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Heart Failure With Reduced Ejection Fraction
Heart Failure With Reduced Ejection Fraction
Heart failure is a pathophysiological state in which an artery disease, myocardial infarction and dilated cardio
abnormality in cardiac function results in the failure of myopathy), that leads to the reduced contraction of the
the heart to pump blood under normal cardiac pressures ventricles. Initially, several compensatory mechanisms
at a rate that meets the requirements of metabolizing are activated, which can promote enhanced ventricular
tissues1. Symptoms of heart failure include dyspnoea, contraction. However, these mechanisms ultimately fail,
fatigue and limitations in exercise tolerance, and often resulting in the progression of disease and worsening
also include concomitant fluid accumulation, most of symptoms.
notably in the lungs, abdomen and lower extremi The identification of precipitating factors of HFrEF
ties (that is, congestion). Consequently, heart failure is enables the classification of patients into those ‘at risk’
accompanied by a substantial morbidity and mortality of developing HFrEF and those with symptomatic dis
risk, and impairs quality of life and functional capacity 2. ease. Classification enables the targeting of preventive
Broadly speaking, heart failure can be divided into therapies to high-risk individuals, in an attempt to delay
heart failure with reduced ejection fraction (HFrEF) the development of structural heart disease, ventricular
and heart failure with preserved ejection fraction (HFpEF; impairment and clinical HFrEF. Management of heart
FIG. 1). In healthy individuals, the left ventricular ejection failure has assumed centre stage in modern cardio
Correspondence to J.B.
fraction (LVEF; that is, the percentage of blood pumped vascular medicine. Practicing clinicians recognize the
Division of Cardiology,
Stony Brook University
from the left ventricle each time the heart contracts) challenges that are associated with the management of
Medical Center, 101 Nicolls ranges from 52% to 72% in men and from 54% to 74% in heart failure, as this condition is difficult to recognize
Road, HSC, T-16, Rm 080, women, and a value of 40% is sufficient for the classifi and diagnose because the symptoms might be vari
Stony Brook, New York cation of HFrEF3. In the United States, approximately able. Assessing prognosis and risk of complications is
11794–8167, USA.
50% of the total cases of heart failure are attributable similarly hard to accomplish. Although several therapies
Javed.Butler@
stonybrookmedicine.edu to patients with reduced ejection fraction2. The patho for the management of heart failure have been developed,
physiology of HFrEF is complex and usually commences the most success has been in the management of patients
Article number: 17058
doi:10.1038/nrdp.2017.58 with a precipitating event, such as direct injury to the with HFrEF, and the development of care options for
Published online 24 Aug 2017 myocardium or a disease state (for example, coronary patients with HFpEF has remained elusive.
and the most important attributable risk factor for with which the heart contracts against to eject blood)
HFrEF is hypertension24. Other cardiovascular aetio and chronic pressure overload (that is, the overload
logies of HFrEF include cardiomyopathies, myocardial of the cardiac muscle when it must contract in a state of
infarction, myocarditis, valvular diseases and cardiac increased afterload), such as severe aortic stenosis and
infections. Extra-cardiac causes of HFrEF are numer uncontrolled hypertension27.
ous and include endocrine aetiologies (such as thyroid In patients with pre-existing HFrEF who are stable,
disorders), systemic diseases (such as sarcoidosis and several factors can precipitate a worsening of symptoms,
systemic lupus erythematosus), those related to a high clinical decompensation or hospitalization. These include
intake of alcohol and other illicit drugs2, and those arrhythmias, ischaemia, infection, non-compliance with
following chemotherapy for cancer 25. medications and dietary indiscretions (such as excessive
The inciting event of ventricular impairment can intake of fluid or sodium)2. Several drugs can exacer
be either acute in onset (for example, viral myocarditis bate HFrEF, meaning that a careful review of patients’
and myocardial infarction) or insidious in onset (for medication is crucially important 28 (BOX 1).
example, genetic cardiomyopathy and anthracycline-
induced cardiomyopathy), in which the clinical symp Pathophysiology
toms of HFrEF manifest weeks, months or even years The relationship between the initial insult and the
after the original insult 26. Inciting events that are insidi development and progression of HFrEF is extremely
ous in onset can be grouped into events that lead to complex. At the genetic and molecular levels, changes
impaired contractility (such as valvular abnormalities, in cell structure (such as sarcomere depletion and glyco
coronary artery disease and dilated cardiomyopathies gen deposition) might occur. In the failing myocardium,
due to alcohol or genetic factors), events that lead pathological alterations in contractile, regulatory and
to increased afterload (that is, the pressure in the left cytoskeletal proteins that lead to myofibril dysfunction
ventricle during the ejection of blood or the pressure can be found (including dephosphorylation and altered
expression, activity and localization of proteins)29.
a b At the cellular level, the prolongation of action poten
tials is present in both patients and animal models due
to abnormalities in sodium and potassium channels on
the myocardial membrane, which leads to arrhythmias29.
HFrEF is also characterized by abnormalities in cellular
calcium regulation and altered calcium kinetics, which
modify myocardial contraction29. Abnormalities in
myocardial energy metabolism have also been reported,
including a heavier reliance on glucose metabolism,
LA decreases in oxidative phosphorylation and patho
RA logical mitochondrial function 29. A unique area of
interest is the improvement of myocardial metabolism
in ‘stunned’ or hibernating myocardium to alter patho
logical cellular remodelling, and the rationale for the
LV
use of currently accepted heart failure therapies can be
RV found in targeting these pathological cellular responses
in dysfunctional myocardium29. Finally, other changes,
such as altered stress responses, apoptosis and auto
Weakened Thickened phagy, might be involved in propagating heart failure.
myocardium myocardium
Although several molecular and cellular abnormalities in
Figure 1 | Subtypes of heart failure. Heart failure can be classified as left-sided or the failing heart have been identified, the timing of these
right-sided, depending on which chambers and circulation, systemic
Nature or pulmonary,
Reviews | Disease Primers
alterations in terms of the initial myocardial insult to
respectively, are affected. Right-sided heart failure typically develops as a consequence of
left-sided heart failure and, therefore, we use the term ‘heart failure’ to refer to left-sided the progression of disease is poorly understood. In addi
heart failure. Heart failure can be broadly divided into heart failure with reduced ejection tion, little is known about the cause of the progression
fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF). In both HFrEF from a compensated to an acutely decompensated state,
and HFpEF, the amount of blood that is pumped out with each heart beat is reduced, but or the molecular basis upon which certain patients fully
the mechanisms underlying these conditions are different. a | In patients with HFrEF, the recover ventricular function, whereas other patients clin
ejection fraction (that is, the proportion of blood pumped from the ventricles) is usually ically worsen30. What is clear, however, is that once the
defined as ≤40%2. The ventricular myocardium can no longer contract with a force that initial compensatory mechanisms become m aladaptive,
is sufficient to adequately pump the blood either because it has weakened or impaired cardiac remodelling leads to progression to HFrEF.
contractility or because it cannot overcome an increased afterload (the pressure in the
wall of the left ventricle (LV) or the pressure against which the heart contracts to eject
Compensatory mechanisms. Although the pathophysio
blood). b | Conversely, HFpEF is a clinical syndrome of heart failure in the presence of
preserved or normal left ventricular ejection fraction, with evidence of diastolic logy underlying HFrEF is incompletely understood,
dysfunction by non-invasive or invasive haemodynamic measurement2. In this case, several principles prevail (FIG. 2). Cardiac output is deter
the ventricular myocardium fails to relax during diastole, for example, because the tissue mined by the product of stroke volume (the volume of
has thickened or stiffened, and as a result the chamber cannot adequately fill with blood. blood that is expelled from each systolic contraction
LA, left atrium; RA, right atrium; RV, right ventricle. of the heart) and heart rate. The Frank Starling principle
describes a physiological mechanism by which an i nitial Although neurohormonal activation is initially benefi
reduction in left ventricular contraction ultimately leads cial in maintaining cardiac output, the chronic activation
to a compensatory increase in stroke volume. In healthy of these systems can be maladaptive, and can result in
individuals, a decrease in left ventricular contraction pathological ventricular remodelling and in a worsen
initially causes a reduction in stroke volume27 and ing of heart failure29. Long-standing sympathetic activity
incomplete ventricular chamber emptying. This leads results in the downregulation of β‑adrenergic receptors
to an accumulation of blood in the ventricle at the end on cardiomyocytes, which contributes to decreased myo
of diastole (that is, an increase in end diastolic volume), cardial sensitivity to catecholamines and an associated
which increases the stretch of the ventricles (and, at the reduced inotropic response, which reduces ventricular
cellular level, increases myocardial fibre stretch), thereby contractility 29. In addition, chronic SNS activity leads
increasing the strength of subsequent ventricular con to tachycardia (increased heart rate) and arrhythmias
traction and increasing stroke volume, which allows the that may lead to further clinical deterioration or even to
emptying of the enlarged left ventricle. However, this sudden cardiac death. Chronic activation of the RAAS
mechanism falls short in HFrEF when a reduction in leads to prolonged increases in the levels of angiotensin II
cardiovascular reserve (that is, the difference between and aldosterone, which initiate pathological processes,
the rate at which the heart can pump blood and the including myocyte hypertrophy and interstitial fibrosis,
maximum capacity to pump blood) results in ventricu both of which are hallmarks of pathological ventricular
lar impairment and reduced ventricular contraction, remodelling (see below)31.
leading to a reduction in stroke volume, cardiac output In a counterbalance to the deleterious chronic neuro
and an increase in end diastolic volume27. Ultimately, hormonal activation, counter regulatory factors,
elevations in end diastolic volume and pressure lead to including the natriuretic peptides, bradykinin and prosta
an increase in left atrial pressure and pulmonary venous glandins, are upregulated29,32. Circulating natriuretic
congestion27, which can c linically lead to dyspnoea and peptides (BNP; also known as brain natriuretic pep
other congestive symptoms. tides) counterbalance the deleterious effects of chronic
A fall in cardiac output due to ventricular impair RAAS and sympathetic activation by promoting natri
ment leads to several compensatory mechanisms that uresis (the excretion of sodium in the urine), in addition
are initially adaptive in order to promote an increase in to vasodilation and diuresis. Despite increased circulating
cardiac output and to maintain end-organ perfusion. levels of natriuretic peptides as heart failure progresses,
These mechanisms include neurohormonal activation their effects become attenuated. Reasons for this include
of the sympathetic nervous system (SNS) and the renin– the reduced availability of the active natriuretic peptide
angiotensin–aldosterone system (RAAS 29; FIG. 3 ). forms, reduced end-organ response and overactivation
of the RAAS and SNS32.
Box 1 | Factors leading to acute heart failure Cardiac remodelling. Cardiac remodelling refers to
structural changes to the myocardium that occur in
Medical factors
response to haemodynamic alterations, neurohormo
• Changes to cardiac medications (such as negative
nal activation and myocardial injury, which are initially
inotropes, including β-blockers or non‑dihydropyridine
calcium channel blockers)
adaptive but can lead to the development and progression
of HFrEF29.
• Accelerated or uncontrolled hypertension
Indeed, myocardial hypertrophy develops in patients
• Ischaemia
with HFrEF in response to a sustained increase in wall
• Valvular disease stress from either ventricular dilation or excessive after
• Unstable arrhythmia load, in an attempt to maintain adequate stiffness and
• Endocrine abnormalities elevation in ventricular end diastolic pressure, which
• Infections leads to an increase in left atrial pressure, an elevation
• Anaemia in pulmonary venous pressures and dyspnoea29. Other
• Pregnancy factors that can lead to pathological ventricular remodel
• Pulmonary embolus ling and the clinical manifestations of heart failure
include myocardial fibrosis, necrosis and inflammation33.
Psychosocial factors
The identification and treatment of the early ventricular
• Noncompliance with: remodelling process might provide novel therapeutic
-- Sodium restriction
targets to prevent disease progression34.
-- Fluid restriction
-- Medication use
-- Daily weight checking Diagnosis, screening and prevention
The diagnosis of heart failure can be challenging,
• Poor insight into illness
particularly in its early stages. The signs and symptoms
• Poor access to medications or health care owing to cost
can be nonspecific and closely overlap those of other
or physical condition
conditions, such as lung disease, obesity, hypothyroid
• Alcohol or illicit drug use
ism and anaemia. Transthoracic echocardiography
• Over-the-counter drugs, such as NSAIDs, herbal (TTE) is frequently used to determine the presence of
supplements, and dietary and weight loss supplements
systolic and/or diastolic dysfunction, which can confirm
Table 1 | Comparison of ACCF and AHA stages of heart failure with NYHA functional classifications
ACCF Description of ACCF NYHA Description of functional classification
and AHA and AHA stage functional
stage classification
A At high risk of heart failure None NA
but without structural
heart disease or symptoms
B Structural heart disease I No limitation of physical activity; ordinary physical activity
but without signs or does not cause symptoms of heart failure
symptoms of heart failure
C Structural heart disease I No limitation of physical activity; ordinary physical activity
with prior or current does not cause symptoms of heart failure
symptoms of heart failure
II Slight limitation of physical activity; comfortable at rest, but
ordinary physical activity results in symptoms of heart failure
III Marked limitation of physical activity; comfortable at rest, but
less than ordinary activity causes symptoms of heart failure
IV Unable to carry on with any physical activity without
symptoms of heart failure, or symptoms of heart failure at rest
D Refractory heart failure IV Unable to carry on with any physical activity without
requiring specialized symptoms of heart failure, or symptoms of heart failure
interventions at rest
ACCF, American College of Cardiology Foundation; AHA, American Heart Association; NA, not applicable; NYHA, New York Heart
Association. Data taken from REF. 2.
alive after 1 year 92. The availability of a totally artificial a comprehensive evaluation of comorbidities and right
heart remains one possible solution to this dilemma, ventricular function, which is a crucial parameter for
although this device is only currently approved as a short-term and long-term survival97. The Interagency
bridge to transplantation93,94. Registry for Mechanically Assisted Circulatory Support
Decisions regarding the implantation of durable (INTERMACS) classification helps to differentiate the
device support are complex and multifactorial. Typically, level of severity of patients with class III or class IV heart
the criteria for the implantation of bridge-to-transplant failure, which has p rognostic implications100.
devices parallel those used for cardiac t ransplantation; The use of continuous flow LVAD implantations
that is, patients with stage D heart failure despite has increased since 2010 (REF. 92). In the United States,
guideline-directed medical therapy and patients who, 2,642 devices were implanted in 2013, of which 1,152
despite device and surgical management, remain were implanted as destination therapy 92. Among
severely symptomatic and are at high risk of 1‑year patients undergoing bridge-to-transplantation during
mortality 2,94,95. Bridge-to-transplant therapy is particu 2013–2014, 31% received a cardiac transplantation
larly essential in patients for whom the expected waiting within 1 year 92. Compared with pulsatile devices, con
times for cardiac transplantation might affect survival. tinuous flow LVADs have fewer complications, such
Patients considered for destination therapy devices are as pump dysfunction, infection, right ventricular fail
those who require mechanical circulatory support but ure and renal dysfunction88 (FIG. 8). Pump exchange
who have contraindications to cardiac transplantation due to device malfunction or thrombosis is ~9% dur
(such as those with advanced age or those who have ing the first year post-implantation92. Recently, com
had a recent malignancy)96. Often, decisions regarding pared with an axial-f low pump, a new magnetically
long-term mechanical support involve patients with levitated centrifugal continuous flow pump has been
chronic HFrEF, which allows for a comprehensive and shown to be associated with a lower rate of reoperation
extensive evaluation process that might not be possible for pump malfunction, owing to suspected or confirmed
in patients with a more acute presentation, such as those pump thrombosis leading to surgical pump exchange or
with cardiogenic shock97. In a scenario such as cardio to urgent transplantation101. Survival with continuous
genic shock, if the severity of the cardiac dysfunction flow LVADs is 80% at 1 year and 70% at 2 years92. In one
precludes weaning the patient off temporary mechan study, approximately 30% of patients with INTERMACS
ical support and if end-organ dysfunction (includ levels 2–7 who received either a continuous flow LVAD
ing neurological recovery) is thought to be reversible, or a biventricular assist device were free from the com
patients can be considered for long-term mechanical bined event of infection, bleeding, device malfunc
circulatory support 98. The US Centers for Medicare and tion, stroke or death at 12 months92. Compared with
Medicaid Services have issued a statement regarding data from the United States, the European Registry for
decision making for coverage of the implantation of Patients with Mechanical Circulatory Support reports a
ventricular assist devices99,100. Early referral and pre 1‑year, 2‑year and 3‑year survival of 72.5%, 62.8% and
operative risk assessment are crucial for patients who 60.9%, respectively, in 583 adult patients implanted with
require mechanical circulatory support, and this requires a continuous flow LVAD102.
Cardiac transplantation. Heart transplantation offers New immunosuppressive drugs allow personalized
the best quality of life, possibility for socio-professional regimens to decrease complications, but several compli
rehabilitation and the longest survival, and remains the cations remain prevalent. Hypertension remains frequent
best option in eligible patients with advanced heart fail (71% of patients at 1 year and 91% at 5 years), as does
ure77. Eligible patients include those with stage D HFrEF renal dysfunction (25% at 1 year, 51% at 5 years and 68%
who are either dependent on inotropic support or who at 10 years) and allograft vasculopathy (8% at 1 year,
have a poor performance on cardiopulmonary exercise 30% at 5 years and 50% at 10 years)105. To increase the
stress testing, despite optimized medical therapy 96. These number of organs available, the proportion of older
data should be coupled with prognostic scores, such as donors has increased, particularly in Europe. Mean donor
the heart failure survival score, and results from right age increased from 29 in 1994 to 33 years of age in 2014
heart catheterization. Contraindications for cardiac (44 years of age in Europe and 32 years of age in North
transplantation include patients with morbid obesity, America in 2014). To respond to the growing popula
irreversible pulmonary hypertension, irreversible renal tion of older patients, extended listing criteria have been
dysfunction, severe cerebrovascular disease, diabetes developed to match donors and recipients who are u sually
mellitus with end-organ complications, active substance excluded from routine transplant programmes103,106.
abuse, and active or recent malignancy 96.
After a plateau of approximately 4,000 per year Patient monitoring
between 2000 and 2010, the number of heart transplan Strategies for the remote monitoring of patients may
tations reported in the registry of the International Society provide a way to assess worsening heart failure with the
for Heart and Lung Transplantation (ISHLT) progressively hope of decreasing hospital admissions, avoiding clinical
increased to 4,746 in 2014 (REF. 103). Patient 1‑year survival deterioration and decreasing mortality107,108.
is 82% and 5‑year survival is 69%, with a median survival of These strategies include clinical telemonitoring, bio
11 years. The survival of the most recent adult cohorts impedance changes, biomarker approaches and invasive
has improved to 86% at 1-year post-transplantation104. haemodynamic monitoring 109. Non-invasive methods
The primary causes of mortality vary depending on the can provide information directly to the patient and to
time following transplantation. For example, mortal clinical databases, or patients can be asked to enter the
ity at 30 days is mainly related to graft failure (39% of relevant data110, which can include heart rate and rhythm,
cases), followed by multiple organ failure (16% of cases), blood pressure, weight and thoracic impedance 108.
whereas mortality at 1 year is associated with infec Results from telemonitoring trials have been mixed but
tions (31% of cases) and acute rejection (10% of cases), show overall promise108,110–114. Although more sensitive
and mortality at 5 years is associated with malignancies than telemonitoring, strategies based on bioimpedance
(19% of cases) and allograft vasculopathy (14% of cases). information have not yielded overwhelmingly positive
Step 1
Establish diagnosis HFrEF ACEi or ARB and GDMT Class I Class IIa
of HFrEF; NYHA class I–IV β-blockers; diuretics
assess volume; (stage C) as needed (COR I)
initiate GDMT
Step 2
Consider the NYHA class II–IV, NYHA class II–III HF NYHA NYHA class II–IV, NYHA class II–III, NYHA class II–III, NSR,
following provided est. Adequate BP on class II–IV, LVEF ≥35%; LVEF ≤35%; NSR heart rate ≤70 bpm
patient CrCl >30 ml/min ACEi or ARB*; no C/I in black (caveat: >1-year survival, and QRS ≥150 msec on maximally tolerated
scenarios and K+ <5.0 mEq/l to ARB or sacubitril patients >40 days post-MI) LBBB pattern dose of β-blocker
Step 4
Reassess Symptoms Refractory NYHA
symptoms improved class III–IV (stage D)
Step 5
Consider Palliative care§ Transplant§ LVAD§ Investigational
additional (COR I) (COR I) (COR IIa) studies||
therapy
Continue GDMT with serial reassessment and optimized dosing and adherence
Figure 6 | 2017 ACCF, AHA and HFSA guidelines for the treatment of Natureof
and quality of life2. ACCF, American College Reviews | Disease
Cardiology Primers
Foundation;
stage C and stage D HFrEF. Angiotensin-converting enzyme inhibitors AHA, American Heart Association; ARB, angiotensin receptor blocker; ARNI,
(ACEis), β‑blockers and mineralocorticoid antagonists should be angiotensin II receptor–neprilysin inhibitor; BP, blood pressure; COR, class
administered to all patients who present with heart failure with reduced of recommendation; C/I, contraindication; CrCl, creatinine clearance; CRT,
ejection fraction (HFrEF). In patients who remain symptomatic despite an cardiac resynchronization therapy; CRT‑D, CRT defibrillator; est., estimated;
appropriate use of the drugs mentioned above, who are in sinus rhythm GDMT, guideline-determined medical therapy; HFSA, Heart Failure Society
and who have a heart rate of ≥70 beats per minute (bpm), ivabradine, of America; ICD, implantable cardioverter defibrillator; LBBB, left bundle
an I f-channel inhibitor, should be considered to reduce the risk of branch block; LVAD, left ventricular assist device; LVEF, left ventricular
hospitalization183. Other drugs include diuretics to treat or prevent the signs ejection fraction; MI, myocardial infarction; NSR, normal sinus rhythm;
and symptoms of congestion184, oral anticoagulants in patients with atrial NYHA, New York Heart Association. *See REF. 38 for important treatment
fibrillation185, digoxin in certain patients who are still symptomatic despite directions. ‡The combination of hydralazine and isosorbide dinitrate with
the recommended treatment to reduce the risk of hospitalization186, ARNI has not been robustly tested. Blood pressure response should be
omega-3 polyunsaturated fatty acid to reduce the risk of hospitalization or carefully monitored. §See 2013 heart failure guidelines2. ||Participation in
death187. In black patients with heart failure, the addition of combined investigational studies is also appropriate for stage C, NYHA class II and
hydralazine and isosorbide dinitrate has been shown to improve survival class III heart failure. Reproduced with permission from REF. 38, Elsevier.
results and thus are currently limited to patients who patients with heart failure, although these remote-
have other indications for implantable devices109,115. monitoring strategies have challenges that remain to
Other strategies, such as biomarkers, can be remotely be addressed.
examined from finger-prick blood samples, but have
similarly yielded mixed results and require further Biomarkers. Several biomarkers of heart failure have
study 109. Implantable monitors provide a method for been identified118. However, the number of biomarker
measuring invasive haemodynamics. These devices can assays that can be used to guide clinical management
measure heart rate and rhythm, in addition to pulmo remains small because many biomarkers are poorly
nary arterial or atrial pressures116. One such device understood, do not provide clinically actionable
for invasive remote monitoring is the CardioMEMS information and there is a lack of well-powered trials
Champion Heart Failure Monitoring System, a per exploring the use of biomarkers for ‘precision’ care119.
manently implantable pulmonary arterial pressure Most studies have focused on the natriuretic pep
measurement system that is designed to wirelessly tides BNP and NT‑proBNP, which provide prognostic
measure and monitor haemodynamics in ambula information. Levels of BNP and NT‑proBNP rise due to
tory patients to reduce heart failure morbidity 117. This congestion, myocardial remodelling, valvular disease and
device is currently used with the hope of decreasing arrhythmia, all of which are potential targets for therapy,
heart failure hospitalizations. Remote monitoring indicating that natriuretic peptide levels might serve as
in various forms provides a meaningful approach to a target for therapy, as guiding therapy to reduce BNP
complement traditional ambulatory management of or NT‑proBNP levels might improve outcomes better
No
worsening symptoms (P < 0.001)121,122, and lowering the
Therapy with ACEi and β-blocker
c levels of NT‑proBNP led to reverse remodelling 123.
(up-titrate to maximum tolerated evidence-base doses) Biomarker-guided trials are distinct from drug t rials,
Diuretics to relieve symptoms and signs of congestion
ACEi (or ARB)f,g QRS duration ≥130 msec HR ≥70 bpm or clinician unwillingness to titrate therapies despite an
increased NT‑proBNP level or a lack of added utility of
ARNI to replace ACEi Evaluate need for CRTi,j Ivabradine biomarkers needs to be investigated.
Beyond the natriuretic peptides, few biomarker
These above treatments may be combined if indicated candidates are ready for consideration for personaliz
ing care. Markers of fibrosis such as galectin 3 and ST2
(also known as soluble interleukin 1 receptor-like 1)
Resistant symptoms
seem to provide prognostic information beyond BNP
Yes No and NT‑proBNP levels125,126, but data are lacking about
Class I Consider digoxin or HYD-ISDN No further action required their additive value for therapy decision making.
Class IIa or LVAD, or heart transplantation Consider reducing diuretic dose Importantly, levels of ST2 provide information regard
ing the risk of death and heart failure hospitalization
Figure 7 | European Society of Cardiology 2016 guidelines Naturefor the treatment
Reviews | DiseaseofPrimers
when measured serially 126,127 and also respond to vari
patients with symptomatic HFrEF. Green boxes indicate class I recommendations and
ous heart failure therapies128, whereas galectin 3 levels
yellow boxes indicate class IIa recommendations. aSymptomatic heart failure is defined
as New York Heart Association (NYHA) class II–IV (TABLE 1). bLeft ventricular ejection do not126,129. However, biological variability is apparent in
fraction (LVEF) of 40% is sufficient for the classification of heart failure with reduced levels of several established biomarkers in both healthy
ejection fraction (HFrEF). cIf an angiotensin-converting enzyme inhibitor (ACEi) individuals and patients with chronic heart failure, with
is not tolerated or contraindicated, use an angiotensin receptor blocker (ARB). large variations in the levels of NT‑proBNP and smaller
d
If a mineralocorticoid receptor (MR) antagonist is not tolerated or contraindicated, variations in the levels of ST2 and galectin 3. Further
use an ARB. eWith a hospital admission for heart failure within the past 6 months or understanding of these variations will be important to
with increased levels of natriuretic peptides (natriuretic peptide B (BNP) levels of guide interpretation130.
>250 pg per ml or N‑terminal-pro BNP (NT-proBNP) levels of >500 pg per ml in men and
750 pg per ml in women). fWith an increased plasma natriuretic peptide level (BNP level Disease management programmes
of ≥150 pg per ml or plasma NT‑proBNP level of ≥600 pg per ml), or if hospitalization for
Several current heart failure guidelines stress the
heart failure occurred within the past 12 months (plasma BNP level of ≥100 pg per ml or
plasma NT‑proBNP level of ≥400 pg per ml). gIn doses equivalent to enalapril 10 mg b.i.d. importance of a disease management approach for
h
With a hospital admission for heart failure within the previous year. iCardiac the optimal management of these patients. A disease
resynchronization therapy (CRT) is recommended if there is a QRS duration of ≥130 msec management approach includes several key elements,
and left bundle branch block (LBBB; in sinus rhythm). jCRT should be considered if the such as a coordinated system of care, delivery system
QRS duration is ≥130 msec with non-LBBB (in a sinus rhythm) or for patients in atrial support (such as home visits and telecare), support for
fibrillation, provided a strategy to ensure biventricular capture is in place (individual patient self-care, the identification of at‑risk popula
decision). ARNI, angiotensin II receptor–neprilysin inhibitor; HYD‑ISDN, hydralazine/ tions, a continual feedback loop between patients and
isosorbide dinitrate; HR, heart rate; ICD, implantable cardioverter defibrillator; care providers, measures of clinical and other outcomes,
LVAD, left ventricular assist device; OMT, optimal medical therapy; VF, ventricular and improving overall health131. Disease management
fibrillation; VT, ventricular tachycardia. Reproduced from Ponikowski, P., et al. 2016 ESC
programmes have been shown to reduce heart failure
guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task
Force for the diagnosis and treatment of acute and chronic heart failure of the European hospitalizations and mortality in patients discharged
Society of Cardiology (ESC) developed with the special contribution of the Heart Failure from hospital after an acute decompensation episode
Association (HFA) of the ESC. Eur. Heart J. 2016; 37 (27): 2129–2200. doi: 10.1093/ (that is, a sudden worsening of the symptoms of heart
eurheartj/ehw128,. Reproduced with permission of Oxford University Press on behalf failure)132–134. In a meta-analysis and a Cochrane analysis,
of the European Society of Cardiology. Please visit: www.escardio.org. the effects of multidisciplinary heart failure clinics were
separated from other programmes that provided special to the maximally tolerated doses in all patients is prob
ized follow‑up in a community setting. Programmes in lematic, as not all patients respond the same way to the
a home-based setting were found to be as effective as same dose. Unfortunately, the optimization of med
heart failure clinics in reducing mortality and readmis ications can be limited by clinical intolerance (such as
sions135,136. More than 50 trials have so far evaluated dis worsening renal failure, orthostatic hypotension and
ease management programmes, with mixed results and complicated comorbidities)2,23.
study designs. An optimal model of heart failure disease The achievement of guideline-directed therapy is
management has not been clearly elucidated and needs challenging owing to the need for frequent drug titration
to be adapted to the relevant health care system, available and skilled clinical assessment to ensure the maximiza
resources and patient needs. tion of doses in a safe manner. In this regard, the data
show large gaps in achievement of guideline-directed
Personalized medicine medical therapy 137, often in the highest-risk patients.
Unlike other chronic diseases, HFrEF is treated with In this context, exploring the means by which therapy
out individualized targets, with an emphasis placed might be dosed using objective targets and providing
on achieving the highest tolerated doses of medical a guide to the application of such therapy are under
therapy. Despite the lack of an accepted method for way 138. The most well-studied tools for this approach
personalizing care, the strategy of titrating therapies are the use of implantable haemodynamic monitors and
a b
Pulse generator
(battery inside)
Intravascular Pulse
lead generator Right atrial lead
Left
Right ventricle lead ventricle
lead
Tip of lead in
contact with
right ventricular
myocardium
c d
Aorta
Left ventricle
External
battery
pack Pulsatile flow Continuous flow
LVAD LVAD
Percutaneous lead
External
system controller
Figure 8 | Implanted devices for the management of heart failure. a | Implantable cardioverter defibrillators
Nature Reviews arePrimers
| Disease
battery-powered devices that are implanted to lower the risk of sudden cardiac death in patients who are at a high risk of
life-threatening ventricular arrhythmias. These devices monitor the heart rhythm and can deliver electric pulses to correct
or to restore arrhythmias. b | Cardiac resynchronization therapy using battery-powered implantable devices is used in
patients with heart failure with reduced ejection fraction with moderate-to-severe symptoms, in whom ventricular
contraction is dyssynchronous. c | A pulsatile flow left ventricular assist device (LVAD). d | Continuous flow LVAD.
Part a adapted with permission from REF. 188, Macmillan Publishers Ltd. Part b used by permission of Mayo Foundation
for Medical Education and Research. All rights reserved. Part c and part d adapted with permission from REF. 189,
Macmillan Publishers Ltd.
circulating biomarkers. Although a dialogue regard to ensure the optimal use of guideline-directed care are
ing the individualization of care has begun, such an topics of ongoing research. The importance of restoring
approach is not currently endorsed as standard, and the cardiac function and of improving symptoms, functional
value of personalized strategies for heart failure therapy capacity and clinical outcomes in patients with HFrEF is
remains debated. underscored by the current poor o utcomes of patients.
Patients can show variable clinical responses to stand
Quality of life ard therapies, which raises the possibility of a future
Heart failure affects the quality of life of both patients and pharmacogenetic approach to heart failure manage
their families. Indeed, the quality of life of patients with ment 156. In addition, a deeper understanding of the fac
heart failure is poor compared with age-matched peers tors related to the development and progression of heart
from the general population and compared with patients failure in individual patients holds promise for a tailored
who have other chronic diseases139,140. All domains of approach to diagnosis and personalized treatment.
quality of life can be affected; for most patients, physical Although some drugs (such as sacubitril/valsartan)
health is affected by symptoms and related conditions can target a secondary neurohormonal imbalance in
(such as difficulty sleeping, depressive symptoms and patients with heart failure, a more focused approach
pain)141, and treatment can affect a patient’s level of inde on other pathophysiological processes (such as energy
pendence and social relationships141. The extent to which production and cardiac metabolism, myocyte protein
a patient accepts their heart failure diagnosis and finds a turnover, mitochondrial function, calcium handling,
way to cope with its consequences has been shown to microcirculation and interstitial fibrosis) remains ripe
favourably affect their quality of life142,143. for future interventions. The identification of targeted
Patient-centred outcomes (such as quality of life) are therapies that can address special subsets of patients
being increasingly incorporated as an outcome in clin with heart failure, including those with genetic poly
ical trials, particularly as life expectancies for patients morphisms or those with infiltrative diseases, such as
with HFrEF have increased144,145. Patients place equal or amyloidosis, also remains a viable option. For new
more importance on quality of life than on length of life, therapies targeting specific pathological alterations,
and approximately 50% of patients with heart failure are a broadening of the approach to novel therapeutic
willing to select therapies that improve their quality of development in heart failure is required. This may
life even if this leads to a shortening of life146,147, although include targeting specific subsets of patients, focusing
one study found the opposite148. Impaired quality of life more on the pharmacodynamic properties of the novel
is associated with a poor outcome in patients with heart interventions to guide clinical trials, the possible simul
failure149,150, and improving quality of life, in addition taneous evaluation of combinations of targets and the
to reducing mortality, hospitalizations and improving redesign of phase II and phase III clinical trials.
function, is a major aim of treatment61,144. Meta-analyses
have shown a positive effect of disease management, New therapies
self-management, better coordination of care, pharma Current therapy for HFrEF is mostly focused on second
ceutical care and exercise programmes on at least one ary manifestations of cardiac dysfunction, including
domain of quality of life151–154. These interventions seem neurohormonal activation, rather than on targeting pri
to be particularly effective for improving outcomes that mary cardiac abnormalities that are responsible for the
are directly related to heart failure, but it is more difficult development and the progression of this disease. Newer
to affect general quality of life151. therapies for HFrEF that are being evaluated in clinical
trials include pharmacological treatments, in addition
Outlook to gene therapy and cellular-based therapies (TABLE 3).
Despite substantial advances in the development of drug
therapies and device-based therapies for HFrEF, the vast Gene therapy. Viral vectors, particularly adeno-
majority of patients continue to have a poor prognosis associated viruses, are the most promising gene-deliv
and a high mortality risk155. In the PARADIGM-HF ery tools for a gene therapy approach to heart failure157,
trials, despite further improvement with the use of as these viruses are avidly taken up by cardiomyo
sacubitril/valsartan, it was sobering to observe the high cytes157,158. Although no available viral vectors are exclu
cardiac event rates (such as heart failure-associated sively taken up in the heart, transcriptional targeting
hospitalization and mortality) in this well-treated patient using cardiac-specific promoters (such as the myosin
population with class II symptoms, highlighting the light chain 2 promoter) can accomplish tissue-specific
crucial importance of continued research63. transgene expression159,160. The delivery of viral vectors
to the heart can be accomplished by infusion into either
Current problems with management the arterial or the venous coronary circulations, using
Much work needs to be done to improve the entire direct injection into the myocardium or by seeding
range of care for patients with heart failure. Increasing the pericardium161.
research has been undertaken to identify patients at a The recognition of specific alterations in several
high risk of heart failure and to prevent the development cellular pathways in patients with heart failure has
of heart failure. For patients with manifest heart failure, identif ied novel targets for gene therapy that might
targeting cardiac function, the optimal management of improve cardiac function. For example, the delivery of
comorbidities and developing the best systems of care SERCA2A (also known as ATP2A2; which encodes an
enzyme that has a crucial role in regulating calcium flux) Although trials investigating cell transplantation
in cardiomyocytes targets calcium homeostasis162,163. in heart failure have indicated a favourable efficacy
Although preliminary studies showed promising results, with few safety concerns, improvements in cardiac
this treatment failed to demonstrate any meaning function and clinical parameters have been modest 166.
ful clinical improvement in a phase IIb trial that assessed One meta-analysis of 31 independent trials with 1,521
clinical outcomes, which might be related to problems particip ants showed that stem cell t ransplantation
in achieving the efficient uptake of the viral vector by significantly reduced the risk of heart failure-associated
the myocardium. Another approach to altering calcium mortality and hospital readmission, in addition to
levels is through the use of S100A1, a cardiac protein that improving other clinical parameters167. However, a con
enhances the activity of both SERCA2a and the ryano siderable risk of performance, selection and report
dine receptor 164. Increasing the levels of cAMP through ing bias among the included trials was reported by
the adenyl-cyclase type VI enzyme is another promising the authors of this analysis. In addition, considerable
target for treating heart failure165. uncertainty remains regarding the most effective cell
type, dose, route and frequency of administration, and
Cell therapy. The regeneration of the myocardium regarding methods for enhancing cell retention, long-
through the delivery of undifferentiated, self-renewing term survival in the heart and lineage commitment 168.
stem cells might cure heart failure, and several cell popu A promising strategy for enhancing the effects of cell
lations and delivery methods to achieve this have been therapy involves embedding cells in a natural (such as
evaluated. The transdifferentiation of transplanted stem Matrigel, collagen or fibrin) or synthetic peptide bio
cells into cardiac myocytes is possible, as is the formation material to promote cell engraftment, retention and
of new blood vessels to augment the nutrient s upply to differentiation167,169. Stem cells can be seeded in vitro
the heart. A more likely mechanism of action is para on pre-formed porous scaffolds before implantation,
crine effects that activate or recruit other stem cells or can be injected simultaneously with biomaterials.
in the heart, stimulate new vessel formation, inhibit The incorporation of growth factors in these bio
cardiomyocyte hypertrophy or apoptosis, and regulate materials could also help to enhance survival, retention
maladaptive extracellular matrix remodelling 166. and lineage commitment 168.
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