Adult cardiomyocytes are postmitotic cells that undergo very limited cell division. Thus, cardiomyocyte death as occurs during myocardial infarction has very detrimental consequences for the heart. Mitochondria have emerged as an important regulator of cardiovascular health and disease. Mitochondria are well established as bioenergetic hubs for generating ATP but have also been shown to regulate cell death pathways. Indeed many of the same signals used to regulate metabolism and ATP production, such as calcium and reactive oxygen species, are also key regulators of mitochondrial cell death pathways. It is widely hypothesized that an increase in calcium and reactive oxygen species activate a large conductance channel in the inner mitochondrial membrane known as the PTP (permeability transition pore) and that opening of this pore leads to necroptosis, a regulated form of necrotic cell death. Strategies to reduce PTP opening either by inhibition of PTP or inhibiting the rise in mitochondrial calcium or reactive oxygen species that activate PTP have been proposed. A major limitation of inhibiting the PTP is the lack of knowledge about the identity of the protein(s) that form the PTP and how they are activated by calcium and reactive oxygen species. This review will critically evaluate the candidates for the pore-forming unit of the PTP and discuss recent data suggesting that assumption that the PTP is formed by a single molecular identity may need to be reconsidered.

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No standardized treatment algorithm exists for the management of continuous‐flow left ventricular assist device (CF‐LVAD)‐specific infections. The aim of this systematic review and meta‐analysis was to compare the outcomes of CF‐LVAD‐specific infections as managed by device exchange to other treatment modalities not involving device exchange. Electronic search was performed to identify all studies in the English literature relating to the management of CF‐LVAD‐specific infections. All identified articles were systematically assessed for selection criteria. Thirteen studies with 158 cases of CF‐LVAD‐specific infection were pooled for analysis. Overall, 18/158 (11.4%) patients underwent CF‐LVAD exchange, and 140/158 (88.6%) patients were treated with non‐exchange modalities. The proportion of patients with isolated driveline infections or pump or pocket infections did not differ significantly between the groups. During a mean follow‐up of 290 days, there were no significant differences in the overall mortality [exchange 17.6% (4.3–50.6) vs. non‐exchange 23.3% (15.8–32.9), P = 0.67] and infection recurrence rates [exchange 26.7% (8.7–58.0) vs. non‐exchange 38.6% (15.4–68.5), P = 0.56]. In the setting of CF‐LVAD‐specific infections, device exchange does not appear to confer an advantage in the overall mortality and infection recurrence as compared to non‐exchange modalities.

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Ischemia/reperfusion (I/R) injury is mediated in large part by opening of the mitochondrial permeability transition pore (PTP). Consequently, inhibitors of the PTP hold great promise for the treatment of a variety of cardiovascular disorders. At present, PTP inhibition is obtained only through the use of drugs (e.g. cyclosporine A, CsA) targeting cyclophilin D (CyPD) which is a key modulator, but not a structural component of the PTP. This limitation might explain controversial findings in clinical studies. Therefore, we investigated the protective effects against I/R injury of small-molecule inhibitors of the PTP (63 and TR002) that do not target CyPD. Both compounds exhibited a dose-dependent inhibition of PTP opening in isolated mitochondria and were more potent than CsA. Notably, PTP inhibition was observed also in mitochondria devoid of CyPD. Compounds 63 and TR002 prevented PTP opening and mitochondrial depolarization induced by Ca 2+ overload and by reactive oxygen species in neonatal rat ventricular myocytes (NRVMs). Remarkably, both compounds prevented cell death, contractile dysfunction and b.