The renin–angiotensin hypothesis for the pathogenesis of cardiac allograft vasculopathy

The precise molecular mechanism for the development of cardiac allograft vasculopathy (CAV) after heart transplantation is not known. We, thus, hypothesize that increased activity of renin–angiotensin system (RAS) is important for the progression of CAV. There is evidence to support this concept. RAS via its principal effector molecule, angiotensin II exerts multitude of actions on vascular structure and function including regulation of vasomotor tone, cell growth/apoptosis, fibrosis and inflammation, which are particularly relevant to the genesis of atherosclerotic lesions. Risk factors, which increase predisposition to CAD, are known to activate tissue RAS and thus influence its progression. Importantly, CAD risk factors are also associated with accelerated CAV progression after transplantation. Whereas angiotensin converting enzyme (ACE) gene polymorphism increases the predisposition, pharmacological inhibition of RAS seems to reduce the incidence of CAV. These observations may support our hypothesis, provide a plausible explanation for the molecular mechanisms underlying the development of accelerated CAV and has predictions that can be tested.