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

Abstract

BackgroundAngiotensin 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).MethodsWe 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).ResultsWe 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).ConclusionsPlasma ACE2 activity independently increased the hazard of adverse long-term cardiovascular outcomes in patients with obstructive CAD.

Plasma and tissue angiotensin‐converting enzyme 2 activity and plasma equilibrium concentrations of angiotensin peptides in dogs with heart disease

“…The clinical implication of circulating ACE2 appears complex. For example, although previous observational studies [32][33][34] determined that increased ACE2 activity was associated with poor outcome, in a study involving patients after intensive treatment for acute CHF, 65…”

“…In 1 such study, 31 serum ACE2 activity was significantly increased secondary to ischemic and nonischemic heart disease and was independent of medications or comorbidities. In other studies, [32][33][34] portions of the cell membrane, which then are released into the surrounding extracellular space. 33,35,36 The resultant ectosomes contain ACE2 as well as the immediate surrounding extracellular environment and enter the circulation or urine.…”

Renin-angiotensin-aldosterone system and COVID-19 infection

“…In-vitro models free of COVID-19 reported that ACEi and ARB treatment increased membrane expression of ACE2, especially in the heart (9,16,35). In-vitro findings in the few human studies of healthy (COVID-19-free) subjects were discordant (36)(37)(38)(39). It should also be borne in mind that circulating ACE2 levels may not match membrane expression and tissue activity (the latter possibly varying depending on the tissue).…”

Understanding the renin–angiotensin–aldosterone–SARS-CoV axis: a comprehensive review

“…Therefore, ACE2 functions as a counterbalance to its structurally similar counterpart ACE [53] through the conversion of Ang II into Ang-(1-7), which in contrast to ACE, promotes vasodilation, reduces proliferation, and prevents apoptosis. [53] ACE2 levels are known to be low in healthy individuals [54] and ACE2 levels decrease with age. [55] Chronically elevated levels of ACE2 are an independent predictor of disease progression; but evidence suggests these changes are compensatory rather than causal.…”