Altered Cardiac Energetics and Mitochondrial Dysfunction in Hypertrophic Cardiomyopathy

Abstract

Background: Hypertrophic cardiomyopathy (HCM) is a complex disease partly explained by the effects of individual gene variants on sarcomeric protein biomechanics. At the cellular level, HCM mutations most commonly enhance force production, leading to higher energy demands. Despite significant advances in elucidating sarcomeric structure-function relationships, there is still much to be learned about the mechanisms that link altered cardiac energetics to HCM phenotypes. In this work, we test the hypothesis that changes in cardiac energetics represent a common pathophysiologic pathway in HCM. Methods: We performed a comprehensive multi-omics profile of the molecular (transcripts, metabolites, and complex lipids), ultrastructural, and functional components of HCM energetics using myocardial samples from 27 HCM patients and 13 normal controls (donor hearts). Results: Integrated omics analysis revealed alterations in a wide array of biochemical pathways with major dysregulation in fatty acid metabolism, reduction of acylcarnitines, and accumulation of free fatty acids. HCM hearts showed evidence of global energetic decompensation manifested by a decrease in high energy phosphate metabolites [ATP, ADP, and phosphocreatine (PCr)] and a reduction in mitochondrial genes involved in creatine kinase and ATP synthesis. Accompanying these metabolic derangements, electron microscopy showed an increased fraction of severely damaged mitochondria with reduced cristae density, coinciding with reduced citrate synthase (CS) activity and mitochondrial oxidative respiration. These mitochondrial abnormalities were associated with elevated reactive oxygen species (ROS) and reduced antioxidant defenses. However, despite significant mitochondrial injury, HCM hearts failed to upregulate mitophagic clearance. Conclusions: Overall, our findings suggest that perturbed metabolic signaling and mitochondrial dysfunction are common pathogenic mechanisms in patients with HCM. These results highlight potential new drug targets for attenuation of the clinical disease through improving metabolic function and reducing mitochondrial injury.

Critical Evaluation of Current Hypotheses for the Pathogenesis of Hypertrophic Cardiomyopathy

“…Together with hypercontractility, this effect may contribute to the inefficient energy usage, which seems to be unequivocally observed in HCM. Here, downstream disturbances in mitochondrial function and metabolic pathways [13,154,208] may exacerbate the situation. Furthermore, both hypercontractility and contractile imbalance (with locally high tension) may stimulate mechanotransductioninitiated signaling pathways in cardiomyocytes (cf.…”

“…Additional support for a central role of energy depletion in triggering pathologic HCM remodeling comes from the findings that not only sarcomere protein mutations, but also mutations of key proteins in metabolic pathways, lead to a cardiac phenotype of the HCM type [11,13]. Furthermore, disturbed metabolic signaling and mitochondrial dysfunction seem to be quite central, more generally, in HCM [154]. Here, we do not treat inefficient energy usage or energy depletion as primary effects of the HCM mutations in sarcomere proteins, and the phenomenon is not included among our three key hypotheses (Table 1).…”

“…Further evidence in support of inefficient energy usage (low work output per O 2 consumption) in HCM mutation carriers have been provided by using [11C]-acetate positron emission tomography (PET) and magnetic resonance imaging [80,168]. Evidence for severe metabolic disturbances was also provided by a multi-omics study [154] applied to human septal myectomy samples from HCM patients (with ejection fraction >55%) compared to donor hearts. These findings, suggesting "perturbed metabolic signaling and mitochondrial dysfunction", are consistent with ideas [11,13,208], emphasizing the importance of energy deficiency and dysfunctional mitochondria in HCM pathogenesis.…”

The association between the clinical severity of heart failure and docosahexaenoic acid accumulation in hypertrophic cardiomyopathy

“…Therefore, it can be assumed that FA pooling is enhanced in hypertrophied myocardium. Ranjbarvaziri et al reported that free FA accumulation in HCM myocardium was significantly higher than that in normal myocardium [ 14 ]. Additionally, they stated that the dysregulation in FA metabolism in HCM myocardium may be caused by mitochondrial damage and reduced citrate synthase activity which was associated with increased reactive oxygen species, based on the findings from electron microscopy and integrated molecular pathway level analysis.…”

The Imbalance of Mitochondrial Homeostasis of Peripheral Blood-Derived Macrophages Mediated by MAFLD May Impair the Walking Ability of Elderly Patients with Osteopenia

“…The average fluorescence intensities of mtROS and intracellular ROS were determined using FCM (FACS Aria TM II, BD Bioscience, NJ, China). Transmission electron microscopy (TEM) (suht7700, Hitachi, Japan) was used to examine mitochondrial morphology which was used to examine mitochondrial ultrastructural damage by other researchers [ 25 , 26 ].…”