeated 'tiptoe' while leaning on the couch may be a practical
alternative to this (Figure 16.3). The patient returns to the couch so that the pulses can be
examined immediately after exercising for 1 minute. More importantly, the post-exercise ABPI
is measured and a drop in ABPI of more than 0.15 from baseline and/or drop in ankle pressure
more than 30mmHg is significant. In moderate to severe PAD, a sustained drop in post exercise
ABPI is noted which persists for the observation period from 10 minutes to 15 minutes.
Figure 16.3. Simple “tiptoe” exercise of the calf muscle causes vasodilatation with disappearance of pulses
and the emergence of bruits on-examination immediately after the exercise.
d. ABPI Measurement using a hand-held Doppler Device
The perfusion pressure at the ankle can be measured using a tourniquet and insonating the
pedal arteries with Doppler ultrasound. The patient should be rested for more than 5 minutes,
lying supine, and a standard blood pressure tourniquet applied just above the ankle, with the
tourniquet being 50% wider than the limb diameter. The tourniquet cuff is inflated above the
systolic pressure when the pedal Doppler signal should disappear. On gradually lowering the cuff
pressure, the Doppler signal reappears at the ankle systolic pressure (Figure 16.4). The probe
should be held at a 30–60° angle to the vessel to achieve the optimal signal. The systolic blood
pressure is then taken from the brachial artery in the same way and the ABPI calculated as the
ratio of the ankle to the brachial systolic pressures. Blood pressures should be assessed on both
arms at the patient's first visit since 3% to 5% of PAD patients may have supra-aortic occlusive
disease as well. The higher of the two brachial blood pressures should be used as the reference
for calculating ABPI.
217
Figure 16.4 A hand-held Doppler can be used to detect the presence of an arterial signal at the ankle. Assess the
waveform – abnormal (monophasic/damped) or normal (biphasic/triphasic) – and measure the ABPI. The systolic
pressure at the ankle is normally higher, due to superimposed pulse waves down the arterial tree with an ABPI of
1.0–1.2. An ABPI of <0.9 suggests arterial disease and serves as the lower limit of normal. An ABPI of <0.5 is often
associated with critical ischaemia.
An ankle arterial pressure of 60 mmHg is required for ulcer healing in patients without
diabetes and a higher pressure of 80mmHg is generally required in the patient with diabetes.
Falsely high ankle arterial pressures may be measured if the calf arteries are rigid due to
calcification because it is often associated with diabetes and chronic kidney disease. The finding
of very high or incompressible ankle pressures (systolic >200mmHg or ABPI >1.3) should
always raise suspicion of a false result. In such cases, measurement of toe pressures will reveal a
true pressure as the small digital arteries infrequently become affected with medial calcification.
Alternatively, if toe pressure measurement is not possible, the pedal Doppler signal should be
assessed for normal triphasic or biphasic waveforms. When the Doppler signal in the foot is
monophasic due to proximal disease, pressures above the brachial pressure suggest falsely high
readings due to vascular calcification.
Assessment of ABPI is indicated for all patients with leg ulceration and foot ulcers. The
technique is particularly important in diabetic ‘neuropathic’ ulcers or infection involving the toes
or feet, where missed proximal arterial disease may lead to avoidable amputation due to rapidly
progressing infection. The ABPI is also useful in elderly patients referred with foot symptoms
that do not appear to be vascular and in these cases a normal measurement is reassuring. Toe
pressure measurements may be useful when the calf arteries are incompressible or when severe
distal arterial disease in the foot is suspected, i.e., in cases with high ABPI but non-healing ulcers
at toe or forefoot level.
218
e. Risk Factors
All patients should be investigated for risk factors for atherosclerosis as modification
reduces both the risk of fatal and non-fatal cardiovascular events and the need for arterial
reconstruction. The risk factors associated with PAD are essentially the same as those for
ischemic heart disease, and include smoking, lack of exercise, unhealthy dietary habits,
dyslipidemia, diabetes mellitus, hypertension, age and male sex. All patients with PAD require a
full blood count, erythrocyte sedimentation rate (ESR), urea and electrolytes, a random blood
glucose and lipid levels. Anemia can present with symptoms of leg ischemia, as can
polycythemia. An elevated ESR (or viscosity) may indicate raised fibrinogen, which seems an
important factor in the development of PAD and vascular thrombosis. Renal impairment is often
associated with PAD and requires detection before contemplating both imaging and intervention.
Arterial thromboembolism is relatively infrequent in patients under the age of 50 years. Young
patients with PAD should have a thrombophilia screen as antiphospholipid antibodies or
antithrombin III deficiency may lead to repeated thrombosis following either angioplasty or
reconstruction. Hyperhomocysteinaemia can cause accelerated atherosclerosis and should be
excluded in young patients with PAD. Acute limb ischemia in a younger patient with no history
of PAD warrants thorough cardiac investigations work-up, including at least an
electrocardiogram (ECG) and echocardiography.
f. Treatment:
Administration of autologous Autologous Adipose Tissue-derived Mesenchymal Stem

Cell (AdMSC) for Buerger’s disease was approved by the Korean Ministry of Food and Drug
Safety with Investigational New Drug Application for Emergency Use. The protocol for
administration of AdMSCs was conducted in compliance with the Helsinki declaration and
approved by the Institutional Review Board of Bethesda Hospital, Yangsan, Korea. Written
informed consent to take part in the treatment was acquired from all patients before the initiation
of treatment.
The three cases presented herein were male patients with smoking history (currently non-
smoking) and aged between 46 and 55 years. All patients showed the corkscrew appearance or
luminal obstruction of the medium-sized or smaller arteries by angiogram and were diagnosed
Buerger’s disease at least six months before the start of AdMSC treatment (Table 16.1). These
patients were suggested for treatment with AdMSCs (between April 2017 and April 2018) as
they were classified as Rutherford class III-59 by clinical description, experienced ischemic rest
pain and ulcers, and showed the recurrence or no improvement after previous treatments. The
baseline characteristics including previous treatment and medications are shown in Table 16.1.
219
Patient 001 (48) 002 (55) 003 (45)

(Age,
years)
Rutherford III-5 III-5 III-5

scale
Rest pain YES YES YES

before
AdMSC
treatment
Ulcers at No Rt big toe No

baseline
Rt 2nd toe
Symptom 18 10 19
onset
(years
ago)
Smoking 6 34 25
duration
(years)
Previous Lt. 1,2,3,4th toe partial Both big toe partial Rt 4,5th toe total
amputation amputation; Rt 3rd amputation; Rt 2nd toe amputation
history toe total amputation partial amputation
Previous Angioplasty 4 times; Hyperbaric oxygen Bypass graft,

treatment Allogenic stem cell therapy angioplasty
treatment: 8yrs ago
Previous Aspirin (100mg, qd), Sarpogrelate Cilostazol (200mg,

medication clopidogrel (75mg, (100mg, tid), ginkgo qd), aspirin (100mg,
(continued to last qd), beraprost leaf extract (80mg, qd), warfarin (5mg,
F/u) (0.06mg, tid), bid), aceclofenac qd), oxycodone
Vytorin (10mg, qd,), (100mg, bid), (10mg, tid)
Mypol (as codeine pregabalin (75mg,
phosphate 20mg, bid), ciprofloxacin
qd) (250mg, bid)
Claudication 30m 300m 50m

Pain area Lt thigh, both Both calves, Both calves,
calves, both both feet, both Rt foot
feet, both hands
hands
Lt leg is more
severe
Allodynia None Allodynia,

Other Raynaud’s
symptoms symptom
Table 16.1 Baseline Characteristics of Patients
220
The isolation and characterization of the autologous AdMSCs were performed using a
previously established culture protocol under good manufacturing practice conditions in the
Stem Cell Research Institute of R Bio (Seoul, Republic of Korea). Briefly, abdominal
subcutaneous adipose tissue was obtained through liposuction three weeks before administration
and digested with collagenase I (Gibco/Life Technologies, Grand Island, NY, USA). After
centrifugation, the pellet was resuspended in DMEM (Invitrogen, Carlsbad, CA, USA)-based
media containing 0.2 mM ascorbic acid and 10% fetal bovine serum (FBS; JR Scientific,
Woodland, CA, USA). The cell fraction was cultured overnight at 37°C/5% CO2, and cell
adhesion was checked after 24 h. Cells were maintained for 4 to 5 days until confluent (passage
0). When the cells reached 90% confluency, they were subcultured to expand in keratinocyte
SFM-based media (Invitrogen, USA) containing 0.2 mM ascorbic acid, 0.09 mM calcium, 5
ng/ml rEGF, and 5% FBS until passage 3. Before transporting the cells for administration,
aliquots of the AdMSCs were tested for cell viability, fungal, bacterial, endotoxin, and
mycoplasma contamination and immunophenotype for MSCs. Cell viability evaluated by trypan
blue exclusion was >91%, and no evidence of bacterial, fungal and mycoplasma contamination
was observed.
The AdMSCs showed a homogenous population of cells with high positive marker
expression levels of CD73 and CD90 at a high level of >92% and >99%, respectively. Negative
markers of CD31, CD34, and CD45 were expressed at a very low level of <0.08%.
Since most patients showed allodynia, intramuscular (IM) injections were carried out under
spinal anesthesia. According to our previously reported protocols, AdMSCs were prepared at a
concentration of 1X107 cells/0.5 ml saline/syringe before IM injection. Finally adjusted AdMSCs
were administered at the dose of 5X106 cells/kg (based on body weight of the patient) were
injected into multiple sites (at least 38 points) of the ischemic zone of the lower extremities (the
feet of the three patients) at one time. Before the IM injection, the ischemic legions on the
affected limbs were identified by Digital Infrared Thermal Imaging (DITI). To assess safety and
efficacy, all the patients were followed up at one, three, and six months after the IM injection.
Safety was assessed during follow-up by looking at vital signs, physical examination, laboratory
tests, adverse events, and serious adverse events as described in our previous reports.
For the evaluation of the efficacy, the following assessment were performed at every
follow-up: Visual Analogue Scale (VAS) for rest pain, designated as 1 (best) to 10 (worst);
King’s College Hospital’s Vascular Quality of Life Questionnaire (VascuQoL), consisting of 25
questions grouped into 5 domains (activity, emotional, pain, symptoms, social), for the disease-
specific quality of life assessment; assess ulcer size and wound healing; assess the risk of
additional amputation; DITI for the identification of ischemic legions before and after the
injection of AdMSC. Computed Tomography (CT)-Angiography was carried out for the
evaluation of angiogenesis at baseline and the last follow-up.
e. Typical Case Study
i. Case 1 (Patient 001)
A man, aged 48 years, whose onset of Buerger’s disease symptoms had begun 18 years
ago, was admitted to the hospital, and identified for treatment with AdMSCs. The patient had a
221
smoking history from age of 24 to 30 and had stopped smoking after the diagnosis of Buerger’s
disease. At the time of visiting the hospital for treatment with AdMSCs, the patient had partial
amputation in the left 1, 2, 3, 4th toes and total amputation in the right 3rd toe, with no ulcers.
The patient already had a history of angioplasty four times and received allogenic stem cell
therapy, but the effect of this treatment disappeared two months after the treatment. The patients
showed severe pain, allodynia, rest pain, claudication (30 m), and pains in the left thigh, both
calves, both feet, and both hands. The patient was on the following medication, which was
maintained during treatment with AdMSCs: Aspirin (100mg, qd), clopidogrel (75mg, qd),
beraprost (0.06mg, tid), Vytorin (10mg, qd), Mypol (as codeine phosphate 20mg, qd)
(summarized in Table 18.1, with other characteristics). The analgesics were decreased in dose
(Mypol 20mg per three days) during the follow-up period as symptoms improved.
No severe adverse events and no adverse drug events were observed during follow-up
after treatment with AdMSCs regarding physical examination (including ulcer size check,
capillary refill test), vital signs (temperature, pulse, and blood pressure respiration), and
laboratory tests (hematology, biochemistry, urinalysis). Vas and VascuQoL scores showed
improvement one month after the treatment. No additional ulcers were observed, and no
amputations were required. Rest pain and allodynia disappeared, and quality of sleep was
improved as night pain disappeared during the follow-up period. Claudication was also improved
from 30 m at baseline to 100 m at the final follow-up. DITI images showed gradual alleviation in
the affected lower limbs after three months from the treatment, and improvement in the non-
affected opposite limb six months after AdMSC injection. The persistence of this alleviation
effect was identified by DITI images in the additional visiting the hospital one year after AdMSC
injection. Angiogenesis in the affected limbs was identified by CT-Angiography after AdMSC
injection. The formation of collateral arteries in the legions was newly observed in the non-
injected right leg.
ii. Case 2 (Patient 002)
A man, aged 55 years, was diagnosed with Buerger’s disease 10 years ago. The patient
had 34 years of smoking history from the age of 20 to 54 and stopped smoking one year ago
prior to treatment with AdMSCs. Both hands and legs were affected and amputations had been
performed partially in both big toes and right 2nd toe. Ulcers were observed in the right big and
2nd toes. The patient had a history of hyperbaric oxygen therapy and no angioplasty. After the
partial amputation of affected toes, the following medication was taken by the patient, and was
continued during the follow-up period after AdMSC treatment: sarpogrelate (100mg, tid), ginkgo
leaf extract (80mg, bid), aceclofenac (100mg, bid), pregabalin (75mg, bid), and ciprofloxacin
(250mg, bid). There were pains in both calves, feet, and hands, and stiffness in the feet and
lumbodynia after long-distance walking, but no signs in the thigh.
capillary refill test), vital signs (temperature, pulse, and blood pressure respiration), laboratory
tests (hematology, biochemistry, urinalysis). Vas and VascuQoL scores showed improvement
one month after the treatment. Claudication was improved from 300 m at baseline to 600 m at
the final follow-up. The ulcers on the right big and 2nd toes at baseline showed bone exposure
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and after six months exhibited a complete healed state with no additional ulcers observed and
amputations required. This complete healed state was identified in the reinspection one year after
AdMSC injection. Rest pain had disappeared, and most symptoms were improved, and all
medications were stopped one month after treatment with AdMSCs. DITI images showed
alleviation in the affected right limb one month after treatment and also showed improvement in
the non-affected opposite limb three months after treatment. The improved state was maintained
six months after treatment. Angiogenesis in the right limb was identified by CT-Angiography
and the formation of new collateral arteries was observed in the right leg after AdMSC injection.
iii. Case 3 (Patient 003)
A man, aged 45 years, whose onset of Buerger’s disease symptoms had begun 19 years
ago, was admitted to the hospital. The patient had 25 years of smoking history from the age of 20
to 45 and stopped smoking after angioplasty 8 months ago prior to the treatment with AdMSCs.
Both legs were affected, and amputations had been carried out on the right 4 and 5th toes. There
were no ulcers at the time of treatment with AdMSCs. The patient had bypass graft on the right
leg 5 years previous to treatment. The patient reported pain in both calves and right foot,
allodynia, rest pain, claudication (50 m.), Raynaud’s symptom in both hands, and slow capillary
filling in both fingers and toes. The patient was on the following medication which was
maintained during treatment with AdMSCs: Cilostazol (200mgm qd), aspirin (100mg, qd),
warfarin (5mg, qd), oxycodone (10mg, tid).
capillary refill test), vital signs (temperature, pulse, and blood pressure respiration), laboratory
tests (hematology, biochemistry, urinalysis) during the study. Vas and VascuQoL scores showed
improvement one month after treatment. Rest pain, allodynia, and Raynaud’s symptoms
disappeared, and quality of sleep was improved as night pain disappeared during the follow-up
period. Most of the symptoms were improved and the analgesics have decreased the dose
(oxycodone 5 mg, tid) during the follow-up period as pains alleviated. Claudication was also
improved from 50 m at baseline to 300 m at final follow-up. DITI images showed the gradual
alleviation process in the affected lower limb three months after treatment, and also showed
improvement in the non-affected opposite limb at the final follow-up (Figure 16.5).
Angiogenesis in the affected left limb was identified by CT-Angiography after AdMSC injection.
Newly formed collateral arteries in the injected lesions was observed in the non-injected right leg
at the final follow-up (Figure 16.6).
iv. Discussion
There are no standard diagnostic criteria and no treatment guidelines or protocols for
Buerger’s disease. Treatment and assessment of its efficacy remain debatable for these reasons.
However, recent studies and clinical trials have indicated that the restoration of angiogenesis is
the key for alleviation of symptoms and the fundamental therapy for Buerger’s disease.
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Figure 16.5 DITI images of patient 003 showing the improvement of the right leg at baseline (Figure 18.5a), three
months (Figure 18.5b), six months (Figure 18.5c) after being administrated AdMSCs.
Figure 16.6 CT-angiography images of the right leg of patient 003 at baseline (Figure 18.6A and Figure 18.6C) and
six months (Figure 18.6B and Figure 18.6D) after the injection of AdMSCs showing thicker and more abundant
arteries (arrows and arrowheads).
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The present cases reported the improvement of patients diagnosed with Buerger’s disease
after the administration of AdMSCs. Ulcers present in some of the patients on affected limbs
were completely healed, a major symptom of Buerger’s disease, and rest pain and claudication
were alleviated. In addition, assessment of the patients using VAS scale and VascuQoL indicated
treatment satisfaction without any adverse events. VascuQoL is vascular disease-specific and is a
reliable and validated assessment. Along with our previous findings demonstrating the safety and
functional improvement in the patients with Buerger’s disease, the present cases suggest that
AdMSCs are involved in modulating inflammation and pain.
Angiogenesis in the ischemic limb in the present cases were identified by non-invasive
CT-angiography after the injection of AdMSC and corresponded with the results of the previous
study using the AdMSC provided by our previous established protocols. Moreover, angiogenesis
was also found in the counterpart limb, which had not been injected. These findings demonstrate
that focally injected AdMSCs could conduct systemic angiogenetic characteristics in patients
with Buerger’s disease. The outcomes of the present clinical cases are considered as a result of
the synergy between angiogenetic properties and anti-inflammatory/immunomodulatory action
of AdMSC. These various functions of the MSCs are known to be exerted by paracrine actions
with the release of extracellular vesicles, exosomes. Previous studies report that AdMSCs secret
soluble angiogenetic factors, such as vascular endothelial growth factor (VEGF), fibroblast grow
factor-2 (FGF-2), interleukin-6 (IL-6). AdMSCs have been reported to show various advantages
over MSCs from other sources, including a less invasive sampling procedure, higher cell
numbers from tissue harvested, higher capacity for proliferation and higher capacity of
angiogenesis. The angiogenetic potential is essential for recovering damaged tissues. Newly
formed blood vessels are extremely helpful for the migration of versatile stem cells to affected
lesions and for the transportation of various factors, which is vital for the regeneration of tissues
and tissue function.
Taken together, these cases would suggest that AdMSCs have potential advantages for
regenerative medicine, and especially AdMSCs may be promising alternatives in orphan disease
or emergency cases, such as Buerger’s disease. However, the restricted numbers of patients
presented here, and the short period of follow-up limit the assessment of the long-lasting
angiogenetic potential of AdMSCs. Nonetheless, the present clinical cases show improvement
and safety of IM injection of AdMSCs in patients with Buerger’s disease, leading to an
alleviation of symptoms and observation of angiogenesis in the affected limbs. Further studies
are needed for continuous follow-up to optimize the treatment protocol. A precise assessment of
the efficacy of AdMSCs in larger clinical trials will also be needed.
225
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Trial Assessing the Safety and Efficacy of Intramuscular Injection of Autologous Adipose Tissue-Derived
Mesenchymal Stem Cells in Patients With Severe Buerger's Disease. Cell Med. 2016
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10. Mazari F, Carradice D, Rahman M, et al.: An analysis of relationship between quality of life indices and
clinical improvement following intervention in patients with intermittent claudication due to femoropopliteal
disease. J Vasc Surg. 2010
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disease-specific quality of life measure for use in lower limb ischemia. J Vasc Surg. 2001
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Chapter 17 Mesenteric Vascular Disease
The mesenteric arteries and veins are affected by a number of diseases. In the clinical
situation it is not always obvious if the ischemia is acute or chronic, or acute-on-chronic. It is
also not always clear whether the main disease is arterial or venous, nor if it is a result of
embolus from the heart, local thrombosis due to atherosclerosis, an underlying aneurysm, or a
dissection. The difficulties in diagnosis provided the rationale behind the 2017 European Society
of Vascular Surgery (ESVS) guidelines on the Management of the diseases of the mesenteric
arteries and veins' which cover all these pathologies. These clinical practice guidelines give 64
recommendations regarding diagnosis and treatment of the different clinical scenarios that are
most encountered.
a. Acute thromboembolic occlusion of the superior mesenteric artery
This condition is more common than expected, and in most epidemiological studies
embolism is more common than primary thrombosis.Without a high grade of clinical suspicion
and targeted diagnostic tests, many patients are diagnosed too late, when the entire bowel is
gangrenous and the patient beyond salvage. The classical clinical triad associated with acute
embolic occlusion of the superior mesenteric artery (SMA) consists of: (1) acute severe
abdominal pain without signs of peritonitis (‘pain out of proportion’); (2) bowel emptying, most
often both diarrhea and vomiting; and (3) a source of embolus, most often atrial fibrillation, or
acute myocardial infarction. Another controversial issue is whether open or endovascular
revascularization is the preferred approach. Here the data suggest that endovascular techniques
are associated with better outcomes if the occlusion is thrombotic, but with an embolic occlusion,
open or endovascular surgery have similar outcomes.
Although a normal D-dimer can exclude the diagnosis, it is not specific and in fact there
is no specific laboratory test to detect acute mesenteric ischemia (AMI). Another controversial
issue is whether open or endovascular revascularization is the preferred approach. Here the data
suggest that endovascular techniques are associated with better outcomes if the occlusion is
thrombotic.However, open, or endovascular surgery have similar outcomeswith an embolic
occlusion.
Lactate is effectively metabolized in the liver, explaining why it is elevated only late. It
becomes diagnostic when the bowel is gangrenous and the patient has become septic and
hypotensive, which explains why the ESVS guidelines34 issued a strong recommendation not to
use lactate to diagnose this condition early. Modern CT angiography is the mainstay
investigation to diagnose an occlusion of the SMA, but it should be performed in all three phases
and with thin slices over the SMA in the arterial phase. When treatment is discussed, one
controversial issue is whether revascularization should be performed before or after bowel
resection (when needed). There are no RCTs, but cohort data suggest that revascularization
should be performed prior to bowel resection.
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Another controversial issue is whether open or endovascular revascularization is the

preferred approach. Here the data suggest that endovascular techniques are associated with better
outcomes if the occlusion is thrombotic, but with an embolic occlusion, open or endovascular
surgery have similar outcomes.
There is consensus regarding the need for second-look laparotomy, completion control
(with angiography or flow measurements) and antibiotic treatment. The damage control strategy,
first developed in trauma patients, should also be considered when treating patients with AMI,
and this may be the explanation why treatment of a thrombotic occlusion with open surgery is
less successful than with stenting. An alternative when antegrade stenting through the aorta is
difficult, and in particular if there is also contamination due to bowel gangrene, is the retrograde
open mesenteric stenting (ROMS), when the SMA is punctured through laparotomy.
There is consensus regarding the need for second-look laparotomy, completion control
(with angiography or flow measurements) and antibiotic treatment. The damage control strategy,
first developed in trauma patients, should also be considered when treating patients with AMI,
and this may be the explanation why treatment of a thrombotic occlusion with open surgery is
less successful than with stenting. An alternative when antegrade stenting through the aorta is
difficult, and in particular if there is also contamination due to bowel gangrene, is the retrograde
open mesenteric stenting (ROMS), when the SMA is punctured through laparotomy.
A case example of how the damage control concept can be applied to a patient with AMI
is illustrated in Figure 17.1. The case involved an 85-year-old man who was admitted with atrial
fibrillation and 2 days of abdominal pain. He had a slightly elevated troponin level, was thought
to have a myocardial infarction, and was admitted to the cardiology unit. Twelve hours later the
diagnosis was questioned, and CTA showed an embolus in the SMA (Figure 17.1a). The patient
had no peritonitis, but severe abdominal pain, and was taken to the hybrid operating room. An
aspiration embolectomy was performed with a stiff 6-Fr introducer (Figure 17.1b), and the final
angiography showed an almost complete revascularization of the branches (Figure 17.1c). The
procedure was performed under local anesthesia and the patient experienced an almost complete
and immediate relief of his abdominal pain, which prevented the need for an exploratory
laparotomy. After 3 days of surveillance at the hospital, and initiation of warfarin treatment, the
patient returned to his home. This case illustrates the potential benefit of endovascular therapy in
these often elderly and frail patients.
b. Mesenteric ischemia----Chronic mesenteric ischemia
The typical clinical presentation of chronic mesenteric ischemia (CMI) is postprandial

pain, weight loss and diarrhea. The typical patient is a female smoker around the age of 60. In
contrast to the patient with malignant disease, the patient’s appetite is not affected. The patient
refrains from eating, or eats very small meals, for fear of the pain that comes after the meal. The
clinical history is the key to the diagnosis.
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Figure 17.1 Treatment of Acute Mesenteric Ischemia in an 85 years old man.
The patient usually has known cardiovascular disease and has often undergone multiple
examinations for abdominal pain. One of the main problems is how to diagnose the condition,
since asymptomatic stenosis and even occlusion of one of the mesenteric arteries is quite
common, explained by the collateral network that is well developed in most people (Figure 17.2).
Duplex ultrasound is the recommended screening examination, when CMI is expected (in
contrast to AMI when it is not recommended due to the risk of false-negative findings) and has
the advantage of also including physiological evaluation of stenoses.
If a single vessel is affected, the diagnosis of CMI is less likely and careful examination
for alternative causes is warranted. If two or three of the mesenteric arteries are affected, and no
other explanation has been identified despite extensive gastroenterological examinations, CMI
should be considered the cause of the symptoms. Before treatment, the anatomy of occlusions
and stenosis needs to be mapped. CTA is most often used for mapping the disease prior to any
intervention, although MRA is an alternative.
If there is severe CMI (defined as significant weight loss, diarrhea and/or continuous pain)
treatment should not be delayed, since there is a risk of developing acute-on-chronic ischemia
with bowel gangrene. Whether the patient with severe CMI should be given parenteral nutritional
support prior to surgery is controversial. Data suggest that this is not advisable, since the delay
may result in worsening ischemia, and the ESVS mesenteric guidelines issue a strong
recommendation not to delay treatment in this clinical scenario.
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Figure 17.2. Collateral Network of the Mesenteric Arteries
When it is decided to treat the patient, several alternatives and controversial issues need
to be addressed. Many vascular centers would consider endovascular treatment as the first option,
but risk factors for failure of endovascular treatment must be considered. These include
anatomical factors such as severe eccentric calcification, flush occlusions and long lesions that
extend into the middle segment of the SMA. In these cases, stenting may still be possible, but is
not optimal since the risks of restenosis and of perioperative complications are increased. The
superior long-term results of open surgery should be balanced against a possible early benefit of
endovascular intervention in relation to the lower immediate mortality and morbidity.
There are two other situations when an open arterial reconstruction may be preferred:
after failed endovascular treatment and in young patients, often with non-atherosclerotic disease
such as vasculitis or mid-aortic syndrome. A special case is also the median arcuate ligament
syndrome (MALS) when the coeliac trunk is compressed by muscular fibers from the diaphragm.
In this situation primary stenting is contraindicated but can sometimes be necessary and
successful after prior open surgical release.
Balloon angioplasty has been replaced by primary stenting in most hospitals because of
the increased risk of elastic recoil and restenosis. The lesions are most often ostial, a result of
atherosclerosis of the aortic wall. However, there are no RCTs comparing different treatment
modalities, making the evidence base weak.
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The SMA has multiple branches, some of which may be sacrificed with a covered stent,
which should be balanced against the fact that data suggest that restenosis is less common after
having used a stent graft. This was shown in a large retrospective study on 225 patients, and a
Dutch RCT is ongoing.
Another controversial issue is whether a bare- metal stent or a covered stent graft should
be used. Another debated issue is whether one or multiple vessels should be revascularized in the
case of multivessel disease, and if the SMA or the coeliac trunk should be treated. The literature
shows retrospective studies with diverging results: some have shown no significant advantage of
two-vessel stenting, others have reported better long-term results after two-
vesselrevascularization.Given the lack of proven benefit of the more extensive procedure, most
centers would focus on the SMA, and treat only that vessel.
In the postoperative management it is obvious that secondary prophylaxis and risk factor
management should be performed, including antiplatelet therapy, smoking cessation and statins.
CMI is a life-threatening disease, and the patient benefits from a multidisciplinary approach.
Since both diagnosis and treatment are rather complex, and these patients are not common, the
patient should ideally be referred to a specialist hospital that can offer a multidisciplinary team,
as well as both open and endovascular treatment.Most patients do benefit from a routine follow-
up to assess the clinical outcome, but it has not been shown that routine imaging adds benefit to
the patient. An asymptomatic patient probably does not require any imaging.
c. Acute mesenteric venous thrombosis
Acute venous thrombosis of the superior mesenteric vein is the most common cause of
acute venous ischemia, also called mesenteric venous thrombosis (MVT). MVT is less common
than AMI by a factor of seven.The condition is underdiagnosed, due to rather diffuse symptoms,
and a less acute onset compared to AMI. It can also be over-diagnosed since many patients with
abdominal symptoms undergo abdominal CT investigations. Incidentally reported MVT was
reported to be present in approximately 2% in one large postmortem study. This explains the
great variations in incidence estimates, but a recent Finnish population-based study estimated it
to be 0.5/100000 inhabitants/year.When bowel gangrene develops, its extension is usually less
than in cases caused by arterial occlusion. Typically, the middle part of the small bowel is
affected, and it is associated with oedema and ascites. The edematous mesentery makes it
technically demanding to perform both anastomosis and stoma.
When MVT is diagnosed, underlying prothrombotic conditions should be considered,

since they may also need to be treated. Considering Virchow’s triad is a systematic approach,
including damage to the vessel wall, reduced flow and/or a pro-coagulant blood. The most
common underlying risk factors are venous thromboembolism (often inherited monogenetic
disorders) and obesity,but malignant disease, undiagnosed portal hypertension, intra-abdominal
infections or injury during surgery should also be considered.
Most patients can be managed without laparotomy or bowel resection, but

especially during the first days this possibility needs to be considered. Bowel gangrene can
develop late. Nevertheless,the ischemic injury is a product of the duration and the depth of
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ischemia. This means that a low-grade ischemic condition, such as MVT, can result in bowel
gangrene after 1–2 weeks. Until resolution of abdominal pain, the risk of gangrene prevails.
This is the background to why unfractionated heparin is the best initial treatment, since it
can be reversed more quickly, if a need for bowel resection develops. Later, low-molecular-
weight heparin (LMWH) may be used. The strong anti- inflammatory effect of heparin is also an
important therapeutic principle that explains why it is so effective in most cases.
In approximately 5% of cases heparin treatment is not successful: the abdominal pain

continues, and the general status of the patient deteriorates.In this situation, catheter-delivered
thrombolysis may be considered. Direct puncture of the liver and delivering the thrombolytic
agent (usually rTPA) directly to the superior mesenteric vein is associated with a rather high risk
of bleeding complications, and since the outflow through the liver is compromised, significant
clearance of the thrombus is seldom achieved. A solution is to puncture the jugular vein, perform
a via-jugular-vein intrahepatic portosystemic shunt (TIPS) and through that perform mechanical
aspiration thrombectomy and direct thrombolysis. This approach has the advantages of both
reducing the bleeding risk and improving the outflow. The TIPS will usually thrombose
spontaneously after some time.
After the acute episode it is important to investigate whether there is an underlying

condition explaining the MVT. In patients with reversible causes such as trauma, infection, or
pancreatitis, anticoagulation for 3–6 months is recommended in the ESVS guidelines.Lifelong
anticoagulation is recommended in case of proven thrombophilia, recurrent venous thrombosis or
when progression or recurrence of thrombosis would have severe clinical consequences, such as
in a patient with short bowel.
d. Non-occlusive mesenteric ischemia
The term non-occlusive mesenteric ischemia (NOMI) was first used by Ende in 1958.In
critically ill patients with low cardiac output, multiple interventions are often performed to save
the life, but as a side-effect the intestinal circulation may suffer.The vasoconstriction can be
caused by vasoactive drugs (vasopressors, but also cocaine or crack-cocaine among drug addicts),
as well as secondary to resuscitation leading to the abdominal compartment syndrome.Other
patients at risk are those with hypovolemia during renal replacement therapy or after burn injury,
as well as those who have undergone cardiac surgery.
As in most cases of mesenteric ischemia, clinical suspicion is the key to a timely

diagnosis. In one study on patients who died from NOMI, 40% had a stenosis at the origin of the
SMA.Dilating and stenting such a stenosis may be lifesaving, as well as placing a catheter for
selective intra-arterial administration of vasodilators into the SMA. For this reason, the ESVS
guidelinesrecommend that a patient with life-threatening NOMI should be taken to a hybrid
operating room, or an operating room with a C-arm, where both endovascular interventions and
laparotomy (if necessary) can be performed.
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e. Case Study: Acute Thrombosis of the Superior Mesenteric Artery in a 39-year-old

Woman with Protein-S Deficiency.
i. Fact of the Case:
A 39-year-old woman presented in our emergency department with acute abdominal pain
associated with nausea, vomiting, and signs of intestinal occlusion. The clinical history of the
patient highlighted two other admissions for the same clinical signs. During the first admission,
she was given an abdominal computed tomography (CT) scan that demonstrated only the
presence of free fluid localized in the pouch of Douglas and the perihepatic region. In relation to
these signs, she was given an emergency, explorative laparotomy, with lavage of the abdomen.
The laparotomy demonstrated only hyperemic jejunal and ileal handles. She was discharged after
nine days without any complications. Two weeks after the patient was readmitted to the same
hospital with similar symptoms, and she was treated with corticosteroids, mesalazine, and
metronidazole with a complete resolution of the symptoms. Five days later, the patient was
admitted to our unit.
At admission, she had leukocytosis (WBC, 19.960 × 106/L) and normal levels of the
coagulation parameters. She was given abdominal ultrasonography in association with Doppler
ultrasonography (EsaoteMegas GPX 7.5-MHz convex probe), highlighting a thrombosis of the
SMA. As a result of this clinical picture, she underwent an abdominal CT scan (Figures 17.3 to
Figure 17.5), demonstrating the presence of a partial thrombosis of the celiac trunk, a thrombosis
of the SMA for a 25- to 30-mm tract, and the lack of a splenic artery. She immediately
underwent an explorative laparotomy, showing ischemic, but viable handles, and a tree
revascularization by thromboendarterectomy with a Fogarty catheter was performed. In the
following postoperative days, she was given a scheduled second and third look, showing necrotic
handles (the first jejunal handle, the last ileal handle, and about 20 cm of the medium ileum) in
the first procedure, and another necrotic tract of small bowel (the other 10 cm of the first jejunal
tract) in the last procedure. During that surgical procedure, we performed duodenojejunal and
three other lateral anastomoses to reestablish the bowel continuity. A T-tube was inserted to
protect the duodenojejunal anastomosis. A cholecystectomy and biliary diversion were
performed to reduce the biliary output. In relation to the risk of dehiscence, we performed a
colonostomy in the right flank. During all the surgical procedures, we performed interoperate
Doppler ultrasound of the SMA and celiac trunk to control the arterial flow without evidence of a
new thrombosis.
The patient stayed in the ICU for 27 days with total parenteral nutrition and antibiotics
therapy. A coagulation screening demonstrated a thrombophilic state for a protein-S (16%)
deficiency with normal values of VIII, IX, and XI factors. The search for antiphospholipid
antibodies was negative, and the genetics test for factors II to V and methylenetetrahydrofolate
reductase (MTHFR; the deficiency of this enzyme is associated with an increased risk to develop
massive thromboembolic events) was negative (no mutations). She was discharged from our unit
after 37 days without any complications. After three months, the patient had a surgical procedure
for restoring the bowel continuity. The patient was evaluated after one week, and one, three, and
six months after discharge with blood and coagulation examinations, abdominal ultrasonography,
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Doppler ultrasound, and abdominal CT scan. She was asymptomatic and stayed well. At one
year, we had successfully restored the bowel continuity without complications.
Figure 17.3 Abdominal Computed Tomography Scans
Figure 17.4 Abdominal Computed Tomography Scans
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Figure 17.5 Abdominal Computed Tomography Scans.
ii. Discussion:
Acute mesenteric ischemia is a rare abdominal emergency that usually requires wide
intestinal resection and carries a high mortality rate with the adverse effects of short-bowel
syndrome in the surviving patients. A critical point that influences the survival rate is prompt
diagnosis in patients with AMI. Numerous surgical reports indicated that acute intestinal
ischemia (AII) is associated with a poor prognosis. The poor signs, symptoms, and nonspecific
laboratory tests are among the causes of the delay in the diagnosis. Other examinations that can
be helpful in the diagnostic process are angiography, computed tomography angiography (CTA),
and magnetic resonance angiography (MRA). When no clinical evidence is found for an
immediate surgical intervention, such as peritonitis or gastrointestinal hemorrhage, angiography
could be considered the treatment of choice in patients with suspected AMI, because this
investigation allows us to distinguish between non-thrombotic and thrombotic causes. Moreover,
angiography allows us to treat the occlusion with a restoration of the blood flow by using an
endovascular approach, such as percutaneous transluminal angioplasty and thrombolysis.
Doctor Simo reported a 90% success rate for lysis of the embolus in patients with SMAE.
However, although the endovascular approach may rapidly restore the blood flow to the bowel,
the time needed for thrombolysis is variable, and the bowel viability cannot be assessed with
laparotomy. This can result in a diagnostic delay that can compromise other viable bowel tracts
[5]. According to Kirkpatric, the CTA has shown a diagnostic sensitivity of 96% and a
specificity of 94%. The magnetic resonance angiography (MRA) is another newer imaging
technique that seems to be promising for the diagnosis of AMI, although this technique cannot
help us to diagnose NOMI secondary to a low-flow state or to identify distal embolic disease.
Generally, the IMA is due to an impaired blood supply to the intestine caused by
thromboembolic phenomena. These phenomena may be associated with a variety of congenital
prothrombotic disorders (PDs), such as protein-C and protein-S deficiencies, AT III deficiencies
(anti-phospholipid antibodies), Factor V Leiden (FVL), Prothrombin G20210A mutation, and
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C677T homozygous mutation of the MTHFR gene. The prevalence of these mutations differs
among geographic areas and ethnic groups. In our patient, we found deficiencies of the S protein,
although some studies demonstrated a prevalence of this disorder in a Chinese population (59%)
compared to a Caucasian population (15%). The level of S protein is higher in men than in
women but increases with age in women but not in men. In women, the levels of an S protein are
lower before menopause, while taking oral contraceptives, or while undergoing hormone-
replacement therapy, and during pregnancies.
The International Society of Thrombosis and Hemostasis Standardization Subcommittee

defined three n-types of hereditary S-protein deficiencies. Type I is defined by low levels of free
and total antigen with decreased APC cofactor activity. Type II protein-S deficiency is
characterized by normal levels of a free and total antigen, with low levels of APC cofactor
activity. Type III protein-S deficiency is defined by normal to low levels of total antigen, low
free protein S, and an elevated fraction of protein S bound to C4BP. The role of the protein S is
based on an increase of the anticoagulant action of protein C. Protein C is a proteinase that
inactivates the coagulation factors V, Leiden, and VIII, and protein S increases the action of
protein C. The SMA normally serves as the primary arterial supply of the jejunum, the ileum,
and the colon to the level of the splenic flexure.
Doctor Ottinger demonstrated a general correspondence between the site of the occlusion,
the extent of the infarcted areas, and the prognosis. To explain this concept, we can divide the
SMA into four regions. The first portion is the artery origin, and the second tract is represented
by the main trunk, including the middle colic artery (MCA). Region three corresponds to the
main trunk beyond the origin of the MCA, and the last region (IV) is the most peripheral portion
of the SMA and its branches. The occlusion of the SMA in the first region produces a more-
extensive infarction than that when the site of occlusion is distal to the origin of some of its
branches.
Another factor that influences the prognosis is the etiologic subsets. We can grossly
distinguish two different origins, thrombotic and non-thrombotic. Non-occlusive mesenteric
ischemia, the more frequent non-thrombotic cause, is caused by low-flow states. The thrombotic
condition includes arterial embolism, arterial thrombosis, and mesenteric venous thrombosis.
According to Schoots, acute mesenteric ischemia due to a venous thrombosis has a better
prognosis compared with arterial causes of MIA. In this case, the improved survival rate can be
explained by the segmental bowel infarction and the need for limited intestinal resection. The
poor prognosis of patients with mesenteric arterial occlusions is most likely due to the proximal
location of the occlusion in the vessel tree; this determines a more extensive bowel infarction and
the need for extended intestinal resection.
A mesenteric arterial embolism results in a different extension of the infarcted areas

because the emboli can occlude the vessel tree to different levels. The prerequisite for success of
a revascularization is prompt diagnosis. The delay from the first examination to laparotomy was
significantly shorter among the patients in whom the diagnosis was suspected; however, early
diagnosis did not improve survival. Moreover, Giulini demonstrated a correlation between of
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prompt diagnosis of an AMI and survival. However, for the non-specific symptoms, during the
early phase, the diagnosis is often delayed.
The second-look laparotomy remains the gold standard for the assessment of further
bowel viability, and, at the same time, it is the only way to remove infarcted tracts of the bowel.
During the surgical procedure, the bowel viability can be assessed by the physical examination
(inspection of bowel and palpation of the vessel) or by ultrasound examination and intravenous
fluorescein. Although the second-look laparotomy is the gold standard for the treatment of AMI,
some authors perform a second-look laparoscopy to decrease the severe anesthesiologic and
surgical trauma in these critically ill patients. Doctor Levy underlined the beneficial role of the
second-look laparoscopy in patients' survival in a series of 92 patients.
iii. Conclusion
Acute thrombosis of SMA is a rare emergency in young female patients. Although the
incidence of mesenteric infarction is low in these patients, acute thrombosis should always be
suspected, especially in young women receiving estrogen and progesterone therapy and showing
signs of acute abdomen. In these cases, CT angiography or, if feasible, arteriography should be
used to rule out acute mesenteric infarction. If CT angiography or arteriography confirms the
diagnosis, early laparotomy should be performed.
In the case, a second-look laparotomy was performed because this surgical procedure
allowed us to conduct a physical examination of the bowel and artery such as palpation of the
vessels, inspection of the bowel, and evaluation of the anastomosis. Moreover, the second-look
and other laparotomies suggest the performance of an intraoperative Doppler ultrasound to
evaluate the artery flow. According to Ottinger, a new thrombosis of the SMA can develop in the
site of the arteriotomy during the first 48 hours. The possibility of evaluating the arteriotomy,
during a repeated laparotomy with a Doppler ultrasound, is crucial; an early planned repeated
laparotomy improves the prognosis of the surgical approach. Although the prognosis of the AMI
due to an acute arterial mesenteric thrombosis remains poor, a prompt diagnosis, aggressive
surgical treatment, and a supportive intensive care unit for a patient with AMI could improve the
prognosis.
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1. Björck M, Koelemay M, Acosta S, et al. Management of the diseases of the mesenteric arteries and veins.
Clinical practice guidelines of the European Society of Vascular Surgery (ESVS). Eur J VascEndovasc Surg
2017
2. Oderich GS, Erdoes LS, Lesar C, et al. Comparison of covered stents versus bare metal stents for treatment of
chronic atherosclerotic mesenteric arterial disease. J Vasc Surg 2013
3. Bjorck M, Wanhainen A. Nonocclusive mesenteric hypoperfusion syndromes: recognition and treatment. Semin
Vasc Surg 2010
4. Björck M, Acosta S, Lindberg F, Troëng T, Bergqvist D: Revascularization of the superior mesenteric artery
after acute thromboembolic occlusion. Br J Surg. 2002
5. Kozuch PL, Brandt LJ: Review article: diagnosis and management of mesenteric ischemia with an emphasis on
pharmacotherapy. Aliment PharmacolTher. 2005, 23: 201-215. 10.1111/j.1365-2036.2005.
6. Schoots IG, Koffeman GI, Legemate DA, Levy M, Van Gulik TM: Systematic review of survival after acute
mesenteric ischemia according to disease aetiology. Br J Surg. 2004
7. Kurland B, Brandt LJ, Delany HM: Diagnostic test for intestinal ischemia. Surg Clin North Am. 1992
8. Endean ED, Barnes SL, Kwolek CJ, Minion DJ, Schwarcz TH, Metzer RM: Surgical management of
thrombotic acute intestinal ischemia. Ann Surg. 2001
9. Ağaoğlu N, Türkyilmanz S, Ovah E, Uçar F, Ağaoğlu C: Prevalence of prothrombotic abnormalities in patients
with acute mesenteric ischemia. World J Surg. 2005
10. Ottinger LW: The surgical management of acute occlusion of the superior mesenteric artery. Ann Surg. 1978
11. Smith JS, Patterson LT: Acute mesenteric infarction. Am Surg. 1976
12. Kairaluoma MI, Karkola P, Heikkinene D, Huttunen R, Larmi TK: Mesenteric infarction. Am J Surg. 1977
13. Hertzer NR, Beven EG, Humphries AW: Acute intestinal Ischemia. Am Surg. 1978
14. Sachs SM, Morton JH, Schwartz SI: Acutemesentericischemia. Surgery. 1982.
15. Bergan JJ, Mc Carthy WJ, Flinn WR, Yao JS: Nontraumatic mesenteric vascular emergencies. J Vasc Surg.
1987, 5: 903-909. 10.1067/mva.1987.avs0050903.
16. Klempnauer J, Grothues F, Bektas H, Pichlmayr R: Long-term results after surgery for acute mesenteric
ischemia. Surgery. 1997, 121: 239-243. 10.1016/S0039-6060(97)90351-2.
17. Barakate MS, Cappe I, Curtin A, Angel KD, Li-Kim-Moy J, Poon MSF, Sandeman MD: Management of acute
superior mesenteric artery occlusion. A NZ J Surg. 2002, 72: 25-29. 10.1046/j. 1445-2197.2002.02289.x.
18. Kirkpatrick LD, Kroeker MA, Greenberg HM: Biphasic CT with mesenteric CT angiography in the evaluation
of acute mesenteric ischemia: initial experience. Radiology. 2003, 229: 91-98. 10.1148/radiol.2291020991.
19. D'angelo A, D'angelo S: Protein-S deficiency. Haematology. 2008, 93: 498-501.
20. Fauci AS, Braunwald E, Isselbacher Kurt J, Wilson JD: Harrison's Principles of Internal Medicine. New York:
McGraw-Hill, 14
21. Giulini S, Bonardelli S, Cangiotti L, Floriani M, Cervi GC, Portolani N, Tiberio G: Factors affecting prognosis
in acute ischemia. Int Angiol. 1987, 72: 157-182.
22. Rush DS, Levy PJ, Haynes JL: Acute embolic and thrombotic mesenteric ischemia. Current Therapy in
Vascular Surgery. Edited by: Ernst CB, Stanley JC. 1995, St. Louis: Mosby, 693-697.
23. Yanar H, Taviloglu K, Ertekin C, Ozcinar B: Planned second-look laparoscopy in the management of acute
mesenteric ischemia. World J Gastroenterol. 2007, 13: 3350-3353.
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Chapter 18 Renal Artery Disease
Vascular involvement of the renal vessels involves a multitude of conditions and

etiopathologies; the treatment options for these are equally broad and evolve constantly. We
present here a brief review of the traditional understanding of these diseases and the current
evidence available in the management of a few specific conditions. Atherosclerotic renal artery
stenosis is the commonest symptomatic renal vascular pathology in the Western world. The renal
arteries may also be affected in many other conditions, like aneurysmal disease, vasculitis,
fibromuscular dysplasia (FMD), trauma and congenital hypoplasia.
a. Atherosclerotic renovascular disease
i. Prevalence
Atherosclerotic renal disease is symptomatic in about 7% of elderly Americans, the

incidence increasing with age. The prevalence of asymptomatic disease is higher, with autopsy
studies showing renal vascular disease in over 40% of those aged 75 years or older.
Atherosclerotic renal vascular disease (ARVD) and renal artery stenosis (RAS) are terms used
interchangeably; however, the former may be a better term as a high-grade stenosis of the renal
artery may not be present in all patients. ARVD is thus a manifestation of generalized
atherosclerotic disease; concomitant disease in coronary, carotid and peripheral vascular fields is
present in 15% to 45%. The correlation of ARVD and end-stage renal disease is complex, and
causality may be difficult to determine in this patient group: Selective use of renal
revascularization also shows inconsistent associations with cardiovascular outcomes, renal
replacement therapy and death.
ii. Definitions
ARVD occurs with between 50% and 75% renal artery diameter loss as diagnosed on
conventional angiography (gold standard); however, lesions less than 50% may also be
associated with significant (15mmHg) pressure gradients.
iii. Pathophysiology
A hemodynamically significant RAS will lead to a reduction in renal artery perfusion

pressure and thus potentially an impairment of renal function simply due to a hydraulic effect,
but only in a minority of patients. More commonly, there is a compensatory rise in renin and
angiotensin levels in the post-stenotic kidney, constricting the postglomerular efferent arteriole,
which in turn helps to support glomerular capillary hydraulic pressure and filtration rate. As
glomerular perfusion in these patients is critically dependent upon angiotensin II, the risk of
developing acute renal failure is significant, especially if the stenosis is bilateral or affects a
solitary functioning kidney.
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Studies in large cohorts of patients with ARVD have shown that there is often poor
correlation between the degree of anatomical atheromatous stenosis, glomerular filtration rate
(GFR) and overall renal function.Patients with unilateral ARVD can have GFRs that range from
normal to stage 5 kidney disease. Nuclear studies in patients with unilateral stenosis reveal that
GFR may be the same or even lower in the non-stenotic kidney. This lack of correlation between
the severity of renal ischemic injury and kidney function may explain why renal function often
fails to improve significantly after revascularization despite restoration of renal artery patency. It
should also be noted that 1–5% of patients with hypertension are diagnosed to have a significant
RAS. Patients with severe aortic atheroma undergoing arterial surgical or angiographic
procedures, thrombolysis or anticoagulation are at risk of developing renal dysfunction
secondary to cholesterol emboli.
iv. Clinical presentation
The clinical index of suspicion remains essential in determining an appropriate diagnostic

andtherapeutic strategy in ARVD. Specific clinical pointers include:
• hypertension; hypertensive crises;
• renal impairment;
• concomitant cardiovascular disease;
• ACE-induced acute renal impairment;
• ‘flash’ pulmonary oedema;
• vascular bruit, pulse deficit.
v. Diagnosis
Laboratory findings other than plasma renin levels are non-specific; their major role is in
ruling out other conditions like Conn’s syndrome or a pheochromocytoma. Duplex scanning is a
good initial diagnostic tool; however, problems with operator dependency and body habitus can
hinder this. Significant lesions can be identified by measurement of peak systolic velocity in the
main renal artery and its branches, along with end diastolic velocity, parenchymal Doppler
signals, the presence of post-stenotic turbulence, nature of waveforms, measurement of
acceleration times, resistivity index, renal size, and the ratio of renal artery to aortic peak systolic
velocity. Assessment protocols differ between institutions and a standardization would be
clinically useful.
Computed tomography angiography (CTA; Figure 18.1a) provides information about the
aorta and visceral vessels, neighboring organs to exclude secondary causes or fibromuscular
dysplasia and is of value in patients under consideration for open or endovascular
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revascularization. The drawback of CTA is the risk of contrast nephropathy in a patient cohort
that is already at risk for renal impairment. An alternative is magnetic resonance imaging (Figure
18.1b), but this requires long scan times with comparatively poor image quality. The risk of
nephrogenic systemic sclerosis in RAS is significant; gadolinium should be avoided in patients
with a glomerular filtration rate of less than 15 mL/min per 1.73m. Other advances like fusion or
cone beam technology may become clinically useful in the future. CO2angiography also has a
limited role in those in whom both MRI and CTA are contraindicated.
Figure 18.1 Bilateral Renal Artery Stenosis (a) CT (b) MRA.
Functional studies such as captopril renography and selective renal vein renin sampling
have a role in the detection of ARVD, with the potential to predict a blood pressure response to
revascularization or to document the functional significance of RAS.
vi. Management
Medical management is twofold: to promote modification of atherosclerotic risk factors

including aspirin, lipid-lowering drugs, cessation of smoking, glycemic control, and targeted
management for hypertension. Involvement of a nephrologist at an early stage is often necessary
as sudden drastic blood pressure reduction may be harmful. All imaging should be done with
adequate hydration; the use of other renal protective agents (NAC) is described but not
universally accepted.
vii. Renal revascularization
(1) Surgical Treatment
A range of surgical options are available to treat renal artery disease including Aortic
Graft and Renal Bypass, Aortorenal Bypass, Aortorenal Endarterectomy and Patchplasty, Extra-
anatomical Bypass and Extracorporeal Bench Surgery. Endarterectomy and bypass grafting are
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the two main surgical options for revascularization. Current guidelines recommend surgery in
patients with ARVD who have indications for revascularization and have multiple small renal
arteries or require aortic reconstruction near the renal arteries for other indications (e.g.,
aneurysm, severe aorto-iliac occlusive disease). The site of the lesion is also important, and if
extra-anatomical bypass is considered, the condition of the donor visceral vessels must be
optimal. In patients with renal artery occlusion, renal biopsy (performed either preoperatively or
perioperatively) can indicate whether the kidney is viable and functionally salvageable based on
collateral vessels. However, this is not without risk of bleeding and potentially the loss of the
kidney.
Nephrectomy is the oldest surgical procedure used in the treatment of ARVD, but it is
rarely performed nowadays. In the presence of a normal contralateral kidney, it remains an
option if the affected kidney measures less than 8cm. In this situation measurement of renal vein
renin levels is of value, with nephrectomy being indicated when the ratio of renal vein renin is
greater than 1.5.
In the presence of aortic aneurysmal disease affecting the renal ostium, aortic graft and
renal bypass may be indicated, particularly if the aneurysm is not suited to endovascular aortic
repair (EVAR). Surgical options include a 6–8-mm limb of Dacron or polytetrafluoroethylene
(PTFE) graft sutured onto the aortic graft with an end-to-end renal anastomosis and then bypass
onto the affected renal artery in either an end-to-end or end-to-side manner. Where bilateral RAS
is present, an inverted bifurcated Dacron graft is preferred. When the pattern of aneurysm disease
dictates that a suprarenal clamp is required for open surgery, transaortic endarterectomy may be
performed. The ostial lesion is then carefully endarterectomized and the procedure is completed
with patch closure. Five-year patency in large hospitals can reach 90%.
Extra-anatomical bypass grafting is an attractive option for patients with unilateral RAS
in the absence of significant aortic disease. Access is obtained via a subcostal incision, without
the need for aortic cross-clamp or extensive dissection, and revascularization is achieved using
inflow from either the hepatic or splenic artery. An interposition saphenous vein graft may be
used where there is insufficient arterial caliber and length for an end-to-end anastomosis. The
inferior vena cava, the right renal vein and often the left renal vein must be fully mobilized. On
the left side, the splenic artery is dissected from its midpoint from the pancreas. Splenectomy can
be avoided, as there is a rich collateral supply and perfusion via the short gastric arteries. The
Cleveland Clinic reports 175 extra-anatomical bypass procedures over a 12- year period, with
2.9% operative mortality. Graft patency reached 96%,renal function improved in 40%and
hypertension was improved or cured in three-quarters of the series.
The surgeon can carry out aortorenal bypass using the long saphenous vein, PTFE,
Dacron or rarely the internal iliac artery (Figure 18.2). The infrarenal aorta is preferred as an
inflow site if it is relatively disease-free. If not, then a ‘rooftop’ incision is necessary to expose
the aorta above the coeliac axis. The thoracic aorta can also be used as an inflow site. Where
multiple small anastomoses are required, extracorporeal or bench surgery is performed for
patientswithdiseaseaffectingrenalarterybranches. Removal of the kidney, cooling, and
preservation as in renal transplantation surgery will allow multiple microvascular anastomoses to
be performed before auto-transplantation takes place. The internal iliac artery is commonly used
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for direct end-to-end anastomosis. The Cleveland Clinic again has the largest reported series of
auto-transplantation, with excellent long-term results.
Figure 18.2 Aortorenal Bypass with PTFE Graft.
Surgical revascularization is a high-risk option when compared to less invasive treatment

methods. Results vary, with cure or improvement of hypertension and renal failure noted in 63%
to 91% and 33–91%, respectively. Primary patency rates of 93% to 97% and mortality rates of
2–8% are reported. These morbidity and mortality rates have set the standards against which
other treatment modalities can be compared. There have been no large trials to date comparing
the outcomes of stenting with surgical revascularization in ARVD. In young, fit patients’ surgery
may be preferred as it is cost-effective, and the long-term restenosis rate is reported to be 3% to
4%. The management of ARVD can be complex and certainly requires a multidisciplinary
approach to maximize the therapeutic potential for each individual patient. Societal
recommendations and guidelines form an effective template for evidence-based management of
ARVD.
(2) Endovascular treatment
Percutaneous transluminal renal angioplasty and stenting (PTRAS) is the current standard
for renal revascularization (Figure 18.3 a and Figure 18.3 b). Following initial reports of
preventing renal vascular recoil in animal models using stents which demonstrated better patency
with the use of stents compared to angioplasty in isolation. In another five studies in patients
with uncontrolled blood pressure, renal dysfunction and/or failed angioplasty and hypertension
undergoing renal artery stent revascularization were combined. Both the systolic and diastolic
blood pressure were significantly lower at 9 months with an elevated baseline SBP (>150mmHg)
being predictive of lowering of blood pressure in response to stenting. There are no robust data
on the utility of drug- eluting balloons or stents in the renal circulation.
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(3) Revascularization versus medical therapy
A reviewreports the results of management strategies for atherosclerotic RAS from 1993
to 16 March 2016. Fifteen comparative studies with a total of 4006 patients were identified;
seven were randomized controlled trials (RCTs) and eight were non-randomized, comparative
studies (NRCSs). Trial designs, interventions, endpoints, outcomes, follow-up, and reporting
were very variable. The meta-analysis demonstrated a low possibility of improvement of kidney
function, with no difference in blood pressure change, subsequent mortality, progression to need
for renal replacement therapy, cardiovascular events, and adverse events. However, the authors
note that most of these studies exclude patients with high-grade lesions, presenting with acute
decompensation. Patients with ARVD are at an overall threefold risk of cardiovascular and all-
cause mortality to age-matched controls; the challenge remains in identifying the patient subset
in ARVD who, if managed and intervened, will have improvement in renal function and
mortality. Current evidence can justify intervention in patients with progressive, but not severe,
chronic renal insufficiency and systolic hypertension with global high-grade stenosis, ARVD and
rapidly declining kidney function or flash pulmonary oedema. It also has a role in the
management of congestive heart failure. Efforts at developing predictors of clinical benefit from
intervention including high blood oxygen level-dependent MRI, brain natriuretic peptide levels.
Figure 18.3 (a) Right Renal Artery Stenosis Due to ARVD. (b) Post Renal Artery Stentinng
(4) Renal stenting during treatment of aortic aneurysmal disease
Advances in the endovascular treatment of aortic aneurysms with surgeon

modified/fenestrated or branched devices have created a subgroup of patients who undergo renal
intervention when grafts cross the renal artery. Adjunctive renal stenting may be needed to
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salvage inadvertent coverage (Figure 18.4a and Figure 18.4b) or as a planned procedure when
suprarenal fixation or endovascular repair of a thoracoabdominal aneurysm or dissection is
planned. Stent placement in these patients may be more challenging due to complex anatomy,
technical risks and risks of arterial embolization leading to a higher complication rate and reports
of late decline in GFR. Occurrence of secondary intimal hyperplasia in such patients and the
need for subsequent intervention is also an area that requires further study.
Figure 18.4 (a) Renal artery stenosis following endovascular aortic repair. (b) Adjunctive renal stenting performed
to salvage as a planned procedure.
(5) Renal artery denervation
Renal artery denervation (RDN) is an endovascular procedure for the treatment of

resistant hypertension. This condition is thought to involve overactivity of the afferent and
efferent sympathetic nerves that run in the adventitia of the renal arteries, the nerves running
closest in the distal renal arteries and renal artery branches. Radical nephrectomy and surgical
sympathectomy have been associated with the normalization of blood pressure in patients with
end-stage renal disease (ESRD) and hypertension. It has also been established that increased
renal sympathetic nerve activity has an important role in the development of essential
hypertension. Following positioning of a sheath within the renal artery, a probe is positioned
with its tip in contact with the inner luminal surface of the vessel. Radiofrequency energy is then
applied to disrupt the nerve fibers running in the renal artery adventitia. The procedure is
repeated at several points in both arteries to interrupt the neurogenic signals thought to be
involved in the maintenance of sympathetic overactivity and, hence, resistant hypertension.
In 2010, the Simplicity HTN-2 study demonstrated for the first time in humans that
endovascular renal denervation is a safe and effective technique to reduce blood pressure in
patients with resistant hypertension.A total of 106 patients with uncontrolled blood pressure
(systolic >160mmHg) and taking at least three antihypertensive agents were randomized to renal
denervation plus best medical therapy or best medical therapy alone. At 6 months the group
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receiving renal denervation showed a significantly reduced blood pressure measurement. The
larger Simplicity HTN-3 study included a total of 535 patients from 88 sites in the United States,
but this did not reveal a significant effect on systolic blood pressure reduction. Pooled data from
SYMPLICITY HTN-3 and the Global SYMPLICITY Registry revealed that reduction in blood
pressure among patients with isolated systolic hypertension was less pronounced than the
reduction in patients with combined systolic–diastolic hypertension.Thus, this trial paradoxically
did not provide the definitive proof in support of RDN that was expected. However, the results
have been analyzed in detail and have generated further insight into the location of the perirenal
sympathetic and there is still a need for further trials in this area.
b. Other renal vascular disorders
i. Renal trauma
Renal traumacan be penetrating or blunt; concomitant renovascular injury is usually

severe (American Association for the Surgery of Trauma grade 4 or 5) and associated with other
injuries. Management options tend to be conservative unless complications occur; nephrectomy,
open vascular repair, angioembolization and endovascular repair have all been reported. The
latter should not delay the management of other life-threatening injuries. Results of vascular
salvage depend on the ischemia time of less than 3 hours and the suitability of anticoagulation.
The role of revascularization is limited.
ii. Fibromuscular dysplasia
Fibromuscular dysplasia (FMD)is a non-inflammatory, non-atherosclerotic disorder that

may be observed in almost any arterial bed and can lead to arterial stenosis. Five different types
are recognized and usually affect younger patients, with a female predominance, involving the
distal main artery and/or the intrarenal branches. Rarely, FMD may be complicated by an
aneurysm. Patients may be asymptomatic, but the most usual presentation is hypertension.
Hypertension is commonly treated successfully with medication, but RAS and renal dysfunction
may progress in up to one-third of patients. Occlusion and complete loss of renal function is
exceptional. Magnetic resonance angiography (MRA) can detect FMD in the proximal vessels
but is less sensitive for visualizing the second and thirdorder branches. The diagnosis will
usually require conventional digital subtraction angiography and selective views maybe
necessary to detect subtle branch lesions. When treating FMD, the results of percutaneous
angioplasty (PTA) are good (Figure 18.5a and Figure 18.5b), with 10-year cumulative patency
rates of 87% and up to 50% of patients cured of their hypertension. The remainder often have a
reduced drug burden and improved blood pressure control. Stenting is usually reserved for
suboptimal PTA.
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Figure 18.5. (a) Renal artery stenosis due to fibromuscular dysplasia. (b) Good result post percutaneous angioplasty.
iii. Post-transplant renal artery stenosis
Post-transplant RASis another area that is being recognized to need further study. A
meta-analysis by Ngo et al. included 32 studies with 884 interventions reporting the results of
post-transplant stenosis managed with angioplasty or stenting. The overall patency rates were
42–100% with technical success in 90% but the diagnostic and reporting criteria were very
heterogeneous and need further study.
REFERENCES:
1. Parikh SA, Shishehbor MH, Gray BH, et al. SCAI expert consensus statement for renal artery stenting
appropriate use. Catheter Cardiovasc Interv 2014;84(7)
2. Anderson JL, Halperin JL, Albert NM, et al. Management of patients with peripheral artery disease
(compilation of 2005 and 2011 ACCF/ AHA guideline recommendations): a report of the American College of
Cardiology Foundation/ American Heart Association Task Force on Practice Guidelines. Circulation
2013;127(13)
3. Tendera M, Aboyans V, et al. ESC Guidelines on the diagnosis and treatment of peripheral artery diseases.
Document covering atherosclerotic disease of extracranial carotid and vertebral, mesenteric, renal, upper and
lower extremity arteries: the Task Force on the Diagnosis and Treatment of Peripheral Artery Diseases of the
European Society of Cardiology (ESC). Eur Heart J 2011;32(22)
4. MA, S. Renal Artery Stenosis With Severe Hypertension: A Case Report. Borno Medical Journal ,14(2), 229–
235. 2017/
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Chapter 19 Ultrasound
Fang Yi, M.D.

a. Vascular Diagnostic Imaging Examination
i. Noninvasive procedures
Computed tomography (CT scan) and magnetic resonance imaging (MRI) are
noninvasive techniques of choice to confirm a diagnosis of aortic aneurysm, thrombus, or
atherosclerotic plaque in arterial walls, especially in the abdominal and carotid circulation. CT
scans are good tests to assess the sizes and stages of vessel occlusions. They can be performed
with or without a contrast medium and very quickly in emergency situations. CT scans are
somewhat expensive and expose the patient to x-rays.
MRI is useful for evaluating a three-dimensional image of the vessel being studied. This
method is contraindicated for patients with stainless steel pacemakers, vena cava filters, or vessel
clips, but many patients can benefit from its use. Nonmagnetic materials are not contraindicated.
MRI is more expensive than CT scans and takes longer to perform.Carotid angiography and
oculoplethysmography (OPG) are techniques to obtain cerebral blood flow measurements to
localize obstructions in the vessels of the head and neck. OPG is contraindicated in patients with
intraocular lens implants.
Pulse volume recording (PVR) or photoplethysmography is used to measure systolic

pressure in the extremities and digital arterial systems. This test is affected by artifacts and
patient positioning. A diagnosis of deep vein thrombosis (DVT) may be made by
phleborheography (PRG), a plethysmographic technique that records the rhythmic changes in
venous volume in the legs; these changes are associated with respiration. PRG is not useful for
small thrombi or for deep iliac or femoral veins, and the process is time consuming and
expensive.
Ultrasonography is a major diagnostic tool for measuring segmental arterial pressures and
venous patency in the extremities; it also may be used for abdominal circulation. Doppler color-
coded flow imaging and transcranial Doppler imaging are replacing carotid angiography and
OPG in the evaluation of carotid circulation. High-resolution, B-mode ultrasound provides real-
time images of venous systems in the upper and lower extremities.Saphenous and cephalic vein
mapping accurately measures vein diameter, location, and quality to determine preoperatively if
the vein is suitable for use as an arterial conduit in arterial reconstruction. Ultrasound also detects
venous thrombosis. With a pulse Doppler blood flow detector, longitudinal and/or transverse
cross-sectional scans are obtained, and the images are recorded by oscilloscope. A computer-
generated print of the image on the screen provides a permanent record of the arteriography or
venography.
Intraoperative assessment of shunt performance or vessel patency or stenosis, as well as
identification of an arteriovenous fistula (AVF), is easily performed with a sterile Doppler probe
248
(Figure 19.1). An audible signal is transduced and is like the sounds transmitted by a Geiger
counter.
Figure 19.1 Doppler box and probe.
ii. Invasive procedures
Selective angiography permits the x-ray study of a particular segment of the vascular
system. Aortography visualizes the aorta (Figure19.2). Arteriography shows the patency of an
artery or a branch of the aorta and its collateral circulation.
Figure 19.2 Normal Abdominal Aortogram
249
Phlebography detects DVT, and a venogram visualizes the veins. An angiogram requires
the injection of a nontoxic contrast media. The pain associated with injection of intravascular
contrast material can be intense. The procedure may be performed under continuous epidural
anesthesia or general anesthesia.
Angioscopy is an endoscopic technique used to visualize the interior of vessels. A small

(1.5- to 3-mm) flexible fiberoptic angioscope is coupled to a camera, which allows the view from
the angioscopy to be seen on a monitor. The lining and structures within the blood vessels are
visualized as the scope is advanced within each vessel. For many patients, angioscopy is an
alternative preoperative diagnostic technique to angiography and may be used to evaluate the
effectiveness of therapy intraoperatively. It can reveal retained atherosclerotic plaque or thrombi
and suture lines.
Intravascular ultrasonic scanning of the coronary or peripheral vasculature uses a

miniaturized ultrasonic probe at the end of a 3.5 French catheter. The probe is introduced over a
guidewire. The probe is irrigated with heparinized saline as it is introduced into the vessel
percutaneously. Images of the entire circumference are obtained and viewed on a monitor to
determine the thickness of the vessel wall and the distribution of plaque within the wall. This
technique may be performed percutaneously or during a surgical procedure. This device is single
use and not reprocessed. This device is not recommended for use on cerebral vessels.
b. The Application of Color Doppler Ultrasound in Arterial Diseases
i. Waveform assessment and segmental pressures
The use of Doppler waveforms, originally implemented using hand-held continuous-

wave Doppler devices, still has an important role in the investigation of PAD. The elasticity in
normal arteries gives a characteristic triphasic waveform (see Figure 19.4c). The blood pressure
may be reduced distal to a stenosis and consequently the resistance in the peripheral vascular bed
is reduced, changing the shape of this waveform. Distal to a moderate stenosis (50% diameter
reduction) the waveform is usually biphasic, and with a >70% stenosis the waveform generally
becomes monophasic (see Figure 19.4 d).Waveform shape can be affected by distal disease,
dilatation of arteries, multisegmented disease, complete occlusion of an artery and ambient
temperature. Waveform shape can only give an indication of disease and should be used in
conjunction with segmental pressures to determine which segments in the leg are diseased, i.e.,
since percutaneous transluminal angioplasty (PTA) is minimally invasive and generally provides
good results in the iliac arteries, knowing that a pressure- reducing lesion is located in this
anatomical region may strengthen the indication for invasive treatment in a patient with severe
IC.
Clinicians frequently see patients with multisegmented disease. Segmental arterial

pressures have some additional value in both determining the level of disease and predicting
whether proximal arterial reconstruction will be adequate to treat critical ischemia (Figure 18.3).
However, duplex ultrasound, CT or MR arteriography are more useful in this respect.
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Figure 19.3 Segmental arterial waveforms may help discriminate the functional significance of multisegmented
disease, such as the right iliac and superficial femoral occlusions in this patient. Theoretically, normalizing the low
thigh pressure will approximately double the ankle arterial pressure to a level that should relieve ischemic rest pain.
ii. Transcutaneous oximetry
This technique can be used to measure the partial pressure of oxygen diffusing through
the surface of the skin as an indirect measure for oxygen tension in the underlying tissue. It was
hoped that tcPO2 measurements of calf skin might be used to determine whether healing would
occur following below-knee amputation. Unfortunately, tcPO2 is unreliable for this purpose as
the changes in the proximal skin perfusion after amputation of the limb cannot be predicted.
However, a recent systematic review suggests that tcPO2 ≥ 25 mmHg is a favorable indicator for
ulcer healing. Along with a toe pressure ≥45 mmHg, this may be reassuring for the treating
clinician and a predictor of a positive outcome.
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Figure 19.4.(a) A longitudinal color Doppler image of a mid to distal left popliteal artery stenosis with a diameter
reduction of approximately 50%. (b) The area reduction of the same lesion on transaxial imaging is 60–70%. (c, d)
Doppler waveforms from common femoral artery, just proximal to stenosis (c) and distal to stenosis (d). Notice how
the waveform is triphasic with steep acceleration phase signaling high resistance (c), and monophasic and dampened
distal to the stenosis, where the stenosis has caused a pressure drop with reduction in resistance as a result (d).
c. Duplex ultrasound (DUS)
DUS of the extremities has been given a class 1 recommendation (supported by multiple
randomized controlled trials or meta-analyses) for the diagnosis, the anatomical location and
determining the degree of stenosis of PAD, as well as for routine surveillance after lower limb
bypass with a venous conduit
DUS has emerged as the most important non-invasive imaging modality to confirm and
assess severity of PAD. DUS allows the visualization of arteries in real time using greyscale (B-
mode) imaging and detailed hemodynamic evaluation of blood flow by color-flow Doppler
mapping, power Doppler and spectral Doppler. DUS is non-invasive and cost-effective which
has also resulted in its widespread use in serial imaging to assess disease progression and
surveillance following intervention. It is an operator-dependent examination and reliability of
DUS is dependent on the experience and knowledge of the operator and interpreting clinician.
Lower extremity scanning requires a variety of transducers. Lower frequency transducers

(2 MHz or 3MHz) are suitable for deeper structures, such as the abdominal aorta and iliac
arteries and a higher frequency (5MHz or 7MHz) is required for the infrainguinal segments. In
general terms, the higher the probe frequency, the greater will be the resolution and hence the
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highest frequency transducer that provides satisfactory depth of view should be used for the
examination.
DUS of lower limb arterial disease is dependent on high quality B-mode which visualizes
echogenic plaques and the anatomy of the artery/disease. Color-flow Doppler and spectral
Doppler are two types of ultrasounds displays which are often used simultaneously during
arterial imaging. Color flow Doppler depicts both direction of blood flow and mean velocity and
is used to visualize blood flow by color encoding Doppler information and displaying the color
through the color box positioned within the grey-scale image. The color box is subdivided into
small sample regions or color pixels and represents the mean velocity within that region. By
convention, flow towards the transducer is depicted in red and flow away from the transducer in
blue. The display of blood flow includes different shades of blue and red to represent the flow
velocity and this color allocation is dependent on the color map provided by the manufacturer.
Color filling will only occur where blood is moving and can therefore be used to enhance the
grey-scale image by identifying ‘soft’ echo lucent atheroma or thrombus as an area of absent
color filling. Color flow allows identification of increased blood velocity by a change in color
within the lumen of the artery. Severe stenosis can be seen as grey echoes reducing the diameter
of the color filling and a ‘mosaic’ of colors indicates increased velocity and turbulence. However,
color flow Doppler does not provide a quantitative means of determining the severity of a
stenosis other than by direct luminal diameter or area loss measurement (Figure 19.4 a and
Figure 19.4 b).
Accurate quantification of the severity of the stenosis requires the use of spectral Doppler.
In this form of ultrasound image display, flow velocities are graphically represented on the Y
axis against time on the X axis. Continuous wave Doppler and pulse wave Doppler are two types
of spectral Doppler with some differences. As the name implies, in continuous wave Doppler the
transducer is emitting and receiving ultrasound waves continuously and hence can measure
velocities along an entire line of interrogation. For the same reason, it can detect very high
velocity flow although it cannot pinpoint where along the line this arises from. In contrast, in
pulse wave Doppler the transducer emits a pulsed ultrasound signal which is pinpointed to a
specific depth by the sampling box.
The change of frequency (Doppler shift) in the reflected signal is determined by the
transmitted frequency, angle of sonic and the velocity of blood flow. Modern DUS machines
allow automated calculation of blood velocity but the accuracy of this relies heavily on the
correct determination of the position of the pulsed- wave Doppler box and angling of the central
cursor to the axis of blood flow. The peak systolic velocity is measured in the normal artery
proximal to a stenosis and then in the stenosis identified by color flow. The shape of the Doppler
waveform (triphasic, biphasic or monophasic), degree of spectral broadening (range of velocity
profiles within the wave spectra secondary to turbulence) and change in peak systolic velocity
relative to the upstream normal artery all help to determine the severity of a given stenosis (Table
19.1).
In the peripheral arteries, a twofold increase in the peak systolic velocity generally
indicates a 50% narrowing of the artery, while a fourfold increase in velocity ratio with
monophasic waveform indicates a high-grade stenosis. Distal to a stenosis, the Doppler
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waveform changes shape due to damping with reduction in peak systolic velocity and a slower
acceleration time (time from end diastole to peak systole; Figure 19.4c).
Degree of Stenosis PSV (cm/s) Velocity Ratio (Vr)

Spectral Waveform
of Distal Artery
Normal Less than 150 Less than 1.5 Triphasic, Normal
PSV
30% to 49% 150 to 200 1.5 to 2 Triphasic Normal
PSV
50% to 75% 200 to 400 2 to 4 Monophasic reduced
PSV
More than 75% More than 400 More than 4 Damped,
Monophasic, reduced
PSV
Occlusion No flow, proximal and distal collaterals help Damped monophasic
estimate occlusion length reduced PSV
Table 19.1. Diagnostic Criteria for peripheral artery diameter reduction
Certainty of the diagnosis of a complete occlusion as opposed to high-grade stenosis with

trickle flow within an artery may be difficult and depends heavily on the experience of the
sonographer. The shape of the Doppler waveform proximally and distally, color-flow images and
the presence of collaterals all contribute to differentiating these lesions. Difficulties can arise
with deep or tortuous arteries, where signal return is reduced and optimum angles of sonic are
difficult to obtain. Multiple stenoses along the length of an artery reduce the accuracy of flow
velocity measurements in the assessment of more distal stenoses. Power Doppler imaging, which
is dependent on the amplitude of Doppler signals and independent of flow velocity and direction,
is a sensitive imaging technique that can help in such situations to differentiate arterial occlusion
from high-grade stenosis. The sonographer must thus use valuable years of experience and
knowledge of more subtle changes in blood velocity to determine the severity of a given stenosis
when there is tandem or multiple stenoses.
i. Assessment of suprainguinal arteries
This can be achieved by direct assessment of the iliac arteries although this pose
challenges due to respiratory movements, the depth of arteries, arterial tortuosity, overlying
bowel gas and arterial wall calcification obscuring the vessel lumen. Changing the plane of sonic
may often help find an acoustic window through obscuring and distracting anatomy and
pathology. It is critical that sonographers communicate difficulties encountered during scanning
to the referring physician. Changes in the Doppler waveform proximal and distal to an
inadequately viewed segment often give an indication of the extent of disease and the need for
further investigation. Evaluation of the Doppler waveform in the common femoral artery is an
indirect method for assessing the iliac arteries. If it is triphasic, the likelihood of a severe
obstructive lesion in the aorto-iliac segment is very low.
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Aorto-iliac DUS arterial assessment using a peak systolic velocity ratio more than two
has been shown to match catheter angiography in detecting a more than 50% stenosis with a
sensitivity of 82% and specificity of 92%.In experienced hands, DUS is accurate at identifying
disease from the common femoral to the distal popliteal artery, with a sensitivity of 84% to 87%
and specificity of 92% to 98% compared to catheter angiography.
ii. Assessment of femora-popliteal segment
DUS assessment of the superficial femoral artery can give accurate information regarding
flow and stenoses although sonic at the level of the adductor canal may pose technical challenges.
The foot arteries can be more difficult, especially when there is severe proximal disease. In large
calves, the depth of sonic attenuates the signal return, making it difficult to visualize the
proximal foot arteries.Accuracy can be improved by using a low frequency transducer such as a
curved-array abdominal probe, which allows for deeper penetration albeit at the cost of reduced
image quality. Alternatively, power Doppler, which is more sensitive to slow flow, can help
detect the optimum tibial artery for revascularization.
iii. Radiological investigations
The choice of imaging modality for the investigation of chronic lower limb ischemia was
reviewed as part of the August 2012 UK National Institute for Clinical Excellence (NICE)
Clinical Guideline 147, ‘Lower limb peripheral artery disease: diagnosis and management. The
question as to the most clinical and cost-effective method for assessment of PAD revealed eight
relevant publications from which the following broad recommendations were made. Aorto-iliac
DUS arterial assessment using a peak systolic velocity ratio >2 has been shown to match catheter
angiography in detecting a >50% stenosis with a sensitivity of 82% and specificity of 92%.
Most vascular centers use DUS as the first-line imaging modality to investigate PAD due
to its greater availability, lower cost, and limited access to MR scanner time. However, relying
solely on DUS prior to lower limb revascularization risks underestimation of the severity and
number of sites of vascular disease, particularly at challenging- to-reach anatomical areas such as
the iliac and proximal infragenicular foot arteries. CE-MRA, on the other hand, provides better
overall diagnostic accuracy and may also serve as a first-line imaging modality.CE-MRA with
images processed by maximum intensity projection (MIP) provides angiogram quality images
that can be viewed from any projection. DUS can then be utilized in a complementary role,
focused on problem-solving, to address specific equivocal hemodynamic questions that may
affect the treatment strategy. This optimizes the sonographer's time and eliminates redundant
duplication of imaging normal arterial segments twice.
d. Magnetic resonance angiography (MRA)
The basic principles of MRI rely on a large external magnetic field which magnetizes the
subject protons to align parallel to the field, a magnetic field gradient which helps alter the
direction of the external magnetic field and a radiofrequency field provided by resonant coils
placed in close proximity to the area of interest. The resonant frequency of the protons is tapped
into by the receivers to process the final image by a complex mathematical algorithm. The
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contrast seen in MRI depends on the characteristics of the imaging object. It is referred to as T1-
weighted and T2-weighted images. MR angiography (MRA) and MR venography (MRV) are
dependent on T1-weighted images and here fat, methemoglobin, flow and contrast agents will
appear bright. T2-weighted images display fluids as bright and are not used for MRA. There are
several MR techniques for the assessment of vessels and vessel patency, all of which continue to
evolve at a rapid pace.
Modern MR scanners provide high- quality angiographic images without exposing the
patient to radiation. In addition, MRA avoids the need for image manipulation to remove
overlying bone and calcification from the arterial wall. MRA can be performed by contrast-
enhanced techniques (CE-MRA) and non-contrast techniques such as time of flight (TOF) MRA
and phase contrast MRI. The non-contrast techniques utilize the ability to differentiate signal
characteristics of flowing blood from static tissues for image acquisition. TOF MRA poses
significant challenges with inadequate signals from deeper vessels with poor image resolution,
flow-related artefacts especially in areas of stenosis, and prolonged scan time. Phase contrast
MRI, although has >90% sensitivity and specificity for detection of stenosis compared to digital
subtraction angiography, once again is limited by prolonged image acquisition time.
In recent years, these two techniques have been supplanted by 3-dimensional contrast-
enhanced MRA (CE-MRA). However, safety concerns related to gadolinium- based CE MRA
and nephrogenic systemic fibrosis (see below) over the last decade have led to a revival of
interest in non-contrast MRA. ECG-gated partial Fourier fast spin echo (FSE), balanced SSFP
with arterial spin labelling and quiescent-interval single-shot MRA are some of the newer
techniques being developed. Early studies with single-shot MRA have shown over 85%
sensitivity and 95% specificity for detecting significant stenosis when comparing with CE-MRA.
CE-MRA employs subtraction, bolus chase and stepping-table movements for image
acquisition. It provides a non-invasive, 3-dimensional luminal assessment of vessels without the
risk of iodine-based contrast agents and ionizing radiation. It has now become the preferred first-
line imaging technique for the investigation of PAD in many centers. This is advocated in
international guidelines, as well as by the TASC II document and the NICE Clinical Guideline
147 on the diagnosis and management of PAD.
i. Technique
There are a wide variety of techniques for performing peripheral lower limb MRA that
depend on the MR hardware, software sequences, moving or continuous- table capability,
peripheral and surface coils, preferred contrast agent and injection protocol. As foot (tibial)
vessel venous contamination has been the Achilles heel of consistently high-quality peripheral
MRA, techniques have been developed to overcome this by obtaining this imaging station either
faster using parallel imaging (acceleration techniques) or by first using dynamic time-resolved
MRA, followed by the more usual three- or four-station stepping-table ‘bolus chase’ technique
(Figure 19.5a). More recent developments have included greater efforts at imaging the distal
calf and foot vessels as distal intervention has become of increasing importance (Figure 19.5b).
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ii. Contraindications
Contraindications to MRA include the presence of a pacemaker or certain types of

metallic prosthetic cardiac valve implants, intracranial aneurysm clips, cochlear implants or
metallic intraocular foreign bodies. Up to 5% of patients may be claustrophobic in the MR bore,
which may be overcome using open bore systems or by using psychotherapy relaxation
techniques. Occasionally, sedation or rarely a general anesthetic may be required.
Nephrogenic systemic fibrosis (NSF) is a phenomenon of skin, muscle and organ fibrosis
that occurs in a setting of severe chronic or acute renal failure following exposure to gadolinium-
based contrast agents (GBCA), which are widely used in MRI. Clinical features include skin
manifestations such as skin plaques, joint contractures, cobblestone skin appearance, marked
induration or peaud’orange of the skin, skin puckering, superficial skin plaques and dermal
papules to multi-organ involvement, which is associated with an increased mortality.
Impaired gadolinium clearance by the kidney leads to tissue accumulation of gadolinium

and the toxicity is primarily attributed to the dissociation of gadolinium ion (Gd3+) which
competitively binds with components of the extracellular matrix and with readily available
phosphates, carbonates, and citrates to form insoluble molecules. Non-complexed Gd3+ deposits
have been documented in skin, kidney, liver, and brain.
The worldwide incidence of NSF has significantly reduced since the United States Food
and Drug Administration (FDA) and European Medicine Agency (EMA) alert in 2007. The
European Medicines Agency has classified GBCAs based on their risk for NSF into Class 1, 2
and 3. The incidence of NSF is significantly high in Class 1 GBCA, ranging from 3 to 7% in
patients with reduced renal function.Class 3, which includes macrocyclic non-ionic GBCAs such
as Gadobutrol (Gadovist) and gadoteridol (Prohance) have a low incidence of NSF.
Although several therapies have been attempted with variable results, only restoration of
renal function by renal transplantation and recovery of acute renal failure has been shown to
slow or arrest the progression of NSF. Hence there is a greater emphasis on preventative
measures. General recommendations for avoidance of NSF are to use the lowest possible dose of
GBCA and avoid re- administration of GBCA for several days to a week.
iii. Computed tomographic angiography
Initial CT imaging had a rotating emitter producing the X-ray beams and a series of
image detectors placed opposite to register the axial slice images. In conventional CT, the table
moved to a new position to acquire the next cross-sectional slice. In spiral CT, the table moves
continuously through the gantry whilst the X-ray emitter and detector are rotated 360o. This
allows for acquiring continuous volume data rather than discontinuous data from separate cross-
sectional slices with the added benefit of quicker scan time and lower radiation exposure.
Multislice (multidetector) CT, as the name suggests has multiple rows of detectors which enable
scanning a larger volume with multiple separate slices simultaneously. This reduces the scan
time dramatically and eliminates many artefacts seen in single-row scanners. Because a volume
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of tissue has been scanned, these slices can be reconstructed in any plane (multiplanar and
curved planar reconstructions) and it allows acquisition of high- resolution images of less than
0.6 mm3 voxel (volume element) size. Multidetector CT scanners with 256 slice capabilities are
currently in routine use.
Computed tomographic angiography (CTA) enables visualization of vessels by

administration of intravenous contrast and the acquisition speed of spiral CT helps chase the
bolus of contrast as it passes through the tissue imaged. Multi-slicing CT enables capture of
inflow and outflow images simultaneously by using a single acquisition and contrast media
injection. CTA today is invaluable in the acute setting for the diagnosis of acute bleeding and
vessel injuries and has a high sensitivity (92%) and specificity (93%) for detecting a stenosis
of >50% in the lower limb arteries.
Complex reconstructions can be performed, with the subtraction of bone or other detail
that may obscure the arteries. As arterial wall calcification is close to the Hounsfield unit of
arterially opacified blood, care must be taken to ensure that no normal part of the vessel has been
subtracted when using automated subtraction algorithms. This also applies to vessels that lie in
close proximity to bone, for example the tibial arteries, which may be subtracted if the bones are
automatically removed. The radiologist must therefore review the source data in the plane of
greatest spatial resolution as well as the reconstructions. Heavy calcification within the lower
limb arterial tree has greatly limited its use for the assessment of chronic lower limb ischemia,
particularly in the calf of patients with diabetes.
Maximum intensity projection (MIP) images can be constructed, selecting the highest-
density voxel along a given plane or planes (Figure 19.6c). This produces a 2-dimensional
angiographic-like image that can be rotated to allow multiple viewing angles. A variety of 3-
dimensional volume-rendered reconstructions can also be displayed in color, with preset color
maps determined to best display the anatomy required (Figure 19.6a,b). These images are useful
for surgical and endovascular planning, producing accurate vessel diameters, permitting
consideration of catheter selection to take place ahead of interventions, or allowing planning of
optimal angulation of fluoroscopic and digital subtraction angiographic tube positions.
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Figure 19.5 (a) Coronal MIP of contrast-enhanced aorta and lower limb MRA at 3T using a stepping, bolus
chase technique and image fusion. (b) Sagittal MIP of optimal arterial filling during dynamic contrast-enhanced
MRA of the foot. Images provided by Dr. A. Holden, Auckland City Hospital.
iv. Contrast media
Iodinated intravascular contrast media, whether for use in catheter angiographic

procedures or for vascular or tissue enhancement in CT examinations, continues to pose risks for
the development of contrast-induced nephrotoxicity (CIN). This is most defined as an increase in
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serum creatinine (SCr) by more than 25% of the baseline value or a 44 μmol/L (0.5 mg/dL)
absolute increase of SCr occurring within 72 hours, following the intravascular administration of
a contrast medium in the absence of an alternative etiology.
In a multivariable analysis several risk factors have been identified for CIN
(Table18.2).Methods to reduce the incidence of CIN have been highly contentious and have
included using alternative imaging techniques, varying the choice of contrast, minimizing
contrast volume, pharmacological manipulation by stopping nephrotoxic drugs, and intravenous
volume expansion.Rehydration remains a cornerstone in our management strategy for prevention
of CIN although evidence to support a particular hydration strategy, fluid composition (sodium
bicarbonate vs sodium chloride) or pharmacological agent (N-acetyl cysteine) is lacking.Most
clinicians consider an eGFR <45 m L/min as a trigger for pre-hydration before contrast imaging.
Figure 19.6 Volume-rendered 3D CTA of the (a) aorta to femoral and (b) femur-popliteal segment in a young
patient with diabetes and renal failure presenting with chronic bilateral lower limb ischemia. Bilateral multifocal
high-grade stenosis of both the superficial femoral arteries is noted. (c) Composite stitched coronal MIP of bilateral
lower limb CTA from aorta to ankle.
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Table 19.2Risk factors of contrast-induced nephropathy (CIN) identified in multivariable

analysis
Chronic kidney disease (stage 3 or greater: eGFR less than 60 ml/min/1.73m2)
Diabetes mellitus (type 1 or 2)
Volume depletion
Nephrotoxic drug use (NSAIDs, ciclosporin, aminoglycosides)
Preprocedural hemodynamic instability
Other comorbidities:
• Anemia
• Congestive heart failure
• Hypoalbuminaemia
eGFR, estimated glomerular filtration rate; NSAIDs, non-steroidal anti-inflammatory drugs.
Metformin is excreted unchanged in the urine. In the presence of renal failure, either pre-
existing or induced by iodinated contrast medium, metformin may accumulate in sufficient
amounts to cause the serious complication of lactic acidosis. Metformin does not cause renal
failure. Contrast agents should therefore be administered with caution, particularly those with
known renal impairment, and it is essential that the renal function is checked in these patients
prior to the examination. If >100mL of intravenous iodinated contrast is to be administered for
intra-arterial contrast, metformin should be withheld for 48 hours after the procedure.
Patients with a baseline serum creatinine of >150μmol/L should not be taking metformin.
If patients are referred on metformin despite this level of chronic kidney disease, the metformin
should be discontinued indefinitely, and the patient referred for alternative hypoglycemic therapy
prior to the procedure.
e. Catheter angiography
Digital subtraction angiography (DSA) is often referred to as the gold standard in the
investigation of PAD due to superior image resolution and the ability to perform both diagnostic
and interventional procedures at the same sitting. However, as an invasive procedure placing
patients at some risk of harm this has now given way to non-invasive imaging modalities and is
no longer recommended for diagnostic imaging of PAD. Diagnostic angiography is also
expensive, requires a day-case bed, ties up numerous members of angiography suite staff and
negatively impacts on time available for planned therapeutic interventions.Modern practice has
thus changed and use of DSA is reserved for situations where there is an intention to proceed to
endovascular intervention.
i. Technique
An initial standard X-ray exposure is captured and digitized, and this is referred to as the
mask image. This mask image is subsequently subtracted from subsequent images known as the
live images. This allows for the display of contrast opacifying the arterial lumen without the
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visual distraction of adjoining anatomy. There are some applications of DSA that facilitate
optimal visualization and improve procedural success.
Road mapping is a technique where a not subtracted fluoroscopic image is superimposed

over a live fluoroscopic image. This enables the observation and manipulation of guide wires and
catheters in real time through a virtual image of the vessel. Image overlay or fade is
superimposition of a live fluoroscopic image on a reference image, and this again provides a
virtual image of the vessel during intervention.
Single injection multi-linear arteriography or bolus chase angiography permits

visualization of entire lower limb arteries in sequence from a single injection of contrast agent.
Image acquisition occurs during a continuous longitudinal movement of the image intensifier. As
this technique takes a considerably longer time, patient movement can affect the image quality.
In addition, asymmetrical disease severity in the lower limbs can limit its use. Cone-beam CT is
an advanced application that has multiple uses. Using this technique, a 3D image data set is
created by rotating the C-arm around the patient and this allows for CT images during
interventions, 3D angiography and 3D road mapping.
Pre-procedural planning is critical to the outcome of any intervention. Access vessel and
puncture site is chosen based on a likely low risk of complications and reasonable proximity to
site of intervention (frequently the common femoral artery). Standard angiographic access is by
the modified Seldinger technique. Arterial puncture under ultrasound guidance is widely
accepted as safe practice and an 18-gauge puncture needle is used. Once pulsatile back bleeding
is confirmed through the needle, a floppy tip guidewire, usually a J-tip, is advanced via the
central lumen of the needle into the artery lumen under fluoroscopic guidance. A sheath is
advanced over this wire or alternatively a catheter may be used bareback.
A flush catheter with multiple side holes allows for even distribution of contrast in
diagnostic studies. Injection of contrast can be performed by power injector or by manual
injection and both have distinct advantages. Large high flow arteries such as the aorto-iliac
segments may require a higher pressure to dispense the contrast for satisfactory images. A micro
puncture set with a 21-gauge needle may be used in scarred groins, pulseless arteries, calcified
arteries or for antegrade access to the femoral artery. With care, diagnostic angiography is safe
with 4-Fr catheters in most patients. Adequate analgesia is essential to ensure a pain-free and
cooperative patient who will comply with the instructions to avoid movement artefacts,
especially during imaging of the foot (tibial) arteries and plantar arch.
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2. Norgren L, Hiatt WR, Dormandy JA, et al. Inter-Society Consensus for the Management of Peripheral Arterial
Disease (TASC II). Eur J VascEndovasc Surg 2007;
3. NICE Lower limb peripheral arterial disease: diagnosis and management. National Institute for Health and
Clinical Excellence: Clinical guideline [CG147]. August 2012.
4. Collins R, Burch J, Cranny G, et al. Duplex ultrasonography, magnetic resonance angiography, and computed
tomography angiography for diagnosis and assessment of symptomatic, lower limb peripheral arterial disease:
systematic review. BMJ 2007
5. Heijenbrok-Kal MH, Kock MC, Hunink MG. Lower extremity arterial disease: multidetector CT angiography
meta-analysis. Radiology 2007
6. Brar SS, Hiremath S, Dangas G, et al. Sodium bicarbonate for the prevention of contrast induced- acute kidney
injury: a systematic review and meta- analysis. Clin J Am Soc Nephrol 2009
7. McDonald JS, Leake CB, McDonald RJ, et al. Acute kidney injury after intravenous versus intra-arterial
contrast material administration in a paired cohort. Invest Radiol 2016
8. Kuhn MJ, Chen N, Sahani DV, et al. The PREDICT study: a randomized double-blind comparison of contrast-
induced nephropathy after low- or isoosmolar contrast agent exposure. AJR Am J Roentgenol 2008
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Chapter 20 Preoperative and Postoperative Care of Vascular Related Diseases
Wang Hao
a. Carotid Artery Stenosis Care
i. Introduction:
Carotid artery stenosis or occlusion is one of the risk factors of intracranial ischemic
cerebrovascular disease, accounting for 20% to 30%. The main causes are carotid atherosclerosis,
aortic arteritis, trauma, and radiation injury. Nursing evaluation includes: (1) Ask the patient's
medical history and understand the previous related medical history. (2) Assess the current
symptoms and signs of the patient. (3) To understand the results of the patient's vascular
examination, blood routine, coagulation function, etc., and (4) To evaluate the patient's
understanding of the disease and mental state.
For non-surgical treatment, nursesneed to closely observe the changes in the patient’s
vital signs and follow the doctor’s prescription for medication. For carotid artery stenting care,
the preoperative doctors need to briefly explain the method and process of the operation to the
patient and family members, eliminate tension, fear and other unhealthy emotions. In addition,
the nurse should complete various routine examinations and antiplatelet therapy. Plavix and
enteric-coated aspirin should be given to the patients orally 3 days before the operation according
to the prescription. It is important to control the patients’ blood pressure which should follow the
doctor’s instructions to use antihypertensive drugs orally or intravenously to control the systolic
blood pressure at 75% to 80%. Iodine allergy test and skin preparation should be conducted on
both sides of the groin and perineum.
ii. Postoperative Care:
According to post-surgical care routines, patients can receive semi-liquid food only four
hours after surgery. Consuming more water is recommended. The patient should be placed in the
supine position after the operation, the lower limbs should be punctured and stretched and
immobilized for 12 hours.The patient’s puncture site should be compressed and bandaged. In
addition, the patients should be closely observed the dorsal artery pulsation, skin temperature and
toe movement. If the toe of the affected extremity is pale, it indicates that the patient may have
thrombosis of the femoral artery. As a consequence, it is necessary to report to the doctor in time
for the treatment.
The doctor needs to remind the patient to avoid violent twisting of the neck. Nursing staff
should be required to closely observe changes in the condition and continue ECG monitoring,
and closely monitor changes in heart rate and blood pressure. Since the release of the stent
during the operation stimulates the carotid baroreceptors, the patient is at risk of slowing reflex
heart rate and lowering blood pressure. If the patient’s heart rate slows down, atropine can be
given as an intravenous bolus as prescribed by the doctor, and dopamine can be used for blood
pressure drop. The nurse should observe the patient’s language, postoperative limb activity,
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muscle strength changes compared with preoperative changes, grasp the outcome of the disease
and observe its renal function. Since more contrast agents are used during the operation, which
causes contrast-induced nephropathy, nursing staff should encourage the patient to drink more
boiled water and appropriate fluids to hydrate the urine and promote the discharge of the contrast
agent after the operation.
After anticoagulation treatment, medical staff should give low molecular weight heparin
calcium, aspirin, warfarin and other anticoagulation drugs as prescribed by the doctor. During
medication, closely observe whether there are bleeding points on the skin of the whole body,
whether there is bleeding in the oral mucosa, whether there is bleeding or hematoma at the
incision or injection site. Perform a blood coagulation test according to the doctor's order, adjust
the dosage of the drug according to the result, and instruct the patient to pay attention to self-
protection, such as brushing with a soft toothbrush, preventing bumps, and not eating hard food.
iii. Observation and Prevention of Complications
Adverse reactions of contrast agentinclude nausea, vomiting, and cold sweats after
surgery. Medical staff should encourage patients to drink more water. Hyper-perfusion syndrome
is caused by carotid artery stenosis that causes the cerebral blood vessels to be in a low perfusion
state for a long time. After the stent is placed, the diseased blood vessel is opened, and the blood
flow increases sharply, resulting in excessive blood perfusion and adverse reactions. The main
clinical manifestations are headache, head swelling, nausea, vomiting, and disturbance of
consciousness. Once the patient has the above symptoms, he should be given a rapid intravenous
infusion of 20% mannitol 250ml in time to reduce cerebral edema and intracranial pressure.
Other complications include vasospasm and cerebral infarction. Further, the stimulation
of catheters, guide wires and contrast agents can lead to vasospasm, manifesting as drowsiness,
irritability, polyphonic, hemiplegia and other symptoms. The patient's mind and pupil changes
should be closely monitored for the symptoms of Dizziness, nausea, and/or numbness of the
limbs. To prevent this complication, nimodipine should be given intravenously for 1 to 2 days
following the doctor's instructions.
Because the release of the stent during the operation stimulates the carotid baroreceptors,
the reflex may have a slower heart rate and a drop in blood pressure. If the patient is pale, blood
pressure drops, or heart rate slows down, medical staff should immediately give atropine,
dopamine, epinephrine, etc., as directed by the doctor.Finally, medical staff need to pay attention
to whether there is a hematoma under the skin of the patient, strictly brake the limb on the
puncture side and observe whether there is any bleeding or hematoma at the puncture site. The
tightness of the compression bandage should be appropriate. The nurse needs to emphasize to the
patient to press the wound with her hand when coughing or defecation to prevent bleeding.
Patients should have a balanced diet, high-fiber foods, and high-protein foods, pay
attention to a light diet, exercise moderate amounts, and avoid strenuous exercise. Avoid
smoking, alcohol, spicy food, coffee and other irritating foods.The patient should take the
medicine as prescribed by the doctor and review 4 items of coagulation regularly. During the
medication, patients should pay attention to whether there are bleeding symptoms. If
265
abnormalities are found, the patients should seek medical attention in time. Limit the patient's
heavy physical activity within 3 to 4 weeks after discharge from the hospital, and then exercise
properly, combine work and rest, avoid strenuous activities, quit smoking and limit
alcoholconsumption.
b. Postoperative Management of Cardiovascular System in the Critical Care
Many intensive care patients face cardiovascular problems including bleeding,

hypovolemia, myocardial infarction and heart failure.
(1) Strict Blood Pressure Control:
Perhaps more than any other type of postoperative patient, blood pressure parameters in
neurosurgical patients need to be strictly monitored and corrected when necessary. Almost all
craniotomy patients should have an arterial line as well as intermittent noninvasive blood
pressure monitoring. In most cases, normotension is advisable, which means within a range
similar to the patient’s baseline systolic blood pressure. It is important to avoid hypertension in
order to reduce the risk of hemorrhage into the surgical bed. Conversely, hypotension must also
be avoided, to reduce the risk of hypoperfusion and ischemia to surrounding edematous brain.
Often, patients tend to be slightly hypertensive in the postoperative period with respect to
baseline. Adequate pain control should be ensured and treatment with antihypertensives should
be used as needed. Most patients are successfully managed using intermittent treatment with beta
blockers. Occasionally, continuous intravenous (IV) infusion of nitroprusside is necessary in the
short term to maintain systolic blood pressure within a safe range. However, this should not be
maintained more than 24 houra because of the risk of thiocyanate toxicity. In certain cases,
controlled hypertension may be required to minimize the risk of vasospasm and hypoperfusion,
such as following intracerebral aneurysm clipping or revascularization procedures.
(2) Volume Resuscitation:
There is a great deal of controversy surrounding the appropriate IV resuscitation and fluid
management of postoperative neurosurgical patients, in an attempt to achieve the optimal
balance between adequate tissue perfusion and minimization of cerebral edema. Most
neurosurgical patients do not have problems with hypovolemia, because the third-spacing and
fluid shifts that are so common during intra-abdominal and thoracic cases are not seen. If a
neurosurgical patient requires volume resuscitation, it should be given as aggressively as
necessary to maintain normovolemia, adequate cardiac output, and tissue perfusion. Isotonic IV
fluids are the appropriate choice for most patients. Most neurosurgeons choose to use normal
saline for routine IV fluid replacement.
Hypotonic saline and lactated ringer’s (LR) solution are generally not used in
postoperative neurosurgical patients, because in experimental animals, they have been found to
increase total brain water and intracranial pressure. It is important to realize, however, that
postoperative neurosurgical patients cannot be assumed to have an intact blood–brain barrier
(BBB). Normal saline should generally be used, to avoid the potential complications associated
266
with the other IV fluids mentioned previously because of the interruption of the BBB at the
surgical site, the normal regulatory mechanisms of cerebral blood flow, ICP, and brain water are
disrupted, and many interventions are therefore less effective. Several studies have revealed that
the injured BBB is unable to maintain either an oncotic or osmotic gradient, and that the amount
of cerebral edema around the site of brain injury is unaffected by the type of IV fluid
administered.
Fluid restriction following ischemic brain injury has not been demonstrated to
significantly reduce cerebral edema. Rats which were under-resuscitated following hemorrhagic
shock were found to have a higher cerebral water content than rats who were adequately
resuscitated with either isotonic or hypertonic IV fluids. Using hypertonic saline or dextran as
resuscitation fluids has been touted because of their ability to both rapidly restore intravascular
volume and decrease brain water. However, again, this effect on cerebral water content relies on
an intact BBB with the ability to maintain an osmotic gradient, and dextran can potentially
worsen cerebral edema by increasing cerebral blood flow. It seems that cerebral edema will
occur to some extent in most postoperative neurosurgical patients. Therefore, the most
reasonable approach to IV fluid use should be an attempt to maintain normovolemia, with
normal serum osmolality.
(3) Arrhythmia:
Most neurosurgical patients who have an arrhythmia usually have an underlying cardiac
problem that can be elicited through history and physical examination (see also Chapter 4).
Based on the patient’s history and admission EKG, appropriate therapy should be instituted
regardless of his or her neurologic disease. Cardiac enzymes should be checked on any
neurosurgical patient with sustained abnormalities on EKG to rule out acute myocardial ischemia.
Myocardial ischemia needs to be treated aggressively to preserve cardiac function and adequate
tissue perfusion. Sometimes, the practitioner considers if a patient whose intracranial pathology
directly affects his or her cardiac status. Patients who present with subarachnoid hemorrhage
(SAH) sometimes suffer characteristic EKG changes and sudden arrhythmias.
These changes usually occur shortly after the initial hemorrhage, and may include
ventricular tachycardia, ventricular fibrillation, and torsades de pointes. It is believed that these
arrhythmias may be responsible for some cases of sudden death following aneurysm rupture. Of
those who present to medical attention, EKG changes may be transiently seen in up to 50% of
SAH patients, and may include inverted T-waves, S-T segment abnormalities, or Q-T
prolongation. If these cardiac abnormalities become life threatening, they should be treated
symptomatically using standard accepted protocols as described elsewhere in this book. However,
the EKG changes usually resolve spontaneously over several days.Surgery may also lead to
hypotension and bradycardia in patients.
c. Vascular Malformation Care:
Vascular malformations are localized collections of abnormal blood vessels that lead to
altered blood flow. While these vascular masses are not cancerous tumors, they can sometimes
grow and cause various symptoms. While in many cases a vascular malformation causes no
267
symptoms and can go unnoticed, some cases of unruptured vascular malformations will cause
problems by pressing on areas in the brain, irritating the brain tissue with inflammation and
leakage of abnormal substances into the brain, and/or altering the blood flow from regions of
normal brain (called “steal” phenomena, for stealing blood flow from where it is otherwise
needed). In these cases, the unruptured vascular malformation can cause symptoms that include
headaches, seizures, or stroke-like symptoms, such as changes in ability to think clearly, changes
in vision or speech, changes in motor function, or numbness and tingling sensations.
Figure 20.1Vascular malformation; Source: The Aneurysm & AVM Foundation; Mayfield Clinic
Vascular malformations can also become unstable and rupture, releasing blood into the
brain and causing a stroke. When a vascular malformation ruptures, the result is called a
hemorrhage. Depending on the severity of the hemorrhage, brain damage or death may result.
Symptoms of a ruptured vascular malformation often come on suddenly and include a sudden,
severe headache (“worst headache of my life”) different from past headaches, nausea and
vomiting, sensitivity to light, weakness, confusion, fainting or loss of consciousness, and
seizures. Vascular malformations are typically classified by size, location, and type of blood
vessels involved, with the four most common including Cavernomas (Cavernous Angioma),
Arteriovenous Malformations (AVMs), Capillary Telangiectasias (CTSs) and Venous
Malformation (developmental venous angiomas- DVAs).
Cavernomas and AVMs in particular may be more serious diagnoses because they may
cause debilitating symptoms, including the risk of brain rupture and bleeding. Telangiectasia
(CTS) is a small area of abnormally dilated capillaries in normal brain tissue. DVAsis an unusual
radial vascular structure that is completely integrated with the body's venous system to provide
normal blood drainage for the brain.
i. Causes and Diagnosis:
A small number of AVMs are discovered at or shortly after birth, but most of them
present later in life, and these masses may form and progress during the later years of life.
Sometimes, a person can inherit a tendency to form these vascular lesions due to abnormalities in
the structure of blood vessels or altered inflammatory responses. It is thought that the same risk
268
factors that lead other vascular lesions (like brain aneurysms) to rupture, are likely to also be
associated with increased rupture risk in vascular malformations. Other risk factors can include
high blood pressure and smoking. One thing that has been clearly shown is that symptomatic
vascular masses that have bled in the past are at higher risk of bleeding again in the future.Not all
people who have AVMs will bleed during their lifetime. The risk is estimated to be about 4-6%
per year. For instance, in a 50-year-old with an AVM who has a life expectancy of 30 years, the
risk of bleeding in his/her lifetime is >70%.
If the doctor believes the patient is at risk for having a vascular malformation, the nurse
may undergo one or more of the following tests in our state-of-the-art facility:
(1) Computed tomography angiogram (CTA) scan:
CTA is a very good method for evaluating blood vessels and can be especially useful in
evaluating AVMs for the presence of aneurysms, which can be associated with AVMs. CTA uses
a combination of CT scanning, special computer techniques, and contrast material (dye) injected
into the blood to produce images of blood vessels. A CTA, however, is not the preferred method
for evaluating cavernomas or venous malformations.
(2) Magnetic resonance angiography (MRA):
Like a CTA, MRA uses a magnetic field and pulses of radio wave energy to provide
pictures of blood vessels inside the body. As with CTA, a dye is often used during MRA to make
blood vessels show up more clearly. MRA can be useful in evaluating both AVMs and
cavernomas.
(3) Cerebral angiogram:
This is the “gold standard” test for the clearest images of the blood vessels. This
procedure takes place in a catheterization lab, under general anesthesia, where a tiny catheter is
inserted through a blood vessel in the groin and moved up from the inside of the blood vessel
into the brain. A dye is then injected into the cerebral artery. As with the above tests, the dye
allows any problems in the artery, including aneurysms and AVMs, to be seen clearly using
specialized X-rays. Although this test is more invasive and carries more risk than the above tests,
it is the best way to locate small brain aneurysms and to clearly visualize the shape and
morphology of AVMs to guide treatment decision-making. While very useful in aneurysms and
AVMs, a cerebral angiogram is not useful for evaluating cavernomas and most venous
malformations.
ii. Treatment and Care:
Doctors in stroke neurology, interventional neuroradiology, and vascular neurosurgery

usually work together using a team-based approach to personalize treatment decisions for each
specific vascular malformation based on the location, size and shape of the lesion, the patient’s
age, overall health, and additional risk factors. Sometimes multiple different treatment options
269
are required to fully cure a vascular malformation. Treatment options used to treat these lesions
include:
(1) Minimally invasive Microvascular Neurosurgery:
This minimally invasive surgery technique involves the use of a surgical microscope to
perform microsurgery through computer-assisted navigation, with the goal of completely
removing vascular malformations and preventing the risk of rupture. If the entire deformity can
be safely removed by surgery, this technique has the advantage of providing a final cure.
Whether microsurgery is the best way to treat vascular malformations depends on the location,
size and shape of the lesion and the overall health of the patient.
(2) Endovascular Embolization and Coiling:
For AVMs and AVM-associated aneurysms endovascular therapy can be an important

part of treatment. During this procedure, a small tube is inserted into the affected artery and
positioned at the vascular malformation. Specialized metal coils or surgical glue are then used to
close off blood flow to the AVM and/or aneurysm. Preventing blood flow into the lesion can
protect against the risk of rupture. In vascular malformations such as AVMs, this is usually done
as part of a combination treatment plan to reduce the size of the lesion and help prepare it for
further definitive treatments.
(3) Non-invasive Stereotactic Radiation Therapy or Radiosurgery:
Stereotactic radiotherapy is a non-surgical procedure that can be used in the treatment of

some AVMs, but does not work on cavernomas, aneurysms and other vascular malformations.
This treatment is also known as radiosurgery or stereotactic radiosurgery, but overall refers to
essentially the same thing. In this treatment, narrow X-ray beams are focused very precisely at
the AVM such that a high dose is concentrated on the AVM itself, with a much lower and safer
amount being exposed to the rest of the head. These focused beams of radiation cause the AVM
to close off. The radiation delivered to the AVM works by inducing changes in the walls of the
blood vessels forming the AVM. As these walls thicken, the vessels gradually close off. But it
can take as long as a period of 2-3 years for this to occur, and it can happen in up to 80% of
patients. Until the AVM is closed off, the risk of bleeding persists. Whether radiosurgery is the
optimal method to treat an AVM depends on the location of the lesion, its size and shape, and the
patient’s general health.
iii. Conclusion:
The field of Carotid Artery Stenosis Care, Moyamoya Disease Care, and Cerebral
Vascular Anomalies Care has seen considerable advancement in the last few years. Treatment
and management options of various types of cerebrovascular malformations have evolved in
neurological, neurosurgical, and neuro-interventional radiology. Better understanding of their
findings assists in determining the appropriate treatment options.
270
d. Postoperative Management in the Neurosciences Critical Care
Nursing for the postoperative neurosurgery patients presents unique challenges to

intensive care physicians. Clinicians not only need to adapt to routine postoperative problems,
but also need expertise in central nervous system function. There are multiple central nervous
system (CNS) pathologies that require surgical intervention, and treatments suitable for one type
of brain injury may prove to be harmful to patients with different disease processes. It is
important to understand these differences and adopt appropriate treatment methods. In addition,
doctors must always keep in mind that patients in the Neuroscience Intensive Care Unit (NSU)
may have problems not only in the central nervous system, but also in various other organ
systems. Preoperative medical conditions often complicate postoperative management. It is
important to understand the effects of neurological interventions on normal body homeostasis,
and vice versa, to provide effective care for patients with NSU. This chapter attempts to cover
most of the topics faced by clinicians working with neurosurgery patients, starting with general
questions and then turning to specific neurological disease entities and their unique concerns.
Basic clinical management, emergency treatment, early diagnosis and prediction of potential
complications will be discussed. The purpose of this chapter is to provide a practical and
accurate overview of the intensive care of patients after neurosurgery.
i. General Postoperative Care
It is essential in NSU to recognize the deterioration of neurological function in time, and

to diagnose and deal with postoperative complications in time. Many complications of
neurological diseases are caused by cerebral ischemia or increased intracranial pressure. These
processes may be reversible, but they must be managed in a timely manner. The fact is that
delays in discovering treatable problems can lead to permanent nerve damage. For convenience,
it is not appropriate to wait for several hours to evaluate the patient or to delay definitive imaging.
Anal hernia and permanent brainstem damage can occur within a few minutes, usually when the
pupil dilates, the patient has already suffered irreversible damage. Therefore, it is necessary to
immediately assess the patient's nervous system status, first by a doctor to conduct a
comprehensive bedside assessment.
(1) Immediate Postoperative Evaluation:
When caring for any neurosurgery patient, the most important first step may be a
thorough evaluation immediately after he or she is admitted to the hospital. Due to the urgency
of diagnosing neurological problems and formulating treatment, it is important to have a good
baseline check as early as possible in the treatment process. Any changes in neurological
examination need to be evaluated immediately after surgery. Due to the area of surgical
intervention, some defects may appear; therefore, the neurologist must have a good grasp of the
neuroanatomy and the surgical operation performed on any patient. For example, a person who
has just received an occipital glioma resection may fully expect the visual field to be removed.
Pupil sluggishness or slow awakening may occur within about 1 hour after administration of
general anesthesia and narcotic administration. However, certain defects should not be
eliminated because of normal surgical intervention. Drowsiness, unresponsiveness, or focal
defects (such as hemiplegia and aphasia) are usually clues to postoperative space-occupying
271
effects and increased intracranial pressure. Most patients with postoperative intracranial
hematomas develop within 6 hours after surgery; therefore, immediate postoperative
neurological examination and close monitoring at NSU are essential to quickly detect this
complication. Nervous system examination should be detailed, including records of cranial nerve
function, level of consciousness, speech, movement, and visual system. It is useful for the nurse
who will take care of the patient during the postoperative period to be present during the initial
bedside examination so that he or she is familiar with the patient’s postoperative baseline.
The postoperative evaluation also needs to include evaluation of cardiac and respiratory
parameters. As soon as the patient enters the NSU, he or she should be connected to continuous
cardiac and respiratory monitors. Continuous electrocardiography (EKG), pulse oximetry, and
arterial blood pressure monitors are typically used. Often the patient may have additional
monitors, such as a ventriculostomy or intracranial pressure (ICP) monitor, or possibly even a
central venous line or Swan-Ganz catheter. Many patients may remain mechanically ventilated in
the immediate postoperative period, and these parameters need to be evaluated and optimized.
Any patient with a cardiac history or with intraoperative arrhythmia or blood pressure instability
also deserves a formal 12-lead EKG upon arrival to the NSU. Most postoperative neurosurgical
patients should get laboratory studies checked as well, including hematocrit, electrolytes,
coagulation parameters, anticonvulsant levels, and blood gases.
ii. Cardiovascular System:
Many of the cardiovascular issues facing the neurosurgical patient including Hemorrhage,
hypovolemia, myocardial infarction, and heart failure as they would be for any intensive care
unit (ICU) patient.
(1) Strict Blood Pressure Control:
Perhaps more than any other type of postoperative patient, blood pressure parameters in
neurosurgical patients need to be strictly monitored and corrected when necessary. Almost all
craniotomy patients should have an arterial line as well as intermittent noninvasive blood
pressure monitoring. In most cases, normotension is advisable, which means within a range
similar to the patient’s baseline systolic blood pressure. It is important to avoid hypertension in
order to reduce the risk of hemorrhage into the surgical bed. Conversely, hypotension must also
be avoided, to reduce the risk of hypoperfusion and ischemia to surrounding edematous brain.
Often, patients tend to be slightly hypertensive in the postoperative period with respect to
baseline. Adequate pain control should be ensured and treatment with antihypertensives should
be used as needed. Most patients are successfully managed using intermittent treatment with beta
blockers. Occasionally, continuous intravenous (IV) infusion of nitroprusside is necessary in the
short term to maintain systolic blood pressure within a safe range. However, this should not be
maintained more than 24 houra because of the risk of thiocyanate toxicity. In certain cases,
controlled hypertension may be required to minimize the risk of vasospasm and hypoperfusion,
such as following intracerebral aneurysm clipping or revascularization procedures.
272
(2) Volume Resuscitation:
There is a great deal of controversy surrounding the appropriate IV resuscitation and fluid
management of postoperative neurosurgical patients to achieve the optimal balance between
adequate tissue perfusion and minimization of cerebral edema. Most neurosurgical patients do
not have problems with hypovolemia, because the third-spacing and fluid shifts that are so
common during intra-abdominal and thoracic cases are not seen. If a neurosurgical patient
requires volume resuscitation, it should be given as aggressively as necessary to maintain
normovolemia, adequate cardiac output, and tissue perfusion. Isotonic IV fluids are the
appropriate choice for most patients. Most neurosurgeons choose to use normal saline for routine
IV fluid replacement.
Hypotonic saline and lactated ringer’s (LR) solution are generally not used in
postoperative neurosurgical patients, because in experimental animals, they have been found to
increase total brain water and intracranial pressure. It is important to realize, however, that
postoperative neurosurgical patients cannot be assumed to have an intact blood–brain barrier
(BBB). Normal saline should generally be used, to avoid the potential complications associated
with the other IV fluids mentioned previously because of the interruption of the BBB at the
surgical site, the normal regulatory mechanisms of cerebral blood flow, ICP, and brain water are
disrupted, and many interventions are therefore less effective. Several studies have revealed that
the injured BBB is unable to maintain either an oncotic or osmotic gradient, and that the amount
of cerebral edema around the site of brain injury is unaffected by the type of IV fluid
administered.
Fluid restriction following ischemic brain injury has not been demonstrated to
significantly reduce cerebral edema. Rats which were under-resuscitated following hemorrhagic
shock were found to have a higher cerebral water content than rats who were adequately
resuscitated with either isotonic or hypertonic IV fluids. Using hypertonic saline or dextran as
resuscitation fluids has been touted because of their ability to both rapidly restore intravascular
volume and decrease brain water. However, again, this effect on cerebral water content relies on
an intact BBB with the ability to maintain an osmotic gradient, and dextran can potentially
worsen cerebral edema by increasing cerebral blood flow. It seems that cerebral edema will
occur to some extent in most postoperative neurosurgical patients. Therefore, the most
reasonable approach to IV fluid use should be an attempt to maintain normovolemia, with
normal serum osmolality.
(3) Arrhythmia:
Most neurosurgical patients who have an arrhythmia usually have an underlying cardiac
problem that can be elicited through history and physical examination (see also Chapter 4).
Based on the patient’s history and admission EKG, appropriate therapy should be instituted
regardless of his or her neurologic disease. Cardiac enzymes should be checked on any
neurosurgical patient with sustained abnormalities on EKG to rule out acute myocardial ischemia.
Myocardial ischemia needs to be treated aggressively to preserve cardiac function and adequate
tissue perfusion. Sometimes, the practitioner considers if a patient whose intracranial pathology
273
directly affects his or her cardiac status. Patients who present with subarachnoid hemorrhage
(SAH) sometimes suffer characteristic EKG changes and sudden arrhythmias.
These changes usually occur shortly after the initial hemorrhage, and may include
ventricular tachycardia, ventricular fibrillation, and torsades de pointes. It is believed that these
arrhythmias may be responsible for some cases of sudden death following aneurysm rupture. Of
those who present to medical attention, EKG changes may be transiently seen in up to 50% of
SAH patients, and may include inverted T-waves, S-T segment abnormalities, or Q-T
prolongation. If these cardiac abnormalities become life threatening, they should be treated
symptomatically using standard accepted protocols as described elsewhere in thisbook. However,
the EKG changes usually resolve spontaneously over several days.Surgery may also lead to
hypotension and bradycardia in patients.
(4) Respiratory System:
Neurosurgery patients are often prone to dyspnea, usually due to decreased consciousness
and/or inconvenience. Doctors caring for these patients need to be familiar with endotracheal
intubation techniques and ventilator management. Nurses and respiratory therapists play an
important role in the prevention and treatment of respiratory diseases.
(5) Pneumonia:
Pneumonia is extremely common in NSU. Intensive care physicians should always be

alert to this complication and actively treat it. Most commonly, pneumonia is caused by
aspiration or failure to clear secretions. Patients with brain injury are prone to aspiration. People
with high spinal cord injuries may not be able to cough or breathe deeply. Protecting the
patient’s airway is the primary task of preventing pneumonia. Sober patients should be mobilized
as soon as possible. Inactive patients require frequent changes in body position, chest
physiotherapy, and sputum suction. If there is clinical evidence of pneumonia, such as fever,
chest X-ray infiltration, peripheral blood leukocytosis, large secretions, and positive sputum
culture, the patient should undergo the treatment with broad-spectrum antibiotics.
(6) Tracheostomy:
Patients with brain injury or postoperative neurologic deficits may require aggressive
pulmonary care for several weeks to months and may be very difficult to wean from the
ventilator. The decision to pursue tracheostomy should come from careful evaluation not only of
the patient’s pulmonary status, but also of their prognosis for neurologic recovery. The timing of
elective tracheostomy is often questioned. Several studies demonstrate that early tracheostomy
(within the first week after injury) shortens ICU stays and reduces the frequency of pneumonia.
In addition, the probability of successful extubation decreases with time. In patients with
infratentorial lesions, only 5.8% of surviving patients can be successfully extubated after 8 d of
endotracheal intubation. A good recommendation is to plan for tracheostomy after 7–10 d of
intubation and mechanical ventilation in patients who have a significant neurologic deficit but
not a terminal diagnosis.
274
iii. Neurogenic Pulmonary Edema:
This is an extremely rare complication of serious nerve injury, usually related to head
injury or subarachnoid hemorrhage. The mechanism of rapid and extensive pulmonary edema
that occasionally occurs after nerve injury is unclear. Treatment is supportive, with positive
pressure ventilation and diuretics as needed.
iv. Positive End-expiratory Pressure:
Positive end-expiratory pressure, or PEEP, is useful in patients with low lung compliance
with risk of alveolar collapse, such as patients with adult respiratory distress syndrome (ARDS).
The use of PEEP has been debated in patients with the potential for increased ICP, because of the
theoretical risk of transmitting the higher pulmonary venous pressure into the cerebralvasculature.
However, levels of PEEP up to 10 cm H2O do not cause clinically significantincreases in ICP
and can be used safely.
v. Infectious Complications:
Postoperative patients are susceptible to many infectious complications. As in the case of

pneumonia mentioned previously, lack of mobility is one reason for this, and the prolonged use
of invasive devices also puts the neurosurgical patient at risk. Foley catheters should be changed
regularly, and other invasive catheters, such as central lines, arterial lines, subarachnoid pressure
monitors, and ventriculostomies need to be evaluated regularly for signs of infection and
removed or replaced if needed.
vi. Antibiotic Prophylaxis:
Most postoperative infections result from contamination with skin flora, namely,
staphylococcus, and sometimes streptococcus. Various antibiotic regimens have been suggested
for perioperative prophylaxis. However, neurosurgical procedures carry, for the most part, a
fairly low risk of infection, and general principles of antibiotic prophylaxis are applicable.
Cefazolin has been demonstrated to have therapeutic levels in brain tissue after intravenous
administration and is active against the most common postoperative infecting organisms. Given
immediately preoperatively and in the first 24 hours following incision, it has been shown to
reduce the risk of infection in patients without foreign implants and has a low risk of side effects.
For invasive catheters including ventriculostomies, central venous lines, ICP monitors, and
arterial lines, most institutions use some sort of antibiotic prophylaxis, although there is no
definitive study to support its necessity. Duration of placement of these catheters relates most
importantly to rate of infection. Cerebrospinal fluid (CSF) infection is four times more likely to
occur if a ventriculostomy is required for more than 5 days, whether antibiotics are administered
or not. Most institutions have their own preferred prophylactic antibiotic regimen, that should be
followed in the NSU.
Patients undergoing craniotomy are at risk for many infectious complications, including
meningitis, encephalitis, or brain abscess. Patients at the highest risk include immunosuppressed
patients, patients with foreign implants, or patients who have undergone prolonged hypothermic
275
surgery. Patients may develop fever, increased peripheral blood white blood cell count,
worsening headache, meningitis, decreased level of consciousness, or focal neurological deficits.
If there is concern about intracranial infection, the patient should undergo imaging tests and
intravenous injection of contrast agent to rule out any large masses or significantly enhanced
fluid accumulation. During the postoperative period, meningeal enhancement is common and
should not be considered as evidence of infection. If imaging excludes any large intracranial
masses, the patient should undergo a lumbar puncture to obtain a cerebrospinal fluid culture
before antibiotics.
A lumbar puncture in someone with bacterial meningitis usually demonstrates

neutrophilia, increased protein and decreased glucose, and the gram stain may be positive.
Broad-spectrum antibiotics, usually a combination of a cephalosporin, vancomycin, and
gentamycin, are commonly begun as soon as CSF cultures are obtained. Antibiotic coverage is
narrowed once the offending organism is identified. Untreated intracranial infections can lead to
loss of neurologic functioning or even death, and so should be treated promptly, without waiting
for final cultures. It is important to realize that the meningitis seen in the postoperative setting is
usually indolent and caused by staphylococcus, and that it does not have the infectious capacity
of community-acquired bacterial meningitis. Therefore, no special isolation needs to be
undertaken. Postoperative meningitis should be treated with antibiotics for 7 days to 10 days,
depending on the organism and response to treatment. If an abscess or subdural empyema is seen
on imaging, the treatment is surgical exploration and debridement, with drainage of the purulent
material and often also removal of the bone flap. Again, broad-spectrum antibiotics should be
started once a sample is obtained, and the regimen refined based on culture sensitivities.
Abscesses, post-surgical or not, are usually treated with at least 6 weeks of antibiotics.
vii. Spinal Epidural Abscess:
This is a rare postoperative complication which most often occurs spontaneously, through
direct expansion of an infection in the intervertebral disc or through blood transmission from a
remote site. Diabetics and those who use intravenous drugs are particularly vulnerable. It is
mentioned here because of the need for urgent surgical intervention. If the patient has severe
back pain and tenderness, fever, and leukocytosis, the patient should undergo emergency spinal
MRI with or without contrast examination to rule out an epidural abscess. The deterioration of
the nervous system in this condition may be rapid, and once it occurs, it is usually irreversible. It
is believed that neurological dysfunction is the result of venous thrombosis and infarction, rather
than simple spinal cord compression. Therefore, the chance of functional recovery is low. Spinal
epidural abscess should be treated with emergency surgical drainage and active intravenous
antibiotics.
viii. Endocrine System:
(1) Syndrome of Inappropriate Antidiuretic Hormone Secretion:
SIADH is sometimes seen in the NSU usually because of trauma or intracranial infection,
namely meningitis. The name of this syndrome is descriptive: there is an oversecretion of anti-
diuretic hormone, regardless of serum osmolar stimulation. The hallmark features of this
276
syndrome are hyponatremia (<134 mEq/L), low serum osmolality (<280 mOsm/L), and a high
ratio of urine to serum osmolality (usually >1.5:1). The definitive test for making the diagnosis is
a water-load test, in which the patient is given a large oral water load, and subsequent urine
output is monitored. In the NSU it is not usually advisable to proceed with this type of testing, as
the risk of worsening hyponatremia exists. Clinical diagnosis is usually sufficient. Patients
usually present with confusion and lethargy, and they may progress to seizure and coma if the
hyponatremia becomes severe (<125 mEq/L).
Treatment for SIADH is usually simple fluid restriction to less than 800 cc/da in most
adults, with absolutely no free water to be given. In severe, symptomatic cases, hypertonic
salinemay be administered judiciously. In an adult, it is possible to start intravenous 3% NaCl
(513mEq/L) at a rate of 25–50 cc/h to help correct severe hyponatremia. It is important to
monitorserum sodium frequently (every 4–6 h), and to maintain a rate of correction not
exceedingapprox1.3 mEq/L/h. The reason behind this relatively slow correction of severe
hyponatremia isthat there is a risk of developing central pontine myelinolysis (CPM) with too
rapid a correction. CPM is a disorder in which the pontine white matter becomes demyelinated,
producing flaccidquadriparesis and cranial nerve deficits, and is most often seen in people who
suffer from malnourishment or alcoholism. Because CPM is such a devastating complication,
many clinicians are hesitant to use hypertonic saline in the correction of hyponatremia; however,
the risk of CPM is extremely low with a carefully measured rate of correction.
(2) Diabetes Insipidus:
This hormonal abnormality can be thought of as the opposite of SIADH. In central

diabetes insipidus (DI), patients do not secrete sufficient antidiuretic hormone (ADH). There also
exists a peripheral form of DI that is rare, in which the kidneys become unresponsive to ADH. In
patients with severe brain injury, or damage to the hypothalamic-pituitary axis, central DI is
frequently seen. Patients with DI present with a high output of dilute urine, and serum
hypernatremia. A sustained urine output of >250 cc/h in an adult, or >3 cc/kg/h in a child, should
prompt workup for DI. The urine osmolarity in DI is usually less than 150 mOsm/L, and the
specific gravity is less than 1.005. Serum sodium and osmolarity may initially be normal,
however, with continued loss of free water these values become elevated. If the patient is awake,
he or she will complain of terrible thirst, and will exhibit polydipsia to compensate for the loss of
water in the urine. The diagnosis is usually made based on these clinical signs and laboratory
values.
A water shortage test can be done to prove the diagnosis of DI; however, this is not
advisable because of the risk of exacerbating existing hypernatremia. If the patient has been
treated with osmotic diuretics such as mannitol, urine osmotic pressure cannot be used to aid
diagnosis, and serum sodium is a more reliable measurement. In unconscious patients, DI can be
life-threatening because these patients cannot consume enough water to maintain normal serum
sodium and osmolality. Usually, patients with NSU need intravenous fluids to replenish lost
water and need to carefully monitor urine output to achieve normal blood volume. Most cases of
DI are self-limiting and last 12-36 hours after neurosurgery.Patients undergoing pituitary
adenoma resection are at the greatest risk because the pituitary stalk often has traction injuries.
277
In most of these transient cases, free access to water and frequent serum sodium checks is
all that is needed for postoperative management. In those cases which seem to be prolonged, or
in which it is difficult to keep up with the loss of water in the urine, it may become necessary to
treat patients with exogenous vasopressin to reduce urine output. Intranasal desmopressin
(DDAVP®) can be used in awake patients, while subcutaneous (SC) or IV formulations can be
used in patients who are intubated or have decreased mentation. Intravenous aqueous vasopressin
(Pitressin®) is most frequently used in the setting of brain death. Patients who suffer brain death
often exhibit refractory DI with profound fluid losses, secondary to the cessation of ADH
production by the hypothalamus. If the patient is a candidate for organ donation, it may become
necessary to control severe DI with Pitressin® to prevent dehydration. A solution of one unit of
Pitressin in 1000 cc of hypotonic IV fluid (D5 water or 0.45% NaCl) is usually infused to match
urine output in these cases until hypernatremia is corrected.
ix. Pain Control and Sedation:
Sometimes it is difficult to strike a balance between patient comfort and the need to
obtain a reliable neurological examination. Analgesics should be given to maintain acceptable
comfort for the patient, while avoiding excessive use of anesthetics. Fortunately, most patients
undergoing craniotomy have less postoperative pain compared to other postoperative patients,
and treatment with acetaminophen and low-dose morphine or codeine is usually sufficient. In
patients with unconsciousness or aphasia, signs of agitation or high blood pressure may indicate
insufficient pain control.Most neurosurgeons avoid treating craniotomy patients with NSAIDs in
the immediate post-operative period, to reduce the risk of platelet dysfunction and hemorrhage.
Patients who have a history of alcoholism require prophylaxis against delirium tremens (DT),
regardless of neurologic examination. The risk of seizures and death with DT is much higher
than the risk of over-sedating these patients, and the small, intermittent doses of benzodiazepine
used to prevent DT usually have no appreciable effect on the patient’s neurologic examination.
x. Intracranial Hypertension:
Elevated ICP is a common complication seen in the NSU and can be caused by a variety
of disparate pathologies, each requiring different treatment. Patients with increased ICP present
with headache, nausea, emesis, decreased level of consciousness, and occasionally with focal
findings such as sixth cranial nerve palsy and hemiparesis. The “Cushing response,” considered
to be the classical presentation for patients with increased ICP, consists of hypertension,
respiration irregularity, and bradycardia. Normal ICP should be roughly equivalent to central
venous pressure, usually between 5 and 15 mmHg at rest.
For postoperative neurosurgery patients, the most common causes of elevated ICP
include hydrocephalus, cerebral edema, or mass effect caused by tumors or hematomas. It is
important to quickly determine the root cause of elevated ICP and adopt appropriate treatment
methods. Any patient suspected of having an elevated ICP should undergo emergency head CT.
Emergency treatment of patients with elevated ICP should be started even before clear imaging
studies are obtained, especially when the patient begins to show signs of brainstem dysfunction.
278
Patients should be quickly intubated and hyperventilated to achieve a PCO2 of 30–35. It

is usually safest to sedate and paralyze the patient before intubation to prevent coughing which
may worsen ICP. Hyperventilation is only useful for short periods and should not be continued
past 24 h after initiation. An osmotic diuretic such as mannitol (0.5–1 g/kg) should be rapidly
infused, as this helps to reduce total brain water and can significantly reduce ICP in the short run.
The patient’s head should be elevated above the level of the heart, to improve venous return.
Once these temporary control measures have been instituted, definitive imaging needs to be
obtained to determine the cause of the elevated ICP. Acute hydrocephalus should be treated with
bedside ventriculostomy. Mass lesions secondary to traumatic or postoperative hematoma
usually require urgent surgical evacuation to control ICP. Cerebral edema, either focal or
generalized, can be more difficult to treat. Often, the edema surrounding brain tumors is very
responsive to high-dose steroids, and these may be all that are necessary to improve the patient’s
examination.
If they are not sufficient, surgical tumor resection should be undertaken, if possible.
Generalized edema following head trauma, if severe enough to produce a decrease in
consciousness, often requires placement of a subdural ICP monitor to provide clinicians with a
measurement to tailor treatment. The goal of such treatment is to maintain a cerebral perfusion
pressure of 60–70 mmHg. Cerebral perfusion pressure is defined as the difference between mean
arterial pressure and ICP, and in normal patients is usually within the range of 70–95 mmHg.
Patients should be treated with intermittent mannitol to keep a serum osmolarity of approximate
300–310 mEq/L, with head elevation, and with sedation and paralytics as needed to keep ICP,
and CPP, within reasonable limits. Increasing the serum osmolarity above 310 has little benefit,
in terms of reducing ICP, and greatly increases the patient’s risk of renal failure. Chapter 5 of
this text contains more details on the pathophysiology and treatment of cerebral edema.
xi. Cerebrospinal Fluid Leak:
Cerebrospinal fluid leakage (CSF) is not a particularly common complication in

neurosurgery patients. However, it is important to realize that because it can lead to further
complications such as meningitis and brain abscess. Three types of patients are particularly at
risk: patients with skull base fractures, patients who have undergone sphenoid surgery, and
patients who have undergone craniotomy for the posterior fossa with dura materopening.
Patients who have suffered trauma, which results in a fracture through the temporal bone
or the cribriform plate, are at risk for CSF otorrhea or rhinorrhea. These patients will present
with frank CSF flowing from the ear or nose or may complain of a salty-sweet taste in their
mouths. Often,1 CSF rhinorrhea can be demonstrated by having the patient sit up and hang his
head between his knees. If in doubt, the fluid can be collected and tested for glucose. Normal
nasal secretions should not contain a significant amount of glucose, while CSF will have a
glucose level approximate 60% of the serum glucose. The patient presenting with CSF otorrhea
or rhinorrhea because of traumatic skull fracture usually has a good prognosis. Patients should be
managed with bed rest, with a head elevation between 0 and 30 degrees. Most patients (<90%)
will be able to seal the leak within 5–7 d without further intervention. Prophylactic antibiotics are
not recommended because they do not reduce the rate of meningitis, and they tend to select for
more virulent organisms. Patients with a persistent CSF leak after 5–7 d should then have a
279
lumbar subarachnoid drain placed, and CSF drained from that at a rate of 5–15 cc/h. By
providing a lower-resistance path for CSF, the flow through the skull fracture is reduced,
allowing for sealing of the leak. If, after another 5–7 d of lumbar drainage, the patient continues
to have a CSF leak, he or she will most likely require surgical exploration and repair of the dura
materdefect.
Patients with cerebrospinal fluid leakage after transsphenoidal approach to sella or

posterior fossa craniotomy may have a more difficult process. There are several factors that may
make patients prone to poor healing and cerebrospinal fluid leakage after surgery: diabetes, long-
term use of steroids, and placement of dural allografts are some of the factors. CSF leakage after
entering the sella through the sphenoid approach may be difficult to treat. If repeated exploration
and repacking of the sella and sphenoid bones cannot solve the problem, the patient may need to
undergo a formal craniotomy for intracranial visualization and repair. Meningeal defect. Some
patients may have an inflammatory reaction to the bovine pericardium, which is usually used to
repair the dural defect in the posterior fossa craniotomy. This "chemical meningitis" leads to an
increase in ICP, which may aggravate the leakage of CSF through the dural suture.
Pseudomeningocele after posterior fossa surgery is not common, but if it occurs and is
large, or if the incision leaks, it requires active treatment. Usually, patients with cerebrospinal
fluid leakage after surgery require lumbar drainage immediately because they usually do not heal
naturally. After the drainage tube is placed, the cerebrospinal fluid should be checked for signs
of infection, and if it is found, it should be treated. If evidence of chemical meningitis is noticed,
patients should start using steroids to reduce inflammation. If the patient does not show signs of
cerebrospinal fluid leakage after 5-7 days of lumbar drainage, or if the surgical wound becomes
infected or heals poorly, the patient will need to return to the surgical exploration, debridement
and closure of the dural defect.
Patients in whom a CSF leak develops following a transsphenoidal approach to the sella
or posterior fossa craniotomy may have a more difficult course. Several factors may predispose
patients to poor healing and CSF leak following surgery: diabetes, chronic steroid use, and
placement of dural allograft are some of these. CSF leaks following a transsphenoidal approach
to the sella may be very difficult to treat, and if a repeat exploration and repacking of the sella
and sphenoid does not rectify the problem, the patient may need to undergo a formal craniotomy
for intracranial visualization and repair of the dural defect. Some patients may develop an
inflammatory reaction to the bovine pericardium often used to patch the dural defect in a
posterior fossa craniotomy. This “chemical meningitis” leads to an increase in ICP, which may
worsen leakage of CSF through the dural suture line.
Psuedomeningoceles are not common following posterior fossa surgery, however if they
occur and are large, or if there is leakage through the incision, aggressive treatment needs to be
undertaken. Usually, patients who develop CSF leak after surgery require lumbar drainage
immediately, as they do not usually heal spontaneously. Once the drain is placed, the CSF should
be checked for evidence of infection, and this should be treated if found. If evidence of chemical
meningitis is noted, the patient should be started on steroids to reduce the inflammatory reaction.
If after 5–7 d of lumbar drainage the patient shows no sign of cessation of the CSF leak, or if the
280
surgical wound appears infected or is not healing well, the patient will need to go back to surgery
for exploration, debridement, and closure of the dural def
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Essentials of Diagnosis, Treatment, and

Application of Cardiac and Peripheral

Jing Yuchen, Master of Medicine

We hope you find this book as an invaluable resource, whether it is as one

First edition 2021

ISBN: 978-0-578-94229-2 LCCN: 2021917020

Working together to grow

Content Strategist: Michael Brunet

Chapter 1 : Epicardial Coronary Artery Related Disease 1

Chapter 2 : Coronary Microcirculation Disorders Related Diseases 14

Chapter 3：Hypertension and its Related Heart Disease 37

Chapter 6：Heart Failure 90

Chapter 7 : Evaluation and Management of Heart Disease 108

SECTION II: Vascular Surgery

Chapter 8： Basic Techniques of Vascular Surgery Diagnosis 110

Chapter 9 ：Basic Skills of Vascular Surgery 123

Chapter 10：Endovascular Intervention Technique 138

Chapter 11 ：Physical Assessment and Evaluation During the Perioperative

Chapter 12： Vascular Trauma 162

Chapter 13 ：Peripheral and Abdominal Aortic Aneurysms 175

Chapter 14 ：Aortic Dissecting Aneurysm 188

Chapter 16 ：Buerger's Disease (Thromboangiitis Obliterans) 215

Chapter 17 ：Mesenteric Vascular Disease 227

Chapter 18 ：Renal Artery Disease 239

SECTION III : Ultrasound

SECTION IV: Preoperative and Postoperative Care

Chapter 1 Epicardial Coronary Artery Related Disease

a. Functional Anatomy of The Coronary Circulation:

The coronary artery system consists of three compartments with different

The middle compartment is represented by the pre-arteriolar vessels. (Figure 1.1B)

b.Regulation of Myocardial Blood Flow:

The cardiac pump is an aerobic organ. It requires continuous perfusion of oxygenated

The decrease in arteriolar resistance drives a series of subsequent vascular adaptions

2. Acute coronary syndrome (ACS)

Figure 1.1(a) Source: Angina Pectoris; Web Page:https://byjus.com/biology/angina-pectoris/

a. Patients with ST-Segment Elevation Myocardial Infarction

When STEMI is diagnosed, Treatment must be conducted. First is to administering drugs

b. The Patient with Non-ST-Elevation Acute Coronary Syndrome

Significant understanding of NSTE-ACS pathophysiology has accumulated, yet diverse

The contemporary Global Registry of Acute Coronary Events (GRACE) reported 6-

Moreover, patients classified as “low risk” exhibited a 2.2% mortality, with a

c. Modern Concepts of Acute Coronary Syndrome Pathophysiology

The extension of knowledge regarding the atherothrombotic process of ACS is perhaps as

A variety of inflammatory mediators result in leukocyte (primarily monocytes)

The focal event resulting in presentation with an ACS is a manifestation of systematic

Multiple complex angiographic lesions and ultrasound-identified plaque ruptures have

d. PCI for Unstable Angina and Non-ST-Elevation Myocardial Infarction

Historically, the procedural success rate of BA in NSTE-ACS is comparable to that in

More contemporary progress in revascularization methods is exemplified by 3,192

3. Chronic Coronary Syndrome

Based on a classic history of angina pectoris10 or known atherosclerotic cardiovascular

With the accumulation of scientific information and technological progress, indications

b. Goal of the Revascularization Treatment

The decision to recommend coronary revascularization for SIHD patients should be

For selective indications, postponement of PCI can consider alternative treatment

a. Medical Record and History:

On that occasion, she reported hypertension, glucose intolerance, hypercholesterolemia,

Figure 1.4 ECG. Sinus rhythm, diffuse ventricular repolarization changes.