Cardiac Allograft Vasculopathy

Abstract

Abstract-Cardiac allograft vasculopathy (CAV) continues to limit the long-term success of cardiac transplantation.Recent insights have underscored the fact that innate and adaptive immune responses are involved in the pathogenesis of CAV. Vascular lesions are the result of cumulative endothelial injuries induced both by alloimmune responses and by nonspecific insults (including ischemia-reperfusion injury, viral infections, and metabolic disorders) in the context of impaired repair mechanisms. Intravascular ultrasound is the most sensitive method for detection of CAV, and progressive intimal thickening in the first posttransplant year identifies patients at high risk for future cardiovascular events. Encouraging results with regard to the detection of CAV by noninvasive methods should be an incentive to apply routine noninvasive imaging during mid-to long-term follow-up. Improved immunosuppressive drugs, including mycophenolate mofetil and proliferation signal inhibitors, as well as statins (in part via immunomodulation), have beneficial effects on CAV progression, although there is still a need to confirm the impact of vasodilators in improving outcome after heart transplantation. Coronary revascularization for CAV is only palliative, with no long-term survival benefit. Three main strategies for CAV prevention are currently under investigation: inhibition of growth factors and cytokines, cell therapy, and tolerance induction. However, because individual responses to an allograft change over time, assays to monitor the recipient's immune response and individualized methods for therapeutic immune modulation are clearly needed. (Circulation. 2008;117:2131-2141.)

Downstream coronary effects of drug-eluting stents

“…[19][20][21][22] A variety of studies investigating coronary artery disease in heart transplant patients, who have baseline endothelial dysfunction, have shown that antiproliferatives such as sirolimus attenuate the rate of atherosclerotic progression. 29,30 In addition, paclitaxel is a well-known immunomodulatory agent and has also been associated with atherosclerotic regression in animal models, as well as reduced inflammation in stented porcine arteries. 23,31 Furthermore, given that the product labeling and pharmacokinetic studies in sirolimus-eluting stents describe serum detectability of antiproliferative agents for over 2.5 weeks and an estimated 3 month elution period after implantation (depending on stent type), one would expect these drugs to have long-term effects on the downstream vascular bed.…”

Transplant coronary heart disease: challenges and solutions

“…The sensitivity of coronary angiography alone for CAV is suboptimal because of the diffuse nature of the disease and lack of a normal reference vessel for grading stenosis in many cases. 3,5,20 Despite the lack of sensitivity for early CAV lesions, angiography provides important prognostic information and reliably excludes obstructive CAV. 3 The International Society of Heart Lung Transplantation (ISHLT) has developed a nomenclature to help standardize the way CAV is reported and compared which has become the preferred classification system 1 ( Figure 4).…”

“…18 Although not completely understood, it is thought that the pathogenesis of CAV involves repeated injuries to the endothelium from a variety of factors such as cellular-mediated rejection, alloimmune factors, ischemiareperfusion injury at time of transplant, CMV infection, immunosuppression medications, systemic inflammation, and traditional atherosclerosis risk factors. 3,[19][20][21] A schematic and theoretical progression of disease is illustrated below. Damage to the endothelium leads to smooth muscle cell proliferation, infiltration of the intima with inflammatory cells, and collagen deposition.…”

“…20,21 Roughly 9% of patients who undergo transplantation are sensitized to HLA antibodies (panel reactive antigen .10%) at the time of the transplant. Clinical outcomes in these patients are worse because of increased rejection and CAV.…”

Monitoring of allograft vasculopathy by intravascular ultrasound one month and one year after heart transplantation: A single center study

“…CAV is characterized by intimal proliferation which progresses at different periods after transplantation, resulting in a luminal narrowing in the allograft arteries and is the leading cause of morbidity and mortality in cardiac transplant recipients 1 . Therefore, CAV represents a major clinical concern and the focus of research 2,3.…”