TY - JOUR T1 - Metabolic Profiling of Aortic Stenosis and Hypertrophic Cardiomyopathy Identifies Mechanistic Contrasts in Substrate Utilisation JF - bioRxiv DO - 10.1101/715680 SP - 715680 AU - Nikhil Pal AU - Animesh Acharjee AU - Zsuzsanna Ament AU - Tim Dent AU - Arash Yavari AU - Masliza Mahmod AU - Rina Ariga AU - James West AU - Violetta Steeples AU - Mark Cassar AU - Neil J. Howell AU - Helen Lockstone AU - Kate Elliott AU - Parisa Yavari AU - Thanh Ha Nguyen AU - William Briggs AU - David L Hare AU - John French AU - Steven Unger AU - Mark Richards AU - Anthony Keech AU - John D Horowitz AU - Michael Frenneaux AU - Bernard Prendergast AU - Jeremy S Dwight AU - Rajesh Kharbanda AU - Hugh Watkins AU - Houman Ashrafian AU - Julian L Griffin Y1 - 2019/01/01 UR - http://biorxiv.org/content/early/2019/08/07/715680.abstract N2 - Background Aortic stenosis (AS) and hypertrophic cardiomyopathy (HCM) are highly distinct disorders leading to LVH, but whether cardiac metabolism substantially differs between these in humans remains to be elucidated.Method We undertook a detailed invasive (aortic root and coronary sinus) metabolic profiling in patients with severe AS and HCM in comparison to non-LVH controls, to investigate cardiac fuel selection and metabolic remodelling. These patients were assessed under different physiological states (at rest and 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 then present findings from the clinical trial using perhexiline, a metabolic modulator of long-chain fatty acid β-oxidation, in patients with severe AS, and contextualise these with the up-stream metabolomic findings.Results We identified a highly discriminant metabolomic signature in severe AS characterised by striking accumulation of long-chain acylcarnitines, intermediates of long-chain transport and fatty acid metabolism, and validated this in a separate cohort. Mechanistically, we identify a down-regulation in the PPAR-α transcriptional network, including expression of genes regulating FAO. Evaluation of the symptomatic impact of perhexiline in severe AS, in contrast to HCM, revealed no significant beneficial effect, suggesting the underlying metabolic changes are attempts at metabolic adaptation.Conclusions 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 fundamental distinctions in substrate preference between AS and HCM, highlighting insufficient long-chain FAO, and the PPAR-α signalling network as a specific metabolic therapeutic target in AS. ER -