Publications by authors named "Charles Antzelevitch"

312 Publications

Distinct Features of Probands With Early Repolarization and Brugada Syndromes Carrying SCN5A Pathogenic Variants.

J Am Coll Cardiol 2021 Oct;78(16):1603-1617

Department of Cardiology and Cardiovascular Research Institute, Renmin Hospital of Wuhan University, Wuhan, Hubei, China; Hubei Key Laboratory of Cardiology, Wuhan, Hubei, China. Electronic address:

Background: Two major forms of inherited J-wave syndrome (JWS) are recognized: early repolarization syndrome (ERS) and Brugada syndrome (BrS).

Objectives: This study sought to assess the distinct features between patients with ERS and BrS carrying pathogenic variants in SCN5A.

Methods: Clinical evaluation and next-generation sequencing were performed in 262 probands with BrS and 104 with ERS. Nav1.5 and Kv4.3 channels were studied with the use of patch-clamp techniques. A computational model was used to investigate the protein structure.

Results: The SCN5A+ yield in ERS was significantly lower than in BrS (9.62% vs 22.90%; P = 0.004). Patients diagnosed with ERS displayed shorter QRS and QTc than patients with BrS. More than 2 pathogenic SCN5A variants were found in 5 probands. These patients displayed longer PR intervals and QRS duration and experienced more major arrhythmia events (MAE) compared with those carrying only a single pathogenic variant. SCN5A-L1412F, detected in a fever-induced ERS patient, led to total loss of function, destabilized the Nav1.5 structure, and showed a dominant-negative effect, which was accentuated during a febrile state. ERS-related SCN5A-G452C did not alter the inward sodium current (INa) when SCN5A was expressed alone, but when coexpressed with KCND3 it reduced peak INa by 44.52% and increased the transient outward potassium current (Ito) by 106.81%.

Conclusions: These findings point to SCN5A as a major susceptibility gene in ERS as much as it is in BrS, whereas the lower SCN5A+ ratio in ERS indicates the difference in underlying electrophysiology. These findings also identify the first case of fever-induced ERS and demonstrate a critical role of Ito in JWS and a higher risk for MAE in JWS probands carrying multiple pathogenic variants in SCN5A.
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http://dx.doi.org/10.1016/j.jacc.2021.08.024DOI Listing
October 2021

Intracellular uptake of agents that block the hERG channel can confound the assessment of QT interval prolongation and arrhythmic risk.

Heart Rhythm 2021 Sep 2. Epub 2021 Sep 2.

Lankenau Institute for Medical Research, Wynnewood, Pennsylvania; Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania; Lankenau Heart Institute, Main Line Health System, Wynnewood, Pennsylvania. Electronic address:

Background: Oliceridine is a biased ligand at the μ-opioid receptor recently approved for the treatment of acute pain. In a thorough QT study, corrected QT (QTc) prolongation displayed peaks at 2.5 and 60 minutes after a supratherapeutic dose. The mean plasma concentration peaked at 5 minutes, declining rapidly thereafter.

Objective: The purpose of this study was to examine the basis for the delayed effect of oliceridine to prolong the QTc interval.

Methods: Repolarization parameters and tissue accumulation of oliceridine were evaluated in rabbit left ventricular wedge preparations over a period of 5 hours. The effects of oliceridine on ion channel currents were evaluated in human embryonic kidney and Chinese hamster ovary cells. Quinidine was used as a control.

Results: Oliceridine and quinidine produced a progressive prolongation of the QTc interval and action potential duration over a period of 5 hours, paralleling slow progressive tissue uptake of the drugs. Oliceridine caused modest prolongation of these parameters, whereas quinidine produced a prominent prolongation of action potential duration and QTc interval as well as development of early afterdepolarization (after 2 hours), resulting in a high torsades de pointes score. The 50% inhibitory concentration values for the oliceridine inhibition of the rapidly activating delayed rectifier current (human ether a-go-go current) and late sodium channel current were 2.2 and 3.45 μM when assessed after traditional acute exposure but much lower after 3 hours of drug exposure.

Conclusion: Our findings suggest that a gradual increase of intracellular access of drugs to the hERG channels as a result of their intracellular uptake and accumulation can significantly delay effects on repolarization, thus confounding the assessment of QT interval prolongation and arrhythmic risk when studied acutely. The multi-ion channel effects of oliceridine, late sodium channel current inhibition in particular, point to a low risk of devloping torsades de pointes.
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http://dx.doi.org/10.1016/j.hrthm.2021.08.028DOI Listing
September 2021

Common variants in SCN10A gene associated with Brugada syndrome.

Hum Mol Genet 2021 Jul 26. Epub 2021 Jul 26.

Department of Cardiology and Cardiovascular Research Institute, Renmin Hospital of Wuhan University, Wuhan, Hubei, 430060, China.

Background: Genome-wide association studies indicate that SCN10A plays an important role in cardiac electrophysiology. Common and rare SCN10A variants are suggested to contribute to Brugada Syndrome (BrS), an inherited channelopathy resulting from genetic-determined loss-of-function in cardiac sodium channel. This study sought to characterize the role of SCN10A common variants in BrS.

Methods And Results: Clinical and genetic analyses were performed in 197 patients diagnosed with BrS. Baseline ECG parameters were evaluated in patients carrying each of four common variants associated with BrS. Cellular electrophysiological study was performed in SCN5A-SCN10A co-transfected TSA201 cells to investigate the possible electrophysiological characteristics of the allele of rs6795970, which displayed the most significant association with BrS. Four SCN10A common variants (rs7630989, rs57326399, rs6795970, rs12632942) displayed significant association with BrS susceptibility. There were no evident associations between baseline ECG parameters in BrS patients and the different genotypes of the four variants. Rs6795970 (V1073) was strongly associated with a risk for BrS, which suggests the different electrophysiological characters between these two alleles. Functional study showed a positive shift in steady-state activation (V1/2: -62.2 ± 2.6 vs. -53.5 ± 1.6 for A1073 and V1073 group, respectively; P < 0.05) and slower recovery from inactivation in mutant SCN5A-SCN10A co-transfected cells with, which contribute to the slow conduction in BrS patients with rs6795970.

Conclusions: SCN10A common variants are associated with increased susceptibility to BrS. An allele rs6795970 (V1073) increases the risk for BrS. The electrophysiological changes in a positive shift in steady-state activation and slower recovery from inactivation by SCN10A-V1073 contribute to this variant associated BrS.
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http://dx.doi.org/10.1093/hmg/ddab217DOI Listing
July 2021

J wave syndromes: What's new?

Trends Cardiovasc Med 2021 Jul 10. Epub 2021 Jul 10.

Lankenau Institute for Medical Research, Wynnwoddm PA USA.

Among the inherited ion channelopathies associated with potentially life-threatening ventricular arrhythmia syndromes in nominally structurally normal hearts are the J wave syndromes, which include the Brugada (BrS) and early repolarization (ERS) syndromes. These ion channelopathies are responsible for sudden cardiac death (SCD), most often in young adults in the third and fourth decade of life. Our principal goal in this review is to briefly outline the clinical characteristics, as well as the molecular, ionic, cellular, and genetic mechanisms underlying these primary electrical diseases that have challenged the cardiology community over the past two decades. In addition, we discuss our recently developed whole-heart experimental model of BrS, providing compelling evidence in support of the repolarization hypothesis for the BrS phenotype as well as novel findings demonstrating that voltage-gated sodium and transient outward current channels can modulate each other's function via trafficking and gating mechanisms with implications for improved understanding of the genetics of both cardiac and neuronal syndromes.
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http://dx.doi.org/10.1016/j.tcm.2021.07.001DOI Listing
July 2021

Clinical and Functional Genetic Characterization of the Role of Cardiac Calcium Channel Variants in the Early Repolarization Syndrome.

Front Cardiovasc Med 2021 18;8:680819. Epub 2021 Jun 18.

Department of Cardiology and Cardiovascular Research Institute, Renmin Hospital of Wuhan University, Wuhan, China.

Early repolarization syndrome (ERS) is an inherited sudden cardiac death (SCD) syndrome. The present study investigates the role of genetic variants in cardiac calcium-channel genes in the pathogenesis of ERS and probes the underlying mechanisms. Polymerase chain reaction-based next-generation sequencing was carried out using a targeted gene approach. Unrelated ERS probands carrying calcium-channel variants were evaluated clinically and compared with matched healthy controls. Wild-type (WT) and mutant genes were coexpressed with and in HEK293 cells and studied using whole-cell patch-clamp techniques and confocal fluorescence microscope. Among 104 ERS probands, 16 carried pathogenic variants in calcium-channel genes (32.2 ± 14.6 years old, 87.5% male). The symptoms at diagnosis included syncope (56.3%), ventricular tachycardia/fibrillation (62.5%), and SCD (56.3%). Three cases (18.8%) had a family history of SCD or syncope. Eight patients (50.0%) had a single calcium gene rare variant. The other half carried rare variants in other ERS-susceptible genes. Compared with controls, the heart rate was slower (72.7 ± 8.9 vs. 65.6 ± 16.1 beats/min, < 0.05), QTc interval was shorter (408.2 ± 21.4 vs. 386.8 ± 16.9 ms, < 0.01), and Tp-e/QT was longer (0.22 ± 0.05 vs. 0.28 ± 0.04, < 0.001) in single calcium mutation carriers. Electrophysiological analysis of one mutation, -P817S (c.2449C>T), revealed that the density of whole-cell calcium current ( ) was reduced by ~84.61% compared to WT (-3.17 ± 2.53 vs. -20.59 ± 3.60 pA/pF, = 11 and 15, respectively, < 0.01). Heterozygous expression of mutant channels was associated with a 51.35% reduction of . Steady-state inactivation was shifted to more negative potentials and significantly accelerated as well. Confocal microscopy revealed trafficking impairment of -P817S (peripheral/central intensity: 0.94 ± 0.10 in WT vs. 0.33 ± 0.12 in P817S, = 10 and 9, respectively, < 0.01). ERS associated with loss-of-function (LOF) genetic defects in genes encoding the cardiac calcium channel represents a unique clinical entity characterized by decreased heart rate and QTc, as well as increased transmural dispersion of repolarization. In the case of -P817S, impaired trafficking of the channel to the membrane contributes to the LOF.
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http://dx.doi.org/10.3389/fcvm.2021.680819DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8249565PMC
June 2021

Frequency of Irritable Bowel Syndrome in Patients with Brugada Syndrome and Drug-Induced Type 1 Brugada Pattern.

Am J Cardiol 2021 07 24;151:51-56. Epub 2021 May 24.

Department of Cardiology, Ege University School of Medicine, Izmir, Turkey. Electronic address:

Irritable bowel syndrome (IBS) is one of the most widely recognized functional bowel disorders (FBDs) with a genetic component. SCN5A gene and SCN1B loci have been identified in population-based IBS cohorts and proposed to have a mechanistic role in the pathophysiology of IBS. These same genes have been associated with Brugada syndrome (BrS). The present study examines the hypothesis that these two inherited syndromes are linked. Prevalence of FBDs over a 12 months period were compared between probands with BrS/drug-induced type 1 Brugada pattern (DI-Type 1 BrP) (n = 148) and a control group (n = 124) matched for age, female sex, presence of arrhythmia and co-morbid conditions. SCN5A/SCN1B genes were screened in 88 patients. Prevalence of IBS was 25% in patients with BrS/DI-Type 1 BrP and 8.1% in the control group (p = 2.34 × 10). On stepwise logistic regression analysis, presence of current and/or history of migraine (OR of 2.75; 95% CI: 1.08 to 6.98; p = 0.033) was a predictor of underlying BrS/DI-Type 1 BrP among patients with FBDs. We identified 8 putative SCN5A/SCN1B variants in 7 (12.3%) patients with BrS/DI-Type 1 BrP and 1 (3.2%) patient in control group. Five out of 8 (62.5%) patients with SCN5A/SCN1B variants had FBDs. In conclusion, IBS is a common co-morbidity in patients with BrS/DI-Type 1 BrP. Presence of current and/or history of migraine are a predictor of underlying BrS/DI-Type 1 BrP among patients with FBDs. Frequent co-existence of IBS and BrS/DI-Type 1 BrP necessitates cautious use of certain drugs among the therapeutic options for IBS that are known to exacerbate the Brugada phenotype.
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http://dx.doi.org/10.1016/j.amjcard.2021.04.010DOI Listing
July 2021

Fractionated Epicardial Electrograms: Implication for Mechanism of the Brugada Pattern.

JACC Clin Electrophysiol 2021 02;7(2):258-270

Division of Electrophysiology, Department of Cardiology, University of California-San Francisco, San Francisco, California, USA.

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http://dx.doi.org/10.1016/j.jacep.2020.12.009DOI Listing
February 2021

Acacetin suppresses the electrocardiographic and arrhythmic manifestations of the J wave syndromes.

PLoS One 2020 24;15(11):e0242747. Epub 2020 Nov 24.

Lankenau Institute for Medical Research, Wynnewood, PA, United States of America.

Background: J wave syndromes (JWS), including Brugada (BrS) and early repolarization syndromes (ERS), are associated with increased risk for life-threatening ventricular arrhythmias. Pharmacologic approaches to therapy are currently very limited. Here, we evaluate the effects of the natural flavone acacetin.

Methods: The effects of acacetin on action potential (AP) morphology and transient outward current (Ito) were first studied in isolated canine RV epicardial myocytes using whole-cell patch clamp techniques. Acacetin's effects on transmembrane APs, unipolar electrograms and transmural ECGs were then studied in isolated coronary-perfused canine RV and LV wedge preparations as well as in whole-heart, Langendorff-perfused preparations from which we recorded a 12 lead ECG and unipolar electrograms. Using floating glass microelectrodes we also recorded transmembrane APs from the RVOT of the whole-heart model. The Ito agonist NS5806, sodium channel blocker ajmaline, calcium channel blocker verapamil or hypothermia (32°C) were used to pharmacologically mimic the genetic defects and conditions associated with JWS, thus eliciting prominent J waves and provoking VT/VF.

Results: Acacetin (5-10 μM) reduced Ito density, AP notch and J wave area and totally suppressed the electrocardiographic and arrhythmic manifestation of both BrS and ERS, regardless of the experimental model used. In wedge and whole-heart models of JWS, increasing Ito with NS5806, decreasing INa or ICa (with ajmaline or verapamil) or hypothermia all resulted in accentuation of epicardial AP notch and ECG J waves, resulting in characteristic BrS and ERS phenotypes. Phase 2-reentrant extrasystoles originating from the RVOT triggered VT/VF. The J waves in leads V1 and V2 were never associated with a delay of RVOT activation and always coincided with the appearance of the AP notch recorded from RVOT epicardium. All repolarization defects giving rise to VT/VF in the BrS and ERS models were reversed by acacetin, resulting in total suppression of VT/VF.

Conclusions: We present experimental models of BrS and ERS capable of recapitulating all of the ECG and arrhythmic manifestations of the JWS. Our findings provide definitive support for the repolarization but not the depolarization hypothesis proposed to underlie BrS and point to acacetin as a promising new pharmacologic treatment for JWS.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0242747PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7685455PMC
January 2021

Recognition and clinical implications of high prevalence of migraine in patients with Brugada syndrome and drug-induced type 1 Brugada pattern.

J Cardiovasc Electrophysiol 2020 12 23;31(12):3311-3317. Epub 2020 Oct 23.

Lankenau Institute for Medical Research, Wynnewood, Pennsylvania, USA.

Introduction: We have previously reported high 1-year prevalence of migraine in patients with atrial arrhythmias associated with DI-type 1 BrP. The present study was designed to determine the lifetime prevalence of migraine in patients with Brugada syndrome (BrS) or drug-induced type 1 Brugada pattern (DI-type 1 BrP) and control group, to investigate the demographic and clinical characteristics, and to identify clinical variables to predict underlying BrS/DI-type 1 BrP among migraineurs.

Methods And Results: Lifetime prevalence of migraine and migraine characteristics were compared between probands with BrS/DI-type 1 BrP (n = 257) and control group (n = 370). Lifetime prevalence of migraine was 60.7% in patients with BrS/DI-type 1 BrP and 30.3% in control group (p = 3.6 × 10 ). On stepwise regression analysis, familial migraine (odds ratio [OR] of 4.4; 95% confidence interval [CI]: 2.0-9.8; p = 1.3 × 10 ), vestibular migraine (OR of 5.4; 95% CI: 1.4-21.0); p = .013), migraine with visual aura (OR of 1.8; 95% CI: 1.0-3.4); p = .04) and younger age-at-onset of migraine (OR of 0.95; 95% CI: 0.93-0.98); p = .004) were predictors of underlying BrS/DI-type 1 BrP among migraineurs. Use of anti-migraine drugs classified as "to be avoided" or "preferably avoided" in patients with BrS and several other anti-migraine drugs with potential cardiac I /I channel blocking properties was present in 25.6% and 26.9% of migraineurs with BrS/DI-type 1 BrP, respectively.

Conclusion: Migraine comorbidity is common in patients with BrS/DI-type 1 BrP. We identify several clinical variables that point to an underlying type-1 BrP among migraineurs, necessitating cautious use of certain anti-migraine drugs.
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http://dx.doi.org/10.1111/jce.14778DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7749067PMC
December 2020

Susceptibility to Ventricular Arrhythmias Resulting from Mutations in , , and Evaluated in hiPSC Cardiomyocytes.

Stem Cells Int 2020 1;2020:8842398. Epub 2020 Sep 1.

Department of Experimental Cardiology, Masonic Medical Research Institute, Utica, NY, USA.

Background: We report an inherited cardiac arrhythmia syndrome consisting of Brugada and Early Repolarization Syndrome associated with variants in , , and . The proband inherited the 3 mutations and exhibited palpitations and arrhythmia-mediated syncope, whereas the parents and sister, who carried one or two of the mutations, were asymptomatic.

Methods And Results: We assessed the functional impact of these mutations in induced pluripotent stem cell cardiomyocytes (hiPSC-CMs) derived from the proband and an unaffected family member. Current and voltage clamp recordings, as well as confocal microscopy analysis of Ca transients, were evaluated in hiPSC-CMs from the proband and compared these results with hiPSC-CMs from undiseased controls. Genetic analysis using next-generation DNA sequencing revealed heterozygous mutations in , , and in the proband. The proband displayed right bundle branch block and exhibited episodes of syncope. The father carried a mutation in , whereas the mother and sister carried the mutation. None of the 3 family members screened developed cardiac events. Action potential recordings from control hiPSC-CM showed spontaneous activity and a low upstroke velocity. In contrast, the hiPSC-CM from the proband showed irregular spontaneous activity. Confocal microscopy of the hiPSC-CM of the proband revealed low fluorescence intensity Ca transients that were episodic in nature. Patch-clamp measurements in hiPSC-CM showed no difference in but reduced in the proband compared with control. Coexpression of -R391Q with -WT displayed lower density compared to -WT. In addition, coexpression of -R391Q with -WT displayed significantly higher density compared to -WT.

Conclusion: , , and variants appeared to alter spontaneous activity in hiPSC-CM. Only the proband carrying all 3 mutations displayed the ERS/BrS phenotype, whereas one nor two mutations alone did not produce the clinical phenotype. Our results suggest a polygenic cause of the BrS/ERS arrhythmic phenotype due to mutations in these three gene variants caused a very significant loss of function of and and gain of function of .
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http://dx.doi.org/10.1155/2020/8842398DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7481990PMC
September 2020

Enhancing rare variant interpretation in inherited arrhythmias through quantitative analysis of consortium disease cohorts and population controls.

Genet Med 2021 01 7;23(1):47-58. Epub 2020 Sep 7.

Member of the European Reference Network for rare, low prevalence and/or complex diseases of the heart: ERN GUARD-Heart, Amsterdam, Netherlands.

Purpose: Stringent variant interpretation guidelines can lead to high rates of variants of uncertain significance (VUS) for genetically heterogeneous disease like long QT syndrome (LQTS) and Brugada syndrome (BrS). Quantitative and disease-specific customization of American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines can address this false negative rate.

Methods: We compared rare variant frequencies from 1847 LQTS (KCNQ1/KCNH2/SCN5A) and 3335 BrS (SCN5A) cases from the International LQTS/BrS Genetics Consortia to population-specific gnomAD data and developed disease-specific criteria for ACMG/AMP evidence classes-rarity (PM2/BS1 rules) and case enrichment of individual (PS4) and domain-specific (PM1) variants.

Results: Rare SCN5A variant prevalence differed between European (20.8%) and Japanese (8.9%) BrS patients (p = 5.7 × 10) and diagnosis with spontaneous (28.7%) versus induced (15.8%) Brugada type 1 electrocardiogram (ECG) (p = 1.3 × 10). Ion channel transmembrane regions and specific N-terminus (KCNH2) and C-terminus (KCNQ1/KCNH2) domains were characterized by high enrichment of case variants and >95% probability of pathogenicity. Applying the customized rules, 17.4% of European BrS and 74.8% of European LQTS cases had (likely) pathogenic variants, compared with estimated diagnostic yields (case excess over gnomAD) of 19.2%/82.1%, reducing VUS prevalence to close to background rare variant frequency.

Conclusion: Large case-control data sets enable quantitative implementation of ACMG/AMP guidelines and increased sensitivity for inherited arrhythmia genetic testing.
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http://dx.doi.org/10.1038/s41436-020-00946-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7790744PMC
January 2021

Inter-Regulation of K4.3 and Voltage-Gated Sodium Channels Underlies Predisposition to Cardiac and Neuronal Channelopathies.

Int J Mol Sci 2020 Jul 17;21(14). Epub 2020 Jul 17.

Department of Cardiovascular Research, Lankenau Institute for Medical Research, Wynnewood, PA 19096, USA.

Background: Genetic variants in voltage-gated sodium channels (Na) encoded by genes, responsible for I, and K4.3 channels encoded by , responsible for the transient outward current (I), contribute to the manifestation of both Brugada syndrome (BrS) and spinocerebellar ataxia (SCA19/22). We examined the hypothesis that K4.3 and Na variants regulate each other's function, thus modulating I/I balance in cardiomyocytes and I/I balance in neurons.

Methods: Bicistronic and other constructs were used to express WT or variant Na1.5 and K4.3 channels in HEK293 cells. I and I were recorded.

Results: variants associated with BrS reduced I, but increased I. Moreover, BrS and SCA19/22 variants associated with a gain of function of I, significantly reduced I, whereas the SCA19/22 variants associated with a loss of function (LOF) of I significantly increased I. Auxiliary subunits Naβ1, MiRP3 and KChIP2 also modulated I/I balance. Co-immunoprecipitation and Duolink studies suggested that the two channels interact within the intracellular compartments and biotinylation showed that LOF variants can increase K4.3 cell-surface expression.

Conclusion: Na and K4.3 channels modulate each other's function via trafficking and gating mechanisms, which have important implications for improved understanding of these allelic cardiac and neuronal syndromes.
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http://dx.doi.org/10.3390/ijms21145057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7404392PMC
July 2020

Inherited cardiac arrhythmias.

Nat Rev Dis Primers 2020 07 16;6(1):58. Epub 2020 Jul 16.

European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart (ERN GUARD-HEART), Bruxelles, Belgium.

The main inherited cardiac arrhythmias are long QT syndrome, short QT syndrome, catecholaminergic polymorphic ventricular tachycardia and Brugada syndrome. These rare diseases are often the underlying cause of sudden cardiac death in young individuals and result from mutations in several genes encoding ion channels or proteins involved in their regulation. The genetic defects lead to alterations in the ionic currents that determine the morphology and duration of the cardiac action potential, and individuals with these disorders often present with syncope or a life-threatening arrhythmic episode. The diagnosis is based on clinical presentation and history, the characteristics of the electrocardiographic recording at rest and during exercise and genetic analyses. Management relies on pharmacological therapy, mostly β-adrenergic receptor blockers (specifically, propranolol and nadolol) and sodium and transient outward current blockers (such as quinidine), or surgical interventions, including left cardiac sympathetic denervation and implantation of a cardioverter-defibrillator. All these arrhythmias are potentially life-threatening and have substantial negative effects on the quality of life of patients. Future research should focus on the identification of genes associated with the diseases and other risk factors, improved risk stratification and, in particular for Brugada syndrome, effective therapies.
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http://dx.doi.org/10.1038/s41572-020-0188-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7935690PMC
July 2020

GSTM3 variant is a novel genetic modifier in Brugada syndrome, a disease with risk of sudden cardiac death.

EBioMedicine 2020 Jul 7;57:102843. Epub 2020 Jul 7.

Lankenau Institute for Medical Research and Lankenau Heart Institute, Wynnewood, PA and Sidney Kimmel Medical College of Thomas Jefferson University, Philadelphia, PA, USA. Electronic address:

Background: Brugada syndrome (BrS) is a rare inherited disease causing sudden cardiac death (SCD). Copy number variants (CNVs) can contribute to disease susceptibility, but their role in Brugada syndrome (BrS) is unknown. We aimed to identify a CNV associated with BrS and elucidated its clinical implications.

Methods: We enrolled 335 unrelated BrS patients from 2000 to 2018 in the Taiwanese population. Microarray and exome sequencing were used for discovery phase whereas Sanger sequencing was used for the validation phase. HEK cells and zebrafish were used to characterize the function of the CNV variant.

Findings: A copy number deletion of GSTM3 (chr1:109737011-109737301, hg38) containing the eighth exon and the transcription stop codon was observed in 23.9% of BrS patients versus 0.8% of 15,829 controls in Taiwan Biobank (P < 0.001), and 0% in gnomAD. Co-segregation analysis showed that the co-segregation rate was 20%. Patch clamp experiments showed that in an oxidative stress environment, GSTM3 down-regulation leads to a significant decrease of cardiac sodium channel current amplitude. Ventricular arrhythmia incidence was significantly greater in gstm3 knockout zebrafish at baseline and after flecainide, but was reduced after quinidine, consistent with clinical observations. BrS patients carrying the GSTM3 deletion had higher rates of sudden cardiac arrest and syncope compared to those without (OR: 3.18 (1.77-5.74), P<0.001; OR: 1.76 (1.02-3.05), P = 0.04, respectively).

Interpretation: This GSTM3 deletion is frequently observed in BrS patients and is associated with reduced I, pointing to this as a novel potential genetic modifier/risk predictor for the development of the electrocardiographic and arrhythmic manifestations of BrS.

Funding: This work was supported by the Ministry of Science and Technology (107-2314-B-002-261-MY3 to J.M.J. Juang), and by grants HL47678, HL138103 and HL152201 from the National Institutes of Health to CA.
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http://dx.doi.org/10.1016/j.ebiom.2020.102843DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7341360PMC
July 2020

The Small Conductance Calcium-Activated Potassium Channel Inhibitors NS8593 and UCL1684 Prevent the Development of Atrial Fibrillation Through Atrial-Selective Inhibition of Sodium Channel Activity.

J Cardiovasc Pharmacol 2020 08;76(2):164-172

Lakenau Institute for Medical Research, Wynnewood, PA.

The mechanisms underlying atrial-selective prolongation of effective refractory period (ERP) and suppression of atrial fibrillation (AF) by NS8593 and UCL1684, small conductance calcium-activated potassium (SK) channel blockers, are poorly defined. The purpose of the study was to confirm the effectiveness of these agents to suppress AF and to probe the underlying mechanisms. Transmembrane action potentials and pseudoelectrocardiograms were recorded from canine isolated coronary-perfused canine atrial and ventricular wedge preparations. Patch clamp techniques were used to record sodium channel current (INa) in atrial and ventricular myocytes and human embryonic kidney cells. In both atria and ventricles, NS8593 (3-10 µM) and UCL1684 (0.5 µM) did not significantly alter action potential duration, suggesting little to no SK channel inhibition. Both agents caused atrial-selective: (1) prolongation of ERP secondary to development of postrepolarization refractoriness, (2) reduction of Vmax, and (3) increase of diastolic threshold of excitation (all are sodium-mediated parameters). NS8593 and UCL1684 significantly reduced INa density in human embryonic kidney cells as well as in atrial but not in ventricular myocytes at physiologically relevant holding potentials. NS8593 caused a shift of steady-state inactivation to negative potentials in atrial but not ventricular cells. NS8593 and UCL1684 prevented induction of acetylcholine-mediated AF in 6/6 and 8/8 preparations, respectively. This anti-AF effect was associated with strong rate-dependent depression of excitability. The SK channel blockers, NS8593 and UCL1684, are effective in preventing the development of AF due to potent atrial-selective inhibition of INa, causing atrial-selective prolongation of ERP secondary to induction of postrepolarization refractoriness.
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http://dx.doi.org/10.1097/FJC.0000000000000855DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7416459PMC
August 2020

Transethnic Genome-Wide Association Study Provides Insights in the Genetic Architecture and Heritability of Long QT Syndrome.

Circulation 2020 07 20;142(4):324-338. Epub 2020 May 20.

Masonic Medical Research Institute, Utica, NY (R.P.).

Background: Long QT syndrome (LQTS) is a rare genetic disorder and a major preventable cause of sudden cardiac death in the young. A causal rare genetic variant with large effect size is identified in up to 80% of probands (genotype positive) and cascade family screening shows incomplete penetrance of genetic variants. Furthermore, a proportion of cases meeting diagnostic criteria for LQTS remain genetically elusive despite genetic testing of established genes (genotype negative). These observations raise the possibility that common genetic variants with small effect size contribute to the clinical picture of LQTS. This study aimed to characterize and quantify the contribution of common genetic variation to LQTS disease susceptibility.

Methods: We conducted genome-wide association studies followed by transethnic meta-analysis in 1656 unrelated patients with LQTS of European or Japanese ancestry and 9890 controls to identify susceptibility single nucleotide polymorphisms. We estimated the common variant heritability of LQTS and tested the genetic correlation between LQTS susceptibility and other cardiac traits. Furthermore, we tested the aggregate effect of the 68 single nucleotide polymorphisms previously associated with the QT-interval in the general population using a polygenic risk score.

Results: Genome-wide association analysis identified 3 loci associated with LQTS at genome-wide statistical significance (<5×10) near , , and , and 1 missense variant in (p.Asp85Asn) at the suggestive threshold (<10). Heritability analyses showed that ≈15% of variance in overall LQTS susceptibility was attributable to common genetic variation ( 0.148; standard error 0.019). LQTS susceptibility showed a strong genome-wide genetic correlation with the QT-interval in the general population (r=0.40; =3.2×10). The polygenic risk score comprising common variants previously associated with the QT-interval in the general population was greater in LQTS cases compared with controls (<10-13), and it is notable that, among patients with LQTS, this polygenic risk score was greater in patients who were genotype negative compared with those who were genotype positive (<0.005).

Conclusions: This work establishes an important role for common genetic variation in susceptibility to LQTS. We demonstrate overlap between genetic control of the QT-interval in the general population and genetic factors contributing to LQTS susceptibility. Using polygenic risk score analyses aggregating common genetic variants that modulate the QT-interval in the general population, we provide evidence for a polygenic architecture in genotype negative LQTS.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.045956DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7382531PMC
July 2020

Identification, clinical manifestation and structural mechanisms of mutations in AMPK associated cardiac glycogen storage disease.

EBioMedicine 2020 Apr 4;54:102723. Epub 2020 Apr 4.

Lankenau Institute for Medical Research, Wynnewood, PA, USA; Lankenau Heart Institute, Sidney Kimmel College of Medicine, Thomas Jefferson University, USA.

Background: Although 21 causative mutations have been associated with PRKAG2 syndrome, our understanding of the syndrome remains incomplete. The aim of this project is to further investigate its unique genetic background, clinical manifestations, and underlying structural changes.

Methods: We recruited 885 hypertrophic cardiomyopathy (HCM) probands and their families internationally. Targeted next-generation sequencing of sudden cardiac death (SCD) genes was performed. The role of the identified variants was assessed using histological techniques and computational modeling.

Findings: Twelve PRKAG2 syndrome kindreds harboring 5 distinct variants were identified. The clinical penetrance of 25 carriers was 100.0%. Twenty-two family members died of SCD or heart failure (HF). All probands developed bradycardia (HRmin, 36.3 ± 9.8 bpm) and cardiac conduction defects, and 33% had evidence of atrial fibrillation/paroxysmal supraventricular tachycardia (PSVT) and 67% had ventricular preexcitation, respectively. Some carriers presented with apical hypertrophy, hypertension, hyperlipidemia, and renal insufficiency. Histological study revealed reduced AMPK activity and major cardiac channels in the heart tissue with K485E mutation. Computational modelling suggests that K485E disrupts the salt bridge connecting the β and γ subunits of AMPK, R302Q/P decreases the binding affinity for ATP, T400N and H401D alter the orientation of H383 and R531 residues, thus altering nucleotide binding, and N488I and L341S lead to structural instability in the Bateman domain, which disrupts the intramolecular regulation.

Interpretation: Including 4 families with 3 new mutations, we describe a cohort of 12 kindreds with PRKAG2 syndrome with novel pathogenic mechanisms by computational modelling. Severe clinical cardiac phenotypes may be developed, including HF, requiring close follow-up.
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http://dx.doi.org/10.1016/j.ebiom.2020.102723DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7132172PMC
April 2020

Abnormal myocardial expression of SAP97 is associated with arrhythmogenic risk.

Am J Physiol Heart Circ Physiol 2020 06 20;318(6):H1357-H1370. Epub 2020 Mar 20.

Departments of Internal Medicine (Cardiovascular) and of Molecular and Integrative Physiology, Center for Arrhythmia Research, University of Michigan, Ann Arbor, Michigan.

Synapse-associated protein 97 (SAP97) is a scaffolding protein crucial for the functional expression of several cardiac ion channels and therefore proper cardiac excitability. Alterations in the functional expression of SAP97 can modify the ionic currents underlying the cardiac action potential and consequently confer susceptibility for arrhythmogenesis. In this study, we generated a murine model for inducible, cardiac-targeted Sap97 ablation to investigate arrhythmia susceptibility and the underlying molecular mechanisms. Furthermore, we sought to identify human SAP97 () variants that were associated with inherited arrhythmogenic disease. The murine model of cardiac-specific Sap97 ablation demonstrated several ECG abnormalities, pronounced action potential prolongation subject to high incidence of arrhythmogenic afterdepolarizations and notable alterations in the activity of the main cardiac ion channels. However, no mutations were found in 40 unrelated cases of genetically elusive long QT syndrome (LQTS). Instead, we provide the first evidence implicating a gain of function in human mutation resulting in an increase in Kv4.3 current () as a novel, potentially pathogenic substrate for Brugada syndrome (BrS). In conclusion, joins a growing list of genes encoding ion channel interacting proteins (ChIPs) identified as potential channelopathy-susceptibility genes because of their ability to regulate the trafficking, targeting, and modulation of ion channels that are critical for the generation and propagation of the cardiac electrical impulse. Dysfunction in these critical components of cardiac excitability can potentially result in fatal cardiac disease. The gene encoding SAP97 () joins a growing list of genes encoding ion channel-interacting proteins (ChIPs) identified as potential channelopathy-susceptibility genes because of their ability to regulate the trafficking, targeting, and modulation of ion channels that are critical for the generation and propagation of the cardiac electrical impulse. In this study we provide the first data supporting encoded SAP97's candidacy as a minor Brugada syndrome susceptibility gene.
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http://dx.doi.org/10.1152/ajpheart.00481.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7311695PMC
June 2020

Tpeak-tend interval as a marker of arrhythmic risk in early repolarization syndrome.

J Cardiovasc Electrophysiol 2019 10 26;30(10):2106-2107. Epub 2019 Aug 26.

Lankenau Institute for Medical Research, Wynnewood, Pennsylvania.

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http://dx.doi.org/10.1111/jce.14118DOI Listing
October 2019

Mutations in Na1.5 Reveal Calcium-Calmodulin Regulation of Sodium Channel.

Front Physiol 2019 5;10:700. Epub 2019 Jun 5.

Heart Center, Sheba Medical Center, Ramat Gan, Israel.

Mutations in the gene, encoding the cardiac voltage-gated sodium channel Na1.5, are associated with inherited cardiac arrhythmia and conduction disease. Ca-dependent mechanisms and the involvement of β-subunit (Naβ) in Na1.5 regulation are not fully understood. A patient with severe sinus-bradycardia and cardiac conduction-disease was genetically evaluated and compound heterozygosity in the gene was found. Mutations were identified in the cytoplasmic DIII-IV linker (K1493del) and the C-terminus (A1924T) of Na1.5, both are putative CaM-binding domains. These mutants were functionally studied in human embryonic kidney (HEK) cells and HL-1 cells using whole-cell patch clamp technique. Calmodulin (CaM) interaction and cell-surface expression of heterologously expressed Na1.5 mutants were studied by pull-down and biotinylation assays. The mutation K1493del rendered Na1.5 non-conductive. Na1.5 altered the gating properties of co-expressed functional Na1.5, in a Ca and Naβ1-dependent manner. Na1.5 impaired Naβ1-dependent gating regulation. Ca-dependent CaM-interaction with Na1.5 was blunted in Na1.5. Electrical charge substitution at position 1493 did not affect CaM-interaction and channel functionality. Arrhythmia and conduction-disease -associated mutations revealed Ca-dependent gating regulation of Na1.5 channels. Our results highlight the role of Na1.5 DIII-IV linker in the CaM-binding complex and channel function, and suggest that the Ca-sensing machinery of Na1.5 involves Naβ1.
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http://dx.doi.org/10.3389/fphys.2019.00700DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6560087PMC
June 2019

Transcriptional changes associated with advancing stages of heart failure underlie atrial and ventricular arrhythmogenesis.

PLoS One 2019 13;14(5):e0216928. Epub 2019 May 13.

Lankenau Institute for Medical Research, Wynnewood, Pennsylvania, United States of America.

Background: Heart failure (HF) is a leading cause of mortality and is associated with cardiac remodeling. Vulnerability to atrial fibrillation (AF) has been shown to be greater in the early stages of HF, whereas ventricular tachycardia/fibrillation develop during late stages. Here, we explore changes in gene expression that underlie the differential development of fibrosis and structural alterations that predispose to atrial and ventricular arrhythmias.

Objective: To study transcriptomic changes associated with the development of cardiac arrhythmias in early and late stages of heart failure.

Methods: Dogs were tachy-paced from right ventricle (RV) for 2-3 or 5-6 weeks (early and late HF). We performed transcriptomic analysis of right atria (RA) and RV isolated from control dogs and those in early and late HF. Transcripts with mean relative log2-fold change ≥2 were included in the differential analysis with significance threshold adjusted to p<0.05.

Results: Early HF remodeling was more prominent in RA with enrichment of extracellular matrix, circulatory system, wound healing and immune response pathways; many of these processes were not present in RA in late HF. RV showed no signs of remodeling in early HF but enrichment of extracellular matrix and wound healing in late HF.

Conclusion: Our transcriptomic data indicate significant fibrosis-associated transcriptional changes in RA in early HF and in RV in late HF, with strong atrial predominance. These alterations in gene expression are consistent with the development of arrhythmogenesis in atria in early but not late HF and in the ventricle in late but not early HF.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0216928PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6513089PMC
January 2020

Pooled Analysis of Risk Stratification of Spontaneous Type 1 Brugada ECG: Focus on the Influence of Gender and EPS.

Front Physiol 2018 31;9:1951. Epub 2019 Jan 31.

Guang'anmen Hospital, Chinese Academy of Chinese Medical Sciences, Beijing, China.

Risk stratification of patients with Brugada syndrome (BrS) is vital for accurate prognosis and therapeutic decisions. Spontaneous Type 1 ST segment elevation is generally considered to be an independent risk factor for arrhythmic events. Other risk factors include gender, syncope, sudden cardiac arrest (SCA), and positive electrophysiological study (EPS). However, the further risk stratification of spontaneous type 1 combined with the other risk factors remains unclear. The present study pooled data from 4 large trials aiming to systematically evaluate the risk of spontaneous Type-1 ECG when combined with one or more of these other recognized risk factors. We searched for related studies published from November 2, 2002 to February 10, 2018 in PubMed, EMBASE, Cochrane Library, MEDLINE, Chinese National Knowledge Infrastructure (CNKI), and Wanfang Databases. The pooled data were evaluated combining each risk factor with the presence of a spontaneous Type-1 ECG. All analyses were performed using Review Manager, version 5.0.12. Four eligible studies involving 1,338 patients (85% males, mean age: 48.1 ± 18.1 years) were enrolled. Spontaneous Type-1 ECG was associated with higher risk for ventricular tachycardia/fibrillation (VT/VF) than cases with non-Type 1 ECG in males (odds ratio: 95% CI: 1.84-5.17; < 0.0001), but not in females ( = 0.29). Among spontaneous Type-1 cases with syncope or with positive EPS, the difference was not statistically significant ( = 0.06 and 0.07, respectively). Patients with Type-1 ECGs and positive EPS were at higher risk than those with negative EPS (95% CI: 1.10-5.04; = 0.03). Pooled analysis showed an association of Spontaneous Type-1 ECG, Type-1 ECGs combined with male, and Type-1 ECGs combined with positive EPS between increased risk of arrhythmic events. Our results indicate that in BrS patients, a spontaneous Type-1 ECG is an independent risk factor for SCD in males, but not in females. A spontaneous Type-1 BrS is associated with a worse prognosis when combined with positive EPS.
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http://dx.doi.org/10.3389/fphys.2018.01951DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6365464PMC
January 2019

Reply to the Editor- Tpeak-Tend is alive and well.

Heart Rhythm 2019 06 23;16(6):e49-e50. Epub 2019 Jan 23.

Lankenau Institute for Medical Research, Wynnewood, Pennsylvania.

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http://dx.doi.org/10.1016/j.hrthm.2019.01.021DOI Listing
June 2019

Impact of Ancestral Differences and Reassessment of the Classification of Previously Reported Pathogenic Variants in Patients With Brugada Syndrome in the Genomic Era: A SADS-TW BrS Registry.

Front Genet 2018 4;9:680. Epub 2019 Jan 4.

Lankenau Institute for Medical Research, Wynnewood, PA, United States.

Brugada syndrome (BrS) is a heritable disease that results in sudden cardiac death. In the exome/genomic era, certain reported pathogenic variants in some genetic diseases have been reclassified as benign owing to their high frequency in some ancestries. In the present study, we comprehensively reassessed all previously reported pathogenic variants of BrS. We collected all pathogenic variants of BrS reported in the Human Gene Mutation Database and ClinVar throughout April 2017. We compared the minor allele frequency (MAF) of each variant among different ancestries by searching public whole-genome and exome databases. After considering the maximum credible allele frequency, variants with a MAF ≥ 0.001 were considered to be of questionable pathogenicity. We also investigated the percentage of SCN5A variants with a MAF ≥ 0.001 in 124 BrS patients from the Han Chinese population. We collected a total of 440 BrS variants, of which 18 had a MAF ≥ 0.001. There was a greater percentage of non-SCN5A variants with a MAF ≥ 0.001 than of SCN5A variants (21.8 versus 1.6%, < 0.0001). There were fewer frameshift and nonsense mutations than missense mutations (0.9 versus 5.6%, = 0.032). Of the 18 variants, 14 (77.8%) were present only in the reference Asian population. In our cohort, we identified two SCN5A variants (p.A226V and p.V1340I) with MAFs ≥ 0.001 (0.45%). In conclusion, ancestral differences are important when considering the pathogenicity of BrS variants, especially in the case of missense variants and non- variants, which may be pathogenic in some ancestries but only disease-predisposing in others.
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http://dx.doi.org/10.3389/fgene.2018.00680DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6328444PMC
January 2019

Tpeak-Tend interval as a marker of arrhythmic risk.

Heart Rhythm 2019 06 17;16(6):954-955. Epub 2019 Jan 17.

Lankenau Institute for Medical Research, Wynnewood, Pennsylvania.

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http://dx.doi.org/10.1016/j.hrthm.2019.01.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6545252PMC
June 2019

Inferolateral J-wave syndromes: A reflection of abnormal repolarization, depolarization, or both?

Heart Rhythm 2019 05 20;16(5):791-792. Epub 2018 Nov 20.

Lankenau Institute for Medical Research, Wynnewood, Pennsylvania; Lankenau Heart Institute, Wynnewood, Pennsylvania; Sidney Kimmel Medical College of Thomas Jefferson University, Philadelphia, Pennsylvania. Electronic address:

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http://dx.doi.org/10.1016/j.hrthm.2018.11.020DOI Listing
May 2019

Mechanisms Underlying the Actions of Antidepressant and Antipsychotic Drugs That Cause Sudden Cardiac Arrest.

Arrhythm Electrophysiol Rev 2018 Aug;7(3):199-209

Lankenau Institute for Medical Research Wynnewood, PA, USA.

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 patients taking antidepressant and antipsychotic drugs that are in clinical use.
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http://dx.doi.org/10.15420/aer.2018.29.2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6141916PMC
August 2018

Epicardial Substrate as a Target for Radiofrequency Ablation in an Experimental Model of Early Repolarization Syndrome.

Circ Arrhythm Electrophysiol 2018 09;11(9):e006511

Masonic Medical Research Laboratory, Utica, NY (N.Y., B.P., C.A.).

Background: Early repolarization syndrome (ERS) is an inherited cardiac arrhythmia syndrome associated with sudden cardiac death. Approaches to therapy are currently very limited. This study probes the mechanisms underlying the electrocardiographic and arrhythmic manifestation of experimental models of ERS and of the ameliorative effect of radiofrequency ablation.

Methods: Action potentials, bipolar electrograms, and transmural pseudo-ECGs were simultaneously recorded from coronary-perfused canine left ventricular wedge preparations (n=11). The I agonist NS5806 (7-10 μmol/L), calcium channel blocker verapamil (3 μmol/L), and acetylcholine (1-3 μmol/L) were used to pharmacologically mimic the effects of genetic defects associated with ERS.

Results: The provocative agents induced prominent J waves in the ECG secondary to accentuation of the action potential notch in epicardium but not endocardium. Bipolar recordings displayed low-voltage fractionated potentials in epicardium because of temporal and spatial variability in appearance of the action potential dome. Concealed phase 2 reentry developed when action potential dome was lost at some epicardial sites but not others, appearing in the bipolar electrogram as discrete high-frequency spikes. Successful propagation of the phase 2 reentrant beat precipitated ventricular tachycardia/ventricular fibrillation. Radiofrequency ablation of the epicardium destroyed the cells displaying abnormal repolarization and thus suppressed the J waves and the development of ventricular tachycardia/ventricular fibrillation in 6/6 preparations.

Conclusions: Our findings suggest that low-voltage fractionated electrical activity and high-frequency late potentials recorded from the epicardial surface of the left ventricle can identify regions of abnormal repolarization responsible for ventricular tachycardia/ventricular fibrillation in ERS and that radiofrequency ablation of these regions in left ventricular epicardium can suppress ventricular tachycardia/ventricular fibrillation by destroying regions of ER.
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http://dx.doi.org/10.1161/CIRCEP.118.006511DOI Listing
September 2018

Effect of autonomic influences to induce triggered activity in muscular sleeves extending into the coronary sinus of the canine heart and its suppression by ranolazine.

J Cardiovasc Electrophysiol 2019 02 2;30(2):230-238. Epub 2018 Nov 2.

Department of Experimental Cardiology, Masonic Medical Research Laboratory, Utica, New York.

Introduction: Extrasystoles arising from the muscular sleeves associated with the pulmonary veins (PV), superior vena cava (SVC), and coronary sinus (CS) are known to precipitate atrial fibrillation (AF). The late sodium channel current (I ) inhibitor ranolazine has been reported to exert antiarrhythmic effects in canine PV and SVC sleeves by suppressing late phase 3 early and delayed after depolarization (EAD and DAD)-induced triggered activity induced by parasympathetic and/or sympathetic stimulation. The current study was designed to extend our existing knowledge of the electrophysiological and pharmacologic properties of canine CS preparations and assess their response to inhibition of late I following autonomic stimulation.

Methods: Transmembrane action potentials were recorded from canine superfused CS using standard microelectrode techniques. Acetylcholine (ACh, 1 µM), isoproterenol (Iso, 1 µM), high calcium ([Ca ]  = 5.4 mM), or a combination were used to induce EADs, DADs, and triggered activity.

Results: Action potentials (AP) recorded from the CS displayed short and long AP durations (APD), with and without phase 4 depolarization (n = 19). Iso induced DAD-mediated triggered activity. The combination of sympathetic and parasympathetic agonists resulted in late phase 3 EAD-induced triggered activity in all CS preparations. Ranolazine (5-10 µM) suppressed late phase 3 EAD- and DAD-induced triggered activity in 8 of 8 preparations. Subthreshold stimulation induced a prominent hyperpolarization that could be suppressed by atropine.

Conclusions: Our results suggest the important role of parasympathetic innervation in the activity of the CS. Autonomic influences promote DAD- and late phase-3-EAD-mediated triggered activity in canine CS, thus generating extrasystolic activity capable of initiating atrial arrhythmias. Ranolazine effectively suppresses these triggers.
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http://dx.doi.org/10.1111/jce.13770DOI Listing
February 2019

Multiple serial ECGs aid with the diagnosis and prognosis of Brugada syndrome.

Int J Cardiol 2019 Feb 30;277:130-135. Epub 2018 Aug 30.

Lankenau Institute for Medical Research, Wynnewood, PA, United States of America; Lankenau Heart Institute, Main Line Health System, Wynnewood, PA, United States of America; Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, United States of America. Electronic address:

Background: A spontaneous coved-type ST segment elevation in the electrocardiogram (ECG) has long been recognized as a risk stratification tool in patients with Brugada syndrome (BrS). This Type-I ST segment elevation is known to exhibit high dynamicity, fluctuating between coved-type and non-coved ST segment elevation. Our objectives in this study were to: 1) Compare ECG parameters in patients with spontaneous coved-type (Type-I) vs. non-coved-type ST segment ECGs; 2) Determine the variability of these ECG parameters with repeated measurements; and 3) Assess the predictive value of ECG parameters in these two groups during follow-up.

Methods: Forty-two consecutive patients with BrS and implanted ICD were studied between 2000 and 2017. Serial ECGs and clinical characteristics were obtained over a period of 199 months.

Results: QT-interval, QTc-interval, QRS duration, Tp-e interval and Tp-e dispersion were all significantly longer in spontaneous Type I vs. non-Type 1 ECGs and all ECG parameters displayed significant variability during serial recording obtained throughout the follow-up period. Patients with a spontaneous Type I ECG during the 114 ± 56 months follow-up period were at a much higher risk for VT/VF than those without a Type I ECG (p = 0.016). Moreover, the risk for development of life-threatening ventricular arrhythmias was directly related to the fraction of ECGs displaying a spontaneous Type I pattern during follow-up.

Conclusion: Our study illustrates the need for multiple ECGs to aid with both the diagnosis and prognosis of BrS. Serial ECGs can assist with risk stratification based on the fraction of ECGs that display a spontaneous Type-I BrS ECG.
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http://dx.doi.org/10.1016/j.ijcard.2018.08.089DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6340719PMC
February 2019
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