MI/R results in cardiac contractile dysfunction and increased cell death. MI/R is initiated in part by uncoupling of the electron transport chain in mitochondria, which generates reactive oxygen species (ROS). Increased ROS lead to the loss of mitochondrial membrane potential, which augments mitochondrial fission in MI/R. Mitochondrial fission is in turn associated with shortening of mitochondria, decreased ATP production, and is thought to promote cardiac contractile dysfunction and post‐reperfused cardiomyocyte loss, leading to increased infarct size. Therefore, inhibiting mitochondrial fission may be an effective new strategy to salvage injured cardiac myocytes during MI/R. Mdivi‐1 (MW= 353 g/mol), a mitochondrial fission inhibitor, that acts by selectively inhibiting dynamin related protein 1, a GTPase that promotes mitochondrial fission via interaction with outer mitochondrial membrane proteins, was used to test this strategy. Isolated perfused rat hearts subjected to I (30 min)/R (90 min) were infused with Mdivi‐1 (25 µM) given for 5 min at the beginning of reperfusion. Mdivi‐1 treated hearts (n=6) significantly reduced infarct size to 25% ± 2%, as compared to control I/R hearts (n=9) 44% ± 4% (p< 0.01). However, Mdivi‐1 only transiently improved post‐reperfused cardiac function at this dose, compared to control I/R hearts. These preliminary results suggest that inhibition of mitochondrial fission salvages cardiac tissue in MI/R. Future studies will test whether other Mdivi‐1 treatment regimens will prove to be more effective.

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Mitochondrial dynamics are altered in favor of mitochondrial fission during MI/R. Mitochondrial fission is associated with shortening of mitochondria, decreased ATP production, and increased reactive oxygen species during MI/R, and is thought to promote cardiomyocyte loss. Therefore, inhibition of mitochondrial fission may be a new strategy to salvage injured cardiac myocytes and limit infarct size. To test this hypothesis, the cardioprotective effects of a novel mitochondrial fission inhibitor, P110 (MW=2427 g/mol), a cell permeable peptide, that selectively inhibits the interaction between dynamin related protein 1 and fission protein 1, were determined in isolated perfused rat hearts subjected to I (30 min)/R (45 min). P110 (1 µM) given for 10 min before ischemia and for 20 min post‐reperfusion, significantly restored left ventricular developed pressure (LVDP) and the peak of the first derivative of left ventricular pressure (dP/dtmax) to 77 ± 9% and 58 ± 7% of baseline values at 45 min post‐reperfusion, respectively, as compared to control I/R hearts (both p<0.01, n=6). The LVDP and dP/dtmax of control I/R hearts (n=8) only recovered to 34 ± 8% and 29 ± 4% of baseline values at 45 min post‐reperfusion, respectively. P110 also significantly reduced infarct size to 20 ± 3% compared to 41 ± 4% in control I/R hearts (p<0.01). The preliminary results suggest that inhibition of mitochondrial fission during MI/R improves post‐reperfused cardiac contractile function and reduces infarct size.

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