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Metabolic profiling of aortic stenosis and hypertrophic cardiomyopathy identifies mechanistic contrasts in substrate utilization.

Published version
Peer-reviewed

Repository DOI


Change log

Authors

Pal, Nikhil 
Dent, Tim 
Yavari, Arash 

Abstract

Aortic stenosis (AS) and hypertrophic cardiomyopathy (HCM) are distinct disorders leading to left ventricular hypertrophy (LVH), but whether cardiac metabolism substantially differs between these in humans remains to be elucidated. We undertook an invasive (aortic root, coronary sinus) metabolic profiling in patients with severe AS and HCM in comparison with non-LVH 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-chain 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-α transcriptional network, including expression of genes regulating fatty acid oxidation (FAO). In silico modeling of β-oxidation demonstrated that flux could be inhibited by both the accumulation of fatty acids as a substrate for mitochondria and the accumulation of medium-chain carnitines which induce competitive inhibition of the acyl-CoA 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 β-oxidation from HCM to AS, particularly for FAO of long-chain fatty acids, and that the PPAR-α signaling network may be a specific metabolic therapeutic target in AS.

Description

Publication status: Published


Funder: British Heart Foundation (BHF); doi: http://dx.doi.org/10.13039/501100000274


Funder: NIHR | NIHR Oxford Biomedical Research Centre (OxBRC)

Keywords

cardiac gradient, cardiac metabolism, ischemic heart disease, metabolomics, precision medicine, Humans, Peroxisome Proliferator-Activated Receptors, Cardiomyopathy, Hypertrophic, Hypertrophy, Left Ventricular, Aortic Valve Stenosis, Fatty Acids

Journal Title

FASEB J

Conference Name

Journal ISSN

0892-6638
1530-6860

Volume Title

38

Publisher

Wiley
Sponsorship
UKRI | Medical Research Council (MRC) (MR/P011705/1, MC_UP_A090_1006, MR/S010483)