Abstract 16121: Recombinant Human Placental Growth Factor 2 is a Safe and Effective Therapy for Ischemic Cardiomyopathy in Atherosclerotic Mice

Abstract

Aim: Angiogenic growth factor therapy carries a risk of stimulating atherosclerotic plaque growth. We evaluated whether systemic infusion of recombinant human placental growth factor (rhPlGF) 2 improves myocardial neovascularization, left ventricular (LV) function and adverse remodeling in a murine model of advanced atherosclerosis and chronic myocardial infarction (MI) without increasing atherosclerotic plaque size and plaque vulnerability. Methods: ApoE -/- mice were fed a high cholesterol diet and MI was induced 4 weeks (w) later using 60 min LAD occlusion followed by reperfusion. After 8 w, we assessed LV function using echocardiography and randomized mice to receive rhPlGF2 (450μg/kg/day, n=20) or PBS (n=20) via osmotic minipumps for 28 days. Echocardiography and histological analyses were performed at 12 and 20 w. Results: Infusion of rhPlGF2 increased PlGF plasma levels for 3 w up to ~1600-fold without adverse side effects, or changes in total cholesterol and high sensitive CRP levels. In rhPlGF2-treated mice, capillary and arteriolar density was significantly higher in ischemic myocardium (2813±212 capillaries/mm 2 at 12 w vs 2144±478 in PBS, P <0.05; 125±18 arterioles/mm 2 at 20 w vs 77±13 in PBS, P =0.001). RhPlGF2 significantly improved ejection fraction (EF), reduced LV end-systolic and end-diastolic volume indices at 12 w and prevented further LV dilation and EF deterioration at 20 w (Figure). RhPlGF2 did not increase plaque area in the aortic arch, or the degree of fibrosis, calcification, capillary or arteriolar density and MAC3-positive cell areas in plaques at 12 and 20 w. Conclusion: Systemic rhPlGF2 infusion significantly improves neovascularization and contractile function, and prevents LV adverse remodeling in chronic ischemic cardiomyopathy without increasing atherosclerotic plaque burden or plaque vulnerability. RhPlGF2 may represent a promising and safe therapeutic strategy in chronic ischemic cardiomyopathy.