The long term objective of our planned studies remains as before, that is, to increase our understanding of the relationship between Ca2+ waves, altered Ca, cycling in the mechanisms of arrhythmias. The overall hypothesis is that increased probability of the fundamental Ca2+ release-event (the Ca2+ spark) leads to local summation of events(macro sparks) and, then by CICR to coupling of Ca2+ release from different SR-sites causing Ca2+ waves of increasing, amplitude, spatial extent and propagation velocity. Ca2+ waves, in proportion to their amplitude and extent, cause delayed afterdepolarizations (DADs) and therefore are arrhythmogenic. We propose that increased probability of Ca2+ release both due to transient elevations of SR-Ca2+ content and nonuniformity of the myocardium is involved in several diseases and contributes to the arrhythmias. We will use two approaches. One approach will be to use Purkinje cells dispersed from the arrhythmogenic infarcted heart (IZPCs) with electrical, epifluorescent and confocal imaging techniques. In our second approach, we use a multicellular trabecular preparation that is arrhythmogenic (due to nonuniformity of EC coupling and to CHF). The initiation and propagation of Ca2+ waves will be examined using epi- and confocal microscopy, electronmicoroscopy.
Aim#1 We hypothesize that nonuniform Ca2+ transients and abnormal micro Ca2+ wave events in IZPCs are due to differences a) in Ca2+ spark/event characteristics vs. those of normal cells, b) in SR content by subcellular region, c) in different spatial/regional types of Ca2+ release channels (e g. lP3R, RYR2, RYR3) /SERCA and NCX isoforms, d) in Ca2+ dependence of Ca2+ release in the subsarcolemmal vs. core compartments and sensitivity to IP3R agents, e) in response of Ca2+ release in these two cell compartments to voltage.
In Aim#2, we will determine whether Ca2+ dissociation from the filaments determines the initial Ca transient (a surge) that leads to Ca2+ waves and arrhythmias in the nonuniform muscle; whether Ca2+ wave propagation requires SR Ca2+ release and diffusion to adjacent SR release sites using epi- and confocal microscopy. Finally, we will determine whether the threshold for initiation and propagation of Ca2+ waves in trabeculae from hearts of animals with CHF is substantially lower than that in muscles from animals without CHF. In sum, these studies will provide a subcellular basis for the relationship between diseased-induced nonuniformities of Ca2+ cycling within a myocyte, Ca2+ waves and arrhythmias and thus will help in identifying new molecular targets for Ca2+ dependent nonreentrant arrhythmias.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL058860-09
Application #
7477943
Study Section
Electrical Signaling, Ion Transport, and Arrhythmias Study Section (ESTA)
Program Officer
Przywara, Dennis
Project Start
1998-05-01
Project End
2011-06-30
Budget Start
2008-07-01
Budget End
2011-06-30
Support Year
9
Fiscal Year
2008
Total Cost
$443,404
Indirect Cost
Name
Columbia University (N.Y.)
Department
Pharmacology
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
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
Pallante, Benedetta A; Giovannone, Steven; Fang-Yu, Liu et al. (2010) Contactin-2 expression in the cardiac Purkinje fiber network. Circ Arrhythm Electrophysiol 3:186-94
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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