The long term objective of this application is to combine the expertise of the Boyden and Wit laboratories to understand at a more cellular/subcellular level the electrical abnormalities defined in myocytes that have survived in the epicardial border zone of the infarcted heart 5 days, 14 days and 2 months post coronary artery occlusion. These abnormalities contribute to the occurrence of serious life threatening ventricular arrhythmias post myocardial infarction.
Our specific aims are as follows: 1) to determine the function of specific ionic currents in cells dispersed from the select regions of mapped reentrant circuits of the epicardial border zone of the 5 day infarcted heart and then by using these experimental data develop 1D and 2D computer models of the EBZ, 2) to determine the function of specific ionic currents (INa, ICaL and IK) of cells dispersed from select regions of the border zone of the 14 day and 2month infarcted heart, and 3) to determine the function and pharmacology of delayed rectifier K+ currents in border zone cells in particular to identify the electrical sequelae of observed cell surface redistribution pattern of Kvl.5 channel proteins. Studies will be completed using insitu mapping, whole cell voltage clamp techniques using single cells dispersed from the reentrant circuits of the epicardial border zone of hearts post coronary artery occlusion and computer simulation techniques. Our results will provide a more detailed understanding of the ionic basis of electrical remodeling in cells surviving in the healing and healed hearts post infarction as well as the mechanism of the reentrant arrhythmias occurring during this time. In so doing they will help to identify new molecular targets for treatment of reentrant ventricular arrhythmias in this remodeled substrate.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL066140-02
Application #
6537921
Study Section
Cardiovascular and Pulmonary Research A Study Section (CVA)
Program Officer
Spooner, Peter
Project Start
2001-09-01
Project End
2005-06-30
Budget Start
2002-07-01
Budget End
2003-06-30
Support Year
2
Fiscal Year
2002
Total Cost
$466,345
Indirect Cost
Name
Columbia University (N.Y.)
Department
Pharmacology
Type
Schools of Medicine
DUNS #
167204994
City
New York
State
NY
Country
United States
Zip Code
10032
Dun, Wen; Wright, Patrick; Danilo Jr, Peter et al. (2014) SAP97 and cortactin remodeling in arrhythmogenic Purkinje cells. PLoS One 9:e106830
Dun, Wen; Lowe, John S; Wright, Patrick et al. (2013) Ankyrin-G participates in INa remodeling in myocytes from the border zones of infarcted canine heart. PLoS One 8:e78087
Liu, Nian; Denegri, Marco; Dun, Wen et al. (2013) Abnormal propagation of calcium waves and ultrastructural remodeling in recessive catecholaminergic polymorphic ventricular tachycardia. Circ Res 113:142-52
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Koval, Olha M; Snyder, Jedidiah S; Wolf, Roseanne M et al. (2012) Ca2+/calmodulin-dependent protein kinase II-based regulation of voltage-gated Na+ channel in cardiac disease. Circulation 126:2084-94
Miura, Masahito; Hattori, Taiki; Murai, Naomi et al. (2012) Regional increase in extracellular potassium can be arrhythmogenic due to nonuniform muscle contraction in rat ventricular muscle. Am J Physiol Heart Circ Physiol 302:H2301-9
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
Boyden, Penelope A; Robinson, Richard B (2012) Potential players in the hood. J Interv Card Electrophysiol 35:1-2
Boyden, Penelope A (2012) Chasing calcium. Heart Rhythm 9:143-4

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