Elsevier

Journal of Cardiac Failure

Volume 15, Issue 7, September 2009, Pages 565-571
Journal of Cardiac Failure

Clinical Investigation
Soluble Angiotensin-Converting Enzyme 2 in Human Heart Failure: Relation With Myocardial Function and Clinical Outcomes

https://doi.org/10.1016/j.cardfail.2009.01.014Get rights and content

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] ≤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.

Section snippets

Study Design and Population

The neurohormonal sub-study of the Assessment of Doppler Echocardiography in Prognosis and Therapy study has been previously described,13 and was approved by the Cleveland Clinic Institutional Review Board. After informed consent, 113 ambulatory patients with stable, chronic systolic heart failure (left ventricular ejection fraction [LVEF] ≤35%, New York Heart Association functional Class II to IV) underwent echocardiographic evaluation of systolic and diastolic performance as well as plasma

Results

In our study cohort, the mean and median sACE2 plasma activity were 27.8 ± 20.8 ng/mL and 21.7 ng/mL (interquartile range = 15.8–33.0 ng/mL), respectively. Table 1 demonstrates the baseline clinical and biochemical characteristics of the cohort stratified by tertiles of sACE2 activity, comparing the 3rd to the 1st tertile. Increased sACE2 correlated significantly with LV systolic dysfunction, LV dilatation, and also right ventricular (RV) systolic dysfunction and increased estimated pulmonary

Discussion

The RAAS plays a crucial role in both regulating normal cardiac function and perpetuating the ultimately detrimental pathways mediating the progression of heart failure. Targeted inhibition at nearly every level has resulted in important clinical progress in the treatment of heart failure, in particular, blockade of Ang II activity. As is common in other essential biological systems, ACE2 likely evolved as a natural counter-regulatory mechanism to limit Ang II overactivation. Our mechanistic

Conclusion

We report that sACE2, a key cardioprotective counter-regulatory member of the RAAS, is elevated in patients with worsening left and right ventricular performance that is independent of systemic inflammation, and is a prognostic indicator of adverse clinical events.

References (30)

  • M. Packer et al.

    Comparative effects of low and high doses of the angiotensin-converting enzyme inhibitor, lisinopril, on morbidity and mortality in chronic heart failure. ATLAS Study Group

    Circulation

    (1999)
  • P.K. Mehta et al.

    Angiotensin II cell signaling: physiological and pathological effects in the cardiovascular system

    Am J Physiol Cell Physiol

    (2007)
  • G.I. Rice et al.

    Evaluation of angiotensin-converting enzyme (ACE), its homologue ACE2 and neprilysin in angiotensin peptide metabolism

    Biochem J

    (2004)
  • R.A. Santos et al.

    Angiotensin-(1-7) is an endogenous ligand for the G protein-coupled receptor Mas

    Proc Natl Acad Sci U S A

    (2003)
  • J.L. Grobe et al.

    Prevention of angiotensin II-induced cardiac remodeling by angiotensin-(1-7)

    Am J Physiol Heart Circ Physiol

    (2007)

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    All decisions regarding this manuscript were made by a guest editor.

    The original Assessment of Doppler Echocardiography in Prognosis and Therapy study was supported by the 2003 American Society of Echocardiography Outcomes Research Award (Drs. Troughton and Klein), GlaxoSmithKline Pharmaceuticals, and Roche Diagnostics Inc.

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