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

Abstract

BackgroundAortic stenosis (AS) and hypertrophic cardiomyopathy (HCM) are highly distinct disorders leading to left ventricular hypertrophy (LVH), but whether cardiac metabolism substantially differs between these in humans remains to be elucidated.MethodWe 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.ResultsWe 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.ConclusionsWe 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.

Altered Cardiac Energetics and Mitochondrial Dysfunction in Hypertrophic Cardiomyopathy

“…Despite several clinical and experimental studies showing metabolic remodeling and inflexibility in hypertrophic and failing hearts, [46][47][48] there are few comprehensive studies in human cardiomyopathies, especially in HCM. 21,49 Here, we present an in-depth multiomics characterization of human HCM myocardium combined with analysis of mitochondrial structure and function. This integrative omics analysis reveals potential molecular mechanisms underlying HCM pathophysiology, including major metabolic derangements across all main biochemical pathways (summarized in Figure 6).…”

Metabolic flux between organs measured by arteriovenous metabolite gradients

“…Voros et al (2018) found increased uptake of ketone bodies and FFAs in both patients with heart failure/reduced ejection fraction and patients with aortic stenosis-induced left ventricular hypertrophy 73 . Pal et al (2019) further compared substrate utilization between patients with aortic stenosis and those with hypertrophic cardiomyopathy 74 and identified differential metabolism of longchain acylcarnitines. As described above, Murashige et al (2020) performed comprehensive mapping of cardiac uptake and release of numerous circulating metabolites in patients with preserved or reduced ejection fraction, which revealed that the failing heart relies on more ketones and lactate, has higher protein breakdown, and surprisingly uses almost no glucose 32 .…”