The overall goal of this proposal is to investigate new mechanisms that underlie SCD through the application of innovative technology, computer modeling and the use of new genetic models of long QT syndrome type 1and type 2 (LQT1 and LQT2). This multi-pronged approach includes the investigation of orchiectomized male LQT2 rabbits and LQT1 rabbits that underwent ablation of the AV node (LQT1-AVB). Studies at the cellular levels with myocytes derived from these rabbits will be used to investigate the role of sex hormones in modulation of the function of key proteins that regulate calcium dynamics in cardiomyocytes. Since the calcium (Ca) transients and action potential dynamics are bi-directionally coupled through Ca-induced-Ca-release and the feedback of the Ca transient on Ca-sensitive membrane current (ICa,L, INCX, and IKs), assessing the relative contributions of unstable Ca cycling and altered repolarization to triggered activity is in general difficult. Here e propose to investigate the subcellular Ca cycling dynamics first without Vm influence to characterize RyR sensitivity, and then with a clamped action potential waveform to investigate the uni-directional effect of Vm on Ca cycling dynamics (i.e. without feedback of Cai on Vm), thereby identify conditions leading to arrhythmogenic whole cell Cai oscillations, Vm dynamics without CaT influence to study EADs facilitated by reopening of ICa,L in the presence of altered repolarization, and finally bi-directionally coupled free Cai and free Vm dynamics to investigate synergistic effects of Cai oscillations and reopening of ICa,. Iteration will consist of functional electrophysiological measurements of the specific currents and their biophysical properties, and biochemical and electrophysiological studies (as well as measured subcellular Ca dynamical properties-spark frequency and Ca wave threshold), to calibrate relevant ranges of computational model parameters to be used in the exploration of arrhythmogenic state (unsafe zone) and safe zone (no spontaneous arrhythmias or SCD). Studies at the tissue and organ levels will examine the role synchronization of the triggered activity combined with bi-stable wave conduction (bi- excitability) and tissue heterogeneities mediate the R-on-T phenomenon as well as test whether short-long-short sequence increases EAD formations and tissue heterogeneities, thus self propels until the onset of TdP and weather TdP and PVT are maintained by Ica-mediated wavefronts and chaos synchronization.

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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL110791-03
Application #
8852165
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Lathrop, David A
Project Start
2013-08-01
Project End
2016-05-31
Budget Start
2015-06-01
Budget End
2016-05-31
Support Year
3
Fiscal Year
2015
Total Cost
Indirect Cost
Name
Rhode Island Hospital
Department
Type
DUNS #
075710996
City
Providence
State
RI
Country
United States
Zip Code
Choi, Bum-Rak; Li, Weiyan; Terentyev, Dmitry et al. (2018) Transient Outward K+ Current (Ito) Underlies the Right Ventricular Initiation of Polymorphic Ventricular Tachycardia in a Transgenic Rabbit Model of Long-QT Syndrome Type 1. Circ Arrhythm Electrophysiol 11:e005414
Zhong, Mingwang; Rees, Colin M; Terentyev, Dmitry et al. (2018) NCX-Mediated Subcellular Ca2+ Dynamics Underlying Early Afterdepolarizations in LQT2 Cardiomyocytes. Biophys J 115:1019-1032
Boutin, Molly E; Kramer, Liana L; Livi, Liane L et al. (2018) A three-dimensional neural spheroid model for capillary-like network formation. J Neurosci Methods 299:55-63
Behar, Joachim A; Rosenberg, Aviv A; Shemla, Ori et al. (2018) A Universal Scaling Relation for Defining Power Spectral Bands in Mammalian Heart Rate Variability Analysis. Front Physiol 9:1001
Kim, Tae Yun; Terentyeva, Radmila; Roder, Karim H F et al. (2017) SK channel enhancers attenuate Ca2+-dependent arrhythmia in hypertrophic hearts by regulating mito-ROS-dependent oxidation and activity of RyR. Cardiovasc Res 113:343-353
Song, Zhen; Qu, Zhilin; Karma, Alain (2017) Stochastic initiation and termination of calcium-mediated triggered activity in cardiac myocytes. Proc Natl Acad Sci U S A 114:E270-E279
Sadick, Jessica S; Boutin, Molly E; Hoffman-Kim, Diane et al. (2016) Protein characterization of intracellular target-sorted, formalin-fixed cell subpopulations. Sci Rep 6:33999
Huang, Xiaodong; Kim, Tae Yun; Koren, Gideon et al. (2016) Spontaneous initiation of premature ventricular complexes and arrhythmias in type 2 long QT syndrome. Am J Physiol Heart Circ Physiol 311:H1470-H1484
Petry, Clive J; Sanz Marcos, Nuria; Pimentel, Gracielle et al. (2016) Associations Between Fetal Imprinted Genes and Maternal Blood Pressure in Pregnancy. Hypertension 68:1459-1466
Song, Zhen; Karma, Alain; Weiss, James N et al. (2016) Long-Lasting Sparks: Multi-Metastability and Release Competition in the Calcium Release Unit Network. PLoS Comput Biol 12:e1004671

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