Given the relative scarcity of donor organs, it is essential to determine if end-stage HF patients are truly refractory to maximal medical therapy and merit transplant evaluation. The commonly acceptable indications for heart transplantation are shown in Table 72–1. Generally, the three major indications for heart transplantation are severe functional limitations, refractory angina, and ventricular arrhythmias refractory to maximal medical therapy.13 The most common indication for heart transplantation is intractable HF. Patients with severe angina in the absence of HF are often not considered, since the survival benefit is unclear. Intractable ventricular arrhythmias, commonly referred to as “VT storm,” may merit heart transplant evaluation and often urgent listing given the associated hemodynamic compromise and mortality.
TABLE 72–1.Commonly Accepted Indications for Cardiac Transplantation ||Download (.pdf) TABLE 72–1. Commonly Accepted Indications for Cardiac Transplantation
|Systolic heart failure with severe functional limitations or refractory symptoms despite optimal medical and device therapy |
| NYHA functional class IIIb-IV |
LVEF usually < 35%a
VO2 max of ≤ 12-14 mL/kg/min and/or VO2 max < 50% predicted and/or VE/VCO2 slope > 35 on cardiopulmonary exercise stress testingb
|Cardiogenic shock not expected to recover |
| Acute myocardial infarction |
| Acute myocarditis |
|Ischemic heart disease with intractable angina not amenable to surgical or percutaneous revascularization and refractory to maximal medical therapy |
|Intractable ventricular arrhythmias, uncontrolled with standard antiarrhythmic, device, or ablative therapy |
|Severe symptomatic hypertrophic or restrictive cardiomyopathy |
|Congenital heart disease in which severe, fixed pulmonary hypertension is not a complication |
|Cardiac tumors with a low likelihood of metastasis |
Although these indications for cardiac transplantation are generally well accepted, identifying the subgroup of patients that is most likely to derive a benefit from transplantation can be challenging. Optimization of medical therapy is a crucial part of determining if a patient would benefit from heart transplantation. Standard of care for patients with HF with reduced systolic function includes an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker, β-receptor antagonist, and mineralocorticoid antagonists to improve symptoms and survival.14 A new class of medication, the angiotensin receptor–neprilysin inhibitor combination sacubitril/valsartan, has proven superior to an ACE inhibitor alone in reducing HF hospitalization and mortality, and will likely become standard of care instead of ACE inhibitors in HF patients.15 Digoxin reduces rehospitalization in HF patients.16 In addition to optimal medical therapy, device therapy with implantable defibrillators saves lives.17 In appropriate candidates with increased QRS duration > 120 ms, especially in those with left bundle branch block, cardiac resynchronization improves symptoms and survival.18,19,20 For patients with ischemic cardiomyopathy, surgical revascularization may also be indicated to improve long-term survival.19 Aggressive medical therapy has led to significant improvement in stable HF patients, with a survival of close to 75% at 5 years. However, in patients refractory to medical management, survival is estimated at 20% at 5 years.1 It is in these end-stage patients that more advanced therapy should be considered.
Thus, the goal of a heart transplant evaluation is to determine if (1) the patient’s cardiac status is limited enough, on optimal medical therapy, to benefit from heart transplantation (ie, “sick enough”); (2) the patient does not have comorbidities that would preclude heart transplantation (ie, “well enough”); and (3) the patient demonstrates compliance and possesses adequate social support (“can adapt to new transplant lifestyle”). At an advanced HF center, patients may undergo right heart and pulmonary arterial catheterization for optimization of filling pressures and cardiac output and to ensure absence of severe pulmonary hypertension, revascularization of coronary artery disease, or ablation of ventricular tachycardia, before considering heart transplantation. As a result, most heart transplant centers have evolved into centers for advanced HF management in addition to providing the opportunity for transplantation or mechanical support.
In ambulatory patients, evaluation often includes cardiopulmonary exercise stress testing to determine if a patient is limited enough to merit heart transplant evaluation.21,22 The cardiopulmonary exercise stress test measures maximal oxygen consumption (VO2 max), which is proportional to cardiac output. Patients with a peak VO2 of more than 14 mL/kg/min have 1- and 2-year survival rates that are comparable or better than those achieved with transplantation, and these patients should be managed medically and undergo serial exercise testing.21,22 In the original publication, the threshold of 14 mL/kg/min was not based on a sensitivity/specificity analysis. Instead, this threshold was selected as a criterion for acceptance for cardiac transplant based on the investigators’ prior experience that patients with peak VO2 levels below this threshold had significant functional limitations and based on exercise data in the literature. The literature at the time suggested that peak VO2 level was an independent predictor of death23 and that an exercise capacity under 4 metabolic equivalents (equivalent to a peak VO2 under 14 mL/kg/min) was a stronger predictor of death in patients with HF after myocardial infarction.24
Patients with a peak VO2 between 10 and 14 mL/kg/min constitute an intermediate-risk group in which continued medical therapy may offer a survival benefit similar to heart transplantation among selected patients who are able to tolerate β-blockers and have the protection of an internal defibrillator.25,26 In patients tolerating β-blockers, a peak VO2 of less than 12 mL/kg/min has been suggested as an appropriate threshold to identify individuals who are likely to derive a survival benefit from transplantation.27 Patients with a peak VO2 of 10 mL/kg/min or less, regardless of β-blocker use, have significantly reduced survival rates with medical therapy compared with cardiac transplantation, and these patients should be listed for transplantation.24,28 Adequate effort is defined as the patient’s achievement of anaerobic threshold, at which point CO2 production exceeds O2 consumption (indicated by the respiratory exchange ratio > 1.10).29,30,31 Other parameters of cardiopulmonary exercise testing that are also associated with increased mortality include a predicted VO2 max < 50%32 and minute ventilation/CO2 production slope > 3533 and may be considered in the evaluation for heart transplantation. A score developed by Myers and colleagues34 may offer further refine the use of cardiopulmonary exercise testing in HF. Based on their score, which combines ventilator efficiency, VO2 max, heart rate recovery, O2 uptake efficiency slope, expired CO2, and chronotropic response, a score > 15 portends a high 1-year mortality, in excess of 40%.
At an advanced HF center, end-stage patients may also be evaluated for MCS. MCS is considered for patients with end-stage HF as (1) a bridge to recovery, for those individuals who require temporary circulatory support and are expected to recover; (2) a bridge to transplantation, for those patients with progressive decline in organ perfusion on escalating inotropic therapy while awaiting transplantation; and (3) destination therapy, for those individuals with contraindications to heart transplantation, include advanced age.35 The decision to proceed with MCS in the form of a left ventricular assist device, biventricular assist device, or total artificial heart as a bridge to transplantation will vary from center to center, depending on the patient’s projected wait time to transplantation, degree of hemodynamic compromise, and anatomic consideration (for total artificial heart). In general, heart transplantation is usually the preferred option for end-stage HF patients, and MCS is reserved for patients who are not candidates for transplantation or who cannot survive until a heart becomes available. The options considered for patients may also vary by regions as donor wait time may be significantly different.
Appropriate candidates for cardiac transplantation should have severe functional limitations, limited life expectancy from their heart disease, and a limited number of established contraindications (Table 72–2). Many of these factors are not absolute and need to be considered in the context of the severity of the patient’s heart disease and associated comorbidities. The degree to which they are interpreted and applied may vary considerably among transplant programs.
TABLE 72–2.Contraindications to Heart Transplantation ||Download (.pdf) TABLE 72–2. Contraindications to Heart Transplantation
|Age ||Over 70 years is an relative contraindication depending on associated comorbidities |
|Obesity ||BMI < 30 kg/m2 is recommended; most centers will tolerate BMI < 35 kg/m2a |
|Malignancy ||Active neoplasm, except nonmelanoma skin cancer, is an absolute contraindication; cancers that are low grade or in remission may be acceptable in consultation with an oncologist |
|Pulmonary hypertension ||The inability to achieve PVR < 2.5 Wood units with vasodilator or inotropic therapy is a contraindication; such patients may benefit from unloading with a ventricular assist device |
|Diabetes ||Uncontrolled diabetes or that associated with significant end-organ damage is an absolute contraindication |
|Renal dysfunction ||If caused by diabetes, may be an absolute contraindication (unless combined heart-kidney transplantation is considered) |
|Cirrhosis ||May be secondary to cardiac disease and is an absolute contraindication in most centers (unless combined heart/liver transplant is considered) |
|Peripheral vascular disease ||Severe disease not amenable to revascularization is an absolute contraindication, especially if associated with ischemic ulcers |
|Infection ||HIV and hepatitis C are absolute contraindications at most centers; with novel hepatitis C therapy, some centers may consider such patients |
|Substance use ||6 months of abstinence from smoking, alcohol, and illicit drugs are required; in critically ill patients, consultation with psychiatry and social work is essential |
|Psychosocial issues ||Noncompliance, lack of caregiver support (either provided by family or agencies), and dementia are absolute contraindications; mental retardation may be a relative contraindication |
In general, patients are considered for heart transplantation if they are 70 years of age or less, since advances in post-transplant care have shown that survival in the older age group is comparable to that of younger recipients.12 Patients over the age of 70 years have also been reported to have acceptable outcome, but careful consideration of associated comorbidities is essential in these cases. At some centers, such patients are offered nonstandard donor hearts, including those with coronary artery disease, mildly decreased left ventricular ejection fraction, left ventricular hypertrophy, or donor age older than 55 years. This practice allows older patients to undergo heart transplantation without denying the scarce resource to younger potential recipients, with comparable outcomes.36 Physiologic age may be more important than chronologic age with respect to survival and rehabilitation potential. As a result, many programs are moving away from fixed upper age limits and instead focus on a patient’s functional status, integrity of major organ systems, and the presence of comorbidities that might impact survival, rehabilitation potential, and quality of life.
Pulmonary hypertension from chronic elevation of left ventricular end-diastolic pressure is a common complication of long-standing HF and can result in irreversible changes to the pulmonary vasculature over time if left unrecognized and untreated.37 In the early years of heart transplantation, it was discovered that a normal donor right ventricle is unable to increase its external workload acutely to overcome elevated pulmonary vascular resistance (PVR), resulting in acute right ventricular failure and cardiogenic shock postoperatively.38 Elevated PVR remains a strong risk factor for right ventricular failure and early postoperative mortality in the modern era. Potential heart transplant candidates must therefore undergo measurements of pulmonary artery pressures and calculation of PVR in the cardiac catheterization laboratory or in the intensive care unit as part of their transplant evaluation.
A pulmonary artery systolic pressure above 50 to 60 mm Hg, a PVR value above 5 Wood units, or a transpulmonary gradient above 15 to 20 mm Hg is usually considered prohibitive of successful heart transplantation. A vasodilator challenge should be administered when the pulmonary artery systolic pressure is ≥ 50 mm Hg and either the transpulmonary gradient is ≥ 15 or the PVR is > 3 Wood units. Pharmacologic interventions for reducing PVR include administration of intravenous agents such as nitroprusside, prostaglandin E1, nesiritide, milrinone, and dobutamine or use of inhaled nitric oxide. The use of oral phosphodiesterase-5 inhibitors (sildenafil) has been shown to improve pulmonary hypertension caused by left ventricular systolic dysfunction sufficiently to allow heart transplantation.39
A vasodilator challenge is considered successful if the PVR can be reduced below 2.5 Wood units with a vasodilator while maintaining a systolic arterial blood pressure over 85 mm Hg. If the PVR cannot be reduced below 2.5 Wood units or if the systolic blood pressure falls below 85 mm Hg with reduction in the PVR, the patient remains at high risk of right HF and death after cardiac transplantation. In this situation, hospitalization with continuous hemodynamic monitoring should be performed, as often the PVR will decline after 24 to 48 hours of treatment consisting of diuretics, inotropes, and vasoactive agents. If this strategy is unsuccessful, longer-term unloading with an intra-aortic balloon pump or left ventricular assist device may be considered.22 In one study, after 6 months of left ventricular assist device support, mean PVR decreased from 3.5 to 1.5 Wood units.40 In another study, mean PVR decreased from 5 to 2.1 Wood units after 3 months of left ventricular assist device support.13,22,41
Patients must be free of active infection before transplantation because infections can be exacerbated by the immunosuppression that is required after transplantation to prevent rejection. The presence of an active systemic infection or severe localized infection is often considered a temporary contraindication to transplantation. Patients with a history of infection should not be activated or reactivated on the transplant waiting list until there is sufficient evidence that the infection is resolved or under control, as demonstrated by absence of fever for a minimum of 72 hours on appropriate antibiotics, a normal white blood cell count, negative blood culture results, and resolving signs or symptoms of infection.
The evaluation of patients with chronic viral infections such as hepatitis B, hepatitis C, or human immunodeficiency virus (HIV) remains controversial, and such patients are considered poor transplant candidates by many centers.42,43 Whether the use of the new nucleotide polymerase inhibitors that may achieve a sustained virologic response in patients with hepatitis C will change this relative contraindication is not yet clear, but is changing practice at many centers. At some centers, HIV infection is no longer considered a contraindication to heart transplantation as long as the patient has no opportunistic infections, acceptable CD4 count, and an undetectable viral load and acceptable outcomes have been achieved in selected patients.44,45,46 Chagas disease, while uncommon in the United States, is a common indication for transplantation in South America, and reactivation of disease can occur.47 The decision to proceed with transplantation in these situations must be made in collaboration with an infectious disease specialist well-versed in transplantation.
In general, patients with active malignancies, with the exception of nonmelanoma cutaneous cancers, primary cardiac tumors restricted to the heart, and low-grade neoplasms of the prostate, should be excluded from cardiac transplantation. However, pre-existing neoplasms are diverse with respect to their response to immunosuppressive therapy and risk of recurrence. Consultation with an oncologist should be obtained for any patient with a history of previous or active malignancy to assess the risk of tumor recurrence. Cardiac transplantation should be considered when the risk of tumor recurrence is low based on the tumor type, response to therapy, and negative metastatic workup. The specific amount of time to wait before transplantation after neoplasm remission should depend on the aforementioned factors, and no arbitrary time period for observation should be used.
Potential cardiac transplant recipients are screened for the existence of other conditions or systemic diseases that may independently limit their survival or rehabilitation potential. Obese patients have a greater risk of poor wound healing, infections, and pulmonary complications after cardiac surgery, although the outcomes in heart transplant recipients are less clear.12 Nevertheless, it is recommended that patients achieve a body mass index < 30 kg/m2 before listing. This may be difficult to achieve in patients with poor functional status, and most centers will consider patients with a body mass index < 35 kg/m2 or slightly higher thresholds in patients of African or Pacific Islander race.
The presence of pre-existing insulin-requiring diabetes mellitus was once considered a relative contraindication to heart transplantation because of concerns regarding diminished survival, increased infection rates, and worsening glycemic control with the initiation of corticosteroid immunosuppression. However, several reports have demonstrated similar short- and long-term survival rates in diabetic and nondiabetic groups, as well as similar rates of infection, rejection, renal function, and cardiac allograft vasculopathy.48,49,50 Although the safety and efficacy of heart transplantation in these very carefully selected patients have been documented in the literature, most transplant programs continue to consider the presence of diabetes with end-organ damage (proliferative retinopathy, neuropathy, or nephropathy) a relative contraindication to transplantation. Corticosteroid therapy may worsen glycemic control in patients with pre-existing diabetes, and thus the presence of poorly controlled diabetes is also considered a relative contraindication for transplantation. At most centers, patients are expected to achieve control with a hemoglobin A1c under 7.5% before listing for transplantation; ongoing collaboration with an endocrinologist is helpful in achieving this goal. In patients with poorly controlled diabetes mellitus, early weaning of steroids before 6 months is sometimes considered.
Other comorbid conditions must be considered on an individual basis, but irreversible organ dysfunction, such as pulmonary fibrosis, severe emphysema, and hepatic or renal dysfunction, out of proportion to that predicted as a consequence of severe HF are strong relative contraindications. Selected patients with irreversible renal or hepatic dysfunction may be considered for multiorgan transplantation.51,52,53,54 The presence of cardiac cirrhosis has been considered a contraindication to heart transplantation as a result of concern for progressive liver failure and increased mortality, although data are sparse.55
Advanced noncardiac vascular disease, in the form of symptomatic cerebrovascular disease or peripheral vascular disease that is not amenable to revascularization, is considered a relative contraindication to transplantation if the condition is expected to limit survival or impair rehabilitation after transplantation.
Experience has shown that pulmonary infarcts have a high probability of becoming pulmonary abscesses after the institution of immunosuppression. For this reason, potential recipients who sustain a pulmonary infarction are usually temporarily removed from the waiting list until the infarct resolves as shown radiographically.
All cardiac transplant candidates should undergo a careful psychosocial assessment with emphasis on current and previous substance abuse history, compliance with medical therapy and follow-up, comprehension of, and ability to follow, a complex medical regimen, and adequacy of social support. Active cigarette smoking is a contraindication to heart transplantation, and smoking during the previous 6 months before transplant is a risk factor for poor outcomes.13,22 At most centers, patients must display abstinence from smoking for 6 months, documented by urine nicotine screens, prior to listing. Addiction to alcohol or illicit drugs is an absolute contraindication, as it suggests that these patients will have poor compliance after transplantation, and 6 months of abstinence with participation in counseling programs are required. This assessment may be difficult to make in the critically ill patient in whom transplantation cannot be delayed for 6 months. In this scenario, consultation with social workers and psychiatrists is essential to gauge the patient’s commitment to abstinence.
In addition to freedom from dependence on cigarettes, alcohol, and illicit substances, patients must be able to demonstrate the ability to comply with medications and follow-up after transplantation, which includes social support with a dedicated caregiver. Patients have been denied transplantation as a result of lack of compliance and social support. Mental retardation and dementia are relative contraindications to heart transplantation; the former because of concerns of compliance and the latter because of overall poor prognosis.
A small, but substantial, proportion of patients with advanced HF are affected by diseases expressing a phenotype not characterized by left ventricular dilation and hypokinesis, and are usually unresponsive to traditional pharmacologic and device therapy. These diseases include hypertrophic cardiomyopathy, restrictive cardiomyopathies, and infiltrative cardiomyopathies such as sarcoidosis or amyloidosis.56 These diseases represent a challenge to the traditional management of end-stage systolic HF. Prognosis, therapeutic strategies, and indications for heart transplantation in these patients require disease-specific considerations and often assessment of extracardiac organ involvement. Furthermore, experience with MCS is limited in patients with restrictive or infiltrative cardiomyopathies57 and not currently recommended.22
Changing Face of Heart Transplantation
Although heart transplantation has become standard of care for the management of end-stage HF, the role of heart transplantation is changing as the characteristics of heart transplant candidates continue to evolve.58 Heart transplant candidates are increasingly more complex: they are older, recipients of MCS, and sensitized.
The proportion of candidates aged 65 years or older has increased; in 2013, 18.2% of candidates in the United States were aged 65 years or older, compared with 10.8% in 2003.59 The proportion of candidates with MCS (most commonly ventricular assist devices) at listing has also increased dramatically, from 7.5% in 2003 to 27.4% in 2013.59 Furthermore, the number of heart transplant candidates with antibodies to human leukocyte antigens (HLA), so-called “sensitization,” has increased over the past decade.60
The heart transplant candidates of the modern era—older, sensitized, with MCS—are at higher risk for poor outcomes, including primary graft dysfunction and antibody-mediated rejection.12,59,61 Strategies to mitigate this risk are ongoing, including proposed changes in heart transplant allocation policy for more equitable organ distribution,62,63 a better understanding of the definition and management of primary graft dysfunction,64 and advances in the management of sensitized heart transplant candidates.65,66 Developments in these areas could result in more equitable distribution and expansion of the donor pool and improved quality of life and survival for heart transplant recipients.