Introduction: We examined the effects of the selective late INa inhibitor eleclazine on the 50% probability of successful defibrillation (DFT50) before and after administration of amiodarone to determine its suitability for use in patients with implantable cardioverter defibrillators (ICDs).Methods and Results: In 20 anesthetized pigs, transvenous active-fixation cardiac defibrillation leads were fluoroscopically positioned into right ventricular apex through jugular vein. ICDs were implanted subcutaneously. Dominant frequency of ventricular fibrillation was analyzed by fast Fourier transform. The measurements were made before drug administration (control), and at 40 minutes after vehicle, eleclazine (2 mg/kg, i.v., bolus over 15 minutes), or subsequent/single amiodarone administration (10 mg/kg, i.v., bolus over 10 minutes). Eleclazine did not alter DFT50, dominant frequency, heart rate, or mean arterial pressure (MAP). Subsequent amiodarone increased DFT50 (P = 0.006), decreased dominant frequency (P = 0.022), and reduced heart rate (P = 0.031) with no change in MAP. Amiodarone alone increased DFT50 (P = 0.005; NS compared to following eleclazine) and decreased dominant frequency (P = 0.003; NS compared to following eleclazine).Conclusion: Selective late INa inhibition with eleclazine does not alter DFT50 or dominant frequency of ventricular fibrillation when administered alone or in combination with amiodarone. Accordingly, eleclazine would not be anticipated to affect the margin of defibrillation safety in patients with ICDs.

Background— Atrial fibrillation (AF) requires arrhythmogenic changes in atrial ion channels/receptors and usually altered atrial structure. AF is commonly treated with antiarrhythmic drugs; the most effective block many ion channels/receptors. Modest efficacy, intolerance, and safety concerns limit current antiarrhythmic drugs. We hypothesized that combining agents with multiple anti-AF mechanisms at reduced individual drug doses might produce synergistic efficacy plus better tolerance/safety. Methods and Results— HARMONY tested midrange ranolazine (750 mg BID) combined with 2 reduced dronedarone doses (150 mg BID and 225 mg BID; chosen to reduce dronedarone’s negative inotropic effect—see text below) over 12 weeks in 134 patients with paroxysmal AF and implanted pacemakers where AF burden (AFB) could be continuously assessed. Patients were randomized double-blind to placebo, ranolazine alone (750 mg BID), dronedarone alone (225 mg BID), or one of the combinations. Neither placebo nor either drugs alone significantly reduced AFB. Conversely, ranolazine 750 mg BID/dronedarone 225 mg BID reduced AFB by 59% versus placebo ( P =0.008), whereas ranolazine 750 mg BID/dronedarone 150 mg BID reduced AFB by 43% ( P =0.072). Both combinations were well tolerated. Conclusions— HARMONY showed synergistic AFB reduction by moderate dose ranolazine plus reduced dose dronedarone, with good tolerance/safety, in the population enrolled. Clinical Trial Registration— ClinicalTrials.gov ; Unique identifier: NCT01522651.

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.

BACKGROUND Ranolazine has been shown to have antiarrhythmic properties.OBJECTIVE We tested the hypothesis that intravenous ranolazine would terminate induced atrial flutter (AFL) or atrial fibrillation (AF) in the canine sterile pericarditis model.METHODS In 6 dogs with sterile pericarditis, we performed electrophysiological measurements of the atrial effective refractory period (AERP) and conduction time (CT) while pacing from the right atrial appendage, Bachmann bundle, and the posteroinferior left atrium at cycle Lengths (CLs) of 400, 300, and 200 ms before and after the administration of ranolazine. In 13 induced episodes of AFL (n = 9) and AF (n = 4), ranolazine was administered intravenously as a 3.2 mg/kg bolus, followed by a maintenance infusion of 0.17 mg/(kg . min). Six episodes (4 AFL and 2 AF) were induced in the open-chest state to perform simultaneous, multisite (486 electrodes), epicardial mapping of the arrhythmia and its termination.RESULTS Ranolazine terminated 7 of 9 AFL and 3 of 4 AF episodes. Ranolazine significantly prolonged the AFL CL by a mean of 43 ms (P < .001) and the AF CL by a mean of 34 ms (P < .01). The AERP was prolonged (P < .05 overall), and the atrial capture threshold increased minimally (P < .01 for all). Ranolazine prolonged CTs (P < .01 overall). During open-chest, multisite mapping, block in the region of slow conduction in the reentrant circuit terminated AFL and interruption of the regular driver terminated AF.CONCLUSION Ranolazine terminated AFL/AF in our canine sterile pericarditis model by interrupting the regular driver. Ranolazine was found to significantly prolong the AERP, CT, and tachycardia CLs.

BACKGROUND:If channels are functionally expressed in atrioventricular (AV) nodal tissue. OBJECTIVE:The purpose of this study was to address whether the prototypical If inhibitor, ivabradine, at clinically safe concentrations can slow AV node conduction to reduce ventricular rate (VR) during atrial fibrillation (AF). METHODS:Effects of ivabradine (0.1 mg/kg i.v. bolus) were studied in an anesthetized Yorkshire pig (N = 7) model of AF and in isolated guinea pig hearts (N = 7). RESULTS:Ivabradine reduced heart rate (P = .0001) without affecting mean arterial pressure during sinus rhythm. The agent lengthened PR intervals in a rate-dependent manner (P = .0009) by 14 ± 2.7 ms (P = .003) and 25 ± 3.0 ms (P = .0004) and increased atrial-His (A-H) intervals in a rate-dependent manner (P = .020) by 10 ± 1.7 ms and 17 ± 2.8 ms during pacing at 130 and 180 bpm, respectively (both P = .0008). Similar rate-dependent effects were observed in isolated guinea pig hearts. Ivabradine slowed VR during AF from 240 ± 21 bpm to 211 ± 25 bpm (P = .041). The ivabradine-induced increase in A-H interval was inversely correlated with VR (r = -0.85, P = .03, at 130 bpm; r = -0.95, P = .003, at 180 bpm). QT and HV intervals, AF dominant frequency (8.5 ± 0.9 to 8.7 ± 1.1 Hz, P = NS), mean arterial pressure, and left ventricular dP/dt (1672 ± 222 to 1889 ± 229 mm Hg/s, P = NS) during AF were unaffected. CONCLUSION:Ivabradine's rate-dependent increase in A-H interval is highly correlated with VR during AF. As dominant frequency was unaltered, AV node conduction slowing during high nodal activation rates appears to be the main mechanism of ivabradine's VR reduction. If inhibition in the AV node may provide a promising target to slow VR during AF without depression in contractility.

BACKGROUND Remodeling occurs after myocardial infarction (MI), leading to fibrosis, dysfunction, and ventricular tachycardias (VTs). Adenosine via the A(2B) adenosine receptor (A(2B)AdoR) has been implicated in promoting fibrosis.OBJECTIVE To determine the effects of GS-6201, a potent antagonist of the A(2B)AdoR, on arrhythmogenic and functional cardiac remodeling after MI.METHODS Rats underwent ischemia-reperfusion MI and were randomized into 4 groups: control (treated with vehicle), angiotensin-converting enzyme inhibitor (treated with enalapril 1 day after MI), GS-6201-1d (treated with GS-6201 1 day after MI), GS-6201-1w (treated with GS-6201 administered 1 week after MI). Echocardiography was performed at baseline and 1 and 5 weeks after MI. Optical mapping, VT inducibility, and histologic analysis were conducted at follow-up.RESULTS Treatment with the angiotensin-converting enzyme inhibitor improved ejection fraction (57.8% +/- 2.5% vs 43.3% +/- 1.7% in control; P < .01), but had no effect on VT inducibility. Treatment with GS-6201 improved ejection fraction (55.6 +/- 2.6% vs 43.3% +/- 1.7% in control; P < .01) and decreased VT inducibility (9.1% vs 68.4% in control; P < .05). Conduction velocities were significantly higher at border and infarct zones in hearts of rats treated with GS-6201 than in those of other groups. The conduction heterogeneity index was also significantly lower in hearts of rats treated with GS-6201. Histologic analysis showed that while both GS-6201 and enalapril decreased fibrosis in the noninfarct zone, only GS-6201 reduced the heterogeneity of fibrosis at the border, which is consistent with its effect on VT reduction.CONCLUSIONS Treatment with an A(2B)AdoR antagonist at 1 week results in the improvement in cardiac function and decreased substrate for VT. The inhibition of fibrogenesis by A(2B)AdoR antagonists may be a new target for the prevention of adverse remodeling after MI.

BACKGROUND In clinical trials, dronedarone lowers ventricular rate during atrial fibrillation (AF). This agent was recently demonstrated to inhibit I-f in the sinoatrial node.OBJECTIVE The purpose of this study was to examine whether dronedarone inhibits I-f at the atrioventricular (AV) node to reduce ventricular rate during AF by slowing conduction at the AV node.METHODS We studied the effects of dronedarone (1.0 mg/kg IV bolus) before and after administration of the I-f inhibitor ivabradine (0.5 mg/kg IV). Ventricular rate, mean arterial pressure, dominant frequency of AF, PR and QT intervals, and atrial (AERP) and ventricular effective refractory periods (VERP) were measured during atrial pacing at 150 bpm in an anesthetized pig model of AF induced by intrapericardial acetylcholine and burst pacing.RESULTS Dronedarone reduced ventricular rate during AF by 22.1% (from 213 +/- 11.1 bpm to 166 +/- 8.3 bpm, P = .01) and increased PR interval by 8.7% (from 173 +/- 5.6 ms to 188 +/- 5.2 ms, P = .001), QT interval by 3.3% (from 272 +/- 6.2 ms to 281 +/- 4.9 ms, P = .05), and AERP and VERP by 6.2% and 11.7%, respectively. ALL other parameters remained unchanged. Dronedarone plasma levels were Low (29 +/- 4 nM), and concentration in tissue was 15- to 21-fold higher than in plasma. Ivabradine reduced ventricular rate during AF by 39.5% (from 200 +/- 14.6 bpm to 121 +/- 20.1 bpm, P = .005) and increased PR interval by 20.4% (from 157 +/- 9.5 ms to 189 +/- 7.4 ms, P < .05). Administration of dronedarone after ivabradine did not further alter these endpoints.CONCLUSION Dronedarone, which is concentrated in myocardial tissue, reduces ventricular rate during AF by slowing AV conduction. Absence of this effect after ivabradine administration implicates I-f inhibition as a mechanism.

AIMS:Clinical utility of QTc prolongation as a predictor for sudden cardiac death (SCD) has not been definitely established. Ranolazine causes modest QTc prolongation, yet it shows antiarrhythmic properties. We aimed to determine the association between prolonged QTc and risk of SCD, and the effect of ranolazine on this relationship.METHODS AND RESULTS:The relationship between baseline QTc and SCD was studied in 6492 patients with non-ST elevation acute coronary syndrome (NSTEACS) randomized to placebo or ranolazine in the MERLIN-TIMI 36 trial. In the placebo group, an abnormal QTc interval (≥450 ms in men, ≥470 ms in women) was associated with a two-fold increased risk of SCD (hazard ratio, HR, 2.3, P = 0.005) after adjustment for other risk factors (age ≥75 years, NYHA class III/IV, high TIMI risk score, ventricular tachycardia ≥8 beats, digitalis, and antiarrhythmics). In the ranolazine group, the association between abnormal QTc and SCD was similar to placebo, but not significant (HR 1.8, P = 0.074). There was no significant difference between placebo and ranolazine in the risk for SCD in patients with abnormal QTc (HR 0.78, P = 0.48). When QTc was used as a continuous variable, for every 10 ms increase in QTc, hazard rate for SCD increased significantly by 8% (P = 0.007) in the placebo group, and only by 2.9% (P = 0.412; P for interaction=0.25) in the ranolazine group.CONCLUSION:In NSTEACS patients treated with placebo, prolonged QTc was a significant independent predictor for SCD. Ranolazine, compared with placebo, was not associated with increased risk for SCD in patients with prolonged QTc.

Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death worldwide. The development of pulmonary hypertension (PH) in patients with COPD is strongly associated with increased mortality. Chronic inflammation and changes to the lung extracellular matrix (ECM) have been implicated in the pathogenesis of COPD, yet the mechanisms that lead to PH secondary to COPD remain unknown. Our experiments using human lung tissue show increased expression levels of the adenosine A2B receptor (ADORA2B) and a heightened deposition of hyaluronan (HA; a component of the ECM) in remodeled vessels of patients with PH associated with COPD. We also demonstrate that the expression of HA synthase 2 correlates with mean pulmonary arterial pressures in patients with COPD, with and without a secondary diagnosis of PH. Using an animal model of airspace enlargement and PH, we show that the blockade of ADORA2B is able to attenuate the development of a PH phenotype that correlates with reduced levels of HA deposition in the vessels and the down-regulation of genes involved in the synthesis of HA.

Dronedarone's Bradycardic EffectIntroductionThe mechanism(s) whereby dronedarone reduces sinus rate are not well understood, although L-type calcium channel antagonism, beta-adrenergic blockade, and inhibition of I-f are plausible.Methods and ResultsIn anesthetized pigs, we compared the effects of dronedarone to the prototypical I-f inhibitor, ivabradine, and the L-type calcium channel antagonist diltiazem on heart rate, mean arterial blood pressure (MAP), and contractility. Dronedarone's effects on the phenylephrine-induced rise in MAP and on the chronotropic response to isoproterenol were also investigated. Cumulative doses of dronedarone (0.5mg/kg, i.v., and 5.0mg/kg, i.v.; plasma level: 8016.1 nM) progressively reduced heart rate (P<0.02) without changes in MAP or contractility as assessed by LV dP/dt (N = 6). Ivabradine (0.5mg/kg, i.v.) similarly reduced heart rate (P<0.01) without change in MAP (N = 6). Diltiazem (0.8mg/kg, i.v.) reduced heart rate and MAP and decreased contractility (N = 6). Dronedarone blunted phenylephrine's alpha-receptor-mediated increase in MAP but did not alter the marked beta-adrenergic receptor (BAR)-mediated increase in heart rate induced by isoproterenol. When dronedarone injection was preceded by ivabradine, no further decrease in heart rate or change in MAP was observed (N = 6).ConclusionsDronedarone reduced heart rate without affecting MAP or contractility, effects that differ from L-type calcium channel blockade. Dronedarone did not antagonize BAR stimulation, and its heart-rate lowering effects were eliminated by prior administration of ivabradine. Thus, dronedarone's bradycardic action is likely due to inhibition of I-f and not to blockade of either L-type calcium channels or BAR.