{"doi":"10.1161/circulationaha.123.065298","title":"Novel Role for Cardiolipin as a Target of Therapy to Mitigate Myocardial Injury Caused by Venoarterial Extracorporeal Membrane Oxygenation","abstract":"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.","journal":"Circulation","year":2024,"id":425856,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":18,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9607,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":275864,"name":"Shreyas Bhave","orcid":"0000-0003-0393-0978","position":1,"is_corresponding":false},{"id":155920,"name":"Xiaoying Qiao","orcid":null,"position":2,"is_corresponding":false},{"id":275863,"name":"Lara Reyelt","orcid":"0000-0001-6242-5926","position":3,"is_corresponding":false},{"id":1224141,"name":"Kay Everett","orcid":"0000-0002-5949-0812","position":4,"is_corresponding":false},{"id":825374,"name":"Junya Awata","orcid":null,"position":5,"is_corresponding":false},{"id":1224142,"name":"Rahul Raghav","orcid":"0000-0001-8288-7992","position":6,"is_corresponding":false},{"id":1224702,"name":"Sarah Powers","orcid":null,"position":7,"is_corresponding":false},{"id":1224703,"name":"Genya Sunagawa","orcid":null,"position":8,"is_corresponding":false},{"id":680267,"name":"Peter Natov","orcid":"0000-0001-9200-2385","position":9,"is_corresponding":false},{"id":1224704,"name":"Elena Mahmoudi","orcid":null,"position":10,"is_corresponding":false},{"id":1224705,"name":"Mary Grace Warner","orcid":null,"position":11,"is_corresponding":false},{"id":1224706,"name":"Greg Couper","orcid":null,"position":12,"is_corresponding":false},{"id":527071,"name":"Masashi Kawabori","orcid":"0000-0002-3580-5664","position":13,"is_corresponding":false},{"id":263781,"name":"Satoshi Miyashita","orcid":"0000-0003-3464-5862","position":14,"is_corresponding":false},{"id":1224707,"name":"Tejasvi Aryaputra","orcid":null,"position":15,"is_corresponding":false},{"id":420697,"name":"Gordon S. Huggins","orcid":"0000-0002-8035-0312","position":16,"is_corresponding":false},{"id":510213,"name":"Michael T. Chin","orcid":"0000-0003-3065-8498","position":17,"is_corresponding":false},{"id":230592,"name":"Navin K. Kapur","orcid":"0000-0002-8302-6796","position":18,"is_corresponding":false},{"id":275862,"name":"Lija Swain","orcid":"0000-0001-7713-606X","position":0,"is_corresponding":true}],"reference_count":41,"raw_metadata":null,"created_at":"2026-07-19T01:58:32.160975Z","pmid":"38235580","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}