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Hui Huang, Georg Kuenze, Jarrod A Smith, Keenan C Taylor, Amanda M Duran, Arina Hadziselimovic, Jens Meiler, Carlos G Vanoye, Alfred L George, Charles R Sanders
Mutations that induce loss of function (LOF) or dysfunction of the human KCNQ1 channel are responsible for susceptibility to a life-threatening heart rhythm disorder, the congenital long QT syndrome (LQTS). Hundreds of KCNQ1 mutations have been identified, but the molecular mechanisms responsible for impaired function are poorly understood. We investigated the impact of 51 KCNQ1 variants with mutations located within the voltage sensor domain (VSD), with an emphasis on elucidating effects on cell surface expression, protein folding, and structure...
March 2018: Science Advances
Diana João Fonseca, Manuel Joaquim Vaz da Silva
INTRODUCTION AND OBJECTIVES: The importance of sodium channels for the normal electrical activity of the heart is emphasized by the fact that mutations (inherited or de novo) in genes that encode for these channels or their associated proteins cause arrhythmogenic syndromes such as the Brugada syndrome and the long QT syndrome (LQTS). The aim of this study is to conduct a review of the literature on the mutations in the sodium channel complex responsible for heart disease and the implications of a close relationship between genetics and the clinical aspects of the main cardiac channelopathies, namely at the level of diagnosis, risk stratification, prognosis, screening of family members and treatment...
March 7, 2018: Portuguese Journal of Cardiology: An Official Journal of the Portuguese Society of Cardiology
Timothy L Surman, Robert G Stuklis, Justin C Chan
BACKGROUND: Multiple case studies have suggested that video-assisted thoracoscopic sympathectomy (VATS) reduces the occurrence and frequency of symptoms in long QT syndrome (LQTS) [1,2,3]. To date there has not been a literature review to report on the short-term and long-term outcomes of this procedure. Our primary aims are to review the literature findings on the clinical outcomes of VATS sympathectomy for long QT and present a local centre case report on the outcomes of T2-T5 sympathectomy...
February 13, 2018: Heart, Lung & Circulation
Valentina Kutyifa, Usama 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...
March 5, 2018: Annals of Noninvasive Electrocardiology
Andrew P Landstrom, Ernesto Fernandez, Jill A Rosenfeld, Yaping Yang, Andrew L Dailey-Schwartz, Christina Y Miyake, Hugh D Allen, Daniel J Penny, Jeffrey J Kim
BACKGROUND: Due to rapid expansion of clinical genetic testing, an increasing number of genetic variants of undetermined significance are being identified in children with unclear diagnostic value. Variants found in genes associated with heritable channelopathies, such as long QT syndrome (LQTS), are particularly difficult to interpret given the risk of sudden cardiac death associated with pathologic mutations. OBJECTIVE: To determine whether variants in LQTS-associated genes from whole exome sequencing (WES) represent disease-associated biomarkers or background genetic "noise...
March 1, 2018: Heart Rhythm: the Official Journal of the Heart Rhythm Society
Cecilia Villa Etchegoyen, Guillermo Alberto Keller, Sebastian Mrad, Sixuan Cheng, Guillermo DiGirolamo
Drug-induced QT interval prolongation is the most frequent cause of Long QT syndrome (LQTS) in the clinical practice. This electrophysiological entity, produced by an extended duration of the myocardial repolarization and reflected as a prolonged QT interval in the superficial electrocardiogram (EKG), increases the risk of polymorphic ventricular tachycardia (Torsades de Pointes) appearance and sudden death. Certain antiarrhythmic drugs such as amiodarone, sotalol, quinidine, procainamide, verapamil and diltiazem are known as drugs that, due to their mechanism of action, prolong the QT interval, demanding constant monitorization...
February 23, 2018: Current Clinical Pharmacology
Jie Wu, Yuka Mizusawa, Seiko Ohno, Wei-Guang Ding, Takashi Higaki, Qi Wang, Hirohiko Kohjitani, Takeru Makiyama, Hideki Itoh, Futoshi Toyoda, Andrew F James, Jules C Hancox, Hiroshi Matsuura, Minoru Horie
Congenital long QT syndrome (LQTS) caused by compound mutations is usually associated with more severe clinical phenotypes. We identified a LQTS family harboring three compound mutations in different genes (KCNQ1-R174C, hERG-E1039X and SCN5A-E428K). KCNQ1-R174C, hERG-E1039X and SCN5A-E428K mutations and/or relevant wild-type (WT) cDNAs were respectively expressed in mammalian cells. I Ks -like, I Kr -like, I Na -like currents and the functional interaction between KCNQ1-R174C and hERG-E1039X channels were studied using patch-clamp and immunocytochemistry techniques...
February 15, 2018: Scientific Reports
Horia Jalily Hasani, Aravindhan Ganesan, Marawan Ahmed, Khaled H Barakat
The voltage-gated KCNQ1 potassium ion channel interacts with the type I transmembrane protein minK (KCNE1) to generate the slow delayed rectifier (IKs) current in the heart. Mutations in these transmembrane proteins have been linked with several heart-related issues, including long QT syndromes (LQTS), congenital atrial fibrillation, and short QT syndrome. Off-target interactions of several drugs with that of KCNQ1/KCNE1 ion channel complex have been known to cause fatal cardiac irregularities. Thus, KCNQ1/KCNE1 remains an important avenue for drug-design and discovery research...
2018: PloS One
Noriaki Yagi, Hideki Itoh, Takashi Hisamatsu, Yukinori Tomita, Hiromi Kimura, Yusuke Fujii, Takeru Makiyama, Minoru Horie, Seiko Ohno
BACKGROUND: The relationship between mutation locations in KCNQ1 which is a major gene in long QT syndrome (LQTS) and phenotype has been analyzed and used for risk stratification. Mutations in the transmembrane region (TM) or cytoplasmic-loop (C-loop) are associated with more frequent cardiac events than those in other regions. However, accumulation of LQTS type 1 (LQT1) patients poses the question of whether the location specific risk stratification is really effective. METHODS: The study cohort consisted of 67 KCNQ1 mutation carriers and 13 family members who were suspected as having LQTS due to sudden cardiac death or syncope from 36 unrelated families...
February 10, 2018: Journal of Cardiology
Kazuaki Miyata, Seiko Ohno, Hideki Itoh, Minoru Horie
Background Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a lethal inherited disease characterized by ventricular arrhythmias induced by physical exercise or emotional stress. The major cause of CPVT is mutations in RYR2, which encodes the cardiac ryanodine receptor channel. Recent advances in sequencing technology have yielded incidental findings of RYR2 variants in other cardiac diseases. Analyzing the characteristics of RYR2 variants related to CPVT will be useful for differentiation from those related to other cardiac diseases...
February 9, 2018: Internal Medicine
Sam Chai, Xiaoping Wan, Angelina Ramirez-Navarro, Paul J Tesar, Elizabeth S Kaufman, Eckhard Ficker, Alfred L George, Isabelle Deschênes
Congenital long QT syndrome (LQTS) is an inherited channelopathy associated with life-threatening arrhythmias. LQTS type 2 (LQT2) is caused by mutations in KCNH2, which encodes the potassium channel hERG. We hypothesized that modifier genes are partly responsible for the variable phenotype severity observed in some LQT2 families. Here, we identified contributors to variable expressivity in an LQT2 family by using induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) and whole exome sequencing in a synergistic manner...
February 12, 2018: Journal of Clinical Investigation
Nobuhiro Takasugi, Mieko Takasugi, Hiroko Goto, Takashi Kuwahara, Takashi Nakashima, Tomoki Kubota, Hiromitsu Kanamori, Masanori Kawasaki, Kazuhiko Nishigaki, Shinya Minatoguchi, Richard L Verrier
BACKGROUND: In patients with long QT syndrome (LQTS), a sudden increase in heart rate can cause T-wave alternans (TWA) with beat-to-beat alternating polarity of T wave. We hypothesized that LQTS patients at a high risk of Torsade de Pointes (TdP) may exhibit momentary atrial or sinoatrial premature beat-induced T-wave inversion (APB-TWI). OBJECTIVE: To assess the association of APB-TWI with TdP history and with microvolt TWA. METHODS: 24-h continuous 12-lead electrocardiograms (ECGs) were recorded in 18 healthy subjects and 39 consecutive patients with LQTS types 1 (n=21), 2 (n=4), 3 (n=4), and unidentified (n=10)...
February 7, 2018: Heart Rhythm: the Official Journal of the Heart Rhythm Society
James Winter, Michael Tipton, Michael J Shattock
This study tested the hypothesis that concomitant sympathetic and parasympathetic stimulation ("autonomic conflict") may act as a trigger for arrhythmia in long QT syndrome (LQTS). Studies were performed in isolated innervated rabbit hearts treated with clofilium (100 nmol/L); a potassium channel blocker. The influence of vagus nerve stimulation (VNS) on spontaneous ventricular arrhythmia was assessed in the absence/presence of sustained noradrenaline perfusion (100 nmol/L) and with sudden adrenergic stress (injections of noradrenaline into the perfusion line)...
February 2, 2018: Journal of Molecular and Cellular Cardiology
Nabil El-Sherif, Gioia Turitto, Mohamed Boutjdir
Since its initial description by Jervell and Lange-Nielsen in 19571 , the congenital long QT syndrome (LQTS) has been the most investigated cardiac ion channelopathy. Although congenital LQTS continues to remain the domain of cardiologists, cardiac electrophysiologists, and specialized centers, the by far more frequent acquired drug-induced LQTS is the domain of all physicians and other members of the health care team who are required to make therapeutic decisions. This report will review the electrophysiological mechanisms of LQTS and TdP, electrocardiographic (ECG) characteristics of acquired LQTS, its clinical presentation, management, and future directions in the field...
February 6, 2018: Pacing and Clinical Electrophysiology: PACE
Christian Ellermann, Magdalena Sterneberg, Simon Kochhäuser, Dirk G Dechering, Michael Fehr, Lars Eckardt, Gerrit Frommeyer
Aims: Antazoline is a first-generation antihistamine with antiarrhythmic properties. This study examines potential electrophysiological effects of antazoline in short-QT-syndrome (SQTS) and long-QT-syndrome (LQTS). Methods and results: Sixty-five rabbit hearts were Langendorff-perfused. Action potential duration at 90% of repolarization (APD90), QT-interval, spatial dispersion (DISP), and effective refractory period (ERP) were measured. The IK, ATP-opener pinacidil (1 µM, n = 14) reduced APD90 (-14 ms, P < 0...
January 25, 2018: Europace: European Pacing, Arrhythmias, and Cardiac Electrophysiology
Yanan Jiang, Weijie Du, Qun Chu, Ying Qin, Gulnara Tuguzbaeva, Hui Wang, Anqi Li, Guiyang Li, Yanyao Li, Lu Chai, Er Yue, Xi Sun, Zhiguo Wang, Valentin Pavlov, Baofeng Yang, Yunlong Bai
BACKGROUND/AIMS: Arsenic trioxide (ATO) is a known anti-acute promyelocytic leukemia (APL) reagent, whose clinical applications are limited by its serious cardiac toxicity and fatal adverse effects, such as sudden cardiac death resulting from long QT syndrome (LQTS). The mechanisms of cardiac arrhythmia due to ATO exposure still need to be elucidated. Long non-coding RNAs (lncRNAs) are emerging as major regulators of various pathophysiological processes. This study aimed to explore the involvement of lncRNAs in ATO-induced LQTS in vivo and in vitro...
January 15, 2018: Cellular Physiology and Biochemistry
Valentine Sergeev, Frances Perry, Thomas M Roston, Shubhayan Sanatani, Glen F Tibbits, Thomas W Claydon
Long QT syndrome (LQTS) is the most common cardiac ion channelopathy and has been found to be responsible for approximately 10% of sudden infant death syndrome (SIDS) cases. Despite increasing use of broad panels and now whole exome sequencing (WES) in the investigation of SIDS, the probability of identifying a pathogenic mutation in a SIDS victim is low. We report a family-based study who are afflicted by recurrent SIDS in which several members harbor a variant, p.Pro963Thr, in the C-terminal region of the human-ether-a-go-go (hERG) gene, published to be responsible for cases of LQTS type 2...
December 20, 2017: Forensic Science International
Gerrit Frommeyer, Julius Krawczyk, Christian Ellermann, Nils Bögeholz, Simon Kochhäuser, Dirk G Dechering, Michael Fehr, Lars Eckardt
AIMS: A significant antiarrhythmic potential of ryanodine receptor inhibition was reported in experimental studies. The aim of the present study was to assess potential antiarrhythmic effects of dantrolene in an experimental whole-heart model of drug-induced long-QT syndrome (LQTS). METHODS: In 12 isolated rabbit hearts long-QT-2-syndrome was simulated by infusion of erythromycin (300μM). 12 rabbit hearts were treated with veratridine (0.5μM) to mimic long-QT-3-syndrome...
January 4, 2018: Journal of Cardiovascular Electrophysiology
Audrey Dionne, Anne Fournier, Nagib Dahdah, Dominic Abrams, Paul Khairy, Sylvia Abadir
BACKGROUND: QT-interval variations in response to exercise-induced increases in heart rate have been reported in children and adults in the diagnosis of long QT syndrome (LQTS). A quick standing challenge has been proposed as an alternative provocative test in adults, with no pediatric data yet available. METHODS: A standing test was performed in 100 healthy children (mean age, 9.7 ± 3.1 years) after 10 minutes in a supine position with continuous electrocardiographic recording...
January 2018: Canadian Journal of Cardiology
Ai Kojima, Fumiaki Shikata, Toru Okamura, Takashi Higaki, Seiko Ohno, Minoru Horie, Shunji Uchita, Yujiro Kawanishi, Kenji Namiguchi, Takumi Yasugi, Hironori Izutani
BACKGROUND: Congenital long QT syndrome (LQTS) can cause ventricular arrhythmic events with syncope and sudden death resulting from malignant torsades de pointes (TdP) followed by ventricular fibrillations (VFs). However, the syndrome is often overlooked prior to the development of arrhythmic events in patients with congenital heart diseases demonstrating right bundle branch block on electrocardiogram (ECG). We present a case of an adult patient with congenital heart disease who developed VFs postoperatively, potentially due to his mutation in a LQTS related gene, which was not identified on preoperative assessment due to incomplete evaluation of his family history...
December 19, 2017: Journal of Cardiothoracic Surgery
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