title: Myocardial Ca(2+)- and ATP-cycling imbalances in end-stage dilated and ischemic cardiomyopathies.
abstract: OBJECTIVE
  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 Ca(2+)-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 (x 10(-3) s-1) for sarcoplasmic reticulum Ca(2+)-pumping (41.6 +/- 16.0 versus 15.1 +/- 5.9) and Ca(2+)-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.
authors.affiliation: Department of Pathology, Ontario Veterinary College, University of Guelph, Ont., Canada.
authors.forename: P J
authors.initials: PJ
authors.lastname: O'Brien
authors.forename: J K
authors.initials: JK
authors.lastname: Gwathmey
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000187:drug effects / Q000378:metabolism; D002311:Cardiomyopathy, Dilated / Q000378:metabolism; D003402:Creatine Kinase / Q000378:metabolism; D015536:Down-Regulation; D006801:Humans; D017202:Myocardial Ischemia / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism*; D009211:Myoglobin / Q000378:metabolism; D010085:Oxidative Phosphorylation; D012433:Ryanodine / Q000494:pharmacology
chemical_list: D015220:Calcium Channels; D009211:Myoglobin; D012433:Ryanodine; D000255:Adenosine Triphosphate; D003402:Creatine Kinase; D002118:Calcium