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We undertook an invasive (aortic root, coronary sinus) metabolic profiling in patients with severe AS and HCM in comparison with non\u2010LVH controls to investigate cardiac fuel selection and metabolic remodeling. These patients were assessed under different physiological states (at rest, during stress induced by pacing). The identified changes in the metabolome were further validated by metabolomic and orthogonal transcriptomic analysis, in separately recruited patient cohorts. We identified a highly discriminant metabolomic signature in severe AS in all samples, regardless of sampling site, characterized by striking accumulation of long\u2010chain acylcarnitines, intermediates of fatty acid transport across the inner mitochondrial membrane, and validated this in a separate cohort. Mechanistically, we identify a downregulation in the PPAR\u2010\u03b1 transcriptional network, including expression of genes regulating fatty acid oxidation (FAO). In silico modeling of \u03b2\u2010oxidation demonstrated that flux could be inhibited by both the accumulation of fatty acids as a substrate for mitochondria and the accumulation of medium\u2010chain carnitines which induce competitive inhibition of the acyl\u2010CoA dehydrogenases. We present a comprehensive analysis of changes in the metabolic pathways (transcriptome to metabolome) in severe AS, and its comparison to HCM. Our results demonstrate a progressive impairment of \u03b2\u2010oxidation from HCM to AS, particularly for FAO of long\u2010chain fatty acids, and that the PPAR\u2010\u03b1 signaling network may be a specific metabolic therapeutic target in AS.<\/jats:p>","DOI":"10.1096\/fj.202301710rr","type":"journal-article","created":{"date-parts":[[2024,3,20]],"date-time":"2024-03-20T12:33:52Z","timestamp":1710938032000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Metabolic profiling of aortic stenosis and hypertrophic cardiomyopathy identifies mechanistic contrasts in substrate utilization"],"prefix":"10.1096","volume":"38","author":[{"given":"Nikhil","family":"Pal","sequence":"first","affiliation":[{"name":"Division of Cardiovascular Medicine University of Oxford, John Radcliffe Hospital  Oxford UK"},{"name":"Department of Experimental Therapeutics, Radcliffe Department of Medicine University of Oxford, John Radcliffe 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