Physiology

BRIAN P. DELISLE, Ph.D. Office: MS-577 Medical Center 0298 Tel: (859) 323-2797 E-mail: brian.delisle@uky.edu

Research Program

The ordered electrical excitation of the heart via the cardiac conduction system coordinates the efficient pumping of blood. Electrical impulses normally originate in the sinoatrial node and then propagate through the atria, atrioventricular node, and into the ventricles. Arrhythmias are electrical disturbances that disrupt the normal initiation or propagation of the cardiac impulse. They cause abnormal impulse rates (bradycardia or tachycardia), block impulse propagation, or initiate the impulse to circle in a “reentry” loop. Atrial arrhythmias can result in the formation of blood clots and increase the risk of stroke, and ventricular arrhythmias can cause inefficient pumping of blood, loss of consciousness, and sometimes death.

Congenital Long QT syndrome (LQT) is one of the most common monogenic arrhythmia syndromes, and occurs in ~1:2,500 healthy births. LQT patients have a delay in the repolarization of their ventricles and are at increased risk for polymorphic ventricular tachycardia (torsade de pointes), which can cause a loss of cardiac output, syncope, and sudden death. LQT typically follows a dominant inheritance pattern and is linked to thirteen different genes (LQT1-LQT13). This heterogeneity has identified ion channel genes and macromolecular signaling complexes that are important for normal cardiac excitability and arrhythmia susceptibility.

About 80% of genotype positive LQT patients have LQT1 or LQT2, which are caused by mutations in genes that encode the a-subunits of voltage-activated K+ (Kv) channels. Kv a-subunits consist of six transmembrane segments (S1-S6) that form a voltage-sensor (S1-S4) and a pore (S5-S6) domain, and they tetramerize to generate an aqueous channel. LQT1 and LQT2-linked mutations typically cause a “loss of function” by disrupting Kv channel synthesis, intracellular transport (trafficking), gating, and/or permeation (Figure 1). About 60-70% of LQT1 and LQT2 mutations are missense, and the rest are splice site, nonsense, or fameshift. Our research program focuses on studying mechanisms that underlie the loss of function for different LQT1 and LQT2 missense mutations. Our long-term goal is to identify strategies that im prove the treatment of arrhythmias.

Publications