- Dr. Antzelevitch is Professor and Executive Director of the Cardiovascular Research Program at the Lankenau Institute... moreDr. Antzelevitch is Professor and Executive Director of the Cardiovascular Research Program at the Lankenau Institute for Medical Research (LIMR), Director of Research at the Lankenau Heart Institute in Wynnewood, PA and Professor of Medicine and Pharmacology and Experimental Therapeutics at the Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA. Recent honors include the Distinguished Scientist Award from the North American Society of Pacing and Electrophysiology (NASPE, currently Heart Rhythm Society (HRS), 2002), Excellence in Cardiovascular Science Award of the NE Affiliate American Heart Association (AHA, 2003), the Carl J. Wiggers Award from the American Physiological Society (2007), the Distinguished Scientist Award of the American College of Cardiology (2011), the Distinguished Service Award of the Cardiac Electrophysiology Society, the Distinguished Service Award of the RAM Medical Research Foundation (1994), and the Distinguished Achievement Medal of the Grand Lodge of Masons of NYS (2001). He was elected a Fellow of the Cardiovascular Section of the American Physiological Society in 1984, the American College of Cardiology in 1996, American Heart Association in 2001 and the Heart Rhythm Society in 2006. He served as President of the International Cardiac Electrophysiology Society (1996 to 1998) and as Secretary/Treasurer since 1988. His contributions to the scientific literature include over 530 original papers and book chapters, over 372 abstracts, and 7 books. He is an internationally renowned authority in these areas. His work is highly cited earning him an h-index of 114. His contribution to the training of promising young physician-scientists is evidenced by his students' first place or finalist standing in over a dozen international Young Investigator Award competitions at the American College of Cardiology, NASPE, HRS and the International Society for Computerized Electrocardiography. He is a member of and has served as Chairman of a number of committees at the National Institutes of Health, the AHA, HRS and the American College of Cardiology. He is currently Associate Editor of the Heart Rhythm journal, Senior Editor for Pacing and Clinical Electrophysiology and is on the Editorial Board of several leading biomedical journals.(Dr. Antzelevitch is Professor and Executive Director of the Cardiovascular Research Program at the Lankenau Institute for Medical Research (LIMR), Director of Research at the Lankenau Heart Institute in Wynnewood, PA and Professor of Medicine and Pharmacology and Experimental Therapeutics at the Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA. Recent honors include the Distinguished Scientist Award from the North American Society of Pacing and Electrophysiology (NASPE, currently Heart Rhythm Society (HRS), 2002), Excellence in Cardiovascular Science Award of the NE Affiliate American Heart Association (AHA, 2003), the Carl J. Wiggers Award from the American Physiological Society (2007), the Distinguished Scientist Award of the American College of Cardiology (2011), the Distinguished Service Award of the Cardiac Electrophysiology Society, the Distinguished Service Award of the RAM Medical Research Foundation (1994), and the Distinguished Achievement Medal of the Grand Lodge of Masons of NYS (2001). He was elected a Fellow of the Cardiovascular Section of the American Physiological Society in 1984, the American College of Cardiology in 1996, American Heart Association in 2001 and the Heart Rhythm Society in 2006. He served as President of the International Cardiac Electrophysiology Society (1996 to 1998) and as Secretary/Treasurer since 1988. His contributions to the scientific literature include over 530 original papers and book chapters, over 372 abstracts, and 7 books. He is an internationally renowned authority in these areas. His work is highly cited earning him an h-index of 114. His contribution to the training of promising young physician-scientists is evidenced by his students' first place or finalist standing in over a dozen international Young Investigator Award competitions at the American College of Cardiology, NASPE, HRS and the International Society for Computerized Electrocardiography. He is a member of and has served as Chairman of a number of committees at the National Institutes of Health, the AHA, HRS and the American College of Cardiology. He is currently Associate Editor of the Heart Rhythm journal, Senior Editor for Pacing and Clinical Electrophysiology and is on the Editorial Board of several leading biomedical journals.)edit
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Research Interests: Cardiology, Medicine, Patch-clamp and imaging techniques, Dogs, Internal Medicine, and 14 moreFemale, Animals, Male, Cardiac Arrhythmias, Pericardium, Action Potentials, Heart Ventricles, Syndrome, Brugada Syndrome, Ventricular Fibrillation, Verapamil, Tetrazoles, Cardiovascular medicine and haematology, and In Vitro Techniques
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Research Interests: Cardiology, Biomedical Engineering, Kinetics, Medicine, Sudden Death, and 13 moreInternal Medicine, Phenotype, Clinical Sciences, Electrocardiogram, Sodium channel, Lidocaine, Sudden Cardiac Death, Arrhythmia, Ventricular Tachycardia, Brugada Syndrome, Ventricular Fibrillation, ajmaline, and Cardiovascular medicine and haematology
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Research Interests: Biomedical Engineering, Confocal Microscopy, Adolescent, Medicine, Humans, and 15 moreMutation, Female, Male, Polymerase Chain Reaction, Pedigree, Phenotype, Clinical Sciences, Middle Aged, Sodium channel, Analysis of Variance, Brugada Syndrome, Bradycardia, Heart Block, sodium channels, and alleles
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Research Interests: Clinical Trial, Terminology, Medicine, Electrocardiography, Humans, and 13 moreDifferential Diagnosis, Risk factors, Phenotype, Prevalence, Sex Factors, Risk Stratification, Intensive Care Medicine, Risk Factors, Syndrome, Brugada Syndrome, Bundle Branch Block, Cardiovascular medicine and haematology, and Genetic predisposition to disease
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<p>Range of days post-differentiation (Age) at which E-4031 (5 µM) induced EADs <i>with little to no change in MDP</i> vs. those at which it led to depolarization of BC <i>without exhibiting EADs</i>.... more
<p>Range of days post-differentiation (Age) at which E-4031 (5 µM) induced EADs <i>with little to no change in MDP</i> vs. those at which it led to depolarization of BC <i>without exhibiting EADs</i>. <b>B:</b> Range of age of BC that depolarized in response to 100 µM BaCl<sub>2</sub> (Depolarization) vs. those that did not (No depolarization). Each point represents an individual BC; horizontal lines are the mean values for each group.</p
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To elucidate the genetic architecture of amyotrophic lateral sclerosis (ALS) and find associated loci, we assembled a custom imputation reference panel from whole-genome-sequenced patients with ALS and matched controls (n = 1,861).... more
To elucidate the genetic architecture of amyotrophic lateral sclerosis (ALS) and find associated loci, we assembled a custom imputation reference panel from whole-genome-sequenced patients with ALS and matched controls (n = 1,861). Through imputation and mixed-model association analysis in 12,577 cases and 23,475 controls, combined with 2,579 cases and 2,767 controls in an independent replication cohort, we fine-mapped a new risk locus on chromosome 21 and identified C21orf2 as a gene associated with ALS risk. In addition, we identified MOBP and SCFD1 as new associated risk loci. We established evidence of ALS being a complex genetic trait with a polygenic architecture. Furthermore, we estimated the SNP-based heritability at 8.5%, with a distinct and important role for low-frequency variants (frequency 1-10%). This study motivates the interrogation of larger samples with full genome coverage to identify rare causal variants that underpin ALS risk.
Research Interests: Genetics, Biology, Medicine, Amyotrophic Lateral Sclerosis, Biological Sciences, and 14 moreHumans, Mutation, Heritability, Netherlands, Proteins, Myelin Proteins, Genetic Architecture, Rc, Genetic Association, R, Case Control Studies, Cohort Studies, Medical and Health Sciences, and Genetic predisposition to disease
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In 1992 a syndrome consisting of syncope episodes and/or sudden death in patients with a structurally normal heart and a characteristic electrocardiogram (ECG) displaying a pattern resembling right bundle branch block with ST segment... more
In 1992 a syndrome consisting of syncope episodes and/or sudden death in patients with a structurally normal heart and a characteristic electrocardiogram (ECG) displaying a pattern resembling right bundle branch block with ST segment elevation in leads V1 to V3 was described. The disease is genetically determined with an autosomal dominant pattern of transmission in 50% of the familial cases. Several different mutations have been identified affecting the structure and the function of the sodium channel gene SCN5A. These mutations result in loss of function of the sodium channel. The syndrome appears ubiquitous. The incidence of the disease is difficult to estimate worldwide, but it may cause 4 to 10 sudden deaths per 10,000 inhabitants per year in areas like Thailand and Laos. In these countries, the disease represents the most frequent cause of natural death in young adults. It is estimated that 20 to 50% of sudden deaths in patients with a normal heart result from this syndrome. The disease has been linked to the sudden infant death syndrome and to the sudden unexpected death syndrome by showing that the electrocardiogram and mutations are the same as in Brugada syndrome. The diagnosis is easily made by means of the ECG when it is typical. There exist, however, patients with concealed and intermittent electrocardiographic forms that make the diagnosis difficult. The ECG can be modulated by changes in autonomic balance, body temperature, glucose level, and the administration of drugs like antiarrhythmics, but also neuroleptic and antimalaria drugs.
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Background Brugada (BrS) and early repolarization syndromes (ERS), the so-called J wave syndromes (JWS), are associated with life-threatening ventricular arrhythmias. Pharmacologic approaches to therapy are currently limited. In this... more
Background Brugada (BrS) and early repolarization syndromes (ERS), the so-called J wave syndromes (JWS), are associated with life-threatening ventricular arrhythmias. Pharmacologic approaches to therapy are currently limited. In this study, we examine the effects of ARumenamide-787 (AR-787) to suppress the electrocardiographic and arrhythmic manifestations of JWS and hypothermia. Methods We studied the effects of AR-787 on INa and IKr in HEK-293 cells stably expressing the α- and β1-subunits of the cardiac (NaV1.5) sodium channel and hERG channel, respectively. In addition, we studied its effect on Ito, INa and ICa in dissociated canine ventricular myocytes along with action potentials and ECG from coronary-perfused right (RV) and left (LV) ventricular wedge preparations. The Ito agonist, NS5806 (5–10 μM), ICa blocker, verapamil (2.5 μM), and INa blocker, ajmaline (2.5 μM), were used to mimic the genetic defects associated with JWS and to induce the electrocardiographic and arrhythm...
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The electrocardiogram (ECG) was reconstructed from extracellular fields generated by action potentials propagating along a 2-cm linear cable comprising 200 myocardial cells coupled through gap junctions (GJs). Intrinsic APD was varied by... more
The electrocardiogram (ECG) was reconstructed from extracellular fields generated by action potentials propagating along a 2-cm linear cable comprising 200 myocardial cells coupled through gap junctions (GJs). Intrinsic APD was varied by altering the maximal conductance of the delayed rectifier (Gx). A longer APD was simulated in the M region by a uniform decrease of Gx. APD prolongation in the
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Background: Genetic variants in voltage-gated sodium channels (Nav) encoded by SCNXA genes, responsible for INa, and Kv4.3 channels encoded by KCND3, responsible for the transient outward current (Ito), contribute to the manifestation of... more
Background: Genetic variants in voltage-gated sodium channels (Nav) encoded by SCNXA genes, responsible for INa, and Kv4.3 channels encoded by KCND3, responsible for the transient outward current (Ito), contribute to the manifestation of both Brugada syndrome (BrS) and spinocerebellar ataxia (SCA19/22). We examined the hypothesis that Kv4.3 and Nav variants regulate each other’s function, thus modulating INa/Ito balance in cardiomyocytes and INa/I(A) balance in neurons. Methods: Bicistronic and other constructs were used to express WT or variant Nav1.5 and Kv4.3 channels in HEK293 cells. INa and Ito were recorded. Results: SCN5A variants associated with BrS reduced INa, but increased Ito. Moreover, BrS and SCA19/22 KCND3 variants associated with a gain of function of Ito, significantly reduced INa, whereas the SCA19/22 KCND3 variants associated with a loss of function (LOF) of Ito significantly increased INa. Auxiliary subunits Navβ1, MiRP3 and KChIP2 also modulated INa/Ito balance....
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Research Interests: Biochemistry, Genetics, Cardiology, Developmental Biology, Immunology, and 15 moreMolecular Biology, Computational Biology, Cancer, Cell Biology, Infectious Diseases, Medicine, Gene expression, Extracellular Matrix, Heart Failure, Internal Medicine, Atrial Fibrillation, Fibrosis, Cardiac Arrhythmias, HF, and Af
A number of antipsychotic and antidepressant drugs are known to increase the risk of ventricular arrhythmias and sudden cardiac death. Based largely on a concern over the development of life-threatening arrhythmias, a number of... more
A number of antipsychotic and antidepressant drugs are known to increase the risk of ventricular arrhythmias and sudden cardiac death. Based largely on a concern over the development of life-threatening arrhythmias, a number of antipsychotic drugs have been temporarily or permanently withdrawn from the market or their use restricted. While many antidepressants and antipsychotics have been linked to QT prolongation and the development of torsade de pointes arrhythmias, some have been associated with a Brugada syndrome phenotype and the development of polymorphic ventricular arrhythmias. This article examines the arrhythmic liability of antipsychotic and antidepressant drugs capable of inducing long QT and/or Brugada syndrome phenotypes. The goal of this article is to provide an update on the ionic and cellular mechanisms thought to be involved in, and the genetic and environmental factors that predispose to, the development of cardiac arrhythmias and sudden cardiac death among patien...
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Prominent J waves are encountered in a number of life-threatening cardiac arrhythmia syndromes, including the Brugada (BrS) and early repolarization (ERS) syndromes. BrS and ERS differ with respect to the magnitude and lead location of... more
Prominent J waves are encountered in a number of life-threatening cardiac arrhythmia syndromes, including the Brugada (BrS) and early repolarization (ERS) syndromes. BrS and ERS differ with respect to the magnitude and lead location of abnormal J waves and are thought to represent a continuous spectrum of phenotypic expression termed J wave syndromes. Both are associated with the development of polymorphic ventricular tachycardia (VT) and ventricular fibrillation (VF) leading to sudden cardiac death (SCD) in young adults. J wave syndromes are characterized by J-onset and ST-elevation in distinct ECG-leads. The region most affected by BrS is the anterior right ventricular outflow tract, accounting for why J-onset and ST-segment elevation are limited to the right precordial leads. The region most affected in ERS is the inferior wall of the left ventricle, accounting for why the appearance of J waves or early repolarization in the inferior ECG leads is associated with the highest risk for development of arrhythmias and SCD. Risk stratification and the approach to therapy of the J wave syndromes continue to be mired in controversy. Our objective in this chapter is to provide an integrated review of the clinical characteristics, risk stratifiers, as well as the molecular, ionic, cellular and genetic mechanisms underlying the J wave syndromes.
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... 10. Clark RB, Bouchard RA, Salinas-Stefanon E, Sanchez-Chapula J, Giles WR. Heterogeneity of action potential waveforms and potassium currents in rat ventricle. ... 39. Gussak I, Bjerregaard P, Egan TM, Chaitman BR. ECG phenomenon... more
... 10. Clark RB, Bouchard RA, Salinas-Stefanon E, Sanchez-Chapula J, Giles WR. Heterogeneity of action potential waveforms and potassium currents in rat ventricle. ... 39. Gussak I, Bjerregaard P, Egan TM, Chaitman BR. ECG phenomenon called the J wave. ...
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... QT interval (QTI) is the surrogate electrocardio-graphic index of ventricular repolarization and its duration under normal conditions is mainly deter-mined by expression, properties, and balance of the repolarising inward sodium and... more
... QT interval (QTI) is the surrogate electrocardio-graphic index of ventricular repolarization and its duration under normal conditions is mainly deter-mined by expression, properties, and balance of the repolarising inward sodium and calcium and outward potassium and chloride ...
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Background— The Brugada syndrome is an arrhythmogenic disease caused in part by mutations in the cardiac sodium channel gene, SCN5A. The electrocardiographic pattern characteristic of the syndrome is dynamic and is often absent in... more
Background— The Brugada syndrome is an arrhythmogenic disease caused in part by mutations in the cardiac sodium channel gene, SCN5A. The electrocardiographic pattern characteristic of the syndrome is dynamic and is often absent in affected individuals. Sodium channel blockers are effective in unmasking carriers of the disease. However, the value of the test remains controversial. Methods and Results— We studied 147 individuals representing 4 large families with SCN5A mutations. Of these, 104 were determined to be at possible risk for Brugada syndrome and underwent both electrocardiographic and genetic evaluation. Twenty-four individuals displayed an ECG diagnostic of Brugada syndrome at baseline. Of the remaining, 71 received intravenous ajmaline. Of the 35 genetic carriers who received ajmaline, 28 had a positive test and 7 a negative ajmaline test. The sensitivity, specificity, and positive and negative predictive values of the drug challenge were 80% (28:35), 94.4% (34:36), 93.3%...
Research Interests: Cardiology, Risk, Medicine, Electrocardiography, Humans, and 15 moreInternal Medicine, Genetic Testing, Female, Male, Pedigree, Clinical Sciences, Public health systems and services research, Circulation, Sensitivity and Specificity, Brugada Syndrome, Bundle Branch Block, Heart Block, right bundle branch block, ajmaline, and Cardiovascular medicine and haematology(Internal Medicine, Genetic Testing, Female, Male, Pedigree, Clinical Sciences, Public health systems and services research, Circulation, Sensitivity and Specificity, Brugada Syndrome, Bundle Branch Block, Heart Block, right bundle branch block, ajmaline, and Cardiovascular medicine and haematology)
(Internal Medicine, Genetic Testing, Female, Male, Pedigree, Clinical Sciences, Public health systems and services research, Circulation, Sensitivity and Specificity, Brugada Syndrome, Bundle Branch Block, Heart Block, right bundle branch block, ajmaline, and Cardiovascular medicine and haematology)
Background. Mutations in the SCN5A gene have been linked to Brugada syndrome (BrS), conduction disease, Long QT syndrome (LQT3), atrial fibrillation (AF), and to pre- and neonatal ventricular arrhythmias. Objective. The objective of this... more
Background. Mutations in the SCN5A gene have been linked to Brugada syndrome (BrS), conduction disease, Long QT syndrome (LQT3), atrial fibrillation (AF), and to pre- and neonatal ventricular arrhythmias. Objective. The objective of this study is to characterize a novel mutation in Nav1.5 found in a newborn with fetal chaotic atrial tachycardia, post-partum intraventricular conduction delay, and QT interval prolongation. Methods. Genomic DNA was isolated and all exons and intron borders of 15 ion-channel genes were sequenced, revealing a novel missense mutation (Q270K) in SCN5A. Nav1.5 wild type (WT) and Q270K were expressed in CHO-K1 with and without the Navβ1 subunit. Results. Patch-clamp analysis showed ∼40% reduction in peak sodium channel current (INa) density for Q270K compared with WT. Fast and slow decay of INa were significantly slower in Q270K. Steady-state activation and inactivation of Q270K channels were shifted to positive potentials, and window current was increased. ...
Research Interests: Genetics, Electrophysiology, Biology, Medicine, Ion Channels, and 15 moreCanadian, Humans, Internal Medicine, Female, Animals, Long QT syndrome, Medical Physiology, Newborn Infant, Cardiac Arrhythmias, Brugada Syndrome, Nav, DNA mutational analysis, CHO cells, Cricetinae, and Pharmacology and pharmaceutical sciences
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Previous studies indicate that action potential duration (APD) alternans is initiated in the endocardial (END) and midmyocardial (MID) regions rather than the epicardium (EPI) in the canine left ventricle (LV). This study examines... more
Previous studies indicate that action potential duration (APD) alternans is initiated in the endocardial (END) and midmyocardial (MID) regions rather than the epicardium (EPI) in the canine left ventricle (LV). This study examines regional differences in the rate dependence of Ca2+ transient characteristics under conditions that give rise to APD and associated T wave alternans. The role of the sarcoplasmic reticulum (SR) was further evaluated by studying Ca2+ transient characteristics in myocytes isolated from neonates, where an organized SR is poorly developed. All studies were performed in cells and tissues isolated from the canine LV. Isolated canine ENDO, MID, and EPI LV myocytes were either field stimulated or voltage clamped, and Ca2+ transients were measured by confocal microscopy. In LV wedge preparations, increasing the basic cycle length (BCL) from 800 to 250 ms caused alternans to appear mainly in the ENDO and MID region; alternans were not observed in EPI under these con...