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.

Purpose MD–PhD training programs provide an integrated approach for training physician–scientists. The goal of this study was to characterize the career path taken by MD–PhD program alumni during the past 40 years and identify trends that affect their success. Method In 2007–early 2008, 24 programs enrolling 43% of current trainees and representing half of the National Institutes of Health-funded MD–PhD training programs submitted anonymous data on 5,969 current and former trainees. Results The average program enrolled 90 trainees, required 8.0 years to complete, and had an attrition rate of 10%. Nearly all (95%) of those who graduated entered residencies. Most (81%) were employed in academia, research institutes, or industry; 16% were in private practice. Of those in academia, 82% were doing research and at least 61% had identifiable research funding. Whereas two-thirds devoted more than 50% effort to research, only 39% devoted more than 75% effort. Many with laboratory-based PhDs reported doing clinical, as well as basic and translational, research. Emerging trends include decreasing numbers of graduates who forego residencies or hold primary appointments in nonclinical departments, increasing time to graduation, and expanding residency choices that include disciplines historically associated with clinical practice rather than research. Conclusions Most MD–PhD program graduates follow career paths generally consistent with their training as physician–scientists. However, the range of their professional options is broad. Further thought should be given to designing their training to anticipate their career choices and maximize their likelihood of success as investigators.

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Chagas heart disease is an inflammatory cardiomyopathy that develops in approximately one-third of people infected with the protozoan parasite Trypanosoma cruzi. One way T. cruzi is transmitted to people is through contact with infected kissing bugs, which are found in much of the Western Hemisphere, including in vast areas of the United States. The epidemiology of T. cruzi and Chagas heart disease and the varied mechanisms leading to myocyte destruction, mononuclear cell infiltration, fibrosis, and edema in the heart have been extensively studied by hundreds of scientists for more than 100 years. Despite this wealth of knowledge, it is still impossible to predict what will happen in an individual infected with T. cruzi because of the tremendous variability in clonal parasite virulence and human susceptibility to infection and the lack of definitive molecular predictors of outcome from either side of the host–parasite equation. Further, while several distinct mechanisms of pathogenesis have been studied in isolation, it is certain that multiple coincident mechanisms combine to determine the ultimate outcome. For these reasons, Chagas disease is best considered a collection of related but distinct illnesses. This review highlights the pathology and pathogenesis of the most common adverse sequela of T. cruzi infection—Chagas heart disease—and concludes with a discussion of key unanswered questions and a view to the future.