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The mechanism of Atrial Fibrillation (AF) that emerges spontaneously during acute oxidative stress is poorly defined and its drug therapy remains suboptimal. We hypothesized that oxidative activation of Ca-calmodulin dependent protein kinase (CaMKII) promotes Early Afterdepolarization-(EAD)-mediated triggered AF in aged fibrotic atria that is sensitive to late Na current (INa-L) blockade. High-resolution voltage optical mapping of the Left and Right Atrial (LA & RA) epicardial surfaces along with microelectrode recordings were performed in isolated-perfused male Fisher 344 rat hearts in Langendorff setting. Aged atria (23-24 months) manifested 10-fold increase in atrial tissue fibrosis compared to young/adult (2-4 months) atria (P

BACKGROUND: There is a need for improved approaches to rhythm control therapy of atrial fibrillation (AF). METHODS: The effectiveness of flecainide (1.5 µmol/L) and ibutilide (20 nmol/L), alone and in combination, to cardiovert and prevent AF recurrence was studied in canine-isolated coronary--perfused right atrioventricular preparations. We also examined the safety of the combination of flecainide (1.5 µmol/L) and ibutilide (50 nmol/L) using canine left ventricular wedge preparations. RESULTS: Sustained AF (>1 hour) was inducible in 100%, 60%, 20%, and 0% of atria in the presence of acetylcholine alone, acetylcholine+ibutilide, acetylcholine+flecainide, and acetylcholine+ibutilide+flecainide, respectively. When used alone, flecainide and ibutilide cardioverted sustained AF in 40% and 20% of atria, respectively, but in 100% of atria when used in combination. Ibutilide prolonged atrial and ventricular effective refractory period by 15% and 8%, respectively, at a cycle length of 500 ms (P<0.05 for both). Flecainide increased the effective refractory period in atria by 27% (P<0.01) but by only 2% in the ventricles. The combination of the 2 drugs lengthened the effective refractory period by 42% in atria (P<0.01) but by only 7% (P<0.05) in the ventricles. In left ventricular wedges, ibutilide prolonged QT and Tpeak-Tend intervals by 25 and 55%, respectively (P<0.05 for both; cycle length, 2000 ms). The addition of flecainide (1.5 µmol/L) partially reversed these effects (P<0.05 for both parameters versus ibutilide alone). Torsades de Pointes score was relatively high with ibutilide alone and low with the drug combination. CONCLUSIONS: In our experimental model, a combination of flecainide and ibutilide significantly improves cardioversion and prevents the recurrence of AF compared with monotherapies with little to no risk for the development of long-QT--mediated ventricular proarrhythmia. [ABSTRACT FROM AUTHOR]

Background: The negative inotropic effect of Class IC antiarrhythmic drugs limits their use for acute cardioversion of atrial fibrillation (AF).Objective: The purpose of this study was to examine, in an intact porcine model, the effects of pulmonary and intravenous (IV) administration of flecainide on left ventricular (LV) contractility and QRS complex width at doses that are effective in converting new-onset AF to sinus rhythm.Methods: Flecainide (1.5 mg/kg bolus) was delivered by intratracheal administration and compared to 2.0 mg/kg 10-minute IV administration (European Society of Cardiology guideline) and to 0.5 and 1.0 mg/kg 2-minute IV doses in 40 closed-chest, anesthetized Yorkshire pigs. Catheters were fluoroscopically positioned in the LV to monitor QRS complex width and contractility and at the bifurcation of the main bronchi to deliver intratracheal flecainide.Results: Peak flecainide plasma concentrations (Cmax) were similar, but the 30-minute area under the curve (AUC) of plasma levels was 1.4- to 2.8-fold greater for 2.0 mg/kg 10-minute IV infusion than for the lower, more rapidly delivered intratracheal and IV doses. AUC for LV contractility (ie, negative inotropic burden) was 2.2- to 3.6-fold greater for 2.0 mg/kg 10-minute IV dose than for the lower, more rapidly delivered doses. QRS complex widening by flecainide was highly correlated with the decrease in LV contractility (r2 = 0.890, P <.0001, for all IV doses; r2 = 0.812, P = .01, for intratracheal flecainide).Conclusion: QRS complex widening in response to flecainide is strongly correlated with decrease in LV contractility. Rapid pulmonary or IV flecainide delivery reduces the negative inotropic burden while quickly achieving Cmax levels associated with conversion of AF. [ABSTRACT FROM AUTHOR]

Background: There is still an unmet need for pharmacologic treatment of atrial fibrillation (AF) with few effects on ventricular electrophysiology. Ranolazine is an antiarrhythmic drug reported to have strong atrial selectivity.Objective: The purpose of this study was to investigate the electrophysiological effects of ranolazine in atria with AF-induced electrical remodeling in a model of lone AF in awake goats.Methods: Electrode patches were implanted on the atrial epicardium of 8 Dutch milk goats. Experiments were performed at baseline and after 2 and 14 days of electrically maintained AF. Several electrophysiological parameters and AF episode duration were measured during infusion of vehicle and different doses of ranolazine (target plasma levels 4, 8, and 16 μM, respectively).Results: The highest dose of ranolazine significantly prolonged atrial effective refractory period and decreased atrial conduction velocity at baseline and after 2 days of AF. After 2 weeks of AF, ranolazine prolonged the p5 and p50 of AF cycle length distribution in a dose-dependent manner but was not effective in restoring sinus rhythm. No adverse ventricular arrhythmic events (eg, premature ventricular beats or signs of hemodynamic instability) were observed during infusion of ranolazine at any point in the study.Conclusion: The lowest investigated dose of ranolazine, which is expected to block both late INa and atrial peak INa, had no effect on the investigated electrophysiological parameters. The highest dose affected both atrial and ventricular electrophysiological parameters at different stages of AF-induced remodeling but was not efficacious in cardioverting AF to sinus rhythm in a goat model of lone AF. [ABSTRACT FROM AUTHOR]

Background: Pulmonary delivery of antiarrhythmic agents has the potential to increase rapidly targeted drug concentrations in pulmonary veins and left atrium to terminate atrial fibrillation (AF).Objective: We evaluated the efficacy of flecainide administered via intratracheal instillation in terminating AF in a reliable preclinical model.Methods: In 11 closed-chest anesthetized Yorkshire pigs, AF was induced by intrapericardial administration of acetylcholine (1 mL of 102.5 mM solution) followed by burst pacing and allowed to continue for 2 minutes before intratracheal flecainide (0.4 or 0.75 mg/kg) administration.Results: Both the 0.4- and 0.75-mg/kg doses of intratracheal flecainide significantly reduced AF duration by 35% (P = .02) and 54% (P = .001), respectively, compared to no-drug baseline. There was a strong inverse correlation (r2 = 0.87; P = .03) between the duration of AF and the change in atrial depolarization duration in response to intratracheal flecainide. Induction of AF resulted in a marked increase in ventricular rate and corresponding reduction in mean arterial pressure, which returned to baseline levels within 5 minutes after conversion.Conclusion: Intratracheal flecainide instillation is effective in rapidly converting AF to normal sinus rhythm and restoring mean arterial pressure and heart rate to baseline values. The basis for this efficacy is likely rapid absorption of the drug through the lungs and delivery as a first-pass bolus to the left atrial and ventricular chambers and then to the coronary arterial circulation. The anti-AF effect of flecainide is inversely correlated with the drug's prolongation of atrial depolarization, implicating slowing of intra-atrial conduction as an important mechanism underlying conversion of AF to normal sinus rhythm. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Detection of atrial repolarization waves free of far-field signal contamination by ventricular activation would allow investigation of atrial electrophysiology and factors that influence susceptibility to atrial tachycardia and atrial fibrillation (AF).Objective: The purpose of this study was to identify means for high-resolution intracardiac recording of atrial repolarization (Ta) waves using standard clinical electrocatheters and to assess fundamental electrophysiologic properties relevant to AF risk.Methods: In alpha-chloralose anesthetized Yorkshire pigs, we studied effects of vagus nerve stimulation (VNS) on PTa and QT intervals and effects of acute atrial ischemia or administration of intrapericardial acetylcholine followed by intravenous epinephrine on susceptibility to AF.Results: Electrocatheters with closely spaced (1-mm) electrode pairs yielded high-resolution tracings of atrial repolarization waves. These recordings permitted detection of differential effects of right or left VNS, which shortened atrial PTa interval by 30% vs. 21% (P <.01) and lengthened QT interval by 1.5% vs. 9%, respectively (P < .05). During atrial ischemia, STa segments were elevated 3.4-fold (P < .01), and the threshold for inducing AF was reduced 3.1-fold (P = .004). Ischemia amplified atrial T-wave alternans (TWAa) and spatiotemporal heterogeneity (TWHa) by 23- and 13-fold, respectively, in inverse correlation to AF threshold (r = 0.74, P <.01; r = 0.61, P = .03). TWAa and TWHa increased by 4.5- and 2-fold shortly before autonomically triggered atrial premature beats and AF.Conclusion: This study used standard electrocatheters to demonstrate that TWAa and TWHa analysis provides means to assess vulnerability to AF without provocative electrical stimuli. These parameters could be evaluated in the clinical electrophysiology laboratory to determine risk for this prevalent arrhythmia and efficacy of contemporary and new agents. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background The availability of safe and effective drugs for the management of atrial fibrillation (AF) remains an unmet medical need. Objectives The purpose of this study was to test the hypothesis that the inhibition of the rapidly activating delayed rectifier potassium current (I Kr ) greatly potentiates the development of atrial-selective sodium channel current (I Na ) block, leading to more effective suppression of AF. Methods Electrophysiological and anti-AF effects of highly selective I Na and I Kr blockers (lidocaine and E-4031) individually and in combination were determined in canine coronary-perfused atrial and ventricular preparations. Acetylcholine (1 µM) was used to induce persistent AF. Results Lidocaine (10 µM) caused a relatively small abbreviation of the action potential duration measured at 90% repolarization in both atria and ventricles, but caused atrial-selective prolongation of the effective refractory period owing to the induction of post-repolarization refractoriness. Lidocaine also caused modest atrial-selective depression of other I Na -mediated parameters including excitability, maximum rate of rise of the action potential upstroke, and conduction time. E-4031 (1 µM) prolonged the action potential duration measured at 90% repolarization and effective refractory period in an atrial-predominant manner. A combination of lidocaine and E-4031 caused a greater atrial-selective depression of I Na -mediated parameters. Persistent acetylcholine-mediated AF developed in 100% of atria under control conditions, in 80% (4 of 5) after pretreatment with lidocaine (10 µM), in 100% (4 of 4) after E-4031 (1 µM), and in only 14% (1 of 7) after the combination of lidocaine and E-4031. Conclusion Our results provide a proof of concept that I Kr block greatly potentiates the effects of rapidly dissociating I Na blockers to depress sodium channel–dependent parameters in the canine atria but not in the ventricles, thus contributing significantly to suppression of AF. [ABSTRACT FROM AUTHOR]

Background I f channels are functionally expressed in atrioventricular (AV) nodal tissue. Objective The purpose of this study was to address whether the prototypical I f 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 IV 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. I f inhibition in the AV node may provide a promising target to slow VR during AF without depression in contractility. [ABSTRACT FROM AUTHOR]

Background Ischemic heart disease is associated with dual risk for atrial and ventricular arrhythmias. Objective We examined whether selectively targeting late sodium channel current (I Na ) with GS-458967 (hereafter GS967) can reduce cardiac electrical instability and compared its effects to a clinically relevant dose of flecainide. Methods Electrode catheters were positioned on the left atrial appendage and left ventricle of anesthetized pigs to monitor repolarization alternans and electrocardiographic heterogeneity before and during left circumflex coronary artery stenosis (75% flow reduction) before and after GS967 (0.4 mg/kg, intravenously [IV]) or flecainide (1 mg/kg, IV, bolus over 2 minutes followed by 1 mg/(kg·h), IV, for 1 hour) administration. Results Left circumflex coronary artery stenosis increased atrial repolarization alternans by 520% (from 9.4 ± 1.2 to 58.3 ± 11.3 μV; P = .029) and T-wave alternans by 1038% (from 30.7 ± 8.2 to 349.3 ± 103.8 μV; P = .049). GS967 prevented ischemia-induced increases in alternans in the left atrium (19.3 ± 5.6 μV vs 58.3 ± 11.3 μV; P = .023) and left ventricle (217.9 ± 95.8 μV vs 349.3 ± 103.8 μV; P < .001) (n = 7). GS967 reduced ischemia-induced increases in depolarization heterogeneity (atrium: from 45% to 28%; ventricle: from 92% to 51%) and repolarization heterogeneity (atrium: 43% to 23%; ventricle: 137% to 91%). GS967 did not alter heart rate, arterial blood pressure, PR and QT intervals, or QRS duration, but it mildly decreased contractility (left ventricular dP/dt) during ischemia, which was consistent with late I Na inhibition. Flecainide (n = 7) amplified ischemia-induced increase in atrial and ventricular repolarization alternans, electrocardiographic heterogeneity, and ventricular fibrillation incidence. Conclusion Selective late I Na inhibition with GS967 exerts potent protective effects against ischemia-induced depolarization and repolarization abnormalities in both atria and ventricles. [ABSTRACT FROM AUTHOR]

Background: In clinical trials, dronedarone lowers ventricular rate during atrial fibrillation (AF). This agent was recently demonstrated to inhibit If in the sinoatrial node. Objective: The purpose of this study was to examine whether dronedarone inhibits If 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 If 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 If inhibition as a mechanism. [Copyright &y& Elsevier]

Background: Coronary artery disease carries dual risk for atrial tachyarrhythmias and sudden cardiac death. Objective: To examine whether low-dose ranolazine and/or dronedarone can protect against vulnerability to atrial fibrillation (AF) and ventricular tachyarrhythmias. Methods: In chloralose-anesthetized, open-chest Yorkshire pigs (n = 15), the proximal segment of left circumflex (LCx) coronary artery was occluded to reduce flow by 75%. An electrode catheter was positioned on the left atrial appendage to measure AF threshold (AFT) before and during LCx coronary artery stenosis before and at 1 hour after dronedarone (0.5 mg/kg intravenous bolus over 5 minutes) and/or ranolazine administration (0.6 mg/kg intravenous bolus followed by 0.035 mg/kg/min). Results: Before drug administration, LCx coronary artery stenosis lowered AFT from 25.2±1.7 mA control (mean±SEM) to 4.9±1.0 mA baseline (P<.01). At the low doses, neither ranolazine (plasma concentration 2.4±0.6 μM) nor dronedarone (plasma concentration 20.9±3.5 nM) alone blunted the ischemia-induced reduction in AFT but were effective together (from 25.2±1.7 mA control to 22.0±3.0 mA during stenosis; P = not significant). AF duration (P<.03) and AF inducibility (P = .012) were reduced by ranolazine and dronedarone together but not by either drug alone. Concurrently, combined but not separate administration blunted the ischemia-induced surge in T-wave heterogeneity, a marker of risk for ventricular tachyarrhythmias (from 43.1±11.1 μV control to 149.7±15.1 μV during stenosis, P<.001, compared to 61.7±13.7 μV control to 83.7±15.8 μV during stenosis, P = not significant). Conclusions: Combined administration of low doses of ranolazine and dronedarone exerts a potent antiarrhythmic action on ischemia-induced vulnerability to AF and ventricular tachyarrhythmias due to direct effects on myocardial electrical properties. [Copyright &y& Elsevier]

The article presents a study that evaluated the electrophysiological properties of canine superior vena cava (SVC) sleeve preparations. The study also investigated the effect of ranozaline on late phase 3 early and delayed afterdepolarization-induced triggered activity in SVC sleeves. It compared SVC and pulmonary veine sleeve electrophysiological properties.

Ranolazine is a Food and Drug Administration–approved antianginal agent. Experimental and clinical studies have shown that ranolazine has antiarrhythmic effects in both ventricles and atria. In the ventricles, ranolazine can suppress arrhythmias associated with acute coronary syndrome, long QT syndrome, heart failure, ischemia, and reperfusion. In atria, ranolazine effectively suppresses atrial tachyarrhythmias and atrial fibrillation (AF). Recent studies have shown that the drug may be effective and safe in suppressing AF when used as a pill-in-the pocket approach, even in patients with structurally compromised hearts, warranting further study. The principal mechanism underlying ranolazine''s antiarrhythmic actions is thought to be primarily via inhibition of late INa in the ventricles and via use-dependent inhibition of peak INa and IKr in the atria. Short- and long-term safety of ranolazine has been demonstrated in the clinic, even in patients with structural heart disease. This review summarizes the available data regarding the electrophysiologic actions and antiarrhythmic properties of ranolazine in preclinical and clinical studies. [Copyright &y& Elsevier]

Background: Dronedarone is approved by the U.S. Food and Drug Administration for the treatment of patients with atrial fibrillation (AF) as a safe alternative to amiodarone. There are no full-length published reports describing the effectiveness of acute dronedarone use against AF in experimental or clinical studies. Objective: The purpose of this study was to determine the effect of acute dronedarone and amiodarone on electrophysiological parameters, and their anti-AF efficacy in canine isolated arterially perfused right atria. Methods: Transmembrane action potentials and pseudoelectrocardiograms were recorded. Acetylcholine (ACh, 1.0 μM) was used to induce persistent AF. Results: Amiodarone-induced changes were much more pronounced than those of dronedarone on (1) action potential duration (ΔAPD90, +51 ± 17 ms vs. 4 ± 6 ms, P >.01), (2) effective refractory period (ΔERP, +84 ± 23 ms vs. 18 ± 9 ms, P <.001), (3) diastolic threshold of excitation (ΔDTE, +0.32 ± 0.11 mA vs. 0.03 ± 0.02 mA, P <.001), and (4) Vmax (ΔVmax, −43 ± 14% vs. −11 ± 4%, P <.01, n = 5 to 6; all recorded at 10 μM, cycle length = 500 ms). Persistent AF was induced in 10 of 10 atria exposed to ACh alone; subsequent addition of dronedarone or amiodarone terminated AF in 1 of 7 and 4 of 5 atria, respectively. Persistent ACh-mediated AF was induced in 5 of 6 and 0 of 5 atria pretreated with dronedarone and amiodarone, respectively. Conclusion: The electrophysiological effects and anti-AF efficacy of acute dronedarone are much weaker than those of amiodarone in a canine model of AF. The efficacy of acute dronedarone to prevent induction of acetylcholine-mediated AF as well as to terminate persistent AF in canine right atria is relatively poor. Our data suggest that acute dronedarone is a poor substitute for amiodarone for acute cardioversion of AF or prevention of AF recurrence. [Copyright &y& Elsevier]

Background: Amiodarone and ranolazine have been characterized as inactivated- and activated-state blockers of cardiac sodium channel current (I(Na)), respectively, and shown to cause atrial-selective depression of I(Na)-related parameters. This study tests the hypothesis that their combined actions synergistically depress I(Na)-dependent parameters in atria but not ventricles.Methods and Results: The effects of acute ranolazine (5 to 10 micromol/L) were studied in coronary-perfused right atrial and left ventricular wedge preparations and superfused left atrial pulmonary vein sleeves isolated from chronic amiodarone-treated (40 mg/kg daily for 6 weeks) and untreated dogs. Floating and standard microelectrode techniques were used to record transmembrane action potentials. When studied separately, acute ranolazine and chronic amiodarone caused atrial-predominant depression of I(Na)-dependent parameters. Ranolazine produced a much greater reduction in V(max) and much greater increase in diastolic threshold of excitation and effective refractory period in atrial preparations isolated from amiodarone-treated versus untreated dogs, leading to a marked increase in postrepolarization refractoriness. The drug combination effectively suppressed triggered activity in pulmonary vein sleeves but produced relatively small changes in I(Na)-dependent parameters in the ventricle. Acetylcholine (0.5 micromol/L) and burst pacing induced atrial fibrillation in 100% of control atria, 75% of ranolazine-treated (5 micromol/L) atria, 16% of atria from amiodarone-treated dogs, and in 0% of atria from amiodarone-treated dogs exposed to 5 micromol/L ranolazine.Conclusions: The combination of chronic amiodarone and acute ranolazine produces a synergistic use-dependent depression of I(Na)-dependent parameters in isolated canine atria, leading to a potent effect of the drug combination to prevent the induction of atrial fibrillation. [ABSTRACT FROM AUTHOR]

Background: Oral and intravenous flecainide is recommended for cardioversion of atrial fibrillation. In this open-label, dose-escalation study, the feasibility of delivering flecainide via oral inhalation (flecainide acetate inhalation solution) for acute conversion was evaluated. We hypothesized that flecainide delivered by oral inhalation would quickly reach plasma concentrations sufficient to restore sinus rhythm in patients with recent-onset atrial fibrillation.Methods: Patients (n=101) with symptomatic atrial fibrillation (for ≤48 hours) self administered flecainide acetate inhalation solution using a nebulizer (30 mg [n=10], 60 mg [n=22], 90 mg [n=21], 120 mg [n=19], and 120 mg in a formulation containing saccharin [n=29]). Electrocardiograms and flecainide plasma concentrations were obtained, cardiac rhythm using 4-hour Holter was monitored, and adverse events were recorded.Results: Conversion rates increased with dose and with the maximum plasma concentrations of flecainide. At the highest dose, 48% of patients converted to sinus rhythm within 90 minutes from the start of inhalation. Among patients who achieved a maximum plasma concentration >200 ng/mL, the conversion rate within 90 minutes was 50%; for those who achieved a maximum plasma concentration <200 ng/mL, it was 24%. Conversion was rapid (median time to conversion of 8.1 minutes from the end of inhalation), and conversion led to symptom resolution in 86% of the responders. Adverse events were typically mild and transient and included: cough, throat pain, throat irritation; at the highest dose with the formulation containing saccharin, these adverse events were reported by 41%, 14%, and 3% of patients, respectively. Cardiac adverse events consistent with those observed with oral and intravenous flecainide were uncommon and included postconversion pauses (n=2), bradycardia (n=1), and atrial flutter with 1:1 atrioventricular conduction (n=1); none required treatment, and all resolved without sequelae.Conclusions: Administration of flecainide via oral inhalation was shown to be safe and to yield plasma concentrations of flecainide sufficient to restore sinus rhythm in patients with recent-onset atrial fibrillation.Registration: URL: https://www.Clinicaltrials: gov; Unique identifier: NCT03539302. [ABSTRACT FROM AUTHOR]

Background: Ectopic activity arising from the pulmonary veins (PV) plays a prominent role in the development of atrial fibrillation (AF). Objective: This study sought to determine the electrophysiological effects of ranolazine in canine PV sleeve preparations. Methods: Transmembrane action potentials were recorded from canine superfused left superior or inferior PV sleeves using standard microelectrode techniques. Acetylcholine (ACh, 1 μM), isoproterenol (1 μM), high calcium ([Ca2+]o = 5.4 mM) or a combination was used to induce early or delayed afterdepolarizations (EADs or DADs) and triggered activity. Results: Ranolazine (10 μM) significantly accentuated use-dependent depression of maximal rate of increase of action potential upstroke (Vmax). Reducing basic cycle length (BCL) from 2000 to 200 ms resulted in a decrease of Vmax from 279 ± 58 to 146 ± 23 V/s (47.7%) in control subjects and from 241 ± 71 to 72 ± 63 V/s (70.2%) after 10 μM ranolazine (n = 4, P <.05). Ranolazine slightly abbreviated action potential duration, but induced significant rate-dependent prolongation of effective refractory period due to development of postrepolarization refractoriness (n = 6, P <.05). Ranolazine (10 μM) caused loss of excitability resulting in 2:1 activation failure at BCLs ≤ 200 ms (n = 3) and suppressed late phase 3 EADs, DADs, and triggered activity elicited by exposure of the PV sleeves to Ach + isoproterenol, or high [Ca2+]o + rapid pacing (n = 11). Conclusion: Ranolazine causes marked use-dependent inhibition of sodium channel activity leading to prolongation of effective refractory period, conduction slowing, and block as well as suppression of late phase 3 EAD and DAD-mediated triggered activity in canine PV sleeves. Our data suggest that ranolazine may be useful in suppressing AF triggers arising from the PV sleeves. [Copyright &y& Elsevier]

Coronary artery disease and heart failure carry concurrent risk for atrial fibrillation and life-threatening ventricular arrhythmias. We review evidence indicating that at therapeutic concentrations, ranolazine has potential for dual suppression of these arrhythmias. Mechanisms and clinical implications are discussed.

Background: Ranolazine inhibits Na+ current (INa), but whether it can convert atrial fibrillation (AF) to sinus rhythm remains unclear. We investigated antiarrhythmic mechanisms of ranolazine in sheep models of paroxysmal (PxAF) and persistent AF (PsAF).Methods: PxAF was maintained during acute stretch (N=8), and PsAF was induced by long-term atrial tachypacing (N=9). Isolated, Langendorff-perfused sheep hearts were optically mapped.Results: In PxAF ranolazine (10 μmol/L) reduced dominant frequency from 8.3±0.4 to 6.2±0.5 Hz (P<0.01) before converting to sinus rhythm, decreased singularity point density from 0.070±0.007 to 0.039±0.005 cm-2 s-1 (P<0.001) in left atrial epicardium (LAepi), and prolonged AF cycle length (AFCL); rotor duration, tip trajectory, and variance of AFCL were unaltered. In PsAF, ranolazine reduced dominant frequency (8.3±0.5 to 6.5±0.4 Hz; P<0.01), prolonged AFCL, increased the variance of AFCL, had no effect on singularity point density (0.048±0.011 to 0.042±0.016 cm-2 s-1; P=ns) and failed to convert AF to sinus rhythm. Doubling the ranolazine concentration (20 μmol/L) or supplementing with dofetilide (1 μmol/L) failed to convert PsAF to sinus rhythm. In computer simulations of rotors, reducing INa decreased dominant frequency, increased tip meandering and produced vortex shedding on wave interaction with unexcitable regions.Conclusions: PxAF and PsAF respond differently to ranolazine. Cardioversion in the former can be attributed partly to decreased dominant frequency and singularity point density, and prolongation of AFCL. In the latter, increased dispersion of AFCL and likely vortex shedding contributes to rotor formation, compensating for any rotor loss, and may underlie the inefficacy of ranolazine to terminate PsAF. [ABSTRACT FROM AUTHOR]