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Combined Actions of Ivabradine and Ranolazine Reduce Ventricular Rate During Atrial Fibrillation RICHARD L. VERRIER, Ph.D.,∗ ,† ANA F.G. SILVA, B.S.,∗ ,‡ RODOLFO BONATTI, B.S.,∗ ,‡ JULIO A.P. BATATINHA, B.S.,∗ ,‡ BRUCE D. NEARING, Ph.D.,∗ ,† GONGXIN LIU, Ph.D.,§ SRIDHARAN RAJAMANI, Ph.D.,§ DEWAN ZENG, Ph.D.,§ and LUIZ BELARDINELLI, M.D.§ From the ∗ Department of Medicine, Beth Israel Deaconess Medical Center; †Harvard Medical School, Boston, Massachusetts, USA; ‡Faculdade de Medicina de Universidade de S˜ao Paulo, S˜ao Paulo, Brazil; and §Gilead Sciences, Inc, Foster City, California, USA
Drug Combination Reduces Ventricular Rate in AF. Introduction: Ventricular rate during atrial fibrillation (AF) can be reduced by slowing atrioventricular (AV) node conduction and/or by decreasing dominant frequency of AF. We investigated whether combined administration of ivabradine and ranolazine reduces ventricular rate during AF. Methods and Results: Ivabradine (maximum clinical dose, 0.25 mg/kg, and 0.10 mg/kg, i.v.) and ranolazine (2.4 mg/kg, i.v., bolus followed by 0.135 mg/kg/min) were studied in an anesthetized pig (N = 16) model of AF. Combined administration of 0.25 mg/kg ivabradine with ranolazine reduced ventricular rate during AF by 51.9 ± 9.7 beats/min (23%, P = 0.017) and dominant frequency of AF by 2.8 ± 0.5 Hz (32%, P = 0.005). It increased PR (P = 0.0002, P = 0.0007) and A-H intervals (P = 0.047, P = 0.002) during pacing at 130 and 180 beats/min, respectively, to a greater degree than additive effects of single agents. Combined administration of 0.1 mg/kg ivabradine with ranolazine exceeded additive effects of single agents on A-H intervals and dominant frequency of AF. Moreover, ranolazine potentiated low-dose ivabradine’s reduction in ventricular rate, as combined administration more than doubled effects of the higher ivabradine dose alone and was similar to the combination with the higher dose. Neither drug nor their combination affected contractility (left ventricular [LV] dP/dt), QT or His-ventricular (H-V) intervals, or mean arterial pressure during sinus rhythm or AF. Conclusion: Combined administration of ivabradine and ranolazine at clinically safe levels decreases ventricular rate during AF by reducing AV node conduction and AF dominant frequency without QT prolongation or depression in contractility. Targeting these actions offers intrinsic advantages over conventional nodal agents, which can reduce contractility. (J Cardiovasc Electrophysiol, Vol. 26, pp. 329-335, March 2015) atrial fibrillation, atrioventricular node, dominant frequency, funny current, sodium current, ventricular rate Introduction Recently, a novel potential therapeutic target for ventricular rate reduction during atrial fibrillation (AF) has emerged, namely, the funny current (If ), which is functionally expressed in the atrioventricular (AV) node.1-4 In humans, zatebradine increases atrial-His (A-H) interval, suggesting a capacity to slow AV node conduction.5 Experimentally, we This work was supported by Gilead Sciences. Dr. Verrier is Principal Investigator of grants from Gilead Sciences, Inc. (Foster City, CA), to Beth Israel Deaconess Medical Center (Boston, MA), and is co-inventor with Gilead on a patent assigned to Gilead Sciences, Inc., and BIDMC. Messrs. Bonatti and Batatinha and Ms. Silva received support from the Lemann family, Dr. Miguel Srougi, Col´egio Bandeirantes, Ciˆencias Sem Fronteiras, and Harvard University’s David Rockefeller Center for Latin American Studies. Drs. Liu, Rajamani, Zeng, and Belardinelli are employed by Gilead Sciences, Inc. Address for correspondence: Richard L. Verrier, Ph.D., F.A.C.C., Associate Professor of Medicine, Harvard Medical School, Beth Israel Deaconess Medical Center, 99 Brookline Avenue, RN-301, Boston, MA 02215. Fax: 617-975-5270; E-mail: [email protected] Manuscript received 15 August 2014; Revised manuscript received 15 October 2014; Accepted for publication 16 October 2014. doi: 10.1111/jce.12569
demonstrated in a porcine model that dronedarone, which is equipotent to ivabradine in affecting If in the sinoatrial (SA) node, also increases PR interval and reduces ventricular rate during AF induced by intrapericardial acetylcholine (Ach).6 The goal of this study was to test whether combined administration of ivabradine and ranolazine in clinically relevant dosages is capable of inducing a significant reduction in ventricular rate during AF. Our hypothesis was that ivabradine, through its effect on If in the AV node, would increase A-H interval and reduce the rate of ventricular activation. Ranolazine would add to this action through its effects on peak and late Na+ current (INa ) and delayed-rectifier K+ current (IKr ), to reduce dominant frequency of AF7 and thereby diminish the rapidity of impulses bombarding the AV node, and consequently, the rate of ventricular firing. As neither of these agents exert negative inotropic effects, unlike conventional nodal agents, ventricular rate reduction during AF would occur in the absence of changes in contractility.
Methods Experimental Preparation This study conformed to the Guide for the Care and Use of Laboratory Animals and the Position of the American
330
Journal of Cardiovascular Electrophysiology
Vol. 26, No. 3, March 2015
Heart Association on Research Animal Use, as well as the Declaration of Helsinki. The protocols were approved by the animal use committees of Beth Israel Deaconess Medical Center (Boston, MA, USA) and Gilead Sciences (Fremont, CA, USA). Data from large animal experiments were gathered from male Yorkshire pigs (N = 16) weighing 35 ± 1.0 kg (mean ± SEM) following preanesthesia with telazol (4.7 mg/kg, intramuscularly) and anesthesia with alphachloralose (100 mg/kg, i.v., bolus followed by 40 mg/kg/h, i.v., continuous infusion). The experimental setup, physiologic monitoring, and plasma level determinations were conducted as previously described.6-8 Ranolazine was administered via a 7 Fr sheath inserted into the right femoral vein at a 2.4 mg/kg, i.v., bolus followed by 0.135 mg/kg/min continuous infusion, which has been shown to yield plasma levels in the clinical range (2–8 μM).9,10 Plasma levels of ranolazine alone at 30 minutes were 10.8 ± 1.2 μM and were not different at 30 minutes following ivabradine (9.8 ± 1.5 μM). Ivabradine was administered at a dose of 0.25 mg/kg, i.v., bolus infused over 5 minutes, to approximate the 0.20 mg/kg, i.v., found clinically to be safe11-13 and at a 0.1 mg/kg dose, which has recently been shown to exert use-dependent slowing of AV node conduction and to reduce ventricular rate during AF8 to determine whether a significant effect was demonstrable at this lower dose. Plasma levels of ivabradine alone at the 0.25 mg/kg, i.v., dose at 30 minutes were 304 ± 20.0 nM and were not different at 30 minutes following ranolazine (312 ± 13.1 nM). Plasma levels of ivabradine at the 0.10 mg/kg dose at 30 minutes were 139 ± 15.9 nM and were not different at 30 minutes after ranolazine (140.1 ± 20.8 nM). Cardiac Catheterization A nonsteerable, quadripolar electrode catheter (Bard Electrophysiology, Lowell, MA, USA) was placed in the right atrium via the femoral vein and a second quadripolar electrode catheter was placed in the right ventricle via the jugular vein. A bipolar electrode was placed in the noncoronary cusp of the aorta through the left carotid artery to record the His bundle electrogram. A pigtail catheter was inserted in the left ventricle via the left femoral artery to record and calculate contractility (left ventricular [LV] dP/dt). Transatrial access7 was employed to deliver ACh into the pericardial space. AF Induction and Analysis AF was defined as an irregular atrial rhythm with an average cycle length
Combined Actions of Ivabradine and Ranolazine Reduce Ventricular Rate During Atrial Fibrillation RICHARD L. VERRIER, Ph.D.,∗ ,† ANA F.G. SILVA, B.S.,∗ ,‡ RODOLFO BONATTI, B.S.,∗ ,‡ JULIO A.P. BATATINHA, B.S.,∗ ,‡ BRUCE D. NEARING, Ph.D.,∗ ,† GONGXIN LIU, Ph.D.,§ SRIDHARAN RAJAMANI, Ph.D.,§ DEWAN ZENG, Ph.D.,§ and LUIZ BELARDINELLI, M.D.§ From the ∗ Department of Medicine, Beth Israel Deaconess Medical Center; †Harvard Medical School, Boston, Massachusetts, USA; ‡Faculdade de Medicina de Universidade de S˜ao Paulo, S˜ao Paulo, Brazil; and §Gilead Sciences, Inc, Foster City, California, USA
Drug Combination Reduces Ventricular Rate in AF. Introduction: Ventricular rate during atrial fibrillation (AF) can be reduced by slowing atrioventricular (AV) node conduction and/or by decreasing dominant frequency of AF. We investigated whether combined administration of ivabradine and ranolazine reduces ventricular rate during AF. Methods and Results: Ivabradine (maximum clinical dose, 0.25 mg/kg, and 0.10 mg/kg, i.v.) and ranolazine (2.4 mg/kg, i.v., bolus followed by 0.135 mg/kg/min) were studied in an anesthetized pig (N = 16) model of AF. Combined administration of 0.25 mg/kg ivabradine with ranolazine reduced ventricular rate during AF by 51.9 ± 9.7 beats/min (23%, P = 0.017) and dominant frequency of AF by 2.8 ± 0.5 Hz (32%, P = 0.005). It increased PR (P = 0.0002, P = 0.0007) and A-H intervals (P = 0.047, P = 0.002) during pacing at 130 and 180 beats/min, respectively, to a greater degree than additive effects of single agents. Combined administration of 0.1 mg/kg ivabradine with ranolazine exceeded additive effects of single agents on A-H intervals and dominant frequency of AF. Moreover, ranolazine potentiated low-dose ivabradine’s reduction in ventricular rate, as combined administration more than doubled effects of the higher ivabradine dose alone and was similar to the combination with the higher dose. Neither drug nor their combination affected contractility (left ventricular [LV] dP/dt), QT or His-ventricular (H-V) intervals, or mean arterial pressure during sinus rhythm or AF. Conclusion: Combined administration of ivabradine and ranolazine at clinically safe levels decreases ventricular rate during AF by reducing AV node conduction and AF dominant frequency without QT prolongation or depression in contractility. Targeting these actions offers intrinsic advantages over conventional nodal agents, which can reduce contractility. (J Cardiovasc Electrophysiol, Vol. 26, pp. 329-335, March 2015) atrial fibrillation, atrioventricular node, dominant frequency, funny current, sodium current, ventricular rate Introduction Recently, a novel potential therapeutic target for ventricular rate reduction during atrial fibrillation (AF) has emerged, namely, the funny current (If ), which is functionally expressed in the atrioventricular (AV) node.1-4 In humans, zatebradine increases atrial-His (A-H) interval, suggesting a capacity to slow AV node conduction.5 Experimentally, we This work was supported by Gilead Sciences. Dr. Verrier is Principal Investigator of grants from Gilead Sciences, Inc. (Foster City, CA), to Beth Israel Deaconess Medical Center (Boston, MA), and is co-inventor with Gilead on a patent assigned to Gilead Sciences, Inc., and BIDMC. Messrs. Bonatti and Batatinha and Ms. Silva received support from the Lemann family, Dr. Miguel Srougi, Col´egio Bandeirantes, Ciˆencias Sem Fronteiras, and Harvard University’s David Rockefeller Center for Latin American Studies. Drs. Liu, Rajamani, Zeng, and Belardinelli are employed by Gilead Sciences, Inc. Address for correspondence: Richard L. Verrier, Ph.D., F.A.C.C., Associate Professor of Medicine, Harvard Medical School, Beth Israel Deaconess Medical Center, 99 Brookline Avenue, RN-301, Boston, MA 02215. Fax: 617-975-5270; E-mail: [email protected] Manuscript received 15 August 2014; Revised manuscript received 15 October 2014; Accepted for publication 16 October 2014. doi: 10.1111/jce.12569
demonstrated in a porcine model that dronedarone, which is equipotent to ivabradine in affecting If in the sinoatrial (SA) node, also increases PR interval and reduces ventricular rate during AF induced by intrapericardial acetylcholine (Ach).6 The goal of this study was to test whether combined administration of ivabradine and ranolazine in clinically relevant dosages is capable of inducing a significant reduction in ventricular rate during AF. Our hypothesis was that ivabradine, through its effect on If in the AV node, would increase A-H interval and reduce the rate of ventricular activation. Ranolazine would add to this action through its effects on peak and late Na+ current (INa ) and delayed-rectifier K+ current (IKr ), to reduce dominant frequency of AF7 and thereby diminish the rapidity of impulses bombarding the AV node, and consequently, the rate of ventricular firing. As neither of these agents exert negative inotropic effects, unlike conventional nodal agents, ventricular rate reduction during AF would occur in the absence of changes in contractility.
Methods Experimental Preparation This study conformed to the Guide for the Care and Use of Laboratory Animals and the Position of the American
330
Journal of Cardiovascular Electrophysiology
Vol. 26, No. 3, March 2015
Heart Association on Research Animal Use, as well as the Declaration of Helsinki. The protocols were approved by the animal use committees of Beth Israel Deaconess Medical Center (Boston, MA, USA) and Gilead Sciences (Fremont, CA, USA). Data from large animal experiments were gathered from male Yorkshire pigs (N = 16) weighing 35 ± 1.0 kg (mean ± SEM) following preanesthesia with telazol (4.7 mg/kg, intramuscularly) and anesthesia with alphachloralose (100 mg/kg, i.v., bolus followed by 40 mg/kg/h, i.v., continuous infusion). The experimental setup, physiologic monitoring, and plasma level determinations were conducted as previously described.6-8 Ranolazine was administered via a 7 Fr sheath inserted into the right femoral vein at a 2.4 mg/kg, i.v., bolus followed by 0.135 mg/kg/min continuous infusion, which has been shown to yield plasma levels in the clinical range (2–8 μM).9,10 Plasma levels of ranolazine alone at 30 minutes were 10.8 ± 1.2 μM and were not different at 30 minutes following ivabradine (9.8 ± 1.5 μM). Ivabradine was administered at a dose of 0.25 mg/kg, i.v., bolus infused over 5 minutes, to approximate the 0.20 mg/kg, i.v., found clinically to be safe11-13 and at a 0.1 mg/kg dose, which has recently been shown to exert use-dependent slowing of AV node conduction and to reduce ventricular rate during AF8 to determine whether a significant effect was demonstrable at this lower dose. Plasma levels of ivabradine alone at the 0.25 mg/kg, i.v., dose at 30 minutes were 304 ± 20.0 nM and were not different at 30 minutes following ranolazine (312 ± 13.1 nM). Plasma levels of ivabradine at the 0.10 mg/kg dose at 30 minutes were 139 ± 15.9 nM and were not different at 30 minutes after ranolazine (140.1 ± 20.8 nM). Cardiac Catheterization A nonsteerable, quadripolar electrode catheter (Bard Electrophysiology, Lowell, MA, USA) was placed in the right atrium via the femoral vein and a second quadripolar electrode catheter was placed in the right ventricle via the jugular vein. A bipolar electrode was placed in the noncoronary cusp of the aorta through the left carotid artery to record the His bundle electrogram. A pigtail catheter was inserted in the left ventricle via the left femoral artery to record and calculate contractility (left ventricular [LV] dP/dt). Transatrial access7 was employed to deliver ACh into the pericardial space. AF Induction and Analysis AF was defined as an irregular atrial rhythm with an average cycle length
