Patients with congenital and acquired Long QT Syndrome (LQTS) have a high risk for Torsade de Pointe (a variant of polymorphic ventricular tachycardia, VT) and sudden death. A hallmark of LQTS is a prolonged QT interval, a prelude to VT. A number of electrophysiological and cellular abnormalities have been associated with LQTS. Enhanced Dispersion of Repolarization (DR) has been invoked as the arrhythmogenic mechanism based on measurements of QT intervals and T wave changes. Electrode recordings suggest that early after-depolarizations (EADs) are coincident in time with extra-systolic responses that initiate VT. In turn, EADS can be induced by interventions that increase action potential (AP) durations (APDS) and/or increase cytosolic (Ca+2),; Cai causing cell depolarization. Key to all these issues are the heterogeneities of APDs and Cai transients from cells in different regions of the heart. Other factors may be important to precipitate VT in LQTS, such as Cai load, serum K+, and autonomic imbalance. These mechanisms are poorly understood and remain a matter of conjecture.
The aims are: 1) To develop an optical system to simultaneously map APs, DR, and Cai transients by staining hearts with voltage-sensitive and Cai indicator dyes; 2) To develop models of drug-induced LQTS in rabbits using Anthopluerin A (AP-A) and d-Sotasol and characterize the models by mapping APs, Cai and correlating EADS to changes in Cai. Optical maps from different regions of the heart (e.g., the Purkinje fibers on the endocardium, the epicardium and midwall) will identify the sites with the greatest propensity to EADs and/or Cai anomalies. 3) To determine the factors that precipitate LQT-induced arrhythmias by altering the myocardial substrate, interventions (e.g., serum K+, Cai load, alpha and/or beta-agonists) known to increase the incidence of VT in the clinical setting will be applied uniformly in the heart through the coronary perfusate or locally by micro-injections at selected sites on the heart to provoke VTs. The project addresses important questions given the high risk of sudden death in patients with LQTS. It will test basic hypothesis that QT prolongation enhances a) the DR, b) the incidence of EADs, c) that the conduction of EADS provokes VT and d) that intervention(s) applied at key sites are needed to trigger EADs.
Showing the most recent 10 out of 42 publications
