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Pregnancy is associated with substantial physiological changes of the heart, and disruptions in these processes can lead to peripartum cardiomyopathy (PPCM). The molecular processes that cause physiological and pathological changes in the heart during pregnancy are not well characterized. Here, we show that mTORc1 was activated in pregnancy to facilitate cardiac enlargement that was reversed after delivery in mice. mTORc1 activation in pregnancy was negatively regulated by the mRNA-destabilizing protein ZFP36L2 through its degradation of Mdm2 mRNA and P53 stabilization, leading to increased SESN2 and REDD1 expression. This pathway impeded uncontrolled cardiomyocyte hypertrophy during pregnancy, and mice with cardiac-specific Zfp36l2 deletion developed rapid cardiac dysfunction after delivery, while prenatal treatment of these mice with rapamycin improved postpartum cardiac function. Collectively, these data provide what we believe to be a novel pathway for the regulation of mTORc1 through mRNA stabilization of a P53 ubiquitin ligase. This pathway was critical for normal cardiac growth during pregnancy, and its reduction led to PPCM-like adverse remodeling in mice.

Abstract Excess cellular iron increases reactive oxygen species (ROS) production and causes cellular damage. Mitochondria are the major site of iron metabolism and ROS production; however, few studies have investigated the role of mitochondrial iron in the development of cardiac disorders, such as ischemic heart disease or cardiomyopathy (CM). We observe increased mitochondrial iron in mice after ischemia/reperfusion (I/R) and in human hearts with ischemic CM, and hypothesize that decreasing mitochondrial iron protects against I/R damage and the development of CM. Reducing mitochondrial iron genetically through cardiac‐specific overexpression of a mitochondrial iron export protein or pharmacologically using a mitochondria‐permeable iron chelator protects mice against I/R injury. Furthermore, decreasing mitochondrial iron protects the murine hearts in a model of spontaneous CM with mitochondrial iron accumulation. Reduced mitochondrial ROS that is independent of alterations in the electron transport chain's ROS producing capacity contributes to the protective effects. Overall, our findings suggest that mitochondrial iron contributes to cardiac ischemic damage, and may be a novel therapeutic target against ischemic heart disease.

Background The trend towards hospitalist medicine can lead to disjointed patient care. Outpatient clinicians may be unaware of patients’ encounters with a disparate healthcare system. Electronic notifications to outpatient clinicians of patients’ emergency department (ED) visits and inpatient admissions and discharges using health information exchange can inform outpatient clinicians of patients’ hospital-based events.Objective Assess outpatient clinicians’ impressions of a new, secure messaging-based, patient event notification system.Methods Twenty outpatient clinicians receiving notifications of hospital-based events were recruited and 14 agreed to participate. Using a semi-structured interview, clinicians were asked about their use of notifications and the impact on their practices.Results Nine of 14 interviewed clinicians (64%) thought that without notifications, they would have heard about fewer than 10% of ED visits before the patient’s next visit. Nine clinicians (64%) thought that without notifications, they would have heard about fewer than 25% of inpatient admissions and discharges before the patient’s next visit. Six clinicians (43%) reported that they call the inpatient team more often because of notifications. Eight users (57%) thought that notifications improved patient safety by increasing their awareness of the patients’ clinical events and their medication changes. Key themes identified were the importance of workflow integration and a desire for more clinical information in notifications.Conclusions The notification system is perceived by clinicians to be of value. These findings should instigate further message-oriented use of health information exchange and point to refinements that can lead to even greater benefits.