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Myocardial Ca(2+)- and ATP-cycling imbalances in end-stage dilated and ischemic cardiomyopathies
1Department of Pathology, Ontario Veterinary College, University of Guelph, Ont., Canada.
Insights
Heart failure (HF) in humans shows impaired calcium (Ca2+) cycling and ATP turnover, similar to animal models. These biochemical changes are significant in dilated and ischemic cardiomyopathies.
Area of Science:
- Cardiology
- Biochemistry
- Molecular Biology
Background:
- Previous studies indicated impaired myocardial cycling of calcium (Ca2+) and ATP turnover in animal models of heart failure (HF).
- The clinical relevance of these biochemical alterations in human HF remained to be elucidated.
Purpose of the Study:
- To investigate the role of Ca2+ cycling and ATP turnover in human heart failure.
- To compare these biochemical processes in patients with ischemic cardiomyopathy (ISCM) and dilated cardiomyopathy (DCM) against non-failing controls.
Main Methods:
- Utilized the Ca2+ dye indo-1 and ryanodine to assess Ca2+ cycling in myocardial homogenates from 12 HF patients and 11 organ donors.
- Assayed key enzymes involved in ATP production and utilization to evaluate energy metabolism.
Main Results:
- HF patients exhibited significantly reduced sarcoplasmic reticulum Ca2+-pumping (64% decrease) and Ca2+-channel activities (75% decrease) compared to controls.
- ATP turnover, including creatine kinase and oxidative phosphorylation, was reduced by 30-39% in HF.
- Myoglobin levels, crucial for oxidative phosphorylation, were approximately 50% lower in HF patients.
Conclusions:
- Myocardial Ca2+ cycling and ATP turnover are markedly impaired in human heart failure (HF), mirroring findings in animal models.
- Biochemical differences between ISCM and DCM were minimal, except for a greater myoglobin deficiency in ISCM.
- The study concludes that impaired Ca2+ and ATP cycling are significant contributors to human HF pathophysiology in DCM and ISCM.
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 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.