Heart failure & cardiomyopathies
Hypercontractility and Oxidative Stress Drive Creatine Kinase Dysfunction in Hypertrophic Cardiomyopathy
Authors' conclusion
This study reveals a mechanistic link between hypercontractility, mitochondrial reactive oxygen species, and CK dysfunction in HCM, perpetuating a cycle of energetic dysfunction.
Study context
- Population
- LV myocardial tissue from patients with hypertrophic cardiomyopathy (HCM); isolated cardiomyocytes from wild-type, catalase-overexpressing, CK knockout, Mybpc3 knock-in and mito-roGFP2-Orp1 mice
- Participants
- 92 vs 30
- Comparison
- HCM vs Non-failing controls
- HCMn = 92
- Non-failing controlsn = 30reference
- Outcome
- CK function in HCM myocardium and mouse cardiomyocytes
Main finding
As reported in the abstract
- Significantly reduced myofilament and mitochondrial CK protein levels and CK activity in HCM myocardium, primarily due to oxidative modifications of CK
- EMD-57033-induced hypercontractility elevated mitochondrial H2O2, causing cellular arrhythmias and CK inactivation (wild-type and CK knockout cardiomyocytes)
- Hypercontractility-induced oxidative stress, arrhythmias and CK dysfunction also in Mybpc3 knock-in cardiomyocytes
- Mitochondrial-targeted catalase-overexpressing mice protected against EMD-57033-mediated arrhythmias and CK dysfunction
- MYK-581 in Mybpc3 knock-in cardiomyocytes reduced hypercontractility, H2O2 production and arrhythmias, and preserved CK function
- CK inhibition with DNFB elevated mitochondrial H2O2 and triggered cellular arrhythmias (confirmed in mito-roGFP2-Orp1 cardiomyocytes); catalase-overexpressing mice protected
Original publication
Hypercontractility and Oxidative Stress Drive Creatine Kinase Dysfunction in Hypertrophic Cardiomyopathy. Circulation. Published 20 October 2025. doi:10.
Summarised from the published abstract; every number is checked against it