Plasma angiotensin-converting enzyme 2 (ACE2) concentration was found to be associated with risk for major cardiovascular events, according to a study published in the Lancet.

In this case-cohort analysis, data for the 2005 to 2006 period from the Prospective Urban Rural Epidemiology study of 10,753 individuals living in 14 countries across 5 continents were examined. Protein concentrations were measured from fasting blood samples using immunoassays. Participants were genotyped with the Thermofisher Axiom Precision Medicine Research Array and assessed for major cardiovascular events.

Plasma ACE2 concentration was higher among men than women (increase, 0.58 standard deviation [SD] units; 95% CI, 0.54-0.61). Geographic ancestry was a major contributing factor to variations in ACE2 concentration, with individuals from East vs South Asia displaying an average increase of 0.69 SD units (95% CI, 0.56-0.82).

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Common genetic variants accounting for variations in ACE2 concentration had the following heritability estimates: Persian (66%; 95% CI, 0-1), Latin (44%; 95% CI, 0.14-0.74), and European (33%; 95% CI, 0.11-0.55) ethnicity. Two variants reached genome-wide significance for their association with ACE2 concentration in a genome-wide meta-analysis (chrX:15726446-C-T: b, 0.14; 95% CI, 0.12-0.17; P =2.2×10-28 and chr12:121415390-T-C: b, -0.16; 95% CI, -0.18 to -0.13; P =5.1×10-26).

After adjusting for demographic characteristics and clinical risk factors, ACE2 plasma concentration was associated with an increased risk for all-cause mortality (hazard ratio [HR] per SD, 1.35; 95% CI, 1.29-1.43), cardiovascular death (HR per SD, 1.40; 95% CI, 1.27-1.54), non-cardiovascular-related death (HR per SD, 1.34; 95% CI, 1.27-1.43), myocardial infarction (HR per SD, 1.23; 95% CI, 1.13-1.33), stroke (HR per SD, 1.21; 95% CI, 1.10-1.32), heart failure (HR per SD, 1.27; 95% CI, 1.10-1.46), and diabetes (HR per SD, 1.44; 95% CI, 1.36-1.52).

When assessing the role of an array of clinical risk factors, risk for cardiovascular death was most strongly associated with ACE2 plasma concentrations (HR per SD, 1.52; 95% CI, 1.38-1.68) followed by systolic blood pressure (HR per SD, 1.32; 95% CI, 1.22-1.43).

Study limitations include the fact that the impact of environment was not examined.

“Compared with established clinical risk factors, ACE2 consistently emerges as a strong predictor of cardiovascular disease or death. Regardless of cause, plasma ACE2 might present a readily measurable indicator of renin– angiotensin system dysregulation,” concluded the study authors.

Disclosure: Multiple authors declared affiliations with industry. Please refer to the original article for a full list of disclosures.


Narula S, Yusuf S, Chong M, et al. Plasma ACE2 and risk of death or cardiometabolic diseases: a case-cohort analysis. Lancet. 2020;396(10256):968-976. doi:10.1016/S0140-6736(20)31964-4