Sudden cardiac death (SCD) claims the lives of approximately 350,000 Americans each year. Emerging evidence indicates an important role for genetic predisposition to SCD;however, the molecular determinants have remained elusive. The overall goal of this proposal is to investigate new mechanisms that underlie SCD through the application of innovative technology and the novel use of new genetic models of long QT syndrome 1 (LQT1). This multi-pronged approach includes the investigation of LQT1 rabbits with myocardial damage/cardiomyopathy induced by either tachypacing (TICM) or coronary embolization (MI). The proposal is composed of three Specific Aims: 1) To create and characterize a model of myocardial infarction (MI) and a model of tachycardia induced cardiomyopathy (TICM) in male littermate controls (LMC) and LQT1 rabbits and to characterize of the incidence of spontaneous ventricular arrhythmias and sudden cardiac death with the use of telemetric ECG monitoring and in vivo invasive electrophysiological studies. 2) To elucidate the contribution of IKs down-regulation to triggers and substrate of arrhythmias by analyses (ex vivo) of spontaneous arrhythmias, action potential duration, dispersion of repolarization, conduction, triggered activity and the heterogeneities in electrical/mechanical restitution, and conduction block using surface optical mapping of action potential and calcium transients and fiberoptic fibers-mediated in depth optical mapping of rabbit heart preparation of these models. 3) a. To perform a comparative analysis of action potential and calcium-handling properties in myocytes isolated from the LV of TICM and MI LQT1 and LMC rabbits under control conditions and during autonomic receptor stimulation, using patch-clamp and fluorescent-indicator techniques;b. To use cellular electrophysiology, histochemistry, protein expression studies, quantitative real-time PCR to elucidate the cellular and molecular basis of the arrhythmias observed in Aims 1&2 by comparing the molecular determinants of the differences in cardiac repolarization, conduction, and calcium-handling proteins expressed in models of MI and TICM induced in LMC and LQT1 rabbits.

Public Health Relevance

Public Health Relevance The characterization of transgenic rabbit models for cardiac arrhythmias, the effects of myocardial dysfunction, and the identification of the relationship between mutant LQTS genes that encode for dysfunctional ion channels and life-threatening ventricular tachyarrhythmias should provide more complete knowledge into the genetic and electrophysiologic factors involved in repolarization disorders. These studies into altered ventricular repolarization should contribute important new insights into sudden cardiac death mechanisms associated with acquired cardiac disorders that accompany ischemic and nonischemic cardiomyopathy and QT- prolonging drugs. This enhanced knowledge should lead to more effective strategies for prevention of sudden death in a broad spectrum of genetic and acquired cardiac disorders with meaningful public health benefits.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-CVRS-L (03))
Program Officer
Lathrop, David A
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Rhode Island Hospital
United States
Zip Code
Lau, Emily; Kossidas, Konstantinos; Kim, Tae Yun et al. (2015) Spatially Discordant Alternans and Arrhythmias in Tachypacing-Induced Cardiac Myopathy in Transgenic LQT1 Rabbits: The Importance of IKs and Ca2+ Cycling. PLoS One 10:e0122754
Kim, Tae Yun; Kunitomo, Yukiko; Pfeiffer, Zachary et al. (2015) Complex excitation dynamics underlie polymorphic ventricular tachycardia in a transgenic rabbit model of long QT syndrome type 1. Heart Rhythm 12:220-8
Terentyev, Dmitry; Rochira, Jennifer A; Terentyeva, Radmila et al. (2014) Sarcoplasmic reticulum Ca²? release is both necessary and sufficient for SK channel activation in ventricular myocytes. Am J Physiol Heart Circ Physiol 306:H738-46
Organ-Darling, Louise E; Vernon, Amanda N; Giovanniello, Jacqueline R et al. (2013) Interactions between hERG and KCNQ1 ?-subunits are mediated by their COOH termini and modulated by cAMP. Am J Physiol Heart Circ Physiol 304:H589-99
Liu, Gong-Xin; Choi, Bum-Rak; Ziv, Ohad et al. (2012) Differential conditions for early after-depolarizations and triggered activity in cardiomyocytes derived from transgenic LQT1 and LQT2 rabbits. J Physiol 590:1171-80
Ziv, Ohad; Schofield, Lorraine; Lau, Emily et al. (2012) A novel, minimally invasive, segmental myocardial infarction with a clear healed infarct borderzone in rabbits. Am J Physiol Heart Circ Physiol 302:H2321-30
Jindal, Hitesh K; Merchant, Elisabeth; Balschi, James A et al. (2012) Proteomic analyses of transgenic LQT1 and LQT2 rabbit hearts elucidate an increase in expression and activity of energy producing enzymes. J Proteomics 75:5254-65
Odening, Katja E; Choi, Bum-Rak; Liu, Gong Xin et al. (2012) Estradiol promotes sudden cardiac death in transgenic long QT type 2 rabbits while progesterone is protective. Heart Rhythm 9:823-32
Cooper, Leroy L; Odening, Katja E; Hwang, Min-Sig et al. (2012) Electromechanical and structural alterations in the aging rabbit heart and aorta. Am J Physiol Heart Circ Physiol 302:H1625-35
Biermann, Jurgen; Wu, Kezhong; Odening, Katja E et al. (2011) Nicorandil normalizes prolonged repolarisation in the first transgenic rabbit model with Long-QT syndrome 1 both in vitro and in vivo. Eur J Pharmacol 650:309-16

Showing the most recent 10 out of 25 publications