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, Kenneth B. Margulies, Jeff Nirschl, Diederik W.D. Kuster, Jolanda Van Der Velden*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

12 Citations (Scopus)
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Aims: 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. Conclusion: 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)1170-1185
Number of pages16
JournalEuropean Heart Journal
Issue number13
Publication statusPublished - 1 Apr 2023

Bibliographical note

Funding Information:
We acknowledge support from the Netherlands Organization for Scientific Research (NWO VICI, grant 91818602) and the Leducq Foundation (20CVD01).

Publisher Copyright:
© 2023 The Author(s). Published by Oxford University Press on behalf of the European Society of Cardiology.


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