The long QT syndrome (LQTS) is a repolarization disorder characterized by marked prolongation of the QT interval and the recurrent syncope during episodes of polymorphic VT (pVT), called Torsade de Pointes (TdP), which leads to sudden cardiac death. The current consensus is that LQT-related arrhythmias are initiated by the firing of early afterdepolarization (EADs), which in the presence of an enhanced dispersion of repolarization results in reentry and pVTs. The induction of EADs and pVTs has been associated with increased sympathetic tone, which could likely augment the dispersion of repolarization, exacerbating conditions for reentrant arrhythmias. In addition, heart rate variation such as short-long-short cycle length (pause-dependent mode) or acceleration of heart rates often precedes TdPs formation, suggesting that generation of EADs and dispersion of repolarization are dynamically dependent on previous history of cycle lengths. Despite intense studies, the exact mechanisms and conditions for EADs &TdPs are not clearly understood yet. The overall goals of this proposal are to investigate mechanisms of long QT related arrhythmias including tissue characteristics as substrate for reentry and conditions that exacerbate EAD inductions and pVTs. Addressing theses questions requires the mapping of dynamic changes in cardiac repolarization from different regions and identifying preferential locations of EAD propagations, and correlating it with Ca2+ transients in the intact heart. We propose to use novel transgenic rabbit models of long QT syndrome (LQT1 and LQT2) created by Dr. Koren's laboratory and investigate LQT related arrhythmia mechanisms using simultaneous optical mapping of transmembrane potentials and Ca2+ transients. We hypothesize that arrhythmias in LQT1 rabbits are caused by sympathetic stimulation- induced imbalance between cardiac repolarization reserve and Ca2+ overload, which initiates EADs and supports the maintenance of TdPs. By contrast, In LQT2 rabbits, we hypothesize that the dynamic repolarization changes such as discordant alternans play a critical role in reentry formation and its degeneration into VF. We will measure dynamic changes in APD and Ca2+ from intact heart in order to investigate the adaptation of Ca2+ transients and APD to heart rate changes with or without infusion of isoproterenol to identify the pattern of cycle length change that can augment Ca2+ overload and APD dispersion. We will investigate maintenance of pVTs by mapping the propagation of EADs from the whole surface of the heart using two cameras and identifying patterns of local cycle length changes that precede focal activity. We will map dynamic changes in APDs including discordant alternans and their nodal line behavior and correlate with tissue heterogeneities and Ca2+ handling to identify major factors that create discordant alternans and pVTs. This study will provide mechanistic insights of LQT related arrhythmias which can be used as a basis for further molecular studies.

Public Health Relevance

The long QT syndrome (LQTS) is a repolarization disorder characterized by marked prolongation of the QT interval. Patients with LQTS exhibit the recurrent syncope during episodes of polymorphic VT, which causes sudden cardiac death. The most common forms of congenital LQTS, type 1 and type 2 (LQT1 and LQT2), are caused by mutations in the genes coding for the delayed rectifying potassium currents. However, mechanisms linking these mutations to cardiac arrhythmias are not clearly understood. This proposal investigates arrhythmia mechanisms in these LQTS using transgenic rabbit models and high speed imaging devices. The data obtained here should provide more complete knowledge into the genetic and electrophysiologic factors involved in long QT related arrhythmias. 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 #
5R01HL096669-05
Application #
8476251
Study Section
Special Emphasis Panel (ZRG1-CVS-N (02))
Program Officer
Lathrop, David A
Project Start
2009-09-01
Project End
2014-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
5
Fiscal Year
2013
Total Cost
$364,033
Indirect Cost
$128,413
Name
Rhode Island Hospital
Department
Type
DUNS #
075710996
City
Providence
State
RI
Country
United States
Zip Code
02903