Soluble angiotensin converting enzyme 2 levels in chronic heart failure is associated with decreased exercise capacity and increased oxidative stress-mediated endothelial dysfunction

The aim of this study was to explore the relationship between serum soluble angiotensin converting enzyme 2 (sACE2), parameters of cardiopulmonary exercise testing and plasma asymmetric dimethylarginine (ADMA), a marker of oxidative stress-induced endothelial dysfunction. This has not been previously evaluated. We assessed 50 consecutive ambulatory patients with chronic systolic heart failure and left ventricular ejection fraction (LVEF) ≤45%. Their blood samples were collected for sACE2 and ADMA tests before they underwent symptom-limited cardiopulmonary exercise testing and transthoracic echocardiography. The majority of our study subjects had New York Heart Association functional class II (74%) and III (18%) presentation, and 42% of patients had ischemic etiology. Median sACE2 activity was 10.36 (7.00-14.47) ng/mL and mean ADMA was 0.90 ± 0.22. sACE2 activity was inversely correlated with pVO₂ (r = -0.42, P = 0.00283), exercise time (r = -0.35, P = 0.0138) and LVEF (r = -0.548, P < 0.001), and positively correlated with VE/VCO₂ slope (r = 0.294, P = 0.0405), ΔDBP (r = 0.315, P = 0.0278), mitral E/Ea ratio (r = 0.442, P = 0.00158) and ADMA levels (r = 0.351, P = 0.0134). Meanwhile, we observed a negative correlation between ADMA and pVO₂ (r = -0.424, P = 0.00227) and positive correlations between ADMA and VE/VCO₂ slope (r = 0.515, P < 0.001), ΔDBP (r = 0.391, P = 0.00568), mitral E/Ea ratio (r = 0.426, P = 0.00219). In multivariate logistic regression analysis, sACE2 was independently associated with peak oxygen uptake (% predicted) after adjusting for body mass index (BMI) and mitral E/Ea ratio (odds ratio [OR] 0.81 (0.58-0.94), P = 0.041) and associated with oxygen pulse (VO₂/HR) (%) after adjusting for age, gender, BMI and mitral E/Ea ratio (OR 0.83 [0.68-0.95], P = 0.025). Therefore in stable chronic systolic heart failure patients, higher sACE2 activity is independently associated with diminished exercise capacity and correlates with elevated systemic oxidative stress-mediated endothelial dysfunction.