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Idiopathic ventricular fibrillation (IVF) causes sudden death in young adult patients without structural or ischemic heart disease. Most IVF cases are sporadic and some patients present with short-coupled torsade de pointes, the genetics of which are poorly understood. A man who had a first syncope at the age of 35 presented with frequent short-coupled premature ventricular beats with bursts of polymorphic ventricular tachycardia and then died suddenly. By exome sequencing, we identified three rare variants: p.I784F in the SPRY1 of the ryanodine receptor 2 (RyR2), p.A96S in connexin 40 (Cx40), reported to affect electrical coupling and cardiac conduction, and a nonsense p.R244X in the cardiac-specific troponin I-interacting kinase (TNNI3K). We assessed intracellular Ca 2+ handling in WT and mutant human  RYR2 transfected HEK293 cells by fluorescent microscopy and an enhanced store overload-induced Ca 2+ release in response to cytosolic Ca 2+ was observed in RyR2-I784F cells. In addition, crystal structures and thermal melting temperatures revealed a conformational change in the I784F-SPRY1 domain compared to the WT-domain. The novel RyR2-I784F variant in SPRY1 domain causes a leaky channel under non-stress conditions. The presence of several variants affecting Ca 2+ handling and cardiac conduction suggests a possible oligogenic origin for the ectopies originating from Purkinje fibres.

Background Blockage of some ion channels and in particular, the hERG (human Ether-a’-go-go-Related Gene) cardiac potassium channel delays cardiac repolarization and can induce arrhythmia. In some cases it leads to a potentially life-threatening arrhythmia known as Torsade de Pointes (TdP). Therefore recognizing drugs with TdP risk is essential. Candidate drugs that are determined not to cause cardiac ion channel blockage are more likely to pass successfully through clinical phases II and III trials (and preclinical work) and not be withdrawn even later from the marketplace due to cardiotoxic effects. The objective of the present study is to develop an SAR (Structure-Activity Relationship) model that can be used as an early screen for torsadogenic (causing TdP arrhythmias) potential in drug candidates. The method is performed using descriptors comprised of atomic NMR chemical shifts ( 13 C and 15 N NMR) and corresponding interatomic distances which are combined into a 3D abstract space matrix. The method is called 3D-SDAR (3-dimensional spectral data-activity relationship) and can be interrogated to identify molecular features responsible for the activity, which can in turn yield simplified hERG toxicophores. A dataset of 55 hERG potassium channel inhibitors collected from Kramer et al. consisting of 32 drugs with TdP risk and 23 with no TdP risk was used for training the 3D-SDAR model. Results An artificial neural network (ANN) with multilayer perceptron was used to define collinearities among the independent 3D-SDAR features. A composite model from 200 random iterations with 25% of the molecules in each case yielded the following figures of merit: training, 99.2%; internal test sets, 66.7%; external (blind validation) test set, 68.4%. In the external test set, 70.3% of positive TdP drugs were correctly predicted. Moreover, toxicophores were generated from TdP drugs. Conclusion A 3D-SDAR was successfully used to build a predictive model for drug-induced torsadogenic and non-torsadogenic drugs based on 55 compounds. The model was tested in 38 external drugs.

Introduction Concurrent abuse of alcohol and cocaine results in the formation of cocaethylene, a powerful cocaine metabolite. Cocaethylene potentiates the direct cardiotoxic and indirect neurotoxic effects of cocaine or alcohol alone. Case Report A 44-year-old female with history of cocaine and alcohol abuse presented with massive stroke in the emergency department. CT scan revealed extensive left internal carotid artery dissection extending into the left middle and anterior cerebral arteries resulting in a massive left hemispheric infarct, requiring urgent decompressive craniectomy. The patient had a stormy hospital course with multiple episodes of torsades de pointes in the first 4 days requiring aggressive management. She survived all events and was discharged to a nursing home with residual right hemiplegia and aphasia. Conclusion The combination of ethanol and cocaine has been associated with a significant increase in the incidence of neurological and cardiac emergencies including cerebral infarction, intracranial hemorrhage, myocardial infarction, cardiomyopathy, and cardiac arrhythmias. The alteration of cocaine pharmacokinetics and the formation of cocaethylene have been implicated, at least partially, in the increased toxicity of this drug combination.

Recent studies have reported the relation between Torsade de Pointes (TdP) and midmyocardial (M) cell function associated with long QT syndrome. To investigate this relation, we conducted a simulation study with a three-dimensional (3D) heart model incorporating M cells in the anterolateral areas of the model. Parameters of premature cycle-length dependent shortening of action potential duration (APD) and conduction velocity for the M cells were adjusted to induce tachyarrhythmias of TdP type. Under a basic pacing cycle length of 1,000 msec at the sinus node, four successive premature beats of 160-ms interval were generated 300 ms after the first sinus pacing. Setting lower conduction velocity and longer APD to M cells induced sustained TdP-like tachyarrhythmia resembling ECG findings. TdP could not be induced without the presence of M cells. This study suggests that TdP might be caused by reentry around M cells and dispersive refractory areas due to prolonged APD and slow conduction velocity.

Marked prolongation of the QT interval and polymorphic ventricular tachycardia following medication (drug-induced long QT syndrome, diLQTS) is a severe adverse drug reaction (ADR) that phenocopies congenital long QT syndrome (cLQTS) and is one of the leading causes for drug withdrawal and relabeling. We evaluated the frequency of rare non-synonymous variants in genes contributing to the maintenance of heart rhythm in cases of diLQTS using targeted capture coupled to next-generation sequencing. Eleven of 31 diLQTS subjects (36%) carried a novel missense mutation in genes with known congenital arrhythmia associations or with a known cLQTS mutation. In the 26 Caucasian subjects, 23% carried a highly conserved rare variant predicted to be deleterious to protein function in these genes compared with only 2–4% in public databases ( P <0.003). We conclude that the rare variation in genes responsible for congenital arrhythmia syndromes is frequent in diLQTS. Our findings demonstrate that diLQTS is a pharmacogenomic syndrome predisposed by rare genetic variants.

Background Several quinoline and structurally related antimalarial drugs are associated with cardiovascular side effects, particularly hypotension and electrocardiographic QT interval prolongation. A prolonged QT interval is a sensitive but not specific risk marker for the development of Torsade de Pointes—a potentially lethal polymorphic ventricular tachyarrhythmia. The increasing use of quinoline and structurally related antimalarials in mass treatments to eliminate malaria rapidly highlights the need to review their cardiovascular safety profiles. Methods The primary objective of this systematic review was to describe the documented clinical and electrocardiographic cardiovascular side effects of quinine, mefloquine, lumefantrine, piperaquine, halofantrine, chloroquine, sulfadoxine-pyrimethamine, amodiaquine, and primaquine. Trials in healthy subjects or patients with Plasmodium falciparum or P. vivax infection were included if at least two ECGs were conducted during the trial. All trial designs were included except case reports and pooled analyses. Secondary outcomes were the methods adopted by trials for measuring and reporting the QT interval. Results Data from trials published between 1982 and July 2016 were included. A total of 177 trials met the inclusion criteria. 35,448 participants received quinoline antimalarials in these trials, of which 18,436 participants underwent ECG evaluation. Subjects with co-medication use or comorbidities including cardiovascular disease were excluded from the majority of trials. Dihydroartemisinin-piperaquine was the drug most studied (5083 participants). Despite enormous use over the past 60 years, only 1076, 452, and 150 patients had ECG recordings reported in studies of chloroquine, amodiaquine, and primaquine respectively. Transiently high concentrations of quinine, quinidine, and chloroquine following parenteral administration have all been associated with hypotension, but there were no documented reports of death or syncope attributable to a cardiovascular cause, nor of electrocardiographic recordings of ventricular arrhythmia in these trials. The large volume of missing outcome information and the heterogeneity of ECG interval reporting and measurement methodology did not allow pooled quantitative analysis of QT interval changes. Conclusions No serious cardiac adverse effects were recorded in malaria clinical trials of 35,548 participants who received quinoline and structurally related antimalarials with close follow-up including 18,436 individuals who underwent ECG evaluation. While these findings provide further evidence of the rarity of serious cardiovascular events after treatment with these drugs, they also underscore the need for continued strengthening of pharmacovigilance systems for robust detection of rare drug adverse events in real-world populations. A standardised approach to measurement and reporting of ECG data in malaria trials is also needed. Trial registration PROSPERO CRD42016036678

Long QT syndrome (LQTS) is caused by functional alterations in cardiac ion channels and is associated with prolonged cardiac repolarization time and increased risk of ventricular arrhythmias. Inherited type 2 LQTS (LQT2) and drug-induced LQTS both result from altered function of the hERG channel. We investigated whether the electrophysiological characteristics of LQT2 can be recapitulated in vitro using induced pluripotent stem cell (iPSC) technology. Spontaneously beating cardiomyocytes were differentiated from two iPSC lines derived from an individual with LQT2 carrying the R176W mutation in the KCNH2 (HERG) gene. The individual had been asymptomatic except for occasional palpitations, but his sister and father had died suddenly at an early age. Electrophysiological properties of LQT2-specific cardiomyocytes were studied using microelectrode array and patch-clamp, and were compared with those of cardiomyocytes derived from control cells. The action potential duration of LQT2-specific cardiomyocytes was significantly longer than that of control cardiomyocytes, and the rapid delayed potassium channel (IKr) density of the LQT2 cardiomyocytes was significantly reduced. Additionally, LQT2-derived cardiac cells were more sensitive than controls to potentially arrhythmogenic drugs, including sotalol, and demonstrated arrhythmogenic electrical activity. Consistent with clinical observations, the LQT2 cardiomyocytes demonstrated a more pronounced inverse correlation between the beating rate and repolarization time compared with control cells. Prolonged action potential is present in LQT2-specific cardiomyocytes derived from a mutation carrier and arrhythmias can be triggered by a commonly used drug. Thus, the iPSC-derived, disease-specific cardiomyocytes could serve as an important platform to study pathophysiological mechanisms and drug sensitivity in LQT2.

Several antimalarial drugs are known to prolong ventricular repolarization as evidenced by QT/QTc interval prolongation. This can lead to Torsades de Pointes, a potentially lethal ventricular arrhythmia. Whether this is the case with artemisinin-based combination therapies (ACTs) remains uncertain. Assessment of the extent of QTc prolongation with antimalarials is hampered by important variations of heart rate during malaria crises and previous studies have reported highly variable values of QTc prolongations with ACTs. We assessed QTc prolongation with four ACTs, using high quality ECG recording and measurement techniques, during the first episode of malaria in 2,091 African patients enrolled in the WANECAM study which also monitored clinical safety. Using an original and robust method of QTc assessment, independent from heart rate changes and from the method of QT correction, we were able to accurately assess the extent of mean maximum QTc prolongation with the four ACTs tested. There was no evidence of proarrhythmia with any treatment during the study although dihydroartemisinin-piperaquine, artesunate-amodiaquine and artemether-lumefantrine significantly prolonged QTc. The extent of prolongation of ventricular repolarization can be accurately assessed in studies where heart rate changes impede QTc assessment.

Background/Purpose(s). We have extensively used HCQ at 200 mg three times a day (tid) to treat various infections such as Q fever and Whipple’s disease. Serum levels of between 1 μg/ml and 2 μg/ml serum level are recommended to achieve the safety and efficacy of these treatments. Our aim in this paper is to describe our experience regarding the pharmacokinetics and toxicity of HCQ in another infection caused by SARS-CoV-2. Methods. As recommended, we performed electrocardiograms before administering HCQ off-label. The HCQ concentration in the serum was monitored to ensure the effectiveness and safety of the treatment. We retrospectively analysed HCQ serum concentrations measured over time and toxicity data in patients with COVID-19 who were treated with HCQ at the IHU Marseille Infection. We did not treat patients with HCQ contraindications with this medication. Results. We measured HCQ concentrations in 1310 serum samples from 989 patients with COVID-19. The mean ± SD HCQ concentration increased in patients’ sera during treatment from day 1 (0.10 μg/ml ± 0.08) to day 11 (0.85 μg/ml ± 0.44), confirming that HCQ accumulates in the body during short-term therapy. However, the observed concentrations did not exceed the therapeutic range for other indications (0.80–1.20 μg/mL in Q fever patients treated for between 18 and 24 months). In patients treated with HCQ, major side effects included intestinal disorders (nausea, vomiting, and gastric pain) and QT prolongation. No conduction disorders (including torsades de pointes and ventricular arrhythmia), cardiomyopathy, retinopathy, or HCQ-related deaths were observed. Conclusions. In patients treated over a short time period with 200 mg tid of HCQ, therapeutic concentrations in serum were obtained in most patients without significant side effects or complications. Although patients must be carefully evaluated for HCQ contraindications, HCQ 200 mg tid for ten days can be considered an appropriate and safe dosage in patients with COVID-19.