Unmasking atrial repolarization to assess alternans, spatiotemporal heterogeneity, and susceptibility to atrial fibrillation.

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.

Electrophysiologic basis for the antiarrhythmic actions of ranolazine.

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 I(Na) in the ventricles and via use-dependent inhibition of peak I(Na) and I(Kr) 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.

Antifibrillatory effect of ranolazine during severe coronary stenosis in the intact porcine model.

BACKGROUND: Clinical evidence suggests that the antianginal agent ranolazine has antiarrhythmic properties, but its effects on vulnerability to ventricular fibrillation (VF) and T-wave alternans (TWA) during coronary artery stenosis have not been measured. OBJECTIVE: We investigated whether the antiarrhythmic effect of ranolazine during acute coronary stenosis could be quantified by measuring VF threshold and TWA magnitude. METHODS: Electrode catheters placed in the left ventricular apex were used to determine VF threshold during ventricular pacing at 130 beats/min, and TWA was quantified from epicardial electrograms using modified moving average method (N = 18). Left anterior descending coronary flow was reduced with a balloon occluder by 75% for 10 minutes. The I(Kr) blocker E-4031 was used to distinguish effects of late I(Na) and I(Kr) inhibition by ranolazine. RESULTS: Before stenosis, ranolazine and E-4031 increased VF threshold from 32 ± 4 mA to 46 ± 4 mA (mean ± SEM), P = .02, and from 33 ± 5 mA to 40 ± 9 mA, P = .02, respectively. During stenosis, ranolazine increased VF threshold from 19 ± 2 mA to 33 ± 3 mA (P = .02), whereas E-4031 decreased VF threshold from 21 ± 3 mA to 15 ± 3 mA (P = .02). The ischemia-induced increase in TWA was suppressed by ranolazine but not by E-4031, consistent with effects of these agents on VF threshold. CONCLUSION: Ranolazine exerts significant antifibrillatory effects during coronary stenosis through direct effects on cardiac electrical properties independent of coronary flow. Ranolazine's antifibrillatory action during myocardial ischemia does not appear to be mediated by blockade of I(Kr) but rather by inhibition of late I(Na). TWA changes paralleled vulnerability to VF as indicated by VF threshold testing.

Acute dronedarone is inferior to amiodarone in terminating and preventing atrial fibrillation in canine atria.

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 muM) was used to induce persistent AF. RESULTS: Amiodarone-induced changes were much more pronounced than those of dronedarone on (1) action potential duration (DeltaAPD(90), +51 +/- 17 ms vs. 4 +/- 6 ms, P >.01), (2) effective refractory period (DeltaERP, +84 +/- 23 ms vs. 18 +/- 9 ms, P <.001), (3) diastolic threshold of excitation (DeltaDTE, +0.32 +/- 0.11 mA vs. 0.03 +/- 0.02 mA, P <.001), and (4) V(max) (DeltaV(max), -43 +/- 14% vs. -11 +/- 4%, P <.01, n = 5 to 6; all recorded at 10 muM, 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.

Synergistic electrophysiologic and antiarrhythmic effects of the combination of ranolazine and chronic amiodarone in canine atria.

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.

Potent antiarrhythmic effects of chronic amiodarone in canine pulmonary vein sleeve preparations.

OBJECTIVES: To examine the effects of chronic amiodarone on the electrophysiology of canine pulmonary vein (PV) sleeve preparations and left ventricular wedge preparation. BACKGROUND: Amiodarone is commonly used for the treatment of ventricular and supraventricular arrhythmias. Ectopic activity arising from the PV plays a prominent role in the development of atrial fibrillation (AF). METHODS: Standard microelectrode techniques were used to evaluate the electrophysiological characteristics of superfused PV sleeve (left superior or inferior) and arterially perfused left ventricular (LV) wedge preparations isolated from untreated and chronic amiodarone-treated dogs (amiodarone, 40 mg/kg daily for 6 weeks). RESULTS: In PV sleeves, chronic amiodarone (n = 6) induced a significant increase in action potential duration at 90% repolarization (APD90) and a significant use-dependent reduction in Vmax leading to 1:1 activation failure at long cycle lengths (basic cycle length of 124 +/- 15 ms in control vs 420 +/- 320 ms after chronic amiodarone [P < 0.01]). Diastolic threshold of excitation increased from 0.3 +/- 0.2 to 1.8 +/- 0.7 mA (P < 0.01). Delayed and late phase 3 early afterdepolarizations and triggered activity could be induced in PV sleeve preparations using acetylcholine (ACh, 1 microM), high calcium ([Ca2+]o = 5.4 mM), isoproterenol (Iso, 1 microM), or their combination in 6 of 6 untreated PV sleeves, but in only 1 of 5 chronic amiodarone-treated PV sleeve preparations. Vmax, conduction velocity, and 1:1 activation failure were much more affected in PV sleeves versus LV wedge preparations isolated from amiodarone-treated animals. CONCLUSIONS: The results point to potent effects of chronic amiodarone to preferentially suppress arrhythmogenic substrates and triggers arising from the PV sleeves of the dog.

Ranolazine exerts potent effects on atrial electrical properties and abbreviates atrial fibrillation duration in the intact porcine heart.

INTRODUCTION: In vitro studies and ambulatory ECG recordings from the MERLIN TIMI-36 clinical trial suggest that the novel antianginal agent ranolazine may have the potential to suppress atrial arrhythmias. However, there are no reports of effects of ranolazine on atrial electrophysiologic properties in large intact animals. METHODS AND RESULTS: In 12 closed-chest anesthetized pigs, effects of intravenous ranolazine (approximately 9 microM plasma concentration) on multisite atrial effective refractory period (ERP), conduction time (CT), and duration and inducibility of atrial fibrillation (AF) initiated by intrapericardial acetylcholine were investigated. Ranolazine increased ERP by a median of 45 ms (interquartile range 29-50 ms; P < 0.05, n = 6) in right and left atria compared to control at pacing cycle length (PCL) of 400 ms. However, ERP increased by only 28 (24-34) ms in right ventricle (P < 0.01, n = 6). Ranolazine increased atrial CT from 89 (71-109) ms to 98 (86-121) ms (P = 0.04, n = 6) at PCL of 400 ms. Ranolazine decreased AF duration from 894 (811-1220) seconds to 621 (549-761) seconds (P = 0.03, n = 6). AF was reinducible in 1 of 6 animals after termination with ranolazine compared with all 6 animals during control period (P = 0.07). Dominant frequency (DF) of AF was reduced by ranolazine in left atrium from 11.7 (10.7-20.5) Hz to 7.6 (2.9-8.8) Hz (P = 0.02, n = 6). CONCLUSIONS: Ranolazine, at therapeutic doses, increased atrial ERP to greater extent than ventricular ERP and prolonged atrial CT in a frequency-dependent manner in the porcine heart. AF duration and DF were also reduced by ranolazine. Potential role of ranolazine in AF management merits further investigation.

Atrium-selective sodium channel block as a strategy for suppression of atrial fibrillation: differences in sodium channel inactivation between atria and ventricles and the role of ranolazine.

BACKGROUND: The development of selective atrial antiarrhythmic agents is a current strategy for suppression of atrial fibrillation (AF). METHODS AND RESULTS: Whole-cell patch clamp techniques were used to evaluate inactivation of peak sodium channel current (I(Na)) in myocytes isolated from canine atria and ventricles. The electrophysiological effects of therapeutic concentrations of ranolazine (1 to 10 micromol/L) and lidocaine (2.1 to 21 micromol/L) were evaluated in canine isolated coronary-perfused atrial and ventricular preparations. Half-inactivation voltage of I(Na) was approximately 15 mV more negative in atrial versus ventricular cells under control conditions; this difference increased after exposure to ranolazine. Ranolazine produced a marked use-dependent depression of sodium channel parameters, including the maximum rate of rise of the action potential upstroke, conduction velocity, and diastolic threshold of excitation, and induced postrepolarization refractoriness in atria but not in ventricles. Lidocaine also preferentially suppressed these parameters in atria versus ventricles, but to a much lesser extent than ranolazine. Ranolazine produced a prolongation of action potential duration (APD90) in atria, no effect on APD90 in ventricular myocardium, and an abbreviation of APD90 in Purkinje fibers. Lidocaine abbreviated both atrial and ventricular APD90. Ranolazine was more effective than lidocaine in terminating persistent AF and in preventing the induction of AF. CONCLUSIONS: Our study demonstrates important differences in the inactivation characteristics of atrial versus ventricular sodium channels and a striking atrial selectivity for the action of ranolazine to produce use-dependent block of sodium channels, leading to suppression of AF. Our results point to atrium-selective sodium channel block as a novel strategy for the management of AF.

A mechanistic approach to assess the proarrhythmic risk of QT-prolonging drugs in preclinical pharmacologic studies.

Drugs with diverse structures and from several therapeutic classes are reported to increase the risk that a patient will experience ventricular tachyarrhythmias (e.g., torsades de pointes [TdP]) during drug therapy. This review discusses the use of preclinical assays to assess the risk that a QT-prolonging drug will cause TdP. The mechanisms underlying the development of TdP and the factors that increase the risk of TdP are described and applied to the design of preclinical experimental models for detection of proarrhythmic drug actions. Recommended assays, conditions, and preparations for preclinical assessment of the drug-induced risk to TdP are given. No single preparation can simulate all conditions that cause TdP in patients. However, the assays described herein are capable of detecting the proarrhythmic effects of currently used drugs, even when these effects are reported to be extremely rare in clinical practice.

Electrophysiologic properties and antiarrhythmic actions of a novel antianginal agent.

Ranolazine is a novel antianginal agent capable of producing anti-ischemic effects at plasma concentrations of 2 to 6 microM without a significant reduction of heart rate or blood pressure. This review summarizes the electrophysiologic properties of ranolazine. Ranolazine significantly blocks I(Kr) (IC(50) = 12 microM), late I(Na), late I(Ca), peak I(Ca), I(Na-Ca) (IC(50) = 5.9, 50, 296, and 91 microM, respectively) and I(Ks) (17% at 30 microM), but causes little or no inhibition of I(to) or I(K1). In left ventricular tissue and wedge preparations, ranolazine produces a concentration-dependent prolongation of action potential duration (APD) in epicardium, but abbreviation of APD of M cells, leading to either no change or a reduction in transmural dispersion of repolarization (TDR). The result is a modest prolongation of the QT interval. Prolongation of APD and QT by ranolazine is fundamentally different from that of other drugs that block I(Kr) and induce torsade de pointes in that APD prolongation is rate-independent (ie, does not display reverse rate-dependent prolongation of APD) and is not associated with early after depolarizations, triggered activity, increased spatial dispersion of repolarization, or polymorphic ventricular tachycardia. Torsade de pointes arrhythmias were not observed spontaneously nor could they be induced with programmed electrical stimulation in the presence of ranolazine at concentrations as high as 100 microM. Indeed, ranolazine was found to possess significant antiarrhythmic activity, acting to suppress the arrhythmogenic effects of other QT-prolonging drugs. Ranolazine produces ion channel effects similar to those observed after chronic exposure to amiodarone (reduced late I(Na), I(Kr), I(Ks), and I(Ca)). Ranolazine's actions to reduce TDR and suppress early after depolarization suggest that in addition to its anti-anginal actions, the drug possesses antiarrhythmic activity.

Electrophysiological effects of ranolazine, a novel antianginal agent with antiarrhythmic properties.

BACKGROUND: Ranolazine is a novel antianginal agent capable of producing antiischemic effects at plasma concentrations of 2 to 6 micromol/L without reducing heart rate or blood pressure. The present study examines its electrophysiological effects in isolated canine ventricular myocytes, tissues, and arterially perfused left ventricular wedge preparations. METHODS AND RESULTS: Transmembrane action potentials (APs) from epicardial and midmyocardial (M) regions and a pseudo-ECG were recorded simultaneously from wedge preparations. APs were also recorded from epicardial and M tissues. Whole-cell currents were recorded from epicardial and M myocytes. Ranolazine inhibited I(Kr) (IC50=11.5 micromol/L), late I(Na), late I(Ca), peak I(Ca), and I(Na-Ca) (IC50=5.9, 50, 296, and 91 micromol/L, respectively) and I(Ks) (17% at 30 micromol/L), but caused little or no inhibition of I(to) or I(K1). In tissues and wedge preparations, ranolazine produced a concentration-dependent prolongation of AP duration of epicardial but abbreviation of that of M cells, leading to reduction or no change in transmural dispersion of repolarization (TDR). At [K+]o=4 mmol/L, 10 micromol/L ranolazine prolonged QT interval by 20 ms but did not increase TDR. Extrasystolic activity and spontaneous torsade de pointes (TdP) were never observed, and stimulation-induced TdP could not be induced at any concentration of ranolazine, either in normal or low [K+]o. Ranolazine (5 to 20 micromol/L) suppressed early afterdepolarizations (EADs) and reduced the increase in TDR induced by the selective I(Kr) blocker d-sotalol. CONCLUSIONS: Ranolazine produces ion channel effects similar to those observed after chronic amiodarone (reduced I(Kr), I(Ks), late I(Na), and I(Ca)). The actions of ranolazine to suppress EADs and reduce TDR suggest that, in addition to its antianginal actions, the drug may possess antiarrhythmic activity.

Cisapride-induced transmural dispersion of repolarization and torsade de pointes in the canine left ventricular wedge preparation during epicardial stimulation.

BACKGROUND: Cisapride, a gastrointestinal prokinetic agent, was recently withdrawn from the market because of its propensity to induce torsade de pointes (TdP) arrhythmias. The present study examines the electrophysiological actions of cisapride in the isolated arterially perfused canine left ventricular wedge preparation. METHODS AND RESULTS: Transmembrane action potentials from epicardial and M regions and a pseudo-ECG were simultaneously recorded. Cisapride (0.1 to 5 micromol/L) was added to the coronary perfusate. Cisapride prolonged the QT interval and increased transmural dispersion of repolarization (TDR) at relatively low but not at high concentrations. TdP could be induced with programmed electrical stimulation only at a low concentration of drug (0.2 micromol/L), when TDR was maximally prolonged. Moreover, TdP could only be induced during epicardial (but not endocardial) activation of the wedge, which was found to augment TDR. At higher concentrations of cisapride, QT was further prolonged, TDR was diminished, and TdP could no longer be induced. Tpeak-Tend interval and Tpeak-Tend area provided reasonable electrocardiographic indices of TDR. CONCLUSIONS: Our data (1) demonstrate a biphasic concentration/response relationship for the effect of cisapride to induce long-QT syndrome and TdP, (2) show the value of the left ventricular wedge preparation in identifying drugs that pose an arrhythmic risk, (3) support the hypothesis that risk for development of TdP is related to the increase in TDR rather than to prolongation of the QT interval, and (4) indicate that epicardial activation of the left ventricle, as occurs during biventricular pacing, can facilitate the development of TdP under long-QT conditions.

Contribution of I(K,ADO) to the negative dromotropic effect of adenosine.

OBJECTIVE: Despite the pathophysiological and therapeutic significance of the negative dromotropic effect of adenosine, its underlying ionic mechanism, and specifically the role of the adenosine-activated K(+) current (I(K,ADO)) is not experimentally defined. Therefore, we studied the contribution of I(K,ADO) to the negative dromotropic effect of adenosine. METHODS: Effects of adenosine on single atrioventricular nodal and left atrial myocytes from rabbits were studied using the whole cell configuration of the patch clamp technique. Complementary experiments were done in rabbit and guinea pig isolated hearts instrumented to measure the atrium-to-His bundle interval. RESULTS: In contrast to its effect in atrial myocytes, Ba(2+) selectively and completely blocked I(K,ADO) at membrane potentials from -70 to 0 mV in atrioventricular nodal myocytes and abolished the adenosine-induced leftward shift of the reversal membrane potential. Ba(2+) alone did not significantly prolong the A-H interval, but markedly attenuated the A-H interval prolongation caused by adenosine. In guinea pig heart, EC(50) values ( pD(2) +/- SEM) for adenosine-induced atrium-to-His bundle interval prolongation were 3.3 micromol/L (5.48 +/- 0.04) and 13.2 micromol/L (4.88 +/- 0.05, P < 0.001) in the absence and presence of Ba(2+), respectively. Despite species-dependent differences in sensitivities to adenosine (guinea pig > rabbit), the relative contribution of adenosine-activated K(+) current to the atrium-to-His bundle interval prolongation was nearly identical. In guinea pig hearts it ranged from 37.8 % (P = 0.013) to 72.5 % (P < 0.001) at 2 to 6 micromol/L adenosine, respectively. CONCLUSION: I(K,ADO) contributes significantly to the negative dromotropic effect of adenosine, but predominantly at relatively high concentrations of the nucleoside.