Association of Endothelin-1 With Accelerated Cardiac Allograft Vasculopathy and Late Mortality Following Heart Transplantation

Abstract

Background: Endothelin-1 (ET-1) has been implicated in the development of post-heart transplantation (HT) cardiac allograft vasculopathy (CAV), but has not been well studied in humans.

Methods and results: In 90 HT patients, plasma ET-1 was measured within 8 weeks after HT (baseline) via a competitive enzyme-linked immunosorbent assay. Three-dimensional volumetric intravascular ultrasound of the left anterior descending artery was performed at baseline and at 1 year. Accelerated CAV (lumen volume loss) was defined with the 75th percentile as a cutoff. Patients were followed beyond the first year after HT for late death or retransplantation. A receiver operating characteristic (ROC) curve demonstrated that a baseline ET-1 concentration of 1.75 pg/mL provided the best accuracy for diagnosis of accelerated CAV at 1 year (area under the ROC curve 0.69, 95% confidence interval [CI] 0.57-0.82; P = .007). In multivariate logistic regression, a higher baseline ET-1 concentration was independently associated with accelerated CAV (odds ratio [OR] 2.13, 95% CI 1.15-3.94; P = .01); this relationship persisted when ET-1 was dichotomized at 1.75 pg/mL (OR 4.88, 95% CI 1.69-14.10; P = .003). Eighteen deaths occurred during a median follow-up period of 3.99 (interquartile range 2.51-9.95) years. Treated as a continuous variable, baseline ET-1 was not associated with late mortality in multivariate Cox regression (hazard ratio [HR] 1.22, 95% CI 0.72-2.05; P = .44). However, ET-1 >1.75 pg/mL conferred a significantly lower cumulative event-free survival on Kaplan-Meier analysis (P = .047) and was independently associated with late mortality (HR 2.94, 95% CI 1.12-7.72; P = .02).

Conclusions: Elevated ET-1 early after HT is an independent predictor of accelerated CAV and late mortality, suggesting that ET-1 has durable prognostic value in the HT arena.

Keywords: Endothelin-1; cardiac allograft vasculopathy; heart transplantation; mortality.

Copyright © 2018 Elsevier Inc. All rights reserved.

Figures

Figure 1.

Comparison of Baseline ET-1 Levels Between HT Patients With and Without Accelerated Changes in IVUS Indices. HT patients with accelerated CAV and negative remodeling had significantly increased baseline ET-1 levels compared to those patients without accelerated disease. There was no difference in baseline ET-1 levels between patients with and without accelerated intimal hyperplasia. Accelerated disease was defined using the 75th percentile as a cutoff. CAV, cardiac allograft vasculopathy; ET-1, endothelin-1; HT, heart transplantation

Figure 2.

Diagnostic Accuracy of Baseline ET-1 in Identifying Accelerated CAV Area under the receiver operating characteristic curve is 0.69 (0.57-0.82), p=0.007. A baseline ET-1 concentration of 1.75 pg/ml provides the greatest diagnostic accuracy (73% sensitivity, 68% specificity) to detect accelerated CAV. Abbreviations as in Figure 1.

Figure 3.

Association of Baseline ET-1 Levels with Lumen Volume Loss Baseline ET-1 levels are categorized as high or low and are plotted against lumen volume loss at 1-year post-HT. The dashed line represents the cutoff for accelerated CAV. CAV, cardiac allograft vasculopathy; ET-1, endothelin-1; HT, heart transplantation

Figure 4.

Impact of ET-1 on late death and re-transplantation Kaplan-Meier analysis demonstrated significantly lower event-free survival among HT patients with baseline plasma ET-1 >1.75 pg/mL. Abbreviations as in Figure 1.