Non-immunologic vascular failure of the transplanted heart

Challenging scientific dogmas, particularly in medicine, is extremely difficult because our natural tendency is to be suspicious of new ideas—secure as we are with what is familiar, especially when treating the afflicted. However, as Martin recently pointed out, the purpose of science, and especially medical science, is to change the world, and changing the world is only possible by introducing new ideas. An accepted dogma in transplant immunology is the idea that rejection of a transplanted organ is mediated by the incompatibility of the recipient’s immune cells to the cells within donor’s allografts. It is also widely recognized that the failure of a transplanted organ—in either the short or the long term—is due to acute or chronic rejection, which always involves the presence of an immunologic event—cellular and/or humoral. However, organs often fail or are rejected without cellular infiltration. Therefore, it is our contention that failure of a transplanted organ is caused by the failure of the microvessels within the allograft to remain open, and not due to an immunologic process mediated by the presence of cellular infiltrates that compromise the allograft. This concept is not limited to organ transplantation, but is relevant to medicine more generally. As comparative analogies, cancer and pregnancy share a common characteristic with solid organ transplantation. Engraftment, cancer growth and metastasis and placentation can only occur if a patent microvasculature is present and if new vessel growth and vascular “remodeling” occur. In cancer, the status of the microvasculature is relevant because tumor growth and metastasis can be impeded by promoting microvascular thrombosis. Conversely, during normal placentation and in tissue engraftment of a transplanted organ, thromboresistance must be promoted to favor vascular patency, vascular remodeling and new vessel growth. Based on our extensive research into heart transplantation, we have found that the failure of a transplanted heart is strongly associated with the loss of the microvasculature within the allograft. It is evident that the long-term survival of a transplanted heart is jeopardized mainly by the development of a vascular disease that we call “transplantassociated coronary artery disease.” This disease is nothing more than a particular form of atherosclerosis. Failure of the microvasculature of the donor allograft occurs because the vessels become prothrombogenic (Figure 1). Three risk factors contribute to prothrombogenicity in allograft vessels: (1) loss of vascular antithrombin; (2) loss of vascular tissue plasminogen activator; and (3) microvascular endothelial activation. We have found that each of these risk factors is associated with the development of transplant-associated coronary artery disease and failure. Our primary finding is that, during the immediate post-transplant period, the microvessels become prothrombogenic, as demonstrated by the presence of microvascular fibrin. The appearance of microvascular fibrin within the first month after transplantation is associated with transplantassociated coronary artery disease and failure. Other findings also support the presence of prothrombogenic microvessels in the allografts as a determinant of outcome. For example, both the depletion of fibrinolytic activators, such as tissue plasminogen activator, and the loss of vascular anti-coagulation, as evidenced by depletion of vascular antithrombin shortly after transplantation, precede the development of transplant-associated coronary artery disease and failure. FurtherFrom the Methodist Research Institute, Clarian Health Partners (Methodist, Indiana University and Riley Hospitals), Indianapolis, Indiana and Department of Biostatistics and Epidemiology, Cleveland Clinic Foundation, Cleveland, Ohio. Supported by the Methodist Research Institute, Clarian Health; Showalter Foundation (Methodist Hospital), Indianapolis, IN; and the American Heart Association, Midwest Affiliate. Reprint requests: Carlos A. Labarrere, MD, Methodist Research Institute, Clarian Health Partners (Methodist, Indiana University and Riley Hospitals), 1701 N. Senate Boulevard, Indianapolis, Indiana 46202. Telephone: 317-962-3537. Fax: 317-9629369. E-mail: clabarrere@clarian.org J Heart Lung Transplant 2003;22:236–240. Copyright © 2003 by the International Society for Heart and Lung Transplantation. 1053-2498/03/$–see front matter PII: 1053-2498(02)00669-1