Chronic Rejection Series: Cardiac Allograft Vasculopathy

Cardiac allograft vasculopathy (CAV) is a leading contributor to late allograft failure, mortality, and morbidity after heart transplantation. The prevalence of moderate to severe CAV over time has not changed significantly, and CAV remains an important contemporary consideration in post–heart transplantation management. The diagnosis and surveillance of CAV include both established and emerging invasive and noninvasive modalities, with a growing interest in understanding microvascular function and coronary physiology. The management of CAV is primarily focused on the prevention of CAV progression and optimizing traditional cardiovascular risk factors. Although mammalian target of rapamycin inhibitors and statins are central to the prevention of CAV progression, there is a lack of novel therapeutics for CAV. The development of new therapies for CAV will require a better understanding of the immune mechanisms underlying the initiation and perpetuation of this condition. CAV is mediated through a complex process involving cells and soluble factors of both innate and adaptive immune systems. Animal studies demonstrated that T cells play a central role in CAV. Both alloreactive T cells, which recognize donor major histocompatibility complex peptides (indirect allorecognition), and autoreactive T cells directed against heart tissue-specific antigens such as cardiac myosin have been shown to trigger CAV in mice. These processes involve the production of donor-specific antibodies and autoantibodies, respectively. Other studies suggest that CAV could be mediated by bystander T cells in a T cell receptor-independent manner and that CAV requires cooperation between T cells and natural killer cells. In addition, the essential role of interferon-γ in CAV has been documented. Whether any of these mechanisms pertain to CAV observed in transplanted patients has not been thoroughly investigated. Gaining insights into this question will be instrumental to the design of immune-based therapies for CAV.