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- W4387620968 abstract "Cardiolipin (CL) is a mitochondrial specific phospholipid that maintains integrity of the electron transport chain (ETC) and plays a central role in myocardial ischemia-reperfusion injury. VA-ECMO use to provide hemodynamic support for acute myocardial infarction (AMI) has grown exponentially; is associated with poor outcomes; and is the subject of active clinical trials, yet the mechanistic impact of VA-ECMO on myocardial damage in AMI remains poorly understood. We hypothesized that VA-ECMO acutely depletes myocardial CL and promotes myocardial damage in AMI. We first report that levels of CL and tafazzin, a key enzyme required for CL synthesis, are significantly reduced in the left ventricles (LV) of human subjects requiring VA-ECMO compared to subjects without VA-ECMO prior to heart transplantation. Six hours of exposure to VA-ECMO also decreased LV levels of CL and tafazzin in healthy swine compared to sham controls. To explore whether CL depletion by VA-ECMO increases infarct size, we performed left anterior descending artery (LAD) occlusion for a total of 120 minutes followed by 180 minutes of reperfusion in adult swine in the presence and absence of MTP-131, an amphipathic molecule that interacts with CL to stabilize the inner mitochondrial membrane. Compared to reperfusion alone, VA-ECMO activation beginning after 90 minutes of LAD occlusion increased infarct size (33±11% vs 48±7%, p<0.001). VA-ECMO also decreased CL and tafazzin levels, disrupted mitochondrial structural integrity, reduced ETC function and promoted oxidative stress. Compared to reperfusion alone or VA-ECMO before reperfusion, intracoronary delivery of MTP-131 five minutes before VA-ECMO activation reduced infarct size (22±8%, p=0.03 vs IRI and p<0.001 vs VA-ECMO). Treatment with MTP-131 also restored CL and tafazzin levels, stabilized mitochondrial function, and reduced oxidative stress in the LV. Our results identify a novel mechanism by which VA-ECMO promotes myocardial dysfunction and further identify cardiolipin as an important target of therapy to reduce infarct size and preserve mitochondrial function for patients requiring VA-ECMO for acute myocardial infarction. Future clinical studies are required to test the translational utility of this approach." @default.
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- W4387620968 date "2023-08-04" @default.
- W4387620968 modified "2023-10-15" @default.
- W4387620968 title "Abstract GS.08: Cardiolipin Is A Novel Target Of Therapy To Mitigate Myocardial Injury Due To Veno-arterial Extracorporeal Membrane Oxygenation (va-ecmo)" @default.
- W4387620968 doi "https://doi.org/10.1161/res.133.suppl_1.gs.08" @default.
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