Cardiac allograft vasculopathy

Did You Know?

• A few recipients regain nerve supply years after transplantation and may develop unusual chest pain.
• The risk of major adverse cardiovascular events is increased 3.4-fold if CAV is present on angiography.
• Donor brain death, particularly explosive brain death, is a significant risk factor for CAV.

Mechanism

The pathogenesis of CAV involves both immunological (innate and adaptive) and nonimmunological factors. Unlike typical atherosclerosis, CAV histology shows concentric intimal thickening of the main epicardial and intramyocardial arteries, often obliterating smaller vessels within a few years. Smooth muscle cell migration, foamy macrophages, and lymphocytic infiltrates are present, and the disease affects the entire length of the arteries. Compensatory arterial dilation does not occur, and calcification, if present, appears late. Thrombotic occlusion is rare. Inflammation and endothelial injury may be triggered by donor arrest, organ procurement, and allograft ischemia-reperfusion.

Diagnosis

Because symptoms are often absent or variable, regular surveillance is essential. Coronary angiography, the diagnostic test of choice, is typically performed annually for the first five years after transplantation. Angiography characteristically shows diffuse stenoses in large coronary arteries and a reduced number of smaller arteries, termed peripheral pruning. However, CAV may not be apparent by angiography alone because it frequently affects the entire length of the artery. Intravascular ultrasound (IVUS) is more sensitive for detecting subtle increases in intimal thickness; a greater than 0.5 mm increase at one year predicts angiographic CAV within five years. IVUS is mainly used in research due to its invasiveness, contrast requirement, and cost. Dobutamine stress echocardiography has 85% sensitivity for CAV, and a negative result correlates with good prognosis. Other noninvasive tests include positron emission tomography and CT angiography. ECGs may show atypical ischemic features. Biomarkers such as C-reactive protein, brain natriuretic peptide, and troponin I have been suggested as indicators of increased risk.

Treatment

Prevention of progression is important, as established CAV is often resistant to treatment. Statins such as pravastatin and simvastatin are started early after transplantation to reduce incidence and severity. Vitamins C and E, combined with immunosuppressants, may slow progression. Aspirin is routinely given. Upon detection, mTOR inhibitors like sirolimus and everolimus can slow disease progression. For clinically significant focal disease, percutaneous coronary interventions may be used, but restenosis is common. Repeat heart transplantation may be considered.

History

CAV was not initially anticipated as a complication; early survivors of heart transplantation were found to have this vasculopathy at post-mortem. Early suggestions emerged that preventing cytomegalovirus infection could reduce CAV prevalence. Over time, recipient characteristics changed: earlier recipients were younger, had more rejection and cardiovascular risk factors, and used statins less often. Later recipients routinely received statins, mycophenolate mofetil, and CMV prophylaxis, and were monitored for antibody-mediated rejection. Before 2010, no uniform nomenclature existed; the ISHLT published a consensus statement on standard language for CAV that year.