Plasma ACE2 and Risk of Death or Cardiometabolic Diseases

Quick Takes

  • In this case-cohort study of 10,753 subjects, determinants of plasma ACE2 levels included sex (men >women), ancestry (east Asians highest, south Asians lowest), higher BMI, older age, presence of diabetes, higher cholesterol, higher blood pressure, and smoking.
  • In models including clinical risk factors, ACE2 was the highest-ranked predictor of total deaths and cardiovascular deaths.

Study Questions:

Are plasma angiotensin-converting enzyme 2 (ACE2) concentrations associated with risk of death or cardiovascular (CV) events?

Methods:

This case-cohort study included subjects from the PURE (Prospective Urban Rural Epidemiology) project, involving 14 countries across five continents (Africa, Asia, Europe, North America, and South America). Plasma concentrations of ACE2, a counter-regulator of the renin–angiotensin cascade that cleaves angiotensin II, were measured from biobank samples. Clinical outcomes of interest were all-cause and CV death, myocardial infarction (MI), stroke, heart failure (HF), and diabetes mellitus (DM).

Results:

A total of 10,753 participants were included: 5,084 in the randomly selected subcohort and an additional 5,669 subjects with at least 1 clinical event. Median follow-up was 9.42 years. Determinants of plasma ACE2 levels included sex (greatest relative importance, with men exhibiting higher levels than women), ancestry (east Asians highest, south Asians lowest), higher body mass index (BMI), older age, presence of DM, higher cholesterol, higher blood pressure, and smoking. In Mendelian randomization analyses, genetically mediated higher BMI and greater risk of type 2 DM were associated with increased ACE2 levels. ACE2 levels were not associated with use of common antihypertensive medications.

Plasma concentration of ACE2 was associated with higher risk of overall death (hazard ratio [HR] 1.35 per standard deviation [SD]; 95% confidence interval [CI], 1.29-1.43) and CV death (HR 1.40 per SD; 95% CI, 1.27-1.54), after adjusting for demographics and clinical risk factors. In models including clinical risk factors, ACE2 was the highest-ranked predictor of total deaths and CV deaths, the third-highest ranked predictor of MI (after smoking and DM), and the third-highest ranked predictor of both stroke and HF (after systolic blood pressure and DM). Subgroup analysis showed no differential effect of ACE2 levels based on sex. When adjusted for B-type natriuretic peptide levels, ACE2 levels remained associated with death, MI, stroke, and DM, while the association between ACE2 and HF was attenuated.

Conclusions:

Plasma ACE2 levels are independently associated with all-cause and CV death and CV events.

Perspective:

Cell-bound ACE2 is the receptor to which the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus binds, and thus, it has garnered great interest in the literature in recent months. The relationship between cell-bound and plasma ACE2 levels is a subject of ongoing study. The gene encoding ACE2 is located on the X chromosome, and as the authors note, X chromosome inactivation escape might play a part in observed differences in ACE2 between sexes. It remains to be seen whether treatments aimed at modifying plasma ACE2 levels could be protective against CV events.

Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Heart Failure and Cardiomyopathies, Prevention, Lipid Metabolism, Nonstatins, Acute Heart Failure, Heart Failure and Cardiac Biomarkers, Smoking

Keywords: Angiotensin-Converting Enzyme Inhibitors, Angiotensin II, Antihypertensive Agents, Blood Pressure, Body Mass Index, Cholesterol, COVID-19, Diabetes Mellitus, Dyslipidemias, Heart Failure, Metabolic Syndrome X, Myocardial Infarction, Natriuretic Peptide, Brain, Primary Prevention, Renin-Angiotensin System, Risk Factors, severe acute respiratory syndrome coronavirus 2, Smoking, Stroke


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