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https://www.readbyqxmd.com/read/28431243/cryo-em-structure-of-the-open-human-ether-%C3%A3-go-go-related-k-channel-herg
#1
Weiwei Wang, Roderick MacKinnon
The human ether-à-go-go-related potassium channel (hERG, Kv11.1) is a voltage-dependent channel known for its role in repolarizing the cardiac action potential. hERG alteration by mutation or pharmacological inhibition produces Long QT syndrome and the lethal cardiac arrhythmia torsade de pointes. We have determined the molecular structure of hERG to 3.8 Å using cryo-electron microscopy. In this structure, the voltage sensors adopt a depolarized conformation, and the pore is open. The central cavity has an atypically small central volume surrounded by four deep hydrophobic pockets, which may explain hERG's unusual sensitivity to many drugs...
April 20, 2017: Cell
https://www.readbyqxmd.com/read/28405995/recurrent-ventricular-tachycardia-due-to-long-qt-syndrome
#2
Rambabu Singh, Kshitiz Nath, Archana
Long QT syndrome (LQTS) is a rare inherited heart condition in which delayed repolarization of the heart following a heartbeat, increases the risk of episodes of Torsades de pointes (TdP, a form of irregular heartbeat that originates from the ventricles). These episodes may lead to palpitations, fainting, and sudden death due to ventricular fibrillation. Episodes may be provoked by various stimuli, depending on the subtype of the condition. We are reporting a case of 37 years old male whom we diagnosed to have long QT syndrome on the basis of clinical and ECG findings...
December 2016: Journal of the Association of Physicians of India
https://www.readbyqxmd.com/read/28383310/short-term-variability-of-repolarization-is-superior-to-other-repolarization-parameters-in-the-evaluation-of-diverse-antiarrhythmic-interventions-in-the-chronic-av-block-dog
#3
A Bossu, R Varkevisser, Hdm Beekman, Mjc Houtman, Mag van der Heyden, M A Vos
Short-term variability (STV), to quantify beat-to-beat variability of repolarization (BVR), is a surrogate parameter that reliably identifies proarrhythmic risk in preclinical models. Examples include not only the use in the chronic atrioventricular block (CAVB) dog model whereby it was developed, but also in vulnerable patients with heart failure or drug-induced long QT syndrome. In the CAVB dog model, STV can specifically distinguish between safe and unsafe drugs in proarrhythmic screening. Conversely, this dog model also offers the possibility to evaluate antiarrhythmic strategies in a setting of Torsades de Pointes (TdP) induction with a standard IKr inhibitor...
March 31, 2017: Journal of Cardiovascular Pharmacology
https://www.readbyqxmd.com/read/28364778/clinical-and-molecular-findings-in-a-moroccan-family-with-jervell-and-lange-nielsen-syndrome-a-case-report
#4
N Adadi, N Lahrouchi, R Bouhouch, I Fellat, R Amri, M Alders, A Sefiani, C Bezzina, I Ratbi
BACKGROUND: Jervell and Lange-Nielsen syndrome (Online Mendelian Inheritance in Man 220400) is a rare autosomal recessive cardioauditory ion channel disorder that affects 1/200,000 to 1/1,000,000 children. It is characterized by congenital profound bilateral sensorineural hearing loss, a long QT interval, ventricular tachyarrhythmias, and episodes of torsade de pointes on an electrocardiogram. Cardiac symptoms arise mostly in early childhood and consist of syncopal episodes during periods of stress, exercise, or fright and are associated with a high risk of sudden cardiac death...
April 2, 2017: Journal of Medical Case Reports
https://www.readbyqxmd.com/read/28363206/recent-developments-in-the-science-of-proarrhythmic-cardiac-safety-of-new-drugs
#5
J Rick Turner, Dilip R Karnad, Christopher H Cabell, Snehal Kothari
Following marketing withdrawals of several drugs due to proarrhythmic safety concerns, the ICH Guidelines S7B and E14 were released in 2005 and have guided pre-approval cardiac safety assessments in multiple regulatory jurisdictions. While this S7B-E14 paradigm has successfully prevented drugs with unanticipated potential for inducing Torsades de Pointes entering the market, it has unintentionally resulted in the termination of development programs for potentially important compounds that could have exhibited a favourable benefit-risk balance...
April 1, 2017: European Heart Journal. Cardiovascular Pharmacotherapy
https://www.readbyqxmd.com/read/28359306/clinicians-adherence-to-clinical-practice-guidelines-for-cardiac-function-monitoring-during-antipsychotic-treatment-a-retrospective-report-on-434-patients-with-severe-mental-illness
#6
Mirko Manchia, Giorgio Firinu, Bernardo Carpiniello, Federica Pinna
BACKGROUND: Severe mental illness (SMI) has considerable excess morbidity and mortality, a proportion of which is explained by cardiovascular diseases, caused in part by antipsychotic (AP) induced QT-related arrhythmias and sudden death by Torsade de Point (TdP). The implementation of evidence-based recommendations for cardiac function monitoring might reduce the incidence of these AP-related adverse events. To investigate clinicians' adherence to cardiac function monitoring before and after starting AP, we performed a retrospective assessment of 434 AP-treated SMI patients longitudinally followed-up for 5 years at an academic community mental health center...
March 31, 2017: BMC Psychiatry
https://www.readbyqxmd.com/read/28335691/cases-of-drug-induced-torsade-de-pointes-a-review-of-belgian-cases-in-the-eudravigilance-database
#7
Eline Vandael, Bert Vandenberk, Joris Vandenberghe, Rik Willems, Veerle Foulon
OBJECTIVES: Post-marketing surveillance is very important, especially for rare adverse drug reactions like QTc-prolongation and Torsade de Pointes (TdP). The objective of this study was to investigate the characteristics of Belgian cases of drug-related TdP reported in the EudraVigilance database. METHODS: The EudraVigilance database was searched for Belgian post-marketing cases of TdP reported between December 2001-April 2015. These cases were identified with MedDRA preferred terms...
March 24, 2017: Acta Clinica Belgica
https://www.readbyqxmd.com/read/28281228/development-of-a-risk-score-for-qtc-prolongation-the-risq-path-study
#8
Eline Vandael, Bert Vandenberk, Joris Vandenberghe, Isabel Spriet, Rik Willems, Veerle Foulon
Background More than 170 drugs are linked with QTc-prolongation, which in extreme cases can lead to Torsade de Pointes. Monitoring of this potential side effect is an important challenge in clinical practice. Objective To investigate the risk of QTc-prolongation in hospital patients who started a QTc-prolonging drug, and to develop a risk score to identify patients at high/low risk for QTc-prolongation. Setting University Hospitals Leuven, Belgium. Method All patients starting with haloperidol or a QTc-prolonging antibiotic/antimycotic were eligible for this observational study...
March 9, 2017: International Journal of Clinical Pharmacy
https://www.readbyqxmd.com/read/28275963/adverse-drug-event-causality-analysis-adeca-a-process-for-evaluating-evidence-and-assigning-drugs-to-risk-categories-for-sudden-death
#9
Raymond L Woosley, Klaus Romero, Craig W Heise, Tyler Gallo, Jared Tate, Raymond David Woosley, Sophie Ward
Growing evidence indicates that many drugs have the ability to cause a potentially lethal cardiac arrhythmia, torsades de pointes (TdP). This necessitates the development of a compilation of drugs that have this potential toxicity. Such a list is helpful in identifying the etiology of TdP in patients taking multiple drugs and assists decision making by those caring for patients at high risk of TdP. The Arizona Center for Education and Research on Therapeutics (AZCERT) has developed a process to standardize the identification of drugs and place them in risk categories for their clinical ability to cause TdP and QT prolongation...
March 8, 2017: Drug Safety: An International Journal of Medical Toxicology and Drug Experience
https://www.readbyqxmd.com/read/28274542/hypokalemia-in-women-and-methadone-therapy-are-the-strongest-non-cardiologic-factors-associated-with-qt-prolongation-in-an-emergency-department-setting
#10
Keith A Marill, Emily S Miller
BACKGROUND: Our primary objective was to determine the adjusted quantitative associations of clinical predictors with QT prolongation, a defining cause of Torsades de Pointes (TdP). METHODS: A retrospective cohort study was performed on consecutive emergency department patients identified by ECG acquisition date, and heart rate corrected QT (QTc) and QRS durations. QTc was modeled as a function of clinical predictors with multiple linear regression. RESULTS: 1010 patients were included...
February 10, 2017: Journal of Electrocardiology
https://www.readbyqxmd.com/read/28267474/results-of-a-curtailed-randomized-controlled-trial-evaluating-the-efficacy-and-safety-of-azimilide-in-patients-with-implantable-cardioverter-defibrillators-the-shield-2-trial
#11
Victoria M Robinson, David B Bharucha, Kenneth W Mahaffey, Paul Dorian, Peter R Kowey
BACKGROUND: Frequent hospital attendances in patients with implantable cardioverter-defibrillators (ICDs) result in significant morbidity and health care costs. Current drugs to reduce ICD shocks and hospital visits have limited efficacy and considerable toxicity. We evaluated the efficacy and safety of azimilide, a novel oral class III antiarrhythmic, for use in ICD patients. METHODS: A total of 240 patients were enrolled in a prospective, randomized, double-blind, placebo-controlled trial to evaluate the effect of oral azimilide 75 mg daily in ICD patients with previously documented ventricular tachycardia or ventricular fibrillation, and a left ventricular ejection fraction ≤40%...
March 2017: American Heart Journal
https://www.readbyqxmd.com/read/28229241/acquired-prolongation-of-qt-interval-as-a-risk-factor-for-torsade-de-pointes-ventricular-tachycardia-a-narrative-review-for-the-anesthesiologist-and-intensivist
#12
REVIEW
Arsen Uvelin, Jasmina Pejaković, Vesna Mijatović
More than 70% of intensive care unit (ICU) patients experience heart rhythm disturbances, and these patients have correspondingly higher mortality rates. Consequently, one of the standards of care in ICUs is continuous electrocardiography monitoring. One of the potentially preventable dysrhythmic events is the occurrence of torsade de pointes ventricular tachycardia in the setting of acquired prolonged QT interval. This type of ventricular tachycardia can be malignant because it often progresses to ventricular fibrillation...
February 22, 2017: Journal of Anesthesia
https://www.readbyqxmd.com/read/28220940/pharmacologic-conversion-during-dofetilide-treatment-for-persistent-atrial-fibrillation
#13
Jonathan S Steinberg, Yash Shah, Barbara Szepietowska
BACKGROUND: Dofetilide is a pure IKr blocker and is one of the few drugs specifically studied and approved in the United States for the management of persistent AF. Dofetilide has been noted to have a high rate of pharmacologic conversion during initial dosing in prior smaller studies. The intent of the study was to examine the safety of an inpatient loading strategy, and the incidence and patterns of pharmacologic conversion by dofetilide during the treatment of persistent AF in a large consecutive cohort...
February 21, 2017: Pacing and Clinical Electrophysiology: PACE
https://www.readbyqxmd.com/read/28213480/common-genetic-variant-risk-score-is-associated-with-drug-induced-qt-prolongation-and-torsade-de-pointes-risk-a-pilot-study
#14
David G Strauss, Jose Vicente, Lars Johannesen, Ksenia Blinova, Jay W Mason, Peter Weeke, Elijah R Behr, Dan M Roden, Ray Woosley, Gulum Kosova, Michael A Rosenberg, Christopher Newton-Cheh
BACKGROUND: Drug-induced QT interval prolongation, a risk factor for life-threatening ventricular arrhythmias, is a potential side effect of many marketed and withdrawn medications. The contribution of common genetic variants previously associated with baseline QT interval to drug-induced QT prolongation and arrhythmias is not known. METHODS: We tested the hypothesis that a weighted combination of common genetic variants contributing to QT interval at baseline, identified through genome-wide association studies, can predict individual response to multiple QT-prolonging drugs...
April 4, 2017: Circulation
https://www.readbyqxmd.com/read/28213055/electrophysiological-measurements-that-can-explain-and-guide-temporary-accelerated-pacing-to-avert-re-occurrence-of-torsade-de-pointes-arrhythmias-in-the-canine-chronic-atrioventricular-block-model
#15
Sofieke C Wijers, Alexandre Bossu, Albert Dunnink, Jet D M Beekman, Rosanne Varkevisser, Alfonso Aranda Hernández, Mathias Meine, Marc A Vos
BACKGROUND: Pacing at higher rates is known to suppress torsade de pointes (TdP) arrhythmias. Nevertheless, exact application and mechanism need further clarification. In the anesthetized canine chronic atrioventricular block model, ventricular remodeling is responsible for a high and reproducible incidence of TdP upon a challenge with dofetilide. OBJECTIVE: We used this model to investigate by what mechanism accelerated pacing averts TdP and what repolarization parameter could be used to guide temporary accelerated pacing (TAP)...
May 2017: Heart Rhythm: the Official Journal of the Heart Rhythm Society
https://www.readbyqxmd.com/read/28202629/improving-the-in-silico-assessment-of-proarrhythmia-risk-by-combining-herg-human-ether-%C3%A3-go-go-related-gene-channel-drug-binding-kinetics-and-multichannel-pharmacology
#16
Zhihua Li, Sara Dutta, Jiansong Sheng, Phu N Tran, Wendy Wu, Kelly Chang, Thembi Mdluli, David G Strauss, Thomas Colatsky
BACKGROUND: The current proarrhythmia safety testing paradigm, although highly efficient in preventing new torsadogenic drugs from entering the market, has important limitations that can restrict the development and use of valuable new therapeutics. The CiPA (Comprehensive in vitro Proarrhythmia Assay) proposes to overcome these limitations by evaluating drug effects on multiple cardiac ion channels in vitro and using these data in a predictive in silico model of the adult human ventricular myocyte...
February 2017: Circulation. Arrhythmia and Electrophysiology
https://www.readbyqxmd.com/read/28202194/study-of-factors-affecting-the-progression-and-termination-of-drug-induced-torsade-de-pointes-in-two-dimensional-cardiac-tissue
#17
Ponnuraj Kirthi Priya, M Ramasubba Reddy
INTRODUCTION: To study the conditions leading to the initiation and termination of drug induced Torsade de pointes (TdP) along with QT prolongation. METHODS: A 2D anisotropic transmural section of the ventricular myocardium is modeled using the TP06 equations and the cells are interconnected with gap junction conductances (GJC). The tissue is remodeled by reducing the repolarization reserve (by increasing calcium current (ICaL)) of all cells thus making them vulnerable to development of early after depolarizations (EADs)...
February 2, 2017: Journal of Electrocardiology
https://www.readbyqxmd.com/read/28188930/microrna-135a-regulates-sodium-calcium-exchanger-gene-expression-and-cardiac-electrical-activity
#18
Eric Duong, Jiening Xiao, Xiao Yan Qi, Stanley Nattel
BACKGROUND: Complete atrioventricular block (CAVB) causes arrhythmogenic remodeling and increases the risk of torsades de pointes arrhythmias. MicroRNAs (miRNAs) are key regulators of gene expression that contribute to cardiac remodeling. OBJECTIVE: The purpose of this study was to assess miRNA changes after CAVB and identify novel candidates potentially involved in arrhythmogenic cardiac remodeling. METHODS: CAVB was induced in mice via His-bundle ablation...
May 2017: Heart Rhythm: the Official Journal of the Heart Rhythm Society
https://www.readbyqxmd.com/read/28186837/methadone-and-corrected-qt-prolongation-in-pain-and-palliative-care-patients-a-case-control-study
#19
Katherine M Juba, Tina M Khadem, David J Hutchinson, Jack E Brown
BACKGROUND: Methadone (ME) is commonly used in pain and palliative care (PPC) patients with refractory pain or intolerable opioid adverse effects (AEs). A unique ME AE is its corrected QT (QTc) interval prolongation risk, but most evidence exists in methadone maintenance therapy patients. OBJECTIVE: Our goal was to identify QTc interval prolongation risk factors in PPC patients receiving ME and other medications known to prolong the QTc interval and develop a risk stratification tool...
February 10, 2017: Journal of Palliative Medicine
https://www.readbyqxmd.com/read/28185059/severe-proarrhythmic-potential-of-the-antiemetic-agents-ondansetron-and-domperidone
#20
Gerrit Frommeyer, Christina Fischer, Christian Ellermann, Philipp S Lange, Dirk G Dechering, Simon Kochhäuser, Michael Fehr, Lars Eckardt
The potential of ondansetron and domperidone, both clinically established antiemetic agents, to increase the QT-interval has been described in several case reports. Therefore, the aim of the present study was to investigate whether these drugs may provoke polymorphic ventricular tachycardia in a sensitive experimental model of drug-induced proarrhythmia. In 10 female rabbits, ondansetron (1, 5 and 10 µM, n = 10) or domperidone (0.5, 1 and 2 µM, n = 8) was infused after obtaining baseline data. Eight endo- and epicardial monophasic action potentials and a simultaneously recorded 12-lead ECG reproduced the clinically observed QT-prolongation (ondansetron: 1 µM:+17 ms, 5 µM:+41 ms, 10 µM:+78 ms, p < 0...
February 9, 2017: Cardiovascular Toxicology
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