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Pathogenesis and management of cardiac allograft vasculopathy

Pathogenesis and morphology Cardiac transplantation is definitive therapy for severe congestive heart failure. As the management of patients with end-stage heart failure improves and with improved management of infectious complications and acute cellular rejection, survival after heart transplantation has significantly improved in the past 20 years. The major limitations to survival in the first year post-transplantation, acute cellular rejection and infection, can now be successfully treated with improved immunosuppressive agents or antiviral/antibacterial agents. Cardiac allograft vasculopathy (CAV), however, remains the major cause of morbidity and mortality after the first year after heart transplantation [1]. CAV remains a major therapeutic challenge because the therapies that have been attempted have generally been unsuccessful or only partially successful for ameliorating or preventing this disease. The histologic appearance of CAV includes intimal hyperplasia and vascular smooth muscle cell proliferation and resembles restenosis after angioplasty, This indicates that the pathophysiology of this disease, as with restenosis, is a response to injury [2]. For CAV, the exact forms of injury have not been well defined but potentially include the alloimmune response, cytomegalovirus infection, ischemia/reperfusion, the classic atherosclerotic risk factors in nontransplant patients, such as hyperlipidemia and diabetes mellitus and etiologies that are currently unknown [3–17]. CAV can be considered the sum total of a number of stresses and injuries to the allograft. Events involved in the development of CAV include those that occur in the preand posttransplantation periods. Donor brain death may enhance expression of a major histocompatibility complex class I and II antigens and enhanced expression of intracellular adhesion molecule 1 on endothelial surfaces [18,19]. Recurrent lower grades of rejection, reflecting ongoing alloimmune responses may result in vascular damage [20]. Donor-specific antibodies have also been associated with the development of CAV [8–10,21]. There is also an association between cytomegalovirus infections and CAV, with evidence from at least one study that aggressive treatment of cytomegalovirus can ameliorate the development of CAV [11,12]. The use of older donors, which is becoming increasingly common as expanded donor criteria are used, may result in an increased likelihood of CAV [22].