Cardio-omentopexy Requires a Cardioprotective Innate Immune Response to Promote Myocardial Angiogenesis in Mice

Introduction: The greater omentum is replete with angiogenic factors and macrophages. Cardio-omentopexy (COP), wherein the pedicled greater omentum is applied onto ischemic or pressure-overloaded hearts, has been shown to be protective in both humans and animals. However, the protective mechanisms of COP remain unclear. Hypothesis: We hypothesized that COP protects the heart against pressure overload-induced cardiac hypertrophy and dysfunction via a macrophage-dependent mechanism of myocardial angiogenesis. Methods: C57BL/6 mice underwent transverse aortic constriction (TAC) for 6 weeks followed by COP for 8 weeks. Cardiac geometry and function were evaluated using echocardiography (n=12-13 mice/group). Histochemical analyses quantified cardiomyocyte size, fibrosis, microvessel density, and macrophages. Flow cytometry was performed to analyze neutrophil/monocyte/macrophage populations. Gene expression array was also performed. A group of mice receiving both TAC and COP were intraperitoneally injected with clodronate-liposomes (5 mg/kg every three days for 8 weeks) starting on day 3 after COP. Results: TAC produced concentric left ventricular hypertrophy, reduced mitral E/A ratio, increased cardiomyocyte size, and myocardial fibrosis in the mice undergoing sham COP surgery (TAC + /COP - ). These maladaptive effects of TAC were abrogated by COP (TAC + /COP + ). Myocardial microvessel density was elevated in TAC + /COP + mice. Gene array analysis showed activation of angiogenesis gene networks by COP. Flow cytometry revealed that COP resulted in the accumulation of cardiac MHCII lo Lyve1+TimD4+ resident macrophages at the omental-cardiac interface. Moreover, the depletion of macrophages with clodronate-liposomes (Clo + /TAC + /COP + ) resulted in the failure of COP to prevent left ventricular hypertrophy, enhance mitral E/A ratio, decrease cardiomyocyte size and myocardial fibrosis, and promote angiogenesis. Conclusions: COP protects the pressure-overloaded left ventricle from hypertrophy and dysfunction, with associated angiogenesis. Cardiac resident macrophages accumulate near COP, and macrophage depletion eliminates the benefits of COP. These studies support a novel macrophage-dependent effector function of COP.