Angiotensin-Converting Enzyme Inhibition Early After Heart Transplantation

Abstract

Background: Cardiac allograft vasculopathy (CAV) remains a leading cause of mortality after heart transplantation (HT). Angiotensin-converting enzyme inhibitors (ACEIs) may retard the development of CAV but have not been well studied after HT.

Objectives: This study tested the safety and efficacy of the ACEI ramipril on the development of CAV early after HT.

Methods: In this prospective, multicenter, randomized, double-blind, placebo-controlled trial, 96 HT recipients were randomized to undergo ramipril or placebo therapy. They underwent coronary angiography, endothelial function testing; measurements of fractional flow reserve (FFR) and coronary flow reserve (CFR) and the index of microcirculatory resistance (IMR); and intravascular ultrasonography (IVUS) of the left anterior descending coronary artery, within 8 weeks of HT. At 1 year, the invasive assessment was repeated. Circulating endothelial progenitor cells (EPCs) were quantified at baseline and 1 year.

Results: Plaque volumes at 1 year were similar between the ramipril and placebo groups (162.1 ± 70.5 mm3 vs. 177.3 ± 94.3 mm3, respectively; p = 0.73). Patients receiving ramipril had improvement in microvascular function as shown by a significant decrease in IMR (21.4 ± 14.7 to 14.4 ± 6.3; p = 0.001) and increase in CFR (3.8 ± 1.7 to 4.8 ± 1.5; p = 0.017), from baseline to 1 year. This did not occur with IMR (17.4 ± 8.4 to 21.5 ± 20.0; p = 0.72) or CFR (4.1 ± 1.8 to 4.1 ± 2.2; p = 0.60) in the placebo-treated patients. EPCs decreased significantly at 1 year in the placebo group but not in the ramipril group.

Conclusions: Ramipril does not slow development of epicardial plaque volume but does stabilize levels of endothelial progenitor cells and improve microvascular function, which have been associated with improved long-term survival after HT. (Angiotensin Converting Enzyme [ACE] Inhibition and Cardiac Allograft Vasculopathy; NCT01078363).

Keywords: cardiac allograft vasculopathy; coronary physiology; microcirculation.

Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Figures

Figure 1. Enrollment flowchart

A total of 96 patients were randomized to ramipril (n = 47) or placebo (n = 49). Comparisons of baseline IVUS data were performed between 43 patients in the ramipril group and 44 patients in the placebo group where IVUS images were analyzable. Comparisons of 1 year IVUS data were performed between 39 patients in the ramipril group and 41 patients in the placebo group where IVUS images were available (survived at 1 year) and analyzable. In patients both baseline and 1 year IVUS were analyzed, we performed paired comparisons within the group (39 serial IVUS cases in the ramipril group and 38 serial IVUS cases in the placebo group). IVUS = Intravascular Ultrasound.

Figure 2. Percent change in FFR, CFR and IMR from baseline to 1 year

In patients assigned to the ramipril therapy, improvement of microvascular function as assessed by CFR and IMR were observed. CFR = Coronary Flow Reserve; FFR = Fractional Flow Reserve; IMR = Index of Microcirculatory Resistance.

Figure 3. Log10 of the percentage of circulating EPCs at baseline and at 1 year after transplant for the placebo group or the ramipril-treated group

Percentage of circulating EPCs significantly decreased in the placebo group from baseline to 1 year whereas it was similar in the ramipril group. EPC = Endothelial Progenitor Cell.

Central Illustration. Effects of ACE Inhibition Early After Heart Transplantation

Key positive and negative effects of the ACEI ramipril when administered early after heart transplantation.