Impaired epicardial activation–repolarization coupling contributes to the proarrhythmic effects of hypokalaemia and dofetilide in guinea pig ventricles

Osadchii, Oleg E.

doi:10.1111/apha.12259

Cited by 11 publications

(14 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Proarrhythmic modifications of ventricular repolarization by dofetilide were analysed in experimental studies. Consistent with spatial heterogeneities in the distribution of I Kr , dofetilide was found to produce non‐uniform lengthening of APD and/or the refractory period in canine, rabbit, and guinea‐pig hearts (Osadchii 2012c; 2012d, 2014c: studies IV, V, and X, respectively) . Over the transepicardial plane, dofetilide evokes a greater APD lengthening in LV than RV chamber, an effect that contributes to attenuated RV‐to‐LV activation–repolarization coupling, as evidenced by markedly reduced slope of the local APD‐to‐activation time linear relationships (Fig.…”

Section: Arrhythmogenic Responses To Antiarrhythmic Drugsmentioning

confidence: 73%

“…The impaired activation–repolarization coupling may also contribute to abnormal repolarization gradients during steady‐state beating, an effect that has been invoked to explain proarrhythmic effects produced by adrenergic agonist infusion, hypokalaemia, and class I and III antiarrhythmic drugs (Osadchii 2012e, 2014a, 2014c: studies VI, VIII, and X, respectively) . Collectively, these findings raise the point that the slope of APD‐to‐activation time relationships may serve as a sensitive metric of arrhythmic susceptibility, and the therapies that improve activation–repolarization coupling are likely to prevent arrhythmia.…”

Section: Activation–repolarization Couplingmentioning

confidence: 94%

“…One proarrhythmic challenge that could be used to illustrate this principle is the closely coupled extrasystolic stimulation. Figure shows the data based on assessments of the activation–repolarization coupling in perfused guinea‐pig hearts (Osadchii 2014c: study X), wherein local monophasic APDs and corresponding activation times were measured at multiple epicardial recording sites, both during steady‐state pacing and extrasystolic stimulations. The pacing protocols were applied at RV endocardium, the stimulation site commonly used in a clinical setting.…”

Section: Activation–repolarization Couplingmentioning

confidence: 99%

“…In normal conditions, spatial repolarization heterogeneities are minimized owing to the activation–repolarization coupling (see Chapter 5). This mechanism, nevertheless, is impaired in the setting of hypokalaemia (Osadchii 2014c: study X), as schematically illustrated in Figure . During normokalaemic perfusion of guinea‐pig hearts, there is an inverse relationship between APD and activation time over the RV‐to‐LV transepicardial plane (panel a and line a in panel d).…”

Section: Arrhythmogenic Responses In Hypokalaemiamentioning

confidence: 99%

“…Second, hypokalaemia increases interventricular conduction delay (as shown by double arrow in panel c), which again translates to increased RV‐to‐LV dyssynchrony in final repolarization time, in association with a flattened linear slope of the APD‐to‐activation time relationship (shown by line c in panel e). The aforementioned changes may be further exacerbated in extrasystolic beats (Osadchii 2014c: study X), wherein hypokalaemia accentuates spatial non‐uniformities in APD as well as conduction slowing provoked by premature ventricular activation.…”

Section: Arrhythmogenic Responses In Hypokalaemiamentioning

confidence: 99%

See 4 more Smart Citations

Role of abnormal repolarization in the mechanism of cardiac arrhythmia

Osadchii

2017

Acta Physiologica

Self Cite

View full text Add to dashboard Cite

In cardiac patients, life-threatening tachyarrhythmia is often precipitated by abnormal changes in ventricular repolarization and refractoriness. Repolarization abnormalities typically evolve as a consequence of impaired function of outward K currents in cardiac myocytes, which may be caused by genetic defects or result from various acquired pathophysiological conditions, including electrical remodelling in cardiac disease, ion channel modulation by clinically used pharmacological agents, and systemic electrolyte disorders seen in heart failure, such as hypokalaemia. Cardiac electrical instability attributed to abnormal repolarization relies on the complex interplay between a provocative arrhythmic trigger and vulnerable arrhythmic substrate, with a central role played by the excessive prolongation of ventricular action potential duration, impaired intracellular Ca handling, and slowed impulse conduction. This review outlines the electrical activity of ventricular myocytes in normal conditions and cardiac disease, describes classical electrophysiological mechanisms of cardiac arrhythmia, and provides an update on repolarization-related surrogates currently used to assess arrhythmic propensity, including spatial dispersion of repolarization, activation-repolarization coupling, electrical restitution, TRIaD (triangulation, reverse use dependence, instability, and dispersion), and the electromechanical window. This is followed by a discussion of the mechanisms that account for the dependence of arrhythmic vulnerability on the location of the ventricular pacing site. Finally, the review clarifies the electrophysiological basis for cardiac arrhythmia produced by hypokalaemia, and gives insight into the clinical importance and pathophysiology of drug-induced arrhythmia, with particular focus on class Ia (quinidine, procainamide) and Ic (flecainide) Na channel blockers, and class III antiarrhythmic agents that block the delayed rectifier K channel (dofetilide).

show abstract

Section: Arrhythmogenic Responses To Antiarrhythmic Drugsmentioning

confidence: 73%

Section: Activation–repolarization Couplingmentioning

confidence: 94%

Section: Activation–repolarization Couplingmentioning

confidence: 99%

Section: Arrhythmogenic Responses In Hypokalaemiamentioning

confidence: 99%

Section: Arrhythmogenic Responses In Hypokalaemiamentioning

confidence: 99%

See 3 more Smart Citations

Role of abnormal repolarization in the mechanism of cardiac arrhythmia

Osadchii

2017

Acta Physiologica

Self Cite

View full text Add to dashboard Cite

show abstract

Inactivation of Native K Channels

et al. 2021

View full text Add to dashboard Cite

Cardiac disease and arrhythmogenesis: Mechanistic insights from mouse models

Choy

Yeo

Tse

et al. 2016

IJC Heart & Vasculature

View full text Add to dashboard Cite

The mouse is the second mammalian species, after the human, in which substantial amount of the genomic information has been analyzed. With advances in transgenic technology, mutagenesis is now much easier to carry out in mice. Consequently, an increasing number of transgenic mouse systems have been generated for the study of cardiac arrhythmias in ion channelopathies and cardiomyopathies. Mouse hearts are also amenable to physical manipulation such as coronary artery ligation and transverse aortic constriction to induce heart failure, radiofrequency ablation of the AV node to model complete AV block and even implantation of a miniature pacemaker to induce cardiac dyssynchrony. Last but not least, pharmacological models, despite being simplistic, have enabled us to understand the physiological mechanisms of arrhythmias and evaluate the anti-arrhythmic properties of experimental agents, such as gap junction modulators, that may be exert therapeutic effects in other cardiac diseases. In this article, we examine these in turn, demonstrating that primary inherited arrhythmic syndromes are now recognized to be more complex than abnormality in a particular ion channel, involving alterations in gene expression and structural remodelling. Conversely, in cardiomyopathies and heart failure, mutations in ion channels and proteins have been identified as underlying causes, and electrophysiological remodelling are recognized pathological features. Transgenic techniques causing mutagenesis in mice are extremely powerful in dissecting the relative contributions of different genes play in producing disease phenotypes. Mouse models can serve as useful systems in which to explore how protein defects contribute to arrhythmias and direct future therapy.

show abstract

Impaired epicardial activation–repolarization coupling contributes to the proarrhythmic effects of hypokalaemia and dofetilide in guinea pig ventricles

Abstract: Impaired RV-to-LV activation-repolarization coupling is an important determinant of electrical instability in the setting of non-uniformly prolonged epicardial APD90 or slowed interventricular conduction.

Cited by 11 publications

References 41 publications

Role of abnormal repolarization in the mechanism of cardiac arrhythmia

Role of abnormal repolarization in the mechanism of cardiac arrhythmia

Inactivation of Native K Channels

Cardiac disease and arrhythmogenesis: Mechanistic insights from mouse models

Contact Info

Product

Resources

About