Safe electrophysiologic profile of dexmedetomidine in different experimental arrhythmia models

AbstractPrevious studies suggest an impact of dexmedetomidine on cardiac electrophysiology. However, experimental data is sparse. Therefore, purpose of this study was to investigate the influence of dexmedetomidine on different experimental models of proarrhythmia. 50 rabbit hearts were explanted and retrogradely perfused. The first group (n = 12) was treated with dexmedetomidine in ascending concentrations (3, 5 and 10 µM). Dexmedetomidine did not substantially alter action potential duration (APD) but reduced spatial dispersion of repolarization (SDR) and rendered the action potentials rectangular, resulting in no proarrhythmia. In further 12 hearts, erythromycin (300 µM) was administered to simulate long-QT-syndrome-2 (LQT2). Additional treatment with dexmedetomidine reduced SDR, thereby suppressing torsade de pointes. In the third group (n = 14), 0.5 µM veratridine was added to reduce the repolarization reserve. Further administration of dexmedetomidine did not influence APD, SDR or the occurrence of arrhythmias. In the last group (n = 12), a combination of acetylcholine (1 µM) and isoproterenol (1 µM) was used to facilitate atrial fibrillation. Additional treatment with dexmedetomidine prolonged the atrial APD but did not reduce AF episodes. In this study, dexmedetomidine did not significantly alter cardiac repolarization duration and was not proarrhythmic in different models of ventricular and atrial arrhythmias. Of note, dexmedetomidine might be antiarrhythmic in acquired LQT2 by reducing SDR.

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Beneficial electrophysiologic effects of sacubitril in different arrhythmia syndromes

European Heart Journal ◽

10.1093/ehjci/ehaa946.0327 ◽

2020 ◽

Vol 41 (Supplement_2) ◽

Author(s):

G Frommeyer ◽

D Dimanski ◽

C Ellermann ◽

J Wolfes ◽

L Eckardt

Keyword(s):

Long Qt Syndrome ◽

Cardiac Electrophysiology ◽

Torsade De Pointes ◽

Additional Treatment ◽

Long Qt ◽

Beneficial Effects ◽

Dispersion Of Repolarization ◽

Qt Syndrome ◽

The Impact ◽

Antiarrhythmic Effects

Abstract Background Previous studies report conflicting data regarding anti- or proarrhythmic effects of sacubitril. The aim of the presents study was to assess the impact of sacubitril in different arrhythmia models. Methods and results In 12 isolated rabbit hearts, sacubitril was infused in rising concentrations (3, 5, 10μM) after obtaining baseline data. In 12 further hearts, erythromycin was administered to simulate long QT syndrome-2 (LQT2). Other 12 hearts were perfused with veratridine to mimic long QT syndrome-3 (LQT3). Both LQT groups were treated with sacubitril (5μM). Ventricular vulnerability was assessed by a pacing protocol. AV-blocked bradycardic hearts were perfused with a hypokalemic solution to trigger torsade de pointes (TdP). In further 13 hearts, AF was induced by a combination of acetylcholine and isoproterenol (ACH/ISO) and sacubitril (5μM) was added afterwards. With sacubitril, action potential duration (APD) was abbreviated whereas spatial dispersion of repolarization (SDR) remained stable. In both LQT groups, APD and SDR were increased. Infusion of sacubitril reduced APD and SDR in the LQT2-group (APD: −21 ms, p<0.05; SDR: −8 ms, p=ns) and did not alter APD but reduced SDR in the LQT3-group (APD: +2 ms, p=ns; SDR: −9 ms, p<0.05). Ventricular vulnerability was not altered by sacubitril. No TdP were observed with sacubitril treatment or under baseline conditions in any group. Erythromycin provoked 43 episodes of TdP (p<0.05). Additional treatment with sacubitril significantly suppressed TdP (3 episodes, p<0.05). With veratridine, 16 episodes of TdP (p=0.07) occurred. Further treatment with sacubitril did not reduce TdP (10 episodes, p=ns) significantly. Infusion of ACH/ISO led to an increased inducibility of atrial fibrillation (31 vs. 7 episodes). Additional infusion of sacubitril increased atrial ERP (+21ms, p<0.05) and reduced inducibility of AF (9 episodes). Conclusion Sacubitril abbreviated APD and was not proarrhythmic. SDR is a major pathomechanism of TdP and was reduced by sacubitril in both LQT groups. Thereby, sacubitril exhibits antiarrhythmic effects in LQT2 and may be beneficial in LQT3. Furthermore, sacubitril suppressed AF by prolonging aERP. Our results indicate beneficial effects of sacubitril on cardiac electrophysiology. Funding Acknowledgement Type of funding source: None

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

Archives of Toxicology ◽

10.1007/s00204-021-03086-0 ◽

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.

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Reduction of repolarization reserve unmasks the proarrhythmic role of endogenous late Na+ current in the heart

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00467.2009 ◽

2009 ◽

Vol 297 (3) ◽

pp. H1048-H1057 ◽

Cited By ~ 42

Author(s):

Lin Wu ◽

Sridharan Rajamani ◽

Hong Li ◽

Craig T. January ◽

John C. Shryock ◽

...

Keyword(s):

Torsade De Pointes ◽

Polymorphic Ventricular Tachycardia ◽

Isolated Hearts ◽

T Wave ◽

Dispersion Of Repolarization ◽

Transmural Dispersion Of Repolarization ◽

Repolarization Reserve ◽

Monophasic Action Potentials ◽

Transmural Dispersion

Reduction of repolarization reserve increases the risk of arrhythmia. We hypothesized that inhibition of K+ current ( IK) to decrease repolarization reserve would unmask the proarrhythmic role of endogenous, physiological late Na+ current (late INa). Monophasic action potentials (MAP) and 12-lead electrocardiogram were recorded from female rabbit isolated hearts. To block IK and reduce repolarization reserve, E-4031, 4-aminopyridine, and BaCl2 were used; to block endogenous late INa, tetrodotoxin (TTX) and ranolazine were used. E-4031 (1–60 nM) concentration-dependently prolonged MAP duration (MAPD90) and increased duration of the T wave from Tpeak to Tend (Tpeak-Tend), transmural dispersion of repolarization (TDR), and beat-to-beat variability (BVR) of MAPD90. E-4031 caused spontaneous and pause-triggered polymorphic ventricular tachycardia [ torsade de pointes (TdP)]. In the presence of 60 nM E-4031, TTX (0.6–3 μM) and ranolazine (5–10 μM) shortened MAPD90, decreased TDR, BVR, and Tpeak-Tend ( n = 9–20, P < 0.01), and abolished episodes of TdP. In hearts treated with BaCl2 or 4-aminopyridine plus E-4031, TTX (0.6–3 μM) shortened MAPD90 and decreased Tpeak-Tend. Ranolazine could not reverse the effect of E-4031 to inhibit human ether-a-go-go-related gene (HERG) K+ current; thus, the reversal by ranolazine of effects of E-4031 was likely due to inhibition of late INa and not to antagonism of the HERG-blocking action of E-4031. We conclude that endogenous, physiological late INa contributes to arrhythmogenesis in hearts with reduced repolarization reserve. Inhibition of this current partially reverses MAPD prolongation and abolishes arrhythmic activity caused by IK inhibitors.

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Novel experimental results in human cardiac electrophysiology: measurement of the Purkinje fibre action potential from the undiseased human heart

Canadian Journal of Physiology and Pharmacology ◽

10.1139/cjpp-2014-0532 ◽

2015 ◽

Vol 93 (9) ◽

pp. 803-810 ◽

Cited By ~ 2

Author(s):

Norbert Nagy ◽

Tamás Szél ◽

Norbert Jost ◽

András Tóth ◽

Julius Gy. Papp ◽

...

Keyword(s):

Action Potential ◽

Action Potentials ◽

Cardiac Electrophysiology ◽

Human Heart ◽

Expression Profiles ◽

Purkinje Fibre ◽

Purkinje Fibres ◽

Repolarization Reserve ◽

Protein Expression Profiles ◽

First Time

Data obtained from canine cardiac electrophysiology studies are often extrapolated to the human heart. However, it has been previously demonstrated that because of the lower density of its K+ currents, the human ventricular action potential has a less extensive repolarization reserve. Since the relevance of canine data to the human heart has not yet been fully clarified, the aim of the present study was to determine for the first time the action potentials of undiseased human Purkinje fibres (PFs) and to compare them directly with those of dog PFs. All measurements were performed at 37 °C using the conventional microelectrode technique. At a stimulation rate of 1 Hz, the plateau potential of human PFs is more positive (8.0 ± 1.8 vs 8.6 ± 3.4 mV, n = 7), while the amplitude of the spike is less pronounced. The maximal rate of depolarization is significantly lower in human PKs than in canine PFs (406.7 ± 62 vs 643 ± 36 V/s, respectively, n = 7). We assume that the appreciable difference in the protein expression profiles of the 2 species may underlie these important disparities. Therefore, caution is advised when canine PF data are extrapolated to humans, and further experiments are required to investigate the characteristics of human PF repolarization and its possible role in arrhythmogenesis.

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Severe Bradycardia Increases the Incidence and Severity of Torsade de Pointes Arrhythmias by Augmenting Preexistent Spatial Dispersion of Repolarization in the CAVB Dog Model

Frontiers in Physiology ◽

10.3389/fphys.2021.642083 ◽

2021 ◽

Vol 12 ◽

Author(s):

Valerie Y. H. van Weperen ◽

Albert Dunnink ◽

Alexandre Bossu ◽

Jet D. M. Beekman ◽

Veronique M. F. Meijborg ◽

...

Keyword(s):

Spatial Dispersion ◽

Torsade De Pointes ◽

Left Ventricular ◽

Dispersion Of Repolarization ◽

Dog Model ◽

Severe Bradycardia ◽

Idioventricular Rhythm ◽

Surface Electrocardiogram ◽

Temporal Dispersion ◽

Unipolar Electrograms

IntroductionTorsade de pointes arrhythmias (TdP) in the chronic atrioventricular block (CAVB) dog model result from proarrhythmic factors, which trigger TdP and/or reinforce the arrhythmic substrate. This study investigated electrophysiological and arrhythmogenic consequences of severe bradycardia for TdP.MethodsDofetilide (25 μg/kg per 5 min) was administered to eight anesthetized, idioventricular rhythm (IVR) remodeled CAVB dogs in two serial experiments: once under 60 beats per minute (bpm), right ventricular apex paced (RVA60) conditions, once under more bradycardic IVR conditions. Recordings included surface electrocardiogram and short-term variability (STV) of repolarization from endocardial unipolar electrograms. TdP inducibility (three or more episodes within 10 min after start of dofetilide) and arrhythmic activity scores (AS) were established. Mapping experiments in 10 additional dogs determined the effect of lowering rate on STV and spatial dispersion of repolarization (SDR) in baseline.ResultsIVR-tested animals had longer baseline RR-interval (1,403 ± 271 ms) and repolarization intervals than RVA60 animals. Dofetilide increased STV similarly under both rhythm strategies. Nevertheless, TdP inducibility and AS were higher under IVR conditions (6/8 and 37 ± 27 vs. 1/8 and 8 ± 12 in RVA60, respectively, both p < 0.05). Mapping: Pacing from high (128 ± 10 bpm) to middle (88 ± 10 bpm) to experimental rate (61 ± 3 bpm) increased all electrophysiological parameters, including interventricular dispersion, due to steeper left ventricular restitution curves, and intraventricular SDR: maximal cubic dispersion from 60 ± 14 (high) to 69 ± 17 (middle) to 84 ± 22 ms (p < 0.05 vs. high and middle rate).ConclusionIn CAVB dogs, severe bradycardia increases the probability and severity of arrhythmic events by heterogeneously causing electrophysiological instability, which is mainly reflected in an increased spatial, and to a lesser extent temporal, dispersion of repolarization.

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Dexmedetomidine reduces ventricular arrhythmias in a model of drug-induced QT-prolongation

European Heart Journal ◽

10.1093/ehjci/ehaa946.0398 ◽

2020 ◽

Vol 41 (Supplement_2) ◽

Author(s):

G Frommeyer ◽

J Brandt ◽

C Ellermann ◽

J Wolfes ◽

L Eckardt

Keyword(s):

Qt Interval ◽

Ventricular Arrhythmias ◽

Spatial Dispersion ◽

Torsade De Pointes ◽

Qt Prolongation ◽

Recent Experimental Data ◽

Moderate Increase ◽

Drug Induced ◽

Dispersion Of Repolarization ◽

Significant Prolongation

Abstract Background Dexmedetomidine is increasingly employed for conscious sedation during electrophysiological procedures. Recent experimental data have suggested direct effects of dexmedetomidine on cardiac electrophysiology. The aim of the present study was to assess the effects of dexmedetomidin on drug-induced QT-prolongation. Methods and results In 12 isolated rabbit hearts the macrolide antibiotic erythromycin (300μM) was infused as a potent Ikr blocker after obtaining baseline data. Eight endo- and epicardial monophasic action potentials and a simultaneously recorded 12-lead ECG showed a significant prolongation of QT-interval (+25ms, p<0.05) accompanied by a moderate increase of action potential duration (APD, +5ms, p=ns) after infusion of erythromycin as compared with baseline. Effective refractory period (ERP) was also elevated (+33ms, p<0.05). Erythromycin (+26ms, p<0.05) also significantly increased spatial dispersion of repolarisation. Additional infusion of dexmedetomidine (3μM) resulted in a rather stable QT-interval (+7ms, p=ns) and APD (+7ms, p=ns) as compared with sole erythromycin treatment. Of note, a significant decrease of spatial dispersion (−24ms, p<0.05) was observed while ERP was moderately increased (+13ms, p=ns). Lowering of potassium concentration in bradycardic AV-blocked hearts resulted in the occurrence of early afterdepolarizations (EAD) and drug induced proarrhythmia with torsade de pointes in 6 of 12 erythromycin-treated hearts (40 episodes). Additional infusion of dexmedetomidine reduced the occurrence of torsade de pointes (4 of 12 hearts, 9 episodes). Conclusion Infusion of dexmedetomidine resulted in a reduction of spatial dispersion of repolarization in the presence of a prolonged repolarization period. This resulted in a reduction of torsade de pointes with dexmedetomidine. Furthermore, an increase of ventricular refractory periods reduced inducibility of ventricular arrhythmias. Thus, in an experimental setting dexmedetomidine shows significant antiarrhythmic effects, which may influence electrophysiologic findings during clinical electrophysiologic studies. This needs to be studied in the clinical setting. Funding Acknowledgement Type of funding source: None

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