Spatial correlation of action potential duration and diastolic dysfunction in transgenic and drug-induced LQT2 rabbits

Odening, Katja E.; Jung, Bernd; Lang, Corinna N.; Lozoya, Rocío Cabrera; Ziupa, David; Menza, Marius; Relan, Jatin; Franke, Gerlind; Feliz, Stefanie Perez; Koren, Gideon; Zehender, Manfred; Bode, Christoph; Brunner, Michael; Sermesant, Maxime; Föll, Daniela

doi:10.1016/j.hrthm.2013.07.038

Cited by 40 publications

(38 citation statements)

References 32 publications

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“…I). Additionally, detected increase in RyR-mediated SR Ca 2+ diastolic leak, which is expected to interfere with relaxation, provides mechanistic insight into recently discovered diastolic dysfunction in LQT2 (31). …”

Section: Discussionmentioning

confidence: 96%

Hyperphosphorylation of RyRs Underlies Triggered Activity in Transgenic Rabbit Model of LQT2 Syndrome

Terentyev

Rees

et al. 2014

Circulation Research

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Rationale Loss-of function mutations in HERG potassium channels underlie long QT syndrome (LQTS) type 2 (LQT2), and are associated with fatal ventricular tachyarrhythmia. Previously, most studies focused on plasmamembrane-related pathways involved in arrhythmogenesis in LQTS, while pro-arrhythmic changes in intracellular Ca2+ handling remained unexplored. Objective We investigated the remodeling of Ca2+ homeostasis in ventricular cardiomyocytes derived from transgenic rabbit model of LQT2 in order to determine whether these changes contribute to triggered activity in the form of early afterdepolarizations (EADs). Methods and Results Confocal Ca2+ imaging revealed decrease in amplitude of Ca2+ transients and SR Ca2+ content in LQT2 myocytes. Experiments using SR-entrapped Ca2+ indicator demonstrated enhanced RyR-mediated SR Ca2+ leak in LQT2 cells. Western blot analyses showed increased phosphorylation of RyR in LQT2 myocytes vs. controls. Co-immunoprecipitation experiments demonstrated loss of protein phosphatases type 1 and type 2 from the RyR complex. Stimulation of LQT2 cells with β-adrenergic agonist isoproterenol resulted in prolongation of the plateau of action potentials accompanied by aberrant Ca2+ releases and EADs, which were abolished by inhibition of CaMKII. Computer simulations showed that late aberrant Ca2+ releases caused by RyR hyperactivity promote EADs and underlie the enhanced triggered activity through increased forward mode of NCX1. Conclusions Hyperactive, hyperphosphorylated RyRs due to reduced local phosphatase activity enhance triggered activity in LQT2 syndrome. EADs are promoted by aberrant RyR-mediated Ca2+ releases that are present despite a reduction of sarcoplasmic reticulum (SR) content. Those releases increase forward mode NCX1, thereby slowing repolarization and enabling L-type Ca2+ current reactivation.

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Section: Discussionmentioning

confidence: 96%

Hyperphosphorylation of RyRs Underlies Triggered Activity in Transgenic Rabbit Model of LQT2 Syndrome

Terentyev

Rees

et al. 2014

Circulation Research

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“…Nevertheless, another line of evidence points out the role played by eliminated or reversed repolarization gradients in diseased hearts. Spatial repolarization gradients existing in the normal heart can be important for setting an ordered sequence of ventricular activation and relaxation, hence maintaining optimal mechanical function . This implies that elimination, or even reversal, of the physiological APD difference at distinct myocardial regions may lead to impaired contractile performance and provoke arrhythmia via mechanisms related to mechanoelectrical feedback.…”

Section: Spatial Repolarization Gradientsmentioning

confidence: 99%

Role of abnormal repolarization in the mechanism of cardiac arrhythmia

Osadchii

2017

Acta Physiologica

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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).

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“…Adult LQT1 and LMC females were subjected to monophasic action potential (MAP) measurements as described previously [16], [18].…”

Section: Methodsmentioning

confidence: 99%

“…Data were only included in the analyses if good quality MAP (defined as in [18]) were measured in at least three electrode positions from baseline to highest drug concentration. Experiments of eighteen transgenic LQT1 (9 for each drug) and fourteen LMC rabbits (7 for each drug) met the inclusion criteria.…”

Section: Methodsmentioning

confidence: 99%

“…To date, cellular and computer models cannot sufficiently predict drug induced pro-arrhythmia [13] and tissue preparations and whole heart models still need further optimization [14]. Ex vivo monophasic action potential (MAP) measurements in Langendorff-perfused rabbit hearts [15], [16], [17], [18] have been established to derive action potential durations (APD) at different positions and to record arrhythmia susceptibility, combining the advantages of cellular and animal models. Since preclinical measurement of drug-induced prolongation of APD or QT intervals alone has not achieved a sufficient sensitivity for reliable detection of pro-arrhythmic drugs [19], [20], [21], additional parameters, such as spatial APD dispersion [22] and triangulation of MAP shape (indicating slowing of phase-3-repolarization) [19], [23], [24], were established to increase the performance of ex vivo assays for pro-arrhythmia.…”

Section: Introductionmentioning

confidence: 99%

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Pronounced Effects of HERG-Blockers E-4031 and Erythromycin on APD, Spatial APD Dispersion and Triangulation in Transgenic Long-QT Type 1 Rabbits

et al. 2014

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BackgroundProlongation of action potential duration (APD), increased spatial APD dispersion, and triangulation are major factors promoting drug-induced ventricular arrhythmia. Preclinical identification of HERG/IKr-blocking drugs and their pro-arrhythmic potential, however, remains a challenge. We hypothesize that transgenic long-QT type 1 (LQT1) rabbits lacking repolarizing IKs current may help to sensitively detect HERG/IKr-blocking properties of drugs.MethodsHearts of adult female transgenic LQT1 and wild type littermate control (LMC) rabbits were Langendorff-perfused with increasing concentrations of HERG/IKr-blockers E-4031 (0.001–0.1 µM, n = 9/7) or erythromycin (1–300 µM, n = 9/7) and APD, APD dispersion, and triangulation were analyzed.ResultsAt baseline, APD was longer in LQT1 than in LMC rabbits in LV apex and RV mid. Erythromycin and E-4031 prolonged APD in LQT1 and LMC rabbits in all positions. However, erythromycin-induced percentaged APD prolongation related to baseline (%APD) was more pronounced in LQT1 at LV base-lateral and RV mid positions (100 µM, LQT1, +40.6±9.7% vs. LMC, +24.1±10.0%, p<0.05) and E-4031-induced %APD prolongation was more pronounced in LQT1 at LV base-lateral (0.01 µM, LQT1, +29.6±10.6% vs. LMC, +19.1±3.8%, p<0.05) and LV base-septal positions. Moreover, erythromycin significantly increased spatial APD dispersion only in LQT1 and increased triangulation only in LQT1 in LV base-septal and RV mid positions. Similarly, E-4031 increased triangulation only in LQT1 in LV apex and base-septal positions.ConclusionsE-4031 and erythromycin prolonged APD and increased triangulation more pronouncedly in LQT1 than in LMC rabbits. Moreover, erythromycin increased APD dispersion only in LQT1, indicating that transgenic LQT1 rabbits could serve as sensitive model to detect HERG/IKr-blocking properties of drugs.

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Spatial correlation of action potential duration and diastolic dysfunction in transgenic and drug-induced LQT2 rabbits

Cited by 40 publications

References 32 publications

Hyperphosphorylation of RyRs Underlies Triggered Activity in Transgenic Rabbit Model of LQT2 Syndrome

Hyperphosphorylation of RyRs Underlies Triggered Activity in Transgenic Rabbit Model of LQT2 Syndrome

Role of abnormal repolarization in the mechanism of cardiac arrhythmia

Pronounced Effects of HERG-Blockers E-4031 and Erythromycin on APD, Spatial APD Dispersion and Triangulation in Transgenic Long-QT Type 1 Rabbits

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