Hypercontractility and Oxidative Stress Drive Creatine Kinase Dysfunction in Hypertrophic Cardiomyopathy

Area of Science:

• Cardiology
• Biochemistry
• Molecular Biology

Background:

• Hypertrophic cardiomyopathy (HCM) is a common inherited heart disorder characterized by left ventricular hypertrophy and hypercontractility, leading to an energy deficit.
• Creatine kinase (CK) is crucial for cardiac energy homeostasis, but its role in HCM pathophysiology is not fully understood.
• This study explores how mitochondrial stress and increased hydrogen peroxide (H₂O₂) production in HCM disrupt CK function.

Purpose of the Study:

• To investigate the impact of hypercontractility-driven mitochondrial stress on creatine kinase (CK) function in hypertrophic cardiomyopathy (HCM).
• To elucidate the mechanisms linking mitochondrial reactive oxygen species (ROS) and CK dysfunction in HCM.
• To evaluate potential therapeutic strategies targeting hypercontractility and oxidative stress in HCM.

Main Methods:

• Analyzed myocardial tissue from HCM patients and controls for CK isoforms using various biochemical and proteomic techniques.
• Utilized mouse models, including CK knockout and HCM-associated variants, to study hypercontractility, mitochondrial ROS, and CK function.
• Investigated the effects of pharmacological agents like Ca²⁺ sensitizers, CK inhibitors, and myosin inhibitors on cardiomyocyte function and oxidative stress.

Main Results:

• HCM myocardium showed reduced CK levels and activity, primarily due to oxidative damage.
• In mouse models, hypercontractility induced by EMD-57033 increased mitochondrial H₂O₂, leading to CK inactivation and arrhythmias.
• Mice with enhanced H₂O₂ scavenging and treatment with myosin inhibitor MYK-581 demonstrated protection against oxidative stress, arrhythmias, and preserved CK function.

Conclusions:

• Established a mechanistic link between hypercontractility, mitochondrial ROS, and CK dysfunction in HCM, creating a cycle of energetic impairment.
• Myosin inhibition emerges as a promising therapeutic strategy to address hypercontractility and oxidative stress, thereby restoring cardiac energy balance and reducing arrhythmia risk in HCM.