Frequency-dependent effects of quinidine on the ventricular action potential and QRS duration in humans.

Nademanee, Koonlawee; Stevenson, William G.; Weiss, James N.; Frame, V.; Antimisiaris, M.; Suithichaiyakul, T; Pruitt, Clara

doi:10.1161/01.cir.81.3.790

Cited by 33 publications

(14 citation statements)

References 24 publications

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“…Additionally, dofetilide, Sotalol and quinidine have been found to prolong ventricular repolarization in healthy human hearts (QT duration; Johannsen et al, 2014; Lande et al, 1998; Vicente et al, 2015) and patients (QT duration (Echt et al, 1982; McComb, McGovern, McGowan, Ruskin, & Garan, 1987); monophasic AP recordings (Melicherick et al, 1999; Nademanee et al, 1990; Yuan, Wohlfart, Rasmussen, Olsson, & Blomstrom-Lundqvist, 1994)). Our AP data from healthy donor hearts are in agreement with those reported for dofetilide, Sotalol and quinidine by these groups.…”

Section: Discussionmentioning

confidence: 99%

Human ex-vivo action potential model for pro-arrhythmia risk assessment

Page

Ratchada

Miron

et al. 2016

Journal of Pharmacological and Toxicological Methods

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While current S7B/E14 guidelines have succeeded in protecting patients from QT-prolonging drugs, the absence of a predictive paradigm identifying pro-arrhythmic risks has limited the development of valuable drug programs. We investigated if a human ex-vivo action potential (AP)-based model could provide a more predictive approach for assessing pro-arrhythmic risk in man. Human ventricular trabeculae from ethically consented organ donors were used to evaluate the effects of dofetilide, d,l-sotalol, quinidine, paracetamol and verapamil on AP duration (APD) and recognized pro-arrhythmia predictors (short-term variability of APD at 90% repolarization (STV(APD90)), triangulation (ADP90-APD30) and incidence of early afterdepolarizations at 1 and 2 Hz to quantitatively identify the pro-arrhythmic risk. Each drug was blinded and tested separately with 3 concentrations in triplicate trabeculae from 5 hearts, with one vehicle time control per heart. Electrophysiological stability of the model was not affected by sequential applications of vehicle (0.1% dimethyl sulfoxide). Paracetamol and verapamil did not significantly alter anyone of the AP parameters and were classified as devoid of pro-arrhythmic risk. Dofetilide, d,l-sotalol and quinidine exhibited an increase in the manifestation of pro-arrhythmia markers. The model provided quantitative and actionable activity flags and the relatively low total variability in tissue response allowed for the identification of pro-arrhythmic signals. Power analysis indicated that a total of 6 trabeculae derived from 2 hearts are sufficient to identify drug-induced pro-arrhythmia. Thus, the human ex-vivo AP-based model provides an integrative translational assay assisting in shaping clinical development plans that could be used in conjunction with the new CiPA-proposed approach.

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Section: Discussionmentioning

confidence: 99%

Human ex-vivo action potential model for pro-arrhythmia risk assessment

Page

Ratchada

Miron

et al. 2016

Journal of Pharmacological and Toxicological Methods

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“…Effective refractory period (ERP) represents the maximal interval between the prior stimulation and the following stimulation that cannot develop the next action potential. ERP is usually dependent on action potential duration (APD) (Nademanee et al 1990). In the previous human heart study, repetitive burst stimuli shortened both ERP and APD, and the encroachment of stimuli onto the preceding repolarization phase was associated with induction of tachyarrhythmia (Koller et al 1995).…”

Section: Fig 2 Effects Of Pilsicainide On Action Potential (Bcl 500mentioning

confidence: 99%

“…Although ERP is usually dependent of and shorter than APD (Costard-Jackle and Franz 1989;Nademanee et al 1990), it can be prolonged beyond the repolarization of action potential in some situations. Lazzara et al (1975) reported this phenomenon in the ventricular myocardium and termed it post-repolarization refractoriness (PRR).…”

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confidence: 99%

A Sodium Channel Blocker, Pilsicainide, Produces Atrial Post-Repolarization Refractoriness through the Reduction of Sodium Channel Availability

Fukuda

Watanabe

Yagi

et al. 2011

Tohoku J. Exp. Med.

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Atrial fibrillation (AF) is the most common tachyarrhythmia. Shortening of atrial action potential duration (APD) and effective refractory period (ERP) is one of the crucial factors in the occurrence and maintenance of AF. ERP is usually shorter than APD, but ERP can be prolonged beyond action potential repolarization in some situations. It is termed as post-repolarization refractoriness (PRR) that is thought to be one of main anti-arrhythmic mechanisms of class I sodium channel blockers (SCBs). Most of anti-arrhythmic agents, including SCBs, have multi-channel blocking effects. It is unknown whether atrial PRR with SCBs is associated with the reduction of sodium channel availability. We therefore explored the relationship between the reduction of sodium channel availability with a pure SCB (pilsicainide or tetrodotoxin) and atrial PRR using the left atrial appendage from male guinea pigs (each group, n = 3~10). Employing a standard microelectrode technique, we evaluated APD measured at 90% repolarization (APD 90 ) and the sodium channel availability, judged from the maximal rate of rise of action potential (Vmax). At a 500-msec basic cycle length (BCL), pilsicainide prolonged atrial ERP assessed by a single extra-stimulus in response to the decrement of the Vmax in a dose-dependent manner without affecting APD 90 . Furthermore, pilsicainide increased the ERP and decreased the Vmax in a rate-dependent manner without APD 90 prolongation at a shorter BCL (200 msec). Importantly, tetrodotoxin reproduced the effects of pilsicainide on atrial ERP, APD 90 , and Vmax. These results indicate that SCBs produce atrial PRR through the reduction of sodium channel availability.

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“…Additionally, dofetilide, Sotalol and quinidine have been found to prolong ventricular repolarization in healthy human hearts (QT duration;Johannsen et al, 2014;Lande et al, 1998;Vicente et al, 2015) and patients (QT duration (Echt et al, 1982;McComb, McGovern, McGowan, Ruskin, & Garan, 1987); monophasic AP recordings (Melicherick et al, 1999;Nademanee et al, 1990;Yuan, Wohlfart, Rasmussen, Olsson, & Blomstrom-Lundqvist, 1994)). Our AP data from healthy donor hearts are in agreement with those reported for dofetilide, Sotalol and quinidine by these groups.…”

Section: Discussionmentioning

confidence: 99%

Human ex-vivo action potential model for pro-arrhythmia risk assessment

Page

Ratchada

Miron

et al. 2016

Journal of Pharmacological and Toxicological Methods

View full text Add to dashboard Cite

While current S7B/E14 guidelines have succeeded in protecting patients from QT-prolonging drugs, the absence of a predictive paradigm identifying pro-arrhythmic risks has limited the development of valuable drug programs. We investigated if a human ex-vivo action potential (AP)-based model could provide a more predictive approach for assessing pro-arrhythmic risk in man. Human ventricular trabeculae from ethically consented organ donors were used to evaluate the effects of dofetilide, d,l-sotalol, quinidine, paracetamol and verapamil on AP duration (APD) and recognized pro-arrhythmia predictors (short-term variability of APD at 90% repolarization (STV(APD90)), triangulation (ADP90-APD30) and incidence of early afterdepolarizations at 1 and 2 Hz to quantitatively identify the pro-arrhythmic risk. Each drug was blinded and tested separately with 3 concentrations in triplicate trabeculae from 5 hearts, with one vehicle time control per heart. Electrophysiological stability of the model was not affected by sequential applications of vehicle (0.1% dimethyl sulfoxide). Paracetamol and verapamil did not significantly alter anyone of the AP parameters and were classified as devoid of pro-arrhythmic risk. Dofetilide, d,l-sotalol and quinidine exhibited an increase in the manifestation of pro-arrhythmia markers. The model provided quantitative and actionable activity flags and the relatively low total variability in tissue response allowed for the identification of pro-arrhythmic signals. Power analysis indicated that a total of 6 trabeculae derived from 2 hearts are sufficient to identify drug-induced proarrhythmia. Thus, the human ex-vivo AP-based model provides an integrative translational assay assisting in shaping clinical development plans that could be used in conjunction with the new CiPA-proposed approach.

show abstract

Frequency-dependent effects of quinidine on the ventricular action potential and QRS duration in humans.

Cited by 33 publications

References 24 publications

Human ex-vivo action potential model for pro-arrhythmia risk assessment

Human ex-vivo action potential model for pro-arrhythmia risk assessment

A Sodium Channel Blocker, Pilsicainide, Produces Atrial Post-Repolarization Refractoriness through the Reduction of Sodium Channel Availability

Human ex-vivo action potential model for pro-arrhythmia risk assessment

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