Mitochondrial dysfunction in human hypertrophic cardiomyopathy is linked to cardiomyocyte architecture disruption and corrected by improving NADH-driven mitochondrial respiration

Edgar E Nollet, Inez Duursma, Anastasiya Rozenbaum, Moritz Eggelbusch, Rob C I Wüst, Stephan A C Schoonvelde, Michelle Michels, Mark Jansen, Nicole N van der Wel, Kenneth C Bedi, Jr, Kenneth B Margulies, Jeff Nirschl, Diederik W D Kuster, Jolanda van der Velden

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15 Citations (Scopus)


Genetic hypertrophic cardiomyopathy (HCM) is caused by mutations in sarcomere protein-encoding genes (i.e. genotype-positive HCM). In an increasing number of patients, HCM occurs in the absence of a mutation (i.e. genotype-negative HCM). Mitochondrial dysfunction is thought to be a key driver of pathological remodelling in HCM. Reports of mitochondrial respiratory function and specific disease-modifying treatment options in patients with HCM are scarce.

Methods and results
Respirometry was performed on septal myectomy tissue from patients with HCM (n = 59) to evaluate oxidative phosphorylation and fatty acid oxidation. Mitochondrial dysfunction was most notably reflected by impaired NADH-linked respiration. In genotype-negative patients, but not genotype-positive patients, NADH-linked respiration was markedly depressed in patients with an indexed septal thickness ≥10 compared with <10. Mitochondrial dysfunction was not explained by reduced abundance or fragmentation of mitochondria, as evaluated by transmission electron microscopy. Rather, improper organization of mitochondria relative to myofibrils (expressed as a percentage of disorganized mitochondria) was strongly associated with mitochondrial dysfunction. Pre-incubation with the cardiolipin-stabilizing drug elamipretide and raising mitochondrial NAD+ levels both boosted NADH-linked respiration.

Mitochondrial dysfunction is explained by cardiomyocyte architecture disruption and is linked to septal hypertrophy in genotype-negative HCM. Despite severe myocardial remodelling mitochondria were responsive to treatments aimed at restoring respiratory function, eliciting the mitochondria as a drug target to prevent and ameliorate cardiac disease in HCM. Mitochondria-targeting therapy may particularly benefit genotype-negative patients with HCM, given the tight link between mitochondrial impairment and septal thickening in this subpopulation.
Original languageEnglish
Pages (from-to)1170-1185a
Number of pages16
JournalEuropean Heart journal
Issue number13
Early online date3 Feb 2023
Publication statusPublished - 1 Apr 2023


  • Cardiomyocyte architecture
  • Hypertrophic cardiomyopathy
  • Metabolism
  • Mitochondrial dysfunction
  • Mitochondrial therapy

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