Randomized Placebo-Controlled Trial to Evaluate Effects of Eplerenone on Myocardial Perfusion and Function Among Persons With Human Immunodeficiency Virus (HIV)-Results From the MIRACLE HIV Study

Abstract

Background: Increased renin angiotensin aldosterone system (RAAS) activity may contribute to excess cardiovascular disease in people with HIV (PWH). We investigated how RAAS blockade may improve myocardial perfusion, injury, and function among well-treated PWH.

Methods: Forty PWH, on stable ART, without known heart disease were randomized to eplerenone 50 mg PO BID (n = 20) or identical placebo (n = 20) for 12 months. The primary endpoints were (1) myocardial perfusion assessed by coronary flow reserve (CFR) on cardiac PET or stress myocardial blood flow (sMBF) on cardiac MRI or (2) myocardial inflammation by extracellular mass index (ECMi) on cardiac MRI.

Results: Beneficial effects on myocardial perfusion were seen for sMBF by cardiac MRI (mean [SD]: 0.09 [0.56] vs -0.53 [0.68] mL/min/g; P = .03) but not CFR by cardiac PET (0.01 [0.64] vs -0.07 [0.48]; P = .72, eplerenone vs placebo). Eplerenone improved parameters of myocardial function on cardiac MRI including left ventricular end diastolic volume (-13 [28] vs 10 [26] mL; P = .03) and global circumferential strain (GCS; median [interquartile range 25th-75th]: -1.3% [-2.9%-1.0%] vs 2.3% [-0.4%-4.1%]; P = .03), eplerenone versus placebo respectively. On cardiac MRI, improvement in sMBF related to improvement in global circumferential strain (ρ = -0.65, P = .057) among those treated with eplerenone. Selecting for those with impaired myocardial perfusion (CFR <2.5 and/or sMBF <1.8), there was a treatment effect of eplerenone versus placebo to improve CFR (0.28 [0.27] vs -0.05 [0.36]; P = .04). Eplerenone prevented a small increase in troponin (0.00 [-0.13-0.00] vs 0.00 [0.00-0.74] ng/L; P = .03) without effects on ECMi (0.9 [-2.3-4.3] vs -0.7 [-2.2--0.1] g/m2; P = .38). CD4+ T-cell count (127 [-38-286] vs -6 [-168-53] cells/μL; P = .02) increased in the eplerenone- versus placebo-treated groups.

Conclusions: RAAS blockade with eplerenone benefitted key indices and prevented worsening of myocardial perfusion, injury, and function among PWH with subclinical cardiac disease when compared with placebo.

Clinical trials registration: NCT02740179 (https://clinicaltrials.gov/ct2/show/NCT02740179?term=NCT02740179&draw=2&rank=1).

Keywords: HIV; eplerenone; myocardial blood flow; myocardial dysfunction; renin-angiotensin-aldosterone system.

Figure 1.

Flowchart of the participants in the study. One hundred and ten participants were assessed for eligibility. Seventy participants were excluded, as 53 did not meet the inclusion criteria per protocol, 10 declined to participate, and 7 were lost to follow-up. A total of 40 participants were randomized and evenly allocated to the eplerenone and placebo treatment arms. Within the eplerenone arm, 1 participant declined to participate further and 5 other participants discontinued intervention, leaving 14 participants for the primary analysis. Within the placebo arm, 1 participant discontinued intervention, leaving 19 participants for the primary analysis. Abbreviations: CTA, computed tomography angiography; VAT, visceral adipose tissue.

Figure 2.

Change in stress myocardial blood flow and global circumferential strain on cardiac MRI over 12 months among treatment groups. A, The bar graph shows the mean change in stress myocardial blood flow measured on cardiac MRI among those treated with eplerenone versus placebo. Error bars represent the standard deviation. B, The box plot shows the median change in global circumferential strain measured on cardiac MRI among those treated with eplerenone versus placebo. The box plot represents the 25th and 75th percentile, and the line within the box represents the median. Abbreviation: MRI, magnetic resonance imaging.

Figure 3.

Change in CFR over 12 months by impaired versus normal total flow capacity on cardiac PET among treatment groups. A, Participants categorized based on integrating CFR and maximal MBF both obtained by cardiac PET to assess total flow capacity identify unique prognostic at-risk phenotypes for CVD. B, The bar graph shows the mean change in CFR stratified by impaired total flow capacity (groups 1–3) versus normal total flow capacity (group 4) in the eplerenone- versus placebo-treated groups. Eplerenone significantly improves mean CFR among those participants with impaired total flow capacity. Abbreviations: CFR, coronary flow reserve; MBF, myocardial blood flow; PET, positron emission tomography.