Study of Ventricular Repolarization in Long QT Syndrome

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DESCRIPTION (provided by applicant): The long QT syndrome (LQTS), a familial disorder caused by mutations of genes encoding myocardial potassium sodium ion channels, is manifest clinically by prolongation of the QT interval in the ECO and by a propensity life-threatening ventricular arrhythmias. Genetic forms of LQTS are caused by mutations of sodium and potassium channel genes and are associated with distinct T-wave patterns in the ECG and different clinical outcome over time. However, there is a substantial overlap of ECG patterns and clinical manifestation between LQT1 and LQT2 types caused by mutations of two different potassium channel genes (KVLQT1 and HERG, respectively). Experimental data and some anecdotal clinical observations indicate that in LQT1 and LQT2 conditions, the dynamic response of repolarization various stimuli is a critical factor contributing to arrhythmogenesis. However, there is limited knowledge regarding clinically applicable noninvasive and invasive tests and parameters that reliably identify and quantify the magnitude dynamic repolarization abnormalities in LQTS patients, especially those with LQT1 and LQT2 types that account for majority of patients with known genotype. Therefore, the primary aims of this study are: 1) to improve the clinical accuracy of diagnosing patients with LQTS using noninvasive and invasive electrophysiologic testing; 2) to determine response of ventricular repolarization to physiologic/pharmacologic stimuli in LQTS patients when compared to control non-LQTS subjects; 3) to identify differences in ventricular repolarization parameters between LQTS patients with LQT1 and LQT2 gene mutations. These goals will be accomplished by conducting a series of noninvasive and invasive electrophysiologic tests with physiological/pharmacological stimuli in 50 LQT1 carriers, 50 LQT2 carriers, and 50 healthy control non-LQTS subjects as well as noninvasive tests in equivalent numbers of non-carriers from LQT1 and LQT2 families. The secondary aims of this study are: 1) to develop and validate standardized noninvasive and invasive electrophysiologic protocols for evaluating abnormal ventricular repolarization in LQTS; 2) to determine the clinical usefulness of noninvasive and invasive testing to identify LQTS patients with borderline prolonged QTc intervals from non-carriers with similar QTc intervals; 3) to determine the response in ventricular repolarization dynamics to beta-blocker therapy in LQT1 and LQT2 patients; 4) to understand the relationship/association between noninvasive and invasive electrophysiologic findings in LQTS and normal subjects.