The anaesthetized rabbit with acute atrioventricular block provides a new model for detecting drug‐induced Torsade de Pointes

Hagiwara, Mihoko; Shibuta, Seiji; Takada, Kazuyuki; Kambayashi, Ryuichi; Nakajo, Misako; Aimoto, Megumi; Nagasawa, Yoshinori; Takahara, Akira

doi:10.1111/bph.13870

Cited by 10 publications

(8 citation statements)

References 55 publications

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“…In the chronic atrioventricular block monkey heart, each of the dl -sotalol-induced TdP spontaneously terminated, which is consistent with that reported for the acute atrioventricular block rabbit model ( Hagiwara et al, 2017 ); however, in the chronic atrioventricular block canine model, most of TdP degenerated into ventricular fibrillation ( Sugiyama, 2008 ; Smoczynska et al, 2019 ). In order to better understand underlying mechanism for spontaneous termination of TdP, we calculated “effective size of the heart ( I )” for spiral rotation ( Panfilov, 2006 ) using the formula: I =

.…”

Section: Discussionsupporting

confidence: 87%

Characterization of pathological remodeling in the chronic atrioventricular block cynomolgus monkey heart

Izumi-Nakaseko

Sakamoto²,

Goto

et al. 2023

Front. Pharmacol.

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We studied time course of pathological remodeling occurring in the cynomolgus monkey hearts against persistent atrioventricular block condition (n = 10). The atrioventricular block induced the ventricular and atrial dilation followed by the ventricular hypertrophy. Interstitial fibrosis in the ventricle was also observed along with gradual increases in the plasma angiotensin II and aldosterone concentrations. These adaptations were associated with the changes in gene expression profiling reflecting fibrosis and hypertrophy. Atrioventricular block reduced the ventricular rate and cardiac output, but the ejection fraction and stroke volume increased, whereas the cardiac output was gradually restored to its basal level. Systolic/diastolic blood pressure after the atrioventricular block was kept equal to or lower than that before the block, according with lack of increase in the plasma catecholamine levels. Chronic atrioventricular block gradually prolonged the QRS width and JT interval, leading to the QT interval prolongation in conscious state. 10 mg/kg of dl-sotalol hydrochloride induced torsade de pointes (TdP) in 6 out of 10 animals by 15 months. Animals showing longer QTcF under anesthesia after the atrioventricular block developed dl-sotalol-induced TdP earlier. No marked difference was observed in pharmacokinetics of dl-sotalol between 1 and 7 months after the atrioventricular block. Each TdP spontaneously terminated, reflecting a monkey’s relatively small “effective size of the heart (=∛(left ventricular weight)/wavelength of reentry)”. These fundamental knowledge will help better utilize the chronic atrioventricular block monkeys as an in vivo proarrhythmia model for detecting drug-induced TdP.

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.…”

Section: Discussionsupporting

confidence: 87%

Characterization of pathological remodeling in the chronic atrioventricular block cynomolgus monkey heart

Izumi-Nakaseko

Sakamoto²,

Goto

et al. 2023

Front. Pharmacol.

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“…Subgroup analysis in this study showed that glioblastoma patients with high hERG expression who received hERG blockers had improved survival ( P = 0.0458) whereas there was no difference in survival for low hERG–expressing glioblastoma patients who received hERG blockers ( P = 0.4136). Sparfloxacin is a fluoroquinolone antibiotic that was withdrawn from the market because, apart from its phototoxicity, it induced QT interval prolongation and torsade de pointes by inhibiting the hERG channel . A study with hERG‐transfected HEK293 cells and siRNA‐knock‐down HCT116 cells confirmed that sparfloxacin‐inhibited cell viability and this inhibition correlated with hERG expression.…”

Section: Resultsmentioning

confidence: 99%

“…Sparfloxacin is a fluoroquinolone antibiotic that was withdrawn from the market because, apart from its phototoxicity, it induced QT interval prolongation and torsade de pointes by inhibiting the hERG channel. [185][186][187][188][189][190] A study with hERG-transfected HEK293 cells and siRNA-knock-down HCT116 cells confirmed that sparfloxacin-inhibited cell viability and this inhibition correlated with hERG expression. When combined with 5-fluorouracil, sparfloxacin showed synergistic antiproliferation activity in HCT116 and HT-29 cells.…”

Section: Potential Use In Oncologymentioning

confidence: 99%

Repurposing old drugs in oncology: Opportunities with clinical and regulatory challenges ahead

Shah

Stonier

2018

J Clin Pharm Ther

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“…This relatively high heart rate leads to a reduced heart rate reserve, which limits the use of rabbits for the investigation of exercise-induced effects on the cardiovascular system (Milani-Nejad & Janssen, 2014). Partial solutions to this problem may be obtained by surgical ablation of the atrioventricular node (Hagiwara et al, 2017;Tsuji et al, 2006), although this may predispose the rabbit heart to arrhythmias. Other disadvantages of rabbits, compared to mice, are their relative high housing/breeding costs, lower reproduction rate and lower efficacy of genetic manipulation, which is outweighed by their high clinical relevance as cardiac disease models as highlighted in the following.…”

Section: Advantages and Disadvantages Of Animal Models Of Different Species For (Monogenic) Cardiac Disease Researchmentioning

confidence: 99%

Transgenic rabbit models for cardiac disease research

Hornyik

Rieder

Castiglione

et al. 2021

British J Pharmacology

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To study the pathophysiology of human cardiac diseases and to develop novel treatment strategies, complex interactions of cardiac cells on cellular, tissue and on level of the whole heart need to be considered. As in vitro cell-based models do not depict the complexity of the human heart, animal models are used to obtain insights that can be translated to human diseases. Mice are the most commonly used animals in cardiac research. However, differences in electrophysiological and mechanical cardiac function and a different composition of electrical and contractile proteins limit the transferability of the knowledge gained. Moreover, the small heart size and fast heart rate are major disadvantages. In contrast to rodents, electrophysiological, mechanical and structural cardiac characteristics of rabbits resemble the human heart more closely, making them particularly suitable as an animal model for cardiac disease research. In this review, various methodological approaches for the generation of transgenic rabbits for cardiac disease research, such as pronuclear microinjection, the sleeping beauty transposon system and novel genome-editing methods (ZFN and CRISPR/Cas9)will be discussed. In the second section, we will introduce the different currently available transgenic rabbit models for monogenic cardiac diseases (such as long QT syndrome, short-QT syndrome and hypertrophic cardiomyopathy) in detail, especially in regard to their utility to increase the understanding of pathophysiological disease mechanisms and novel treatment options.

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The anaesthetized rabbit with acute atrioventricular block provides a new model for detecting drug‐induced Torsade de Pointes

Abstract: These results suggest that our model of the unremodelled and bradycardic heart of the anaesthetized rabbit is a useful test system for the detection of drug-induced TdP arrhythmias.

Cited by 10 publications

References 55 publications

Characterization of pathological remodeling in the chronic atrioventricular block cynomolgus monkey heart

Characterization of pathological remodeling in the chronic atrioventricular block cynomolgus monkey heart

Repurposing old drugs in oncology: Opportunities with clinical and regulatory challenges ahead

Transgenic rabbit models for cardiac disease research

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