Idiopathic ventricular tachycardia (VT) is a generic term that describes various forms of VT that occur in patients without structural heart disease, metabolic or electrolyte abnormalities, or in the absence of the long QT syndrome. Through the application of electrophysiologic techniques and pharmacological probes, several distinct mechanistic entities have been identified in the last decade. Two forms of VT, paroxysmal exercise-induced VT and repetitive monomorphic VT, typically originate from the right ventricular outflow tract (RVOT) and present with a left bundle branch block (LBBB) inferior axis morphology. These tachycardias are mediated by intracellular calcium overload and terminate with b-blockers, verapamil, vagal maneuvers and adenosine, and are thought to be due to cAMP-mediated triggered activity. The applicant hypothesizes that a molecular defect in the G protein coupled-b-adrenergic receptor signaling pathway might result in constitutive elevation of intracellular cAMP and VT due to triggered activity. Such a defect could arise from a somatic mutation present at the site of origin of VT. Somatic cell mutations in G proteins that elevate intracellular cAMP levels have been described in a number of endocrine tumors. Since myocardial cells do not divide after cardiogenesis is complete, this would necessitate that the mutation occur in utero. The proposed studies test the hypothesis that certain forms of ventricular tachycardia arise from somatic cell mutations which abnormally stimulate cAMP generation in cardiac tissues.
Specific Aims of this proposal are: (1) To identify mutations in genes encoding G proteins and other components of cAMP-dependent signal transduction pathways that might cause or facilitate VT; (2) To determine the cellular localization of new mutations that might be identified; (3) To test the effects of mutations which may be identified in (1) for their effects on cAMP accumulation by transfection of cells in culture; and (4) To develop an animal model for VT by locally expressing mutant genes which we would predict to confer an arrhythmogenic phenotype.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL056139-01A1
Application #
2029878
Study Section
Cardiovascular and Pulmonary Research A Study Section (CVA)
Project Start
1997-05-01
Project End
2000-04-30
Budget Start
1997-05-01
Budget End
1998-04-30
Support Year
1
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Weill Medical College of Cornell University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
201373169
City
New York
State
NY
Country
United States
Zip Code
10065
Lerman, Bruce B; Ip, James E; Shah, Bindi K et al. (2014) Mechanism-specific effects of adenosine on ventricular tachycardia. J Cardiovasc Electrophysiol 25:1350-8
Markowitz, Steven M; Weinsaft, Jonathan W; Waldman, Louis et al. (2014) Reappraisal of cardiac magnetic resonance imaging in idiopathic outflow tract arrhythmias. J Cardiovasc Electrophysiol 25:1328-35
Markowitz, Steven M; Lewen, Jason M; Wiggenhorn, Christopher J et al. (2009) Relationship of reverse anatomical remodeling and ventricular arrhythmias after cardiac resynchronization. J Cardiovasc Electrophysiol 20:293-8
Deale, O Carlton; Ng, Kwong T; Lerman, Bruce B (2008) Orthogonal field calibration analysis for myocardial electrode arrays used in defibrillation studies. IEEE Trans Biomed Eng 55:2823-6
Lerman, Bruce B (2007) Mechanism of outflow tract tachycardia. Heart Rhythm 4:973-6
Morin, Daniel P; Zacks, Eran S; Mauer, Andreas C et al. (2007) Effect of bundle branch block on microvolt T-wave alternans and electrophysiologic testing in patients with ischemic cardiomyopathy. Heart Rhythm 4:904-12
Cantillon, Daniel J; Stein, Kenneth M; Markowitz, Steven M et al. (2007) Predictive value of microvolt T-wave alternans in patients with left ventricular dysfunction. J Am Coll Cardiol 50:166-73
Markowitz, Steven M; Nemirovksy, Dmitry; Stein, Kenneth M et al. (2007) Adenosine-insensitive focal atrial tachycardia: evidence for de novo micro-re-entry in the human atrium. J Am Coll Cardiol 49:1324-33
Kim, Robert J; Iwai, Sei; Markowitz, Steven M et al. (2007) Clinical and electrophysiological spectrum of idiopathic ventricular outflow tract arrhythmias. J Am Coll Cardiol 49:2035-43
Markowitz, Steven M; Lerman, Bruce B (2006) How to interpret electroanatomic maps. Heart Rhythm 3:240-6

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