Novel Role for Cardiolipin as a Target of Therapy to Mitigate Myocardial Injury Caused by Venoarterial Extracorporeal Membrane Oxygenation

• Published in: Circulation (New York, N.Y.) Vol. 149; no. 17; pp. 1341 - 1353
• Main Authors: Swain, Lija, Bhave, Shreyas, Qiao, Xiaoying, Reyelt, Lara, Everett, Kay D., Awata, Junya, Raghav, Rahul, Powers, Sarah N., Sunagawa, Genya, Natov, Peter S., Mahmoudi, Elena, Warner, Mary, Couper, Greg, Kawabori, Masashi, Miyashita, Satoshi, Aryaputra, Tejasvi, Huggins, Gordon S., Chin, Michael T., Kapur, Navin K.
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott Williams & Wilkins 23.04.2024
• Subjects: Acyltransferases - metabolism; Animals; Cardiolipins - metabolism; Disease Models, Animal; Extracorporeal Membrane Oxygenation - adverse effects; Female; Heart Failure - metabolism; Heart Failure - therapy; Humans; Male; Middle Aged; Mitochondria, Heart - drug effects; Mitochondria, Heart - metabolism; Mitochondria, Heart - pathology; Myocardial Infarction - metabolism; Myocardial Infarction - therapy; Myocardial Reperfusion Injury - etiology; Myocardial Reperfusion Injury - metabolism; Myocardial Reperfusion Injury - pathology; Myocardial Reperfusion Injury - prevention & control; Myocardium - metabolism; Myocardium - pathology; Swine; mitochondria; myocardial infarction
• ISSN: 0009-7322; 1524-4539; 1524-4539
• DOI: 10.1161/CIRCULATIONAHA.123.065298

BACKGROUND: Cardiolipin is a mitochondrial-specific phospholipid that maintains integrity of the electron transport chain (ETC) and plays a central role in myocardial ischemia/reperfusion injury. Tafazzin is an enzyme that is required for cardiolipin maturation. Venoarterial extracorporeal membrane oxygenation (VA-ECMO) use to provide hemodynamic support for acute myocardial infarction has grown exponentially, is associated with poor outcomes, and is under active clinical investigation, yet the mechanistic effect of VA-ECMO on myocardial damage in acute myocardial infarction remains poorly understood. We hypothesized that VA-ECMO acutely depletes myocardial cardiolipin and exacerbates myocardial injury in acute myocardial infarction. METHODS: We examined cardiolipin and tafazzin levels in human subjects with heart failure and healthy swine exposed to VA-ECMO and used a swine model of closed-chest myocardial ischemia/reperfusion injury to evaluate the effect of VA-ECMO on cardiolipin expression, myocardial injury, and mitochondrial function. RESULTS: Cardiolipin and tafazzin levels are significantly reduced in the left ventricles of individuals requiring VA-ECMO compared with individuals without VA-ECMO before heart transplantation. Six hours of exposure to VA-ECMO also decreased left ventricular levels of cardiolipin and tafazzin in healthy swine compared with sham controls. To explore whether cardiolipin depletion by VA-ECMO increases infarct size, we performed left anterior descending artery 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 cardiolipin to stabilize the inner mitochondrial membrane. Compared with reperfusion alone, VA-ECMO activation beginning after 90 minutes of left anterior descending artery occlusion increased infarct size (36±8% versus 48±7%; P<0.001). VA-ECMO also decreased cardiolipin and tafazzin levels, disrupted mitochondrial integrity, reduced electron transport chain function, and promoted oxidative stress. Compared with reperfusion alone or VA-ECMO before reperfusion, delivery of MTP-131 before VA-ECMO activation reduced infarct size (22±8%; P=0.03 versus reperfusion alone and P<0.001 versus VA-ECMO alone). MTP-131 restored cardiolipin and tafazzin levels, stabilized mitochondrial function, and reduced oxidative stress in the left ventricle. CONCLUSIONS: We identified a novel mechanism by which VA-ECMO promotes myocardial injury and further identify cardiolipin as an important target of therapy to reduce infarct size and to preserve mitochondrial function in the setting of VA-ECMO for acute myocardial infarction.