Anesthesia and Arrhythmogenesis in the Chronic Atrioventricular Block Dog Model

Dunnink, Albert; Sharif, Shahnam; Oosterhoff, Peter; Winckels, Stephan K.G.; Montagne, Denise; Beekman, Jet D.M.; Nagel, Roel van der; Heyden, Marcel A.G. van der; Vos, Marc A.

doi:10.1097/fjc.0b013e3181da7768

Cited by 20 publications

(13 citation statements)

References 26 publications

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“…In this model, compensated hypertrophy and numerous adaptations in ion channels and calcium handling proteins have been reported (Oros et al ., ),including down‐regulation of the delayed rectifier potassium currents, increase of the sodium‐calcium exchange current and increased calcium content of the sarcoplasmic reticulum, which provides larger calcium transients, and an increase of LV contractility parameters (Volders et al ., ; De Groot et al ., ; Sipido et al ., ). Besides the ventricular remodelling, the anaesthetic regimen is a key ingredient for TdP induction (Dunnink et al ., ).…”

Section: Discussionmentioning

confidence: 97%

The electromechanical window is no better than QT prolongation to assess risk of Torsade de Pointes in the complete atrioventricular block model in dogs

Stams

Bourgonje

Beekman

et al. 2014

British J Pharmacology

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BACKGROUND AND PURPOSEThe electromechanical window (EMW), the interval between the end of the T-wave and the end of the left ventricular pressure (LVP) curve, has recently been proposed as a predictor of risk of Torsade de Pointes (TdP) in healthy animals, whereby a negative EMW (mechanical relaxation earlier than repolarization) after drug administration indicates an increased TdP risk. The aims of this study were to assess (i) the effect of the ventricular remodelling in the canine chronic, complete atrioventricular block (CAVB) model on EMW; (ii) the effect of the IKr-blocker dofetilide on EMW; and (iii) the correlation of EMW with TdP inducibility. EXPERIMENTAL APPROACHOur 11 year database of experiments of CAVB in dogs under general anaesthesia was reviewed and experiments included if ECG and LVP were recorded simultaneously at spontaneous rhythm. In total, 89 experiments in 44 dogs were appropriate and were analysed. KEY RESULTSDuring normally conducted sinus rhythm or acute atrioventricular block, EMW was positive. During CAVB, EMW was decreased to negative values. Dofetilide further reduced EMW before inducing repetitive TdP in 82% of the experiments. However, subclassification into inducible and non-inducible dogs revealed no difference in EMW. Analysis of the components of EMW revealed that the observed changes in EMW were solely caused by QT prolongation. CONCLUSIONS AND IMPLICATIONSIn the canine CAVB model, ventricular remodelling and IKr block by dofetilide are associated with negative EMW values, but this reflects QT prolongation, and implies that the EMW lacks specificity to predict dofetilide-induced TdP. AbbreviationsAAVB, acute complete atrioventricular block; AV, atrioventricular; CAVB, chronic complete AV block; DAD, delayed afterdepolarization; EAD, early afterdepolarization; EMW, electromechanical window; IKr, rapidly activating delayed rectifier potassium current; IKs, slowly activating delayed rectifier potassium current; LV, left ventricle; LVP, left ventricular pressure; Q-LVPend, interval from QRS onset to the end of the LVP curve; QTC, heart rate corrected QT interval; TdP, Torsade de Pointes

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Section: Discussionmentioning

confidence: 97%

The electromechanical window is no better than QT prolongation to assess risk of Torsade de Pointes in the complete atrioventricular block model in dogs

Stams

Bourgonje

Beekman

et al. 2014

British J Pharmacology

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“…Detailed description of the experimental set-up has been reported previously (Dunnink et al, 2010, 2012). In brief, all experiments were performed under general anesthesia with induction via pentobarbital sodium 25 mg/kg i.v.…”

Section: Methodsmentioning

confidence: 99%

Pro-Arrhythmic Ventricular Remodeling Is Associated With Increased Respiratory and Low-Frequency Oscillations of Monophasic Action Potential Duration in the Chronic Atrioventricular Block Dog Model

et al. 2019

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In addition to beat-to-beat fluctuations, action potential duration (APD) oscillates at (1) a respiratory frequency and (2) a low frequency (LF) (<0.1 Hz), probably caused by bursts of sympathetic nervous system discharge. This study investigates whether ventricular remodeling in the chronic AV block (CAVB) dog alters these oscillations of APD and whether this has consequences for arrhythmogenesis. We performed a retrospective analysis of 39 dog experiments in sinus rhythm (SR), acute AV block (AAVB), and after 2 weeks of chronic AV block. Spectral analysis of left ventricular monophasic action potential duration (LV MAPD) was done to quantify respiratory frequency (RF) power and LF power. Dofetilide (0.025 mg/kg in 5 min) was infused to test for inducibility of Torsade de Pointes (TdP) arrhythmias. RF power was significantly increased at CAVB compared to AAVB and SR (log[RF] of −1.13 ± 1.62 at CAVB vs. log[RF] of −2.82 ± 1.24 and −3.29 ± 1.29 at SR and AAVB, respectively, p < 0.001). LF power was already significantly increased at AAVB and increased even further at CAVB (−3.91 ± 0.70 at SR vs. −2.52 ± 0.85 at AAVB and −1.14 ± 1.62 at CAVB, p < 0.001). In addition, LF power was significantly larger in inducible CAVB dogs (log[LF] −0.6 ± 1.54 in inducible dogs vs. −2.56 ± 0.43 in non-inducible dogs, p < 0.001). In conclusion, ventricular remodeling in the CAVB dog results in augmentation of respiratory and low-frequency (LF) oscillations of LV MAPD. Furthermore, TdP-inducible CAVB dogs show increased LF power.

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“… 13 In addition, electrical remodeling occurs and mainly comprises the downregulation of the slow and rapid components of the delayed rectifier outward potassium currents (I Ks and I Kr ) along with disturbed calcium handling. 13 Besides ventricular remodeling, 18 also anesthesia 19 and bradycardia 20 predispose approximately 75% of canine hearts to develop TdP on a class III antiarrhythmic (eg, dofetilide or sertindole) challenge (Fig. 1 A).…”

Section: Arrhythmogenesis In the Cavb Dog Modelmentioning

confidence: 99%

Short-term Variability of Repolarization Is Superior to Other Repolarization Parameters in the Evaluation of Diverse Antiarrhythmic Interventions in the Chronic Atrioventricular Block Dog

Bossu

Varkevisser²,

Beekman³

et al. 2017

Journal of Cardiovascular Pharmacology

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Anesthesia and Arrhythmogenesis in the Chronic Atrioventricular Block Dog Model

Abstract: Thiopental anesthesia causes arrhythmias sec, whereas anesthesia in general predisposes for drug-induced TdP in the CAVB dog. In combination with dofetilide, T + I has a more arrhythmic outcome than P + I or P + H.

Cited by 20 publications

References 26 publications

The electromechanical window is no better than QT prolongation to assess risk of Torsade de Pointes in the complete atrioventricular block model in dogs

The electromechanical window is no better than QT prolongation to assess risk of Torsade de Pointes in the complete atrioventricular block model in dogs

Pro-Arrhythmic Ventricular Remodeling Is Associated With Increased Respiratory and Low-Frequency Oscillations of Monophasic Action Potential Duration in the Chronic Atrioventricular Block Dog Model

Short-term Variability of Repolarization Is Superior to Other Repolarization Parameters in the Evaluation of Diverse Antiarrhythmic Interventions in the Chronic Atrioventricular Block Dog

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