The overall goals of the proposed studies are to understand the biochemical and electrophysiologic bases for arrhythmogenesis in HF in response to beta-adrenergic stimulation, and to assess whether modulating ion channels and SR Ca handling in HF by gene transfer can be antiarrhythmic and inotropic. Our main hypotheses are: 1) There is altered beta2-AR responsiveness in HF that is arrhythmogenic (due to increased SR Ca load and DADs); 2) Decreased SR Ca load in HF (due partly to decreased phospholamban (PLB) phosphorylation) can be enhanced without increased arrhythmogenesis; and enhancing IK1 in HF may be antiarrhythmic but may be negatively inotropic; 3) In vivo whole heart gene transfer can provide proof-of-principle that genetic modulation of ion channels and Ca handling expression can be antiarrhythmic and inotropic. All animal studies will use our extensively characterized arrhythmogenic rabbit model of nonischemic HF (with severe contractile dysfunction and nonreentrant VT). We will measure [Ca]i current and voltage (patch clamp), mRNA & protein levels, and in vivo arrhythmias. We will explore novel in vitro and in vivo gene transfer approaches to enhance contractility and prevent and treat arrhythmias in HF (and we have intriguing preliminary data with in vitro and in vivo gene transfer by a PLB dominant-negative approach). We will validate our findings in HF rabbits with selected studies in tissue and isolated myocytes from failing and nonfailing human hearts. Results of these studies will help develop a new paradigm for modulating arrhythmogenesis in HF (Figure 1A), and will provide a foundation for developing new therapeutic approaches to enhance inotropy and prevent sudden death in HF patients by modulating Ca handling and ion currents affected by arrhythmogenic actions of beta-adrenergic stimulation on the heart.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL046929-14
Application #
7214092
Study Section
Cardiovascular and Pulmonary Research A Study Section (CVA)
Program Officer
Przywara, Dennis
Project Start
1991-08-09
Project End
2008-03-31
Budget Start
2007-04-01
Budget End
2008-03-31
Support Year
14
Fiscal Year
2007
Total Cost
$332,267
Indirect Cost
Name
University of Illinois at Chicago
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
098987217
City
Chicago
State
IL
Country
United States
Zip Code
60612
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Zhang, Xin; Ramachandra, Indiresha; Liu, Zhongming et al. (2005) Noninvasive three-dimensional electrocardiographic imaging of ventricular activation sequence. Am J Physiol Heart Circ Physiol 289:H2724-32

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