Transmural dispersion of repolarization as a key factor of arrhythmogenicity in a novel intact heart model of LQT3

Milberg, Peter; Reinsch, Nico; Wasmer, Kristina; Mönnig, Gerold; Stypmann, Jörg; Osada, Nani; Breithardt, Günter; Haverkamp, Wilhelm; Eckardt, Lars

doi:10.1016/j.cardiores.2004.10.016

Cited by 72 publications

(68 citation statements)

References 25 publications

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“…Our results are consistent with the finding ) that ATX-II and blockers of I K have synergistic actions to increase the duration of the action potential of guinea pig ventricular myo- Proarrhythmic Activity of Low-Risk QT-Prolonging Drugs 723 cytes. Our results are also consistent with the report that veratridine, an inhibitor of sodium channel inactivation, caused EADs, TdP, and increased transmural dispersion of repolarization in Langendorff-perfused rabbit hearts (Milberg et al, 2005). Although the increase of late I Na caused by ATX-II may not accurately mimic the many other conditions that predispose to drug-induced VT, inasmuch as the effect of these conditions to cause VT depends on a reduction of repolarization reserve, that effect may be reproduced by exposure of the heart to ATX-II.…”

Section: Discussionsupporting

confidence: 93%

An Increase in Late Sodium Current Potentiates the Proarrhythmic Activities of Low-Risk QT-Prolonging Drugs in Female Rabbit Hearts

Shryock²,

Song³

et al. 2005

J Pharmacol Exp Ther

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Assessment of the proarrhythmic risk associated with drugs that prolong the QT interval is difficult. We hypothesized that the proarrhythmic activities of drugs with very low to moderate risk of causing torsades de pointes would be well differentiated when the late sodium current (I NaL ) was greater than normal. The effects of selected QT-prolonging drugs on electrical activity of female rabbit isolated hearts were determined in the absence and presence of sea anemone toxin (ATX-II; an enhancer of I NaL ). I NaL recorded from ventricular myocytes isolated from female rabbit hearts was slightly increased by 1 and 3 nM ATX-II (n ϭ 13, P Ͻ 0.01). ATX-II (1 nM) prolonged the duration of the monophasic action potential (MAPD 90 ) of the isolated heart by 19 Ϯ 3% (P Ͻ 0.001, n ϭ 31) and shifted the concentration-response relationships for cisapride (1-30 nM), ziprasidone (0.01-3 M), quinidine (0.1-1 M), and moxifloxacin (0.01-1 M) to prolong MAPD 90 to the left by 2-to 12-fold. In contrast, the increases in MAPD 90 caused by 1 nM ATX-II and pentobarbital were only additive, and the increases in MAPD 90 caused by ATX-II and ranolazine [(Ϯ)-N-(2,6-dimethylphenyl)-(4[2-hydroxy-3-(2-methoxyphenoxy)propyl]-1-piperazine] were less than additive. Episodes of arrhythmic activity were commonly observed, and beat-to-beat variability of action potential duration was increased, during exposure of hearts to cisapride, ziprasidone, quinidine, and moxifloxacin but not during exposure of hearts to ranolazine or pentobarbital, in the presence of ATX-II. Thus, in the female rabbit heart, ATX-II potentiated the effects of QT-prolonging drugs to increase MAPD 90 and unmasked the proarrhythmic activities of these drugs at clinically relevant drug concentrations.

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Section: Discussionsupporting

confidence: 93%

An Increase in Late Sodium Current Potentiates the Proarrhythmic Activities of Low-Risk QT-Prolonging Drugs in Female Rabbit Hearts

Shryock²,

Song³

et al. 2005

J Pharmacol Exp Ther

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“…This has been linked to an increased risk of cardiac death [151] and, in particular, to a higher risk of arrhythmogenicity in short QT, long QT and Brugada syndromes [152][153][154][155]. In Brugada syndrome, for instance, dispersion of repolarization is thought to be caused by an abbreviation of the APD of the right ventricular epicardium due to loss of the action potential dome [156].…”

Section: Gradients Of Electrophysiological Propertiesmentioning

confidence: 99%

Nonlinear physics of electrical wave propagation in the heart: a review

2016

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Abstract. The beating of the heart is a synchronized contraction of muscle cells (myocytes) that are triggered by a periodic sequence of electrical waves (action potentials) originating in the sino-atrial node and propagating over the atria and the ventricles. Cardiac arrhythmias like atrial and ventricular fibrillation (AF,VF) or ventricular tachycardia (VT) are caused by disruptions and instabilities of these electrical excitations, that lead to the emergence of rotating waves (VT) and turbulent wave patterns (AF,VF). Numerous simulation and experimental studies during the last 20 years have addressed these topics. In this review we focus on the nonlinear dynamics of wave propagation in the heart with an emphasis on the theory of pulses, spirals and scroll waves and their instabilities in excitable media and their application to cardiac modeling. After an introduction into electrophysiological models for action potential propagation, the modeling and analysis of spatiotemporal alternans, spiral and scroll meandering, spiral breakup and scroll wave instabilities like negative line tension and sproing are reviewed in depth and discussed with emphasis on their impact in cardiac arrhythmias.

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“…Slowing of rate is associated with an increase in the spatiotemporal dispersion of repolarisation 48 (DOR) in electrically paced hearts [2][3][4][5]. However, stimulation of the 49 vagus nerve, which mediates the slowing of heart rate in vivo, has 50 been reported to reverse the sequence of ventricular repolarisation, 51 without altering the magnitude of DOR, in isolated rabbit hearts [6].…”

mentioning

confidence: 99%