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Mitochondrial dysfunction in human hypertrophic cardiomyopathy is linked to cardiomyocyte architecture disruption and

Edgar E Nollet1,2, Inez Duursma1,2, Anastasiya Rozenbaum1,2

  • 1Department of Physiology, Amsterdam UMC, Location VUmc, O2 Science building-11W53, De Boelelaan 1108, 1081HZ Amsterdam, The Netherlands.

European Heart Journal
|February 3, 2023
PubMed

Insights

Mitochondrial dysfunction drives hypertrophic cardiomyopathy (HCM) in patients without genetic mutations. Restoring mitochondrial function, particularly in genotype-negative HCM, offers a promising therapeutic strategy for this cardiac disease.

Area of Science:

  • Cardiovascular Medicine
  • Mitochondrial Biology
  • Genetics

Background:

  • Hypertrophic cardiomyopathy (HCM) can be genetic (genotype-positive) or occur without known mutations (genotype-negative).
  • Mitochondrial dysfunction is implicated in HCM's pathological remodeling, but research on respiratory function and treatments is limited.
  • Understanding mitochondrial roles is crucial for developing targeted therapies for HCM patients.

Purpose of the Study:

  • To investigate mitochondrial respiratory function in patients with genotype-positive and genotype-negative HCM.
  • To explore the relationship between mitochondrial dysfunction, septal hypertrophy, and cardiomyocyte organization.
  • To assess the potential of mitochondria-targeted therapies for HCM.

Main Methods:

  • Septal myectomy tissue from 59 HCM patients underwent respirometry to assess oxidative phosphorylation and fatty acid oxidation.
  • Transmission electron microscopy evaluated mitochondrial abundance, fragmentation, and organization relative to myofibrils.
  • NADH-linked respiration was measured and correlated with septal thickness and genotype.

Main Results:

  • Mitochondrial dysfunction, characterized by impaired NADH-linked respiration, was observed in HCM patients.
  • NADH-linked respiration was significantly depressed in genotype-negative HCM patients with greater septal thickness (≥10 mm).
  • Mitochondrial dysfunction correlated with disorganized mitochondria, not reduced abundance or fragmentation. Elamipretide and NAD+ boosting improved respiration.

Conclusions:

  • Mitochondrial dysfunction in genotype-negative HCM is linked to cardiomyocyte architectural disruption and septal hypertrophy.
  • Mitochondria remain responsive to interventions, highlighting their potential as a therapeutic target for HCM.
  • Mitochondria-targeting therapies may be particularly beneficial for genotype-negative HCM patients due to the strong link between mitochondrial impairment and cardiac remodeling.
Abstract

Keywords:
Cardiomyocyte architectureHypertrophic cardiomyopathyMetabolismMitochondrial dysfunctionMitochondrial therapy

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