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. 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 improve the treatment of LQT-related arrhythmias. Here is a brief summary of our current projects:

Determine the pathophysiological importance of variants of uncertain significance linked to LQT1 and LQT2. Genetic studies are identifying disease‑associated genetic variants at rates far greater than our ability to study their causal roles. Lack of gene to function information not only hinders our ability to understand the mechanistic basis for a given disease, but also the corresponding absence of a genotype-to-phenotype link delays the development of meaningful diagnostic screens. A related, and equally important, issue is that, once a specific gene is definitively associated with a given disease, genetic tests designed to survey that gene often identify novel, private variants. Despite a lack of any genetic or functional link between the newly discovered alleles and disease causation, physicians often act on these “variants of uncertain significance” (VUS), which can lead to mis- or over‑treatment for a disease, and unnecessary emotional and physical trauma for the patient. We are developing innovative strategies to address this issue using LQT1 and LQT2 as our model diseases. Our goal is to develop efficient methods for establishing the functional impacts of VUS in LQTS-linked genes.

Assess the LQTS vulnerability in Sudden Infant Death Syndrome (SIDS). Sudden infant death syndrome (SIDS) is defined as the unexpected and unexplained death of an infant < 1 year of age. SIDS is currently explained by the combination of a vulnerable infant, a critical period in development, and the presence of an extrinsic stressor. Another goal of the laboratory is to improve our ability to identify infants who have a congenital condition that makes them vulnerable to cardiac arrhythmias. To begin addressing the link between LQTS and SIDS, several groups have performed retrospective postmortem genetic testing for the most common types of LQTS (LQT1-LQT3) in dozens of SIDS incidents. They found a LQTS mutation in 10-15% of the cases. However, functional studies performed on a small number of SIDS-linked mutations suggested that several of them function normally and thus are likely benign. Since these studies were performed, a large number of genetic variants have been linked to LQTS or identified in healthy control subjects. The goal of our laboratory is to use this information to help predict whether many of the SIDS-linked variants identified are dysfunctional. We expect that these results will contribute to improvements in the diagnostic and therapeutic value for infants who test positive for a mutation in a major LQTS-susceptibility gene.

Determine the impact of the molecular clock and circadian rhythms on arrhythmia susceptibility. A new area of research for our laboratory is to determine whether disrupted circadian rhythms are an environmental mechanism contributing to the manifestation of arrhythmias. Circadian rhythms are generated by highly conserved evolutionary processes that integrate the timing of the body’s physiology to daily changes in the environment. The molecular mechanism driving circadian rhythms is a transcription/translation feedback mechanism (the molecular clock) that runs on a 24-hour cycle.We are testing the hypothesis that disruptions in the molecular clock decrease repolarization reserve and increase arrhythmia susceptibility. We will determine how genetic and environmental alterations in circadian rhythms affect repolarization reserve and arrhythmia susceptibility in control mice and a mouse model of LQTS. This project mechanistically identifies gene-environment interactions that influence the manifestation of life-threatening symptoms. We expect that it will contribute to the identification of new risk factors for arrhythmia expressivity, including lifestyles, environmental stressors, and medical disorders that impact circadian rhythms (e.g. larks vs. owls, jet lag, diabetes, metabolic syndrome, shift work, sleep disorders, etc.).