Publications by authors named "Hector Barajas-Martinez"

78 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jacc.2021.08.024DOI Listing
October 2021

p.Glu903Gln Is a Pathogenic Variant Associated With Hypertrophic Cardiomyopathy.

Circ Genom Precis Med 2021 Oct 24;14(5):e003476. Epub 2021 Sep 24.

Instituto Nacional de Cardiologia, Rio de Janeiro, Brazil (G.M.D., M.S., A.C.C.d.C., F.E.S.C.F.).

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/CIRCGEN.121.003476DOI 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/hmg/ddab217DOI Listing
July 2021

Overlap Arrhythmia Syndromes Resulting from Multiple Genetic Variations Studied in Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes.

Int J Mol Sci 2021 Jul 1;22(13). Epub 2021 Jul 1.

Department of Experimental Cardiology, Masonic Medical Research Institute, Utica, NY 13501, USA.

Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are used for genetic models of cardiac diseases. We report an arrhythmia syndrome consisting of Early Repolarization Syndrome (ERS) and Short QT Syndrome (SQTS). The index patient (MMRL1215) developed arrhythmia-mediated syncope after electrocution and was found to carry six mutations. Functional alterations resulting from these mutations were examined in patient-derived hiPSC-CMs. Electrophysiological recordings were made in hiPSC-CMs from MMRL1215 and healthy controls. ECG analysis of the index patient showed slurring of the QRS complex and QTc = 326 ms. Action potential (AP) recordings from MMRL1215 myocytes showed slower spontaneous activity and AP duration was shorter. Field potential recordings from MMRL1215 hiPSC-CMs lack a "pseudo" QRS complex suggesting reduced inward current(s). Voltage clamp analysis of I showed no difference in the magnitude of current. Measurements of I reveal a 60% reduction in I density in MMRL1215 hiPSC-CMs. Steady inactivation and recovery of I was unaffected. mRNA analysis revealed ANK2 and SCN5A are significantly reduced in hiPSC-CM derived from MMRL1215, consistent with electrophysiological recordings. The polygenic cause of ERS/SQTS phenotype is likely due to a loss of I due to a mutation in coupled with and a gain of function in I due to a mutation in .
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms22137108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8268422PMC
July 2021

Clinical characteristics, risk factors, and cardiac manifestations of cancer patients with COVID-19.

J Appl Physiol (1985) 2021 09 8;131(3):966-976. Epub 2021 Jul 8.

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

Coronavirus disease 2019 (COVID-19) due to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has been associated with cardiovascular features, which may be deteriorated in patients with cancer. However, cardiac outcomes of cancer patients with COVID-19 have not been closely examined. We retrospectively assessed 1,244 patients with COVID-19 from February 1 to August 31, 2020 (140 cancer and 1,104 noncancer patients). Demographic and clinical data were obtained and compared between cancer and noncancer groups. Including the cardiac biomarkers, we also analyzed laboratory findings between these two groups. Risk factors for in-hospital mortality were identified by multivariable Cox regression models. For cancer group, 56% were in severe and critical status with more diabetes and immune deficiency, whereas the proportion was 10% for noncancer group. Patients with cancer had increased levels of leukocyte, neutrophil count, and blood urea nitrogen (BUN) (all < 0.01), whereas lymphocyte count was significantly lower ( < 0.001). The most common solid tumor types were gastrointestinal cancer (26%), lung cancer (21%), and breast and reproductive cancer (both 19%). There is a rising for cardiac biomarkers, including pro-B-type natriuretic peptide (Pro-BNP), sensitive troponin I (cTnI), myoglobin (MYO), creatine kinase-MB (CK-MB), as well as D-Dimer in COVID-19 cancer population, especially in deceased subjects with cancer. The 30-day in-hospital mortality in cancer group was dramatically raised than that in noncancer group (12.9% vs. 4.0%, < 0.01). In multivariable Cox regression models, fever, disease severity status, and underlying diseases were risk factors for mortality. COVID-19 patients with cancer relate to deteriorating conditions and poor cardiac outcomes accompanied by a high in-hospital mortality, which warrants more aggressive treatment. Our study indicates that the 30-day mortality is higher in COVID-19 patients with cancer; more COVID-19 patients with cancer are in severe and critical status; age, respiratory rate, neutrophil count, AST, BUN, MYO, Pro-BNP, disease severity status, underlying diseases, and fever are risk factors for in-hospital mortality among COVID-19 cancer cases; COVID-19 patients with cancer display severely impaired myocardium, damaged heart function, and imbalanced homeostasis of coagulation; what is more, those with both cancer and CVD have more significantly increased Pro-BNP and D-Dimer level.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1152/japplphysiol.00325.2021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8422422PMC
September 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.amjcard.2021.04.010DOI Listing
July 2021

Hypertension as a sequela in patients of SARS-CoV-2 infection.

PLoS One 2021 28;16(4):e0250815. Epub 2021 Apr 28.

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

Background: COVID-19 is a respiratory infectious disease caused by SARS-CoV-2, and cardiovascular damage is commonly observed in affected patients. We sought to investigate the effect of SARS-CoV-2 infection on cardiac injury and hypertension during the current coronavirus pandemic.

Study Design And Methods: The clinical data of 366 hospitalized COVID-19-confirmed patients were analyzed. The clinical signs and laboratory findings were extracted from electronic medical records. Two independent, experienced clinicians reviewed and analyzed the data.

Results: Cardiac injury was found in 11.19% (30/268) of enrolled patients. 93.33% (28/30) of cardiac injury cases were in the severe group. The laboratory findings indicated that white blood cells, neutrophils, procalcitonin, C-reactive protein, lactate, and lactic dehydrogenase were positively associated with cardiac injury marker. Compared with healthy controls, the 190 patients without prior hypertension have higher AngⅡ level, of which 16 (8.42%) patients had a rise in blood pressure to the diagnostic criteria of hypertension during hospitalization, with a significantly increased level of the cTnI, procalcitonin, angiotensin-II (AngⅡ) than those normal blood pressure ones. Multivariate analysis indicated that elevated age, cTnI, the history of hypertension, and diabetes were independent predictors for illness severity. The predictive model, based on the four parameters and gender, has a good ability to identify the clinical severity of COVID-19 in hospitalized patients (area under the curve: 0.932, sensitivity: 98.67%, specificity: 75.68%).

Conclusion: Hypertension, sometimes accompanied by elevated cTnI, may occur in COVID-19 patients and become a sequela. Enhancing Ang II signaling, driven by SARS-CoV-2 infection, might play an important role in the renin-angiotensin system, and consequently lead to the development of hypertension in COVID-19.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0250815PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8081193PMC
May 2021

[Haz muscular apicobasal del ventrículo izquierdo, ¿un marcador de miocardiopatía hipertrófica?]

Arch Cardiol Mex 2021 May 7. Epub 2021 May 7.

Department of Cardiovascular Research, Lankenau Institute for Medical Research, Pennsylvania, Wynnewood, EE.UU.

El haz muscular apicobasal (HAB) del ventrículo izquierdo (VI) es un posible marcador morfológico de miocardiopatía hipertrófica (MCH), adicional a otras expresiones fenotípicas asociadas a la enfermedad, como criptas miocárdicas, alteraciones en la válvula mitral, la arquitectura muscular papilar o la morfología ventricular derecha1, además de la propia hipertrofia del VI2. La HAB se extiende desde la región apical a la porción más basal del septum o de la pared anterior.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.24875/ACM.20000423DOI Listing
May 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0242747PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7685455PMC
January 2021

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 .
View Article and Find Full Text PDF

Download full-text PDF

Source
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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41436-020-00946-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7790744PMC
January 2021

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/FJC.0000000000000855DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7416459PMC
August 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ebiom.2020.102723DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7132172PMC
April 2020

Association of the Vascular Endothelial Growth Factor Gene Polymorphism +936 C/T with Diabetic Neuropathy in Patients with Type 2 Diabetes Mellitus.

Arch Med Res 2019 05 6;50(4):181-186. Epub 2019 Sep 6.

Cardiovascular Research, Lankenau Institute for Medical Research, Wynnewood, PA, USA.

Background: Peripheral neuropathy is one of the most common late complications of diabetes. Vascular endothelial growth factor (VEGF) gene polymorphisms have been associated with the development of peripheral neuropathy in different populations of patients with type 2 diabetes mellitus (DM2).

Objective: To analyze the prevalence of the +936 C/T VEGF gene polymorphism among patients with DM2 with and without peripheral neuropathy.

Study Design And Methodology: 218 unrelated DM2 patients, 90 with and 128 without peripheral neuropathy were genotyped for the +936 C/T VEGF gene polymorphism using PCR amplification followed by restriction length polymorphism analysis.

Results: The CC homozygous VEGF+936 C/T (rs3025039) was the predominant genotype in DM2 patients with peripheral neuropathy, whereas the predominant genotype in patients without neuropathy was the heterozygous C/T. No statistical association was found between genotype distribution and the presence of neuropathy (p = 0.063). The distribution of the genotypes according to the dominant (CC vs. CT + TT) and recessive (TT vs. CT + CC) models showed that the homozygous CC and TT genotypes, respectively, are not risk factors for neuropathy. The CT genotype conferred a protective effect as seen in the over-dominant model (CT vs. CC + TT) (OR = 0.52; 95% CI = 0.300-0.90; p = 0.019).

Conclusion: We conclude that the VEGF+936 C/T (rs3025039) gene polymorphisms are related to peripheral neuropathy in Mexican DM2 patients, with the heterozygous genotype potentially conferring a protective effect.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.arcmed.2019.07.012DOI Listing
May 2019

Acquired short QT syndrome in a cancer patient treated with Toad.

Pacing Clin Electrophysiol 2019 09 20;42(9):1273-1275. Epub 2019 May 20.

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

Although drug-induced short QT syndrome (SQTS) has been recognized, we currently report the first acquired SQTS case induced by bufotalinin (toad, an antineoplastic drug), which is a traditional Chinese folk prescription. It has cross reaction with digoxin and affects the Na -K -ATPase, the SR Ca release from ryanodine receptor-2 (RyR2), the reactive oxygen species (ROS) production from the mitochondria. The case presented with bradycardia, extreme QT shortening, and sinoatrial block that were resolved after gastric lavage, rehydration, electrolyte (hyperkalemia, hyponatremia, hypocalcemia) correction, and atropine injection. Clinicians should recognize a potential association between toad poisoning and SQTS from this case.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/pace.13708DOI Listing
September 2019

Meta-Analysis of Risk Stratification of SCN5A With Brugada Syndrome: Is SCN5A Always a Marker of Low Risk?

Front Physiol 2019 19;10:103. Epub 2019 Feb 19.

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

with Brugada syndrome (BrS) is not commonly considered as an independent risk marker for subsequent cardiac events. However, the risk of combined with other clinical characteristics has not been fully investigated. The aim of this study is to investigate and evaluate risk stratification and related risk factors of in BrS. The databases of PubMed, EMBASE, Cochrane Library, MEDLINE, Chinese National Knowledge Infrastructure (CNKI) and Wanfang Data were searched for related studies published from January 2002 to May 2018 followed by meta-analysis. The BrS patients who underwent gene tests were included. The prognosis and risk stratification of combined with symptoms and asymptoms diagnosis in BrS, electrophysiology study (EPS) were then investigated and evaluated. Outcomes were defined as ventricular tachycardia/fibrillation (VT/VF), sudden cardiac death (SCD). Eleven suitable studies involving 1892 BrS patients who underwent gene tests were identified. (+) was not considered to be a significant predictor of future cardiac events (95% CI: 0.89-2.11; = 0.15; = 0%). However, (+) patients with symptoms at diagnosis revealed a higher prevalence of future VT/VF, SCD compared to (-) patients with symptoms at diagnosis. (95% CI: 1.06-3.70; = 0.03 = 0%) Among asymptomatic patients, the risk did not significantly differ between (+) patients and (-) patients. (95% CI: 0.51-4.72; = 0.45 = 0 %). In an investigation involving patients in EPS (-) BrS electrocardiogram (ECG), the risk of (+) is higher than that of (-) ( < 0.001). In BrS patients with symptoms at diagnosis or EPS (-), the meta-analysis suggests that (+) are at a higher risk of arrhythmic events than (-).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fphys.2019.00103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6389868PMC
February 2019

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fphys.2018.01951DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6365464PMC
January 2019

Gender Differences in Prognosis and Risk Stratification of Brugada Syndrome: A Pooled Analysis of 4,140 Patients From 24 Clinical Trials.

Front Physiol 2018 22;9:1127. Epub 2018 Aug 22.

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

Male gender has been consistently shown to be a risk factor for a greater number of arrhythmic events in patients with Brugada Syndrome (BrS). However, there have been no large-scale comprehensive pooled analyses to statistically and systematically verify this association. Therefore, we conducted a pooled analysis on gender differences in prognosis and risk stratification of BrS with a largest sample capacity at present. We searched PubMed, Embase, Medline, Cochrane Library databases, Chinese National Knowledge Infrastructure, and Wanfang Data for relevant studies published from 2002 to 2017. The prognosis and risk stratification of BrS and risk factors were then investigated and evaluated according to gender. Twenty-four eligible studies involving 4,140 patients were included in the analysis. Male patients (78.1%) had a higher risk of arrhythmic events than female patients (95% confidence interval: 1.46-2.91, < 0.0001). Among the male population, there were statistical differences between symptomatic patients and asymptomatic patients (95% CI: 2.63-7.86, < 0.00001), but in the female population, no statistical differences were found. In the female subgroup, electrophysiological study (EPS) positive patients had a tendency toward a higher risk of arrhythmic events than EPS-negative patients (95% CI: 0.93-29.77, = 0.06). Male patients are at a higher risk of arrhythmic events than female patients. Within the male population, symptomatic patients have a significantly higher risk profile compared to asymptomatic patients, but no such differences are evident within the female population. Consequently, in the female population, the risk of asymptomatic patterns cannot be underestimated.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fphys.2018.01127DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6113678PMC
August 2018

A novel three base-pair deletion in domain two of the cardiac sodium channel causes Brugada syndrome.

J Electrocardiol 2018 Jul - Aug;51(4):667-673. Epub 2018 Mar 21.

National Heart Centre Singapore, 5 Hospital Drive, Singapore 169609. Electronic address:

Introduction: Mutations within SCN5A are found in a significant proportion (15-30%) of Brugada syndrome (BrS) cases and impair sodium transport across excitable cardiac cells that mediate ventricular contractions. Genetic testing offers a means to clinically assess and manage affected individuals and their family members.

Methods And Results: The proband at age 44 years old exhibited a syncopal event during exercise, and presented later with a spontaneous type-I BrS pattern on 12‑lead resting electrocardiogram (ECG). Mutational analysis performed across all SCN5A exons revealed a unique three base-pair deletion p.M741_T742delinsI (c.2223_2225delGAC), in a heterozygous state in the proband and 2 siblings. This mutation was not seen in a cohort of 105 ethnicity-matched controls or in public genome databases. Patch clamp electrophysiology study conducted in TSA201 cells showed an abolishment of sodium current (I). The proband, and several relatives, also harboured a known SCN5A variant, p.R1193Q (c.3578G>A).

Conclusion: Our study has demonstrated the deleterious effect of a novel SCN5A mutation p.M741_T742delinsI (c.2223_2225delGAC). The findings highlight the complex effects of gender and age in phenotype manifestation. It also offers insights into improving the long-term management of BrS, and the utility of cascade genetic screening for risk stratification.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jelectrocard.2018.03.009DOI Listing
May 2019

The Phenotypic Spectrum of a Mutation Hotspot Responsible for the Short QT Syndrome.

JACC Clin Electrophysiol 2017 07 1;3(7):727-743. Epub 2017 Feb 1.

Molecular Genetics Department, Masonic Medical Research Laboratory, Utica, New York. Electronic address:

Objectives: This study sought to evaluate the phenotypic and functional expression of an apparent hotspot mutation associated with short QT syndrome (SQTS).

Background: SQTS is a rare channelopathy associated with a high risk of life-threatening arrhythmias and sudden cardiac death (SCD).

Methods: Probands diagnosed with SQTS and their family members were evaluated clinically and genetically. KCNH2 wild-type (WT) and mutant genes were transiently expressed in HEK293 cells, and currents were recorded using whole-cell patch clamp and action potential (AP) clamp techniques.

Results: KCNH2-T618I was identified in 18 members of 7 unrelated families (10 men; median age: 24.0 years). All carriers showed 100% penetrance with variable expressivity. Eighteen members in 7 families had SCD. The average QTc intervals of probands and all carriers was 294.1 ± 23.8 ms and 313.2 ± 23.8 ms, respectively. Seven carriers received an implantable cardioverter-defibrillator. Quinidine with adequate plasma levels was effective in prolonging QTc intervals among 5 cases, but 3 cases still had premature ventricular contraction or nonsustained ventricular tachycardia. Bepridil successfully prevented drug-refractory ventricular fibrillation in 1 case with 19-ms prolongation of the QTc interval. Functional studies with KCNE2 revealed a significant increase of I (rapidly activating delayed rectifier potassium channel) tail-current density in homozygous (119.0%) and heterozygous (74.6%) expression compared with WT. AP clamp recordings showed I was larger, and peak repolarizing current occurred earlier in mutant versus WT channels.

Conclusions: We reported the clinical characteristics and biophysical properties of the highly frequent mutation that contributes to genetically identified SQTS probands. These findings extend our understanding of the spectrum of KCNH2 channel defects in SQTS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jacep.2016.11.013DOI Listing
July 2017

Relation of the Brugada Phenocopy to Hyperkalemia (from the International Registry on Brugada Phenocopy).

Am J Cardiol 2018 03 29;121(6):715-717. Epub 2017 Dec 29.

Department of Medicine, Queen's University, Kingston, Ontario, Canada. Electronic address:

Brugada phenocopies (BrPs) are clinical entities that differ in etiology from true congenital Brugada syndrome but have identical electrocardiographic (ECG) patterns. Hyperkalemia is known to be one of the causes of BrP. The aim of this study was to determine the clinical characteristics and evolution of hyperkalemia-induced BrP. Data from 27 cases of hyperkalemia-induced BrP were collected from the International Registry at www.brugadaphenocopy.com. Data were extracted from publications. Of the 27 patients included in the analysis, 18 (67%) were male; mean age was 53 ± 15 years (range 31 to 89). Mean serum potassium concentration was 7.45 ± 0.89 mmol/L. Type-1 Brugada ECG pattern was observed in 21 cases (78%), whereas 6 cases (22%) showed a type-2 Brugada ECG pattern. The Brugada ECG pattern resolved once the hyperkalemia was corrected, with no arrhythmic events. Estimated time to resolution was 7 ± 3 hours. In 4 cases (16%), a concurrent metabolic abnormality was detected: 3 (11%) presented with acidosis, 2 (7%) with hyponatremia, 1 (4%) with hypocalcaemia, 1 (4%) with hyperphosphatemia, and 1 (4%) with hyperglycemia. In 7 cases (26%), provocative testing using sodium channel blockers was performed, and all failed to reproduce a BrS ECG pattern (BrP class A). Additionally, no sudden cardiac death or malignant ventricular arrhythmias were detected. Hyperkalemia was found a common cause of BrP in our International Registry. The Brugada ECG pattern appears to occur at high serum potassium concentrations (>6.5 mmol/L). The ECG normalizes within hours of correcting the electrolyte imbalance. Importantly, hyperkalemia-induced BrP has not been associated with sudden cardiac death or ventricular arrhythmia.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.amjcard.2017.12.008DOI Listing
March 2018

Prevalence of spontaneous Brugada ECG pattern recorded at standard intercostal leads: A meta-analysis.

Int J Cardiol 2018 03 5;254:151-156. Epub 2017 Dec 5.

Department of Cardiology & Cardiovascular Research Institute, Renmin Hospital of Wuhan University, Wuhan 430060, China; Hubei Key Laboratory of Cardiology, Wuhan 430060, China; Masonic Medical Research Laboratory, Utica, NY 13501, USA. Electronic address:

Objective: Typical Brugada ECG pattern is the keystone in the diagnosis of Brugada syndrome. However, the exact prevalence remains unclear, especially in Asia. The present study was designed to systematically evaluate the prevalence of spontaneous Brugada ECG pattern recorded at standard leads.

Methods: We searched the Medline, Embase and Chinese National Knowledge Infrastructure (CNKI) for studies of the prevalence of Brugada ECG pattern, published between Jan 1, 2003, and September 1, 2016. Pooled prevalence of type 1 and type 2-3 Brugada ECG pattern were estimated in a random-effects model, and group prevalence data by the characteristic of studies. Meta-regression analyses were performed to explore the potential sources of heterogeneity, and sensitivity analyses were conducted to assess the effect of each study on the overall prevalence.

Results: Thirty-nine eligible studies involving 558,689 subjects were identified. Pooled prevalence of type 1 and 2-3 Brugada ECG pattern was 0.03% (95%CI, 0.01%-0.06%), and 0.42% (95%CI, 0.28%-0.59%), respectively. Regions, sample size, year of publication were the main source of heterogeneity. The prevalence of type 1 Brugada ECG pattern was higher in male, Asia, adult, patient, and fever subjects; but the relation between fever and type 2-3 Brugada ECG pattern was not significant. Sensitivity analysis showed that each study did not lonely affect the prevalence of type 1 and type 2-3 Brugada ECG pattern.

Conclusion: Brugada ECG pattern is not rare, especially preponderant in adult Asian males, and fever subjects. Clinical screening and further examination of Brugada syndrome in potential population need to be highlighted.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ijcard.2017.11.113DOI Listing
March 2018

T Wave Safety Margin during the Process of ICD Implantation As a Novel Predictor of T Wave Oversensing.

Front Physiol 2017 1;8:659. Epub 2017 Sep 1.

Masonic Medical Research LaboratoryUtica, NY, United States.

T wave oversensing (TWOS) is a major drawback of implantable cardioverter defibrillator (ICD) and data on predictors of TWOS in ICD is limited. We aimed to calculate a novel index of T wave safety margin (TWSM) and assess its potential for evaluating TWOS during the procedure of ICD implantation. Thirty-two consecutive patients with ICD implantation were enrolled. During each procedure of ICD implantation, different ICD generators were connected to implanted sensing lead through active-fixation leads and bridging cables. R and T wave amplitudes were measured on ICD printouts according to the gain. The ICDs were programed to the most sensitive settings to reveal possible TWOS. A novel index TWSM was calculated according to the corresponding sensing algorithm of ICD. There was discrepancy of R wave amplitudes measured by different ICDs ( < 0.01). In Fortify and Teligen ICDs, T wave amplitudes showed no difference ( > 0.05) and TWSMs were sufficiently high (post sensing: 13.0 ± 7.6 and 28.3 ± 16.5, respectively, post pacing: 5.0 ± 2.2 and 4.6 ± 0.9, respectively). In nine patients with 10 TWOS episodes detected during the procedure of ICD implantation, generators with the highest TWSM were chosen. Only one TWOS episode during pacing was recorded during the 25 ± 7 mo follow-up period. We first propose the index of TWSM during ICD implantation as a potentially efficient predictor for TWOS. Evaluation of TWSM might help to reduce TWOS episodes in patients with high risk of TWOS. Prospective studies are warranted to validate this index and its potential to reduce TWOS episodes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fphys.2017.00659DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5585188PMC
September 2017

Comparative Effectiveness of Acupuncture and Antiarrhythmic Drugs for the Prevention of Cardiac Arrhythmias: A Systematic Review and Meta-analysis of Randomized Controlled Trials.

Front Physiol 2017 8;8:358. Epub 2017 Jun 8.

Masonic Medical Research LaboratoryNew York, NY, United States.

This study was designed to systematically evaluate the effectiveness of acupuncture treatment for arrhythmia compared to existing drug therapy. Randomized controlled trials (RCTs) were identified through searches of the MEDLINE, CNKI, Embase, and Cochrane databases (1970 through 2016) and hand searches of cross-references from original articles and reviews. Clinical trials that randomized arrhythmia patients to acupuncture therapy vs. conventional drugs, sham acupuncture, or bed rest were included for analysis. A total of 13 trials with 797 patients met the criteria for analysis. The results of the meta-analysis showed no statistically significant difference between acupuncture and conventional treatment for paroxysmal supraventricular tachycardia (PSVT) ( = 203; RR, 1.18; 95% CI 0.78-1.79; = 80%; = 0.44). However, in the ventricular premature beat (VPB) group, it showed a significant benefit of acupuncture plus oral administration of anti-arrhythmic drug (AAD) on response rates compared with the oral administration of AAD ( = 286; RR, 1.15; 95% CI 1.05-1.27; = 0%; = 0.002). Finally, when compared with the sinus tachycardia (ST) cases without any treatment, acupuncture has benefited these patients ( = 120; MD, 18.80, 95% CI 12.68-24.92; = 81%; < 0.00001). In summary, our meta-analysis demonstrates that clinical efficacy of acupuncture is not less than AAD for PSVT. Furthermore, in sub-group analysis, acupuncture with or without AAD, shows a clear benefit in treating VPB and ST. However, more definitive RCTs are warranted to guide clinical practice.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fphys.2017.00358DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5463903PMC
June 2017

Genetic Polymorphisms Associated With Increased Defibrillator Shocks in Brugada Syndrome.

J Am Heart Assoc 2017 Jun 5;6(6). Epub 2017 Jun 5.

Department of Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand

Background: Brugada syndrome (BrS) is an inherited primary arrhythmia disorder leading to sudden cardiac arrest. , encoding the α-subunit of the cardiac sodium channel (Nav1.5), is the most common pathogenic gene of BrS. An implantable cardioverter defibrillator (ICD) is the standard treatment for secondary prevention. This study aimed to evaluate association of the variant with this cardiac conduction disturbance and appropriate ICD shock therapy in Thai symptomatic BrS patients with ICD implants.

Methods And Results: Symptomatic BrS patients diagnosed at university hospital were enrolled from 2008 to 2011. The primary outcome of the study was an appropriate ICD shock defined as having non-pacing-associated ICD shock after the occurrence of ventricular tachycardia or ventricular fibrillation. Associations between polymorphisms, cardiac conduction disturbance, and potential confounding factors associated with appropriate ICD shock therapy were analyzed. All 40 symptomatic BrS patients (median age, 43 years) with ICD implantations were followed for 24 months. There were 16 patients (40%) who had the appropriate ICD shock therapy after ICD treatment. An independent factor associated with appropriate ICD shock therapy was R1193Q with an adjusted hazard ratio of 10.550 (95% CI, 1.631-68.232).

Conclusions: R1193Q is associated with cardiac conduction disturbances. It may be a genetic marker associated with ventricular arrhythmia leading to appropriate ICD shock therapy in symptomatic BrS patients with ICD treatment. Because of the small sample size of study population and the appropriate ICD shock outcome, further large studies are needed to confirm the results of this study.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/JAHA.116.005009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5669154PMC
June 2017
-->