Changes in Plasma Levels of VEGF-C and Endothelin-1 During the First Post-Transplant Year Are Predictive of Cardiac Allograft Vasculopathy: Results From the CTOT-05 Study.

Abstract

Background: We tested the hypothesis that sequential monitoring of angiogenesis-related factors predicts early cardiac allograft vasculopathy (CAV). Subjects were randomly selected from 106 subjects in the CTOT-05 study who had paired IVUS evaluations; 20 test subjects, who had an increase in MIT of > 0.5 mm in the LAD in the first year after transplant (CAV group), and 40 control subjects were included. We measured 17 candidate biomarkers by Luminex multiplex analysis. Data on pre-transplant plasma samples (N=52) and paired pre-transplant and 1 year post-transplant plasma samples (N=46), were analyzed using logistic regression in a multivariate forward selection model. Results: The study population was 20% female with a mean age of 53 years. Indication for transplant was idiopathic DCM in 41% and ischemic CM in 32% of patients. Clinical characteristics associated with CAV included white race (P=0.03), male recipient (P=0.04), and negative recipient CMV IgG (P=0.03). In pre-transplant samples, higher plasma levels of Endothelin-1 (OR 20.2; CI 1.42-286) and Leptin (OR 11.32; CI 1.13-113) were associated with an increased risk of CAV, while EGF (OR 0.11; CI 0.01-0.95), FGF-2 (OR 0.04; CI 0-1.03) and IL-8 (OR 0.36; 0.1-1.2) were protective. A bootstrapped multivariate model using these 5 molecules was used to construct a receiver operating characteristic (ROC) curve with an area under the curve (AUC) of 0.768. An increase in VEGF-C (OR 2.6; CI 1.12-6.20) and FGF-1 (OR 12; CI 0.8-177) from the pre-transplant visit to 1 year post-transplant was associated with CAV, while Endothelin-1 was found to be protective (OR 0.25; CI 0.07-0.91). A second bootstrapped multivariate model using changes in concentrations of these 3 molecules revealed a ROC with an AUC of 0.766. Conclusions: Increases in plasma levels of VEGF-C and decreases in levels of Endothelin-1 over the first post-transplant year are associated with the development of CAV by IVUS. Sequential measurements of these biomarkers will identify patients in whom medical interventions to prevent CAV can be tested in future clinical trials.