Research Article: Elevated plasma angiotensin converting enzyme 2 activity is an independent predictor of major adverse cardiac events in patients with obstructive coronary artery disease

Date Published: June 13, 2018

Publisher: Public Library of Science

Author(s): Jay Ramchand, Sheila K. Patel, Piyush M. Srivastava, Omar Farouque, Louise M. Burrell, Tatsuo Shimosawa.

http://doi.org/10.1371/journal.pone.0198144

Abstract

Angiotensin converting enzyme 2 (ACE2) is an endogenous regulator of the renin angiotensin system. Increased circulating ACE2 predicts adverse outcomes in patients with heart failure (HF), but it is unknown if elevated plasma ACE2 activity predicts major adverse cardiovascular events (MACE) in patients with obstructive coronary artery disease (CAD).

We prospectively recruited patients with obstructive CAD (defined as ≥50% stenosis of the left main coronary artery and/or ≥70% stenosis in ≥ 1 other major epicardial vessel on invasive coronary angiography) and measured plasma ACE2 activity. Patients were followed up to determine if circulating ACE2 activity levels predicted the primary endpoint of MACE (cardiovascular mortality, HF or myocardial infarction).

We recruited 79 patients with obstructive coronary artery disease. The median (IQR) plasma ACE2 activity was 29.3 pmol/ml/min [21.2–41.2]. Over a median follow up of 10.5 years [9.6–10.8years], MACE occurred in 46% of patients (36 events). On Kaplan-Meier analysis, above-median plasma ACE2 activity was associated with MACE (log-rank test, p = 0.035) and HF hospitalisation (p = 0.01). After Cox multivariable adjustment, log ACE2 activity remained an independent predictor of MACE (hazard ratio (HR) 2.4, 95% confidence interval (CI) 1.24–4.72, p = 0.009) and HF hospitalisation (HR: 4.03, 95% CI: 1.42–11.5, p = 0.009).

Plasma ACE2 activity independently increased the hazard of adverse long-term cardiovascular outcomes in patients with obstructive CAD.

Partial Text

Cardiovascular (CV) disease is a major cause of morbidity and mortality,[1] and is associated with activation of the renin-angiotensin system (RAS). Within the RAS, angiotensin converting enzyme (ACE) converts angiotensin (Ang) I to the vasoconstrictor and pro-atherosclerotic peptide Ang II,[2] whilst ACE2 is an endogenous inhibitor of the RAS through its major action to degrade Ang II.[3] ACE2 is highly expressed in the heart and blood vessels[4] and is cleaved from the cell surface to release the catalytically active ectodomain[5] into the circulation through the action of tumour necrosis factor alpha converting enzyme (TACE).[6] In human myocardium, ACE2 is localized to the endothelium of the microcirculation,[7] and is also present in the media of atherosclerotic radial arteries.[8] In healthy individuals, circulating ACE2 activity levels are low[9, 10] but increase in the presence of CV disease or risk factors including heart failure (HF),[11] atrial fibrillation (AF),[12] kidney disease[13, 14] and type 1 diabetes.[15] To date, there is limited information on the prognostic role of circulating ACE2 activity levels and the results are conflicting. For example, increased ACE2 activity predicted adverse CV outcomes in heart failure,[16] but not in patients after emergency orthopedic surgery[17] or with chronic kidney disease.[13, 14] These differences may reflect the patient population, the relative cardiovascular risk of the patient population or the length of follow up. The aim of this study was to investigate the utility of plasma ACE2 activity levels to predict CV events in a high-risk cohort of patients with angiographically proven obstructive CAD with more than 10 years of follow-up.

Consecutive patients aged >18 years were prospectively recruited between November 2004 and January 2006 after referral to a tertiary cardiovascular centre for a coronary angiogram to investigate suspected CAD. Only those with significant obstructive CAD were eligible for this study. Patients in cardiogenic shock, with a past history of congestive heart failure or with a left ventricular (LV) ejection fraction < 30% on angiography were excluded. Ethical approval was obtained from the Human Research Ethics Committee at Austin Health, Melbourne and the study complied with the Declaration of Helsinki. All patients gave informed written consent. We recruited 79 patients with angiographically proven obstructive CAD. No patient was lost to follow up and the median follow-up was 10.6 years (IQR 9.6–10.9 years). The clinical and biochemical characteristics of the study population are presented in Table 1. The cohort comprised 65% males with a mean ± SD age of 66 ± 12 years and BMI of 27.4 ± 4.4 kg/m2. Patients were at significant CV risk with 69% having a smoking history, and a history of CAD in 66%, dyslipidaemia in 60%, hypertension in 82%, diabetes in 24% and AF in 11%. With regard to pharmacological therapy at the time of presentation, 59% were on angiotensin converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARB), 58% on beta-blockers, 72% on statins and 100% on aspirin. The major finding of the current study was that plasma ACE2 activity independently increased the hazard for adverse cardiovascular events in patients with significant obstructive CAD. In this study in high-risk patients followed for a median of 10.6 years, elevated ACE2 activity remained an independent predictor of CV mortality and morbidity even after comprehensive multivariable adjustment in a model that included prognostically meaningful variables. The median ACE2 level in patients with CAD was 29 pmol/ml/min which is higher than levels we previously reported in young healthy volunteers (4.44 ± 0.56 pmol/ml/min)[9] and in elderly patients (median 19.4 pmol/ml/min).[17] We excluded patients with known HF or severe LV systolic dysfunction as both are associated with increased circulating ACE2 levels.[11, 16] Consistent with results of other studies,[13–15, 22] plasma ACE2 activity was higher in male patients but we found no other independent predictors of plasma ACE2 activity levels.   Source: http://doi.org/10.1371/journal.pone.0198144

 

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