Altered Cardiac Energetics and Mitochondrial Dysfunction in Hypertrophic Cardiomyopathy

Area of Science:

• Cardiovascular Medicine
• Molecular Biology
• Metabolomics

Background:

• Hypertrophic cardiomyopathy (HCM) is linked to gene variants affecting sarcomeric protein biomechanics.
• HCM mutations often increase force production, raising cellular energy demands.
• Mechanisms connecting altered cardiac energetics to HCM phenotypes require further elucidation.

Purpose of the Study:

• To test the hypothesis that altered cardiac energetics are a common pathophysiologic pathway in HCM.
• To comprehensively profile the molecular, ultrastructural, and functional aspects of cardiac energetics in HCM.

Main Methods:

• Collected myocardial samples from 27 HCM patients and 13 normal controls.
• Performed comprehensive multiomics profiling (transcripts, metabolites, lipids).
• Utilized electron microscopy and biochemical assays to assess mitochondrial function.

Main Results:

• HCM hearts showed dysregulated fatty acid metabolism, reduced acylcarnitines, and accumulated free fatty acids.
• Global energetic decompensation observed, with decreased high-energy phosphates and reduced mitochondrial ATP synthesis genes.
• Mitochondrial damage, reduced oxidative respiration, elevated reactive oxygen species, and impaired mitophagy were evident in HCM hearts.

Conclusions:

• Perturbed metabolic signaling and mitochondrial dysfunction are common pathogenic mechanisms in HCM.
• These findings identify potential drug targets for treating HCM by improving metabolic function and reducing mitochondrial injury.