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Modeling the cellular basis of altered excitation-contraction coupling in heart failure
1Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. rwinslow@bme.jhu.edu
Insights
Calcium transients in failing heart cells show reduced amplitude and slower relaxation, with a blunted response to increased heart rate. This impacts cardiac function in heart failure.
Area of Science:
- Cardiology
- Cellular Biology
- Physiology
Background:
- Heart failure is characterized by impaired cardiac contractility and relaxation.
- Abnormal intracellular calcium handling is a key feature of failing cardiomyocytes.
- Previous studies indicate alterations in calcium transients in heart failure models.
Purpose of the Study:
- To investigate the characteristics of calcium transients in failing human ventricular myocytes.
- To assess the amplitude, relaxation, and frequency dependence of these transients.
- To contribute to understanding the cellular mechanisms underlying heart failure.
Main Methods:
- Measurement of calcium transients in isolated human ventricular myocytes from failing hearts.
- Analysis of transient amplitude and decay kinetics.
- Evaluation of the force-frequency relationship and response to varying stimulation rates.
Main Results:
- Failing human ventricular myocytes exhibited significantly reduced amplitude of calcium transients.
- Slower relaxation (prolonged decay) of calcium transients was observed.
- A blunted frequency dependence of contraction and calcium transients was evident, indicating impaired calcium handling at higher heart rates.
Conclusions:
- Reduced calcium transient amplitude and slowed relaxation contribute to contractile dysfunction in heart failure.
- Impaired calcium cycling and blunted frequency response in cardiomyocytes are critical cellular abnormalities in heart failure.
- These findings highlight the importance of intracellular calcium handling in the pathophysiology of heart failure.
Abstract:
Ca transients measured in failing human ventricular myocytes exhibit reduced amplitude and slowed relaxation [Beuckelmann, D.J., Nabauer, M., Erdmann, E., 1992. Intracellular calcium handling in isolated ventricular myocytes from patients with terminal heart failure. Circulation 85, 1046-1055; Gwathmey, J.K., Copelas, L., MacKinnon, R., Schoen, F.J., Feldman, M.D., Grossman, W., Morgan, J.P., 1987. Abnormal intracellular calcium handling in myocardium from patients with end-stage heart failure. Circ. Res. 61, 70-76; Kaab, S., Nuss, H. B., Chiamvimonvat, N., O'Rourke, B., Pak, P.H., Kass, D.A., Marban, E., Tomaselli, G.F., 1996. Ionic mechanism of action potential prolongation in ventricular myocytes from dogs with pacing-induced heart failure. Circ. Res. 78(2); Li, H.G., Jones, D.L., Yee, R., Klein, G.J., 1992. Electrophysiologic substrate associated with pacing-induced hert failure in dogs: potential value of programmed stimulation in predicting sudden death. J. Am. Coll. Cardiol. 19(2), 444-449; Vermeulen, J.T., McGuire, M.A., Opthof, T., Colonel, R., Bakker, J.M.T.d., Klopping, C., Janse, M.J., 1994. Triggered activity and automaticity in ventricular trabeculae of failing human and rabbit hearts. Cardiovasc. Res. 28, 1547-1554.] and blunted frequency dependence [Davies, C.H., Davia, K., Bennett, J.G., Pepper, J.R., Poole-Wilson, P.A., Harding, S.E., 1995. Reduced contraction and altered frequency response of isolated ventricular myocytes from patients with heart failure. Circulation, 92, 2540-2549; Hasenfuss, G., Reinecke, H., Studer, R., Meyer, M., Pieske, B., Holtz, J., Holubarsch, C., Posival, H., Just, H., Drexler, H., 1994. Relation between myocardial function and expression of sarcoplasmic reticulum Ca-ATPase in failing and nonfailing human myocardium. Circ. Res. 75, 434-442; Hasenfuss, G., Reinecke, H., Studer, R., Pieske, B., Meyer, M., Drexler, H., Just, H., 1996. Calcium cycling proteins and force-frequency relationships in heart failure. Basic Res. Cardiol. 91, 17-22; Monte, F.D., O'Gara, P., Poole-Wilson, P.A., Yacoub, M., Harding, S.E., 1995. Cell geometry and contractile abnormalities of myocytes from failing human left ventricle.