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Mitochondrial dysfunction in human hypertrophic cardiomyopathy is linked to cardiomyocyte architecture disruption and corrected by improving NADH-driven mitochondrial respiration
- Source :
- Nollet , E E , Duursma , I , Rozenbaum , A , Eggelbusch , M , Wüst , R C I , Schoonvelde , S A C , Michels , M , Jansen , M , Van Der Wel , N N , Bedi , K C , Margulies , K B , Nirschl , J , Kuster , D W D & Van Der Velden , J 2023 , ' Mitochondrial dysfunction in human hypertrophic cardiomyopathy is linked to cardiomyocyte architecture disruption and corrected by improving NADH-driven mitochondrial respiration ' , European Heart Journal , vol. 44 , no. 13 , pp. 1170-1185 .
- Publication Year :
- 2023
-
Abstract
- 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.
Details
- Database :
- OAIster
- Journal :
- Nollet , E E , Duursma , I , Rozenbaum , A , Eggelbusch , M , Wüst , R C I , Schoonvelde , S A C , Michels , M , Jansen , M , Van Der Wel , N N , Bedi , K C , Margulies , K B , Nirschl , J , Kuster , D W D & Van Der Velden , J 2023 , ' Mitochondrial dysfunction in human hypertrophic cardiomyopathy is linked to cardiomyocyte architecture disruption and corrected by improving NADH-driven mitochondrial respiration ' , European Heart Journal , vol. 44 , no. 13 , pp. 1170-1185 .
- Notes :
- application/pdf, English
- Publication Type :
- Electronic Resource
- Accession number :
- edsoai.on1394345441
- Document Type :
- Electronic Resource