Kobashigawa JA, Katznelson S, Laks H, Johnson JA, Yeatman L, Wang XM, Chia D, Terasaki PI, Sabad A, Cogert GA, Trosian K. 1995.
Effect of pravastatin on outcomes after cardiac transplantation.
New England Journal of Medicine 333: 621-627.
This landmark paper presents the findings of a randomized controlled trial in heart transplantation examining the effects of the hydroxy-methylglutaryl coenzyme A (HMG-CoA) inhibitor pravastatin on post-transplant outcomes. The study enrolled 97 adults who underwent cardiac transplantation at the UCLA Medical Center between July 1992 and February 1994. The patients were randomly assigned to receive pravastatin (47 patients) or no pravastatin (50 patients) commencing one or two weeks after transplantation. The primary end points included cholesterol levels, rejection, survival, and the development of cardiac allograft vasculopathy (CAV) at one year after transplantation. All patients who presented with symptoms and signs of heart failure were assumed to have rejection. Angiography and intravascular ultrasound (IVUS) were performed at baseline and one year after transplantation.
The results of the study showed that pravastatin safely lowered cholesterol levels, increased one-year survival, decreased rates of rejection with hemodynamic compromise, and lowered the incidence of CAV in heart transplant recipients. When this study was published, there was a dearth of treatment options for CAV and little was known about the underlying causes. Even in the modern era, CAV remains a formidable barrier to long-term survival. Therefore, the discovery of a safe and widely available drug capable of reducing the development of CAV was of major significance to the field.
An interesting question that arose from the results was whether the benefits of taking pravastatin after transplantation were secondary to lower cholesterol levels or instead were from direct immune system modulation. Before the study was completed it became apparent that pravastatin caused a reduction in the rate of rejection with hemodynamic compromise. To elucidate the underlying mechanisms of this benefit, natural killer (NK) cell assays were conducted by Dr. Terasaki’s laboratory on the final 20 patients enrolled in the trial. The NK cytotoxicity assay made use of the eponymous Terasaki trays: Microwells that allow a tenfold reduction in the number of effector cells needed.
Even though the analysis of NK cell cytotoxicity was not the primary focus of this study, the findings proved to be invaluable in demonstrating a pleiotropic immunomodulatory property of statins that was cholesterol independent. In addition, this study further shaped our understanding of rejection and, in particular, antibody-mediated rejection (AMR). At the time of this study, AMR was contentious and many transplant specialists doubted its existence. They believed rejection was a solely T cell mediated process. As everyone knows, Paul Terasaki was one of the few that insisted on the existence of AMR and more specifically an antibody role in chronic rejection. We now know from analyzing gene transcripts in endomyocardial biopsy samples that NK cells play a significant role in AMR. It is also believed that AMR is a major contributor to the development of chronic rejection known in heart transplantation as cardiac allograft vasculopathy (CAV). In fact, CAV was reduced in the pravastatin-treated group. The truly innovative laboratory methods of Dr. Terasaki used in this and subsequent studies improved our understanding of the pathophysiology of cellular and antibody mediated rejection.
Jon A. Kobashigawa MD
DSL/Thomas D. Gordon Professor of Medicine
Director, Advanced Heart Disease Section
Director, Heart Transplant Program
Associate Director, Cedars-Sinai Heart Institute
Associate Director, Comprehensive Transplant Center
Cedars-Sinai Medical Center, Los Angeles, California