Metabolic Profiling of Aortic Stenosis and Hypertrophic Cardiomyopathy Identifies Mechanistic Contrasts in Substrate Utilisation

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 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 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 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 …