Mitochondrial Creatine Kinase Attenuates Pathologic Remodeling in Heart Failure.

Area of Science:

• Cardiology
• Biochemistry
• Metabolic Research

Background:

• Heart failure (HF) involves cardiac energy metabolism abnormalities contributing to contractile dysfunction.
• The role of creatine kinase (CK), a key energy reserve, in HF-related remodeling is less understood.
• CK is downregulated in experimental and human HF, impacting ATP regeneration.

Purpose of the Study:

• To investigate the relationship between impaired cardiac CK energy metabolism and pathologic remodeling in human HF.
• To determine if rescuing CK function can attenuate maladaptive hypertrophy in experimental HF.

Main Methods:

• Noninvasive magnetic resonance 31P spectroscopy and MRI were used to measure cardiac energetics and remodeling in HF patients and healthy subjects.
• Cardiac-specific overexpression of myofibrillar CK (Ckmyofib) or mitochondrial CK (Ckmito) was tested in mouse models of HF.

Main Results:

• In humans, pathologic left ventricular hypertrophy and dilatation correlated with reduced ATP levels and CK-dependent ATP synthesis.
• In mice, CKmito overexpression attenuated hypertrophy and dilatation in response to transverse aortic constriction and isoproterenol stimulation.
• CKmito overexpression reduced reactive oxygen species and upregulated antioxidants, with protection lost upon creatine depletion, highlighting the importance of ADP regeneration.

Conclusions:

• Pathologic hypertrophy and remodeling in human HF are linked to deficits in ATP levels and the CK energy reserve.
• Mitochondrial CK (CKmito) plays a critical role in attenuating pathologic HF remodeling by influencing cardiac energetics and redox balance.