Effects of (-)-epicatechin on myocardial infarct size and left ventricular remodeling after permanent coronary occlusion

Abstract

Objectives: We examined the effects of the flavanol (-)-epicatechin on short- and long-term infarct size and left ventricular (LV) structure and function after permanent coronary occlusion (PCO) and the potential involvement of the protective protein kinase B (AKT)/extracellular signal-related kinase (ERK) signaling pathways.

Background: (-)-epicatechin reduces blood pressure in hypertensive patients and limits infarct size in animal models of myocardial ischemia-reperfusion injury. However, nothing is known about its effects on infarction after PCO.

Methods: (-)-epicatechin (1 mg/kg daily) treatment was administered via oral gavage to 250 g male rats for 10 days before PCO and was continued afterward. The PCO controls received water. Sham animals underwent thoracotomy and treatment in the absence of PCO. Immunoblots assessed AKT/ERK involvement 2 h after PCO. The LV morphometric features and function were measured 48 h and 3 weeks after PCO.

Results: In the 48-h group, treatment reduced infarct size by 52%. There were no differences in hemodynamics among the different groups (heart rate and aortic and LV pressures). Western blots revealed no differences in AKT or ERK phosphorylation levels. At 3 weeks, PCO control animals demonstrated significant increases in LV end-diastolic pressure, heart and body weight, and LV chamber diameter versus sham. The PCO plus (-)-epicatechin group values were comparable with those of the sham plus (-)-epicatechin group. Treatment resulted in a 33% decrease in myocardial infarction size. The LV pressure-volume curves demonstrated a right shift in control PCO animals, whereas the (-)-epicatechin curves were comparable with those of the sham group. The LV scar area strains were significantly improved with (-)-epicatechin.

Conclusions: These results demonstrate the unique capacity of (-)-epicatechin to confer cardioprotection in the setting of a severe form of myocardial ischemic injury. Protection is sustained over time and preserves LV structure and function. The cardioprotective mechanism(s) of (-)-epicatechin seem to be unrelated to AKT or ERK activation. (-)-epicatechin warrants further investigation as a cardioprotectant.

Copyright (c) 2010 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Figures

Figure 1. Infarct area (IA) as a function of LV area 48 h post-permanent coronary occlusion (PCO) in rats subjected to 10 days vehicle or (−)-epicatechin pretreatment

A: Representative LV equatorial ring sections of control and (−)-epicatechin treated animals stained with TTC. B: dispersion plot of the IA in PCO (n=8) and PCO + (−)-epicatechin (n=11) groups. Values are means ± SE. *p

Figure 2. Infarct area (IA) as a function of LV area 3 wks post-permanent coronary occlusion (PCO) in rats subjected to 10 days vehicle or (−)-epicatechin pretreatment

A: Representative LV equatorial ring sections of control and (−)-epicatechin treated animals stained with TTC. B: dispersion plot of the IA in PCO (n=12) and PCO + (−)-epicatechin (n=12) groups. Values are means ± SE. *p

Figure 3. Average passive left ventricular pressure volume relations for sham (n=6; closed circles), sham + (−)-epicatechin (n=6, open circles), permanent coronary occlusion (PCO, n=6, closed triangles), and PCO + (−)-epicatechin (n=6, open triangles) after 3 weeks

Two-way ANOVA followed by Bonferroni’s test (30 comparisons) revealed significant differences between PCO and shams (p

Figure 4. Average two-dimensional circumferential (E11) (A) and longitudinal (E22) (B) strains in the scar area as functions of inflation pressure for sham (n=6; closed circles), sham + (−)-epicatechin (n=6, open circles), permanent coronary occlusion (PCO, n=6, closed triangles), and PCO + (−)-epicatechin (n=6, open triangles) after 3 weeks

Two-way ANOVA followed by Bonferroni’s test (30 comparisons) indicates that PCO + (−)-epicatechin yields a stiffer scar in the E11 direction relative to PCO. No interactive effect between treatment and pressure was detected.

Figure 5. ERK and AKT levels (AU=arbitrary units) in animals subjected to 10 days vehicle or (−)-epicatechin pretreatment and 2 h of permanent coronary occlusion (PCO)

A: Densitometric analysis of westerns for phosphorylated ERK (A), phosphorylated AKT (B), total ERK (C), and total AKT (D) in PCO (n=6) and PCO + (−)-epicatechin (n=5) animals.