Antiarrhythmic properties of ivabradine in an experimental model of Short‐<scp>QT</scp>‐ Syndrome

Frommeyer, Gerrit; Weller, Jan; Ellermann, Christian; Kaese, Sven; Kochhäuser, Simon; Lange, Philipp; Dechering, Dirk G.; Eckardt, Lars

doi:10.1111/1440-1681.12790

Cited by 14 publications

(19 citation statements)

References 16 publications

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“…Ivabradine has been shown to be effective in prolonging QT interval and reducing the occurrence of arrhythmias in rabbit models of SQTS induced by a K ATP channel (ATP-sensitive potassium channel) activator pinacidil, 17 but it has not been tested in SQTS patients. Ivabradine is an inhibitor of the pacemaker funny current (I f ).…”

Section: Discussionmentioning

confidence: 99%

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Drug Testing in Human‐Induced Pluripotent Stem Cell–Derived Cardiomyocytes From a Patient With Short QT Syndrome Type 1

Zhao

El‐Battrawy

et al. 2019

Clin Pharma and Therapeutics

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Short QT syndrome (SQTS) predisposes afflicted patients to sudden cardiac death. Until now, only one drug—quinidine—has been shown to be effective in patients with SQTS type 1(SQTS1). The objective of this study was to use human‐induced pluripotent stem cell–derived cardiomyocytes (hiPSC‐CMs) from a patient with SQTS1 to search for potentially effective drugs for the treatment of SQTS1 patients. Patch clamp and single‐cell contraction measurements were employed to assess drug effects. Ivabradine, mexiletine, and ajmaline but not flecainide, ranolazine, or amiodarone prolonged the action potential duration (APD) in hiPSC‐CMs from an SQTS1 patient. Ivabradine, ajmaline, and mexiletine inhibited KCNH2 channel currents significantly, which may underlie their APD‐prolonging effects. Under proarrhythmic epinephrine stimulation in spontaneously beating SQTS1 hiPSC‐CMs, ivabradine, mexiletine, and ajmaline but not flecainide reduced the epinephrine‐induced arrhythmic events. The results demonstrate that ivabradine, ajmaline, and mexiletine may be candidate drugs for preventing tachyarrhythmias in SQTS1 patients.

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Section: Discussionmentioning

confidence: 99%

“…Ivabradine, mexiletine, and ranolazine have been shown to have antiarrhythmic effect in an animal model of SQTS. [16][17][18] Ajmaline has been shown to have multiple ion channel-blocking effects, including the KCNH2 channel. 19,20 However, these drugs have not been tested in SQTS patients.…”

mentioning

confidence: 99%

Drug Testing in Human‐Induced Pluripotent Stem Cell–Derived Cardiomyocytes From a Patient With Short QT Syndrome Type 1

Zhao

El‐Battrawy

et al. 2019

Clin Pharma and Therapeutics

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“…Recently, the pacemaker channel inhibitor ivabradine was found to decrease digitalis-induced ventricular arrhythmias and short QT-induced arrhythmic features in Langendorff-perfused rabbit heart preparations (Frommeyer et al, 2017a;Frommeyer et al, 2017b). Ivabradine is usually prescribed to treat stable angina pectoris and in association with b-blockers to cure heart failure with left ventricular systolic dysfunction (Koruth et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

The Hyperpolarization-Activated Cyclic-Nucleotide-Gated Channel Blocker Ivabradine Does Not Prevent Arrhythmias in Catecholaminergic Polymorphic Ventricular Tachycardia

et al. 2020

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Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited, stressedprovoked ventricular arrhythmia. CPVT is treated by b-adrenergic receptor blockers, Na + channel inhibitors, sympathetic denervation, or by implanting a defibrillator. We showed recently that blockers of SK4 Ca 2+-activated K + channels depolarize the maximal diastolic potential, reduce the heart rate, and attenuate ventricular arrhythmias in CPVT. The aim of the present study was to examine whether the pacemaker channel inhibitor, ivabradine could demonstrate anti-arrhythmic properties in CPVT like other bradycardic agents used in this disease and to compare them with those of the SK4 channel blocker, TRAM-34. The effects of ivabradine were examined on the arrhythmic beating of human induced pluripotent stem cells derived cardiomyocytes (hiPSC-CMs) from CPVT patients, on sinoatrial node (SAN) calcium transients, and on ECG measurements obtained from transgenic mice model of CPVT. Ivabradine did neither prevent the arrhythmic pacing of hiPSC-CMs derived from CPVT patients, nor preclude the aberrant SAN calcium transients. In contrast to TRAM-34, ivabradine was unable to reduce in vivo the ventricular premature complexes and ventricular tachyarrhythmias in transgenic CPVT mice. In conclusion, ivabradine does not exhibit anti-arrhythmic properties in CPVT, which indicates that this blocker cannot be used as a plausible treatment for CPVT ventricular arrhythmias.

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“…Pinacidil‐treated, intact, paced rabbit hearts have also been used to pursue additional potential pharmacological treatments, with recent work showing prolongation of QT interval and of ERP and suppression of VF by both ranolazine and vernakalant . In a new report in this volume of the journal, Frommeyer and colleagues have now employed the pinacidil‐treated whole rabbit heart SQTS model, to demonstrate a potentially beneficial role for ivabradine in the SQTS …”

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confidence: 99%

“…In their paper, Frommeyer and colleagues answer this question using ECG and monophasic ventricular AP recordings from perfused rabbit hearts . The hearts were electrically paced following destruction of the AV node.…”

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confidence: 99%

Could ivabradine be a new treatment for the short QT syndrome?

Hancox

2017

Clin Exp Pharma Physio

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HANCOX under the conditions of this study, ivabradine showed clear antiarrhythmic effects in the pinacidil SQTS model. The findings in this paper are important in two respects: first, they provide further evidence that ivabradine can exert clear electrophysiological actions that are independent of I f /HCN channel inhibition; second, they provide proof-of-concept that, at least under the conditions of this study, ivabradine is antiarrhythmic against abbreviated ventricular repolarization. So, could the drug be beneficial in clinical SQTS? Possibly, yes, though further preclinical work is likely needed first. In particular, it would be useful to verify that submicromolar ivabradine concentrations closer to the clinical range produce similar effects to those seen here.Second, as the authors themselves note, one of the main SQT1 hERG mutations (N588K-hERG) significantly reduces the ability of ivabradine to block the channel 11 and so the drug is unlikely to be effective in forms of SQT1 in which hERG channel inactivation is markedly impaired. Third, the paced preparation used in this study eliminates the bradycardic effect of ivabradine on the sinoatrial node and this would not be the case in the clinical setting. The significance of this point is that some forms of SQTS are themselves associated with bradycardia. For instance, one study has reported that up to 75% of SQT2 cases and 9% of non-SQT2 cases also show sick sinus syndrome/bradycardia. 3 Ivabradine would be expected to exacerbate these and so should be avoided in such cases. Also, as has been commented by others, 1 heterogeneity of repolarization and abnormality of the QT-RR relationship are likely to be greatest at slow rates, and this may facilitate susceptibility to tachyarrhythmia. Thus, if ivabradine were to be pursued further as a potential treatment for the SQTS, it may be important to establish whether or not the drug's prolongation of PRR would suffice to offset any increased vulnerability associated with drug-induced bradycardia. DISCLOSURENone. ACKNOWLEDGEMENTSThe author thanks the British Heart Foundation for research funding on the SQTS.

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Antiarrhythmic properties of ivabradine in an experimental model of Short‐QT‐ Syndrome

Cited by 14 publications

References 16 publications

Drug Testing in Human‐Induced Pluripotent Stem Cell–Derived Cardiomyocytes From a Patient With Short QT Syndrome Type 1

Drug Testing in Human‐Induced Pluripotent Stem Cell–Derived Cardiomyocytes From a Patient With Short QT Syndrome Type 1

The Hyperpolarization-Activated Cyclic-Nucleotide-Gated Channel Blocker Ivabradine Does Not Prevent Arrhythmias in Catecholaminergic Polymorphic Ventricular Tachycardia

Could ivabradine be a new treatment for the short QT syndrome?

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