Journal of the American College of Cardiology Vol. 52, No. 9, 2008 R1. 이 홍 주

 Important final common pathway of HF : Activation of the RAAS.  ACE2 is a recently discovered homolog and seemingly protective in HF.  ACE2 is an integral membrane carboxypeptidase that removes the terminal amino- acid from Ang II, resulting in the production of Ang(1-7)  Ang(1-7) antagonizes the effects of Ang II by activating the Mas receptor.

 Intracardiac overexpression of ACE2 prevents Ang II induced hypertension Cardiac fibrosis in vivo cardioprotective role in addition to suggesting possible therapeutic utility.  ACE2 gene expression is increased in tissue samples from patients with left ventricular dysfunction.  ACE2 has been thought to be tissue bound need for invasive cardiac tissue sampling has limited additional clinical studies.  soluble angiotensin-converting enzyme 2(sACE2) activity in human plasma.  Hypothesis : Endogenous regulatory arm of the RAAS, as measured by sACE2, would be increased in patients with HF.

 ACE2 enzymatic assay : ACE2-specific quenched fluorescent substrate protocol.  Patient sample collection any subject suspected of having clinical HF - measured BNP - at the Cleveland Clinic - between March and August excluded patients - congenital heart diseases - acute coronary syndromes - in the post-operative setting. echocardiographic : within 100 days of sample isolation  Statistical analysis Univariate analyses : with the Student t test or chi-square test between groups 1-way analysis of variance among sACE2 interquartile range for the various clinical parameters. Logistic regression analysis : confounding variables. All statistical analysis was performed with JMP p value 0.05 was considered significant.

 The specific ACE2 inhibitor(DX600) inhibited recombinant ACE2 activity in a dose-dependent fashion.  Both DX600 (1mol/l) and a polyclonal anti-ACE2 antibody (8g/ml) inhibited sACE2 activity in human plasma samples  sACE2 activity was inhibited by DX600 in commercially available plasma.

In the study cohort, 70% had a clinical diagnosis of HF 30% showed no biochemical or clinical evidence of HF.

 sACE2 activity was stratified by quartiles. sACE2 activity also was associated with HF (not associated with any other disease) worsening LVEF increasing BNP levels use of loop diuretics

Odds ratio of predicting HF with sACE2 values above the fourth quartile : 4.8 (2.0 to 11.9, p0.0002, Fisher exact test). In logistic regression analysis, sACE2 activity was independently associated with the presence of HF.

. Greater sACE2 activity worsening NYHA functional class. Using logistic regression analysis, sACE2 activity is associated with - increasing NYHA functional class (p0.023) - log-transformed BNP (p0.003) - inversely associated with LVEF (p0.023) - aldosterone antagonists (chi-square 4.2, p0.040).

 3 important observations in human HF 1) sACE2 activity can be readily measured in heterogeneous patient populations 2) sACE2 activity is elevated in human HF 3) sACE2 activity correlates independently with worsening disease severity as defined by LVEF and NYHA functional class..

 presence of circulating ACE2 in plasma cause/effect of an adaptive/maladaptive physiologic process operative in human HF.  cleavage of membrane ACE2 soluble form TNF-convertase (ADAM17) & a protease upregulated in HF  Up-regulation of proinflammatory cytokines and activation of proteases during HF pathologic mechanism of cardiac remodeling : cleavage of membrane ACE2 relative decrease in local membrane ACE2 levels cardiac dysfunction.  cleavage and release of membrane ACE2 as a soluble form may offer a compensatory mechanism in HF.  release of sACE2 from the vascular endothelium may serve to alter systemic Ang(1-7) concentrations and the relative peripheral balance of ACE2/ACE. (Angiotensin 1-7 has a very short half-life(9s))

 ACE2 expression can be modulated through a variety of mechanisms.  Aldosterone decreases ACE2 transcription through a NAD, phosphate oxidase-mediated pathway  Direct correlation between the use of aldosterone receptor antagonists and greater sACE2 activity -> increased ACE2 production from patients treated with spironolactone -> a potential mechanism of their beneficial effects.  Stimulation through the AT-1 receptor suppress ACE2 expression.  unlike animal studies, patients in our study were exposed to long-term inhibition of the RAAS, which might account for the lack of association between plasma sACE2 and the use of either ACE inhibitors or Ang receptor blockers.  detection of sACE2 activity = the activation of counter-regulatory mechanisms : ultimate clinical utility of measuring sACE2 activity may depend on our ability to possibly target activation of the ACE2–Ang(1-7)–Mas pathway rather than to improve the clinical diagnosis of HF in the acute setting

 Using a specific and sensitive assay, sACE2 activity can be detected in human plasma.  Increased sACE2 activity is associated with more advanced HF.