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

Psaty, 1997, Incidence of and risk factors for atrial fibrillation in older adults, Circulation, 96, 2455, 10.1161/01.CIR.96.7.2455 Huikuri, 2001, Sudden death due to cardiac arrhythmias, N Engl J Med, 345, 1473, 10.1056/NEJMra000650 Alasady, 2011, Coronary artery disease affecting the atrial branches is an independent determinant of atrial fibrillation after myocardial infarction, Heart Rhythm, 8, 955, 10.1016/j.hrthm.2011.02.016 Calkins, 2007, Heart Rhythm, 4, 816, 10.1016/j.hrthm.2007.04.005 Morrow, 2007, Effects of ranolazine on recurrent cardiovascular events in patients with non-ST-elevation acute coronary syndromes: the MERLIN-TIMI 36 randomized trial, JAMA, 297, 1775, 10.1001/jama.297.16.1775 Scirica, 2007, Circulation, 116, 1647, 10.1161/CIRCULATIONAHA.107.724880 Antzelevitch, 2011, Electrophysiologic basis for the antiarrhythmic actions of ranolazine, Heart Rhythm, 8, 1281, 10.1016/j.hrthm.2011.03.045 Zaza, 2013, The late Na+ current: origin and pathophysiological relevance, Cardiovasc Drugs Ther, 27, 61, 10.1007/s10557-012-6430-0 Belardinelli, 2015, Cardiac late Na+ current: proarrhythmic effects, roles in long QT syndromes, and pathologic relationship to CaMKII and oxidative stress, Heart Rhythm, 12, 440, 10.1016/j.hrthm.2014.11.009 Belardinelli, 2013, A novel, potent, and selective inhibitor of cardiac late sodium current suppresses experimental arrhythmias, J Pharmacol Exp Ther, 344, 23, 10.1124/jpet.112.198887 Sicouri, 2013, Antiarrhythmic effects of the highly selective late sodium channel current blocker GS-458967, Heart Rhythm, 10, 1036, 10.1016/j.hrthm.2013.03.023 Rajamani S, Liu G, El-Bizri N, Guo D, Li C, Chen XL, Kahlig K, Mollova N, Elzein E, Zablocki J, Belardinelli L. The novel late Na+ current inhibitor, GS-6615 (eleclazine) and its anti-arrhythmic effects in rabbit isolated heart preparations. Br J Pharmacol (In press). Bonatti, 2014, Selective late sodium current blockade with GS-458967 markedly reduces ischemia-induced atrial and ventricular repolarization alternans and ECG heterogeneity, Heart Rhythm, 11, 1827, 10.1016/j.hrthm.2014.06.017 Bento, 2015, 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, Heart Rhythm, 12, 2508, 10.1016/j.hrthm.2015.07.025 Zareba, 2014, QTc shortening by GS-6615, a new late sodium current blocker, in LQT3 patients [abstract], Heart Rhythm, 11, S81 Fuller H, Justo F, Nearing BD, Kahlig K, Rajamani S, Belardinelli L, Verrier RL. 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. Heart Rhythm 2016;[Epub ahead of print]. Olshansky, 2005, Interrelationships between autonomic nervous system and atrial fibrillation, Prog Cardiovasc Dis, 48, 57, 10.1016/j.pcad.2005.06.004 Shen, 2014, Role of the autonomic nervous system in modulating cardiac arrhythmias, Circ Res, 114, 1004, 10.1161/CIRCRESAHA.113.302549 Hou, 2015, Neuromodulation for cardiac arrhythmia, Heart Rhythm, 15, S1547 Verrier, 2016, Unmasking atrial repolarization to assess alternans, spatio-temporal heterogeneity, and susceptibility to atrial fibrillation, Heart Rhythm, 13, 953, 10.1016/j.hrthm.2015.11.019 Kenttä, 2016, Prediction of sudden cardiac death with automated high throughput analysis of heterogeneity in standard resting 12-lead electrocardiogram, Heart Rhythm, 13, 713, 10.1016/j.hrthm.2015.11.035 Nearing, 2002, Modified moving average method for T-wave alternans analysis with high accuracy to predict ventricular fibrillation, J Appl Physiol, 92, 541, 10.1152/japplphysiol.00592.2001 Kumar, 2009, Ranolazine exerts potent effects on atrial electrical properties and abbreviates atrial fibrillation duration in the intact porcine heart, J Cardiovasc Electrophysiol, 20, 796, 10.1111/j.1540-8167.2009.01437.x Narayan, 2011, Repolarization alternans reveals vulnerability to human atrial fibrillation, Circulation, 123, 2922, 10.1161/CIRCULATIONAHA.110.977827 Jousset, 2012, Kinetics of atrial repolarization alternans in a free-behaving ovine model, J Cardiovasc Electrophysiol, 23, 1003, 10.1111/j.1540-8167.2012.02336.x Comtois, 2012, Atrial repolarization alternans as a path to atrial fibrillation [editorial], J Cardiovasc Electrophysiol, 23, 1013, 10.1111/j.1540-8167.2012.02391.x Weiss, 2006, From pulsus to pulseless: the saga of cardiac alternans, Circ Res, 98, 1244, 10.1161/01.RES.0000224540.97431.f0 Reffelmann, 2010, Ranolazine: an anti-anginal drug with further therapeutic potential, Expert Rev Cardiovasc Ther, 8, 319, 10.1586/erc.09.178 Nieminen, 2011, Antifibrillatory effect of ranolazine during severe coronary stenosis in the intact porcine model, Heart Rhythm, 8, 608, 10.1016/j.hrthm.2010.11.029 Verrier, 2010, T-wave alternans as a therapeutic marker for antiarrhythmic agents, J Cardiovasc Pharmacol, 55, 544, 10.1097/FJC.0b013e3181d6b781 Pezhouman, 2014, Selective inhibition of late sodium current suppresses ventricular tachycardia and fibrillation in intact rat hearts, Heart Rhythm, 11, 492, 10.1016/j.hrthm.2013.11.026 Verrier, 2011, Microvolt T-wave alternans: physiologic basis, methods of measurement, and clinical utility. Consensus guideline by the International Society for Holter and Noninvasive Electrocardiology, J Am Coll Cardiol, 44, 1309, 10.1016/j.jacc.2011.06.029 Bacic, 2015, Inhibition of the late sodium current by GS-6615 is superior to flecainide in suppressing catecholamine-induced VT in an intact porcine model [abstract], Heart Rhythm, 12, S493 Krishnan, 1993, Flecainide-induced arrhythmia in canine ventricular epicardium: phase 2 reentry?, Circulation, 87, 562, 10.1161/01.CIR.87.2.562 Verrier, 2013, Low doses of ranolazine and dronedarone in combination exert potent protection against atrial fibrillation and vulnerability to ventricular arrhythmias during acute myocardial ischemia, Heart Rhythm, 10, 121, 10.1016/j.hrthm.2012.09.015