Immune and Nonimmune Predictors of Cardiac Allograft Vasculopathy Onset and Severity: Multivariate Risk Factor Analysis and Role of Immunosuppression

Abstract

We studied 361 patients, to evaluate risk factors for cardiac allograft vasculopathy (CAV) onset and severity/diffusion in heart transplantation (HT). Rejection scores (RS) on endomyocardial biopsy were calculated (first year and whole follow-up). CAV onset was defined as any lesion seen at yearly angiography. A CAV severity/diffusion index was calculated for each patient summing up the scores of all lesions. Cox multivariate analysis included: donor age, sex, and weight; recipient sex, age, pre-HT diagnosis, hypertension, diabetes and hyperlipidemia post-HT; number of treated rejections and RS; and immunosuppressive dosage at 3, 6, and 12 months. CAV frequency was 2% at 1 year, 22% at 5 and 39% at 10 years. Risk factors for CAV onset were older donor age [p < 0.0001, relative risk (RR) = = 9.9], male donor (p < 0.001, RR = = 3.2), high RS for severe (≥ 3A) grades (p < 0.02, RR = = 2.01), high cyclosporine at 3 months (p < 0.02, RR = = 1.9). Risk factors for CAV severity/diffusion were higher donor weight (p < 0.01, RR = = 7.5), high prednisone dosage at 1 year (p < 0.0001, RR = = 21.1), and coronary disease pre-HT (p < 0.002, RR = = 9.7). High RS was an independent predictor for CAV onset, not severity/diffusion. This suggests an immune basis for CAV onset and nonimmune modulation for progression. High RS for severe grades may provide a predictor for patients at risk.

Late Failing Heart Allografts: Pathology of Cardiac Allograft Vasculopathy and Association With Antibody-Mediated Rejection

“…Experimental data from mouse models have demonstrated that alloantibodies may induce the development of fibrous intimal thickening of coronary arteries, a hallmark of human cardiac allograft vasculopathy (CAV). CAV is a multifaceted disease (8)(9)(10), with a complex pathophysiology involving either nonimmune and/or immune factors (11)(12)(13).…”

Coronary Flow: From Pathophysiology to Clinical Noninvasive Evaluation

“…The CFR assessment does not help in differentiating microcirculatory dysfunction and epiacrdial stenoses when both problems are present, but in one case: in patients who underwent heart transplantation. TTE-CFR provides useful information on microcirculation and on the Cardiac Allograft Vasculopathy (CAV), a condition implying both epicardial coronary and microvasculation disease 44 . Angiograpghy usually underestimate the seriousness of the problem 44 and the Intravascular Ultrasound (IVUS) is the (invasive) gold standard examination to perform 45 .…”

“…TTE-CFR provides useful information on microcirculation and on the Cardiac Allograft Vasculopathy (CAV), a condition implying both epicardial coronary and microvasculation disease 44 . Angiograpghy usually underestimate the seriousness of the problem 44 and the Intravascular Ultrasound (IVUS) is the (invasive) gold standard examination to perform 45 . This is a micro-and macrovascular kind of damage and a reduced TTE-CFR allows a diagnosis of CAV if <2.7 (sensitivity 87%, specificity 82%) 46 .…”

Coronary Flow Reserve by Contrast-Enhanced Echocardiography: A New Noninvasive Diagnostic Tool for Cardiac Allograft Vasculopathy

“…Postoperatively, the majority (83%) of patients had received antilymphocyte and/or antithymocite globulin for 3-5 days. Our immunosuppression protocol consisted of standard cyclosporin A (CsA), azathioprine (Aza) and steroid therapy as previously detailed (7,8). The CsA daily dose was adjusted based on trough target levels (C 0 ), as well as the patient's renal function (assessed by blood creatinine): 150-400 ng/mL (first 3 months), 150-300 (4-12 months), 100-250 (>12 months).…”