Role of Circulating Angiotensin Converting Enzyme 2 in Left Ventricular Remodeling following Myocardial Infarction: A Prospective Controlled Study

<div><p>Angiotensin-converting enzyme 2 (ACE2) cleaves Angiotensin-II to Angiotensin-(1–7), a cardioprotective peptide. Serum soluble ACE2 (sACE2) activity is raised in chronic heart failure, suggesting a compensatory role in left ventricular dysfunction<b>.</b> Our aim was to study the relationship between sACE2 activity, infarct size, left ventricular systolic function and remodeling following ST-elevation myocardial infarction (STEMI). A contrast-enhanced cardiac magnetic resonance study was performed acutely in 95 patients with first STEMI and repeated at 6 months to measure LV end-diastolic volume index, ejection fraction and infarct size. Baseline sACE2 activities, measured by fluorescent enzymatic assay 24 to 48 hours and at 7 days from admission, were compared to that obtained in 22 matched controls. Patients showed higher sACE2 at baseline than controls (104.4 [87.4–134.8] vs 74.9 [62.8–87.5] RFU/µl/hr, p<0.001). At seven days, sACE2 activity significantly increased from baseline (115.5 [92.9–168.6] RFU/µl/hr, p<0.01). An inverse correlation between sACE2 activity with acute and follow-up ejection fraction was observed (r = −0.519, p<0.001; r = −0.453, p = 0.001, respectively). Additionally, sACE2 directly correlated with infarct size (r = 0.373, p<0.001). Both, infarct size (β = −0.470 [95%CI:−0.691:−0.248], p<0.001) and sACE2 at 7 days (β = −0.025 [95%CI:−0.048:−0.002], p = 0.030) were independent predictors of follow-up ejection fraction. Patients with sACE2 in the upper tertile had a 4.4 fold increase in the incidence of adverse left ventricular remodeling (95% confidence interval: 1.3 to 15.2, p = 0.027). In conclusion, serum sACE2 activity rises in relation to infarct size, left ventricular systolic dysfunction and is associated with the occurrence of left ventricular remodeling.</p></div

Patient selection.

<p>Flow-chart detailing patient selection. ce-CMR: contrast-enhanced Cardiac Magnetic Resonance; FU: follow-up.</p

Population demographic characteristics.

<p>Data expressed as mean (SD) or number (%).</p

Predictors of follow-up EF by multivariate analysis.

<p>BNP: B-type natriuretic peptide; MO: microvascular obstruction; sACE2: Soluble Angiotensin Converting Enzyme 2; CI: confidence interval.</p

sACE2 activity in controls and patients.

<p>Panel A: Box-plot showing the differences in the median (horizontal lines), interquartile range (boxes) and 95% of the observed values (whiskers) for sACE2 activity between controls and STEMI patients. Panel B: Scatter-plot detailing individual changes in sACE2 activity among patients. *: p<0.001 for comparison between baseline measurements in patients and controls. †: p<0.01 for comparison between baseline and 7 days measurements by paired analysis. ACE2: Angiotensin Converting Enzyme 2; RFU: relative fluorometric units.</p

Patient characteristics.

*<p>Data expressed in minutes as median [25^th–75^th percentiles].</p><p>ACE: Angiotensin Converting Enzyme.</p

Correlation between sACE2 activity and infarct size.

<p>A weak but significant correlation was observed between infarct size and sACE2 activity at 7 days (panel A) and at 6 months follow-up (panel B). FU: Follow-up. sACE2: Serum Angiotensin Converting Enzyme 2; LV: left ventricular; RFU: relative fluorometric units.</p

sACE2 activity and LV systolic function.

<p>Scatter-plots showing a statistically significant correlation between ACE2 activity at 7 days and EF during admission (panel A) and at 6 months follow-up (panel B). sACE2: Serum Angiotensin Converting Enzyme 2; EF: ejection fraction; RFU: relative fluorometric units.</p

sACE2 laboratory results.

<p>Data expressed as relative fluorometric units per microliter per hour (RFU/µl/hr).</p>*<p>p<0.001 for comparison between baseline values in controls and STEMI patients by Mann-Whitney U test.</p>**<p>p<0.01 for comparison between baseline and 7 days values in patients by paired Wilcoxon test.</p><p>sACE2: Serum Angiotensin Converting Enzyme 2.</p

Blood pressure and kidney function parameters in non-treated non-obese diabetic mice (Diabetic), NOD-insulin treated mice (Diabetic+INS) and non-obese resistant non-diabetic mice (Control).

<p>A: At the end of the early stage study, systolic and diastolic blood pressure measured by tail-cuff method in Diabetic, Diabetic+INS and Control mice. B: Urinary albumin/creatinine ratio of Diabetic, Diabetic+INS and Control mice at both study stages. C: Glomerular filtration rate measured by inulin in Diabetic, Diabetic+INS and Control mice studied at early stage of diabetes. *<i>P≤0.05.</i></p