Patients with congenital and acquired Long QT Syndrome (LQTS) have a high risk for Torsade de Pointe (a variant of polymorphic ventricular tachycardia, VT) and sudden death. A hallmark of LQTS is a prolonged QT interval, a prelude to VT. A number of electrophysiological and cellular abnormalities have been associated with LQTS. Enhanced Dispersion of Repolarization (DR) has been invoked as the arrhythmogenic mechanism based on measurements of QT intervals and T wave changes. Electrode recordings suggest that early after-depolarizations (EADs) are coincident in time with extra-systolic responses that initiate VT. In turn, EADS can be induced by interventions that increase action potential (AP) durations (APDS) and/or increase cytosolic (Ca+2),; Cai causing cell depolarization. Key to all these issues are the heterogeneities of APDs and Cai transients from cells in different regions of the heart. Other factors may be important to precipitate VT in LQTS, such as Cai load, serum K+, and autonomic imbalance. These mechanisms are poorly understood and remain a matter of conjecture.
The aims are: 1) To develop an optical system to simultaneously map APs, DR, and Cai transients by staining hearts with voltage-sensitive and Cai indicator dyes; 2) To develop models of drug-induced LQTS in rabbits using Anthopluerin A (AP-A) and d-Sotasol and characterize the models by mapping APs, Cai and correlating EADS to changes in Cai. Optical maps from different regions of the heart (e.g., the Purkinje fibers on the endocardium, the epicardium and midwall) will identify the sites with the greatest propensity to EADs and/or Cai anomalies. 3) To determine the factors that precipitate LQT-induced arrhythmias by altering the myocardial substrate, interventions (e.g., serum K+, Cai load, alpha and/or beta-agonists) known to increase the incidence of VT in the clinical setting will be applied uniformly in the heart through the coronary perfusate or locally by micro-injections at selected sites on the heart to provoke VTs. The project addresses important questions given the high risk of sudden death in patients with LQTS. It will test basic hypothesis that QT prolongation enhances a) the DR, b) the incidence of EADs, c) that the conduction of EADS provokes VT and d) that intervention(s) applied at key sites are needed to trigger EADs.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL057929-05
Application #
6498939
Study Section
Surgery and Bioengineering Study Section (SB)
Program Officer
Lathrop, David A
Project Start
1998-02-01
Project End
2003-01-31
Budget Start
2002-02-01
Budget End
2003-01-31
Support Year
5
Fiscal Year
2002
Total Cost
$137,318
Indirect Cost
Name
University of Pittsburgh
Department
Physiology
Type
Schools of Medicine
DUNS #
053785812
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Ng, G André (2016) Neuro-cardiac interaction in malignant ventricular arrhythmia and sudden cardiac death. Auton Neurosci 199:66-79
N?mec, Jan; Kim, Jong J; Salama, Guy (2016) The link between abnormal calcium handling and electrical instability in acquired long QT syndrome--Does calcium precipitate arrhythmic storms? Prog Biophys Mol Biol 120:210-21
Kim, Jong J; N?mec, Jan; Li, Qiao et al. (2015) Synchronous systolic subcellular Ca2+-elevations underlie ventricular arrhythmia in drug-induced long QT type 2. Circ Arrhythm Electrophysiol 8:703-12
Kim, Jong J; Yang, Lei; Lin, Bo et al. (2015) Mechanism of automaticity in cardiomyocytes derived from human induced pluripotent stem cells. J Mol Cell Cardiol 81:81-93
Ng, G Andre (2014) Vagal modulation of cardiac ventricular arrhythmia. Exp Physiol 99:295-9
Efimov, Igor; Salama, Guy (2012) The future of optical mapping is bright: RE: review on: ""Optical Imaging of Voltage and Calcium in Cardiac Cells and Tissues"" by Herron, Lee, and Jalife. Circ Res 110:e70-1
Yang, Xiaoyan; Chen, Guojun; Papp, Rita et al. (2012) Oestrogen upregulates L-type Ca²? channels via oestrogen-receptor- by a regional genomic mechanism in female rabbit hearts. J Physiol 590:493-508
Parikh, Ashish; Mantravadi, Rajkumar; Kozhevnikov, Dmitry et al. (2012) Ranolazine stabilizes cardiac ryanodine receptors: a novel mechanism for the suppression of early afterdepolarization and torsades de pointes in long QT type 2. Heart Rhythm 9:953-60
Chen, Guojun; Yang, Xiaoyan; Alber, Sean et al. (2011) Regional genomic regulation of cardiac sodium-calcium exchanger by oestrogen. J Physiol 589:1061-80
Salama, Guy; Akar, Fadi G (2011) Deciphering Arrhythmia Mechanisms - Tools of the Trade. Card Electrophysiol Clin 3:11-21

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