Volume 10, Issue 1, Pages (January 2013)

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Presentation transcript:

Volume 10, Issue 1, Pages 121-127 (January 2013) Low doses of ranolazine and dronedarone in combination exert potent protection against atrial fibrillation and vulnerability to ventricular arrhythmias during acute myocardial ischemia Richard L. Verrier, PhD, FACC, Vitor P.F. Pagotto, BS, Alexandre F. Kanas, BS, Marcel F. Sobrado, BS, Bruce D. Nearing, PhD, Dewan Zeng, PhD, Luiz Belardinelli, MD Heart Rhythm Volume 10, Issue 1, Pages 121-127 (January 2013) DOI: 10.1016/j.hrthm.2012.09.015 Copyright © 2013 Heart Rhythm Society Terms and Conditions

Figure 1 Experimental setup. Upper left panel: Left atrial (LA) and left ventricular (LV) epicardial (epi) electrocardiograms obtained before balloon occlusion of the left circumflex (LCx) coronary artery to reduce flow by 75% during atrial pacing at 150 beats/min. Upper right panel: Induction of atrial fibrillation (AF) by a 6-mA S2 test stimulus following the last S1 pacing stimulus. Note visible T-wave heterogeneity compared to the uniform pattern observed in the upper left panel. Lower panel: Hydraulic balloon occluder positioned around the proximal LCx coronary artery upstream of the Doppler flow probe. Electrode catheters are affixed to the left atrial appendage and left ventricular epicardium within the atrial and ventricular regions supplied by the LCx. Heart Rhythm 2013 10, 121-127DOI: (10.1016/j.hrthm.2012.09.015) Copyright © 2013 Heart Rhythm Society Terms and Conditions

Figure 2 Study protocol. The drugs were given in the reverse order in the second period of drug administration. AF = atrial fibrillation; DRON = dronedarone; RAN = ranolazine; TWH = T-wave heterogeneity. Heart Rhythm 2013 10, 121-127DOI: (10.1016/j.hrthm.2012.09.015) Copyright © 2013 Heart Rhythm Society Terms and Conditions

Figure 3 Plasma and tissue concentrations. Upper left panel: Time course of plasma level of ranolazine (n = 12) following 0.6 mg/kg intravenous bolus and 0.035 mg/kg/min infusion. Lower left panel: Plasma and tissue levels of ranolazine at the time of termination of the study (n = 10). Upper right panel: Time course of plasma level of dronedarone (n = 7) following 0.5 mg/kg intravenous bolus. Lower right panel: Plasma and tissue levels of dronedarone at the time of termination of the study (n = 10). Heart Rhythm 2013 10, 121-127DOI: (10.1016/j.hrthm.2012.09.015) Copyright © 2013 Heart Rhythm Society Terms and Conditions

Figure 4 Effects on PR and QT intervals and left atrial effective refractory period (AERP) without stenosis. Upper and middle panels: Neither ranolazine (RAN) (n = 7), dronedarone (DRON) (n = 7), nor their combination (COMB) (n = 7) significantly altered either PR or QT intervals from control. Lower panel: Both RAN (n = 6) and DRON (n = 5) separately increased left AERP. However, COMB (n = 11) did not exert further effects compared to either agent alone. *p<0.05. Heart Rhythm 2013 10, 121-127DOI: (10.1016/j.hrthm.2012.09.015) Copyright © 2013 Heart Rhythm Society Terms and Conditions

Figure 5 Effects on atrial fibrillation threshold (AFT). Left bars: Left circumflex (LCx) coronary artery stenosis resulted in a marked reduction in AFT (n = 15). Middle bars: Ranolazine (RAN; n = 8) or dronedarone (DRON; n = 7) did not significantly blunt the ischemia-induced decrease in AFT. Right bars: The combination of drugs (COMB; n = 9) prevented a reduction in AFT during stenosis. *p<0.05. NS = not significant. Heart Rhythm 2013 10, 121-127DOI: (10.1016/j.hrthm.2012.09.015) Copyright © 2013 Heart Rhythm Society Terms and Conditions

Figure 6 Effects on T-wave heterogeneity (TWH). Left bars: Before drug administration (n = 15), left circumflex (LCx) coronary artery stenosis provoked a marked surge in TWH. Middle bars: Ranolazine (RAN; n = 7) or dronedarone (DRON; n = 6) alone did not significantly blunt the ischemia-induced surge in TWH. Right bars: The combination of drugs (COMB; n = 7) completely prevented the surge in TWH during stenosis. *p<0.05. NS = not significant. Heart Rhythm 2013 10, 121-127DOI: (10.1016/j.hrthm.2012.09.015) Copyright © 2013 Heart Rhythm Society Terms and Conditions