RESUMO
BACKGROUND: The capacity of catecholamines to induce ventricular tachycardia (VT) is well documented. OBJECTIVE: 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. METHODS: 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. RESULTS: 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). CONCLUSION: 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.
Assuntos
Catecolaminas/metabolismo , Flecainida/farmacologia , Oxazepinas/farmacologia , Taquicardia Ventricular , Administração Intravenosa , Animais , Modelos Animais de Doenças , Monitoramento de Medicamentos/métodos , Eletrocardiografia/métodos , Hemodinâmica/efeitos dos fármacos , Suínos , Taquicardia Ventricular/tratamento farmacológico , Taquicardia Ventricular/metabolismo , Taquicardia Ventricular/fisiopatologia , Resultado do Tratamento , Bloqueadores do Canal de Sódio Disparado por Voltagem/farmacologiaRESUMO
BACKGROUND: Myocardial ischemia carries dual risk for initiating atrial and ventricular arrhythmias that can be exacerbated by adrenergic stimulation. OBJECTIVE: The purpose of this study was to investigate whether selective inhibition of the cardiac late sodium current (INa) with eleclazine decreases susceptibility to ischemia-induced atrial fibrillation (AF) and atrial and ventricular repolarization abnormalities before and after epinephrine infusion. METHODS: 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). RESULTS: Left circumflex coronary artery occlusion significantly increased ventricular dispersion of repolarization (T-wave alternans [TWA] by 861%, T-wave heterogeneity by 286%, Tpeak-Tend interval by 74%) and atrial repolarization alternans (TWAa) 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 Tpeak-Tend by 28% (P = .014), suppressed the ischemia-induced surge in atrial TWAa 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). CONCLUSION: Selective inhibition of cardiac late INa 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.
Assuntos
Adrenérgicos/farmacologia , Fibrilação Atrial/prevenção & controle , Isquemia Miocárdica/complicações , Oxazepinas/farmacologia , Bloqueadores dos Canais de Sódio/farmacologia , Canais de Sódio/efeitos dos fármacos , Animais , Arritmias Cardíacas/diagnóstico , Arritmias Cardíacas/etiologia , Arritmias Cardíacas/fisiopatologia , Arritmias Cardíacas/prevenção & controle , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/etiologia , Fibrilação Atrial/fisiopatologia , Modelos Animais de Doenças , Suscetibilidade a Doenças/terapia , Eletrocardiografia , Epinefrina/farmacologia , Masculino , Isquemia Miocárdica/fisiopatologia , Oxazepinas/uso terapêutico , Bloqueadores dos Canais de Sódio/uso terapêutico , SuínosRESUMO
BACKGROUND: The cardiac late sodium current (INa) has been increasingly implicated in the initiation of atrial fibrillation (AF). Eleclazine (formerly known as GS-6615) is a new selective late INa inhibitor and is undergoing clinical testing for the treatment of cardiac arrhythmias. OBJECTIVE: We tested whether late INa inhibition by eleclazine confers protection against atrial premature beats (APBs) and AF. METHODS: 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. RESULTS: 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 PTa 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 INa of single atrial myocytes with a potency of 736 ± 67 nM. CONCLUSION: Selective cardiac late INa inhibition with eleclazine suppresses autonomically mediated atrial repolarization alternans and heterogeneity, APBs, and AF in an intact porcine model.
Assuntos
Fibrilação Atrial/tratamento farmacológico , Complexos Atriais Prematuros/tratamento farmacológico , Sistema Nervoso Autônomo/fisiopatologia , Átrios do Coração/fisiopatologia , Ventrículos do Coração/fisiopatologia , Oxazepinas/farmacologia , Animais , Fibrilação Atrial/fisiopatologia , Complexos Atriais Prematuros/fisiopatologia , Sistema Nervoso Autônomo/efeitos dos fármacos , Modelos Animais de Doenças , Eletrocardiografia , Átrios do Coração/efeitos dos fármacos , Ventrículos do Coração/efeitos dos fármacos , Masculino , SuínosRESUMO
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 INa inhibition with GS-967 confers significant protection against catecholamine-induced VT and TWA.