Peak oxygen consumption (VO₂), as measured by a cardiopulmonary exercise test (CPX), provides an objective measurement of functional capacity and has proven to be extremely useful in risk stratifying patients with HF. A peak VO₂ of < 14 ml/kg/min has been historically used as an indication for cardiac transplantation; however this threshold was validated in an era prior to the widespread use of current evidence based pharmacologic and device therapies [3, 4]. More recent studies have shown a peak VO₂ of < 10 ml/kg/min to be a better discriminator of risk for those with end stage HF. In a study of 715 patients referred for cardiac transplantation, those with a peak VO₂ of ≤ 10 ml/kg/min had a 1 year event free survival of 65 %, compared to 77 % for peak VO₂ between 10 and 14 ml/kg/min and 86 % for peak VO₂ > 14 ml/kg/min [5].

The 10 year update of the 2006 International Society for Heart Lung Transplantation (ISHLT) listing criteria for heart transplantation was recently published, further refining CPX listing criteria [6]. A maximal CPX is defined as one in which the respiratory exchange ratio is > 1.05 and anaerobic metabolism is achieved in the setting of optimal medical therapy. In addition, a peak VO₂ of ≤ 12 ml/kg/min was recommended as a guide to listing in patients on beta blocker therapy—in those intolerant of beta blocker therapy, a peak VO₂ of ≤ 14 ml/kg/min should be used. In women and patients under the age of 50, using a peak VO₂ of ≤ 50 % of predicted as a guide to listing received a Class IIa recommendation, while in patients with a submaximal CPX, use of a ventilation equivalent of carbon dioxide (VE/VCO₂) of > 35 as a determinant for listing received a Class IIb recommendation. In obese patients, defined as a body mass index (BMI) > 30 kg/m², an adjusted to lean body mass peak VO₂ of < 19 ml/kg/min received a Class IIb recommendation as a guide to selection. Finally, the use of peak VO₂ as the sole criteria for listing received a Class III recommendation. In addition, the presence of a CRT device does not alter the current peak VO₂ cutoff (Class I recommendation).

Although peak VO₂ has been shown to have strong prognostic value in patients referred for cardiac transplant evaluation, the use of any single variable to determine need for transplantation is problematic. With this in mind, several models have been designed, using numerous variables, and have proven to be highly predictive of prognosis in patients with HF.

The Heart Failure Survival Score (HFSS) is a non-invasive risk stratification model that was developed using 80 clinical characteristics from 269 patients and then prospectively validated in 199 patients [7]. Seven characteristics were predictive of survival in multivariate analysis and were used to construct this model: ischemic cardiomyopathy, resting heart rate, left ventricular ejection fraction, interventricular conduction delay (QRS ≥120 ms), mean resting blood pressure, peak VO₂ and serum sodium. Based on the score derived from this model, patients are stratified into low, medium and high risk groups. Events, defined as the need for urgent transplant or death without transplant at 1 year, occurred in 12 %, 40 % and 65 % of the patients in these respective groups. Based on these findings, the authors concluded that patients in the medium and high risk groups should be considered for cardiac transplantation. Although this model was validated in the era prior to widespread use of beta blockers, aldosterone receptor blockers and device therapy, it has been more recently validated in a modern cohort [5, 8]. The inherent variability of several of the risk factors used, as well as the somewhat arbitrary use of urgent transplantation as a part of the combined endpoint has resulted in some criticism of this model.

The Seattle Heart Failure Score (SHFM) is another multivariate risk model, derived from a cohort of 1125 patients, used to predict one, 2 and 3 year survival in patients with HF. Patients were risk stratified into one of five groups based on a score of −1 to 4. The 2 year survival rate was approximately 93 %, 89 %, 78 %, 58 %, 29 % and 10 % respectively in these five groups. In addition, this model predicts the impact of the addition of pharmacologic and device based therapy on survival—making it a more useful and illustrative tool for patients. This model, which was prospectively validated in 9942 patients with HF with over 17,000 years of follow-up, also benefits from the fact that it was derived in an era with more wide-spread use of current evidence-based pharmacologic and device therapies [9].

The updated 2016 ISHLT guidelines are more explicit in recommending use of prognosis scoring in addition to CPX testing to determine whether and when to list a candidate for transplantation. The new guidelines suggest a HFSS in the high/medium risk range or a SHFM estimated 1 year survival of < 80 % along with an appropriately low peak VO₂ are adequate criteria for transplant candidacy [6].In addition to the focus on patients with ambulatory Stage D HF, there are several other populations of patients who deserve special consideration. Patients who are hospitalized with refractory cardiogenic shock, dependent on intravenous inotropes for maintenance of end organ perfusion, symptomatic with ventricular arrhythmias refractory to pharmacologic and device therapy, symptomatic with severely limiting ischemia refractory to pharmacologic therapies and not amenable to revascularization, and those with severely symptomatic congenital heart disease not amenable to corrective surgeries may also be considered for cardiac transplantation.

Acute right ventricular failure (RVF) is one of the most feared perioperative complications of cardiac transplantation and, therefore, preoperative risk stratification is crucial. It has been estimated that as many as 20 % of early deaths in transplanted patients have resulted from increased pre-operative pulmonary vascular resistance (PVR) and the resultant decline in right ventricular function that may ensue post-operatively [10]. Because of the significant morbidity and mortality associated with this dreaded consequence, many different static and dynamic measurements of pulmonary hemodynamic variables have been described to guide the selection of potential candidates. In addition to PVR, specific cutoffs for pulmonary artery systolic pressure (PASP) and transpulmonary gradient (TPG) have been utilized to identify those at increased risk for RVF. Although these absolute limits have been used, a dichotomy does not exist and, therefore, the degree of hemodynamic abnormality may be used to predict incremental risk [11]. 2016 ISHLT guidelines suggest a PASP ≥ 50 mmHg, a PVR > 3 Woods units or a TPG ≥15 mmHg, may be considered as a relative contraindication for cardiac transplantation [6]. In addition, a PASP > 60 mmHg imposes additional risk for RVF and/or death in those who have either an increased TPG or PVR. In patients with one or more abnormal hemodynamic measurements, a provocative pharmacologic challenge may be considered with one of several different pulmonary and/or systemic vasodilators. Commonly used agents include nitroprusside, nitric oxide, and nitroglycerin. If acceptable hemodynamics cannot be achieved with one or more of these therapies, or such therapy results in significant systemic hypotension (SBP < 85 mmHg), admission for further pharmacologic and/or left ventricular assist device (LVAD) therapies may be considered. In those patients who demonstrate pulmonary vasoreactivity, that is in those who are able to satisfactorily improve their PVR and/or PASP with provocation, their predicted survival post-transplant is unclear with some studies showing worsened survival post-transplant [12] and others showing outcomes similar to those with more normal PVR pre-transplant [13, 14].

When evaluating a patient for cardiac transplantation, advanced age is a relative contraindication to cardiac transplantation. In 2011, the median age of the cardiac transplant recipient was 54 years of age—a number which has not varied much over the years. However, the age distribution of transplant recipients has changed significantly in the last decade with older patients now being transplanted more frequently. From 1982 to 1991, approximately 38 % of cardiac transplant recipients were between the ages of 50 and 59 and 12 % were between the ages of 60 and 69. In contrast, from 2002 to 2010, the former group received 35 % of the available hearts, while the oldest group received 27 % of all implants [2]. This trend is a reflection of the growing experience that carefully selected patients with end-stage HF and advance age may do well with cardiac transplantation.

The previously mentioned supply and demand mismatch in regard to donor hearts and potential recipients has certainly led to many ethical discussions centered on advanced age when determining recipient candidacy. Having said that, instead of asking whether a patient is “too old” for transplant, the better question is “What is the likelihood that the patient will live the average 12.1 years post-transplant in light of their age and other co-morbidities?”. In the early years of cardiac transplantation, age > 55 years old was considered a contraindication to cardiac transplantation due to concerns for decreased survival post-transplant. Over the last two decades, however, numerous single center studies have demonstrated similar outcomes in patients > 60 years of age when compared to younger patients [15–17]. In addition, several other centers have reported individual experiences suggesting that carefully selected patients > 70 years of age may still do well with cardiac transplantation [18–21]. To the contrary, other single-center studies have demonstrated decreased post-transplant survival in patients > 60 years of age. In one of the largest retrospective studies to date, Weiss et al. looked at over 14,000 patients transplanted between 1999 and 2006. In patients ≥ 60 years of age, 30 day, 1 year and 5 year survival was 93 %, 84 %, and 69 % respectively compared to 94 %, 87 %, and 75 % in those < 60 years of age. Despite this survival difference, the authors concluded that results were still encouraging in those ≥ 60 years of age and, therefore, cardiac transplantation should be extended to this age group [22].

Based on the works noted above and other similar single center experiences, the 2016 ISHLT guidelines modified the listing criteria to address the issue of advanced age in assessing recipient candidacy. These guidelines state that patients should be considered for cardiac transplantation if they are ≤ 70 years of age (Class I recommendation). These guidelines further state that carefully selected patients >70 years of age may also be considered for cardiac transplantation (Class IIb) [6].

In determining a patient’s candidacy for cardiac transplantation, appropriate cancer screening is crucial. All patients should undergo age and gender appropriate screening which may include colonoscopy, mammography, Pap smear, pelvic examination and assessment of prostate-specific antigen levels. Based on patient comorbidities and/or family history, additional imaging of the chest, abdomen and pelvis and other tumor markers may also be considered.

In addition to appropriate cancer screening, patients with a known malignancy should undergo careful evaluation and risk stratification. Historically, most centers have required that a potential recipient be in remission for at least 5 years prior to transplantation due to the necessary immunosuppression and incumbent risk of provoking previously treated malignancies. This approach is somewhat supported by recent evidence suggesting that the risk of recurrence is directly related to cancer-free duration prior to transplantation, with those patients being in remission for ≥ 5 years having the lowest risk of recurrence post-transplant [23]. Along similar lines, smaller single center studies have shown no significant difference in regard to survival or the development of a malignancy after transplant in those with an appropriate interval free of malignancy prior to transplantation [24]. This delineation however is somewhat arbitrary, as pre-existing neoplasms are quite diverse in regard to response to treatment, risk of recurrence and metastatic potential. Numerous studies have demonstrated that patients with pre-existing malignancies have undergone cardiac transplantation without recurrence of their primary tumor after transplantation [25–28]. Realizing that a single, defined cancer-free period prior to cardiac transplantation is arbitrary, the 2016 ISHLT guidelines maintained the following Class I recommendation: “Cardiac transplantation should be considered when tumor recurrence is low based on tumor type, response to therapy and negative metastatic work-up. The specific amount of time to wait to transplant after neoplasm remission will depend on the aforementioned factors and no arbitrary time period for observation should be used” [6].

Morbid obesity has long been considered a relative contraindication to cardiac transplantation. Numerous trials have demonstrated a direct relationship between obesity and morbidity and mortality after cardiac surgery. Using various methods to measure obesity, several single-center studies have shown a similar correlation between pre-transplant obesity and unfavorable outcomes after cardiac transplantation. These outcomes included increased risk of primary graft failure, mortality, infection, frequency of high-grade rejection and decreased time to first high-grade rejection [29–32]. Other small studies have shown no difference in similar meaningful outcomes, such as survival, rejection or infection, after cardiac transplantation [29, 31]. Although this data is conflicting, the weight of the evidence supports the notion that pre-transplant obesity is associated with worse outcomes after cardiac transplantation. As a result, the 2016 ISHLT guidelines issued a Class IIa recommendation stating that patients with a body mass index > 35 kg/m² are at a greater risk of poor outcomes after cardiac transplantation and, therefore, it is reasonable to recommend weight loss to a target BMI below 35 kg/m² prior to listing [6].