Impacts of Surgically Performed Renal Denervation on the Cardiovascular and Electrophysiological Variables in the Chronic Atrioventricular Block Dogs　– Comparison With Those of Amiodarone Treatment –

Wada, Takeshi; Ohara, Hiroshi; Nakamura, Yuji; Yokoyama, Hirofumi; Cao, Xin; Izumi-Nakaseko, Hiroko; Ando, Kentaro; Murakoshi, Nobuyuki; Sato, Akira; Aonuma, Kazutaka; Takahara, Akira; Nakazato, Yuji; Sugiyama, Atsushi

doi:10.1253/circj.cj-16-0198

Cited by 4 publications

(3 citation statements)

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“…The CAVB dog model is a widely used animal model to study ventricular remodelling and its relation with ventricular arrhythmias. [16–18] It is a model of compensated biventricular hypertrophy with a long QT phenotype and is reproducibly inducible for torsades de pointes (TdP) arrhythmias when challenged with a delayed rectifier outward potassium current (IKr)-blocker such as dofetilide. [19–21] Creation of complete atrioventricular block, by means of His bundle ablation, forces the ventricles to activate from an infranodal focus of the conduction system resulting in a slow idioventricular rhythm.…”

Section: Ventricular Remodelling In the Chronic Complete Atrioventricmentioning

confidence: 99%

“…[13,22–28] The most striking feature of electrical remodelling is the prolongation of repolarisation time. [15,18,28] On a cellular level, this is explained by the downregulation of the slow and rapid components of the delayed rectifier outward potassium currents (IKs and IKr). [29] The prolonged action potential duration (APD) provides more time for the contractile process of the cardiomyocyte.…”

Section: Ventricular Remodelling In the Chronic Complete Atrioventricmentioning

confidence: 99%

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The Increment of Short-term Variability of Repolarisation Determines the Severity of the Imminent Arrhythmic Outcome

Smoczyńska

Beekman

Vos

2019

Arrhythm Electrophysiol Rev

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Ventricular remodelling can make the heart more susceptible to ventricular arrhythmias like torsades de pointes. Understanding the underlying mechanisms of initiation of ventricular arrhythmias and the determining factors for its severity has the potential to uncover new interventions. Beat-to-beat variation of repolarisation, quantified as short-term variability of repolarisation (STV), has been identified as an important factor contributing to arrhythmogenesis. This article provides an overview of experimental data about STV in relation to the initiation of torsades de pointes in a canine model of complete chronic atrioventricular block susceptible to torsades de pointes arrhythmias. Furthermore, it explores STV in relation to the severity of the arrhythmic outcome.

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Section: Ventricular Remodelling In the Chronic Complete Atrioventricmentioning

confidence: 99%

Section: Ventricular Remodelling In the Chronic Complete Atrioventricmentioning

confidence: 99%

The Increment of Short-term Variability of Repolarisation Determines the Severity of the Imminent Arrhythmic Outcome

Smoczyńska

Beekman

Vos

2019

Arrhythm Electrophysiol Rev

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“…The chronic AV-block (CAVB) dog model is a widely used animal model to study ventricular remodeling and its relation with ventricular arrhythmias ( Oros et al, 2008 ; Zhou et al, 2008 ; Wada et al, 2016 ). In this model, creation of third degree AV-block results in bradycardia and volume overload.…”

Section: Introductionmentioning

confidence: 99%

An Augmented Negative Force-Frequency Relationship and Slowed Mechanical Restitution Are Associated With Increased Susceptibility to Drug-Induced Torsade de Pointes Arrhythmias in the Chronic Atrioventricular Block Dog

et al. 2018

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Introduction: In the chronic AV-block (CAVB) dog model, structural, contractile, and electrical remodeling occur, which predispose the heart to dofetilide-induced Torsade de Pointes (TdP) arrhythmias. Previous studies found a relation between electrical remodeling and inducibility of TdP, while structural remodeling is not a prerequisite for arrhythmogenesis. In this study, we prospectively assessed the relation between in vivo markers of contractile remodeling and TdP inducibility.Methods: In 18 anesthetized dogs, the maximal first derivative of left ventricular pressure (LV dP/dtmax) was assessed at acute AV-block (AAVB) and after 2 weeks of chronic AV-block (CAVB2). Using pacing protocols, three markers of contractile remodeling, i.e., force-frequency relationship (FFR), mechanical restitution (MR), and post-extrasystolic potentiation (PESP) were determined. Infusion of dofetilide (0.025 mg/kg in 5 min) was used to test for TdP inducibility.Results: After infusion of dofetilide, 1/18 dogs and 12/18 were susceptible to TdP-arrhythmias at AAVB and CAVB2, respectively (p = 0.001). The inducible dogs at CAVB2 showed augmented contractility at a CL of 1200 ms (2354 ± 168 mmHg/s in inducible dogs versus 1091 ± 59 mmHg/s in non-inducible dogs, p < 0.001) with a negative FFR, while the non-inducible dogs retained their positive FFR. The time constant (TC) of the MR curve was significantly higher in the inducible dogs (158 ± 7 ms versus 97 ± 8 ms, p < 0.0001). Furthermore, a linear correlation was found between a weighted score of the number and severity of arrhythmias and contractile parameters, i.e., contractility at CL of 1200 ms (r = 0.73, p = 0.002), the slope of the FFR (r = -0.58, p = 0.01) and the TC of MR (r = 0.66, p = 0.003). Thus, more severe arrhythmias were seen in dogs with the most pronounced contractile remodeling.Conclusion: Contractile remodeling is concomitantly observed with susceptibility to dofetilide-induced TdP-arrhythmias. The inducible dogs show augmented contractile remodeling compared to non-inducible dogs, as seen by a negative FFR, higher maximal response of MR and PESP and slowed MR kinetics. These altered contractility parameters could reflect disrupted Ca2+ handling and Ca2+-overload, which predispose the heart to delayed- and early afterdepolarizations that could trigger TdP-arrhythmias.

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Precise safety pharmacology studies of lapatinib for onco-cardiology assessed using in vivo canine models

Ando

Wada

Cao

2020

Sci Rep

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cancer chemotherapies have improved prognosis in cancer patients, resulting in a large and rapidly increasing number of cancer survivors. "onco-cardiology" or "cardio-oncology" is a new discipline for addressing the unanticipated cardiac side effects of newly developed cancer drugs. Lapatinib, a tyrosine kinase inhibitor suppressing the epidermal growth factor receptor and ErbB2, has been used in advanced or metastatic breast cancer treatment. Reportedly, lapatinib has induced cardiovascular adverse events including Qt-interval prolongation and heart failure. However, they have not been predicted by preclinical studies. Hence, a new method to assess the tyrosine kinase inhibitor-induced adverse effects needs to be established. Here, we intravenously administered lapatinib to halothaneanaesthetised dogs, evaluating cardiohemodynamic, electrophysiological, and echocardiographic profiles for pharmacological safety assessments. We intravenously administered lapatinib to chronic atrioventricular block beagle dogs to assess its proarrhythmic potential. the therapeutic concentration of lapatinib significantly increased total peripheral vascular resistance, QT, QTc, monophasic action potential (MAp) 90(sinus), MAp 90(CL400) , effective refractory period, and plasma concentration of cardiac troponin i (ctni), suggesting that lapatinib prolonged the ventricular repolarization without inducing lethal ventricular arrhythmia. careful monitoring of plasma ctni concentration and an electrocardiogram could be supportive biomarkers, predicting the onset of lapatinib-induced cardiovascular adverse events.

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Impacts of Surgically Performed Renal Denervation on the Cardiovascular and Electrophysiological Variables in the Chronic Atrioventricular Block Dogs　– Comparison With Those of Amiodarone Treatment –

Cited by 4 publications

References 46 publications

The Increment of Short-term Variability of Repolarisation Determines the Severity of the Imminent Arrhythmic Outcome

The Increment of Short-term Variability of Repolarisation Determines the Severity of the Imminent Arrhythmic Outcome

An Augmented Negative Force-Frequency Relationship and Slowed Mechanical Restitution Are Associated With Increased Susceptibility to Drug-Induced Torsade de Pointes Arrhythmias in the Chronic Atrioventricular Block Dog

Precise safety pharmacology studies of lapatinib for onco-cardiology assessed using in vivo canine models

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Impacts of Surgically Performed Renal Denervation on the Cardiovascular and Electrophysiological Variables in the Chronic Atrioventricular Block Dogs – Comparison With Those of Amiodarone Treatment –

Cited by 4 publications

References 46 publications

The Increment of Short-term Variability of Repolarisation Determines the Severity of the Imminent Arrhythmic Outcome

The Increment of Short-term Variability of Repolarisation Determines the Severity of the Imminent Arrhythmic Outcome

An Augmented Negative Force-Frequency Relationship and Slowed Mechanical Restitution Are Associated With Increased Susceptibility to Drug-Induced Torsade de Pointes Arrhythmias in the Chronic Atrioventricular Block Dog

Precise safety pharmacology studies of lapatinib for onco-cardiology assessed using in vivo canine models

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Impacts of Surgically Performed Renal Denervation on the Cardiovascular and Electrophysiological Variables in the Chronic Atrioventricular Block Dogs　– Comparison With Those of Amiodarone Treatment –