Myocardial creatine kinase kinetics and isoform expression in hearts with severe LV hypertrophy

Area of Science:

• Biochemistry
• Cardiovascular Physiology
• Molecular Biology

Background:

• Left ventricular hypertrophy (LVH) is associated with altered myocardial energy metabolism.
• Creatine kinase (CK) plays a critical role in cellular energy transport and utilization.
• Previous studies suggest a shift in CK isoform expression during LVH.

Purpose of the Study:

• To investigate changes in creatine kinase (CK) expression and flux in a canine model of pressure-overload induced LVH.
• To characterize the functional consequences of altered CK expression on myocardial energy metabolism.

Main Methods:

• Induction of LVH via ascending aortic banding in adult dogs.
• Quantification of CK isoform mRNA and protein levels (CK-M, CK-B, mitochondrial CK).
• Assessment of myocardial CK flux using (31)P magnetic resonance spectroscopy magnetization transfer.
• Evaluation of LV performance and oxygen consumption with dobutamine administration.

Main Results:

• LVH significantly altered CK expression: decreased CK-M mRNA and protein, increased CK-B mRNA and protein, and decreased mitochondrial CK protein.
• Total CK activity remained normal in LVH hearts.
• Myocardial CK forward flux rate was reduced by approximately 60% in LVH and decreased further with dobutamine.
• Despite altered CK expression and flux, LV performance and oxygen consumption were normal during dobutamine stress.
• Myocardial free ADP levels were elevated in LVH hearts.

Conclusions:

• Pressure-overload LVH induces significant changes in myocardial creatine kinase (CK) isoform expression and reduces CK flux.
• Elevated ADP levels in LVH hearts suggest a compensatory mechanism to maintain ATP synthesis despite altered CK function.
• These findings highlight the complex adaptations in myocardial energy metabolism during cardiac hypertrophy.