The long-term objective of this proposal is to increase our understanding of the relationship of Ca2+ waves, altered intracellular Ca2+ cycling in the mechanisms of cardiac arrhythmias. The applicant proposes that the identification of the cellular and subcellular mechanisms of Ca2+ waves is crucial for the understanding of the initiating events of both normal and abnormal rhythms. Intracellular Ca2+ homeostasis will be studied on three levels including: 1) single Purkinje cells isolated from the subendocardium of normal and arrhythmogenic infarcted canine hearts; 2) aggregates or """"""""strands"""""""" of Purkinje cells isolated from normal and arrhythmogenic infarcted canine hearts; and 3) working trabeculae isolated from the right ventricles of normal and arrhythmogenic infarcted rat hearts.
Specific aim 1 will test the hypotheses that Purkinje cells that survive after a myocardial infarction have abnormal Ca2+ cycling and that this altered calcium cycling contributes to abnormal (i.e., arrhythmogenic) electrical activity. This will involve the measurement of whole-cell Ca2+ transients (fura-2 fluorescence) and whole-cell Ca2+ currents via standard whole-cell voltage clamp techniques.
Specific aim 2 tests the hypothesis that Ca2+ oscillations are important regulatory signals both within a single cell as well as between cells. Aggregates of Purkinje cells will be studied with the perforated patch technique and intracellular Ca2+ will be visualized as fluo-3 fluorescence.
Specific aim 3 tests the hypotheses that the initiation and propagation of triggered propagated contraction (TPCs) are due to abnormal electrical activity and propagating Ca2+ waves, and that the sarcolemma modulates calcium propagation by its ability to buffer Ca2+ and depolarization induced Ca2+ release. A multicellular preparation (i.e., working trabeculae) will be used to study Ca2+ waves that are visualized as fluo-3 fluorescence.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Cardiovascular and Pulmonary Research A Study Section (CVA)
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Columbia University (N.Y.)
Schools of Medicine
New York
United States
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ter Keurs, Hendrick E D J (2012) The interaction of Ca2+ with sarcomeric proteins: role in function and dysfunction of the heart. Am J Physiol Heart Circ Physiol 302:H38-50
de Tombe, Pieter P; ter Keurs, Henk E D J (2012) The velocity of cardiac sarcomere shortening: mechanisms and implications. J Muscle Res Cell Motil 33:431-7
ter Keurs, Henk E D J (2011) Electromechanical coupling in the cardiac myocyte; stretch-arrhythmia feedback. Pflugers Arch 462:165-75
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ter Keurs, Henk E D J; Diao, Ni; Deis, Nathan P (2010) Nonuniform activation and the mechanics of myocardial trabeculae with fast or slow myosin. Ann N Y Acad Sci 1188:165-76
Miura, Masahito; Nishio, Taichi; Hattori, Taiki et al. (2010) Effect of nonuniform muscle contraction on sustainability and frequency of triggered arrhythmias in rat cardiac muscle. Circulation 121:2711-7
Macia, Ester; Boyden, Penelope A (2009) Stem cell therapy is proarrhythmic. Circulation 119:1814-23
Dun, Wen; Boyden, Penelope A (2009) Aged atria: electrical remodeling conducive to atrial fibrillation. J Interv Card Electrophysiol 25:9-18
Hirose, Masanori; Stuyvers, Bruno D; Dun, Wen et al. (2008) Function of Ca(2+) release channels in Purkinje cells that survive in the infarcted canine heart: a mechanism for triggered Purkinje ectopy. Circ Arrhythm Electrophysiol 1:387-95
Hirose, Masanori; Stuyvers, Bruno; Dun, Wen et al. (2008) Wide long lasting perinuclear Ca2+ release events generated by an interaction between ryanodine and IP3 receptors in canine Purkinje cells. J Mol Cell Cardiol 45:176-84

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