Chapter 28

Current Status of Heart Transplantation

Sunu S. Thomas and Mandeep R. Mehra
The Center for Advanced Heart Disease, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA

Chapter Outline
28.1 The Heart Failure Syndrome 403 28.6.6 Hyperacute Rejection 411
28.2 Cardiac Transplantation: Historical Achievement 405 28.6.7 Acute Graft Rejection 411
28.3 Heart Transplant Evaluation 406 28.7 Immunosuppression Strategies and Rejection
28.3.1 Age and Comorbidites 406 Surveillance 411
28.3.2 Chronic Kidney Disease 407 28.7.1 Induction Therapy 412
28.3.3 Malignancy 407 28.8 Maintenance Immunosuppression 413
28.3.4 Infection 407 28.8.1 Corticosteroids 413
28.3.5 Pulmonary Hypertension 407 28.8.2 Calcineurin Inhibitors 413
28.3.6 Psychosocial Functioning 408 28.8.3 Antiproliferative Agents 414
28.3.7 Sensitization 408 28.8.4 mTOR Inhibitors 414
28.4 Listing Status 408 28.9 Rejection Surveillance 414
28.5 The Ideal Donor Heart 409 28.9.1 Endomyocardial Biopsy 414
28.5.1 Donor Characteristics 409 28.9.2 Biomarker Tests 415
28.5.2 Evaluation of the Donor Heart 409 28.10 Transplantation Outcomes 415
28.6 Perioperative Management 409 28.10.1 Cardiac Allograft Vasculopathy 415
28.6.1 Graft Preservation and Optimizing Ischemic 28.11 Mechanical Horizon: VADs as a Bridge to
Time 409 Transplant 417
28.6.2 Early Postoperative Care 410 28.12 Future Directions in Cardiac Transplantation 419
28.6.3 Cardiac Allograft Function 410 28.13 Conclusion 419
28.6.4 Right Ventricular Failure 410 Acknowledgments 419
28.6.5 Primary Graft Failure 410 References 419

28.1 THE HEART FAILURE SYNDROME
There are nearly 6 million individuals in the United
States with a diagnosis of heart failure. The annual inci-
dence approximates 600,000 new cases, which is further
complicated by a high hospitalization rate and yearly
mortality rate in excess of 30% in patients with advanced
disease. With economic costs continuing to spiral out of
control, the burden and severity of this epidemic cannot
be understated [1].
The cardinal feature of heart failure is the elevation of
ventricular filling pressures that eventually lead to a com-
promised cardiac output. This may arise from poor sys-
tolic function resulting from impairment of ventricular
contractility, termed Heart Failure with Reduced Ejection
Fraction (HFrEF). Alternatively, heart failure may arise
from poor ventricular compliance leading to impairment
of diastolic parameters, termed Heart Failure with
Preserved Ejection Fraction (HFpEF). Regardless of eti-
ology, patients presenting with signs and symptoms of
heart failure may do so acutely with de novo ventricular
dysfunction, or as an exacerbation of a known chronic
heart failure condition. Patients universally complain of
similar symptoms including dyspnea, fatigue, presyncope,
syncope, orthopnea, and paroxysmal nocturnal dyspnea
reflecting the consequences of impaired circulatory flow
and overall fluid retention. Physical examination typically
reveals hallmark findings of volume overload including
pulmonary congestion, jugular venous distension, increas-
ing abdominal girth and peripheral edema, and signs of
poor perfusion including relative hypotension, cool

Regenerative Medicine Applications in Organ Transplantation.

© 2014 Elsevier Inc. All rights reserved. 403
404 PART | IV Heart

Advanced Heart Failure

NYHA Class IIIb / IV Symptoms

Optimize Neurohormonal Blockade Cardiac Resynchronization Therapy

Beta-Blockers, ACE inhibitors, ARBs, Aldosterone antagonists LVEF < 35%, QRS ≥ 120 ms (ideally QRS ≥ 150 ms, LBBB, NSR)

Medical Futility
Intolerance of medical therapy due to hypotension
Initiation of inotropes for systemic perfusion
Worsening end-organ function BUN ≥ 40 mg/dl, rising Cre)
Diuretic resistance
Persistent hyponatremia (< 136 mEq/L)

Refractory symptoms
>2 Hospitalizations/year

Poor predicted survival

( www.seattleheartfailuremodel.org)

Evaluation for Advanced Cardiac Therapies

Referral to heart failure specialist
Candidacy for heart replacement therapy
(Cardiac Transplant vs. Mechanical Circulatory Support vs. Palliation)

FIGURE 28.1 Algorithm for medical decision-making in patients with end-stage heart failure. Modified from Mehra et al. [23].

extremities, and end-organ dysfunction. These bedside
findings may be further categorized into four prognosti-
cally important hemodynamic profiles on the basis of
adequacy of perfusion (warm versus cold) and measure of
volume overload (dry versus wet) [2]. Patients who are
“cold and wet” represent the most advanced stages of dis-
ease and have a 1 year increased risk of death and need
for cardiac transplantation which is also two times worse
than those who are “warm and dry” [3,4].
The management of heart failure has evolved over the
course of the last two decades toward an evidence-based
strategy incorporating the use of beta-blockers, angioten-
sin converting enzyme inhibitors, or angiotensin receptor
blockers and aldosterone antagonists [5 15]. In addition,
survival and quality of life have significantly improved
with the use of implantable defibrillators and cardiac
resynchronization therapy in eligible patients. However,
the clinical challenge lies in the relative ceiling effect of
the benefits derived from these medical and device-based
therapies [16 18]. Although mortality rates have
improved by the use of disease modifying therapy, with
few exceptions such as fulminant myocarditis or a peri-
partum cardiomyopathy, the etiology of the underlying
cardiomyopathy is generally nonreversible [19,20].
It appears that regardless of inciting injury or disease
process, all cardiomyopathies share a common pathophys-
iological pathway. While our current therapies target the
mediators of neurohormonal imbalance, for reasons still
poorly understood, the impaired ventricle negatively
remodels through a process of dilatation and myocardial
thinning [21]. Clinically, this amounts to persistence and
worsening of symptoms, deteriorating ventricular func-
tion, hemodynamic and electrical instability, and frequent
rehospitalizations, culminating in a medically refractory
state and inevitable death [22].
Stage D heart failure, characterized by a refractory
state of structural heart disease, unrelenting symptomol-
ogy and grave prognosis, often requires the escalation of
medical therapies [1] (Figure 28.1). This typically
requires incremental use of diuretics to relieve conges-
tion, and for the hemodynamically compromised patient,
the judicious use of inotropic therapy either for
temporary relief of congestion or as a longer-term
bridging or palliation strategy to augment a low cardiac
output state. However, symptomatic relief with such
medications does not improve prognosis or reverse the
downward spiral leading to disease progression, and
may hasten patient mortality [24,25]. For some patients,
Chapter | 28 Current Status of Heart Transplantation
marginal blood pressures necessitate the withdrawal of
medications, such as beta-blockers and antagonists of the
renin angiotensin aldosterone system, originally pre-
scribed for their mortality benefit. For others too hemody-
namically compromised, ventricular assist devices
(VADs) have provided a necessary bridge to transplanta-
tion for mechanical circulatory support [26,27]. However,
the arduous path traveled by the heart failure patient
eventually reaches a crossroad at which point a decision
must be made jointly by the patient and their advanced
cardiac care providers as to whether to pursue a path of
palliation and comfort, or to engage in the process leading
to possible cardiac transplantation.
This chapter will outline our current progress and
understanding of cardiac transplantation as a heart
replacement therapy for selected patients with end-stage
heart failure.
28.2 CARDIAC TRANSPLANTATION:
HISTORICAL ACHIEVEMENT
The first successful human cardiac transplantation by Dr.
Christian Baarnard in 1967 ushered in the modern age of
heart replacement therapy [28]. This achievement was the
result of decades of earnest investigation examining surgi-
cal technique and the biology of organ rejection.
Beginning in 1905, the first case of a successful heart
transplant involved the implantation of a canine heart into
the neck of a canine recipient [29]. The transplant donor
organ was anastomosed heterotopically to the recipient’s
cardiopulmonary circulation without removal of the
native heart. In 1964, Dr. James Hardy performed the first
successful xenotransplantation in which the heart of a
chimpanzee was transplanted into a human and was func-
tional for 90 minutes at which point it began to fail [30].
405
FIGURE 28.2 Cardiac transplan-
tation trends according to time and
region. Figure reprinted from [33].
With the development of cardiopulmonary bypass,
improved organ preservation with cardioplegia, and
refinement of surgical technique including orthotopic
transplantation, early investigators were able to improve
graft survival in animal models and recognize the need
for improved immunosuppression.
The success of the first human cardiac transplant was
followed promptly by both a surge in optimism and in the
number of surgeries to at least 100 in 17 countries,
including the first US transplantation by Dr. Norman
Shumway 1 month after Dr. Barnaard’s achievement.
However, poor posttransplant survival, attributed to poor
allograft survival and opportunistic infections, resulted in
contraction in both the number of transplant surgeries and
programs offering them. Yet, not unlike many innovations
in modern medicine requiring refinement of process, the
field was revitalized with the development of endomyo-
cardial biopsies for rejection surveillance [31], improved
immunosuppression strategies primarily involving the use
of cyclosporine [32], and the formation of the United
Network for Organ Sharing (UNOS) to proctor the pro-
curement and allocation of donor hearts to eligible
recipients.
According to the most recent 2012 report from the
Registry of the International Society for Heart and Lung
Transplantation, nearly 4000 heart transplants are now
performed worldwide annually, consistent with trends
over the last decade (Figure 28.2) [33]. Overall, more
than 100,000 heart transplants have been performed since
Dr. Barnard’s seminal surgery. Unfortunately, however,
there continues to be great imbalance in the available
donor heart pool and the number of patients requiring
them, with those in need numbering close to half a mil-
lion in the United States alone [1]. In fact, the number of
patients active on the transplant list has grown by 19.2%
since 2005 [34].
406
TABLE 28.1 Listing Criteria for Cardiac Transplant
Indications
Anticipated poor 1 year survival
Advanced symptoms (NYHA Class IV) refractory to medical
therapy
Peak VO2 , 12 mL/kg/min with beta-blockers; ,14 mL/kg/min
without beta-blockers
Refractory angina not amenable to revascularization
Intractable arrhythmia not amenable to pharmacotherapy,
ablation, or defibrillator therapy
Contraindications
Absolute
Fixed pulmonary hypertension
Pulmonary artery systolic pressure .60 mmHg
Pulmonary vascular resistance .6 Wood units
Transpulmonary gradient .15 mmHg
Concomitant illness adversely limiting life expectancy
(,2 years)
Malignancy within 5 years
Persistent renal failure despite
medication adjustments or
augmentation of perfusion with inotropes or circulatory
support
Irreversible hepatic dysfunction
Severe obstructive pulmonary disease (FEV1 ,1 L/min)
AIDS with recurrent opportunistic infection
Active disease with multisystem involvement, e.g., SLE,
amyloidosis, sarcoidosis
Relative
Age .72 years
Morbid obesity (BMI . 35 kg/m2)
Diabetes with end-organ involvement
Significant cerebrovascular or peripheral vascular disease
Psychosocial issues
Active substance abuse
Active mental illness
Medical noncompliance
Current smoking habit
Modified from Mehra et al. [41] and Leitz and Mancini [40].
28.3 HEART TRANSPLANT EVALUATION
The heart failure patient being evaluated for cardiac trans-
plantation will typically have a dire prognosis. Death is
anticipated within 1 year despite optimization of medical
therapies that may alter symptom status, ventricular func-
tion, or electrical and hemodynamic instability.
Ambulatory patients typically describe severe functional
limitation with NYHA Class IIIb or IV symptoms. The
severity of hemodynamic compromise is obvious in
patients with cardiogenic shock requiring hemodynamic
support using inotropes, intra-aortic balloon pumps, or
mechanical circulatory assist devices. For such patients, a
cardiac transplant may provide a solution to an otherwise
irreversible process with the hope of an improved quality
PART | IV Heart
and years of life. The challenge for the advanced cardiac
care team is in the identification of those patients who
will be both eligible and capable of benefitting from a
valuable, yet limited, resource.
Based on recently published International Society of
Heart and Lung Transplant (ISHLT) registry data, the
typical transplant patient can be characterized as being
male (76.3%), approximately 54 years of age with an
underlying nonischemic cardiomyopathy (53.8%), and
with medical comorbidities including diabetes (25.4%),
hypertension (44.1%), and prior cardiac surgery (45.4%).
The relative medical acuity of the candidate patient await-
ing transplant is high, as inferred by the use of intrave-
nous inotropes (42.6%) and nearly a majority being
hospitalized at the time of transplantation (44.6%).
Patients requiring left ventricular mechanical support
accounted for 27.3% of transplant patients.
A challenge in prognosticating patients with heart fail-
ure is the lack of concordance between clinical symp-
toms, left ventricular function, and overall functional
capacity. In fact, left ventricular ejection fraction is not
itself a sole listing criteria for cardiac transplant. In 1991,
Mancini and colleagues introduced the utility of peak
oxygen consumption as an objective measure of cardiac
performance and transplant eligibility [35]. In their semi-
nal work, they found that a peak VO2 less than 14 mL/kg/
min was associated with a 1 year mortality rate of less
than 50%. By providing a diagnostic cut-off value, they
were able to conclude that cardiac transplant could be
safely postponed in patients with a peak VO2 greater than
14 mL/kg/min, as their 1 year survival rate was 94%. The
peak VO2 may be further modified by patient characteris-
tics including age, gender, and race, and also by specific
therapies such as beta-blockers [36 39]. Accordingly,
cardiac transplantation may be indicated in patients
with a peak VO2 of less than 14 mL/kg/min, or if on
concurrent beta-blocker therapy, a peak VO2 less than
12 mL/kg/min.
Ultimately, a heart failure patient’s candidacy for
transplant is not as dependent on the burden of indication
but on the identification of any contraindication that may
impair graft function and the recipient’s quality of life
following transplant [40,41]. Table 28.1 highlights the list
of indications and contraindications that may determine
patient eligibility for a heart transplant. As such, each
patient must proceed through a battery of clinical investi-
gations, including a thorough evaluation of their psycho-
logical well-being and social circumstances prior to
transplant listing.
28.3.1 Age and Comorbidites
Patients aged over 70 years are not typically considered
for cardiac transplant, owing primarily to age-associated
Chapter | 28 Current Status of Heart Transplantation
medical comorbidities and anticipated limited life expec-
tancy. However, with longer waiting times for a trans-
plant, there is a concern regarding the distinction and
appropriateness of listing age versus age at transplant that
will need to be addressed with a growing and aging heart
failure population. Screening for medical comorbidities
includes diabetes with end-organ complications, severe
pulmonary disease (FEV ,40%), liver cirrhosis, severe
peripheral vascular disease, and osteoporosis which may
complicate perioperative outcomes and limit overall life
expectancy. For similar reasons, caution is exercised in
listing patients with extremes of body mass index
(BMI . 35 kg/m2 and ,18 kg/m2). However, age alone is
no longer an absolute contraindication for cardiac trans-
plantation with several centers having expanded their age
limits or considered using alternative lists where older or
marginal donors who may otherwise not be used for tradi-
tional candidates are paired with older recipients.
28.3.2 Chronic Kidney Disease
Renal failure is common among patients with end-stage
heart failure stemming from systemic disease including
diabetes, hypertension, and atherosclerosis, or from
complex cardiorenal interactions. Efforts to ensure that
renal function is not a consequence of impaired perfu-
sion typically employ a trial of inotropic therapy, an
intra-aortic balloon pump, or mechanical circulatory
support. However, patients with a persistently elevated
creatinine ( . 2.0 mg/dL), particularly with significant
proteinuria, are deemed ineligible for a heart transplant
in isolation. A key posttransplant issue is the near auto-
matic deterioration of renal function as a consequence
of particular immunosuppressive medications, particu-
larly calcineurin inhibitors, and its associated risk with
long-term survival. Therefore, collaborative efforts with
renal specialists may be necessary for consideration of
renal biopsies to delineate underlying kidney pathology
and for potential combined listing for both heart and
kidney transplant. The most recent ISHLT registry data
suggest that heart kidney transplants have increased,
but still remain low with a total of only 67 such cases
in 2010 [33].
28.3.3 Malignancy
All patients undergo age-related cancer screening includ-
ing colonoscopy, mammography, and prostate evaluation.
Patients with a history of malignancy require at least 5
years of remission prior to consideration for transplant.
However, the predisposition to skin and lymphoprolifera-
tive cancers by posttransplant immunosuppressive thera-
pies may render a patient transplant ineligible regardless
407
of remission status [42]. More recent guidelines suggest
that at least in some situations where survival from the
cancer is expected to outlast the median survival from
cardiac transplantation, careful consideration to bending
the 5-year remission rule may be followed in close con-
sultation with an oncological team.
28.3.4 Infection
Patients with an active infection at the time of evaluation
are typically deemed transplant ineligible. An evolving
perspective in the field has involved the eligibility for
patients who possess chronic viral infections, e.g., human
immunodeficiency virus (HIV). The risk of opportunistic
infections with immunosuppression, potential drug inter-
actions with antiretroviral therapy, and presumed limits to
HIV-related life expectancy represent a sampling of rea-
sons explaining the relatively few cases of heart trans-
plantation in patients with the disease [43]. However,
renal transplant outcomes in HIV-positive patients are
comparable to those kidney recipients not infected with
the virus [44]. Personal communications from transplant
centers suggest that candidacy for heart transplant may be
limited by under-referral for advanced cardiac therapies
stemming from prohibitive comorbidities and psychoso-
cial circumstances.
Outcomes in cardiac transplant patients with a preex-
isting history of chronic hepatitis B or C viral infection
may be attributed more to the progression of liver disease
rather than allograft failure [45,46]. Routine transplant
evaluations in such patients may involve a liver biopsy to
assess for pathological cirrhosis, or a serum measurement
of viral titers. In the end, however, transplant candidacy
may be determined largely by center experience.
28.3.5 Pulmonary Hypertension
Prior to listing, patients undergo right heart catheterization
for the assessment of pulmonary pressures. An absolute
contraindication, fixed pulmonary arterial hypertension
can lead to the development of acute right ventricular fail-
ure of the donor heart not accustomed to the severity of
such an afterload. The degree of reversible pulmonary
hypertension is evaluated using pulmonary vasodilators,
including adenosine, prostacyclin, nitroprusside, or nitric
oxide; or inodilators such as milrinone or dobutamine.
Pulmonary hypertension is contraindicated in patients who
maintain a transpulmonary gradient greater than 15, a pul-
monary systolic pressure greater than 50 mmHg or the
indexed pulmonary vascular resistance exceeds 6 Woods
units, despite a vasodilator challenge while maintaining a
systemic pressure greater than 85 mmHg [41].
408 PART | IV Heart

TABLE 28.2 UNOS Status Definitions for Cardiac Transplant Listing According to Medical Urgency

Status Definition
Status 1A A. Acute inpatient mechanical circulatory support
Left and/or right Ventricular Assist Device ( VAD)a
Total Artificial Heart (TAH)
Intra-aortic balloon pump
Extracorporeal Membrane Oxygenation (ECMO)
B. Mechanical circulatory support with device-related complications
Thromboembolism
Device infection
Mechanical failure
Life-threatening ventricular arrhythmias
“Other” complications with approval from a respective cardiac transplant regional review board
C. Continuous mechanical ventilation
D. Continuous infusion of either
i. a single high-dose intravenous inotrope or
ii. multiple intravenous inotropes
plus continuous hemodynamic monitoring of intracardiac pressures using a pulmonary artery catheter

Status 1A Exception Medical urgency despite failure to meet any of the aforementioned criteria
Requires approval from a respective cardiac transplant regional review board
Status 1B Transplant candidate discharged home with either
i. left and/or right VAD or
ii. continuous infusion of intravenous inotropes.
Status 2 Transplant candidate who does not meet the criteria for Status 1A or 1B
Status 7 Inactive on the transplant list despite eligibility due to prohibitive medical or social circumstance
a
Eligible to maintain 1A status for up to 30 days postimplantation.

28.3.6 Psychosocial Functioning
Psychological health and social circumstances are major
determinants of transplant eligibility, even after medical
clearance. Active substance abuse is an absolute contrain-
dication to transplant. While programs vary in their absti-
nence periods, patients are typically challenged to remain
substance free for a period of 6 months. The data is clear
in demonstrating that smoking has a deleterious impact
on graft rejection and mortality posttransplant [47].
Psychological function and overall emotional stability are
evaluated due to their relationship with adherence to med-
ical regimens and self-care, which ultimately impact
rejection status, morbidity, and mortality following trans-
plant [48].
28.3.7 Sensitization
Rejection adversely affects transplant outcomes. As will
be outlined, rejection may be cellular or antibody-
mediated or mixed, with the consequence of graft dys-
function or more severely, overt graft failure. Antigenic
exposure through blood products, pregnancy, VADs, and
prior transplantation sensitizes the recipient by increasing
their risk for the development of preformed antibodies
against donor human leukocyte antigens (HLA). Prior to
active transplant listing, programs often subject their sen-
sitized patients to immunomodulating therapies to lessen
the risk of anticipated rejection within a given donor
pool. These strategies include intravenous immunoglobu-
lin, plasmapheresis, and rituximab to reduce the burden
of preformed antibodies, and in so doing, desensitize the
patient.
28.4 LISTING STATUS
Once deemed eligible, patients in the United States are
listed for cardiac transplant with a priority status in keep-
ing with their medical urgency in accordance with UNOS
guidelines. As highlighted in Table 28.2, Status 1A
patients are considered of the highest priority due to the
severity of their overall clinical acuity. These ICU-bound
patients typically require hemodynamic support with a
mechanical circulatory assist device, an intra-aortic bal-
loon pump, or multiple inotropes with an in situ pulmo-
nary artery catheter for hemodynamic tailoring. Status 1B
may require the use of a mechanical circulatory assist
Chapter | 28 Current Status of Heart Transplantation
device but are typically ambulatory and not admitted to
hospital. Status 2 patients do not meet criteria for Status
1A or 1B listing, and Status 7 patients are typically those
eligible for transplant but not active on the list due to the
development of a clinical circumstance that would make
either the surgery or posttransplant outcome deleterious,
including active infection, stroke, or prohibitive obesity.
28.5 THE IDEAL DONOR HEART
The availability of a donor organ is typically the result of
a fatal accident or self-induced trauma leading to brain
death, but with preserved viability of the heart. Despite
the limited number of donor organs available, appropriate
selection is still necessary to ensure favorable posttrans-
plant outcomes for the recipient. At the time of organ
donation, the potential donor heart is evaluated for mar-
kers of abnormal function and the medical comorbidities
of the deceased. While no single parameter ultimately dis-
qualifies a potential donor, consensus must be reached by
the transplant team taking into account the totality of
such variables.
28.5.1 Donor Characteristics
Initial considerations focus on donor age, mechanism of
death, high-risk social behaviors, and an ongoing assess-
ment of the clinical requirements to ensure preservation
of organ function in the deceased. Even though an upper
age limit has not been defined, current guidelines recom-
mend the use of donor hearts less than 45 years of age,
namely due to the concern for age-related changes to the
heart that may impact long-term graft function. However
due to donor organ scarcity it is not uncommon to extend
this boundary. Death of the donor typically arises from
toxic overdoses or brain death resulting from trauma,
anoxia, or fatal cerebrovascular accident. Although some
studies suggest that traumatic brain injury may portend
poorer long-term survival among transplant recipients,
such a mechanism of death is nonprohibitive [49,50].
However, there is greater concern for death resulting
from toxicity as the transplant outcome data are limited.
Drug abuse, incarceration, and lifestyle practices that pre-
dispose to communicable disease such as HIV and hepati-
tis B and C, must be explored. Current consensus enables
the use of donor hearts from individuals involved in such
high-risk social behaviors as the long-term outcomes
from smaller studies are not necessarily worse. However,
due to the implicit transmissible infectious risks derived
from such patients, careful screening is necessary at the
time of transplant evaluation, in addition to informed con-
sent from the recipient.
409
28.5.2 Evaluation of the Donor Heart
For those hearts obtained from donors older than 40 years
of age, concomitant coronary artery disease should be
ruled out due to its predilection for the development of
coronary allograft vasculopathy and graft failure.
Assessment is made by a coronary angiogram, or if an
invasive evaluation is not feasible, by direct palpation of
the coronary arteries during organ procurement surgery.
While valvular disease is not a contraindication to trans-
plant, surgical repair, or replacement of the affected valve
can be undertaken immediately prior to transplantation.
Echocardiography is an important screening tool used to
evaluate the donor heart structure and function. Typically,
regional wall motion abnormalities must be further evalu-
ated for related coronary artery disease or an underlying
cardiomyopathy in the donor heart. Ventricular hypertro-
phy has been attributed to early graft failure and mortality
posttransplant, particularly if the ventricular thickness
exceeds 14 mm. Even though systolic dysfunction may be
considered a contraindication, its presence may reflect the
transient catecholaminergic imbalance attributed to the
patient’s clinical condition and mechanism of death lead-
ing to global myocardial ischemia and ventricular
impairment. Current recommendations prohibit the use of
a potential donor heart requiring escalating inotropic ther-
apy such as dopamine 20 μg/kg/min or equivalent doses
of other catecholamines [42].
Another important consideration for an orthotopic car-
diac transplantation is ensuring that the donor heart
matches the size and hemodynamic needs of the recipient.
Significant complications arise if a donor-recipient mis-
match occurs. A large donor heart may not permit closure
of the chest wall, and an undersized heart may not ade-
quately perfuse a larger recipient. Consequently, current
guidelines recommend that the weight of donor patient be
no less than 30% below that of the recipient [42].
28.6 PERIOPERATIVE MANAGEMENT
28.6.1 Graft Preservation and Optimizing
Ischemic Time
A major determinant of early transplant outcomes and
overall right ventricular function is the duration of ische-
mic time. Typically, measured from the instance of aortic
cross-clamping at the time of organ procurement until
which time the donor heart is perfused within the recipi-
ent, there is consensus that this duration not exceed 4 h.
This single variable has helped form the basis of geo-
graphical territories from which a given transplant candi-
date’s donor pool resides.
The donor heart is immediately subjected to hypoxic-
ischemic injury at the time of explantation, followed by
410
the risk of reperfusion injury in the posttransplant period.
Current strategies for graft preservation focus on curbing
the perturbations in cellular, tissue, and metabolic distress
associated with these surgical events. To this end, the
donor organ is maintained hypothermic by direct applica-
tion of ice and a cold perfusate, such as the University of
Wisconsin preservation solution consisting of potassium,
magnesium, and free radical scavengers, lactobionate and
raffinose, to achieve homeostasis of electrolytes and limit
myocardial injury [51].
Investigations are ongoing with the use of perfusion
systems to improve donor organ integrity and preserva-
tion across longer ischemic times. Already approved in
Europe, the Transmedics Organ Care System is currently
being studied to compare its perfusion system that sup-
plies the donor heart with warm, nutrient-enriched, oxy-
genated blood with that of conventional cold preservation
techniques. Such strategies may potentially reduce ische-
mic injury and broaden the donor pool across a wider
geographical region for eligible transplant candidates.
28.6.2 Early Postoperative Care
As with all high-risk surgical patients, the early posttrans-
plant period can be marked by challenges in cardiopulmo-
nary stability, surgical bleeding, infection, and recovery of
end-organ function. Generation of an adequate cardiac
output and perfusion pressure may be limited by allograft
function and postoperative vasodilatory shock. In addition
to preexisting comorbidities, ischemic time, and quality of
graft preservation, historical evidence suggests that donor
heart inotropic and chronotropic reserve may be furthered
impaired by sympathetic denervation and myocardial
depletion of stored catecholamines [52,53]. Invasive moni-
toring using pulmonary catheters may facilitate hemody-
namic tailoring according to intracardiac and systemic
pressures, mixed venous oxygen saturations, and
calculated cardiac outputs. Epinephrine, norepinephrine,
and dobutamine are classically infused to provide adrener-
gic support to the systemic circulation. For patients with
elevated central venous pressures, milrinone, a
phosphodiesterase-3 inhibitor, may be added to the inotro-
pic regimen for enhanced myocardial contractility and
reduction of right ventricular afterload due to its pulmo-
nary vasorelaxant properties. In cases of low systemic vas-
cular resistance, vasopressin or phenylephrine may
provide necessary pressor support to maintain an adequate
perfusion pressure [42].
The heart rate of the denervated heart is classically
tachycardic. However, sinus node dysfunction attributed
to graft ischemia, trauma, or inherent donor heart
pathology may result in relative chronotropic incompe-
tence in the early postoperative period following trans-
plantation. Isoproterenol and theophylline have been
PART | IV Heart
recommended to maintain heart rates greater than
90 bpm. Atrioventricular pacing may be required in the
event of medical nonresponsiveness [42].
Persistent hypotension necessitates evaluation for car-
diac tamponade, graft dysfunction, and contributes to a
vasodilatory state such as infection.
28.6.3 Cardiac Allograft Function
For the transplant patient, there is heightened vigilance
for early graft dysfunction attributed to either (i) right
ventricular failure, (ii) primary graft failure, (iii) hyper-
acute rejection, or (iv) acute cellular rejection.
28.6.4 Right Ventricular Failure
Right ventricular dysfunction of the donor heart may arise
as a manifestation of primary graft failure. However, high
pulmonary vascular pressures, excessive volume loading,
and periprocedural factors including direct injury and pro-
longed ischemic times can compromise the right ventricu-
lar function of a normal donor heart. In addition, multiple
factors can lead to an acute rise in pulmonary vascular
resistance in recipients with no prior history of pulmonary
arterial hypertension. Increased pulmonary vascular tone
can develop from hypoxemia, unrecognized intracardiac
shunts and postoperative lung atelectasis, pleural effu-
sions, and infection. Defined hemodynamically, right ven-
tricular failure is characterized by an elevated right atrial
pressure (.20 mmHg), and a low cardiac output in
the absence of high left ventricular filling pressures.
Additional features include hepatic congestion marked by
a transaminitis and hyperbilirubinemia, worsening renal
failure, and normal to low pulmonary pressures due to
poor systolic function of the right ventricle. Management
is typically supportive while monitoring for ventricular
recovery. Strategies range from right-sided afterload
reduction with pulmonary vasodilators, including inhaled
nitric oxide, prostaglandins, or phosphodiesterase
inhibitors; chronotropy achieved pharmacologically with
beta-agonists or with cardiac pacing, and mechanical cir-
culatory support using right VADs.
28.6.5 Primary Graft Failure
Primary graft failure refers to a state of severe cardiac
dysfunction resulting in profound circulatory insuffi-
ciency within the first 24 h following transplantation. It is
defined by a low cardiac output despite adequate filling
pressures, and may arise from either univentricular or
biventricular failure following exclusion of conditions
with similar hemodynamic profiles including hyperacute
rejection and cardiac tamponade. Risk factors for the
development of primary graft failure can be attributed to
Chapter | 28 Current Status of Heart Transplantation
FIGURE 28.3 Acute cellular rejection. Hematoxylin-eosin staining
demonstrating lymphocytic infiltration (thick arrow), and myocyte swell-
ing and necrosis (thin arrows). Image courtesy of Dr. Robert Padera,
Brigham and Women’s Hospital, Boston, MA.
donor, recipient, and perioperative conditions including
older age, inotropic requirements prior to surgery, renal
failure, and graft ischemic time [54,55]. Primary graft
failure is the main cause of 30 day mortality following
transplantation accounting for 39% of all deaths within
this period and nearly 20% within the first 12 months
[56]. Allograft management is supportive while efforts to
restore end-organ perfusion range from aggressive medi-
cal therapy using inotropes and vasopressors, to mechani-
cal circulatory support with intra-aortic balloon pumps,
extracorporeal membrane oxygenation (ECMO), or VADs
to assist either left, right, or to both ventricles [57,58].
Cardiac recovery has been reported to occur within 24 h
and up to 7 days following hemodynamic support [58].
28.6.6 Hyperacute Rejection
Hyperacute rejection represents the most severe of immu-
nological reactions against the donor heart. Graft failure
arises within minutes to hours following transplantation.
Circulating antibodies within the recipient target the HLA
class I molecules within the donor heart vascular endothe-
lium. The consequent inflammatory response leads to
near immediate graft ischemia and necrosis. While
explantation of the donor heart is the only treatment
option, patient mortality is inevitable.
28.6.7 Acute Graft Rejection
Acute cellular rejection is mediated by T-lymphocytes
and can occur as early as within days of transplant, or as
late as several years following. Diagnosis is made by tis-
sue biopsy and can occur in up to 40% of patients within
the first year of transplant. Severity is assessed using
411
TABLE 28.3 ISHLT Acute Cellular Rejection Grades
Rejection Grade Description
None 0 Normal myocardium
Mild 1R # 1 focus of interstitial or perivascular
lymphocytic infiltration with myocyte
damage
Moderate 2R $ 2 foci of lymphocytic infiltration with
myocyte damage
Severe 3R Diffuse lymphocytic infiltration
Evidence of myocyte damage, edema,
hemorrhage, or vasculitis
ISHLT grades of rejection (IR, 2R, and 3R) on the basis
of degree of lymphocytic infiltration and myocyte necro-
sis (Figure 28.3; Table 28.3). However, recent ISHLT
registry data suggests that the threshold to treat rejection
appears to be rising with a 10% decline over a 5-year
period in the treatment of mild rejection occurring within
the first year of transplant [56]. As such, treatment is typi-
cally reserved for moderate to severe rejection and may
consist of pulse corticosteroids, use of cytolytic therapy,
or changes in calcineurin and antiproliferative exposure.
Antibody-mediated rejection (AMR) is characterized
by the adverse humoral response of preformed circulating
antibodies directed against antigens within the cardiac
allograft that can occur days to weeks after transplantation.
Risk factors include prior blood transfusions, multiparity,
pretransplant use of VADs, previous antibody exposure
and retransplantation [59]. AMR is a significant risk factor
for poor long-term transplant outcomes, including sur-
vival, graft failure, and the development of coronary allo-
graft vasculopathy [60,61]. A tissue diagnosis specifically
requiring immunostaining against C4D, which represents a
degradation product of activated complement C4b and is a
marker of antibody activity (Figure 28.4). A mechanistic
approach to the treatment of AMR targets the
inactivation and elimination of circulating antibodies, the
suppression of T- and B-lymphocytes, plasma cell deple-
tion, and complement inhibition (Figure 28.5) [62].
28.7 IMMUNOSUPPRESSION STRATEGIES
AND REJECTION SURVEILLANCE
Immunosuppressive therapy is required to abate the cell-
mediated and humoral immune responses that are directed
against the donor heart. Although a thorough elaboration
of transplant immunology and pharmacology extends
beyond the focus of this chapter, a guiding principle gov-
erning immunosuppression aims to optimally reduce the
incidence of transplant rejection without incurring the
412 PART | IV Heart

FIGURE 28.4 Antibody-

mediated rejection. Hematoxylin-
eosin staining (left) and C4D
staining (right). Images courtesy
of Dr. Robert Padera, Brigham
and Women’s Hospital, Boston,
MA.

Inhibition of circulating
antibodies

Intravenous immunoglobulin

T-cell suppression
Elimination of
circulating antibodies Calcineurin inhibitors
purine synthesis inhibitors
mTOR inhibitors
Plasmapheresis
IL-2 antibody
Plasma exchange
Antibody-mediated
rejection

(AMR)

Complement inhibition B-cell suppression

Eculizimab Rituximab
Splenectomy
Calcineurin inhibitors

Plasma cell depletion

Bortezomib

FIGURE 28.5 Targeted treatment of antibody-mediated rejection. Modified from Nair et al. [62].

untoward consequences of over-suppression, including
opportunistic infection and malignancy risk. Current
approaches to immunosuppression are guided by limited
clinical trials and largely by institutional and transplant
provider experience.
28.7.1 Induction Therapy
Induction therapy refers to the strategy in which an immu-
nomodulating agent is administered to a highly sensitized
recipient immediately prior to transplant to reduce the risk
of acute rejection. Such patients are known to have pre-
formed circulating antibodies, including African
Americans, younger patients, and those with a history of
pregnancy, prior sternotomy, or mechanical circulatory
support [59]. Alternatively, induction agents have been
used as an intermediary antirejection therapy in those
patients in whom renal insufficiency renders initiation of a
calcineurin inhibitor prohibitive. Historically, induction
therapy was implemented as a panacea to promote
immune tolerance; however, its contemporary use has
remained controversial [63]. An observed incidence of
Chapter | 28 Current Status of Heart Transplantation
malignancy, including posttransplant lymphoproliferative
disorder (PTLD) [64], in addition to cytomegalovirus and
fungal infections [65,66] have limited its general use to
approximately only half of all transplant centers [56].
OKT3, a murine antithymoctye monoclonal antibody,
targets the CD3 receptor of human T-cells rendering it
vulnerable to opsonization and clearance by circulating
macrophages. However, its use has largely been elimi-
nated due to intolerable side effects, including a cytokine
release syndrome manifesting as fever, nausea, emesis,
chest pain, and dyspnea [67], and its association with the
delayed emergence of PTLD and opportunistic infections
in a dose-dependent manner [68]. More commonly, poly-
clonal antithymocyte antibodies, including the horse-
derived ATGAM and rabbit-based ATG, are implemented
as induction agents due to a greater potency in reducing
T-lymphocytes without increasing long-term PTLD
malignancy risk [69,70].
IL-2 receptor antagonists, including basiliximab and
dacluzimab, also confer immune tolerance by the deple-
tion of circulating T-lymphocytes. Basiliximab, a
chimeric human/mouse antibody, has been shown to be
well tolerated as compared to placebo in de novo trans-
plant patients treated concomitantly with cyclosporine,
mycophenolate mofetil (MMF), and steroids when admin-
istered on Day 0 and Day 4 posttransplant [71]. When
compared to OKT3 in the randomized multicenter com-
parison of Basiliximab and Muromonab (OKT3) in heart
transplantation (SIMCOR) trial, basiliximab was found to
have greater tolerability with similar rates of infection,
severity of rejection, and actuarial survival [72]. In com-
parison to polyclonal antibody therapy with antithymo-
cyte globulin, additional studies have found basiliximab
to have similar efficacy in composite endpoint and fre-
quency of acute rejection (Grade $ 1R), and better safety
endpoints including infectious death [73]. However, such
results have been contradicted by other findings suggest-
ing that while ATG may have greater infectious risk,
basiliximab was not a superior prophylactic against acute
rejection [74].
The induction benefit of dacluzimab was studied in a
placebo-controlled randomized trial involving 434 new
transplant patients who were concomitantly treated with
cyclosporine, MMF, and corticosteroids [75]. Despite a
reduction in acute cellular rejection, the increased rate of
infection-related mortality signaled the death of dacluzi-
mab, leading to its subsequent withdrawal from market
production.
28.8 MAINTENANCE
IMMUNOSUPPRESSION
Three classes of medications are typically instituted
early after cardiac transplantation for maintenance
413
immunosuppression on the basis of supportive clinical trial
evidence: (i) corticosteroids, (ii) calcineurin inhibitors, (iii)
antiproliferative agents. Mammalian target of rapamycin
(mTOR) inhibitors, also called proliferation signal inhibitors,
represent a fourth and lesser utilized class of maintenance
immunosuppressive therapy.
28.8.1 Corticosteroids
Corticosteroids occupy a central role in the acute treat-
ment of rejection, as an induction agent and for chronic
maintenance immunosuppressive therapy. They provide
broad immunosuppression by inhibiting the transcription
of multiple mediators of the posttransplant inflammatory
cascade including IL-1, IL-2, CD40 ligand, TNF-alpha,
gamma interferon, GM-CSF, and related growth factors.
However, concern with side effects, including psychosis,
cushingoid features, hypertension, avascular necrosis,
dyslipidemia, steroid-induced hyperglycemia, and adrenal
insufficiency have led to the consideration of steroid-free
maintenance immunosuppression regimens. Adult and
pediatric studies suggest that overall rates of survival and
rejection are similar to those on corticosteroids [76,77].
However, as in the case of all immunosuppression strate-
gies, withdrawal of steroids is ultimately patient-specific
depending on individual rejection history and chronicity
of steroid use. Current trends demonstrate that steroid use
has gradually declined further out from transplantation
with more than 50% of patients being steroid-free 5 years
posttransplantation [56]. Whether steroid-free immuno-
suppression alters late complications remains uncertain
since low, relatively physiologic, doses are typically used
in long-term survivors that continue maintenance steroids.
28.8.2 Calcineurin Inhibitors
Cyclosporine and tacrolimus inhibit the enzymatic action
of calcineurin which plays an important role in the pro-
duction of multiple cytokines including IL-2. In so doing,
calcineurin inhibitors limit T-cell activation and prolifera-
tion, a fundamental tenet of an immunosuppression proto-
col. Cyclosporine had once been the de facto calcineurin
inhibitor; however, its use has largely been supplanted by
tacrolimus [56]. Although studies have demonstrated sim-
ilar 1 year survival between cyclosporine and tacrolimus
[78,79], the risk of acute rejection was found to be lower
in one clinical trial [80] and further supported by a recent
meta-analysis [81]. Despite similar efficacy, tacrolimus
has a less adverse complication profile favoring its
current use. Cyclosporine use can be complicated by
hypertension, cholelithiasis, dyslipidemia, and gingival
hyperplasia [78 80], in addition to significant drug inter-
actions. Moreover, the results of the TICTAC trial have
414
reinforced the use of tacrolimus as a pivotal agent in any
immunosuppression regimen. In this trial, tacrolimus
monotherapy resulted in a 6 and 12 month freedom from
severe cellular rejection (ISHLT Grade $ 2) of 93.3% as
compared to 92.9% in the tacrolimus/mycophenolate
combination group [82]. In addition, the 3-arm trial com-
paring combination therapies of tacrolimus/MMF versus
tacrolimus/sirolimus versus cyclosporine/MMF found a
lower incidence of treated rejection among patients trea-
ted with tacrolimus [83]. However, tacrolimus can
increase the risk of diabetes and induce neurological com-
plications. In patients with either chronic renal insuffi-
ciency or acute kidney failure posttransplant, delayed
tacrolimus initiation may be necessary and calcineurin
inhibitor-based immunosuppression preempted by induc-
tion therapy.
28.8.3 Antiproliferative Agents
Antiproliferative agents, also known as antimetabolites,
inhibit cell-cycle pathways to limit T- and B-cell prolifer-
ation and thereby reducing the cytotoxic response directed
toward the cardiac allograft. Azathioprine, the original
antiproliferative drug, mediates its effects through a
purine analog metabolite that arrests DNA synthesis once
incorporated into the lymphocytic nuclei. MMF and
mycophenolic acid are reversible inhibitors of the enzyme
inosine monophosphate dehydrogenase. This enzyme
serves as an important immunosuppression target as it is
both upregulated during T- and B-cell activation and
forms part of an obligate pathway in purine synthesis nec-
essary for their proliferation [84]. Contemporary practice
trends highlight greater utilization of MMF and myoco-
phenolic acid over azathioprine for maintenance immuno-
suppressive therapy [56]. In comparison to azathioprine,
MMF promotes greater survival, less rejection, and less
coronary allograft vasculopathy posttransplant [85 87].
Azathioprine and MMF both can induce significant leuko-
penia from profound bone marrow suppression. MMF can
induce significant gastrointestinal difficulties including
diarrhea, gastritis, and nausea.
28.8.4 mTOR Inhibitors
mTOR is an enzyme kinase that mediates lymphocyte
growth, differentiation, and proliferation. Sirolimus and
everolimus are mTOR inhibitors that in addition to their
effects on T- and B-cells also inhibit the proliferation of
the vascular smooth muscle wall which has broader clini-
cal significance for the treatment of cardiac allograft
vasculopathy (CAV). In comparison to azathioprine, sirio-
limus and everolimus have been shown to have less rejec-
tion and a lower burden of coronary allograft
vasculopathy [88,89]. Sirolimus may be included as part
PART | IV Heart
of a maintenance immunosuppression regimen for those
patients with transplant-related vasculopathy. However,
general mTOR inhibitor use has been limited by their
association with poor wound healing, renal failure, dysli-
pidemia, anemia, thrombocytopenia, and the development
of both pleural and pericardial effusions [88].
28.9 REJECTION SURVEILLANCE
Acute rejection has been reported to occur in 24.5% of
patients within the first year following transplant. Within
5 years, 50.9% of all transplant patients experience at
least one episode of acute rejection [34]. Therefore, each
institution has its own schedule and methodology for
rejection monitoring. Biopsy-proven rejection, particu-
larly those categorized as mild in severity, largely occurs
in the absence of symptoms or even allograft dysfunction.
Rejection may present clinically across a spectrum to also
include new onset brady- or tachyarrhythmias manifesting
as palpitations or more significantly as syncope, the
reemergence of heart failure symptoms due to a failing
graft, or even sudden cardiac death [90]. Symptom-
rejection mismatch consequently results in measures of
routine surveillance requiring the transplant patient to
undergo a potential battery of testing modalities to moni-
tor for cardiac allograft rejection.
28.9.1 Endomyocardial Biopsy
Historically, noninvasive markers, including cardiac
enzymes or low QRS voltage on surface electrocardio-
gram due to myocardial edema or fibrosis, have been
used to signal subclinical rejection. Endomyocardial
biopsy (EMB) remains the contemporary gold standard
for monitoring of graft rejection. Tissue samples are
obtained from the right ventricular septum using a biop-
tome introduced through the right internal jugular vein,
typically under fluoroscopy or by echocardiographic guid-
ance [91]. The additional use of a right heart catheter
facilitates the measurement of intracardiac pressures and
cardiac output. As an invasive procedure, EMBs carry a
complication risk of 0.5% in some reports [92,93].
Complications may arise from central venous access
including inadvertent arterial puncture, bleeding, and
pneumothorax. Alternatively, injury may result from the
biopsy itself including cardiac perforation leading to tam-
ponade, arrhythmia, and accidental sampling of tricuspid
valve leaflets leading to significant valvular regurgitation
[94]. Tissue biopsy yields invaluable information regard-
ing the presence of rejection, type (cellular versus anti-
body), severity, and chronicity, in addition to pathological
tissue changes suggestive of CAV. While institutional
practice may vary, typical biopsy schedules include
EMBs performed weekly for the first 4 weeks with a
Chapter | 28 Current Status of Heart Transplantation
tapered frequency over the course of the first 12 months
following transplant. Beyond the first year, EMBs are
performed annually, or as motivated by patient symptoms.
Some programs advocate cessation of routine biopsy sur-
veillance after the first 2 years of transplant with similar
reported outcomes to those of continued intensive
surveillance.
28.9.2 Biomarker Tests
Gene expression profiling is an alternative noninvasive
strategy to assess for the absence of acute cellular rejec-
tion [95 97]. With one such technique, Allomap (XDS),
RNA from peripheral blood mononuclear cells is isolated
and amplified using polymerase chain reaction (PCR)
techniques to facilitate gene expression profiles of 11
genes known to distinguish between rejection and nonre-
jection in posttransplant patients. A score ranging from 0
to 40 is tabulated using an algorithm based on candidate
gene expression levels. A score less than 30 has a nega-
tive predictive value for biopsy-proven cellular rejection
of 99.6% [95] and is deemed to obviate the need for an
EMB. Although promising, the technique has been lim-
ited by a lack of high specificity and the inability to dis-
tinguish between cellular and antibody-mediated rejection
[98]. In the IMAGE trial [95], the use of this gene expres-
sion profiling biomarker was shown to decrease the num-
ber of biopsies required in surveillance while maintaining
clinical outcomes. However, some have argued that the
gold standard of surveillance biopsies beyond 5 months
may itself be a flawed technique and appropriate compari-
son of the noninvasive biomarker ought to rest on its
incremental value to clinical and allograft functional
based monitoring. The cost-effectiveness of this approach
remains uncertain as does its overall routine use in clini-
cal practice [99].
ImmuKnow (Cylex Inc.) is an immune function assay
which tests the ATP production from a transplant
patient’s isolated T-lymphocytes [100]. By exposing these
cells to a T-cell mitogen, plant phytohemaglutinin, mea-
sured ATP can identify those patients who may be either
excessively or inadequately immunosuppressed. In addi-
tion to tailoring immunosuppression, the assay may be
able to predict patients at high risk for graft rejection.
However, its adoption into mainstream transplant practice
is pending larger-scale clinical trial data. Current observa-
tional evidence suggests that its ability to predict infec-
tion may be greater than its ability to inform on rejection.
28.10 TRANSPLANTATION OUTCOMES
One year life expectancy following heart transplant
ranges from 79% to 86% depending on the underlying
cardiomyopathy of the recipient, with nonischemic
415
etiologies of the highest survivorship. In 2011, the rate of
graft failure within the first 6 weeks posttransplant
improved to 4.9% as compared to previous reports [34].
Risk factors for death within the first year include graft
ischemic times greater than 200 min, extremes of recipi-
ent age, and a pretransplant requirement for mechanical
circulatory support. When stratified according to the first
3 years posttransplant, causes for early death are predomi-
nantly associated with graft failure and overwhelming
infection. Beyond 3 years, mortality is attributed to malig-
nancy and the development of CAV [56]. Overall graft
survival at 5 years approximates 74.9% regardless of
medical urgency (Status 1A, 1B, or 2) or underlying heart
failure etiology [34]. For those patients surviving their
first year posttransplant, data from the Scientific Registry
of Transplant Recipients suggest that their predicted half-
life is 14.0 years. In fact, both graft and patient outcomes
have continued to improve with 21,457 survivors living
in 2011 as compared to 16,259 in 2001 [34], with improv-
ing trends over the last three decades (Figure 28.6).
Posttransplant morbidity is typically associated with
renal failure, malignancy, acute rejection, and CAV [56].
Patients have an increasing risk of renal failure over time
following transplant with an incidence of 6%, 11%, and
16% at 1, 3, and 5 years posttransplant, respectively. Risk
factors include pretransplant recipient comorbidities of
increasing age, history of diabetes, and the preexistence
of an elevated serum creatinine. Within the first year
posttransplant, mortality is typically attributed to acute
rejection, infection, and graft failure. At 5 and 10 years
posttransplant, the mortality burden arises from malig-
nancy contributing to over 20% of deaths with an inci-
dence of 6% and 15%, respectively (Figure 28.7). Skin
cancer is the most common malignancy in the transplant
patient. Other malignancies include lymphoproliferative
disorders and cancers of the prostate, lung, bladder, kid-
ney, breast, and colon. Risk factors include recipient age
and long-term immunosuppression [42].
28.10.1 Cardiac Allograft Vasculopathy
CAV remains the most indolent long-term complication
affecting the donor heart coronary vasculature following
transplantation. Unlike an atherosclerotic plaque, CAV is
classically characterized by the diffuse and progressive
proliferation of the intimal layer of the arterial wall and
can extend from epicardial vessels to deep penetrating
resistance arterioles and capillaries (Figure 28.8).
However, the remodeling process involves all three layers
of the vascular wall and is influenced by adventitial scar-
ring and alterations in medial tone. These hyperplastic
lesions can lead to luminal narrowing sufficient to
obstruct coronary blood flow. Although episodes of cellu-
lar and antibody-mediated rejection have been associated
416 PART | IV Heart

100
1982–1992vs. 1993–2002: p < 0.0001
1982–1992vs. 2003–6/2002: p < 0.0001
1993–2002vs. 2003–6/2010: p < 0.0001
80
Survival (%)

60

1982–1992 (N = 25, 138)

1993–2002 (N = 37, 193)
40
2003–6/2010 (N = 24, 021)

20

Median survival: 1982–1992: 8.5 years: 1993–2002: 10.9 years: 2003–6/20120: NA

0
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
Years

FIGURE 28.6 Cardiac transplant survival curves according to transplant era. Figure reprinted from [33].

100
Acute rejection CAV Graft failure
90 Renal failure Infection (Non-CMV) Malignancy
80

70 11
20
23 23
% of deaths

60 3
0 14
50 2 11
13
29 12 11
40 0 4
27 6 9
30 1 25
34 18 16
20 17
10
10 3 10
12 11 13
1 9
4 5 2 1
0
0–30 days 31 days–1 year >1 year – 3 years >3 year – 5 years >5 year –10 >10 Years
(N=1817) (N=1750) (N=1245) (N=1112) years (N=3321) (N=5035)

FIGURE 28.7 Causes of death posttransplant. Figure reprinted from [33].

with CAV, current immunosuppression protocols are lim-
ited in their ability to prevent or delay its
inevitable occurrence. Numerous risk factors have been
associated with the development of CAV including age,
sex, preexisting coronary artery disease, and cytomegalo-
virus infection in both donor and recipient. Most impor-
tantly, the number and severity of acute cellular rejection
predisposes to the development of CAV suggesting that
its predisposition is more likely a manifestation of the
immunogenicity of the cardiac allograft itself.
Mechanistic studies demonstrate that CAV is the inflam-
matory consequence of a vascular remodeling process
mediated by the complex interplay between numerous
cytokines, including interferon-γ and the cellular agents
of innate immunity, such as T-cells, macrophages, and
monocytes. Although 10% of patients can develop CAV
as early as within the first year of transplant, it is as much
a marker of graft survival with a prevalence of greater
than 50% in those patients surviving at least 10 years fol-
lowing transplantation [56].
Coronary angiography remains the gold standard for
the evaluation of CAV. Severity of CAV is classified
according to the degree of luminal narrowing of the
affected vessel (e.g., left main), its associated anatomic
location (proximal versus distal third), and the total num-
ber of vessels involved [60]. Greater severity is ascribed
Chapter | 28 Current Status of Heart Transplantation
to those lesions associated with allograft dysfunction.
This may be the result of systolic impairment with a
measured ejection fraction of less than 45% or with
hemodynamic or echocardiographic indices of restrictive
physiology, if contractility is preserved. Other imaging
modalities that have been employed to evaluate include
intravascular ultrasound (IVUS), myocardial perfusion
scans including technetium-99m sestamibi, dobutamine
stress echocardiography, and multidetector computed
tomography.
CAV prevention includes the use of statins predomi-
nantly for their lipid lower benefit. Small prospective
clinical trials using pravastatin and simvastatin demon-
strated long-term benefits in the reduction of CAV, inti-
mal thickness, and improved patient survival [101 103].
The early initiation of diltiazem, often used to treat corti-
costeroid or cyclosporine-induced hypertension, was also
found to be beneficial in CAV prevention [104].
However, these studies were conducted in the prestatin
era of transplant management. An adjuvant approach to
immunosuppression in patients with documented CAV
consists of the antiproliferative drugs, everolimus and sir-
olimus. In addition to decreasing rejection events, these
drugs have also been shown to reduce CAV [88,89] as
measured by IVUS detection of intimal thickening.
However, issues with poor wound healing, renal failure,
marrow suppression, and drug interaction have limited
their use, and specifically for everolimus, FDA approval.
It is unclear whether the reduction in surrogate parameters
of intimal thickening will indeed be accompanied by
reduced cardiac allograft adverse events.
Revascularization is often limited due to the diffuse-
ness of disease along the coronary vasculature.
Angioplasty by percutaneous intervention may be an
option for patients with single-vessel disease. However,
stent patency may be at risk to restenosis by the same
immune factors directed against the heart. Coronary
bypass surgery is typically limited due to the lack of via-
ble distal vessel targets due to intimal proliferation. Most
417
FIGURE 28.8 CAV—gross tis-
sue specimen (left) demonstrating
significant CAV-related vascular
narrowing of a coronary artery (*)
as compared to an unaffected adja-
cent larger vessel. Intimal prolifer-
ation with near luminal obliteration
(arrow) by hematoxylin-eosin
staining (right). Images courtesy of
Dr. Robert Padera, Brigham and
Women’s Hospital, Boston, MA.
importantly, revascularization does not reduce the burden
of allograft rejection which is the predominant risk
factor for CAV progression [105,106]. As such, retrans-
plantation remains the definitive treatment for severe
CAV in those patients deemed eligible.
28.11 MECHANICAL HORIZON: VADS AS
A BRIDGE TO TRANSPLANT
VADs provide mechanical circulatory support to the fail-
ing heart. Since the initial use of the first artificial heart
device in 1963 for postcardiotomy shock [107], this tech-
nology has evolved to significantly alter the therapeutic
options for patients with end-stage cardiomyopathy.
There has been a proliferation of their use, with over
6000 VADs implanted in the United States [108].
Technological advancements over the last five decades
has led to the development of smaller VADs that can pro-
vide either pulsatile or continuous blood flow to the left,
right, or both ventricles.
VADs have been implanted in patients for any of four
indications. As destination therapy (DT), VADs provide
long-term hemodynamic support for patients who are
deemed transplant ineligible. Bridge to recovery (BTR)
refers to the strategy by which VADs are implanted in
patients with significant cardiac decompensation but antic-
ipated myocardial recovery, such as postcardiotomy
shock, peripartum cardiomyopathy, or fulminant myocar-
ditis. For transplant candidates awaiting heart replacement,
VADs are used as a bridge to transplantation (BTT).
Bridge to candidacy (BTC) represents a growing popula-
tion of patients implanted with VADs who, although ini-
tially deemed transplant ineligible, are afforded both the
benefits of time and augmented perfusion to enable a
reconsideration of their transplant status.
Initial US FDA approval for BTT VADs took place in
1994 with older generation devices. Since 2006, data
from the Interagency Registry for Mechanically Assisted
418
Circulatory Support (INTERMACS) demonstrate that at
least 1600 VADs were implanted over a 5 year period of
time (2006 2011) as a bridge to transplant strategy.
ISHLT registry data also reveal that 36% of patients
transplanted in 2010 were supported with mechanical cir-
culatory devices reflecting a rising trend in transplant can-
didates with BTT VADs [109] (Figure 28.9).
The predominant contemporary VAD in use is the
HeartMate II (Thoratec, Pleasanton, CA) which provides
left ventricular support for patients for either DT or as a
BTT. It gained FDA approval in 2008 after pivotal clini-
cal trial findings demonstrating improved symptoms sta-
tus, functional capacity, and a 68% 1-year survival rate
following implantation in patients awaiting a heart trans-
plant [110]. More recently, the Heartware Ventricular
Assist Device (HVAD, Framingham, MA) was granted
FDA approval as a BTT strategy following results of the
ADVANCE trial that demonstrated an 86% 1-year sur-
vival rate with improved quality of life parameters in
patients awaiting transplant [26]. Smaller than the
HeartMate II, the HVAD can be surgically implanted
within the intrapericardial space to provide left ventricu-
lar support. However, as left ventricular support devices,
both require a relative preservation of right ventricular
PART | IV Heart
FIGURE 28.9 Use of mechanical
circulatory support (biventricular and
univentricular devices) as a “bridge”
to cardiac transplant. Figure reprinted
from [33].
FIGURE 28.10 VADs currently
FDA approved as a bridge to cardiac
transplantation: Thoratec HeartMate
II LVAD (Pleasanton, CA; left);
HeartWare VAD (Framingham,
MA; middle); Syncardia Systems
Total Artificial Heart (Tuscon, AZ;
right).
function. Unfortunately, such devices are inadequate in
patients with biventricular failure. The total artificial heart
(TAH, Syncardia) provides biventricular mechanical sup-
port. It is true heart replacement therapy as the surgery
requires excision of both right and left ventricles such
that the device can be anastomosed to both atria. In its
clinical trial, patients with the TAH had a 70% 1-year
survival rate and a 79% survival to transplant [111,112]
(Figure 28.10).
Despite clinical benefits and improved survivorship
while waiting for transplant, VAD-related complications
including device failure, infection, and cerebrovascular
events due to embolic strokes or hemorrhage may com-
promise transplant candidacy. In addition, device mainte-
nance requires anticoagulation which can further
compound bleeding diatheses that can result from an
acquired von Willebrand disease and neovascular forma-
tions that arise as consequences of nonpulsatile VAD
flow [113,114]. Excessive blood loss may require transfu-
sions that increase sensitization risks and consequent
allograft rejection or failure [115]. Impact of LVAD ther-
apy on transplant survival has been controversial
[110,116]. Recent data, however, suggest patients, previ-
ously supported with continuous flow VADs, who survive
Chapter | 28 Current Status of Heart Transplantation
beyond the initial 6 months posttransplant, have similar
long-term survival outcomes as compared to conventional
transplantation [56,117].
The era of mechanical circulatory support has also
afforded those patients with DT devices, the opportunity
for transplant reconsideration. At least 10% patients with
DT VADs, originally intended a palliative therapy, were
transplanted within 12 months following implantation
[109]. In fact, the benefits of improved hemodynamics
and organ perfusion by mechanical circulatory support
have rendered the distinction between absolute and rela-
tive contraindication less dichotomous. Traditional exclu-
sion criteria, such as renal failure and pulmonary
hypertension, have been found to be “VAD-modifiable”
due to mechanical unloading and improved cardiac output
[118]. Improved survival with the VAD also affords valu-
able time for reevaluation of other modifiable contraindi-
cations including smoking, illicit drug and alcohol abuse,
BMI, and patient attitude toward transplant. To this end,
from 2006 to 2011, 1765 VADs were implanted in
patients as a BTC allowing more individuals the opportu-
nity for a new heart [109].
28.12 FUTURE DIRECTIONS IN CARDIAC
TRANSPLANTATION
In 2010, the National Heart, Lung, and Blood Institute
Working Group convened to outline research strategies
that will ultimately improve the clinical decision-making
required in the evolving care of cardiac transplant patients
[119]. Over the next 10 years, research efforts will be
encouraged to improve long-term allograft outcomes, fos-
ter tailored immunotherapy, and expand the available
donor pool through improved graft preservation strategies
and marginal candidate optimization. In addition,
advancements in the field will require robust clinical
trials that explore mechanisms and treatment of humoral
and cellular-mediated rejection. This is in addition to the
need for technological advances in both mechanical circu-
latory support and stem cell therapies that may promote
true cardiac regeneration.
28.13 CONCLUSION
The management of end-stage heart disease has evolved
with our improved understanding of its complex patho-
physiology. Since the first heart transplant in 1969, the
field of cardiac transplant medicine continues to evolve.
In the end, however, the promise of heart replacement
therapy is limited foremost by its availability. Until such
time as more effective global donor promotion strategies
are in place, our sights must rest upon a horizon in which
mechanical circulatory support devices and stem cell-
419
based therapies hold greater promise for those with end-
stage heart disease.
ACKNOWLEDGMENTS
We express our sincere gratitude to Dr. Robert Padera for contribut-
ing pathological figures to supplement this manuscript.
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