© 1995 by European Society of Cardiology
Copyright © 1995, European Society of Cardiology
Myocardial Ca2+- and ATP-cycling imbalances in end-stage dilated and ischemic cardiomyopathies
aDepartment of Pathology, Ontario Veterinary College, University of Guelph, Guelph, Ont. N1G 2W1, Canada
bCardiovascular Diseases and Muscle Research Laboratories, Harvard Medical School, Boston, MA, USA
* Corresponding author. Present address: The Procter and Gamble Company, Miami Valley Laboratories, P.O. Box 538707, Cincinnati, OH 45253, USA. Tel. (+1-513) 627-2504; Fax (+1-513) 627-1087.
Objectives: We have previously demonstrated deficiencies in myocardial cycling of Ca2+, and ATP turnover, in animals with heart failure (HF). The objective of this study was to determine the relevance of these changes to human HF. Methods: We used the Ca2+ dye, indo-1, and the Ca2+-channel modulator ryanodine to examine Ca2+-cycling in homogenates containing 2.5% myocardium from 12 patients undergoing cardiac transplantations because of ischemic or idiopathic dilated cardiomyopathies (ISCM, DCM), and compared them to homogenates from 11 organ donors who died from noncardiac causes. Key enzymes of ATP production and utilization were also assayed. Results: In HF due to either ISCM or DCM, compared to nonfailing myocardium, rate constants (x10–3 s–1) for sarcoplasmic reticulum Ca2+-pumping (41.6 ± 16.0 versus 15.1 ± 5.9) and Ca2+-channel (25.1 ± 8.3 versus 6.2 ± 4.1) activities were decreased by 64 and 75%, respectively. These changes in rate constants were associated with a three-fold increase in ionized Ca2+ concentration. Compared to nonfailing myocardium, activities (IU/g) of ATP turnover were also decreased in ISCM and DCM HF by 39%, 30%, and 34%, respectively, for ATP production capacity of creatine kinase (1830 ±130 versus 1110 ±411) and oxidative phosphorylation (20.0 ± 3.3 and 14.1 ± 4.8), and for ATP utilization (28.2 ± 18.7 versus 18.7 ± 4.0). Myoglobin, a key component of oxidative phosphorylation, was approximately 50% lower with HF (1.72 ± 0.30 versus 0.97 ± 0.20 mg/g). Conclusions: As in animal models, cycling of Ca2+ and ATP turnover were markedly impaired in human heart failure. There were no consistent biochemical differences attributable to difference in etiology, excepting that myoglobin deficiency was 33% greater in ISCM than DCM. We conclude that ATP and Ca2+ cycling are significantly impaired in human HF due to DCM and ISCM.
KEYWORDS free calcium Ca2+; CRC Ca2+-release channel; HF heart failure; DCM idiopathic dilated cardiomyopathy; ISCM ischemic cardiomyopathy; sarcoplasmic reticulum SR; creatine kinase CK
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