Evaluation for Heart Transplant Candidacy

Fig. 3.1

The heart transplant evaluation process (Reused with permission from Kittleson et al. [14])

The fundamental indication for cardiac transplantation is a poor quality of life and/or expected survival, despite maximal medical therapy, that has a high likelihood of being improved with transplant. This essentially means patients with Class III/IV symptoms or a 1-year expected cardiac-related survival significantly lower than the 1-year post-transplant survival, with no other life-limiting medical problems. The most common indications for evaluation for transplantation include refractory cardiogenic shock requiring continuous intravenous inotropic support or mechanical support, refractory NYHA class III-IV/AHA stage D heart failure, reduced exercise capacity (as defined by peak V_O2 below a certain threshold), recurrent arrhythmias with the risk of hemodynamic compromise, and severe untreatable angina and end-stage congenital heart disease [2]. Current heart transplant patients who develop significant cardiac allograft vasculopathy with refractory cardiac dysfunction may also be considered for redo-transplant. A full list of indications is summarized in Table 3.1. Once a patient is euvolemic with optimal medical management, physicians are able to assess whether the patient is limited enough to merit transplantation. Of note, the inability to achieve optimal medical therapy because of progressive renal dysfunction or hypotension indicates poor reserve and is also an indication for transplantation [3] as are frequent episodes of decompensation despite medical compliance.

Table 3.1

Recommended tests for initial evaluation of heart transplant candidacy

Recommended tests
Weight/body mass index
Immuno-compatibility
ABO typing
Human leukocyte antigen tissue typing
Panel reactive antibodies and flow cytometry
Assessment of severity of heart failure
Cardiopulmonary exercise test
Echocardiogram
Right heart catheterization
Evaluation of multi-organ function
Routine laboratory work (basic metabolic profile, complete blood count, liver function tests)
Urinalysis with toxicology screen
24-h urine collection for protein and creatinine
Pulmonary function tests
Chest radiograph
Abdominal ultrasonography
Carotid Doppler (if >50 years or with ischemic heart disease)
Ankle-brachial indices (if >50 years or with ischemic heart disease)
Dental examination
Ophthalmologic examination (if diabetic)
Chest and abdomen/pelvic CT scans (if indicated)
Infectious serology and vaccination
Hepatitis B surface, core, envelope antigen, antibody (IgG/IgM)
Hepatitis C antibody
Human immunodeficiency virus (HIV)
Rapid plasma reagin
Immunoglobulin G for herpes simplex virus
cytomegalovirus, toxoplasmosis, Epstein-Barr virus, varicella
Purified protein derivative
If from Latin American: Chagas screen
Immunizations: influenza, pneumovax, hepatitis B
Preventive and malignancy
Stool for occult blood x 3
Colonoscopy (if indicated or if >50 years)
Mammography (if indicated or if >40 years)
Papanicolaou smear test
Prostate-specific antigen and digital rectal examination (men >50 years)
General consultations
Social assessment
Psychiatry
Financial
As indicated: pulmonology, nephrology, infectious disease, endocrinology, hematology

Reused with permission from Mehra et al. [32]

Abbreviations: IgG immunoglobulin G, IgM immunoglobulin M

Evaluation Testing

The first goal of cardiac transplant evaluation is to objectively determine whether or not a patient has sufficiently poor functional capacity and prognosis in order to be listed. Risk stratification of heart failure patients is important, in order that patients with a high probability of survival benefit are selected for transplant, and that appropriate priority criteria can be developed. It is important that the criteria to define eligibility are as objective as possible; however, many of the accepted criteria used to define eligibility for heart transplant are somewhat unreliable, including resting hemodynamic data and NYHA classification. Firstly, NYHA classification as a measure of functional capacity is highly subjective and often inaccurate, and can vary on a day-to-day basis. Furthermore, while hemodynamic measurements accurately reflect the state of cardiac performance at rest, they may not always predict functional capacity and measures such as resting cardiac output may be poorly predictive of outcome after hemodynamic optimization. Cardiopulmonary exercise testing is considered one of the most objective methods of assessment of both functional capacity and prognosis. Ultimately, combinations of several methods are typically employed to objectively estimate clinical status and the likelihood of adverse prognosis with medical/device therapy alone. Scoring tools to improve risk stratification of HF patients have also been developed, and are also frequently used in combination with testing to inform a decision on listing for transplantation; however, even these scoring tools should not be used as the sole determinant of listing [4], and the decision to list/not list should be based on multiple factors.

Cardiopulmonary Exercise Testing

Cardiopulmonary exercise testing (CPET), a bicycle or treadmill based exercise test with gas exchange measurements via a mouthpiece, is considered a gold standard for objectively establishing a severity of functional cardiac impairment that would merit listing for transplantation [4]. The key measurement in CPET that provides prognostic information is the oxygen consumption at peak exercise, or V_O2max. This is particularly relevant because the very basis of heart failure is the lack of ability to provide oxygen to peripheral tissues at a sufficient rate for aerobic respiration. Testing is performed in an incremental fashion in order to identify the point at which the patient reaches their maximal aerobic capacity.

Maximal Oxygen Consumption

The ISHLT guidelines state that a cut-off for V_O2max of ≤14 ml/kg/min in heart failure patients not on beta-blockers should be used to decide which patients are sufficiently impaired for transplantation [4]. In the presence of a beta-blocker, a cutoff of ≤12 ml/kg/min should be used. Studies that have demonstrated that patients with preserved exercise capacity (V_O2max> 14 mL/kg/min) despite severe resting hemodynamic impairment, have survival and functional capacity equal to those afforded by cardiac transplantation [5, 6]. Because beta-blocker therapy has improved survival rates in patients with systolic HF including patients with very low V_O2max to as low as 10 mL/kg per min [6], the threshold is lower in patients on beta-blockers. In younger patients (below 50 years old) and women, it is reasonable to use additional variables such as percentage of predicted V_O2max; below 50% of predicted is considered sufficiently impaired for transplantation [7–9]. In obese patients, adjusting V_O2max to lean body mass should be considered; a lean body mass-adjusted V_O2max of less than 19 ml/kg/min serves as the threshold to decide which patients are sufficiently impaired [4]. Of note, the presence of a cardiac resynchronization therapy device does not alter the V_O2 cut-off recommendations. It must be emphasized that the decision to list must not be made on V_O2max on CPET alone; many other factors, including risk scores and potential contraindications, must be considered.

Reaching anaerobic threshold defines a maximal CPET test, and is necessary to accurately measure V_O2max. The anaerobic threshold is defined as the point during exercise when oxygen delivery (and hence cardiac output) to exercising muscles is insufficient to sustain aerobic respiration, at which point anaerobic pathways are predominantly utilized. It occurs at approximately 60–70% of V_O2max in heart failure patients. When carbon dioxide production is greater than consumable oxygen (respiratory exchange ratio (RER) >1.05) and lactate levels sharply rise, this indicates the anaerobic threshold has been met, and helps differentiate true cardiac limitation from poor effort or potentially confounding pulmonary or musculoskeletal problems. The index of ventilatory efficiency (V_E/V_CO2) on CPET testing, defined as the ratio of minute ventilation (V_E) to the rate of carbon dioxide production (V_CO2), may also be used as a measure for determining whether listing for transplant should be considered, and may be especially useful for patients who do not achieve their anaerobic threshold. Specifically, patients with a V_E/V_CO2 slope of greater than 35 have a worse prognosis and should be considered for transplantation [4]. Recent studies have suggested that ventilatory efficiency may be a more powerful prognostic factor than V_O2max [10, 11]. Ventilatory efficiency has also been shown to maintain prognostic value regardless of body mass index, another potential confounding factor that can limit interpretation of V_O2max [12].

CPET testing may also be a useful tool for identifying patients who have demonstrated clinical stability while on the waiting list and are being considered for delisting.

Hemodynamic Performance Assessment

Initial assessment of resting hemodynamics in heart failure patients typically includes assessment of left and right ventricular function by echocardiogram. Assessment of left ventricular systolic ejection fraction provides a useful initial rapid assessment of the severity of impairment in left ventricular function and therefore likelihood of requiring transplantation; it is also used to assess response to medical or surgical therapies. A left ventricular ejection fraction of less than 25% has been shown to be associated with increased mortality and morbidity compared to an ejection fraction of over 35% [13]. However, low ejection fractions alone within a cohort of patients with advanced heart failure have been shown to be poorly predictive of short-term or medium-term mortality- information needed to make a decision regarding listing. Indeed, there is a wide range of functional capacities associated with a low ejection fraction; some are able to freely ambulate, while some are bedridden and require ventricular assist device support. There are also problems inherent in the technique-to-technique, inter-observer and intra-observer variability of ejection fraction measurement that make it unsuitable as a lone guide to listing for transplantation [4].

Right heart catheterization (RHC) assessment of hemodynamic performance remains an important test for ongoing assessment and maintenance of heart transplant candidacy [4]. It is recommended that right heart catheterization be performed on all adult candidates in preparation for listing for cardiac transplantation, as well as periodically prior to transplantation [4]. Indicators for more frequent assessment would include the presence of reversible pulmonary hypertension or worsening of heart failure symptoms. Of measurements obtained via RHC, higher right atrial pressure, higher pulmonary capillary wedge pressures, lower mean arterial pressure, higher pulmonary artery pressure (>50 mmHg) and lower cardiac index (<2.5 L/min/m²) have all been variably associated with increased mortality [4, 14–17]. However on their own they remain poor prognostic indicators for heart failure patients [4]. In clinical practice, hemodynamic measurements are most useful as a method to gauge response to medical therapy, and to make sure a patient does not have irreversible pulmonary hypertension (see below).

Overall, resting hemodynamic assessment remains an important part of the evaluation process. Combined with CPET data resting hemodynamic measurements have proved highly prognostic [17], and are therefore useful for the purposes of listing.

Heart Failure Survival Score (HFSS)

While certain measurements such as ejection fraction are poor prognostic indicators by themselves, the combination of multiple measures of cardiac function into a survival score has provided greater prognostic value. The Heart Failure Survival Score (HFSS) is one such score. It is derived from a multivariable analysis of 268 ambulatory patients referred for consideration of cardiac transplantation from 1986 to 1991 and was subsequently validated in a population of 199 similar patients from 1993 to 1995 [18]. The component predictors of survival in the HFSS include: Presence or absence of coronary artery disease; resting heart rate; left ventricular ejection fraction as per echocardiography; mean arterial blood pressure; presence or absence of an intraventricular conduction delay on electrocardiogram; serum sodium; and V_O2max as determined by CPET.

Scores are categorized into low-risk (score ≥8.1), medium-risk (score ≥7.2 and <8.1), and high-risk (<7.2). It was demonstrated that patients in medium and high-risk groups are most likely to die or require urgent transplant in the following year, with a 1-year survival of 72% and 43%, respectively [18]; consequently, the ISHLT guidelines recommend that these patients should be considered for cardiac transplantation if no contraindications are present [4]. The validation data show that transplantation can be safely deferred in patients in the low-risk group, with a 1-year survival of 93%. Compared to V_O2max alone, HFSS has been demonstrated to be superior for the purposes of heart transplant selection in patients supported with continuous-flow ventricular assist devices [6].

The Seattle Heart Failure Model (SHFM)

The Seattle Heart Failure Model (SHFM) is another scoring tool, derived from a cohort of 1125 heart failure patients and subsequently validated in 9942 patients [16]. It is most useful for estimating the prognosis for ambulatory patients with advanced heart failure. The SHFM incorporates the variables of age, sex, NYHA class, ischemic etiology, body mass index (BMI), ejection fraction, systolic blood pressure, diuretic dosages, laboratory values (serum sodium, cholesterol, hemoglobin, percent lymphocytes, creatinine, uric acid) and other clinical information (see Fig. 3.2). Most pertinently, the model is able to incorporate the impact of newer heart failure therapies on survival (including implantable cardioverter-defibrillators and cardiac resynchronization therapy), and allows evaluation of the estimated effect of interventions on an individual patient’s prognosis. Validation data demonstrate that the model is able to provide an accurate estimate of 1-, 2-, and 3-year survival. The primary limitation of the SHFM is that it was derived from in an ambulatory HF population thus may overestimate survival in the overall advanced heart failure population [19, 20]. Nevertheless, it remains a useful method for estimating the chance of survival for the purposes of transplant listing; the ISHLT guidelines consider a less than 80% estimated chance of 1-year survival as per SHFM to be a reasonable cut-off for consideration of transplantation [4].

Fig. 3.2

An example of the use of the seattle heart failure model (Reused with permission from Levy et al. [16])

Other Factors

Besides the measurements and scoring systems covered, other factors that are typically considered include consideration of NYHA class (the inherent problems of such a subjective classification have been discussed above); assessment to ensure optimal medical and surgical (if applicable) management has been considered; and the duration of heart failure illness, as shorter durations of advanced heart failure have been associated with a greater likelihood of recovery.

Potential Contraindications to Cardiac Transplantation

The 2 major categories of contraindications for heart transplantation are medical and social/psychological (Table 3.2). Many of these factors are not absolute on their own and need to be considered in the context of the severity of the patient’s heart disease and associated comorbidities. Table 3.3 summarizes the screening investigations that should be performed during evaluation of a potential transplant candidate in order to assess indications and contraindications. A useful rule is that the presence of any non-cardiac condition that would substantially increase the peri- or postoperative risks of the transplant or itself shorten life expectancy would represent a medical contraindication. Similarly, any psychosocial issues that would increase the risk of death from rejection due to medical non-compliance would also place the patient at a prohibitively high risk for transplant.

Table 3.2

General indications for cardiac transplantation

Refractory cardiogenic shock requiring intra-aortic balloon pump counterpulsation or mechanical circulatory support (i.e. left ventricular assist device (LVAD), total artificial heart).

Cardiogenic shock requiring continuous intravenous inotropic therapy (i.e. dobutamine, milrinone, etc.).

Cardiopulmonary exercise testing demonstrating V_O2max ≤14 mL/kg/min in patients not on beta-blockers, or V_O2max ≤12 mL/kg/min in patients on beta-blockers.

Persistant NYHA class of III or IV heart failure symptoms despite maximized medical, surgical and/or resynchronization therapy.

Recurrent life-threatening left ventricular arrhythmias despite an implantable cardiac defibrillator, maximal pharmacological antiarrhythmic therapy, or catheter-based ablation.

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