Alloimmunity and nonimmunologic risk factors in cardiac allograft vasculopathy

Abstract

Graft vasculopathy is an accelerated form of coronary artery disease that occurs in transplanted hearts. Despite major advances in immunosuppression, the prevalence of the disease has remained substantially unchanged during the last two decades. According to the 'response to injury' paradigm, graft vasculopathy is the result of a continuous inflammatory response to tissue injury initiated by both alloantigen-dependent and independent stress responses. Experimental evidence suggests that these responses may become self-sustaining, as allograft re-transplantation into the donor strain at a later stage fails to prevent disease progression. Histological evidence of endothelitis and arteritis, in association with intima fibrosis and atherosclerosis, reflects the central role of alloimmunity and inflammation in the development of arterial lesions. Experimental results in gene-targeted mouse models indicate that cellular and humoral immune responses are both involved in the pathogenesis of graft vasculopathy. Circulating antibodies against donor endothelium are found in a significant number of patients, but their pathogenic role is still controversial. Alloantigen-independent factors include donor-transmitted coronary artery disease, surgical trauma, ischaemia-reperfusion injury, viral infections, hyperlipidaemia, hypertension, and glucose intolerance. Recent therapeutic advances include the use of novel immunosuppressive agents such as sirolimus (rapamycin), HMG-CoA reductase inhibitors, calcium channel blockers, and angiotensin converting enzyme inhibitors. Optimal treatment of cardiovascular risk factors remains of paramount importance.

Cardiac Allograft Vasculopathy: A Review of Risk Factors and Pathogenesis

“…It is suggested that in these combined heart-lung and heartkidney transplants, the lung and renal system become the primary regions of interface between recipient and host immune systems; hence, graft coronary vasculature is relatively less affected [26,38,39]. Immunologic mechanisms that regulate CAV are complex and heterogeneous and involve cellular and humoral aspects of adaptive and innate immune response pathways [7,9,19,[35][36][37][40][41][42].…”

“…Immune response is further propagated by recruitment of macrophages and other pro-inflammatory cells on to the vessel wall. Activated macrophages elaborate cytokine production and growth factor secretion [9,60,61]. Intercellular communication and coordination between infiltrating cells, adhesion molecules, endothelium, and various components of the extracellular matrix are required for successful recruitment and transmigration of leukocytes.…”

“…Intercellular communication and coordination between infiltrating cells, adhesion molecules, endothelium, and various components of the extracellular matrix are required for successful recruitment and transmigration of leukocytes. This is followed by altered permeability, smooth muscle cell proliferation and migration along with synthesis and deposition of extracellular matrix [9]. This eventually leads to the characteristic vasculopathic changes of CAV i.e., fibromuscular proliferation of neointima.…”

“…CKD, obesity and smoking have demonstrated risk association with development of CAV [2,9,10,43,50,61,72,138]. Smoking causes endothelial dysfunction and is an important risk factor in the pathogenesis of both CAV and traditional CAD.…”

“…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].…”