MYOCARDIAL CA2-CYCLING AND ATP-CYCLING IMBALANCES IN END-STAGE DILATED AND ISCHEMIC CARDIOMYOPATHIES()

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 Ca 2+-channel modulator ryanodine to examine Ca2+-cycling in homogenates containing 2.5% myocardium from 12 patients undergoing cardiac transpl antations 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 utiliza tion were also assayed. Results: in HF due to either ISCM or DCM, comp ared to nonfailing myocardium, rate constants(X 10(-3) s(-1)) for sarc oplasmic reticulum Ca2+-pumping (41.6 +/- 16.0 versus 15.1 +/- 5.9) an d Ca2+-channel (25.1 +/- 8.3 versus 6.2 +/- 4.1) activities were decre ased 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 w ere also decreased in ISCM and DCM HF by 39%, 30%, and 34%, respective ly, for ATP production capacity of creatine kinase (1830 +/- 130 versu s 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 approxima tely 50% lower with HF (1.72 +/- 0.30 versus 0.97 +/- 0.20 mg/g). Conc lusions: As in animal models, cycling of Ca2+ and ATP turnover were ma rkedly impaired in human heart failure. There were no consistent bioch emical differences attributable to difference in etiology, excepting t hat 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.