Calpain inhibition improves collateral-dependent perfusion in a hypercholesterolemic swine model of chronic myocardial ischemia

Purpose Calpain overexpression is implicated in aberrant angiogenesis. We hypothesized that calpain inhibition (MDL28170) would improve collateral perfusion in a swine model with hypercholesterolemia and chronic myocardial ischemia. Methods Yorkshire swine fed a high cholesterol diet for 4 weeks underwent surgical placement of an ameroid constrictor to their left circumflex coronary artery. Three weeks later, animals received no drug, high cholesterol control group (n = 8); low-dose calpain inhibition (0.12 mg/kg; n = 9); or high-dose calpain inhibition (0.25 mg/kg; n = 8). The heart was harvested after 5 weeks. Results Myocardial perfusion in ischemic myocardium significantly improved with high-dose calpain inhibition at rest and with demand pacing (P =.016 and.011). Endothelium-dependent microvessel relaxation was significantly improved with low-dose calpain inhibition (P =.001). There was a significant increase in capillary density, with low-dose calpain inhibition and high-dose calpain inhibition (P =.01 and.01), and arteriolar density with low-dose calpain inhibition (P =.001). Calpain inhibition significantly increased several proangiogenic proteins, including vascular endothelial growth factor (P =.02), vascular endothelial growth factor receptor 1 (P =.003), vascular endothelial growth factor receptor 2 (P =.003), and talin, a microvascular structural protein (P =.0002). There was a slight increase in proteins implicated in endothelial-dependent (nitric oxide mediated) relaxation, including extracellular signal-regulated kinase, phosphorylated extracellular signal-regulated kinase, and inducible nitric oxide synthase with calpain inhibition. Conclusions In the setting of hypercholesterolemia, calpain inhibition improved perfusion, with a trend toward increased collateralization on angiography and increased capillary and arteriolar densities in ischemic myocardium. Calpain inhibition also improved endothelium-dependent microvessel relaxation and increased expression of proteins implicated in angiogenesis and vasodilatation.