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Randomized Controlled Trial
. 2020 Nov 1;41(41):4037-4046.
doi: 10.1093/eurheartj/ehaa697.

Angiotensin-converting enzyme 2 (ACE2) levels in relation to risk factors for COVID-19 in two large cohorts of patients with atrial fibrillation

Lars Wallentin  1   2 , Johan Lindbäck  2 , Niclas Eriksson  2 , Ziad Hijazi  1   2 , John W Eikelboom  3 , Michael D Ezekowitz  4 , Christopher B Granger  5 , Renato D Lopes  5 , Salim Yusuf  3 , Jonas Oldgren  1   2 , Agneta Siegbahn  2   6
Affiliations
Randomized Controlled Trial

Angiotensin-converting enzyme 2 (ACE2) levels in relation to risk factors for COVID-19 in two large cohorts of patients with atrial fibrillation

Lars Wallentin et al. Eur Heart J. .

Abstract

Aims: The global COVID-19 pandemic is caused by the SARS-CoV-2 virus entering human cells using angiotensin-converting enzyme 2 (ACE2) as a cell surface receptor. ACE2 is shed to the circulation, and a higher plasma level of soluble ACE2 (sACE2) might reflect a higher cellular expression of ACE2. The present study explored the associations between sACE2 and clinical factors, cardiovascular biomarkers, and genetic variability.

Methods and results: Plasma and DNA samples were obtained from two international cohorts of elderly patients with atrial fibrillation (n = 3999 and n = 1088). The sACE2 protein level was measured by the Olink Proteomics® Multiplex CVD II96 × 96 panel. Levels of the biomarkers high-sensitive cardiac troponin T (hs-cTnT), N-terminal probrain natriuretic peptide (NT-proBNP), growth differentiation factor 15 (GDF-15), C-reactive protein, interleukin-6, D-dimer, and cystatin-C were determined by immunoassays. Genome-wide association studies were performed by Illumina chips. Higher levels of sACE2 were statistically significantly associated with male sex, cardiovascular disease, diabetes, and older age. The sACE2 level was most strongly associated with the levels of GDF-15, NT-proBNP, and hs-cTnT. When adjusting for these biomarkers, only male sex remained associated with sACE2. We found no statistically significant genetic regulation of the sACE2 level.

Conclusions: Male sex and clinical or biomarker indicators of biological ageing, cardiovascular disease, and diabetes are associated with higher sACE2 levels. The levels of GDF-15 and NT-proBNP, which are associated both with the sACE2 level and a higher risk for mortality and cardiovascular disease, might contribute to better identification of risk for severe COVID-19 infection.

Trial registration: ClinicalTrials.gov NCT00262600 NCT00412984.

Keywords: ACE2; Age; Atrial fibrillation; Biomarker; COVID-19; Cardiovascular disease.

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Figures

Figure 1
Figure 1
Cumulative distribution of soluble angiotensin-converting enzyme 2 (ACE2) for different subgroups in ARISTOTLE. CHF, Congestive heart failure; ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker.
Figure 2
Figure 2
Estimated mean soluble angiotensin-converting enzyme 2 (ACE2) with 95% pointwise confidence interval for different levels of the most important continuous variables in ARISTOTLE. GDF-15, growth differentiation factor 15; NT-proBNP, N-terminal probrain natriuretic peptide.
Figure 3
Figure 3
(A) Estimated difference of soluble angiotensin-converting enzyme 2 (sACE2) based on the models with clinical variables and treatments for ARISTOTLE (left panel) and RE-LY (right panel). (B) Estimated difference of sACE2 based on the models with clinical variables, treatments, and biomarkers for ARISTOTLE (left panel) and RE-LY (right panel). Unadjusted results (grey, open circles) and adjusted results (black, filled circles). Variables are sorted after estimated effect size in ARISTOTLE. Note that effect sizes for continuous variables are, for a comparison between the third and the first quartile in both studies, estimated using only the ARISTOTLE data. ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; TIA, transient ischaemic attack; BMI, body mass index. NT-proBNP, N-terminal probrain natriuretic peptide; cTnT-hs, high-sensitive cardiac troponin T; GDF-15, growth differentiation factor 15.
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