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Long qt

Ruifeng Liu, Xueping Yu, Anders Wallqvist
Chemical toxicity is conventionally evaluated in animal models. However, animal models are resource intensive; moreover, they face ethical and scientific challenges because the outcomes obtained by animal testing may not correlate with human responses. To develop an alternative method for assessing chemical toxicity, we investigated the feasibility of using chemical-induced genome-wide expression changes in cultured human cells to predict the potential of a chemical to cause specific organ injuries in humans...
October 21, 2016: Chemical Research in Toxicology
Worawan B Limpitikul, Ivy E Dick, David Tester, Nicole J Boczek, Pattraranee Limphong, Wanjun Yang, Myoung Hyun Choi, Jennifer Babich, Deborah DiSilvestre, Ronald J Kanter, Gordon F Tomaselli, Michael J Ackerman, David Yue
RATIONALE: Calmodulinopathies comprise a new category of potentially life-threatening genetic arrhythmia syndromes capable of producing severe long QT syndrome (LQTS) with mutations involving either CALM1, CALM2, or CALM3 The underlying basis of this form of LQTS is a disruption of Ca(2+)/CaM-dependent inactivation (CDI) of L-type Ca(2+) channels (LTCCs). OBJECTIVE: To gain insight into the mechanistic underpinnings of calmodulinopathies and devise new therapeutic strategies for the treatment of this form of LQTS...
October 20, 2016: Circulation Research
Xiaodong Huang, Tae Yun Kim, Gideon Koren, Bum-Rak Choi, Zhilin Qu
The occurrence of early afterdepolarizations (EADs) and increased dispersion of repolarization are two known factors for arrhythmogenesis in long QT syndrome. However, increased dispersion of repolarization tends to suppress EADs due to the source-sink effect, and thus how the two competing factors cause initiation of arrhythmias remains incompletely understood. Here we used optical mapping and computer simulation to investigate the mechanisms underlying spontaneous initiation of arrhythmias in type 2 long QT (LQT2) syndrome...
October 7, 2016: American Journal of Physiology. Heart and Circulatory Physiology
Takehito Kondo, Ichiro Hisatome, Shouichi Yoshimura, Endang Mahati, Tomomi Notsu, Peili Li, Kazuhiko Iitsuka, Masaru Kato, Kazuyoshi Ogura, Junichiro Miake, Takeshi Aiba, Wataru Shimizu, Yasutaka Kurata, Shinji Sakata, Naoe Nakasone, Haruaki Ninomiya, Akira Nakai, Katsumi Higaki, Yasushi Kawata, Yasuaki Shirayoshi, Akio Yoshida, Kazuhiro Yamamoto
BACKGROUND: The human ether-a-go-go-related gene (HERG) encodes the α-subunit of rapidly activating delayed-rectifier potassium channels. Mutations in this gene cause long QT syndrome type 2 (LQT2). In most cases, mutations reduce the stability of the channel protein, which can be restored by heat shock (HS). METHODS: We identified the novel mutant A78T-HERG in a patient with LQT2. The purpose of the current study was to characterize this mutant protein and test whether HS and heat shock factors (HSFs) could stabilize the mutant protein...
October 2016: Journal of Arrhythmia
Nobuyuki Murakoshi, Kazutaka Aonuma
Drug treatment and/or implantable cardioverter defibrillator (ICD) implantation are the most widely accepted first-line therapies for channelopathic patients who have recurrent syncope, sustained ventricular tachycardia (VT), or documented ventricular fibrillation (VF), or are survivors of cardiac arrest. In recent years, there have been significant advances in mapping techniques and ablation technology, coupled with better understanding of the mechanisms of ventricular tachyarrhythmia in channelopathies. Catheter ablation has provided important insights into the role of the Purkinje network and the right ventricular outflow tract in the initiation and perpetuation of VT/VF, and has evolved as a promising treatment modality for ventricular tachyarrhythmia even in channelopathies...
October 2016: Journal of Arrhythmia
Jie Wu, Wei-Guang Ding, Minoru Horie
Long QT syndrome type 1 (LQT1) is a subtype of a congenital cardiac syndrome caused by mutation in the KCNQ1 gene, which encodes the α-subunit of the slow component of delayed rectifier K(+) current (IKs) channel. Arrhythmias in LQT1 are characterized by prolongation of the QT interval on ECG, as well as the occurrence of life-threatening cardiac events, frequently triggered by adrenergic stimuli (e.g., physical or emotional stress). During the past two decades, much advancement has been made in understanding the molecular pathogenesis underlying LQT1...
October 2016: Journal of Arrhythmia
Jennifer L Smith, Corey L Anderson, Don E Burgess, Claude S Elayi, Craig T January, Brian P Delisle
The molecular mechanisms underlying congenital long QT syndrome (LQTS) are now beginning to be understood. New insights into the etiology and therapeutic strategies are emerging from heterologous expression studies of LQTS-linked mutant proteins, as well as inducible pluripotent stem cell derived cardiomyocytes (iPSC-CMs) from LQTS patients. This review focuses on the major molecular mechanism that underlies LQTS type 2 (LQT2). LQT2 is caused by loss of function (LOF) mutations in KCNH2 (also known as the human Ether-à-go-go-Related Gene or hERG)...
October 2016: Journal of Arrhythmia
Christopher Semsarian, Jodie Ingles
Sudden cardiac death (SCD) is a rare but devastating complication of a number of underlying cardiovascular diseases. While coronary artery disease and acute myocardial infarction are the most common causes of SCD in older populations, inherited cardiac disorders comprise a substantial proportion of SCD cases aged less than 40 years. Inherited cardiac disorders include primary inherited arrhythmogenic disorders such as familial long QT syndrome (LQTS), Brugada syndrome (BrS), catecholaminergic polymorphic ventricular tachycardia (CPVT), and inherited cardiomyopathies, most commonly hypertrophic cardiomyopathy (HCM)...
October 2016: Journal of Arrhythmia
Yongkeun Cho
Medications such as ß-blockers are currently the primary treatment for patients with hereditary arrhythmia syndromes such as long QT syndrome (LQTS) and catecholaminergic polymorphic ventricular tachycardia (CPVT). However, these drugs are ineffective in some patients, and the other treatment option, that is implantable cardioverter defibrillator (ICD) implantation, is associated with significant complications in young and active patients. Left cardiac sympathetic denervation (LCSD) may reduce the wide gap between life-long ß-blocker medication and ICD implantation...
October 2016: Journal of Arrhythmia
Shegu Gilbert, Devender Singh, M Lawrance Jesuraj
Severe QT interval prolongation >500ms occurs in one quarter of cardiac surgical patients in the perioperative period while moderate prolongation occurs in most of them. Prolonged QT interval may be associated with torsades de pointes and lead to sudden cardiac death. Because of the high incidence of prolonged QT in cardiac surgery patients and its perioperative adverse outcomes, it is vital to identify it early and take necessary precautions. We report and discuss the catastrophic events and management of two patients with long QT syndrome complicating mitral valve replacement...
September 2016: Indian Heart Journal
Frank F Vincenzi, Philippe Lunetta
While SCUBA diving, a 44-year-old Caucasian patient had an abnormal cardiac rhythm, presumably Torsade de Pointes (TdP), during the initial descent to depth. Upon surfacing, she developed ventricular fibrillation and died. The patient had been treated for mild depression for nearly a year with citalopram 60 mg per day, a drug known to cause prolonged QT interval. She had also been treated with two potentially hepatotoxic drugs. Liver impairment causes selective loss of cytochrome P450 (CYP) 2C19 activity, the major pathway for metabolism of citalopram...
December 2015: Drug Saf Case Rep
Hiroko Izumi-Nakaseko, Yuji Nakamura, Xin Cao, Takeshi Wada, Kentaro Ando, Atsushi Sugiyama
Since an antipsychotic drug haloperidol has been clinically reported to induce QT interval prolongation and torsade de pointes, in this study its risk stratification for the onset of torsade de pointes was performed by using the chronic atrioventricular block canine model with a Holter electrocardiogram. Haloperidol in a dose of 3 mg kg(-1) p.o. prolonged the QT interval, but it did not induce torsade de pointes during the observation period of 21 h (n = 4), indicating that the dose would be safe. Meanwhile, haloperidol in a dose of 30 mg kg(-1) p...
October 13, 2016: Cardiovascular Toxicology
Tal Lorberbaum, Kevin J Sampson, Jeremy B Chang, Vivek Iyer, Raymond L Woosley, Robert S Kass, Nicholas P Tatonetti
BACKGROUND: QT interval-prolonging drug-drug interactions (QT-DDIs) may increase the risk of life-threatening arrhythmia. Despite guidelines for testing from regulatory agencies, these interactions are usually discovered after drugs are marketed and may go undiscovered for years. OBJECTIVES: Using a combination of adverse event reports, electronic health records (EHR), and laboratory experiments, the goal of this study was to develop a data-driven pipeline for discovering QT-DDIs...
October 18, 2016: Journal of the American College of Cardiology
Ehud Chorin, Dan Hu, Charles Antzelevitch, Aviram Hochstadt, Luiz Belardinelli, David Zeltser, Hector Barajas-Martinez, Uri Rozovski, Raphael Rosso, Arnon Adler, Jesaia Benhorin, Sami Viskin
BACKGROUND: The basic defect in long-QT syndrome type III (LQT3) is an excessive inflow of sodium current during phase 3 of the action potential caused by mutations in the SCN5A gene. Most sodium channel blockers reduce the early (peak) and late components of the sodium current (INa and INaL), but ranolazine preferentially reduces INaL. We, therefore, evaluated the effects of ranolazine in LQT3 caused by the D1790G mutation in SCN5A. METHODS AND RESULTS: We performed an experimental study of ranolazine in TSA201 cells expressing the D1790G mutation...
October 2016: Circulation. Arrhythmia and Electrophysiology
Sayaka Sasaoka, Toshinobu Matsui, Yuuki Hane, Junko Abe, Natsumi Ueda, Yumi Motooka, Haruna Hatahira, Akiho Fukuda, Misa Naganuma, Shiori Hasegawa, Yasutomi Kinosada, Mitsuhiro Nakamura
Long QT syndrome (LQTS) is a disorder of the heart's electrical activity that infrequently causes severe ventricular arrhythmias such as a type of ventricular tachycardia called torsade de pointes (TdP) and ventricular fibrillation, which can be fatal. There have been no previous reports on the time-to-onset for LQTS based on data from spontaneous reporting systems. The aim of this study was to assess the time-to-onset of LQTS according to drug treatment. We analyzed the association between 113 drugs in 37 therapeutic categories and LQTS including TdP using data obtained from the Japanese Adverse Drug Event Report database...
2016: PloS One
Gerrit Frommeyer, Catharina Clauss, Christian Ellermann, Harilaos Bogossian, Dirk G Dechering, Simon Kochhäuser, Florian Reinke, Christian Pott, Lars Eckardt
AIMS: The antiarrhythmic drug vernakalant exerts antiarrhythmic effects in atrial fibrillation. Recent experimental data suggest interactions with the late sodium current and antiarrhythmic effects in ventricular arrhythmias. We aimed at investigating whether treatment with vernakalant reduces polymorphic ventricular tachycardia (VT) in an experimental model of Long-QT-syndrome (LQTS). METHODS AND RESULTS: Twenty-nine isolated rabbit hearts were assigned to two groups and treated with erythromycin (300 µM, n = 15) or veratridine (0...
October 4, 2016: Europace: European Pacing, Arrhythmias, and Cardiac Electrophysiology
Anna M May, David R Van Wagoner, Reena Mehra
A surge of data has reproducibly identified strong associations of obstructive sleep apnea (OSA) with cardiac arrhythmias. As an extension of epidemiologic and clinic-based findings, experimental investigations have made strides in advancing our understanding of the putative OSA and cardiac arrhythmogenesis mechanistic underpinnings. While most studies have focused on the links between OSA and atrial fibrillation (AF), relationships with ventricular arrhythmias have also been characterized. Key findings implicate OSA-related autonomic nervous system fluctuations typified by enhanced parasympathetic activation during and sympathetic surges subsequent to respiratory events which contribute to augmented arrhythmic propensity...
September 29, 2016: Chest
James McKinney, Daniel J Lithwick, Barbara N Morrison, Hamed Nazzari, Michael Luong, Christopher B Fordyce, Jack Taunton, Andrew D Krahn, Brett Heilbron, Saul Isserow
BACKGROUND: Sudden cardiac death (SCD) is frequently the first manifestation of underlying cardiovascular disease in young competitive athletes (YCAs), yet there are no Canadian guidelines for preparticipation screening in this population. The goal of this study was to determine the prevalence of potentially lethal cardiovascular disease in a sample of Canadian YCAs by comparing 2 screening strategies. METHODS: We prospectively screened 1419 YCAs in British Columbia, Canada (age 12-35 years)...
June 23, 2016: Canadian Journal of Cardiology
Jeff A Zablocki, Elfatih Elzein, Xiaofen Li, Dmitry O Koltun, Eric Q Parkhill, Tetsuya Kobayashi, Ruben Martinez, Britton Corkey, Haibo Jiang, Thao Perry, Rao Kalla, Gregory T Notte, Oliver Saunders, Michael Graupe, Yafan Lu, Chandru Venkataramani, Juan Guerrero, Jason Perry, Mark Osier, Robert Strickley, Gongxin Liu, Wei-Qun Wang, Lufei Hu, Xiao-Jun Li, Nesrine El-Bizri, Ryoko Hirakawa, Kris Kahlig, Cheng Xie, Cindy Hong Li, Arvinder K Dhalla, Sridharan Rajamani, Nevena Mollova, Daniel Soohoo, Eve-Irene Lepist, Bernard Murray, Gerry Rhodes, Luiz Belardinelli, Manoj C Desai
Late sodium current (late INa) is enhanced during ischemia by reactive oxygen species (ROS) modifying the Nav 1.5 channel, resulting in incomplete inactivation. Compound 4 (GS-6615, eleclazine) a novel, potent, and selective inhibitor of late INa, is currently in clinical development for treatment of long QT-3 syndrome (LQT-3), hypertrophic cardiomyopathy (HCM), and ventricular tachycardia-ventricular fibrillation (VT-VF). We will describe structure-activity relationship (SAR) leading to the discovery of 4 that is vastly improved from the first generation late INa inhibitor 1 (ranolazine)...
October 3, 2016: Journal of Medicinal Chemistry
Sara I Liin, Johan E Larsson, Rene Barro-Soria, Bo Hjorth Bentzen, H Peter Larson
About 300 loss-of-function mutations in the IKs channel have been identified in patients with Long QT syndrome and cardiac arrhythmia. How specific mutations cause arrhythmia is largely unknown and there are no approved IKs channel activators for treatment of these arrhythmias. We find that several Long QT syndrome-associated IKs channel mutations shift channel voltage dependence and accelerate channel closing. Voltage-clamp fluorometry experiments and kinetic modeling suggest that similar mutation-induced alterations in IKs channel currents may be caused by different molecular mechanisms...
September 30, 2016: ELife
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