The overall objective of this project is to obtain new insight concerning the cellular aspects of ventricular repolarization and their relationship to intracellular Ca2_ regulation and electronic interactions. Studies will be performed on left ventricular myocytes from both normal and disease hearts. Project 3 contains three subprojects. Subproject 3.1 focuses on repolarization abnormalities in myocytes surviving chronic myocardial infarction (post-MI myocytes). The experiments are designed to determine the ionic basis of post-MI-induced changes in repolarization and their reversal by the thyroid hormone analogue, DITPA. The central hypothesis is that repolarization abnormalities and their recovery are mediated by changes in I/Kp Ca2+ uptake by the sarcoplasmic reticulum (SR), I/Ca and I/NaCa. Voltage clamping and fluorescence measurements of intracellular Ca2+ (Ca/i) (confocal and conventional epifluorescence) will be used to test this hypothesis. Subject 3.2 focuses on the relationship between Ca+ influx and triggered Ca2+ release from SR. The central hypotheses is that conditions which promote Na+ entry, as occur in one inherited form of the long QT syndrome, will increase the gain of excitation-contradiction coupling and thus promote Cai-induced arrhythmias. Voltage clamp and fluorescence techniques will be used to test this hypothesis in myocytes exposed to anthopleurin-A which prolongs I/Na inactivation. Subproject 3.3 focuses on the relationship between intercellular communication and repolarization. The central hypothesis is that cell-cell electrical coupling during repolarization modulation action potential propagation and the formation of early after-depolarizations. This hypothesis will be tested with an electronic circuit which enables us to electrically connect physically separate myocytes with a variable resistance and thus simulate in vitro change in gap functional resistance.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Specialized Center (P50)
Project #
5P50HL052338-07
Application #
6420547
Study Section
Special Emphasis Panel (ZHL1)
Project Start
2001-01-01
Project End
2001-12-31
Budget Start
Budget End
Support Year
7
Fiscal Year
2001
Total Cost
$206,722
Indirect Cost
Name
University of Utah
Department
Type
DUNS #
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
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Chen, Tiehua; Inoue, Masashi; Sheets, Michael F (2005) Reduced voltage dependence of inactivation in the SCN5A sodium channel mutation delF1617. Am J Physiol Heart Circ Physiol 288:H2666-76

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