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Wataru Shimizu, Hisaki Makimoto, Kenichiro Yamagata, Tsukasa Kamakura, Mitsuru Wada, Koji Miyamoto, Yuko Inoue-Yamada, Hideo Okamura, Kohei Ishibashi, Takashi Noda, Satoshi Nagase, Aya Miyazaki, Heima Sakaguchi, Isao Shiraishi, Takeru Makiyama, Seiko Ohno, Hideki Itoh, Hiroshi Watanabe, Kenshi Hayashi, Masakazu Yamagishi, Hiroshi Morita, Masao Yoshinaga, Yoshiyasu Aizawa, Kengo Kusano, Yoshihiro Miyamoto, Shiro Kamakura, Satoshi Yasuda, Hisao Ogawa, Toshihiro Tanaka, Naotaka Sumitomo, Nobuhisa Hagiwara, Keiichi Fukuda, Satoshi Ogawa, Yoshifusa Aizawa, Naomasa Makita, Tohru Ohe, Minoru Horie, Takeshi Aiba
Importance: Long QT syndrome (LQTS) is caused by several ion channel genes, yet risk of arrhythmic events is not determined solely by the responsible gene pathogenic variants. Female sex after adolescence is associated with a higher risk of arrhythmic events in individuals with congenital LQTS, but the association between sex and genotype-based risk of LQTS is still unclear. Objective: To examine the association between sex and location of the LQTS-related pathogenic variant as it pertains to the risk of life-threatening arrhythmias...
February 13, 2019: JAMA Cardiology
Brett M Kroncke, Tao Yang, Dan M Roden
BACKGROUND: We recently reported a quantitative relationship between the degree of functional perturbation reported in the literature for 356 variants in the cardiac sodium channel gene SCN5A and the penetrance of resulting arrhythmia phenotypes. In the course of that work, we identified multiple SCN5A variants, including R1193Q, that are common in populations but are reported in HEK cells to generate large late sodium current (lNa-L ). OBJECTIVE: To compare the functional properties of R1193Q to those of the well-studied LQT3 mutation ΔKPQ...
January 21, 2019: Heart Rhythm: the Official Journal of the Heart Rhythm Society
Julio Alvarez-Collazo, Alejandro López-Requena, Loipa Galán, Ariel Talavera, Julio L Alvarez, Karel Talavera
BACKGROUND AND PURPOSE: The citrus flavanone hesperetin (HSP) has been proposed for the treatment of several human pathologies, but its cardiovascular actions remain largely unexplored. Here we evaluated HSP effects on cardiac electrical and contractile activities, on aortic contraction, on the wild type voltage-gated Na+ channel NaV 1.5 and on a channel mutant (R1623Q) associated with lethal ventricular arrhythmias in the Long QT syndrome subtype 3 (LQT3). EXPERIMENTAL APPROACH: We used cardiac surface electrocardiogram and contraction force recordings to evaluate HSP effects in isolated rat hearts and aortic rings...
January 16, 2019: British Journal of Pharmacology
Arja Suzanne Vink, Benjamin Neumann, Krystien V V Lieve, Moritz F Sinner, Nynke Hofman, Soufiane El Kadi, Melissa H A Schoenmaker, Hanneke M J Slaghekke, Jonas S S G de Jong, Sally-Ann B Clur, Nico A Blom, Stefan Kääb, Arthur A M Wilde, Pieter G Postema
BACKGROUND: Long QT syndrome (LQTS) is associated with potentially fatal arrhythmias. Treatment is very effective, but its diagnosis may be challenging. Importantly, different methods are used to assess the QT interval, which makes its recognition difficult. QT experts advocate manual measurements with the tangent or threshold method. However, differences between these methods and their performance in LQTS diagnosis have not been established. We aimed to assess similarities and differences between these 2 methods for QT interval analysis to aid in accurate QT assessment for LQTS...
November 20, 2018: Circulation
Wandi Zhu, Andrea Mazzanti, Taylor Voelker, Panpan Hou, Jonathan D Moreno, Paweorn Angsutararux, Kristen M Naegle, Silvia G Priori, Jonathan R Silva
RATIONALE: Mutations in the SCN5A gene, encoding the α subunit of the Nav1.5 channel, cause a life-threatening form of cardiac arrhythmia, Long QT Syndrome Type 3 (LQT3). Mexiletine, which is structurally related to the Na+ channel-blocking anesthetic lidocaine, is used to treat LQT3 patients. However, the patient response is variable, depending on the genetic mutation in SCN5A. OBJECTIVE: The goal of this study is to understand the molecular basis of patients' variable responses and build a predictive statistical model that can be utilized to personalize mexiletine treatment based on patient's genetic variant...
December 18, 2018: Circulation Research
Gerrit Frommeyer, Jan Weller, Christian Ellermann, Patrick Leitz, Simon Kochhäuser, Philipp S Lange, Dirk G Dechering, Lars Eckardt
Ivabradine has recently been demonstrated to have antiarrhythmic properties in atrial fibrillation. The aim of the present study was to assess the electrophysiologic profile of ivabradine in an experimental whole-heart model of long-QT-syndrome. In 12 isolated rabbit hearts long-QT-2-syndrome (LQT2) was simulated by infusion of D,L-sotalol (100 µM). 12 rabbit hearts were treated with veratridine (0.5 µM) to mimic long-QT-3-syndrome (LQT3). Sotalol induced a significant prolongation of QT-interval (+ 40 ms, p < 0...
September 20, 2018: Cardiovascular Toxicology
Alan Sugrue, Ram K Rohatgi, Martijn Bos, Vaibhav R Vaidya, Samuel J Asirvatham, Peter A Noseworthy, Michael J Ackerman
OBJECTIVES: This study sought to determine the prevalence of early repolarization pattern (ERP) within a large cohort of patients with long QT syndrome (LQTS) and examine the correlation and clinical significance of ERP with symptomatic status and subsequent risk of breakthrough cardiac events (BCEs). BACKGROUND: The electrocardiographic ERP is associated with an increased risk of arrhythmic events and sudden cardiac death. METHODS: ERP was defined as an end-QRS notch or slur on the downslope of a prominent R-wave with a J point ≥0...
September 2018: JACC. Clinical Electrophysiology
Ronald Wilders, Arie O Verkerk
Congenital long-QT syndrome (LQTS) is an inherited cardiac disorder characterized by the prolongation of ventricular repolarization, susceptibility to Torsades de Pointes (TdP), and a risk for sudden death. Various types of congenital LQTS exist, all due to specific defects in ion channel-related genes. Interestingly, almost all of the ion channels affected by the various types of LQTS gene mutations are also expressed in the human sinoatrial node (SAN). It is therefore not surprising that LQTS is frequently associated with a change in basal heart rate (HR)...
2018: Frontiers in Cardiovascular Medicine
Ankavipar Saprungruang, Apichai Khongphatthanayothin, John Mauleekoonphairoj, Pharawee Wandee, Supaluck Kanjanauthai, Zahurul A Bhuiyan, Arthur A M Wilde, Yong Poovorawan
BACKGROUND: Congenital long QT syndrome (LQTS) is an inheritable arrhythmic disorder which is linked to at least 17 genes. The clinical characteristics and genetic mutations may be variable among different population groups and they have not yet been studied in Thai population. METHODS: Clinical characteristics were retrospectively reviewed from children and young adults with congenital long QT syndrome whose blood samples were sent for genotyping during 1998-2017...
September 2018: Indian Pacing and Electrophysiology Journal
Rou-Mu Hu, David J Tester, Ryan Li, Tianyu Sun, Blaise Z Peterson, Michael J Ackerman, Jonathan C Makielski, Bi-Hua Tan
INTRODUCTION: Individual mutations in the SCN5A-encoding cardiac sodium channel α-subunit usually cause a single cardiac arrhythmia disorder, some cause mixed biophysical or clinical phenotypes. Here we report an infant, female patient harboring a N406K mutation in SCN5A with a marked and mixed biophysical phenotype and assess pathogenic mechanisms. METHODS AND RESULTS: A patient suffered from recurrent seizures during sleep and torsades de pointes with a QTc of 530 ms...
2018: Channels
Jie Liu, Jason D Bayer, Roozbeh Aschar-Sobbi, Marianne Wauchop, Danna Spears, Michael Gollob, Edward J Vigmond, Robert Tsushima, Peter H Backx, Vijay S Chauhan
BACKGROUND: The SCN5A mutation, P1332L, is linked to a malignant form of congenital long QT syndrome, type 3 (LQT3), and affected patients are highly responsive to the Na+ channel blocking drug, mexiletine. In contrast, A647D is an atypical SCN5A mutation causing Brugada syndrome. An asymptomatic male with both P1332L and A647D presented with varying P wave/QRS aberrancy and mild QTc prolongation which did not shorten measurably with mexiletine. OBJECTIVE: We characterized the biophysical properties of P1332L, A647D and wild-type (WT) Na+ channels as well as their combinations in order to understand our proband's phenotype and to guide mexilitine therapy...
2018: PloS One
Mathilde R Rivaud, Antonius Baartscheer, Arie O Verkerk, Leander Beekman, Sridharan Rajamani, Luiz Belardinelli, Connie R Bezzina, Carol Ann Remme
BACKGROUND: Long QT syndrome mutations in the SCN5A gene are associated with an enhanced late sodium current (INa,L ) which may lead to pro-arrhythmic action potential prolongation and intracellular calcium dysregulation. We here investigated the dynamic relation between INa,L , intracellular sodium ([Na+ ]i ) and calcium ([Ca2+ ]i ) homeostasis and pro-arrhythmic events in the setting of a SCN5A mutation. METHODS AND RESULTS: Wild-type (WT) and Scn5a1798insD/+ (MUT) mice (age 3-5 months) carrying the murine homolog of the SCN5A-1795insD mutation on two distinct genetic backgrounds (FVB/N and 129P2) were studied...
July 15, 2018: International Journal of Cardiology
Conor M Lane, J Martijn Bos, Ram K Rohatgi, Michael J Ackerman
BACKGROUND: Little is known about the spectrum and prevalence of ECG features beyond the length and morphology of repolarization in patients with congenital long QT syndrome (LQTS). OBJECTIVE: The purpose of this study was to characterize the full ECG phenotype of LQTS patients and evaluate differences by age and LQTS genotype. METHODS: Retrospective review of 943 patients with LQTS (57% female; median age 25 years; interquartile range 9-34 years) was performed...
September 2018: Heart Rhythm: the Official Journal of the Heart Rhythm Society
Andrea Mazzanti, Riccardo Maragna, Gaetano Vacanti, Nicola Monteforte, Raffaella Bloise, Maira Marino, Lorenzo Braghieri, Patrick Gambelli, Mirella Memmi, Eleonora Pagan, Massimo Morini, Alberto Malovini, Martin Ortiz, Luciana Sacilotto, Riccardo Bellazzi, Lorenzo Monserrat, Carlo Napolitano, Vincenzo Bagnardi, Silvia G Priori
BACKGROUND: Long QT syndrome (LQTS) is a common inheritable arrhythmogenic disorder, often secondary to mutations in the KCNQ1, KCNH2, and SCN5A genes. The disease is characterized by a prolonged ventricular repolarization (QTc interval) that confers susceptibility to life-threatening arrhythmic events (LAEs). OBJECTIVES: This study sought to create an evidence-based risk stratification scheme to personalize the quantification of the arrhythmic risk in patients with LQTS...
April 17, 2018: Journal of the American College of Cardiology
Valentina Kutyifa, Usama A Daimee, Scott McNitt, Bronislava Polonsky, Charles Lowenstein, Kris Cutter, Coeli Lopes, Wojciech Zareba, Arthur J Moss
BACKGROUND: A comprehensive report on the clinical course of the three major genotypes of the long QT syndrome (LQTS) in a large U.S. patient cohort is lacking. METHODS: Our study consisted of 1,923 U.S. subjects from the Rochester-based LQTS Registry with genotype-positive LQT1 (n = 879), LQT2 (n = 807), and LQT3 (n = 237). We evaluated the risk of a first cardiac event (syncope, aborted cardiac arrest, or sudden cardiac death, whichever occurred first) from birth through age 50 years...
May 2018: Annals of Noninvasive Electrocardiology
Mena Abdelsayed, Manpreet Ruprai, Peter C Ruben
E1784K is the most common mixed syndrome SCN5a mutation underpinning both Brugada syndrome type 1 (BrS1) and Long-QT syndrome type 3 (LQT3). The charge reversal mutant enhances the late sodium current (INa ) passed by the cardiac voltage-gated sodium channel (NaV 1.5), delaying cardiac repolarization. Exercise-induced triggers, like elevated temperature and cytosolic calcium, exacerbate E1784K late INa . In this study, we tested the effects of Ranolazine, the late INa blocker, on voltage-dependent and kinetic properties of E1784K at elevated temperature and cytosolic calcium...
February 26, 2018: Scientific Reports
Andrés Ricardo Pérez-Riera, Raimundo Barbosa-Barros, Rodrigo Daminello Raimundo, Marianne Penachini da Costa de Rezende Barbosa, Isabel Cristina Esposito Sorpreso, Luiz Carlos de Abreu
Congenital long QT syndrome type 3 (LQT3) is the third in frequency compared to the 15 forms known currently of congenital long QT syndrome (LQTS). Cardiac events are less frequent in LQT3 when compared with LQT1 and LQT2, but more likely to be lethal; the likelihood of dying during a cardiac event is 20% in families with an LQT3 mutation and 4% with either an LQT1 or an LQT2 mutation. LQT3 is consequence of mutation of gene SCN5A which codes for the Nav1.5 Na+ channel α-subunit and electrocardiographically characterized by a tendency to bradycardia related to age, prolonged QT/QTc interval (mean QTc value 478 ± 52 ms), accentuated QT dispersion consequence of prolonged ST segment, late onset of T wave and frequent prominent U wave because of longer repolarization of the M cell across left ventricular wall...
January 2018: Indian Pacing and Electrophysiology Journal
Jinhee Ahn, Hyun Jung Kim, Jong-Il Choi, Kwang No Lee, Jaemin Shim, Hyeong Sik Ahn, Young-Hoon Kim
BACKGROUND: Beta-blockers are first-line therapy in patients with congenital long-QT syndrome (LQTS). OBJECTIVE: This study sought to determine the differences in effectiveness of beta-blockers on risk reduction according to LQTS genotype. METHODS: We searched MEDLINE, EMBASE, and CENTRAL databases to investigate the use of beta-blockers (atenolol, nadolol, propranolol, and metoprolol) in patients with LQTS. Hazard ratio (HR) and relative risk (RR) were extracted or calculated from studies reporting cardiac events (syncope, aborted cardiac arrest (ACA), or sudden cardiac death (SCD))...
2017: PloS One
Nesrine El-Bizri, Cheng Xie, Lynda Liu, James Limberis, Michael Krause, Ryoko Hirakawa, Steven Nguyen, Dennis R Tabuena, Luiz Belardinelli, Kristopher M Kahlig
BACKGROUND: Eleclazine (GS-6615) is a sodium channel blocker designed to improve the selectivity for cardiac late Na+ current (INa ) over peak INa . OBJECTIVES: The goals of this study were to investigate the inhibition of late INa by eleclazine using a sample of long QT syndrome type 3 (LQT3) and overlap LQT3/Brugada syndrome mutant channels; to compare the apparent binding rates for eleclazine with those for other class 1 antiarrhythmic agents; and to investigate the binding site...
February 2018: Heart Rhythm: the Official Journal of the Heart Rhythm Society
Wojciech Zareba, Scott McNitt, Slava Polonsky, Jean-Philippe Couderc
The JTp interval gained interest as a marker differentiating effects of drugs on cardiac ion channels. For JTp interval, both the beginning - identification of J point and identification of T wave end remains the subject of substantial variability. We aimed to analyze diagnostic and prognostic performance of JTp interval in the International LQTS Registry data. ECGs from 804 gene carriers and 1139 non-carriers from LQT1 families, 735 carriers and 1145 non-carriers from LQT2 families, and 238 carriers and 554 non-carriers from LQT3 families were evaluated...
November 2017: Journal of Electrocardiology
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