Article Impact Level: HIGH Data Quality: STRONG Summary of Circulation, https://doi.org/10.1161/CIRCULATIONAHA.125.07412 Dr. Anton Xu, et al.
Points
- Analysis of myocardial tissue from 92 HCM patients revealed significant reductions in both myofilament and mitochondrial CK protein levels and corresponding enzyme activity compared to controls.
- This CK dysfunction was primarily driven by oxidative modifications resulting from an excessive increase in mitochondrial H₂O₂, directly caused by HCM-related hypercontractility.
- In mouse cardiomyocytes, hypercontractility-induced oxidative stress led to CK inactivation and cellular arrhythmias, a mechanism confirmed in Mybpc3 knockin models of HCM.
- Scavenging H₂O₂ by overexpressing mitochondrion-targeted catalase successfully protected the cells against hypercontractility-induced CK dysfunction and arrhythmogenic events.
- The myosin inhibitor MYK-581 reduced hypercontractility, lowered oxidative stress, and prevented arrhythmias, suggesting a direct therapeutic strategy to restore energetic balance in HCM patients.
Summary
This study investigated the underlying mechanisms of creatine kinase (CK) dysfunction in hypertrophic cardiomyopathy (HCM), an inherited cardiac disorder characterized by hypercontractility and myocardial energy depletion. The analysis utilized left ventricular tissue from 92 HCM patients (with and without pathogenic sarcomere variants) and 30 non-failing human controls. Examination of human myocardium revealed significant reductions in both myofilament and mitochondrial CK protein levels, along with decreased CK enzymatic activity, primarily attributed to oxidative modifications.
Using isolated mouse cardiomyocytes, researchers confirmed a direct mechanistic link between excessive mechanical workload and CK impairment. Hypercontractility induced by the Ca²⁺ sensitizer EMD-57033 markedly elevated mitochondrial H₂O₂ levels, which led to CK inactivation and triggered cellular arrhythmias in both wild-type and CK knockout models. These effects were also observed in cardiomyocytes from Mybpc3 knockin mice associated with HCM. Importantly, overexpression of mitochondrion-targeted catalase protected cells by scavenging H₂O₂, preventing CK dysfunction and arrhythmias.
Pharmacologic intervention with MYK-581, a mavacamten derivative and myosin inhibitor, reduced hypercontractility in Mybpc3 knockin cardiomyocytes, leading to lower H₂O₂ production, fewer arrhythmias, and preserved CK function. Conversely, direct CK inhibition using 1-fluoro-2,4-dinitrobenzene in wild-type cardiomyocytes independently elevated mitochondrial H₂O₂ and triggered arrhythmias, confirming a self-perpetuating cycle of energetic dysfunction. The study concludes that targeting hypercontractility through myosin inhibition represents a promising therapeutic approach to reduce oxidative stress, restore CK function, and mitigate arrhythmogenic risk in HCM.
Link to the article: https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.125.074120
References
Xu, A., Weissman, D., Ermer, K. J., Bertero, E., Federspiel, J. M., Stadler, F., Grünler, E., Tangos, M., Zervou, S., Waddingham, M. T., Pearson, J. T., Reil, J.-C., Scholtz, S., Dudek, J., Kohlhaas, M., Nickel, A. G., Carrier, L., Eschenhagen, T., Michels, M., … Sequeira, V. (2025). Hypercontractility and oxidative stress drive creatine kinase dysfunction in hypertrophic cardiomyopathy. Circulation, CIRCULATIONAHA.125.074120. https://doi.org/10.1161/CIRCULATIONAHA.125.07412
