TITLE: Arrhythmia mechanisms in Long QT Syndrome
The long QT syndrome (LQTS) is an inherited or acquired disease characterized by QT interval
prolongation and is associated with life threatening arrhythmias and high incidences of sudden
cardiac deaths in young adults. Among the known variants of congenital LQTS, majority are
caused by mutations in genes associated with cardiac repolarizing potassium currents.
Experimental studies have suggested an active role of the cardiac conduction system in initiation
and maintenance of arrhythmia observed in LQTS. However direct evidence is lacking and the
arrhythmia mechanisms are not well understood. In this proposal, a combination of experiments
using adult rabbit cardiomyocytes expressing hERG mutations and advanced multiscale
computer modeling will be utilized to study the role of cardiac Purkinje system in
arrhythmogenesis in inherited as well as drug-induced LQTS, specifically LQT2. The proposers
hypothesize that significant reduction of the repolarization reserve in Purkinje cells in presence
of LQTS conditions increases their propensity to early afterdepolarizations and triggered activity.
Furthermore, the regions within the His-PS exhibit strong differential sensitivity to hERG mutations
resulting into heterogeneous activation patterns in the ventricles, thus initiating arrhythmia. Two
novel dominant negative mutations, P632L and S428P, in HERG channels (LQT2) will be
experimentally studied in transfected cardiomyocytes. The experimental characterizations will be
incorporated into human biophysical computer models at multiple levels of integration– molecular,
single cell and three dimensional– to obtain further mechanistic insights. The detrimental effects
of regional electrical heterogeneity within the Purkinje system and its differential sensitivity to
LQTS mutations as well as drug-induced long QT effects will be studied using three dimensional
computer modeling and concurrent experiments. Systematic study will be conducted to
investigate the role of Purkinje system network in initiating EAD-induced ectopic activity and in
bradycardia-dependent triggered episodes of polymorphic VT. The proposed research has the
potential to provide invaluable insights about the disease and may reveal mechanisms of
arrhythmogenesis in inherited as well as acquired forms of the disease.
Keywords: Long QT syndrome, Purkinje system, arrhythmia, and computer modeling.