Selective late INa inhibition by GS-458967 exerts parallel suppression of catecholamine-induced hemodynamically significant ventricular tachycardia and T-wave alternans in an intact porcine model

doi:10.1016/j.hrthm.2015.07.025

Heart Rhythm

Volume 12, Issue 12, December 2015, Pages 2508-2514

https://doi.org/10.1016/j.hrthm.2015.07.025 Get rights and content

Background

Catecholamines can elicit early and delayed afterdepolarizations (EADs and DADs), resulting in ventricular tachyarrhythmias.

Objective

As inhibition of the cardiac late sodium current (I_Na) suppresses EADs and DADs, we examined whether GS-458967 (GS-967), a potent inhibitor of this current that is devoid of beta-adrenergic blocking action, can prevent epinephrine-induced ventricular tachycardia (VT) induction in an intact porcine model.

Methods

In 12 closed-chest anesthetized pigs, spontaneous VT was induced by epinephrine administration (2.0 µg/kg, intravenous, bolus over 1 minute). Effects of GS-967 (0.4 mg/kg, intravenous, infused over 30 minutes) on VT incidence, T-wave alternans (TWA) level, and hemodynamic and electrophysiologic parameters before and after epinephrine were analyzed (N = 6). Effects of vehicle control were investigated in 6 animals. TWA was measured using the Modified Moving Average method.

Results

Epinephrine elicited spontaneous hemodynamically significant nonsustained VT in all 6 pigs and increased TWA by 28-fold compared to baseline (P < .001). GS-967 reduced mean 3- to 7-beat VT incidence by 55% (from 9.5 ± 2.72 to 4.3 ± 0.76 beats/min, P = .020) and ≥8-beat VT incidence by 56% (from 1.6 ± 0.47 to 0.7 ± 0.42 beats/2 min, P = .033) and eliminated the VT-associated hypotension, with no changes in chronotropic and minimal attenuation of the inotropic responses to epinephrine. Concurrently, GS-967 at 30, 60, and 90 minutes reduced the magnitude of the epinephrine-induced surge in TWA by 56% (from 140 ± 13.2 to 62 ± 12.1 µV, P < .01), 62% (to 53 ± 8.3 µV, P < .01), and 51% (to 69 ± 14.0 µV, P < .01) (means ± SEM), respectively.

Conclusion

Selective cardiac late I_Na inhibition with GS-967 confers significant protection against catecholamine-induced VT and TWA.

Introduction

Excess catecholamines constitute a well-established trigger for malignant ventricular arrhythmias. The underlying arrhythmogenic mechanisms are diverse, including induction of focal arrhythmias due to triggered activity and enhanced automaticity as well as reentrant arrhythmias due to altered conduction and heterogeneity of repolarization.1, 2, 3 The clinical importance of elevated catecholamines in ventricular tachyarrhythmias is evident in their mediation of circadian triggers, behavioral stress, exercise, seizures in patients with epilepsy, and other physiologic and pathophysiologic stimuli.2, 3 Risk for sudden arrhythmic death is significantly reduced by sympathetic nerve ablation⁴ and by blockade of beta-adrenergic receptors.⁵ While the use of beta-blockers has proven to be a mainstay in containing adrenergic triggers of sudden cardiac death, as shown in multiple trials,⁵ this class of agents is associated, in a sizable number of patients, with important side effects including bronchospasm, fatigue, depression, and impotence, as well as others.

Inhibition of the cardiac late sodium current (late I_Na) is emerging as a novel antiarrhythmic modality, as this current has been reported to be arrhythmogenic in a variety of disease states.6, 7, 8 The magnitude of late I_Na is increased in a number of pathologic conditions such as heart failure, acute myocardial ischemia, and the congenital long QT3 syndrome. There is indirect evidence that catecholamines can increase late I_Na in ventricular myocytes, as it has been shown that exposure of canine Purkinje fibers to isoproterenol in Tyrode solution containing high Ca²⁺ can elicit delayed afterdepolarizations (DADs) and DAD-induced triggered activity that are readily suppressed by GS-967.⁹

The main goals of this study were to develop a large-animal model of catecholamine-induced ventricular tachycardia (VT) and to determine the effects of the recently developed, highly selective, potent inhibitor of late I_Na, GS-458967 (6-[4-(trifluoromethoxy) phenyl]-3-(trifluoromethyl)-[1,2,4] triazolo[4,3-a] pyridine; hereafter GS-967).⁷ We performed concurrent measurements of PR and QT intervals as well as T-wave alternans (TWA) to delineate electrophysiologic mechanisms and to provide tools whereby the present findings could be explored in clinical electrocardiogram (ECG) recordings.

Section snippets

Experimental Preparation

This study conformed to the Position of the American Heart Association on Research Animal Use as well as to the Declaration of Helsinki. The protocol was approved by the institutional animal use committee of the Beth Israel Deaconess Medical Center. Data were obtained in male Yorkshire pigs (N = 12) weighing 35.8 ± 1.49 kg (mean ± SEM). The animals were preanesthetized with telazol (4.7 mg/kg, intramuscular) and then anesthetized with alpha-chloralose (100 mg/kg, intravenous [IV], bolus

Pharmacokinetic, Hemodynamic, and Electrocardiographic Responses to GS-967 Administration

The plasma level of GS-967 (0.4 mg/kg, IV) reached a peak of 536 ± 89.1 nM at 30 minutes and declined progressively to a relatively stable level between 60 and 90 minutes after administration of the compound (Figure 2). At 90 minutes, just prior to termination of the experiment, the plasma level was 298 ± 34.1 nM. The cardiac tissue levels of GS-967 in the right (758 ± 79.9 nM) and left atria (623 ± 47.9 nM) and the right (741 ± 65.9 nM) and left ventricles (750 ± 76.9 nM) averaged 2- to 3-fold

Discussion

The present study is the first to demonstrate that selective inhibition of late I_Na achieved by administration of GS-967 provides protection against hemodynamically significant catecholamine-induced nonsustained VT in the intact porcine heart. Interestingly, this potent antiarrhythmic effect of GS-967 was not accompanied by suppression of the stimulatory effects of epinephrine on heart rate or MAP and produced only a mild decrease in the epinephrine-induced rise in LV dP/dt. The compound also

Conclusions

GS-967 exerts potent protective action against hemodynamically significant catecholamine-induced nonsustained VT. This effect occurs in the absence of blunting of heart rate or pressor response to the catecholamine, with only a mild reduction in the inotropic response, consistent with the drug’s inhibition of late I_Na. The central mode of action of the compound offers unique advantages, inasmuch as significant antiarrhythmic actions are evident without impairment of mechanical function of the

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Arrhythmogenic cardiac alternans in heart failure is suppressed by late sodium current blockade by ranolazine
2019, Heart Rhythm
Cardiac alternans is promoted by heart failure (HF)–induced calcium (Ca²⁺) cycling abnormalities. Late sodium current (I_Na,L) is enhanced in HF and promotes Ca²⁺ overload; however, mechanisms underlying an antiarrhythmic effect of I_Na,L blockade in HF remain unclear.
The purpose of this study was to determine whether ranolazine suppresses cardiac alternans in HF by normalizing Ca²⁺ cycling.
Transmural dual optical mapping of Ca²⁺ transients and action potentials was performed in wedge preparations from 8 HF and 8 control (normal) dogs. Susceptibility to action potential duration alternans (APD-ALT) and Ca²⁺ transient alternans (Ca-ALT) was compared at baseline and with ranolazine (5–10 μM).
HF increased APD- and Ca-ALT compared to normal (both P <.05), and ranolazine suppressed APD- and Ca-ALT in both groups (P <.05). The incidence of spatially discordant alternans (DIS-ALT) was increased by HF (8/8) compared to normal (4/8; P <.05), and ranolazine decreased DIS-ALT in HF (4/8; P <.05).Not only did ranolazine mitigate HF-induced Ca²⁺ overload, it also attenuated APD-ALT to Ca-ALT gain (amount of APD-ALT produced by Ca-ALT). In HF, APD-ALT to Ca-ALT gain was significantly increased (0.55 ± 0.02) compared to normal (0.44 ± 0.02; P <.05) and was normalized by ranolazine (0.36 ± 0.05; P <.05), representing a complementary mechanism by which I_Na,L blockade suppressed cardiac alternans.
Ranolazine attenuated arrhythmogenic cardiac alternans in HF, both by suppressing Ca-ALT and decreasing the coupling gain of APD-ALT to Ca-ALT. Blockade of I_Na,L may reverse impaired Ca²⁺ cycling to mitigate cardiac alternans, representing a mechanism underlying the antiarrhythmic benefit of I_Na,L blockade in HF.
Eleclazine, an inhibitor of the cardiac late sodium current, is superior to flecainide in suppressing catecholamine-induced ventricular tachycardia and T-wave alternans in an intact porcine model
2017, Heart Rhythm
Citation Excerpt :
In intact animals, it has been demonstrated that GS-967 reduces ischemia-induced susceptibility to ventricular arrhythmias as indicated by a reduction in atrial and ventricular heterogeneity of repolarization and TWA.6 Bento et al7 reported suppression of catecholamine-induced hemodynamically significant VT and TWA by GS-967, and Pezhouman et al5 demonstrated that GS-967 is effective in suppressing arrhythmias in intact rat hearts. In the present study, we showed the high efficacy of eleclazine in suppressing hemodynamically significant epinephrine-induced VT.
The capacity of catecholamines to induce ventricular tachycardia (VT) is well documented.
The effectiveness of the novel cardiac late sodium inhibitor eleclazine in suppressing catecholamine-induced VT in a large animal model was compared with that of flecainide.
In 13 closed-chest anesthetized Yorkshire pigs, spontaneous VT and surges in T-wave alternans (TWA) level measured using the Modified Moving Average method were induced by epinephrine (2.0 µg/kg, i.v., bolus over 1 minute). Effects of eleclazine (0.3 mg/kg, i.v., infused over 15 minutes; n = 6) or flecainide (1 mg/kg, i.v., bolus over 2 minutes followed by 1 mg/kg/hr, i.v., for 1 hour; n = 7) on VT incidence and TWA level were measured from right intraventricular electrogram recordings.
Epinephrine reproducibly elicited hemodynamically significant spontaneous VT in all 13 pigs and increased TWA level by 33-fold compared to baseline (P < .001). Eleclazine reduced the incidence of epinephrine-induced ventricular premature beats and couplets by 51% (from 31.3 ± 1.91 to 15.2 ± 5.08 episodes; P = .038) and the incidence of 3- to 7-beat VT by 56% (from 10.8 ± 3.45 to 4.7 ± 3.12 episodes; P = .004). Concurrently, the drug reduced the peak epinephrine-induced TWA level by 64% (from 217 ± 22.2 to 78 ± 15.3 µV; P < .001). Flecainide also reduced the incidence of epinephrine-induced ventricular premature beats and couplets by 53% (from 40.4 ± 6.37 to 19.0 ± 2.73 episodes; P = .024) but did not affect the incidence of VT (from 15.0 ± 3.08 to 11.6 ± 2.93 episodes; P = .29) or the peak TWA level (from 207 ± 30.6 to 172 ± 26.2 µV; P = .34).
Selective inhibition of cardiac late sodium current with eleclazine is more effective than flecainide in reducing catecholamine-induced VT and TWA in an intact porcine model.
Electrophysiological mechanisms of long and short QT syndromes
2017, IJC Heart and Vasculature
The QT interval on the human electrocardiogram is normally in the order of 450 ms, and reflects the summated durations of action potential (AP) depolarization and repolarization of ventricular myocytes. Both prolongation and shortening in the QT interval have been associated with ventricular tachy-arrhythmias, which predispose affected individuals to sudden cardiac death. In this article, the molecular determinants of the AP duration and the causes of long and short QT syndromes (LQTS and SQTS) are explored. This is followed by a review of the recent advances on their arrhythmogenic mechanisms involving reentry and/or triggered activity based on experiments conducted in mouse models. Established and novel clinical risk markers based on the QT interval for the prediction of arrhythmic risk and cardiovascular mortality are presented here. It is concluded by a discussion on strategies for the future rational design of anti-arrhythmic agents.
Cardiac dynamics: Alternans and arrhythmogenesis
2016, Journal of Arrhythmia
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SAC inhibitors could potentially exert anti-arrhythmic effects by suppressing discordant alternans. Discordant alternans can also be inhibited by late sodium channel blockers [65], ryanodine receptor stabilizers [57] or anti-fibrotic agents [70], which would prevent conduction block and inhibit arrhythmogenesis. Some of the examples described above illustrate the difficulty in predicting the overall electrophysiological effects of a drug, and some may exert their anti-arrhythmic effects without influencing restitution [71,72].
Pre-existing heterogeneities present in cardiac tissue are essential for maintaining the normal electrical and mechanical functions of the heart. Exacerbation of such heterogeneities or the emergence of dynamic factors can produce repolarization alternans, which are beat-to-beat alternations in the action potential time course. Traditionally, this was explained by restitution, but additional factors, such as cardiac memory, calcium handling dynamics, refractory period restitution, and mechano-electric feedback, are increasingly recognized as the underlying causes. The aim of this article is to review the mechanisms that generate cardiac repolarization alternans and convert spatially concordant alternans to the more arrhythmogenic spatially discordant alternans. This is followed by a discussion on how alternans generate arrhythmias in a number of clinical scenarios, and concluded by an outline of future therapeutic targets for anti-arrhythmic therapy.
Inhibition of the cardiac late sodium current with eleclazine protects against ischemia-induced vulnerability to atrial fibrillation and reduces atrial and ventricular repolarization abnormalities in the absence and presence of concurrent adrenergic stimulation
2016, Heart Rhythm
Citation Excerpt :
The pigs were preanesthetized with telazol (4.7 mg/kg IM) and then anesthetized with alpha-chloralose (80 mg/kg IV bolus followed by 24 mg/kg/h IV continuous infusion). The catheterization methods for cardiac pacing, monitoring systemic and left ventricular blood pressure, electrocardiographic recording, assessment of repolarization alternans13,14,16,22 and heterogeneity,13,16,21 and drug delivery23 are presented in the Online Supplemental Material, along with the description of analysis of plasma and tissue drug concentrations. The experimental protocol is shown in Figure 1.
Myocardial ischemia carries dual risk for initiating atrial and ventricular arrhythmias that can be exacerbated by adrenergic stimulation.
The purpose of this study was to investigate whether selective inhibition of the cardiac late sodium current (I_Na) with eleclazine decreases susceptibility to ischemia-induced atrial fibrillation (AF) and atrial and ventricular repolarization abnormalities before and after epinephrine infusion.
In chloralose-anesthetized, open-chest, male Yorkshire pigs (n = 12), atrial and ventricular ischemia was induced by partial occlusion of the left circumflex coronary artery proximal segment to reduce flow by 75%. Epinephrine (0.5 µg/kg IV bolus over 1 minute; n = 6) was infused before and at 2 hours after eleclazine (0.9 mg/kg IV bolus over 15 minutes).
Left circumflex coronary artery occlusion significantly increased ventricular dispersion of repolarization (T-wave alternans [TWA] by 861%, T-wave heterogeneity by 286%, T_peak–T_end interval by 74%) and atrial repolarization alternans (TWA_a) by 2850% and lowered AF threshold by 65%. Eleclazine reduced the ischemia-induced surge in TWA by 81% (P = .007), T-wave heterogeneity by 23% (P = .035), and T_peak–T_end by 28% (P = .014), suppressed the ischemia-induced surge in atrial TWA_a by 64% (P = .002), and reduced the ischemia-induced fall in AF threshold to 20%. It shortened baseline QT interval by 6% (P <.001), JT interval by 8% (P <.001), and atrial action potential duration (PTa) by 8% (P = .002). Similar beneficial effects of eleclazine were observed after epinephrine infusion without reducing contractility (P = .054).
Selective inhibition of cardiac late I_Na with eleclazine confers dual protection against vulnerability to ischemia-induced AF and reduces atrial and ventricular repolarization abnormalities before and during adrenergic stimulation without negative inotropic effects.
Eleclazine, a new selective cardiac late sodium current inhibitor, confers concurrent protection against autonomically induced atrial premature beats, repolarization alternans and heterogeneity, and atrial fibrillation in an intact porcine model
2016, Heart Rhythm
The cardiac late sodium current (I_Na) has been increasingly implicated in the initiation of atrial fibrillation (AF). Eleclazine (formerly known as GS-6615) is a new selective late I_Na inhibitor and is undergoing clinical testing for the treatment of cardiac arrhythmias.
We tested whether late I_Na inhibition by eleclazine confers protection against atrial premature beats (APBs) and AF.
In closed-chest anesthetized Yorkshire pigs, epinephrine (2.0 µg/kg, intravenous, bolus over 1 minute) was administered alone to induce APBs (n = 6) or in combination with intrapericardial acetylcholine (0.5–4 mL of 12.5 mM solution) to induce spontaneous AF (n = 11). Effects of eleclazine (0.3 and 0.9 mg/kg, intravenous, over 15 minutes) on APBs and AF were determined.
Epinephrine-induced APBs were reduced >3-fold (P < .04) after eleclazine (0.9 mg/kg) infusion. The combined administration of epinephrine and acetylcholine resulted in AF in all animals tested, which was invariably preceded by APBs. Eleclazine pretreatment suppressed AF in all 7 animals in at least 1 test episode during the 60- to 150-minute observation period (P = .04). The plasma eleclazine level at 120 minutes was 828 ± 45.8 nM, within exposure range evaluated clinically. Eleclazine shortened ventricular QT and atrial PT_a intervals by 7% (P < .001 for both) and reduced atrial repolarization alternans (P = .003) and heterogeneity (P = .021) without attenuation of the inotropic response to catecholamine (P = .56). The drug inhibited the enhanced late I_Na of single atrial myocytes with a potency of 736 ± 67 nM.
Selective cardiac late I_Na inhibition with eleclazine suppresses autonomically mediated atrial repolarization alternans and heterogeneity, APBs, and AF in an intact porcine model.

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: This study was funded by a grant from Gilead Sciences to Beth Israel Deaconess Medical Center (Dr Verrier, P.I.). Messrs Bento, Bacic, and Fuller and Mesdames Carneiro and Justo received support from “Science without Borders” (CAPES of the Brazilian Federal Government), Banco Santander Brasil, Dr Miguel Srougi, and Harvard University’s David Rockefeller Center for Latin American Studies. Drs Rajamani and Belardinelli are employees of Gilead Sciences, the company that supported this study. Drs Verrier and Nearing have received royalties from Georgetown University and Beth Israel Deaconess Medical Center for intellectual property on the Modified Moving Average method for T-wave alternans analysis, which was used in this study.

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Selective late INa inhibition by GS-458967 exerts parallel suppression of catecholamine-induced hemodynamically significant ventricular tachycardia and T-wave alternans in an intact porcine model

Background

Objective

Methods

Results

Conclusion

Introduction

Section snippets

Experimental Preparation

Pharmacokinetic, Hemodynamic, and Electrocardiographic Responses to GS-967 Administration

Discussion

Conclusions

Pharmacol Ther

Heart Rhythm

Heart Rhythm

J Am Coll Cardiol

Heart Rhythm

Heart Rhythm

Heart Rhythm

Heart Rhythm

Sympathetic nervous system and cardiac arrhythmias

Autonomic aspects of arrhythmogenesis: the enduring and the new

Curr Opin Cardiol

Selective late I_Na inhibition by GS-458967 exerts parallel suppression of catecholamine-induced hemodynamically significant ventricular tachycardia and T-wave alternans in an intact porcine model