Cardiac allograft vasculopathy: diagnosis,therapy, and prognosis

Development of cardiac allograft vasculopathy represents the major determinant of long-term survival in patients after heart transplantation. Due to graft denervation, these patients seldom present with classic symptoms of angina pectoris, and the first clinical presentations are progressive heart failure or sudden cardiac death. Although coronary angiography remains the routine technique for coronary artery disease detection, it is not sensitive enough for screening purposes. This is especially the case in the first year after transplantation when diffuse and concentric vascular changes can be easily detected only by intravascular ultrasound. The treatment of the established vasculopathy is disappointing, so the primary effort should be directed toward early prevention and diagnosis. Due to diffuse vascular changes, revascularization procedures are restricted only to a relatively small proportion of patients with favorable coronary anatomy. Percutaneous coronary intervention is preferred over surgical revascularization since it leads to better acute results and patient survival. Although there is no proven long-term advantage of drug-eluting stents for the treatment of in-stent restenosis, they are preferred over bare-metal stents. Severe vasculopathy has a poor prognosis and the only definitive treatment is retransplantation. This article reviews the present knowledge on the pathogenesis, diagnosis, treatment, and prognosis of cardiac allograft vasculopathy.The leading causes of death during the first three years after heart transplantation are nonspecific graft failure and infections. Nonspecific graft failure may be caused by chronic graft rejection, while acute graft rejection accounts for no more than 11% of mortality. The major determinants of patient survival after three years are malignancy and cardiac allograft vasculopathy (CAV), also known as transplant coronary artery disease or cardiac transplant vasculopathy. It is detected by coronary angiography in 8% of patients by year 1, 30% by year 5, and 50% by year 10 after transplantation (1). Due to graft denervation, CAV typically develops without the warning symptoms of angina pectoris and manifests with symptoms of graft failure, arrhythmias, or even sudden cardiac death. Patients may present with atypical symptoms such as exertional dyspnea, gastrointestinal distress, diaphoresis, or syncope. It is not unusual that CAV is diagnosed after an incidental finding of Q-waves on ECG or loss of contractile function on a routine echocardiographic exam (2). The vasculopathic lesions in the proximal coronary segments are more focal and eccentric, while the mid and distal coronary segments are affected in a more diffuse and concentric pattern, with typical vessel pruning (Figure 1) (3). Proximal disease is donor-inherited and atherosclerotic in nature, while the mid- and distal disease is more immune-mediated and recipient-acquired. CAV is characterized by diffuse concentric intimal hyperplasia, ie, thickening of the epicardial arteries and concentric medial disease in the coronary microcirculation with the constriction of the external elastic membrane area and lumen loss (4). Unnoticed by coronary angiography, the most of the intimal thickening occurs during the first post-transplant year (5). The disease progression is often complicated by intracoronary thrombosis and subsequent, often silent, acute myocardial infarction (Figure 2) (6). Early mural thrombi primarily contain platelets, while succeeding thrombi are more organized, usually occlusive and primarily consist of fibrin (7). Development and progression of CAV in transplant patients is strongly associated with enhanced platelet activation, although no evidence supports the benefit from aspirin therapy in these patients (8,9).Open in a separate windowFigure 1Diffuse stenosis of the left anterior descending artery and distal pruning of left circumflex artery in a patient 6 years after heart transplantation.Open in a separate windowFigure 2Acute thrombotic occlusion of the right coronary artery manifested as ventricular fibrillation and cardiac arrest in a patient 2 years after heart transplantation.To create uniform definition and enable staging of transplant vasculopathy, the International Society of Heart and Lung Transplantation (ISHLT) proposed a grading system based on the combination of angiographic finding and graft function defined either by ultrasound or invasive hemodynamic measurement (10): CAV₀ (no detectable angiographic lesions) = no vasculopathy; CAV₁ (mild disease) = left main stenosis <50% or primary vessel stenosis <70% (including right coronary artery – RCA) or any branch stenosis <70%, without graft dysfunction; CAV₂ (moderate disease) = left main stenosis <50% or single primary vessel stenosis >70% or isolated branch stenosis >70% in 2 systems, without graft dysfunction; CAV₃ (severe disease) = left main stenosis ≥50% or stenosis >70% in two or more primary vessels or isolated branch stenosis >70% in three systems; or ISHLT CAV₁ or ISHLT CAV₂ with signs of graft dysfunction. Allograft dysfunction is defined as left ventricular ejection fraction ≤45% or evidence of significant restrictive pathology either on echocardiographic exam (E/A ratio >2, isovolumetric relaxation time <60 ms, deceleration time <150 ms) or right heart catheterization (right atrial pressure >12 mm Hg, pulmonary capillary wedge pressure >25 mm Hg, cardiac index <2 L/min/m²). In this nomenclature, primary vessels stand for the proximal and middle thirds of the left anterior descending artery, the left circumflex, the ramus intermedius, and the dominant or co-dominant RCA. Branch vessels denote distal thirds of the primary vessels or large septal, diagonal, and obtuse marginal branch or any portion of a non-dominant RCA (10). CAV is present in 44% of our patients at 5 years after transplantation with the proportion of CAV₁, CAV_2, and CAV₃ of 50%, 32%, and 18%, respectively.