New perspectives in the renin-angiotensin-aldosterone system (RAAS) IV: circulating ACE2 as a biomarker of systolic dysfunction in human hypertension and heart failure

PLoS One. 2014 Apr 1;9(4):e87845. doi: 10.1371/journal.pone.0087845. eCollection 2014.


Background: Growing evidence exists for soluble Angiotensin Converting Enzyme-2 (sACE2) as a biomarker in definitive heart failure (HF), but there is little information about changes in sACE2 activity in hypertension with imminent heart failure and in reverse remodeling.

Methods, findings: Patients with systolic HF (NYHAII-IV, enrolled for cardiac resynchronisation therapy, CRT, n = 100) were compared to hypertensive patients (n = 239) and to a healthy cohort (n = 45) with preserved ejection fraction (EF>50%) in a single center prospective clinical study. The status of the heart failure patients were checked before and after CRT. Biochemical (ACE and sACE2 activity, ACE concentration) and echocardiographic parameters (EF, left ventricular end-diastolic (EDD) and end-systolic diameter (ESD) and dP/dt) were measured. sACE2 activity negatively correlated with EF and positively with ESD and EDD in all patient's populations, while it was independent in the healthy cohort. sACE2 activity was already increased in the hypertensive group, where signs for imminent heart failure (slightly decreased EF and barely increased NT-proBNP levels) were detected. sACE2 activities further increased in patients with definitive heart failure (EF<50%), while sACE2 activities decreased with the improvement of the heart failure after CRT (reverse remodeling). Serum angiotensin converting enzyme (ACE) concentrations were lower in the diseased populations, but did not show a strong correlation with the echocardiographic parameters.

Conclusions: Soluble ACE2 activity appears to be biomarker in heart failure, and in hypertension, where heart failure may be imminent. Our data suggest that sACE2 is involved in the pathomechanism of hypertension and HF.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Angiotensin-Converting Enzyme 2
  • Biomarkers / blood
  • Female
  • Heart Failure / blood*
  • Heart Failure / diagnostic imaging
  • Heart Failure / enzymology
  • Heart Failure / physiopathology*
  • Humans
  • Hypertension / blood*
  • Hypertension / diagnostic imaging
  • Hypertension / enzymology
  • Hypertension / physiopathology*
  • Male
  • Middle Aged
  • Natriuretic Peptide, Brain / metabolism
  • Peptide Fragments / metabolism
  • Peptidyl-Dipeptidase A / blood*
  • Renin-Angiotensin System*
  • Stroke Volume
  • Systole*
  • Ultrasonography
  • Ventricular Remodeling


  • Biomarkers
  • Peptide Fragments
  • pro-brain natriuretic peptide (1-76)
  • Natriuretic Peptide, Brain
  • Peptidyl-Dipeptidase A
  • ACE2 protein, human
  • Angiotensin-Converting Enzyme 2

Grant support

The work was supported by TÁMOP 4.2.2.A-11/1/KONV-2012-0045 and TÁMOP-4.2.2/B-10/1-2010-0024 grants. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.