Nollet 2023 Eur Heart J
| Nollet EE, Duursma I, Rozenbaum A, Eggelbusch M, Wüst RCI, Schoonvelde SAC, Michels M, Jansen M, van der Wel NN, Bedi KC, Margulies KB, Nirschl J, Kuster DWD, 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. https://doi.org/10.1093/eurheartj/ehad028 |
» Eur Heart J 44:1170-85. PMID: 36734059 Open Access
Nollet Edgar E, Duursma Inez, Rozenbaum Anastasiya, Eggelbusch Moritz, Wuest Rob CI, Schoonvelde Stephan AC, Michels Michelle, Jansen Mark, van der Wel Nicole N, Bedi Kenneth C, Margulies Kenneth B, Nirschl Jeff, Kuster Diederik WD, van der Velden Jolanda (2023) Eur Heart J
Abstract: 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.
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. • Keywords: Cardiomyocyte architecture, Hypertrophic cardiomyopathy, Metabolism, Mitochondrial dysfunction, Mitochondrial therapy • Bioblast editor: Plangger M • O2k-Network Lab: NL Amsterdam Nollet E, NL Amsterdam Wuest RC
Labels: MiParea: Respiration, Patients
Pathology: Cardiovascular, Myopathy
Organism: Human Tissue;cell: Heart Preparation: Permeabilized tissue
Coupling state: LEAK, OXPHOS, ET
Pathway: F, N, S, NS, ROX
HRR: Oxygraph-2k
2023-06
