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CLINICAL RESEARCH: HEART FAILURE

Detection of Soluble Angiotensin-Converting Enzyme 2 in Heart Failure

Insights Into the Endogenous Counter-Regulatory Pathway of the Renin-Angiotensin-Aldosterone System

Slava Epelman, MD, PhD^_*, W.H. Wilson Tang, MD, FACC^,, Stephen Y. Chen, MD^_*, Frederick Van Lente, PhD, Gary S. Francis, MD, FACC and Subha Sen, PhD, DSc^,_*

^_* Department of Internal Medicine, Heart and Vascular Institute, Cleveland, Ohio
Department of Cardiovascular Medicine, Heart and Vascular Institute, Cleveland, Ohio
Department of Cell Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio
Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio.

Manuscript received December 3, 2007; revised manuscript received February 7, 2008, accepted February 26, 2008.

^_* Reprint requests and correspondence: Dr. Subha Sen, Department of Molecular Cardiology, NB50, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, Ohio 44195. (Email: sens{at}ccf.org).

Objectives: We sought to determine whether circulating soluble angiotensin-converting enzyme 2 (sACE2) is increased in the plasma of patients with heart failure (HF).

Background: Angiotensin-converting enzyme 2 (ACE2) is an integral membrane protein that antagonizes the actions of angiotensin II and prevents the development of HF in animal models. However, because of the need for invasive cardiac tissue sampling, little is known about whether ACE2 is involved in the pathophysiology of HF in humans.

Methods: We developed a sensitive and specific assay to measure sACE2 activity in human plasma and screened a heterogeneous group of patients suspected of having clinical HF.

Results: Increasing sACE2 plasma activity strongly correlated with a clinical diagnosis of HF (p = 0.0002), worsening left ventricular ejection fraction (p < 0.0001), and increasing B-type natriuretic peptide levels (p < 0.0001). Similar to B-type natriuretic peptide, sACE2 activity reflected the severity of HF, with increasing levels associated with worsening New York Heart Association functional class (p < 0.0001). These associations were independent of other disease states and medication use. We found that sACE2 activity was increased in patients with both ischemic and nonischemic cardiomyopathies and also in patients with clinical HF but a preserved left ventricular ejection fraction.

Conclusions: Soluble ACE2 activity is increased in patients with HF and correlates with disease severity, suggesting that a cardioprotective arm of the renin-angiotensin-aldosterone system is active in HF.

Key Words: heart failure • ACE2 • hypertrophy • soluble

Abbreviations and Acronyms   ACE2 = angiotensin-converting enzyme 2   Ang = angiotensin   BNP = B-type natriuretic peptide   HF = heart failure   NYHA = New York Heart Association   RAAS = renin-angiotensin-aldosterone system   sACE2 = soluble angiotensin-converting enzyme 2

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