Rationale Efficient clearance of apoptotic cells (efferocytosis) is a prerequisite for inflammation resolution and tissue repair. Following myocardial infarction (MI), phagocytes are recruited to the heart and promote clearance of dying cardiomyocytes (CMs). The molecular mechanisms of efferocytosis of CMs and in the myocardium are unknown. The injured heart provides a unique model to examine relationships between efferocytosis and subsequent inflammation resolution, tissue remodeling, and organ function. Objective We set out to identify mechanisms of dying cardiomyocyte (CM) engulfment by phagocytes and to for the first time assess the causal significance of disrupting efferocytosis during MI. Methods and Results In contrast to other apoptotic cell receptors, macrophage MER tyrosine kinase (MER-TK) was necessary and sufficient for efferocytosis of CMs ex vivo. In mice, Mertk was specifically induced in Ly6cLO myocardial phagocytes after experimental coronary occlusion. Mertk deficiency led to an accumulation of apoptotic CMs, independent of changes in non-CMs, and a reduced index of in vivo efferocytosis. Importantly, suppressed efferocytosis preceded increases in myocardial infarct size and led to delayed inflammation resolution and reduced systolic performance. Reduced cardiac function was reproduced in chimeric mice deficient in bone marrow Mertk; reciprocal transplantation of Mertk+/+ marrow into Mertk-/- mice corrected systolic dysfunction. Interestingly, an inactivated form of MERTK, known as solMER, was identified in infarcted myocardium, implicating a natural mechanism of MERTK inactivation post MI. Conclusions These data collectively and directly link efferocytosis to wound healing in the heart and identify Mertk as a significant link between acute inflammation resolution and organ function.

Mutations in the lamin A/C gene (LMNA) encoding A-type lamins cause a diverse range of diseases collectively called laminopathies, the most common of which is dilated cardiomyopathy. Emerging evidence suggests that LMNA mutations cause disease by altering cell signaling pathways but the specific mechanisms involved are poorly understood. Here we show that AKT-mTOR pathway is hyperactivated in hearts of mice with cardiomyopathy caused by Lmna mutation and that in vivo administration of the rapamycin analog temsirolimus prevents deterioration of cardiac function. We also show defective autophagy in hearts of these mice and that improvement in heart function induced by pharmacological interventions is correlated with enhanced autophagy. These findings provide a rationale for a novel treatment of LMNA cardiomyopathy and implicate defective autophagy as a pathogenic mechanism of cardiomyopathy arising from LMNA mutation.

We previously interrogated the transcriptome in heart tissue from Lmna(H222P/H222P) mice, a mouse model of cardiomyopathy caused by lamin A/C gene (LMNA) mutation, and found that the extracellular signal-regulated kinase 1/2 and Jun N-terminal kinase branches of the mitogen-activated protein (MAP) kinase signaling pathway were abnormally hyperactivated prior to the onset of significant cardiac impairment. We have now used an alternative gene expression analysis tool to reanalyze this transcriptome and identify hyperactivation of a third branch of the MAP kinase cascade, p38α signaling. Biochemical analysis of hearts from Lmna(H222P/H222P) mice showed enhanced p38α activation prior to and after the onset of heart disease as well as in hearts from human subjects with cardiomyopathy caused by LMNA mutations. Treatment of Lmna(H222P/H222P) mice with the p38α inhibitor ARRY-371797 prevented left ventricular dilatation and deterioration of fractional shortening compared with placebo-treated mice but did not block the expression of collagen genes involved in cardiac fibrosis. These results demonstrate that three different branches of the MAP kinase signaling pathway with overlapping consequences are involved in the pathogenesis of cardiomyopathy caused by LMNA mutations. They further suggest that pharmacological inhibition of p38α may be useful in the treatment of this disease.

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Patients with pre-operative VA are at risk of recurrent VA while on CF-LVAD support and should have active ICD therapy to minimize sustained VA. Patients without pre-operative VA are at low risk and may not need active ICD therapy.