Increased Plasma ACE2 Activity is a Marker of Subclinical LV Systolic Dysfunction in Patients With Aortic Stenosis

Abstract

Background: Subclinical left ventricular systolic dysfunction (LVSD) determined by global longitudinal strain (GLS) portends a poor prognosis in patients with aortic stenosis (AS). Angiotensin converting enzyme 2 (ACE2) is a membrane bound protein highly expressed in the human heart and functions to degrade the vasoconstrictor, profibrotic peptide, angiotensin II. Plasma ACE2 levels are elevated in patients with heart failure. In patients with AS, it is not known if early maladaptive processes within the myocardium are associated with changes in plasma and/or tissue ACE2. Aim/Methods: To investigate if subclinical LVSD in patients with AS is associated with elevated plasma ACE2 activity and/or reduced myocardial ACE2 gene expression. Plasma ACE2 activity was measured in 111 patients with AS and normal LV ejection fraction with satisfactory (≤ -15%, n = 77) and abnormal (> -15%, n = 34) GLS. Gene expression of ACE2 was measured in atrial samples collected from a subset of patients during aortic valve replacement (n = 20). Results: Median [25th, 75th quartile] plasma ACE2 activity was significantly higher in patients with abnormal versus normal GLS (29.0 [18.5, 45.25] vs. 20.8 [12.8, 35.04] pmol/ml/min; p = 0.03). Myocardial ACE2 gene expression was significantly reduced (0.5-fold, p = 0.01) in those with abnormal GLS (n = 10) compared to normal GLS (n = 10). Plasma ACE2 activity correlated negatively with ACE2 mRNA (R = - 0.45, p = 0.047). Conclusions: In patients with AS, elevated plasma ACE2 activity is associated with subclinical LVSD and reduced myocardial ACE2 gene expression. Approaches to enhance cardiac ACE2 may have a role in preventing progression to overt LV dysfunction in AS.