Abstract 19666: Calpain Inhibition Improves Myocardial Perfusion in a Swine Model of Chronic Myocardial Ischemia
Hypothesis: Calpain overexpression is implicated in aberrant angiogenesis in chronic myocardial ischemia. We hypothesized that calpain inhibition (CI) would improve collateral dependent perfusion in a swine model with hypercholesterolemia.
Methods: Yorkshire swine were divided into 3 groups, fed a high cholesterol diet for 4 weeks, then underwent surgical placement of an ameroid constrictor to their left circumflex artery. Three weeks later animals received either: no drug, high cholesterol control group (HCC; n= 8); low dose CI (0.12 mg/kg; LCI, n= 9); or high dose CI (0.25 mg/kg; HCI, n= 8). The diets and drug were continued for 5 weeks then the heart was harvested for analysis.
Results: Myocardial perfusion in ischemic territory improved in the LCI group and significantly improved in the HCI group at rest and with pacing (p = 0.016 and 0.011, respectively). CI improved endothelium-dependent microvessel relaxation with significant improvement in the LCI group compared to HCC group (p = 0.001). Endothelium-independent microvessel relaxation was similar among groups. There was a slight increase in capillary density in the LCI group compared with the HCC group, and a significant increase compared with the HCI group (p= 0.085). There were no improvements in arteriolar density. In the ischemic myocardium there was a significant increase in several proangiogenic proteins including VEGF (p= 0.02), VEGFR1 (p= 0.003), VEGFR2 (p= 0.003) and there was a slight increase in proteins implicated in endothelial relaxation including ERK, p-ERK and iNOS.
Conclusions: In the setting of metabolic syndrome CI improved perfusion and increased capillary density but did not improve arteriolar density in the ischemic myocardium. CI also improved endothelium-dependent microvessel relaxation, and increased expression of proteins implicated in angiogenesis and vasodilation, which may explain the marked improvement in perfusion in the collateral dependent myocardium.
Author Disclosures: A.A. Sabe: None. N.Y. Elmadhun: None. J. Feng: None. Y. Liu: None. F.W. Sellke: Consultant/Advisory Board; Modest; CSL Behring, Medicines Company.
- © 2014 by American Heart Association, Inc.