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https://www.readbyqxmd.com/read/28527921/drug-induced-fatal-arrhythmias-acquired-long-qt-and-brugada-syndromes
#1
REVIEW
Isik Turker, Tomohiko Ai, Hideki Itoh, Minoru Horie
Since the early 1990s, the concept of primary "inherited" arrhythmia syndromes or ion channelopathies has evolved rapidly as a result of revolutionary progresses made in molecular genetics. Alterations in genes coding for membrane proteins such as ion channels or their associated proteins responsible for the generation of cardiac action potentials (AP) have been shown to cause specific malfunctions which eventually lead to cardiac arrhythmias. These arrhythmic disorders include congenital long QT syndrome, Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia, short QT syndrome, progressive cardiac conduction disease, etc...
May 17, 2017: Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/28525371/arsenic-trioxide-and-angiotensin-ii-have-inhibitory-effects-on-herg-protein-expression-evidence-for-the-role-of-pml-sumoylation
#2
Yu Liu, Duo Li, Dan Nie, Shang-Kun Liu, Fang Qiu, Mei-Tong Liu, Yuan-Yuan Li, Jia-Xin Wang, Yan-Xin Liu, Chang-Jiang Dong, Di Wu, Wei Tian, Jia Yang, Wei Mu, Jia-Tong Li, Dan Zhao, Xiao-Feng Wang, Wen-Feng Chu, Bao-Feng Yang
The human ether-a-go-go-related gene (HERG) channel is a novel target for the treatment of drug-induced long QT syndrome, which causes lethal cardiotoxicity. This study is designed to explore the possible role of PML SUMOylation and its associated nuclear bodies (NBs) in the regulation of HERG protein expression. Both arsenic trioxide (ATO) and angiotensin II (Ang II) were able to significantly reduce HERG protein expression, while also increasing PML SUMOylation and accelerating the formation of PML-NBs. Pre-exposure of cardiomyocytes to a SUMOylation chemical inhibitor, ginkgolic acid, or the silencing of UBC9 suppressed PML SUMOylation, subsequently preventing the downregulation of HERG induced by ATO or Ang II...
May 2, 2017: Oncotarget
https://www.readbyqxmd.com/read/28521790/unintentional-drowning-role-of-medicinal-drugs-and-alcohol
#3
Tuulia Pajunen, Erkki Vuori, Frank F Vincenzi, Pirjo Lillsunde, Gordon Smith, Philippe Lunetta
BACKGROUND: Alcohol is a well-known risk factor in unintentional drownings. Whereas psychotropic drugs, like alcohol, may cause psychomotor impairment and affect cognition, no detailed studies have focused on their association with drowning. Finland provides extensive post-mortem toxicological data for studies on drowning because of its high medico-legal autopsy rates. METHODS: Drowning cases, 2000 through 2009, for which post-mortem toxicological analysis was performed, came from the database of the Toxicological Laboratory, Department of Forensic Medicine, University of Helsinki, using the ICD-10 nature-of-injury code T75...
May 19, 2017: BMC Public Health
https://www.readbyqxmd.com/read/28521025/mechanism-of-as2o3-induced-action-potential-prolongation-and-using-hips-cms-to-evaluate-the-rescue-efficacy-of-drugs-with-different-rescue-mechanism
#4
Meng Yan, Lifang Feng, Yanhui Shi, Junnan Wang, Yan Liu, Fengmei Li, Baoxin Li
Arsenic trioxide (As2O3) has been verified as a breakthrough in the management of acute promyelocytic leukemia in recent decades. However, cardiotoxicity, especially long QT syndrome (LQTS) has become the most important issue during As2O3 treatment. The characterized mechanisms behind this adverse effect are inhibition of cardiac hERG channel trafficking and increase of cardiac calcium currents. In our study, we found a new pathway underlying As2O3-induced cardiotoxicity that As2O3 accelerates lysosomal degradation of hERG on plasma membrane after using brefeldin A (BFA) to block protein trafficking...
May 17, 2017: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/28516454/a-multiscale-computational-modelling-approach-predicts-mechanisms-of-female-sex-risk-in-the-setting-of-arousal-induced-arrhythmias
#5
Pei-Chi Yang, Laura L Perissinotti, Fernando López-Redondo, Yibo Wang, Kevin R DeMarco, Mao-Tsuen Jeng, Igor Vorobyov, Robert D Harvey, Junko Kurokawa, Sergei Y Noskov, Colleen E Clancy
Female sex is a risk factor for inherited and acquired Long-QT associated Torsade de Pointes (TdP) arrhythmias, and sympathetic discharge is a major factor in triggering TdP in female Long-QT syndrome patients. We used a combined experimental and computational approach to predict 'the perfect storm' of hormone concentration, IKr block, and sympathetic stimulation that induces arrhythmia in females with inherited and acquired Long-QT. More specifically, we developed mathematical models of acquired and inherited Long-QT syndrome in male and female ventricular human myocytes by combining effects of a hormone and a hERG blocker dofetilide or hERG mutations...
May 18, 2017: Journal of Physiology
https://www.readbyqxmd.com/read/28510313/categorization-and-theoretical-comparison-of-quantitative-methods-for-assessing-qt-rr-hysteresis
#6
REVIEW
Hugo Gravel, Daniel Curnier, Nagib Dahdah, Vincent Jacquemet
BACKGROUND: In the human electrocardiogram, there is a lag of adaptation of the QT interval to heart rate changes, usually termed QT/RR hysteresis (QT-hys). Subject-specific quantifiers of QT-hys have been proposed as potential biomarkers, but there is no consensus on the choice of the quantifier. METHODS: A comprehensive literature search was conducted to identify original articles reporting quantifiers of repolarization hysteresis from the surface ECG in humans...
May 16, 2017: Annals of Noninvasive Electrocardiology
https://www.readbyqxmd.com/read/28510081/qt-prolongation-as-an-isolated-long-term-cardiac-manifestation-of-dichlorvos-organophosphate-poisoning-in-rats
#7
Arthur Shiyovich, Ran Matot, Sigal Elyagon, Noah Liel-Cohen, Yossi Rosman, Shai Shrot, Michael Kassirer, Amos Katz, Yoram Etzion
Organophosphates (OP) are used extensively as pesticides and as chemical weapons. Cardiotoxicity is a major concern in survivors of the acute poisoning. To characterize the delayed cardiac effects of OP, rats were poisoned by intraperitoneal administration of dichlorvos. In group I, poisoning (0.25-, 0.75-, 1.4-LD50) was followed by application of atropine and obidoxime. In group II, poisoning (0.35-, 0.5-LD50) was done without antidotes. Cardiac evaluation included electrocardiography and echocardiography 2- and 6-week post-exposure, arrhythmia susceptibility following administration of Isoproterenol (150 mcg/kg), and histological evaluation...
May 16, 2017: Cardiovascular Toxicology
https://www.readbyqxmd.com/read/28506915/long-qt-syndrome-who-needs-a-transplant
#8
EDITORIAL
Sairah Khan, Charles I Berul
No abstract text is available yet for this article.
May 12, 2017: Heart Rhythm: the Official Journal of the Heart Rhythm Society
https://www.readbyqxmd.com/read/28506854/long-term-safety-and-efficacy-of-solifenacin-in-children-and-adolescents-with-overactive-bladder
#9
Donald Newgreen, Brigitte Bosman, Adriana Hollestein-Havelaar, Ellen Dahler, Robin Besuyen, Robert Snijder, Will Sawyer, Søren Rittig, Stéphane Bolduc
PURPOSE: To evaluate long-term safety and efficacy of once-daily oral solifenacin suspension in children (aged 5-<12 years) and adolescents (aged 12-<18 years) with overactive bladder. MATERIALS AND METHODS: 40-week, open-label extension of a 12-week double-blind, placebo-controlled trial. OUTCOME MEASURES: incidence and severity of adverse events (primary endpoint), laboratory variables, vital signs, 12-lead electrocardiogram, post-void residual volume, change from baseline to end of treatment in: mean number of micturitions and incontinence episodes/24 hours, number of incontinence-free days/7 days, number of grade 3 or 4 urgency episodes/24 hours (adolescents only)...
May 12, 2017: Journal of Urology
https://www.readbyqxmd.com/read/28506844/proarrhythmic-risk-assessment-using-conventional-and-new-in-vitro-assays
#10
Sonia Goineau, Vincent Castagné
Drug-induced QT prolongation is a major safety issue in the drug discovery process. This study was conducted to assess the electrophysiological responses of four substances using established preclinical assays usually used in regulatory studies (hERG channel or Purkinje fiber action potential) and a new assay (human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs)-field potential). After acute exposure, moxifloxacin and dofetilide concentration-dependently decreased IKr amplitude (IC50 values: 102 μM and 40 nM, respectively) and lengthened action potential (100 μM moxifloxacin: +23% and 10 nM dofetilide: +18%) and field potential (300 μM moxifloxacin: +76% and 10 nM dofetilide: +38%) durations...
May 12, 2017: Regulatory Toxicology and Pharmacology: RTP
https://www.readbyqxmd.com/read/28500657/modulation-of-herg-channels-by-5-1h-indazol-5-yl-oxy-methyl-n-4-trifluoromethoxy-phenyl-pyrimidin-2-amine-itp-2-a-novel-small-molecule-activator
#11
Harinath Sale, Samrat Roy, Jayakumar Warrier, Srinivasan Thangathirupathy, Yoganand Vadari, Shruthi K Gopal, Prasad Krishnamurthy, Manjunath Ramarao
BACKGROUND AND PURPOSE: hERG channel activators have potential utility in the treatment of acquired and congenital long QT syndrome. In this article, we describe a new hERG activator, 5-(((1H-indazol-5-yl)oxy)methyl)-N-(4-(trifluoromethoxy)phenyl)pyrimidin-2-amine (ITP-2), with a chemical structure distinct from the previously reported compounds. EXPERIMENTAL APPROACH: We investigated the effect of ITP-2 on hERG1a and hERG1a/1b channels expressed heterologously in HEK-293 cells using conventional electrophysiological methods...
May 12, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28499268/first-universal-pharmacophore-model-for-herg1-k-channel-activators-acther
#12
Serdar Durdagi, Ismail Erol, Ramin Ekhteiari Salmas, Matthew Patterson, Sergei Y Noskov
The intra-cavitary drug blockade of hERG1 channel has been extensively studied, both experimentally and theoretically. Structurally diverse ligands inadvertently block the hERG1 K(+) channel currents lead to drug induced Long QT Syndrome (LQTS). Accordingly, designing either hERG1 channel openers or current activators, with the potential to target other binding pockets of the channel, has been introduced as a viable approach in modern anti-arrhythmia drug development. However, reports and investigations on the molecular mechanisms underlying activators binding to the hERG1 channel remain sparse and the overall molecular design principles are largely unknown...
April 5, 2017: Journal of Molecular Graphics & Modelling
https://www.readbyqxmd.com/read/28495999/%C3%AE-arrestin-mediated-regulation-of-the-human-ether-a-go-go-related-gene-herg-potassium-channel
#13
Matthew G Sangoi, Shawn M Lamothe, Jun Guo, Tonghua Yang, Wentao Li, Ellen G Avery, John T Fisher, Shetuan Zhang
The rapidly activating delayed rectifier K(+) channel (IKr) is encoded by the human ether-a-go-go-related gene (hERG), which is important for the repolarization of the cardiac action potential. Mutations in hERG or drugs can impair the function or decrease the expression level of hERG channels, leading to long QT syndrome (LQTS). Thus, it is important to understand hERG channel trafficking and its regulation. For this purpose, G protein-coupled receptors (GPCRs), which regulate a vast array of cellular processes, represent a useful route...
May 11, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28495653/in-search-of-the-holy-grail-in-the-channelopathy-field-proving-pathogenicity-of-long-qt-syndrome-associated-variants
#14
EDITORIAL
Arthur A M Wilde, Christopher Semsarian
No abstract text is available yet for this article.
May 8, 2017: Heart Rhythm: the Official Journal of the Heart Rhythm Society
https://www.readbyqxmd.com/read/28494446/mutation-load-of-multiple-ion-channel-gene-mutations-in-brugada-syndrome
#15
Francesca Gualandi, Fatima Zaraket, Michele Malagù, Giulia Parmeggiani, Cecilia Trabanelli, Sergio Fini, Xiao Dang, Xiaoming Wei, Mingyan Fang, Matteo Bertini, Roberto Ferrari, Alessandra Ferlini
Brugada syndrome is a primary arrhythmic syndrome that accounts for 20% of all sudden cardiac death cases in individuals with a structurally normal heart. Pathogenic variants associated with Brugada syndrome have been identified in over 19 genes, with SCN5A as a pivotal gene accounting for nearly 30% of cases. In contrast to other arrhythmogenic channelopathies (such as long QT syndrome), digenic inheritance has never been reported in Brugada syndrome. Exploring 66 cardiac genes using a new custom next-generation sequencing panel, we identified a double heterozygosity for pathogenic mutations in SCN5A and TRPM4 in a Brugada syndrome patient...
May 12, 2017: Cardiology
https://www.readbyqxmd.com/read/28492533/gene-patents-still-alive-and-kicking-their-impact-on-provision-of-genetic-testing-for-long-qt-syndrome-in-the-canadian-public-health-care-system
#16
Sarah E Ali-Khan, E Richard Gold
PurposeAlthough the Supreme Court of the United States limited their availability in Association for Molecular Pathology v. Myriad Genetics, gene patents remain important around the world. We examine the situation in Canada, where gene patents continue to exist, in light of recent litigation relating to familial long QT syndrome (LQTS).MethodsWe conducted in-depth semistructured interviews with 25 stakeholders across five Canadian provinces and supplemented this with a case analysis of the litigation.ResultsThe majority of LQTS testing was carried out outside Canada...
May 11, 2017: Genetics in Medicine: Official Journal of the American College of Medical Genetics
https://www.readbyqxmd.com/read/28491806/atypical-long-qt-syndrome-phenotype-in-heterozygous-homozygous-kcnq1-ala590thr
#17
Justin D Smith, Jeffrey M Vinocur
No abstract text is available yet for this article.
April 2017: HeartRhythm Case Reports
https://www.readbyqxmd.com/read/28491780/complexity-of-ranolazine-and-phenytoin-use-in-an-infant-with-long-qt-syndrome-type-3
#18
Reina Bianca Tan, Sujata Chakravarti, Melissa Busovsky-McNeal, Abigail Walsh, Frank Cecchin
No abstract text is available yet for this article.
January 2017: HeartRhythm Case Reports
https://www.readbyqxmd.com/read/28491768/successful-prenatal-management-of-ventricular-tachycardia-and-second-degree-atrioventricular-block-in-fetal-long-qt-syndrome
#19
Akira Miyake, Heima Sakaguchi, Aya Miyazaki, Takekazu Miyoshi, Takeshi Aiba, Isao Shiraishi
No abstract text is available yet for this article.
January 2017: HeartRhythm Case Reports
https://www.readbyqxmd.com/read/28491690/dexamethasone-suppresses-long-qt-phenotype-in-patient-with-acute-promyelocytic-leukemia-treated-with-arsenic
#20
Jeffrey R Winterfield, David J Milan
No abstract text is available yet for this article.
July 2016: HeartRhythm Case Reports
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