Soluble angiotensin-converting enzyme 2 in human heart failure: relation with myocardial function and clinical outcomes

Abstract

Background: Angiotensin-converting enzyme 2 (ACE2) is an endogenous counterregulator of the renin-angiotensin system. The relationship between soluble ACE2 (sACE2), myocardial function, and clinical outcomes in patients with chronic systolic heart failure is not well established.

Methods and results: We measured sACE2 activity in 113 patients with chronic systolic heart failure (left ventricular ejection fraction [LVEF] <or=35%, New York Heart Association Class II-IV). Comprehensive echocardiography was performed at the time of blood sampling. We prospectively examined adverse clinical events (death, cardiac transplant, and heart failure hospitalizations) over 34 +/- 17 months. Patients who had higher sACE2 plasma activity were more likely to have a lower LVEF (Spearman's r = -0.36, P < .001), greater right ventricular systolic dysfunction (r = 0.33, P < .001), higher estimated pulmonary artery systolic pressure (r = 0.35, P = .002), larger left ventricular end-diastolic diameter (r = 0.23, P = .02), and higher plasma NT-proBNP levels (r = 0.35, P < .001). sACE2 was less associated with diastolic dysfunction (r = 0.19, P = .05), and was similar between patients with ischemic and nonischemic cardiomyopathies. There was no relationship between sACE2 activity and markers of systemic inflammation. After adjusting for NT-proBNP and LVEF, sACE2 activity remained an independent predictor of adverse clinical events (HR = 1.7 [95% CI: 1.1-2.6], P = .018).

Conclusions: Elevated plasma sACE2 activity was associated with greater severity of myocardial dysfunction and was an independent predictor of adverse clinical events.

Figure 1. Kaplan-Meier analysis of all-cause mortality, cardiac transplantation, or heart failure hospitalization

A) Patients were stratified based on tertiles of plasma sACE2 activity (tertile 1: sACE2 < 17.9 ng/mL, tertile 2: 17.9–28.8 ng/mL, tertile 3: >28.8 ng/mL). B) −/+ NT-proBNP = below / above median NT-proBNP (1,240 pg/mL); −/+ sACE2 = below / above ROC-derived value for sACE2 (28.3 ng/mL). sACE2=soluble angiotensin converting enzyme 2. NT-proBNP = Nterminal pro B-type natriuretic peptide.

Figure 2. Adverse Event Rate and Corresponding Hazard Ratios for Subgroups

Adverse event rate is calculated on the combined endpoint of death, heart transplantation and heart failure hospitalizations. Hazard ratios are calculated relative to the group with sACE2 levels below 28.3 ng/mL. Median values are used for left ventricular ejection fraction = (LVEF) and E/Septal Ea ratio; sACE2=soluble angiotensin converting enzyme 2. * P<0.05. n = (15–37).