Cardiovascular complications after transplantation: Treatment options in solid organ recipients

https://doi.org/10.1016/j.trre.2013.12.001Get rights and content

Abstract

Premature cardiovascular disease is the commonest cause of death in solid organ transplant recipients, with coronary artery disease, sudden cardiac death and heart failure being highly prevalent. There are unique factors leading to CV disease in organ transplant recipients that include underlying comorbidities, and metabolic effects of immunosuppression. As a consequence management strategies developed in the general population may have limited benefit. In this review, we will focus on renal transplantation, where most research has been carried out and, despite incomplete understanding of the disease process, the incidence of cardiovascular disease appears to be falling.

Introduction

Solid organ transplantation is the established treatment for end stage organ disease, associated with improved life expectancy and quality of life and, for renal transplantation, substantial cost savings over maintenance dialysis. Improved management of immunosuppression and infection, coupled with improvements in surgical techniques and peri-operative management, have improved transplant survival and significantly reduced short and long term post-transplant morbidity. Partly as a consequence of these developments, we are increasingly aware of the long-term risks to transplant recipients. Cardiovascular disease (CVD) is a leading cause of premature death and hospitalization in solid organ transplant recipients and, due to “death with a functioning graft”, is a leading cause of graft failure. Thus, strategies that reduce the prevalence and impact of CVD would be expected to prolong patients and graft survival.

We have greater understanding of the importance of CVD in renal transplant recipients (RTR) and that will be the focus of this review. Pancreatic transplantation is generally performed in patients with diabetes and end stage renal disease (ESRD), either as simultaneous kidney pancreas transplant (SPK) or pancreas after kidney transplant (PAK). These individuals are therefore covered in the section on renal transplantation. Less is known about recipients of lung and liver transplants, whilst obliterative coronary disease – linked to rejection – is a specific problem for heart transplant recipients.

CVD is the commonest cause of death and graft loss in RTR [1], [2]. This trend is likely to continue, as we expand the criteria for transplant recipients, to include older patients with co-morbid disease, including CV diseases. The incidence of CVD in RTR is 3–5 times that of age-matched patients in the general population, but is substantially lower than the risk in patients treated by maintenance haemodialysis, where the incidence is 10–20 times that of the general population. Moreover, the increase in risk appears to be greatest in younger patients [1], and the pattern of disease is different from the general population, with a greater incidence of sudden, presumed arrhythmic, cardiac death and heart failure, rather than atherosclerotic coronary artery disease (CAD). In this regard, RTR occupy a position between the general population and patients receiving maintenance dialysis – who have a higher incidence of CV events not due to CAD [3], [4], [5]. Patients with ESRD, particularly those receiving maintenance haemodialysis, have a high prevalence of “uraemic cardiomyopathy”, the principal features of which are left ventricular hypertrophy (LVH) and myocardial fibrosis, which predispose to heart failure and arrhythmias.

Our understanding of the incidence, prevalence and the natural history of CVD in RTR comes from registry data, observational follow-up studies and a few large clinical trials. These datasets have strengths and weaknesses: events in clinical trials are independently verified, whilst the numbers of patients in registry and observational analyses are much greater. One caveat is application of caution when pooling end-points. This is commonly used in analyses where end points share common pathophysiology. Thus, in the general population cardiac death, heart failure and myocardial infarction (MI) may all be due to coronary events; however this assumption may not be true in the transplant population.

In RTR the incidence of CVD is high. The Patient Outcomes in Renal Transplantation (PORT) study followed 23, 575 adult RTR over a median of 4.5 years and demonstrated cumulative incidence of CV events (pooled from proven myocardial infarction, coronary intervention and cardiac death) as 3.1, 5.2 and 7.6% at one, three and five years after transplantation respectively [5]. In the placebo arm of the Assessment of LEsecol in Renal Transplantation (ALERT) [3] study, which investigated the effect of fluvastatin on CV outcome in RTR with stable graft function, the rate of CV events (pooled from CV death or non-fatal MI) was 21.5 per 1000 patient-years. In the ALERT study there was a similar rate of fatal and non-fatal CV events, in contrast to populations at comparable, overall CV risk (e.g. WOSCOPS and 4S trial), where non-fatal events predominate. The ALERT study also showed that individual cardiac events may have different determinants. For example, myocardial infarction was dependent upon lipids and conventional risk factors for CAD, whereas the risk factors for cardiac death included renal dysfunction, blood pressure and LVH [6]. Thus, in RTR the risk of CVD is increased, the prevalence of “conventional” CV risk factors is high but the relative proportions of CV events may differ compared to the general population. Individual risk factors may be more strongly associated with one or more CV outcomes and in order to explore the CVD-risk factor relationship, and to understand the management of CVD in RTR, it is necessary to examine individual risk factors (Fig. 1).

Section snippets

Hypertension

Hypertension is a conventional CV risk factor, which affects the majority of RTR. Its development is associated with pre-transplant hypertension, poorer allograft function and the effects of immunosuppression, specifically calcineurin inhibitors (CNIs), especially cyclosporine, and corticosteroids [7], [8]. The mechanism of CNI induced hypertension is believed to be tubular sodium retention and CNI-induced nephrotoxicity, whereas corticosteroids increase blood pressure by increasing salt and

Conclusions

Premature CV disease has become a focus for research and management in solid organ recipients due to its high prevalence and impact on patient and graft survival. There is evidence to support antihypertensive therapy, lipid lowering with statins and the prevention of post-transplant diabetes for prevention of CVD in solid organ transplant recipients. Furthermore, good graft function is significantly associated with reduction in CV risk and, despite the metabolic consequences of

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