Protecting the Heart Allograft With a Statin: The Perfect Intervention or Too Good to Be True?

Josef Stehlik, MD, MPH; Line Kemeyou, MD

Disclosures

Circulation. 2019;140(8):641-644. 

More than 50 years since its first clinical application, heart transplantation provides an opportunity for an increasing number of advanced heart failure patients to regain active lifestyle and longevity.[1] This is a result of ongoing innovation in the field, which has for years been aimed at improving posttransplant survival. Many of the successful interventions have focused on posttransplant care and included, for example, introduction of new immunosuppressive drugs, standardization of rejection surveillance and rejection grading, or implementation of protocolized antimicrobial prophylaxis (Figure).[2] Pretransplant interventions have been explored less frequently. Protection of the donor allograft between procurement and transplant has until recently remained without major change, with use of hypothermic preservation with a choice of several cardioplegia solutions. Donor interventions have focused on optimizing donor hemodynamics, oxygen delivery, and neurohormonal balance after brain death. As far as pharmacological interventions, several investigations tested the administration of steroids and thyroid hormone during donor management, with a goal of improving function of the cardiac allograft before procurement.[3] Although there is some evidence that these drugs may improve hemodynamics in the brain-dead donor and increase the use of donor organs, it is not clear that these interventions have sustained positive effects on the allograft after transplant.

Figure.

Median survival after heart transplantation, approximate time of introduction of key immunosuppressive agents and standardized clinical care approaches, and potential future directions (adapted from Stehlik et al2).

In this issue of the Journal, Nykänen[4] presents results of a randomized clinical trial (RCT) in the cardiac donor. The investigators randomized 84 brain-dead organ donors to 80 mg of simvastatin or placebo. A single dose of the drug was administered through a nasogastric tube within 2 hours of declaration of brain death, and the heart was procured for transplant on average 12 hours later. Donor simvastatin treatment resulted in reduced heart recipient plasma levels of troponin and lower serum levels of NT-proBNP (N-terminal pro-B-type natriuretic peptide) within 1 week of transplant and in a reduction in the number of treated rejections with hemodynamic compromise. Meanwhile, biopsy-proven rejection and survival of the transplant recipients were similar in the 2 groups.

Statins have played a key role in reduction of cardiovascular events in the modern era, and their use in cardiovascular care is now well established.[5] In addition to reducing cholesterol synthesis through inhibition of 3-hydroxy-3-methyl-glutaryl-CoA reductase, statins have other favorable pleiotropic effects. However, it took hundreds of patient-years of exposure to statins in RCTs to ascertain the benefit of the treatment. Is it therefore biologically plausible for a single dose of a statin to alter the health of the heart about to be transplanted such that meaningful benefit could be seen after transplant?

It should be noted that effects of statins on the heart transplant recipient have been studied. All heart transplant recipients are at risk for cardiac allograft vasculopathy, a form of coronary disease characterized by diffuse intimal proliferation of the coronary vasculature, a process that is to a large extent immune-mediated. In a single-center RCT in the 1990s, Kobashigawa et al[6] randomized 97 patients to 20 mg of pravastatin or placebo 1 to 2 weeks after heart transplantation. Twelve months after transplantation, pravastatin-treated patients had less cardiac rejection with hemodynamic compromise, lower incidence of cardiac allograft vasculopathy, and better survival. The rate of biopsy-proven rejection was similar among the 2 treatment groups. The mortality benefit in such a small study was not the only surprising result. Notably, the survival difference was apparent within weeks of randomization. Further, these findings were replicated by Wenke et al,[7] who randomized 72 patients to simvastatin versus placebo; simvastatin was started 4 days after transplant and titrated for a target low-density lipoprotein cholesterol level of 110 to 120 mg/dL. The primary outcome 4 years after transplant showed higher survival, less cardiac allograft vasculopathy, and a trend for lower incidence of serious rejection in the group of patients treated with pravastatin. The outcome assessment was planned for 4 years after transplant because it was expected that significant time would be needed to accrue the benefit of statin therapy. However, again, the survival benefit was seen early, in the first few months after transplant, with no demonstrable divergence of the survival curves between years 2 and 4.[7] The authors of both investigations extended the follow-up of the study subjects for up to a decade after transplant, and the results of these studies indicated that the statin effect on survival after transplant was bimodal. First, there was a survival benefit in the initial few months after transplant, followed within several years by a more gradual survival benefit likely resulting from lower incidence of cardiac allograft vasculopathy.[8,9]

The question at hand therefore is, What is (are) the mechanism(s) of the early mortality benefit and reduction in hemodynamic compromise seen in heart transplant recipients treated with statins? It has been proposed that statins in the presence of calcineurin inhibitors may exert an immunomodulatory effect that leads to reduced natural killer cell activity, reduced T-cell response, reduced chemokine synthesis by mononuclear cells, and inhibition of the expression of MHC-II genes. However, many of these phenomena have been studied in vitro or in experimental models.[10] To what extent these processes play a role in the clinical scenario of a transplant recipient on multiple immunosuppressive medications is unknown. Additional potential mechanisms may include the strong antiinflammatory effects of statins,[11] upregulation of endothelial nitric oxide synthase, and downregulation of growth factor genes responsible for smooth muscle cell proliferation.[12,13] Is it possible that these pleiotropic effects of stains could lead to changes in the donor allograft before transplant that are profound enough to alter its function after transplant? The authors make a convincing argument for this hypothesis with their preclinical data, in which simvastatin administered to heart transplant donors in a rat model resulted in inhibition of microvascular endothelial cell and pericyte RhoA/Rho-associated protein kinase activation and endothelial cell–endothelial cell gap formation, decreased intragraft mRNA levels of hypoxia-inducible factor-1α, nitric oxide synthase, and endothelin-1, and increased heme oxygenase-1.[14] In addition, simvastatin treatment in the donor inhibited cardiac allograft inflammation, transforming growth factor β-1 signaling, and myocardial fibrosis. In sum, these data indicated that simvastatin treatment of the donor resulted in mitigation of a number of noxious processes triggered by brain death and by ischemia and reperfusion of the allograft that take place in the transplant process.

In a bold move, Nykänen[4] took the preclinical findings into the clinic. Administration of simvastatin to the donor before organ procurement reduced posttransplant troponin (but not creatine kinase-MB) and NT-proBNP concentrations in the recipient serum. Although this finding is intriguing, its long-term clinical significance could be questioned, because posttransplant elevation of these markers has not been known to be associated with long-term adverse outcome. Of 47 cytokines tested, donor simvastatin treatment reduced recipient plasma levels of C-X-C motif chemokine 10, platelet-derived growth factor-BB, interleukin-1α, and placental growth factor. Although the large number of cytokines tested made these analyses quite exploratory, the results seem to support the notion that the effects described in the preclinical rat model may also take place in human heart transplantation. The incidence of primary graft dysfunction was not impacted by simvastatin, nor was incidence of biopsy-proven acute cellular or antibody-mediated rejection or mortality. Intriguingly, treatment of rejection (or presumed rejection) with hemodynamic compromise was cut in half in the simvastatin group. It is not immediately clear what processes were responsible for the hemodynamic compromise in these patients, most of whom did not have biopsy-proven rejection, but in whom the clinical team was compelled to treat as such; and, why this event was less likely when donors were treated with simvastatin. Regardless, this clinical scenario, and the apparent reduction of the likelihood of hemodynamic compromise mediated by statin therapy, are extraordinarily similar to what was seen in the statin RCTs conducted in the 1990s.[6,7]

The current study has important limitations. There was significant disbalance in baseline characteristics of the donors in the 2 groups, likely resulting from the expected heterogeneity of donors in this modestly sized study. The absolute rate of rejection with hemodynamic compromise was unusually high in both the treatment and the control arms. It is also not immediately clear whether statins were administered to all recipients after transplant and when these were started.

Despite these limitations, the study provides important new information. It extends findings that showed benefit of donor statin administration in an experimental model to clinical transplantation. These findings are far from definitive; however, the study provides safety and feasibility data for larger-scale testing of this intervention in the multiorgan donor. Importantly, the study results also raise the question of whether additional benefit could be derived from earlier use of statins in the transplant recipient, perhaps when initiated even before the transplant and continued in the immediate posttransplant period. The authors should also be commended for successfully conducting a RCT in the exceptionally challenging circumstances of multiorgan donation, where a number of multidisciplinary teams are involved in clinical decision-making at diverse hospitals at all times of day and night. Many aspects of transplant care are currently guided by expert opinion rather than by firm evidence. Well-powered RCTs with sufficient follow-up are needed to fill this gap.

As the transplant field continues its quest for continued improvement of survival, this study indicates that targeted interventions before transplant may be the next frontier in this endeavor (Figure). This could be in the form of an intervention in the organ donor, the organ recipient, or even the donor allograft, as technological advances in ex situ organ perfusion[15] may provide an additional platform for interventions limited to the specific organ, in a controlled environment, and under less time pressure.

Comments

3090D553-9492-4563-8681-AD288FA52ACE

processing....