It is well known that fixed pulmonary hypertension (PH), unresponsive to acute vasodilator challenge, represents a major risk factor or a contraindication for HTX, being associated with increased probability of early right ventricular failure, multi-organ failure, prolonged mechanical ventilation (with nitric oxide administration), and higher mortality. The recently updated ISHLT guidelines for selection of HTX candidates recommend to evaluate and reevaluate periodically the presence and reversibility of PH with right heart catheterization, considering pulmonary artery systolic pressure ≤50 mmHg and either transpulmonary gradient (TPG) ≤15 mmHg or pulmonary vascular resistance (PVR) ≤3 Wood units (while maintaining a systolic arterial blood pressure > 85 mm Hg) as upper acceptable levels for HTX listing (class I, level of evidence C) [6]. Reversibility may be tested with infusion of sodium nitroprusside or, in case of concomitant severely reduced cardiac output, of an inodilator such as milrinone or enoximone, with an association of an inotropic agent (e.g., dobutamine) and a vasodilator, or after a 24-h infusion of levosimendan. When the patient is severely congested at baseline, it may be better to defer hemodynamic evaluation after volume unloading, with a target right atrial pressure (RAP) <10–12 mmHg, unless hemodynamic monitoring is perceived useful for treating the patient. In most cases, at least partial improvement of the hemodynamic profile may be obtained with pharmacological therapy, but especially when it is accompanied by some renal dysfunction (increased serum creatinine and/or blood urea nitrogen) or the patient is a “frequent flyer,” and obviously when the INTERMACS profile is ≤3, LVAD should be considered to maintain patient conditions suitable for HTX regarding both hemodynamics and end-organ function while awaiting. This strategy appears reasonable, also taking into account that several analyses of multicenter cohorts have shown better survival on the waiting list and better overall survival including post-transplant outcome, when patients listed as status 2A are treated with a LVAD with respect to medical therapy alone [8–10]. In cases of resistant, “fixed” PH under pharmacological treatment, LVAD may still be an option, as BTC or for long-term, indefinite treatment. One paper reports that post-HTX outcome after, on average, more than 400 days from LVAD implant may be still dependent on PH reversibility assessed with pharmacological manipulation before LVAD implant, especially when reduction in TPG and/or PVR has been unsatisfactory [10]. However, in this paper the evolution of PH after LVAD implant had not been addressed. After LVAD implant, the immediate hemodynamic change is a dramatic reduction of pulmonary capillary wedge pressure (PCWP). Reduction in pulmonary artery pressure (PAP), TPG, and PVR, which are important for HTX eligibility, is generally also observed over time, but at a slower rate and inferior proportion. Various studies reporting on this point suggest that hemodynamic profiles suitable for HTX are reached in most cases approximately at 3 months after LVAD implant and that in these patients HTX may be performed with good postoperative outcomes [11–18]. Of note, first experiences include patients treated in the 1990s, and various types of pulsatile- and continuous-flow devices had been utilized, providing similar results, suggesting that (1) LV unloading “per se” is the mechanism for secondary PH resolution and (2) this concept has been gradually incorporated into clinical practices. It is prudent to ascertain PH resolution prior to proceed to listing and transplantation and to reassess periodically pulmonary hemodynamics as it is usual in HTX candidates [6]. If reduction in PAP, TPG, or PVR remains unsatisfactory despite LV mechanical unloading, some authors suggest to add medical treatment targeted to pulmonary arterial hypertension, i.e., an endothelin receptor antagonist (bosentan) [19] or a PDE-5 inhibitor (sildenafil) [20]. Observational experiences in a limited number of cases appear to obtain some additional hemodynamic improvement; however, this approach must be considered with caution, taking into account that (1) these studies were not controlled, (2) controlled clinical trials with the same drugs in patients with heart failure and PH secondary to LV dysfunction did not demonstrate any significant benefit, and (3) in patients with “primary” pulmonary hypertension (PPH), clinical benefit appears superior than expected on the basis of the observed, numerically limited hemodynamic changes, suggesting that the mechanisms of PH and of the effects of drugs on clinical and hemodynamic end points are different in the two conditions of PPH and PH secondary to LV disease [21]. An interesting line of research on advanced HF with preserved LVEF, which is characterized by markedly restrictive physiology, pulmonary hypertension, dilated left atrium, and normal LV size, regards the possibility of long-term use of continuous-flow micropumps that drain blood from the left atrium instead of LV, to circumvent surgical and hemodynamic problems that limit the utilization of currently available LVADs in various forms of restrictive or hypertrophic cardiomyopathy [22]. Patients with these diseases are considered as disadvantaged with respect to those with dilated/hypokinetic cardiomyopathy, due to limited resources for both pharmacological and mechanical treatment [6].

Cancer, together with late graft dysfunction and cardiac allograft vasculopathy, is the leading cause of death after HTX [23]. Post-transplant immunosuppression is known to be associated with increased probability to develop malignant disease, in general and especially regarding some malignancies related to viral infections, such as EBV-positive non-Hodgkin lymphoma and HHV8-positive Kaposi’s sarcoma [23, 24] Moreover, the course of post-transplant malignant diseases may be very dramatic and aggressive, although in recent years some alternative immunosuppressive regimens, based on antiproliferative mammalian target of rapamycin (M-Tor) inhibitors instead of on calcineurin inhibitors, have been proposed as possibly associated with a reduced risk of developing malignancies and a reduced speed of their progression [25–27]. As a consequence, not only patients with active malignant disease but also those who had been recently treated are considered ineligible for HTX, until there are reasonable motives for considering this disease as definitely “cured” and at very, very low probability of recurrence [6, 25].

After completing treatment, the length of disease-free follow-up time required for eligibility for HTX is variable, in relationship with the site and type of malignancy, individual characteristics and treatments, and the degree of certitude that is felt appropriate. In any case, it may be too long for patients’ waiting, especially when INTERMACS profile is 3 and 4; thus, long-term LVAD implant with BTC strategy may be considered [28–30]. Reports regarding outcomes in this specific category of BTC patients are very scant; thus, the strength of pertinent recommendation in the ISHLT guidelines, 2016, is IIb (i.e., possibly recommended, with doubts), and the level of evidence is C (experts’ consensus) [6].

It must also be taken into account that a relevant proportion of patients with severe heart failure and treated cancer have received antineoplastic drugs and/or radiotherapy that may have caused heart disease or at least contributed to it. Post-chemotherapy cardiomyopathy is not rarely characterized by biventricular compromise and mildly dilated LV with severe systolic and diastolic dysfunction, leading to restrictive filling pattern, low/very low cardiac index, pulmonary hypertension, high right filling pressure, and reduced tolerability of standard heart failure treatments [28, 31]. Moreover, chest radiotherapy may damage the heart via several mechanisms, including valvular disease, pericardial thickening with tenacious adhesions to the surrounding tissues, diffuse coronary artery stenosis, and myocardial fibrosis, contributing to restrictive physiology and making it difficult the successful implant of a LVAD, for both hemodynamic and surgical reasons [31]. Unfortunately, these conditions are not ideal either for continuing medical therapy alone or for LVAD implant, and a higher rate of postoperative RV failure has been reported in LVAD recipients with post-chemotherapy cardiomyopathy with respect to other etiologies [27, 28, 30, 32].

The availability of mechanical devices for advanced HF may be seen as an opportunity for expanding the cancer patient population that can be treated with contemporary approach, including surgery, pharmacotherapy, and radiotherapy, despite severe heart disease. Some reports showed the feasibility of surgical tumor resection or debulking [33–35], and the safety of radiotherapy without interferences with device functioning [36, 37] when cancer is diagnosed during follow-up after LVAD implantation. However, it does not mean that long-term simultaneous management of LVAD and cancer should be, at present, prospectically planned and practiced in the majority of patients. Such experiences are very few [38]. Malignancies may imply altered – most often increased – thrombogenicity, and pharmacological therapy may cause anemia, leukopenia, pancytopenia, mucositis, gastroenteric disturbances, and increased lung alveolar permeability, all conditions that may alter blood rheology, drug absorption, and hemodynamic and ventilatory requirements and facilitate infections [29, 30]. Moreover, both LVAD and cancer therapy are highly demanding in terms of economic and human resources and also in terms of suffering, expectations, and coping, for the patient and also for the relatives and caregivers. Thus, a situation in which the interests of individuals and of the community could collide, which 10 years ago had been debated as a theoretical case, may be now a real clinical and ethical dilemma [39]. So far, prospective long-term LVAD implant in patients with active serious malignancy should be evaluated very carefully within an expert multidisciplinary team and should represent, in authors’ opinion, an exception more than a rule. In any case, expectations and uncertainties should be explained with realism and frankness to the patients and their families.

Patients presenting with acute, severe/refractory heart failure or cardiogenic shock are a highly heterogenous group in terms of etiology (acute myocardial infarction, post-cardiotomy shock, fulminant myocarditis, peripartum cardiomyopathy), treatment, and probability of recovery [40]. In this setting, implantation of short-term MCS may be the best initial option, leaving room to evaluate further evolution, while transition to long-term LVAD or TAH are critical choices, also because in relatively young patients without relevant comorbidities they imply to consider also HTX listing. Streamlining very acute patients toward HTX is critical because their attitudes and psychological characteristics are not well known, recovery of cardiac function in some cases occurs after several weeks, and multi-organ dysfunction associated with cardiogenic shock represents a risk factor [23]. These aspects are discussed in Chaps. 7 and 9, and the relationship with HTX listing and prioritization is analyzed later, in the last section of this chapter. In the case of post-cardiotomy heart failure or shock, two different conditions must be recognized: the first corresponds to de novo, unexpected HF due to dramatic complications; the second corresponds to difficulties encountered in patients with already known HF/LV dysfunction, undergoing high-risk conservative/reparative surgery. In the latter, rescue strategies in case of surgery failure should have been already discussed, also with the patient, and planned on an individual basis before entering the operating room.

Hyperimmune status, generally defined as the presence of anti-HLA antibodies against a variety of antigenic profiles that may be encountered in local population (panel-reactive antibody, PRA, >10%), may reduce the probability to get HTX, and when it is performed, post-transplant course may be difficult and survival reduced, due to an immuno-mediated reaction to the graft that may comprise a spectrum from immediate, hyperacute rejection to late graft failure [41]. Hyperacute rejection is a dramatic and lethal event, consisting of immediate aggression to the transplanted heart that happens in the operating room, at reperfusion or early after, due to the cytotoxic effect of pre-existing anti-HLA Class I antibodies. The presence of class II anti-HLA antibodies is associated to an increased probability to experience acute cellular and/or humoral rejection. The burden of cellular rejection has been recognized to facilitate the development and progression of cardiac allograft vasculopathy, while after humoral rejection it is not uncommon to observe a marked acceleration of CAV, with quick development of new, multiple lesions and diffuse arterial narrowing. Although there is an agreement on these general concepts, various criteria, tests, and thresholds for defining sensitization, requiring pre-transplant crossmatch, implementing apheresis at the time of HTX, and pursue desensitization before HTX are used. Desensitization therapies include plasmapheresis, immunoapheresis, immunoadsorption, and administration of high-dose immunoglobulins, cyclophosphamide, and monoclonal antibodies targeted to lymphocyte subpopulations, e.g., rituximab, bortezomib, and others [6, 41]