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BTHS patients develop early onset cardiomyopathy and a derangement of intermediary metabolism consistent with mitochondrial disease, but the precise alterations in cardiac metabolism that distinguish BTHS from idiopathic forms of cardiomyopathy are unknown. We performed the first metabolic analysis of myocardial tissue from BTHS cardiomyopathy patients compared to age\u2010 and sex\u2010matched patients with idiopathic dilated cardiomyopathy (DCM) and nonfailing controls. Results corroborate previous evidence for deficiencies in cardiolipin content and its linoleoyl enrichment as defining features of BTHS cardiomyopathy, and reveal a dramatic accumulation of hydrolyzed (monolyso\u2010) cardiolipin molecular species. Respiratory chain protein deficiencies were observed in both BTHS and DCM, but a selective depletion of complex I was seen only in BTHS after controlling for an apparent loss of mitochondrial density in cardiomyopathic hearts. Distinct shifts in the expression of long\u2010chain fatty acid oxidation enzymes and the tissue acyl\u2010CoA profile of BTHS hearts suggest a specific block in mitochondrial fatty acid oxidation upstream of the conventional matrix beta\u2010oxidation cycle, which may be compensated for by a greater reliance upon peroxisomal fatty acid oxidation and the catabolism of ketones, amino acids, and pyruvate to meet cardiac energy demands. These results provide a comprehensive foundation for exploring novel therapeutic strategies that target the adaptive and maladaptive metabolic features of BTHS cardiomyopathy.<\/jats:p>","DOI":"10.1002\/jimd.12459","type":"journal-article","created":{"date-parts":[[2021,11,25]],"date-time":"2021-11-25T16:39:52Z","timestamp":1637858392000},"page":"111-124","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Long\u2010chain fatty acid oxidation and respiratory complex I deficiencies distinguish Barth Syndrome from idiopathic pediatric cardiomyopathy"],"prefix":"10.1002","volume":"45","author":[{"given":"Kathryn C.","family":"Chatfield","sequence":"first","affiliation":[{"name":"Department of Pediatrics University of Colorado School of Medicine, Children's Hospital of Colorado  Aurora Colorado USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Genevieve 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