- (859) 323-2797
- MS-577 Wm R Willard Medical Ed Bldg, 800 Rose St, Lexington, KY 40536-0298
Ph.D. (Physiology and Biophysics) University of Kentucky, Lexington, KY, 2001.
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.).
Investigate the therapeutic potential of late Na+ current blockers in LQT2. We recently showed that the late Na+ channel blocker ranolazine can improves the functional expression for some LQT2 mutations, and we have data suggesting that this can occur at physiologically relevant drug concentrations and below the IC50 for IKr block. We are testing the hypothesis that ranolazine and several other late INa blockers can mitigate the LQT2 cellular phenotype through their block of late INa and pharmacological chaperone activity.
- Smith BN, Delisle BP. The Long and the Short of It: Seizures Induce Cardiac Remodeling and Arrhythmia. Epilepsy Curr. 2015;90-1.
- Schroder EA, Burgess DE, Zhang X, Lefta M, Smith JL, Patwardhan A, Bartos DC, Elayi CS, Esser KA, Delisle BP. The cardiomyocyte molecular clock regulates the circadian expression of Kcnh2 and contributes to ventricular repolarization. Heart Rhythm. 2015;1306-14.
- Anderson CL, Kuzmicki CE, Childs RR, Hintz CJ, Delisle BP, January CT. Large-scale mutational analysis of Kv11.1 reveals molecular insights into type 2 long QT syndrome. Nat Commun. 2014;5:5535.
- Schroder EA, Burgess DE, Manning CL, Zhao Y, Moss AJ, Patwardhan A, Elayi CS, Esser KA, Delisle BP. Light phase-restricted feeding slows basal heart rate to exaggerate the type-3 long QT syndrome phenotype in mice. Am J Physiol Heart Circ Physiol. 2014;307:H1777-85.
- Bartos DC, Giudicessi JR, Tester DJ, Ackerman MJ, Ohno S, Horie M, Gollob MH, Burgess DE, Delisle BP. A KCNQ1 Mutation Contributes to the Concealed Type 1 Long QT Phenotype by Limiting the Kv7.1 Channel Conformational Changes Associated with PKA Phosphorylation. Heart Rhythm 2014;11(3):459-68.
- Wu J, Naiki N, Ding WG, Ohno S, Kato K, Zang WJ, Delisle BP, Matsuura H, Horie M. A Molecular Mechanism for Adrenergic-induced Long QT Syndrome. J Am Coll Cardiol. 2014;63(8):819-27.
- Hasegawa, K, Ohno S, Ashihara T, Itoh H, Ding W, Toyoda F, Makiyama T, Aoki H, Nakamura Y, Delisle BP, Matsuura H, Horie M. A novel KCNQ1 missense mutation identified in a patient with juvenile-onset atrial fibrillation causes constitutively open IKs channels, Heart Rhythm. 2014;11(1):67-75.
- Smith JL, Reloj AR, Nataraj PS, Bartos DC, Schroder EA, Moss AJ, Ohno S, Horie M, Anderson CL, January CT, Delisle BP. Pharmacological Correction of Long QT-linked Mutations in KCHN2 (hERG) Increases the Trafficking of Kv11.1 Channels Stored in the Transitional ER. Am J Physiol Cell Physiol. 2013;305(9):C919-30.
- Morales GX, Macle L, Khairy P, Charnigo R, Davidson E, Thal S, Ching C, Lellouche N, Whitbeck M, Delisle BP, Thompson J, DI Biase L, Natale A, Nattel S, Elayi CS. Adenosine Testing in Atrial Flutter Ablation: Unmasking of Dormant Conduction Across the Cavotricuspid Isthmus and Risk of Recurrence. J Cardiovasc Electrophysiol. 2013;24(9):995-1001.
- Crotti L, Tester DJ, White WM, Bartos DC, Insolia R, Besana A, Kunic JD, Will ML, Velasco EJ, Bair JJ, Ghidoni A, Cetin I, Van Dyke DL, Wick MJ, Brost B, Delisle BP, Facchinetti F, George AL, Schwartz PJ, Ackerman MJ. Long QT syndrome-associated mutations in intrauterine fetal death. JAMA. 2013 10;309(14):1473-1482.
- McBride CM, Smith AM, Smith JL, Reloj AR, Velasco EJ, Powell J, Elayi CS, Bartos DC, Burgess DE, Delisle BP. Mechanistic basis for type 2 long QT syndrome caused by KCNH2 mutations that disrupt conserved arginine residues in the voltage sensor. J Membr Biol. 2013 ;246(5):355-364.
- Schroder EA, Lefta M, Zhang X, Bartos D, Feng HZ, Zhao Y, Patwardhan A, Jin JP, Esser KA, Delisle BP. The cardiomyocyte molecular clock, regulation of Scn5a, and arrhythmia susceptibility. Am J Physiol Cell Physiol. 2013 15;304(10):C954-C965.
- Burgess DE, Bartos DC, Reloj AR, Campbell KS, Johnson JN, Tester DJ, Ackerman MJ, Fressart V, Denjoy I, Guicheney P, Moss AJ, Ohno S, Horie M, Delisle BP. Malignant Long QT Syndrome Mutations in the Kv7.1 (KCNQ1) Pore Disrupt the Molecular Basis for Rapid K+ Permeation. Biochemistry. 2012 13;51(45):9076-9085.
- Smith JL, McBride CM, Nataraj PS, Bartos DC, January CT, Delisle BP. Trafficking-deficient hERG K⁺ channels linked to long QT syndrome are regulated by a microtubule-dependent quality control compartment in the ER. Am J Physiol Cell Physiol. 2011 301(1):C75-85.
- Bartos DC, Duchatelet S, Burgess DE, Klug D, Denjoy I, Peat R, Lupoglazoff JM, Fressart V, Berthet M, Ackerman MJ, January CT, Guicheney P, Delisle BP. R231C mutation in KCNQ1 causes long QT syndrome type 1 and familial atrial fibrillation. Heart Rhythm. 2011 8(1):48-55.