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Metabolic profiling of aortic stenosis and hypertrophic cardiomyopathy identifies mechanistic contrasts in substrate
Nikhil Pal1,2, Animesh Acharjee3,4,5, Zsuzsanna Ament3,4
1Division of Cardiovascular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK.
Insights
Cardiac metabolism differs significantly between aortic stenosis (AS) and hypertrophic cardiomyopathy (HCM). AS shows impaired fatty acid oxidation due to accumulated long-chain acylcarnitines, suggesting PPAR-α as a therapeutic target.
Area of Science:
- Cardiovascular Medicine
- Metabolomics
- Molecular Biology
Background:
- Aortic stenosis (AS) and hypertrophic cardiomyopathy (HCM) both cause left ventricular hypertrophy (LVH).
- Cardiac metabolic differences between AS and HCM in humans are not well understood.
- Investigating these differences is crucial for understanding disease progression and identifying therapeutic targets.
Purpose of the Study:
- To compare cardiac fuel selection and metabolic remodeling in patients with severe AS and HCM versus controls with no LVH.
- To elucidate the distinct metabolic signatures of AS and HCM.
- To identify potential therapeutic targets for AS based on metabolic pathway analysis.
Main Methods:
- Invasive metabolic profiling of the aortic root and coronary sinus in patients with severe AS, HCM, and controls.
- Assessment of cardiac metabolism at rest and during stress (pacing-induced).
- Validation of metabolomic findings using transcriptomic analysis in separate patient cohorts.
Main Results:
- A distinct metabolomic signature in severe AS characterized by accumulated long-chain acylcarnitines was identified.
- Downregulation of the PPAR-α transcriptional network and impaired fatty acid oxidation (FAO) were observed in AS.
- In silico modeling indicated inhibition of β-oxidation by substrate and product accumulation.
Conclusions:
- Cardiac metabolism progressively impairs from HCM to AS, with a particular deficit in long-chain fatty acid oxidation in AS.
- The PPAR-α signaling network represents a potential specific metabolic therapeutic target for AS.
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.
