scholarly journals Pharmacogenomics of anesthetic drugs in transgenic LQT1 and LQT2 rabbits reveal genotype-specific differential effects on cardiac repolarization

2008 ◽  
Vol 295 (6) ◽  
pp. H2264-H2272 ◽  
Author(s):  
Katja E. Odening ◽  
Omar Hyder ◽  
Leonard Chaves ◽  
Lorraine Schofield ◽  
Michael Brunner ◽  
...  
Keyword(s):  
Heart Rate ◽  
Polymorphic Ventricular Tachycardia ◽  
In Vivo Model ◽  
Delayed Rectifier ◽  
Cardiac Repolarization ◽  
Drug Induced ◽  
Littermate Control ◽  
Anesthetic Agents ◽  
Anesthetic Drugs ◽  
Repolarization Reserve

Anesthetic agents prolong cardiac repolarization by blocking ion currents. However, the clinical relevance of this blockade in subjects with reduced repolarization reserve is unknown. We have generated transgenic long QT syndromes type 1 (LQT1) and type 2 (LQT2) rabbits that lack slow delayed rectifier K+ currents ( IKs) or rapidly activating K+ currents ( IKr) and used them as a model system to detect the channel-blocking properties of anesthetic agents. Therefore, LQT1, LQT2, and littermate control (LMC) rabbits were administered isoflurane, thiopental, midazolam, propofol, or ketamine, and surface ECGs were analyzed. Genotype-specific heart rate correction formulas were used to determine the expected QT interval at a given heart rate. The QT index (QTi) was calculated as percentage of the observed QT/expected QT. Isoflurane, a drug that blocks IKs, prolonged the QTi only in LQT2 and LMC but not in LQT1 rabbits. Midazolam, which blocks inward rectifier K+ current ( IK1), prolonged the QTi in both LQT1 and LQT2 but not in LMC. Thiopental, which blocks both IKs and IK1, increased the QTi in LQT2 and LMC more than in LQT1. By contrast, ketamine, which does not block IKr, IKs, or IK1, did not alter the QTi in any group. Finally, anesthesia with isoflurane or propofol resulted in lethal polymorphic ventricular tachycardia (pVT) in three out of nine LQT2 rabbits. Transgenic LQT1 and LQT2 rabbits could serve as an in vivo model in which to examine the pharmacogenomics of drug-induced QT prolongation of anesthetic agents and their proarrhythmic potential. Transgenic LQT2 rabbits developed pVT under isoflurane and propofol, underlining the proarrhythmic risk of IKs blockers in subjects with reduced IKr.

scholarly journals The electrophysiological effects of cannabidiol on action potentials and transmembrane potassium currents in rabbit and dog cardiac ventricular preparations

2021 ◽  
Author(s):  
Leila Topal ◽  
Muhammad Naveed ◽  
Péter Orvos ◽  
Bence Pászti ◽  
János Prorok ◽  
...  
Keyword(s):  
Side Effects ◽  
Action Potentials ◽  
Oral Intake ◽  
Potassium Currents ◽  
Delayed Rectifier ◽  
Cardiac Repolarization ◽  
Cardiovascular Side Effects ◽  
Channel Inhibition ◽  
Repolarization Reserve ◽  
Electrophysiological Effects

AbstractCannabis use is associated with known cardiovascular side effects such as cardiac arrhythmias or even sudden cardiac death. The mechanisms behind these adverse effects are unknown. The aim of the present work was to study the cellular cardiac electrophysiological effects of cannabidiol (CBD) on action potentials and several transmembrane potassium currents, such as the rapid (IKr) and slow (IKs) delayed rectifier, the transient outward (Ito) and inward rectifier (IK1) potassium currents in rabbit and dog cardiac preparations. CBD increased action potential duration (APD) significantly in both rabbit (from 211.7 ± 11.2. to 224.6 ± 11.4 ms, n = 8) and dog (from 215.2 ± 9.0 to 231.7 ± 4.7 ms, n = 6) ventricular papillary muscle at 5 µM concentration. CBD decreased IKr, IKs and Ito (only in dog) significantly with corresponding estimated EC50 values of 4.9, 3.1 and 5 µM, respectively, without changing IK1. Although the EC50 value of CBD was found to be higher than literary Cmax values after CBD smoking and oral intake, our results raise the possibility that potassium channel inhibition by lengthening cardiac repolarization might have a role in the possible proarrhythmic side effects of cannabinoids in situations where CBD metabolism and/or the repolarization reserve is impaired.

Abstract 637: A Pharmacogenetic Screen for Modifiers of Drug Induced QT Prolongation Reveals 15 Novel Genes.

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
David J Milan ◽  
Ian L Jones ◽  
Adam H Amsterdam ◽  
David S Rosenbaum ◽  
Dan Roden ◽  
...  
Keyword(s):  
Action Potential ◽  
High Throughput Screening ◽  
High Speed ◽  
Sodium Current ◽  
Qt Prolongation ◽  
Model Systems ◽  
Membrane Microdomains ◽  
Cardiac Repolarization ◽  
Drug Induced ◽  
Repolarization Reserve

Introduction: Variability in response to therapeutic drugs is a vexing problem that has recently begun to yield to intense investigatory efforts. Rigorous pharmacogenetic studies will require model systems that recapitulate the complexity of individual drug responses. Methods: We have employed the voltage sensitive fluorescent dye di 4-ANEPPS and high speed CCD camera acquisition to study cardiac repolarization in embryonic zebrafish. We used a known zebrafish KCNH2 mutant, anemone toxin II (ATXII) and dofetilide to perturb cardiac repolarization. We also undertook a screen of a known panel of 294 mutant zebrafish lines to identify genes that modify the response to IKr block. Results: Using optical mapping, we demonstrate action potential prolongation (Figure 1a,b ), reduced repolarization reserve (Figure 1d ), and spontaneous early afterdepolarizations in zebrafish harboring a mutation in KCNH2. We also show that augmentation of late sodium current using anemone toxin II prolongs action potential duration (Figure 1c ). Using this model we have conducted a pharmacogenetic screen for modifiers of drug-induced QT prolongation, and have identified 15 genes that modulate the response to IKr block, including three members of the heg-san-vtn pathway. Conclusion: Together these data implicate a complex network of non-ion channel proteins functioning in membrane microdomains to regulate channel function, and validate high-throughput screening in zebrafish to dissect complex biologic systems.

scholarly journals Drug-induced and transgenic LQTS rabbit models with reduced repolarization reserve to study proarrhythmic drug effects

2021 ◽  
Author(s):  
Tibor Hornyik
Keyword(s):  
Qt Interval ◽  
Class I ◽  
Cardiac Repolarization ◽  
Channel Blockers ◽  
Class Iii ◽  
Long Qt ◽  
Drug Induced ◽  
Repolarization Reserve ◽  
Prolonged Qt Interval ◽  
Prolonged Qt

Proarrhythmia - the triggering of arrhythmias following drug therapy - is a rare, but potentially lethal side-effect of various drugs, and therefore, a major safety concern during drug development. Most often proarrhythmia is caused by the drugs’ potential to interact with various K+-channels in the heart, leading to a prolongation of cardiac repolarization that is usually observed on the ECG as prolonged QT interval (drug-induced acquired long QT syndrome; aLQTS). Although drug-induced long-QT-related proarrhythmia is most frequently found in patients with impaired cardiac repolarization due to disease-induced structural and/or electrophysiological remodelling of the heart; most cellular, tissue and whole animal model systems used for drug safety screening are based on normal, healthy models. This approach has serious limitations; therefore, novel animal models that mimic the pathophysiological conditions under which drugs display the highest proarrhythmic risk - such as models with impaired cardiac repolarization - would be desirable for proarrhythmia safety testing. The aims of the present study: Drug-induced (HMR-1556 to block IKs) acquired LQTS, and various transgenic (congenital) LQTS rabbit models with impaired cardiac repolarization due to cardio-selective overexpression of loss-of-function mutations of human KCNH2 (HERG-G628S, α-subunit of IKr, loss of IKr, LQT2), KCNE1 (KCNE1-G52R, β-subunit of IKs, decreased IKs, LQT5)[1] or both KCNQ1 and KCNE1 transgenes (LQT2-5) were used to investigate: - the proarrhythmic potential of SZV-270, a novel antiarrhythmic drug candidate with combined Class I/B and Class III effects (acquired LQTS model). - the electrophysiological characteristics of a newly generated, double-transgenic LQT2-5 rabbit model - the utility of transgenic LQT2, LQT5 and LQT2-5 rabbit models for more reliable prediction of drug-induced ventricular arrhythmias Main findings: The acquired LQTS rabbit proarrhythmia model with pharmacologically reduced repolarization reserve (by the IKs inhibitor HMR-1556) was able to predict the known torsadogenic potential of the IKr blocker dofetilide, while indicated no SZV-270-induced proarrhythmia risk. This advantageous electrophysiological effect of the SZV-270 - prolongation of ventricular repolarization without increased arrhythmia risk - is assumed to be attributed to its combined IKr (Class III) and INa (Class I/B) blocking characteristics. Transgenic LQTS rabbit models reflected patients with clinically ‘silent’ - normal QT interval (LQT5) - or 'manifest' - prolonged QT interval (LQT2 and LQT2-5) - impairment in cardiac repolarization reserve capacity due to different pathomechanisms. The LQTS animals were more sensitive in detecting IKr - (LQT5) or IK1/IKs - (LQT2 and LQT2-5) blocking properties of drugs compared to healthy wild type (WT) animals. Impaired QT-shortening capacity at fast heart rates was observed due to disturbed IKs function in LQT5 and LQT2-5. Importantly, the transgenic LQTS models did not only show more pronounced changes in different proarrhythmia markers in response to potassium channel blockers but also exhibited higher incidence, longer duration and more malignant type of ex vivo arrhythmias than WT. Conclusions: Drug-induced and transgenic LQTS rabbit models reflect human pathophysiological settings - patients with reduced repolarization reserve - that favour drug-induced arrhythmia formation. As they demonstrate increased sensitivity to different specific ion-channel blockers (IKr-blockade in LQT5 or in HMR-1556 induced acquired LQTS model, IK1 - and IKs - blockade in LQT2 and LQT2-5), their combined use could provide more reliable, and more thorough prediction of (multi-channel-based) pro-arrhythmic potential of novel drug candidates especially in the setting of impaired cardiac repolarization reserve.

Combined inhibition of key potassium currents has different effects on cardiac repolarization reserve and arrhythmia susceptibility in dogs and rabbits

2015 ◽  
Vol 93 (7) ◽  
pp. 535-544 ◽  
Author(s):  
Zoltán Husti ◽  
Katalin Tábori ◽  
Viktor Juhász ◽  
Tibor Hornyik ◽  
András Varró ◽  
...  
Keyword(s):  
Qt Interval ◽  
Potassium Currents ◽  
Torsades De Pointes ◽  
Cardiac Repolarization ◽  
Development Phase ◽  
Short Term ◽  
Drug Induced ◽  
Reliable Assessment ◽  
Repolarization Reserve ◽  
High Incidence

A reliable assessment of the pro-arrhythmic potential for drugs in the development phase remains elusive. Rabbits and dogs are commonly used to create models of pro-arrhythmia, but the differences between them with respect to repolarizing potassium currents are poorly understood. We investigated the incidence of drug-induced torsades de pointes (TdP) and measured conventional ECG parameters and the short-term variability of the QT interval (STVQT) following combined pharmacological inhibition of IK1+IKs and IK1+IKr in conscious dogs and anesthetized rabbits. A high incidence of TdP was observed following the combined inhibition of IK1+IKs in dogs (67% vs. 14% in rabbits). Rabbits exhibited higher TdP incidence after inhibition of IK1+IKr (72% vs. 14% in dogs). Increased TdP incidence was associated with significantly larger STVQT in both models. The relatively different roles of IK1 and IKs in dog and rabbit repolarization reserve should be taken into account when extrapolating the results from animal models of pro-arrhythmia to humans. A stronger repolarization reserve in dogs (likely due to stronger IK1 and IKs), and the more human-like susceptibility to arrhythmia of rabbits argues for the preferred use of rabbits in the evaluation of adverse pro-arrhythmic effects.

scholarly journals Differences in extent of mechano-induced QT-changes in SQTS, WT and LQTS rabbit models

2021 ◽  
Vol 42 (Supplement_1) ◽  
Author(s):  
S Nimani ◽  
T Hornyik ◽  
N Alerni ◽  
R Lewetag ◽  
L Giammarino ◽  
...  
Keyword(s):  
Heart Rate ◽  
Electrical Coupling ◽  
Qt Dispersion ◽  
Mechanical Function ◽  
Qtc Prolongation ◽  
Drug Induced ◽  
German Research Foundation ◽  
Littermate Control ◽  
Funding Sources ◽  
Acute Changes

Abstract Background Electro-mechanical (EMC) and mechano-electrical coupling (MEC) are essential for normal cardiac function. Alterations in these can result in increased arrhythmia formation. In “electrical” cardiac diseases, long-QT and short-QT syndrome, regional mechanical function is altered via EMC. Purpose In this study, we aimed to investigate how acute changes in mechanics may impact on electrical function (MEC) in these diseases. Methods To determine how acute changes in preload impact on QT duration, adult rabbits of both sexes were given a 6ml/kg BW bolus of 0.9% NaCl IV and 12-lead-ECGs were assessed first in wildtype (WT) and acquired drug-induced (E4031 to block IKr) LQT2 (“aLQT2”) rabbits, and in a second step in transgenic short-QT type 1 (“SQT1”, KCNH2-N588K) and WT littermate control rabbits (“WT-LMC”). Results At baseline, aLQT2 rabbits demonstrated a markedly prolonged heart-rate corrected QTc duration compared to WT (p<0.0001; n=13), with increased QT-dispersion (QTMax-Min [ms], WT 21.4±5.7 vs. aLQT2 25.8±5.8; p=0.003; n=13) and increased short-term variability of QT (STVQT [ms], WT 3.5±1.0 vs. aLQT2 5.3±1.7; p=0.02; n=13), markers for regional and temporal heterogeneity of repolarization, respectively. SQT1 rabbits (n=8) demonstrated a shorter QTc duration compared to WT-LMC (n=10; p=0.04), with no differences in QT-dispersion and STVQT between the two groups. Increased preload acutely prolonged QT and heart-rate corrected QTc in all groups (despite a slight increase in heart-rate by an average of 25 beats/min): in WT [ms] 171.6±11.6 to 213.3±20.3 (p<0.0001) vs. aLQT2 208.9±19.6 to 271.0±37.5 (p<0.0001; n=13 each), and in WT-LMC 171.3±4.8 to 199.2±5.4 (p<0.0001; n=10) vs. SQT1 156.0±4.7 to 177.3±3.5 (p=0.0004; n=8). Importantly, the extent of mechano-induced electrical changes differed among genotypes, with less pronounced QTc prolongation in SQT1 compared to WT-LMC (delta QTc [ms], SQT1 21.2±3.4 (n=8) vs. WT-LMC 27.9±2.8 (n=10; p=0.15)), and a more pronounced QTc prolongation in aLQT2 compared to WT (delta QTc [ms], WT 41.6±14.9 vs. aLQT2 62.1±32.1; p=0.006; n=13 each). Moreover, QT-dispersion was increased significantly upon global mechanical change only in aLQTS (QTMax-Min [ms], 25.8±5.5 to 32.7±12.3; p=0.03; n=13). Conclusion Acute changes in mechanical function result in electrical changes via MEC in SQT1, WT and aLQT2 rabbits. The extent of these changes, however, depends on the underlying QTc duration, with the least pronounced QTc prolongation in SQT1 rabbits, with the shortest QTc, and the most pronounced QTc prolongation in aLQT2 rabbits, with the longest QTc. The most pronounced MEC effects on global QT duration as well as on regional QT dispersion in aLQT2 indicate that acute MEC effects may play an additional role in LQTS-related arrhythmogenesis. FUNDunding Acknowledgement Type of funding sources: Foundation. Main funding source(s): German Research Foundation (DFG) andSwiss National Science Foundation (SNF)

scholarly journals Canine Myocytes Represent a Good Model for Human Ventricular Cells Regarding Their Electrophysiological Properties

2021 ◽  
Vol 14 (8) ◽  
pp. 748
Author(s):  
Péter P. Nánási ◽  
Balázs Horváth ◽  
Fábián Tar ◽  
János Almássy ◽  
Norbert Szentandrássy ◽  
...  
Keyword(s):  
Action Potential ◽  
Time Course ◽  
Laboratory Animals ◽  
Delayed Rectifier ◽  
Ion Currents ◽  
Human Cardiomyocytes ◽  
Ventricular Cells ◽  
Repolarization Reserve ◽  
Electrophysiological Studies ◽  
K Current

Due to the limited availability of healthy human ventricular tissues, the most suitable animal model has to be applied for electrophysiological and pharmacological studies. This can be best identified by studying the properties of ion currents shaping the action potential in the frequently used laboratory animals, such as dogs, rabbits, guinea pigs, or rats, and comparing them to those of human cardiomyocytes. The authors of this article with the experience of three decades of electrophysiological studies, performed in mammalian and human ventricular tissues and isolated cardiomyocytes, summarize their results obtained regarding the major canine and human cardiac ion currents. Accordingly, L-type Ca2+ current (ICa), late Na+ current (INa-late), rapid and slow components of the delayed rectifier K+ current (IKr and IKs, respectively), inward rectifier K+ current (IK1), transient outward K+ current (Ito1), and Na+/Ca2+ exchange current (INCX) were characterized and compared. Importantly, many of these measurements were performed using the action potential voltage clamp technique allowing for visualization of the actual current profiles flowing during the ventricular action potential. Densities and shapes of these ion currents, as well as the action potential configuration, were similar in human and canine ventricular cells, except for the density of IK1 and the recovery kinetics of Ito. IK1 displayed a largely four-fold larger density in canine than human myocytes, and Ito recovery from inactivation displayed a somewhat different time course in the two species. On the basis of these results, it is concluded that canine ventricular cells represent a reasonably good model for human myocytes for electrophysiological studies, however, it must be borne in mind that due to their stronger IK1, the repolarization reserve is more pronounced in canine cells, and moderate differences in the frequency-dependent repolarization patterns can also be anticipated.

scholarly journals An explainable algorithm for detecting drug-induced QT-prolongation at risk of torsades de pointes (TdP) regardless of heart rate and T-wave morphology

2021 ◽  
Vol 131 ◽  
pp. 104281
Author(s):  
Alaa Alahmadi ◽  
Alan Davies ◽  
Jennifer Royle ◽  
Leanna Goodwin ◽  
Katharine Cresswell ◽  
...  
Keyword(s):  
At Risk ◽  
Heart Rate ◽  
Torsades De Pointes ◽  
Qt Prolongation ◽  
Drug Induced ◽  
T Wave ◽  
Wave Morphology

scholarly journals Antipsychotics in routine treatment are minor contributors to QT prolongation compared to genetics and age

2021 ◽  
pp. 026988112110034
Author(s):  
Leif Hommers ◽  
Maike Scherf-Clavel ◽  
Roberta Stempel ◽  
Julian Roth ◽  
Matthias Falter ◽  
...  
Keyword(s):  
Qt Interval ◽  
Multivariate Regression Analysis ◽  
Cardiac Repolarization ◽  
Qtc Interval ◽  
Serum Concentrations ◽  
Drug Induced ◽  
Individual Level ◽  
Main Determinants ◽  
The Individual ◽  
Polygenic Variation

Background: Drug-induced prolongation of cardiac repolarization limits the treatment with many psychotropic drugs. Recently, the contribution of polygenic variation to the individual duration of the QT interval was identified. Aims: To explore the interaction between antipsychotic drugs and the individual polygenic influence on the QT interval. Methods: Retrospective analysis of clinical and genotype data of 804 psychiatric inpatients diagnosed with a psychotic disorder. The individual polygenic influence on the QT interval was calculated according to the method of Arking et al. Results: Linear regression modelling showed a significant association of the individual polygenic QT interval score (ßstd = 0.176, p < 0.001) and age (ßstd = 0.139, p < 0.001) with the QTc interval corrected according to Fridericia’s formula. Sex showed a nominal trend towards significance (ßstd = 0.064, p = 0.064). No association was observed for the number of QT prolonging drugs according to AZCERT taken. Subsample analysis ( n = 588) showed a significant association of potassium serum concentrations with the QTc interval (ßstd = −0.104, p = 0.010). Haloperidol serum concentrations were associated with the QTc interval only in single medication analysis ( n = 26, ßstd = 0.101, p = 0.004), but not in multivariate regression analysis. No association was observed for aripiprazole, clozapine, quetiapine and perazine, while olanzapine and the sum of risperidone and its metabolite showed a negative association. Conclusions: Individual genetic factors and age are main determinants of the QT interval. Antipsychotic drug serum concentrations within the therapeutic range contribute to QTc prolongation on an individual level.

scholarly journals Safety and effectiveness of drug therapy for the acutely agitated patient (Part I)

2013 ◽  
pp. 127-136
Author(s):  
Gianluca Airoldi
Keyword(s):  
Heart Rate ◽  
Qt Interval ◽  
Physical Restraint ◽  
Safety Data ◽  
Surrogate Marker ◽  
Diagnostic Procedures ◽  
Torsades De Pointes ◽  
Long Qt ◽  
Drug Induced ◽  
Qt Interval Prolongation

Acute agitation occurs in a variety of medical and psychiatric conditions, and the management of agitated, abusive, or violent patients is a common problem in the emergency department. Rapid control of potentially dangerous behaviors by physical restraint and pharmacologic tranquillization is crucial to ensure the safety of the patient and health-care personnel and to allow diagnostic procedures and treatment of the underlying condition. The purpose of this article (the first in a 2-part series) is to review the extensive safety data published on the antipsychotic medications currently available for managing situations of this type, including older neuroleptics like haloperidol, chlorpromazine, and pimozide as well as a number of the newer atypical antipsychotics (olanzapine, risperidone, ziprasidone). Particular attention is focused on the ability of these drugs to lengthen the QT interval in surface electrocardiograms. This adverse effect is of major concern, especially in light of the reported relation between QT interval and the risk of sudden death. In patients with the congenital long-QT syndrome, a long QT interval is associated with a fatal paroxysmal ventricular arrhythmia knownas torsades de pointes. Therefore, careful evaluation of the QT-prolonging properties and arrhythmogenic potential of antipsychotic drugs is urgently needed. Clinical assessment of drug-induced QT-interval prolongation is strictly dependent on the quality of electrocardiographic data and the appropriateness of electrocardiographic analyses. Unfortunately, measurement imprecision and natural variability preclude a simple use of the actually measured QT interval as a surrogate marker of drug-induced proarrhythmia. Because the QT interval changes with heart rate, a rate-corrected QT interval (QTc) is commonly used when evaluating a drug’s effect. In clinical settings, themost widely used formulas for rate-correction are those of Bazett (QTc=QT/RR^0.5) and Fridericia (QTc=QT/RR^0.33), both of which standardize themeasuredQTinterval to an RRinterval of 1 s (heart rate of 60 bpm).However, QT variability can also be influenced by other factors that are more difficult to measure, including body fat, meals, psycho-physical distress, and circadian and seasonal fluctuations.

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