Copyright © 1990 by the European Society of Cardiology.
© 1990 The European Society of Cardiology
Energetic correlates of cardiac failure: Changes in the creatine kinase system in the failing myocardium
Department of Medicine, Brigham and Women's Hospital and Harvard Medical School Boston MA, U.S.A.
Correspondence: J. S. Ingwall, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, 221 Longwood Avenue, Boston, MA 02115, U.S.A.
To address the hypothesis that impaired ATP synthesis rates caused by changes in the creatine kinase system is an important mechanism underlying cardiac failure, we measured total creatine kinase activity, isoenzyme composition and creatine content in two animal models of hypertrophy with cardiac dysfunction, the spontaneously hypertensive rat in the transition to failure and the creatine-depleted hyperthyroid rat heart challenged by hypoxia. During the transition from stable compensated hypertrophy to failure characterized by decreased functional capacity, we found that total creatine kinase activity and particularly mitochondria1 creatine kinase activity decreased. The decrease in functional capacity, the further increase in heart size and the derangements in the creatine kinase system did not occur if these animals were treated for 6 months with the antihypertensive agents, guanethidine or hydralazine. These results suggest that changes in the creatine kinase system occur coordinately with the transition to failure. To assess whether the changes in the creatine system may be causally linked to decreased functional capacity, we used 31P NMR spectroscopy of isolated perfused hearts to define the high energy phosphate content and cardiac performance of creatinedepleted (50%) hypertrophied hearts challenged by hypoxia. These hearts displayed greater susceptibility to hypoxic injury with regard to both systolic and diastolic function during and following hypoxia. We also measured total creatine kinase activity in right ventricular biopsy specimens from patients with various forms of cardiomyopathy and low ejection fractions, and found a positive correlation between total creatine kinase activity and ejection fraction. Taken together, these results support the hypothesis that decreasing the energy reserve for ATP synthesis renders the heart more susceptible to systolic and diastolic failure.
Key Words: Creatine kinase • cardiac failure
* Current address: University of California, Davis, CA. U.S.A.
|| Current address: Division of Biological Sciences. National Research Council, Ottawa, Canada.
Current address: Department of Medicine, Duke University Medical Center, Durham, NC, U.S.A.
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