Optimizing Outcomes After Heart Transplantation

This article refers to ‘Late graft failure in heart transplant recipients: incidence, risk factors and clinical outcomes’ by Á. López-Sainz et al., published in this issue on pages 385–394. This year marks the 50th anniversary of the worlds first heart transplant. As we consider the remarkable success of randomized clinical trials in heart failure (HF) with reduced ejection fraction (HFrEF) over the last 30 years,1 it is useful to remember that the development of heart transplantation (HTx) long preceded these trials and indeed established the multidisciplinary HF referral centres and clinical research programmes which provided the foundation for the successful pharmacological and device trials that followed. Furthermore, despite a plethora of interventions, HFrEF remains a progressive syndrome and advanced chronic HF affects up to 10% of the HF population and is associated with a dismal quality of life, recurrent hospitalization and mortality rates of up to 50% at 1 year.2, 3 Durable mechanical circulatory support primarily in the form of left ventricular assist systems (LVASs) offers hope in advanced HF,4 but remains associated with frequent and severe complications, and the rapid increase in use observed over the last 10 years has now levelled off.5, 6 It is therefore also useful to consider that HTx remains the only definitive treatment for HF and the only intervention in HF that without evidence from randomized trials is by consensus accepted as improving survival, exercise capacity, quality of life and return to work.1 Improvements in the selection of HTx candidates and in perioperative care have resulted in steady improvements in early post-HTx outcomes over the last decades.5 The introduction of cyclosporine-based immunosuppression in the 1970s and further refinement of immunosuppression protocols have contributed to improved short- and intermediate-term rejection-free survival. One-year survival post-HTx now approaches 90%, which is remarkably high considering that, at the time of HTx, 45% of patients are hospitalized, 40% are on inotropes, and nearly 50% are on mechanical circulatory support.5 However, data from the International Society for Heart and Lung Transplantation (ISHLT) Registry suggest that long-term adult post-HTx outcomes have not improved appreciably since reporting to this worldwide registry begun in the early 1980s and that mortality at 13 years is >50%.5 In this issue of the journal, the large HTx group from A Coruña, Spain, report specifically on late graft failure in 547 HTx recipients aged 16 years or older.7 The study is laudable for its large sample size and detailed analysis of both graft failure and its predictors, and outcomes post-graft failure and their predictors. Over a mean follow-up of >8 years, 32% of subjects were hospitalized for late graft failure (3.6% per year), manifesting as HF, often with preserved EF, and associated with increased risk for death and need for retransplantation.7 Cardiac allograft vasculopathy (CAV), cellular rejection and antibody-mediated rejection were detected in 51%, 45% and 19% of patients admitted, respectively. The independent predictors of late graft failure were higher pre-transplant transpulmonary gradient and a lower donor-to-recipient weight ratio (which suggests that early loading conditions may also impact long-term outcomes, even immune-mediated outcomes), as well as pre-transplant diabetes. Predictors of mortality or retransplant in patients with graft failure were more severe HF (lower EF and need for inotropes), as well as the presence of CAV, worse renal function and lower sodium, a manifestation of neurohormonal activation and cardiorenal syndrome. It is particularly noteworthy that immune-mediated mechanisms are the primary causes of late graft failure, whereas the predictors of poor outcomes after graft failure are those that interact with and occur as a consequence of immunosuppression, such as renal dysfunction. This is in contrast to predictors of early graft failure, which are more closely related to the severity of HF and haemodynamic compromise at the time of transplant.8 It is unfortunate that despite the availability of numerous immunosuppressive agents, we are no better at personalizing long-term immunosuppression. For example, in an analysis of the ISHLT Registry, we observed that younger patients were at considerably greater risk for death from acute rejection, CAV and graft failure, potentially implying inadequate immunosuppression, whereas older patients had greater risk for death from infection and malignancy, consequences of immunosuppression.9 The data from A Coruña7 suggest we should also be vigilant about rejection and by extension adequate immunosuppression in the long term; however, data from the ISHLT suggest that malignancy, a consequence of immunosuppression, is the most common cause of death beyond 5 years post-HTx.8 There is clearly a great need for additional studies of the relative risks for different post-HTx outcomes according to time post-transplant and individual patient characteristics. Thus the challenges in HTx are to improve organ availability, HTx selection and long-term post-HTx care and outcomes. Efforts to increase the donor pool and improve allocation systems have been extensively reviewed, but will have varying applicability according to geographical and cultural region.10 Most medical and device-based HF therapy is considered cost-effective and therapeutic decisions need in principle to consider only net benefit (Figure 1). In contrast, donor hearts are scarce and advanced therapy such as HTx and durable LVASs used as a bridge to transplant or as destination therapy are expensive and associated with potentially high levels of both risk and benefit, and therapeutic decisions are much more difficult. Thus, HTx and LVAS selection must consider not only net benefit (Figure 1A–C), but also maximal benefit (Figure 1C). Heart transplant is at the end of a spectrum of escalating HF therapy with increasing HF severity. The challenges in HFrEF more broadly refer not only to the need to develop novel interventions, but more importantly to the optimizing of the utilization of existing evidence-based, accepted and cost-effective therapy.11 Use of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers and beta-blockers is generally high in Europe,12, 13 but levels of use of mineralocorticoid receptor antagonists, cardiac resynchronization therapy and implantable cardioverter defibrillators are much lower.12, 14 There is evidence that the organization of care, including access to cardiology and HF specialists,15 as well as team-based HF clinics and participation in quality improvement programmes,16 are associated with improved use of evidence-based therapy and improved outcomes. Heart failure is a complex syndrome for which multiple evidence-based interventions are now available. Optimal utilization of these requires better communication and collaboration among primary care, cardiology and surgery practitioners. Conflict of interest: none declared.