Plasma ACE2 Predicts Mortality in Aortic Stenosis

Study Questions:

Are levels of plasma angiotensin-converting enzyme 2 (ACE2) associated with severity of aortic stenosis (AS) and all-cause mortality?


Plasma ACE2 levels were measured in 127 adult patients with AS of varying severity (25% mild, 24% moderate, and 51% severe) recruited as outpatients. Participants with other valvular diseases greater than moderate in severity were excluded. Right atrial appendage tissue was collected in a subset of 22 patients who underwent aortic valve replacement, in which myocardial ACE2 and tumor necrosis factor-α gene expression and myocardial interstitial collagen volume were assessed. Patients were followed for all-cause mortality (median follow-up time of 5 years).


The median plasma ACE2 activity was 34.0 pmol/ml/min. Patients with high (above median) ACE2 were more likely to be men (78% vs. 50%) and have ischemic heart disease (46% vs. 28%). There were no differences in measures of AS severity or other echocardiographic indices of filling pressures or cardiac function between high and low ACE2 groups. Over a median follow-up of 5 years, elevated plasma ACE2 activity using a receiver-operating characteristic–derived cutoff was an independent predictor of all-cause mortality (hazard ratio, 2.28; 95% confidence interval, 1.03-5.06). In 22 patients with plasma and tissue samples, increased circulating ACE2 was associated with reduced myocardial ACE2 gene expression (0.7-fold; p = 0.033) and severe myocardial fibrosis (p = 0.027).


In patients with AS, elevated plasma ACE2 was a marker of myocardial structural abnormalities and an independent predictor of mortality with incremental value over traditional prognostic markers. Loss of ACE2 from the myocardium was associated with increased fibrosis and higher circulating ACE2 levels.


The study findings are at best preliminary, as the sample sizes were small, and the associations between ACE2 and myocardial structure were highly subject to confounding, as no multivariable analyses were reported. The association with all-cause death was examined only using an ACE2 cut-off fit for the data, thus warranting replication in a validation cohort. The authors suggest that ACE2 can be used in conjunction with B-type natriuretic peptide to enhance decision making in AS; however, the data suggest that ACE2 is not an AS-specific biomarker and does not correlate with AS severity. Findings need to be replicated and compared to the multitude of prognostic biomarkers in cardiovascular disease should a useful clinical role be found for ACE2.

Clinical Topics: Cardiac Surgery, Heart Failure and Cardiomyopathies, Invasive Cardiovascular Angiography and Intervention, Noninvasive Imaging, Valvular Heart Disease, Aortic Surgery, Cardiac Surgery and Heart Failure, Cardiac Surgery and VHD, Heart Failure and Cardiac Biomarkers, Interventions and Imaging, Interventions and Structural Heart Disease, Echocardiography/Ultrasound

Keywords: Angiotensin-Converting Enzyme Inhibitors, Aortic Valve Stenosis, Atrial Appendage, Biological Markers, Diagnostic Imaging, Echocardiography, Fibrosis, Heart Valve Diseases, Myocardial Ischemia, Myocardium, Natriuretic Peptide, Brain, Outpatients, Peptidyl-Dipeptidase A, Tumor Necrosis Factors, Transcatheter Aortic Valve Replacement

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