Finding the optimal time to transplant a patient when they are sick enough to justify the morbidity and mortality associated with this major procedure, but not so severely ill that their perioperative mortality is prohibitive, remains a significant challenge. Unfortunately, there are a limited number of tools to risk stratify transplant candidates.

Cardiopulmonary reserves of ambulatory patients are assessed by measuring peak oxygen utilization (aerobic capacity) and altered ventilatory response (ventilatory efficiency). Generally, the peak VO2 (VO2 max) provides an objective assessment of functional capacity in patients with advanced heart failure and is one of the best predictors of when to list a patient for cardiac transplantation [6]. Peak VO2 was initially evaluated as a prognostic tool for determining when to list a patient for cardiac transplant prior to the widespread use of beta-blockers. However, several studies have demonstrated the continued usefulness of peak VO2 with beta-blocker use [7, 8]. Peak VO2 less than 14 ml/kg/min has traditionally been a cut point for cardiac transplantation, but with improved medical and device therapy for advanced heart failure peak VO2 less than 10–12 ml/kg/min appears to be a better threshold [9].

Ventilatory response as assessed by slope of minute ventilation to carbon dioxide production (V _E/VCO₂) [10, 11] or breathing pattern (exercise oscillatory breathing EOB) [12] can improve the predictability of exercise testing and their utility in determining the transplantation candidacy [13]. Assessing ventilatory efficiency is particularly helpful in patients who cannot reach adequate effort on exercise since the performance at submaximal effort can define the slope.

Though the above parameters guide the selection of heart transplant candidates, particularly by third-party payers, no single test or value should be used alone to determine transplant candidacy. Rather, a patient’s entire clinical, social, and support situations should be evaluated.

If candidacy cannot be determined un-equivocally by clinical and objective laboratory assessment, survival assessment models are used to define the high risk patient. Several risk models have been developed to guide the selection of cardiac transplant patients including the Heart Failure Survival Score (HFSS) and Seattle Heart Failure Model (SHFM) . Heart Failure Survival Score (HFSS) is one of the widely used predictive models [14] developed in 1990s by Aaronson et al. Multivariate proportional survival models were created using 80 clinical characteristics of the derivation cohort (n = 286) and validated in a group of 199 subjects. The score is calculated by the seven most significant prognostic factors: presence or absence of coronary artery disease, resting heart rate, left ventricular ejection fraction, mean arterial blood pressure, presence or absence of an intraventricular conduction delay on ECG, serum sodium, and peak VO2 [14]. The HFSS then stratifies patients into low, medium, or high risk with validated 1 year survival rates in these strata of 89, 72, and 60 %. Patients, who are identified as medium or high risk of adverse outcome, can be considered for Heart transplantation. Even though many advances in heart failure treatment have been made since 1997, HFSS retains the discriminatory power between risk groups [13].

The SHFM is a 21-variable risk model prospectively validated in almost 10,000 heart failure patients [15]. The model provides an accurate estimate of 1-, 2-, and 3-year survival and allows the operator to add in an estimated effect of different interventions on a patient’s prognosis. Overall, SHFM tends to under-estimate and HFSS tends to over-estimate the risk of death [3].

Careful investigation is needed to identify patients with coexisting systemic diseases that are not likely to improve or could be worsened by transplantation. Contraindications to transplantation are continually evolving and vary somewhat from center to center. The major hemodynamic factor excluding patients from cardiac transplantation is irreversible pulmonary hypertension (pulmonary vascular resistance >6 Wood Units (WU), Normal PVR <1.5 WU). Fortunately, pulmonary hypertension in many patients with HF is due to neuro-humoral vasoconstriction without irreversible structural changes in the pulmonary vasculature, such as calcification or intimal or medial hyperplasia. Patients with irreversible pulmonary hypertension have an increased risk of postoperative right ventricular failure because the normal donor right ventricle is acutely subjected to a marked increase in afterload. Right heart catheterization is performed in all candidates during the transplant evaluation to identify patients with elevated pulmonary pressures. A vasodilator challenge should be administered when the pulmonary artery systolic pressure is greater than 50 mmHg and either the transpulmonary gradient is greater than 15 mmHg or the pulmonary vascular resistance is greater than 3 WU. Protocol to test the pulmonary vascular responsiveness varies between institutions. Sodium nitroprusside, dobutamine, milrinone, prostaglandin E₁, prostacyclin, phosphodiesterase type 3 inhibitors, and inhaled nitric oxide are some of the agents used to reduce PVR and test for reversibility of elevated PVR [16–20]. In patients with positive response to vasodilator challenge, a continuous infusion of milrinone, dobutamine, or prostaglandin E₁ for several weeks has been used in some patients as a bridge to transplantation [21, 22]. Mechanical circulatory support has also been shown to be effective in decompressing the failing ventricle and decrease the pulmonary pressures.

When an acute vasodilator challenge is unsuccessful, hospitalization with 24–48 h of hemodynamic monitoring and treatment with diuretics, inotropes, and pulmonary vasodilators is done. If the pulmonary hypertension can be reduced with a vasodilator challenge, candidacy may be considered. Serial right heart catheterizations should be performed in patients with borderline pulmonary pressures or response to vasodilator challenge to determine their ongoing acceptability for cardiac transplantation. Patients with irreversible pulmonary hypertension are occasionally considered for combined-heart lung transplantation in select centers.

Active malignancy from origins other than the skin is another absolute contraindication to cardiac transplantation. Malignancy may be worsened by the immunosuppression that is given to prevent transplant rejection. Even without a preexisting cancer, the incidence of malignancy is increased follow transplantation [23]. Patients with a history of prior malignancy where there has been adequate time to determine whether the malignancy has been cured may be considered for transplantation. The required duration of tumor free interval varies depending on the type of prior malignancy. An ISHLT transplant registry study by Oliveira et al indicates that transplantation can be safely performed in selective patients with history of malignancy and chemotherapy-induced cardiomyopathy with results non-inferior to transplant after non-ischemic cardiomyopathy [24]. Therefore, oncology consultation is an important prerequisite prior to listing these patients. Finally, patients with any other systemic illness with a life expectancy less than 2 years despite cardiac transplantation should not be considered.

With few absolute contraindications to cardiac transplantation, a thorough and careful risk assessment of comorbidities that may negatively affect outcomes is essential to ensure optimal allocation of this scarce resource. Consequently, the transplant evaluation focuses on screening for and identifying potential relative contraindications and comorbidities that may increase perioperative and/or long-term risk. We will outline the major comorbidities and how they are assessed as part of the transplant evaluation (Table 11.3).