It is now well established that the Ca++ ion plays a central role in the process of excitation-contraction coupling in the heart. The general purpose of this study is to evaluate the abnormalities in excitation-contraction coupling that occur in cardiac hypertrophy and failure in experimental animals and man, and to determine the effects of therapeutic interventions on hypertrophied heart muscle. A large amount of information has accumulated to suggest that intracellular Ca++ handling is abnormal in cardiac hypertrophy, with or without the onset of failure. By use of aequorin, a bioluminescent calcium indicator that emits light when it combines with Ca++, it is possible to directly record intracellular Ca++ transients during contraction and relaxation of cardiac muscle fibers. Aequorin will be used to determine how changes in intracellular Ca++ handling are related to the mechanical and electrical abnormalities that occur with hypertrophy and hypoxia of mammalian working myocardium. the subcellular actions of inotropic agents on intracellular Ca++ transients in hypertrophied cardiac muscle will be studied, including the triggerable activity that occurs with toxic doses of these agents. Animal experiments will be performed using right ventricular papillary muscles from control cats and cats in which right ventricular hypertrophy is induced by banding of the pulmonary artery. Muscles will be microinjected with aequorin; light (i.e., intracellular Ca++), tension, and electrical activity will be recorded. Human working myocardium removed at the time of cardiac surgery from patients with hypertrophy will also be studied. By directly recording intracellular Ca++ transients in intact and actively contracting cardiac fibers that are hypoxic or hypertrophied, it will be possible for the first time to test the functional significance of abnormalities in intracellular Ca++ handling that have been reported by other investigators. In addition, these studies will provide new information of clinical importance regarding the therapeutic and toxic effects of inotropic drugs on hypertrophied cardiac muscle, and, in the long-term, should help to define the role of Ca++ in the pathogenesis of the hypertrophic response. Moreover, these studies will lay the groundwork for the use of intracellular calcium indicators as diagnostic and prognostic tools in clinical medicine.

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National Heart, Lung, and Blood Institute (NHLBI)
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Cardiovascular and Pulmonary Research B Study Section (CVB)
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Beth Israel Deaconess Medical Center
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Cittadini, A; Grossman, J D; Stromer, H et al. (2001) Importance of an intact growth hormone/insulin-like growth factor 1 axis for normal post-infarction healing: studies in dwarf rats. Endocrinology 142:332-8
Min, J Y; Ding, B; Wang, J F et al. (2001) Metoprolol attenuates postischemic depressed myocardial function in papillary muscles isolated from normal and postinfarction rat hearts. Eur J Pharmacol 422:115-25
Min, J Y; Hampton, T G; Wang, J F et al. (2000) Depressed tolerance to fluorocarbon-simulated ischemia in failing myocardium due to impaired [Ca(2+)](i) modulation. Am J Physiol Heart Circ Physiol 278:H1446-56
Szymanska, G; Stromer, H; Kim, D H et al. (2000) Dynamic changes in sarcoplasmic reticulum function in cardiac hypertrophy and failure. Pflugers Arch 439:339-48
Litwin, S E; Katz, S E; Morgan, J P et al. (1999) Effects of propranolol treatment on left ventricular function and intracellular calcium regulation in rats with postinfarction heart failure. Br J Pharmacol 127:1671-9
Cittadini, A; Mantzoros, C S; Hampton, T G et al. (1999) Cardiovascular abnormalities in transgenic mice with reduced brown fat: an animal model of human obesity. Circulation 100:2177-83
Litwin, S E; Morgan, J P (1999) Effects of stimulation frequency on calcium transients in noninfarcted myocardium: modulation by chronic captopril treatment. J Card Fail 5:224-35
Litwin, S E; Katz, S E; Litwin, C M et al. (1999) Gender differences in postinfarction left ventricular remodeling. Cardiology 91:173-83
Stromer, H; Cittadini, A; Grossman, J D et al. (1999) Intrinsic cardiac muscle function, calcium handling and beta -adrenergic responsiveness is impaired in rats with growth hormone deficiency. Growth Horm IGF Res 9:262-71
Cittadini, A; Ishiguro, Y; Stromer, H et al. (1998) Insulin-like growth factor-1 but not growth hormone augments mammalian myocardial contractility by sensitizing the myofilament to Ca2+ through a wortmannin-sensitive pathway: studies in rat and ferret isolated muscles. Circ Res 83:50-9

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