Gap junction modifier rotigaptide decreases the susceptibility to ventricular arrhythmia by enhancing conduction velocity and suppressing discordant alternans during therapeutic hypothermia in isolated rabbit hearts

Hsieh, Yu Cheng; Lin, Jin-Ching; Hung, Chen Ying; Li, Cheng Hung; Lin, Shien Fong; Yeh, Hung I.; Huang, Jin Long; Lo, Chu Pin; Haugan, Ketil; Larsen, Bjarne Due; Wu, Tsu Juey

doi:10.1016/j.hrthm.2015.07.023

Cited by 36 publications

(44 citation statements)

References 28 publications

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“…Repolarization is initially mediated by I to , followed by a delayed plateau phase mediated by a balance between the inward calcium current ( I Ca ) and outward delayed rectifier potassium currents ( I Kr and I Ks ). Guinea pig and rabbit hearts have the same action potential morphology with similar ionic contributions, and may therefore provide better translational results when used as model systems for studying human arrhythmic syndromes (69–80). …”

Section: Discussionmentioning

confidence: 99%

Anti-arrhythmic effects of hypercalcemia in hyperkalemic, Langendorff-perfused mouse hearts

et al. 2016

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The present study examined the ventricular arrhythmic and electrophysiological properties during hyperkalemia (6.3 mM [K+] vs. 4 mM in normokalemia) and anti-arrhythmic effects of hypercalcemia (2.2 mM [Ca2+]) in Langendorff-perfused mouse hearts. Monophasic action potential recordings were obtained from the left ventricle during right ventricular pacing. Hyperkalemia increased the proportion of hearts showing provoked ventricular tachycardia (VT) from 0 to 6 of 7 hearts during programmed electrical stimulation (Fisher's exact test, P<0.05). It shortened the epicardial action potential durations (APDx) at 90, 70, 50 and 30% repolarization and ventricular effective refractory periods (VERPs) (analysis of variance, P<0.05) without altering activation latencies. Endocardial APDx and VERPs were unaltered. Consequently, ∆APDx (endocardial APDx-epicardial APDx) was increased, VERP/latency ratio was decreased and critical intervals for reexcitation (APD90-VERP) were unchanged. Hypercalcemia treatment exerted anti-arrhythmic effects during hyperkalemia, reducing the proportion of hearts showing VT to 1 of 7 hearts. It increased epicardial VERPs without further altering the remaining parameters, returning VERP/latency ratio to normokalemic values and also decreased the critical intervals. In conclusion, hyperkalemia exerted pro-arrhythmic effects by shortening APDs and VERPs. Hypercalcemia exerted anti-arrhythmic effects by reversing VERP changes, which scaled the VERP/latency ratio and critical intervals.

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Section: Discussionmentioning

confidence: 99%

Anti-arrhythmic effects of hypercalcemia in hyperkalemic, Langendorff-perfused mouse hearts

et al. 2016

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“…In combination with reduced effective refractory periods (ERPs), excitation wavelength (conduction velocity (CV) × ERP) is reduced. Furthermore, increased steepness of APD restitution results in the development of APD alternans [48] and in turn in wavebreak, conduction block, and initiation and maintenance of reentrant activity [7, 49]. …”

Section: Abnormal Repolarizationmentioning

confidence: 99%

Molecular and Electrophysiological Mechanisms Underlying Cardiac Arrhythmogenesis in Diabetes Mellitus

Tse

Lai

Tse

et al. 2016

Journal of Diabetes Research

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Diabetes is a common endocrine disorder with an ever increasing prevalence globally, placing significant burdens on our healthcare systems. It is associated with significant cardiovascular morbidities. One of the mechanisms by which it causes death is increasing the risk of cardiac arrhythmias. The aim of this article is to review the cardiac (ion channel abnormalities, electrophysiological and structural remodelling) and extracardiac factors (neural pathway remodelling) responsible for cardiac arrhythmogenesis in diabetes. It is concluded by an outline of molecular targets for future antiarrhythmic therapy for the diabetic population.

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“…The mechanisms linking AP alternans to ventricular arrhythmias involve the development of spatially discordant alternans [101–104]. Usually AP alternans starts as concordant alternans, i.e.…”

Section: Clinical Relevance Of Cardiac Alternansmentioning

confidence: 99%

“…in some regions APD is prolonged while during the same beat APD is shortened in other regions of the heart. Development of discordant alternans is believed to have major effects on the spatial organization of repolarization across the cardiac tissue and significantly contributes to arrhythmogenicity [101–104]. This notion is supported experimentally by the demonstration that ventricular fibrillation is always preceded by discordant AP alternans [102].…”

Section: Clinical Relevance Of Cardiac Alternansmentioning

confidence: 99%

“…In humans with AF and in AF animal models altered expression and distribution of atrial Cx40 is well documented which can lead to dispersed conduction and thus formation of a substrate for atrial arrhythmias [93,109]. Furthermore, pharmacological enhancement of intercellular coupling effectively suppressed development of discordant alternans, and decreased susceptibility to ventricular arrhythmias [101] and atrial fibrillation [110]. In addition to the changes in connexin expression, cell-to-cell coupling can be disrupted also by increased fibrosis of the tissue.…”

Section: Mechanisms Of Spatially Discordant Alternansmentioning

confidence: 99%

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Alternans in atria: Mechanisms and clinical relevance

Kanaporis

Blatter

2017

Medicina

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Atrial fibrillation is the most common sustained arrhythmia and its prevalence is rapidly rising with the aging of the population. Cardiac alternans, defined as cyclic beat-to-beat alternations in contraction force, action potential (AP) duration and intracellular Ca2+ release at constant stimulation rate, has been associated with the development of ventricular arrhythmias. Recent clinical data also provide strong evidence that alternans plays a central role in arrhythmogenesis in atria. The aim of this article is to review the mechanisms that are responsible for repolarization alternans and contribute to the transition from spatially concordant alternans to the more arrhythmogenic spatially discordant alternans in atria.

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Gap junction modifier rotigaptide decreases the susceptibility to ventricular arrhythmia by enhancing conduction velocity and suppressing discordant alternans during therapeutic hypothermia in isolated rabbit hearts

Cited by 36 publications

References 28 publications

Anti-arrhythmic effects of hypercalcemia in hyperkalemic, Langendorff-perfused mouse hearts

Anti-arrhythmic effects of hypercalcemia in hyperkalemic, Langendorff-perfused mouse hearts

Molecular and Electrophysiological Mechanisms Underlying Cardiac Arrhythmogenesis in Diabetes Mellitus

Alternans in atria: Mechanisms and clinical relevance

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