Allograft Vasculopathy Versus Atherosclerosis

Abstract

Abstract-Over the last 4 decades, heart transplantation (HTx) has evolved as a mainstream therapy for heart failure.Approximately half of patients needing HTx have organ failure consequent to atherosclerosis. Despite advances in immunosuppressive drugs, long-term success of HTx is limited by the development of a particular type of coronary atherosclerosis, referred to as cardiac allograft vasculopathy (CAV). Although the exact pathogenesis of CAV remains to be established, there is strong evidence that CAV involves immunologic mechanisms operating in a milieu of nonimmunologic risk factors. The immunologic events constitute the principal initiating stimuli, resulting in endothelial injury and dysfunction, altered endothelial permeability, with consequent myointimal hyperplasia and extracellular matrix synthesis. Lipid accumulation in allograft arteries is prominent, with lipoprotein entrapment in the subendothelial tissue, through interactions with proteoglycans. The apparent endothelial "intactness" in human coronary arteries of the transplanted heart suggest that permeability and function of the endothelial barrier altered. Various insults to the vascular bed result in vascular smooth muscle cell (SMC) activation. Activated SMCs migrate from the media into the intima, proliferate, and elaborate cytokines and extracellular matrix proteins, resulting in luminal narrowing and impaired vascular function. Arteriosclerosis is a broad term that is used to encompass all diseases that lead to arterial hardening, including native atherosclerosis, postangioplasty restenosis, vein bypass graft occlusion, and CAV. These diseases exhibit many similarities; however, they are distinct from one another in numerous ways as well. The present review summarizes the current understanding of the risk factors and the pathophysiological similarities and differences between CAV and atherosclerosis. (Circ Res. 2006;99:801-815.)

Late Failing Heart Allografts: Pathology of Cardiac Allograft Vasculopathy and Association With Antibody-Mediated Rejection

“…Experimental data from mouse models have demonstrated that alloantibodies may induce the development of fibrous intimal thickening of coronary arteries, a hallmark of human cardiac allograft vasculopathy (CAV). CAV is a multifaceted disease (8)(9)(10), with a complex pathophysiology involving either nonimmune and/or immune factors (11)(12)(13).…”

Cardiac Allograft Vasculopathy: A Review of Risk Factors and Pathogenesis

“…ISHLT issued a consensus statement in 2010 stating that coronary angiography in conjunction with assessment of cardiac allograft function is likely to detect CAV with high degree of confidence [20]. Despite pathological differences, CAV and traditional coronary artery disease (CAD) do share some similarities and have some common contributing factors (Table 2) [10,[21][22][23]. Immunologic factors play a major role in the development of graft coronary artery disease (GCAD) or CAV, while metabolic and genetic factors play a dominant role in the development of traditional CAD.…”

“…The characteristic lesions that are seen in CAV are also noted in other solid organ transplants such as kidney, liver, and lung [24][25][26]. CAV is not a homogenous disease and lesions may vary morphologically ranging from lipid-rich atherosclerotic plaques to fibrointimal proliferation of the allograft vasculature [10,17,21,22]. The atherosclerotic lesions seen in the allografts can be either donor derived lesions or de novo lesions developed after transplantation.…”

“…Traditional CAD is usually characterized by focal eccentric hypertrophy and formation of fibrofatty plaques with disruption of the elastic lamina [21,25,27]. In contrast, in CAV, histologically the elastic lamina is primarily intact, and narrowing of the vasculature is circumferential rather than eccentric [10,[27][28][29][30][31]. Fibrofatty plaques could be seen in cardiac allografts, however, characteristic lesion of CAV is fibrointimal hyperplasia of the vessel wall leading to insidious narrowing of the vasculature of the allograft [10,[27][28][29][30][31].…”

“…Although immune mediated factors play a major role, several studies have demonstrated the role of traditional risk factors of coronary artery disease (CAD) in the progression of CAV [8][9][10]. Based on progress gained in this field, CAV is currently viewed as an "impaired response to vascular injury" resulting in altered permeability, migration of smooth muscle cells and fibroproliferation [10]. This results in diffuse concentric hypertrophy of the vessel wall and microvascular occlusion leading to pathologic remodeling of the transplant heart vasculature [8].…”