Pharmacologic TWIK-Related Acid-Sensitive K+ Channel (TASK-1) Potassium Channel Inhibitor A293 Facilitates Acute Cardioversion of Paroxysmal Atrial Fibrillation in a Porcine Large Animal Model.

Background The tandem of P domains in a weak inward rectifying K+ channel (TWIK)-related acid-sensitive K+ channel (TASK-1; hK2P3.1) two-pore-domain potassium channel was recently shown to regulate the atrial action potential duration. In the human heart, TASK-1 channels are specifically expressed in the atria. Furthermore, upregulation of atrial TASK-1 currents was described in patients suffering from atrial fibrillation (AF). We therefore hypothesized that TASK-1 channels represent an ideal target for antiarrhythmic therapy of AF. In the present study, we tested the antiarrhythmic effects of the high-affinity TASK-1 inhibitor A293 on cardioversion in a porcine model of paroxysmal AF. Methods and Results Heterologously expressed human and porcine TASK-1 channels are blocked by A293 to a similar extent. Patch clamp measurements from isolated human and porcine atrial cardiomyocytes showed comparable TASK-1 currents. Computational modeling was used to investigate the conditions under which A293 would be antiarrhythmic. German landrace pigs underwent electrophysiological studies under general anesthesia. Paroxysmal AF was induced by right atrial burst stimulation. After induction of AF episodes, intravenous administration of A293 restored sinus rhythm within cardioversion times of 177±63 seconds. Intravenous administration of A293 resulted in significant prolongation of the atrial effective refractory period, measured at cycle lengths of 300, 400 and 500 ms, whereas the surface ECG parameters and the ventricular effective refractory period lengths remained unchanged. Conclusions Pharmacological inhibition of atrial TASK-1 currents exerts antiarrhythmic effects in vivo as well as in silico, resulting in acute cardioversion of paroxysmal AF. Taken together, these experiments indicate the therapeutic potential of A293 for AF treatment.

The positive frequency-dependent electrophysiological effects of the IKur inhibitor XEN-D0103 are desirable for the treatment of atrial fibrillation.

BACKGROUND: Selective inhibitors of Kv1.5 channels are being developed for the treatment of atrial fibrillation (AF). OBJECTIVES: The purpose of this study was to investigate the effects of the highly selective Kv1.5 inhibitor XEN-D0103 on human atrial action potentials (APs) at high excitation rates and to assess safety. METHODS: Intracellular APs (stimulation rates 1-5 Hz) were measured in right atrial trabeculae from patients in sinus rhythm (SR), chronic AF (cAF; AF of >6 months duration), and paroxysmal AF (pAF). The safety and tolerability of XEN-D0103 were tested in a double-blind, randomized, placebo-controlled phase 1 study. RESULTS: Depending on its concentration, XEN-D0103 elevated the plateau potential. At 1 Hz, XEN-D0103 (3 µM) shortened action potential duration at 90% repolarization (APD90) and effective refractory period (ERP) in SR preparations, but prolonged these parameters in cAF preparations. In SR and pAF preparations, the shortening effects on APD90 and ERP turned into prolongation at high rates. In cAF trabeculae, XEN-D0103 prolonged APD90 and ERP at 2 and 3 Hz. At high rates, more SR and pAF preparations failed to capture excitation in the presence of the drug than in its absence. XEN-D0103 (10 µM) did not significantly affect human ventricular APs. Even with plasma concentrations reaching 7000 ng/mL, XEN-D0103 did not increase ∆∆QTcF (QT interval corrected by the Fridericia formula) in the analysis of electrocardiograms of healthy volunteers, and no subjects receiving an active treatment had a QT or QTcF interval >450 ms, or increase in QTcF from baseline >30 ms. CONCLUSION: APD prolongation and suppression of APs by XEN-D0103 at high stimulation rates in SR and pAF tissue, but not cAF, could be of therapeutic benefit for reducing AF burden. This concept needs to be confirmed in clinical trials.

Effects of ivabradine on cardiac electrophysiology in dogs with age-related atrial fibrillation.

BACKGROUND: Ivabradine is an inhibitor of mixed Na+-K+ current that could combine with HCN channels to reduce the transmembrane velocity of funny current (If), heart rate, and cardiac efficiency, and thus be used for the treatment of cardiovascular diseases such as chronic heart failure. As an ion channel blocker, Ivabradine is also a potential antiarrhythmic agent. MATERIAL/METHODS: Twelve aging dogs (8-10 years old) underwent rapid atrial pacing for 2 months to induce age-related AF in this study. The dogs were randomly divided into the Ivabradine group and aging-AF group. The effects of Ivabradine on the electrophysiological parameters, including the effective refractory period (ERP) of the pulmonary veins and atrium, duration of AF, and inducing rate of AF, were investigated. RESULTS: As compared to the aging-AF group, the ERPs of the left superior pulmonary vein (139.00±4.18 ms vs. 129.00±4.08 ms, P=0.005) and left auricle (135.00±3.53 ms vs. 122.00±4.47 ms, P=0.001) were significantly increased, while the duration of AF (46.60±5.07 s vs. 205.40±1.14 s, P=0.001) and inducing rate of AF (25% vs. 60%, P=0.001) were significantly decreased. CONCLUSIONS: Ivabradine could effectively reduce the inducing rate of AF, and thus be used as an upstream drug for the prevention of age-related AF.

Is the acetylcholine-regulated inwardly rectifying potassium current a viable antiarrhythmic target? Translational discrepancies of AZD2927 and A7071 in dogs and humans.

AIMS: We aimed at examining the acetylcholine-dependent inward-rectifier current (IKAch) as a target for the management of atrial fibrillation (AF). METHODS AND RESULTS: The investigative agents AZD2927 and A7071 concentration-dependently blocked IKACh in vitro with minimal off-target activity. In anaesthetized dogs (n = 17) subjected to 8 weeks of rapid atrial pacing (RAP), the left atrial effective refractory period (LAERP) was maximally increased by 50 ± 7.4 and 50 ± 4.8 ms following infusion of AZD2927 and A7071. Ventricular refractoriness and the QT interval were unaltered. During sustained AF, both drugs significantly reduced AF frequency and effectively restored sinus rhythm. AZD2927 successfully restored sinus rhythm at 10/10 conversion attempts and A7071 at 14/14 attempts, whereas saline converted 4/17 episodes only (P<0.001 vs. AZD2927 and A7071). In atrial flutter patients (n = 18) undergoing an invasive investigation, AZD2927 did not change LAERP, the paced QT interval, or ventricular refractoriness when compared with placebo. To address the discrepancy on LAERP by IKACh blockade in man and dog and the hypothesis that atrial electrical remodelling is a prerequisite for IKACh blockade being efficient, six dogs were studied after 8 weeks of RAP followed by sinus rhythm for 4 weeks to reverse electrical remodelling. In these dogs, both AZD2927 and A7071 were as effective in increasing LAERP as in the dogs studied immediately after the 8-week RAP period. CONCLUSION: Based on the present series of experiments, an important role of IKACh in human atrial electrophysiology, as well as its potential as a viable target for effective management of AF, may be questioned.

Drug-induced post-repolarization refractoriness as an antiarrhythmic principle and its underlying mechanism.

AIMS: We hypothesized that amiodarone (AM), unlike d-sotalol (DS) (a 'pure' Class III agent), not only prolongs the action potential duration (APD) but also causes post-repolarization refractoriness (PRR), thereby preventing premature excitation and providing superior antiarrhythmic efficacy. METHODS AND RESULTS: We tested this hypothesis in 31 patients with inducible ventricular tachycardia (VT) during programmed stimulation with the use of the 'Franz' monophasic action potential (MAP) catheter with simultaneous pacing capability. We determined the effective refractory period (ERP) for each of three extrastimuli (S2-S4) and the corresponding MAP duration at 90% repolarization (APD90), both during baseline and on randomized therapy with either DS (n = 15) or AM (n = 16). We defined ERP > APD90 as PRR and ERP < APD90 as 'encroachment' on repolarization. A revised computer action potential model was developed to help explain the mechanisms of these in-vivo human-heart phenomena. Encroachment but not PRR was present in all patients at baseline and during DS treatment (NS vs. baseline), and VT was non-inducible in only 2 of 15 DS patients. In contrast, in 12 of 16 AM patients PRR was present (P < 0.001 vs. baseline), and VT was no longer inducible. Our model (with revised sodium channel kinetics) reproduced encroachment and drug-induced PRR. CONCLUSION: Both, AM and DS, prolonged APD90 but only AM produced PRR and prevented encroachment of premature extrastimuli. Our computer simulations suggest that PRR is due to altered kinetics of the slow inactivation of the rapid sodium current. This may contribute to the high antiarrhythmic efficacy of AM.

Inefficacy of a highly selective T-type calcium channel blocker in preventing atrial fibrillation related remodeling.

BACKGROUND: The T-type Ca(2+) channel (I(CaT)) blocker mibefradil prevents AF-promoting remodeling occurring with atrial tachycardia, an action that has been attributed to I(CaT) inhibition. However, mibefradil has other effects, including ability to inhibit L-type Ca(2+) channels, Na(+) channels and cytochromes. Thus, the relationship between I(CaT) inhibition and remodeling protection in AF is still unknown. OBJECTIVE: To assess the effects of a novel highly selective Cav3 (I(CaT)) blocker, AZ9112, on atrial remodeling induced by 1-week atrial tachypacing (AT-P) in dogs. METHODS: Mongrel dogs were subjected to AT-P at 400 bpm for 7 days, with atrioventricular-node ablation and right-ventricular demand pacing (80 bpm) to control ventricular rate. Four groups of dogs were studied in investigator-blinded fashion: (1) a sham group, instrumented but without tachypacing or drug therapy (n = 5); (2) a placebo group, tachypaced but receiving placebo (n = 6); (3) a positive control tachypacing group receiving mibefradil (n = 6); and (4) a test drug group, subjected to tachypacing during oral treatment with AZ9112 (n = 8). RESULTS: One-week AT-P decreased atrial effective refractory period (ERP) at 6 of 8 sites and diminished rate-dependent atrial ERP abbreviation. Mibefradil eliminated AT-P-induced ERP-abbreviation at 4 of these 6 sites, while AZ9112 failed to affect ERP at any. Neither drug significantly affected AF vulnerability or AF duration. CONCLUSIONS: I(CaT) blockade with the highly selective compound AZ9112 failed to prevent rate-related atrial remodeling. Thus, prevention of atrial electrophysiological remodeling by mibefradil cannot be attributed exclusively to I(CaT) blockade. These results indicate that I(CaT) inhibition is not likely to be a useful approach for AF therapy.

Effects of endothelin-1 chronic stimulation on electrical restitution, beat-to-beat variability of repolarization, and ventricular arrhythmogenesis.

Chronically elevated levels of endothelin-1 (ET-1) have been detected in several cardiovascular diseases. In this study, we investigated the chronic effects of ET-1 on the electrophysiological characteristics expected to influence the genesis and maintenance of ventricular arrhythmia (VA). Rabbits were randomized to ET-1 (ET-1 group) or 0.9% saline (control group) for 2 weeks. The S1-S2 protocol and S1-S1 dynamic pacing were performed to assess the action potential duration restitution (APDR) and to induce APD alternans or VA in 4 sites of Langendorff-perfused rabbit hearts. The beat-to-beat variability of repolarization was quantified as short-term variability and long-term variability. Compared with the control group, chronic ET-1 administration significantly prolonged QT intervals, APD at 90% repolarization (APD90), and effective refractory period (ERP), steepened the maximum slopes of the APDR curve, decreased the ERP/APD90 ratio, and increased the spatial dispersions of APD90, ERP, and maximum slopes (P < 0.05 for all). Moreover, chronic ET-1 administration markedly increased the short-term variability and long-term variability (P < 0.01 for all). APD alternans occurred in both groups, but the threshold of APD alternans was decreased at all sites in the ET-1 group (P < 0.01 for all). We also observed that chronic ET-1 stimulation significantly increased the incidence and duration of the VA episodes. These results suggest that chronic stimulation with ET-1 facilitated VA by steepening the APDR curve and increasing the spatial dispersion of APDR and beat-to-beat variability of repolarization.

Importance of atrial surface area and refractory period in sustaining atrial fibrillation: testing the critical mass hypothesis.

OBJECTIVE: The critical mass hypothesis for atrial fibrillation (AF) was proposed in 1914; however, there have been few studies defining the relationship between atrial surface area and AF. This study evaluated the effect of tissue area and effective refractory period (ERP) on the probability of sustaining AF in an in vivo model. METHODS: Domestic pigs (n = 9) underwent median sternotomy. Epicardial activation maps were constructed from bipolar electrograms recorded from form-fitting electrode templates placed on the atria. Baseline ERPs were determined. ERP was lowered with a continuous infusion of acetylcholine (0.005-0.04 mg/Kg/min) until AF could be sustained after burst pacing. The atria were sequentially partitioned using bipolar radiofrequency ablation. ERPs were lowered using acetylcholine until AF could be sustained in each subdivision of atrial tissue. Each subdivision was further divided until AF was no longer inducible. At study completion, the heart was excised and the surface area of each section was measured. RESULTS: Over a range of ERPs from 75 to 250 ms, the probability of AF was correlated with increasing tissue area (range, 19.5-105 cm(2)) and decreasing ERP. Logistic regression analysis identified shorter ERP (P < .001) and larger area (P = .006) as factors predictive of an increased probability of sustained AF (area under the curve of the receiver-operator characteristic = 0.878). CONCLUSIONS: The probability of sustained AF was significantly associated with increasing tissue area and decreasing ERP. These data may lead to a greater understanding of the mechanism of AF and help to design better interventional procedures.

Cardiac responses to the intrapericardial delivery of metoprolol: targeted delivery compared to intravenous administration.

Anti-arrhythmic drugs have narrow therapeutic ranges and typically can engender harmful side effects. The intrapericardial (IP) delivery of anti-arrhythmic agents proposes to achieve higher myocardial levels while minimizing plasma concentrations, thus diminishing systemic side effects. Furthermore, IP delivery enables concentrations at the target site to be more precisely controlled. Our study objective was to compare the relative cardiac effects of intrapericardial administration of metoprolol to standard intravenous (IV) delivery in a swine surgical model. In order to answer the question of how IP metoprolol affects sinus tachycardia, atrial electrophysiology, and pharmacokinetics compared with IV delivery, a medial sternotomy was performed on 21 swine that were divided into three groups: (1) After inducing sinus tachycardia, metoprolol boluses were delivered IP (n = 4) or IV (n = 4); (2) metoprolol was administered either IP (n = 3) or IV (n = 3) with saline controls (n = 3), and electrophysiologic data were collected; (3) metoprolol levels were tracked both in the blood (IV, n = 2) and pericardial (IP, n = 2) fluid. After either IP or IV delivery of metoprolol, heart rates were lowered significantly to 70% and 73% of control rate, respectively. The therapeutic effect of IV-administered metoprolol was considerably reduced after 1 h but was sustained longer in the IP group. Additionally, ventricular contractility and mean arterial pressure parameters were significantly lower in IV-treated animals but were nearly unaffected in IP-treated animals. With IP administration, the elimination half-life of metoprolol in pericardial fluid was 14.4 min with negligible accumulations in the plasma, whereas with IV delivery, the elimination half-life in plasma was 11.1 min with negligible amounts found in the pericardial fluid. The targeted intrapericardial delivery of metoprolol effectively lowers heart rates for sustained periods of time, with minimal effect on either ventricular contractility or mean arterial pressure. We did not observe dramatic changes in induced atrial fibrillation times or refractory periods using this model.

Electrophysiologic profile of dronedarone on the ventricular level: beneficial effect on postrepolarization refractoriness in the presence of rapid phase 3 repolarization.

BACKGROUND: Dronedarone (D) is developed to maintain sinus rhythm in patients suffering from atrial fibrillation. The aim of the present study was to investigate, whether dronedarone also has an antiarrhythmic potential in the ventricle and to elucidate the mechanisms for its low proarrhythmic potential in an experimental whole heart model. METHODS AND RESULTS: Thirty-five rabbits underwent chronic treatment with D (n = 15; 50 mg · kg(-1) · d(-1)) and amiodarone (A; n = 20; 50 mg · kg(-1) · d(-1)). Hearts were perfused on a Langendorff apparatus. Results were compared with hearts acutely treated with sotalol (S; 50-100 µM; n = 14). A 12-lead electrocardiogram and up to 8 ventricular epi- and endocardial monophasic action potentials showed a significant prolongation of QT interval (D: +24 milliseconds, A: +28 milliseconds, S: +35 milliseconds (50 µM), +56 milliseconds (100 µM); P < 0.02) compared with baseline. In contrast to D and A, S led to a significant increase in dispersion of repolarization and exhibited reverse use dependence. D, A, and S increased refractory period, resulting in a significant increase in postrepolarization refractoriness (effective refractory period minus action potential duration; D = +12 milliseconds; A = +14 milliseconds; S = +25 milliseconds; P < 0.05). S led to a triangular action potential configuration, whereas D and A caused a fast phase 3 prolongation. After lowering of potassium concentration, 50% of S-treated hearts showed torsade de pointes, in contrast to an absence of torsade de pointes in D and A. CONCLUSIONS: Prolongation of myocardial repolarization and postrepolarization refractoriness by D may act antiarrhythmic. A fast phase 3 repolarization in the absence of both increased dispersion of repolarization and reverse use dependence prevents proarrhythmia.

Botulinum toxin injection in epicardial autonomic ganglia temporarily suppresses vagally mediated atrial fibrillation.

BACKGROUND: Autonomic denervation may suppress atrial fibrillation (AF) vulnerability. This study was designed to assess the short- to mid-term effects of botulinum toxin, a cholinergic neurotransmission blocker, on AF inducibility. METHODS AND RESULTS: A total of 23 mongrel dogs were studied. The sinus node and atrioventricular node epicardial fat pads were exposed through a right lateral thoracotomy. Botulinum toxin (Botox, 50 U per fat pad) or 0.9% normal saline (control) was injected into the center of each of the 2 fat pads. The electrophysiological effects were evaluated at 1, 2, and 3 weeks (7 to 8 animals at each time point) with and without cervical vagal stimulation. The vagal stimulation effects on the sinus and atrioventricular nodes were inhibited, and dispersion of atrial effective refractory period was lower at 1 week in the Botox group. Significant suppression of AF inducibility was observed at 1 week but disappeared at 2 and 3 weeks. These changes were not observed in the control group. CONCLUSIONS: Temporary suppression of vagally mediated AF, for at least 1 week, was achieved with botulinum toxin injection in this canine model. This effect might be associated with reduced dispersion of effective refractory period. A temporary autonomic block using botulinum toxin might be a novel therapeutic option for several clinical conditions such as post-cardiac surgery AF.

Blockade of angiotensin II improves hyperthyroid induced abnormal atrial electrophysiological properties.

BACKGROUND: Previous studies reported that RAS inhibitors prevented atrial fibrillation by improving atrial electrical and structural remodeling. However, the effect of RAS inhibitors on the substrates of atrial fibrillation (AF) underlying hyperthyroid is unclear. METHODS: Forty rabbits were assigned to four groups: sham group, thyroxine group, benazepril group and irbesartan group (10 per group). The atrial effective refractory period (AERP) was measured. The physiologic rate adaptation and the AF vulnerability were evaluated. The real-time PCR, Western blot or fluorescent immunohistochemistry was performed to detect the expression of AF related Ca+, K+ channel and gap junction. RESULTS: No significant difference was found in AERP among the thyroxine group, benazepril group and irbesartan group (75.13±5.41ms vs. 76.63±4.44ms, 79±4.95ms, P=0.28). However, benazepril or irbesartan could reduce AF vulnerability underlying hyperthyroid (75% vs. 37%, 44%, for thyroxine group, benazepril group and irbesartan group, respectively), and significantly improved physiologic rate adaptation of the AERP. Furthermore, both drugs significantly reduced L-Ca(2+) channel related subunits (α1C or α1D) and interstitial fibrosis (17.1±2.2% vs. 12.3±1.8, 11.7±1.2%, P<0.01, for thyroxine group, benazepril group and irbesartan group, respectively), increased lateral/polar connection of Cx43 (1.04±0.16 vs. 1.33±0.29,1.28±0.25, P<0.01, for thyroxine group, benazepril group and irbesartan group, respectively) and improved the abnormal distribution of gap junctions (Cx40, Cx43) underlying hyperthyroid. CONCLUSION: Blockade of angiotensin II could improve abnormal atrial electrophysiological properties and further reduce AF vulnerability by extenuating ion channel, gap junction and structural remodeling in experimental thyrotoxic rabbits.

Vernakalant selectively prolongs atrial refractoriness with no effect on ventricular refractoriness or defibrillation threshold in pigs.

Vernakalant is a novel antiarrhythmic agent that has demonstrated clinical efficacy for the treatment of atrial fibrillation. Vernakalant blocks, to various degrees, cardiac sodium and potassium channels with a pattern that suggests atrial selectivity. We hypothesized, therefore, that vernakalant would affect atrial more than ventricular effective refractory period (ERP) and have little or no effect on ventricular defibrillation threshold (DFT). Atrial and ventricular ERP and ventricular DFT were determined before and after treatment with vernakalant or vehicle in 23 anesthetized male mixed-breed pigs. Vernakalant was infused at a rate designed to achieve stable plasma levels similar to those in human clinical trials. Atrial and ventricular ERP were determined by endocardial extrastimuli delivered to the right atria or right ventricle. Defibrillation was achieved using external biphasic shocks delivered through adhesive defibrillation patches placed on the thorax after 10 seconds of electrically induced ventricular fibrillation. The DFT was estimated using the Dixon "up-and-down" method. Vernakalant significantly increased atrial ERP compared with vehicle controls (34 ± 8 versus 9 ± 7 msec, respectively) without significantly affecting ventricular ERP or DFT. This is consistent with atrial selective actions and supports the conclusion that vernakalant does not alter the efficacy of electrical defibrillation.

A randomized invasive cardiac electrophysiology study of the combined ion channel blocker AZD1305 in patients after catheter ablation of atrial flutter.

BACKGROUND: This study assessed the cardiac electrophysiological and hemodynamic effects of an intravenous infusion of the combined ion channel blocker AZD1305. METHODS: After successful ablation of atrial flutter, patients were randomized to receive placebo (n = 12) or AZD1305 (n = 38) in 4 ascending dose groups. Electrophysiological and hemodynamic measurements were performed before and commencing 20 minutes after start of infusion. RESULTS: Left atrial effective refractory period increased dose and the primary outcome measure increased dose and plasma concentration dependently, with a mean increase of 55 milliseconds in dose group 3. There was a corresponding increase in right atrial effective refractory period of 84 milliseconds. The right ventricular effective refractory period and the paced QT interval also increased dose and concentration dependently, by 59 and 70 milliseconds, respectively, in dose group 3. There were indications of moderate increases of atrial, atrioventricular nodal, and ventricular conduction times. No consistent changes in intracardiac pressures were observed, but there was a small transient decrease in systolic blood pressure. Adverse events were consistent with the study population and procedure, and there were no signs of proarrhythmia despite marked delay in ventricular repolarization in some individuals. CONCLUSIONS: AZD1305 shows electrophysiological characteristics indicative of potential antiarrhythmic efficacy in atrial fibrillation.

Should sevoflurane be used in the electrophysiology assessment of accessory pathways?

Sevoflurane has been shown to significantly prolong the action potential duration and the QTc interval. Despite this, clinical studies have shown only minor clinical effects on accessory pathway properties under general anaesthesia with sevoflurane compared with conscious sedation with midazolam. This case demonstrates significant prolongation of accessory pathway effective refractory period (APERP) under general anaesthetic with sevoflurane compared with propofol.

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.

[Antiarrhythmic effect of ethyl acetate extract from Chrysanthemum Morifolium Ramat on rats].

OBJECTIVE: To investigate the effect of ethyl acetate extract from Chrysanthemum Morifolium Ramat (CME) on experimental arrhythmia induced by ischemia/reperfusion or aconitine in rats and to explore its underlying mechanisms. METHODS: Arrhythmia model in intact rat was induced by aconitine (30 microg/kg body weight, i.v.). In isolated Langendorff perfused rat hearts, regional ischemia and reperfusion was induced by ligation and release of left anterior descending artery. The ventricular fibrillation threshold (VFT), effective refractory period (ERP), and diastolic excitation threshold (DET) in the isolated heart were measured. The action potentials of papillary muscle in rat right ventricle were recorded by conventional glass microelectrode technique. RESULTS: Compared with control group CME significantly decreased the number and duration of ventricular tachycardia (VT); delayed the occurrence of ventricular premature beats (VPB) and VT induced by aconitine. Arrhythmia score of the CME group was lower than that in aconitine-treated group. CME markedly prolonged the ERP and increased the VFT in the isolated perfused rat hearts during ischemia and reperfusion. CME prolonged action potential duration at 50% and 90% repolarization of the right ventricular papillary muscles and decreased the maximal rate of rise of the action potential upstroke, but did not affect the resting potential, amplitude of action potential. CONCLUSION: CME can reduce myocardial vulnerability and exerts its antiarrhythmic effects induced by aconitine or ischemia/reperfusion, which may be related to its prolongation of action potential duration and effective refractory period that enhance the electrophysiological stability of myocardiaium.

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.

Omega-3 polyunsaturated fatty acids prevent atrial fibrillation associated with heart failure but not atrial tachycardia remodeling.

BACKGROUND: There is epidemiological evidence that omega-3 polyunsaturated fatty acids (PUFAs) reduce the risk of atrial fibrillation (AF), but clinical data are conflicting. The present study assessed the effects of PUFA on AF in experimental models. METHODS AND RESULTS: We studied the effects of oral PUFA supplements in 2 experimental AF paradigms: electrical remodeling induced by atrial tachypacing (400 bpm for 1 week) and congestive heart failure-associated structural remodeling induced by ventricular tachypacing (240 bpm for 2 weeks). PUFA pretreatment did not directly change atrial effective refractory period (128+/-6 [mean+/-SEM] versus 127+/-2 ms; all effective refractory periods at 300-ms cycle lengths) or burst pacing-induced AF duration (5+/-4 versus 34+/-18 seconds). Atrial tachypacing dogs had shorter refractory periods (73+/-6 ms) and greater AF duration (1185+/-300 seconds) than shams (119+/-5 ms and 20+/-11 seconds; P<0.01 for each). PUFAs did not significantly alter atrial tachypacing effects on refractory periods (77+/-8 ms) or AF duration (1128+/-412 seconds). PUFAs suppressed ventricular tachypacing-induced increases in AF duration (952+/-221 versus 318+/-249 seconds; P<0.05) and attenuated congestive heart failure-related atrial fibrosis (from 19.2+/-1.1% to 5.8+/-1.0%; P<0.001) and conduction abnormalities. PUFAs also attenuated ventricular tachypacing-induced hemodynamic dysfunction (eg, left ventricular end-diastolic and left atrial pressure from 12.2+/-0.5 and 11.4+/-0.6 mm Hg, respectively, to 6.4+/-0.5 and 7.0+/-0.8 mm Hg; P<0.01) and phosphorylation of mitogen-activated protein kinases (extracellular-signal related and P38 kinase). CONCLUSIONS: PUFAs suppress congestive heart failure-induced atrial structural remodeling and AF promotion but do not affect atrial tachycardia-induced electrical remodeling. The beneficial effects of PUFAs on structural remodeling, possibly related to prevention of mitogen-activated protein kinase activation, may contribute to their clinical anti-AF potential.

Reduction of dispersion of repolarization and prolongation of postrepolarization refractoriness explain the antiarrhythmic effects of quinidine in a model of short QT syndrome.

BACKGROUND: Short QT syndrome (SQTS) is a newly described ion channelopathy, characterized by a short QT interval resulting from an accelerated cardiac repolarization, associated with syncope, atrial fibrillation, and sudden cardiac death due to ventricular fibrillation. As therapeutic options in SQTS are still controversial, we examined antiarrhythmic mechanisms in an experimental model of SQTS. METHODS AND RESULTS: Pinacidil, an I(K-ATP) channel opener, was administered in increasing concentrations (50-100 microM) in 48 Langendorff-perfused rabbit hearts and led to a significant reduction of action potential duration and QT interval, thereby mimicking SQTS. Eight simultaneously recorded monophasic action potentials demonstrated an increase in dispersion of repolarization, especially between the left and the right ventricle. During programmed ventricular stimulation with up to two extrastimuli, pinacidil significantly increased the inducibility of ventricular fibrillation (1 heart under baseline conditions, 29 hearts during pinacidil administration; P = 0.0001). Additional treatment with the I(Kr) blocker sotalol (100 microM) and the class I antiarrhythmic drugs flecainide (2 microM) and quinidine (0.5 microM) randomly assigned to three groups of 16 hearts led to prolongation of repolarization as well as refractory period. Sotalol or flecainide did not reduce the rate of inducibility of ventricular fibrillation significantly (P = 0.63; P = 0.219). However, quinidine reduced the inducibility of ventricular fibrillation by 73% (P = 0.008). The antiarrhythmic potential of quinidine was associated with a significantly greater prolongation of MAP duration, refractoriness, and postrepolarization refractoriness (PRR) as compared with sotalol and flecainide. Moreover, quinidine, in contrast to sotalol and flecainide, reduced dispersion of repolarization. CONCLUSION: Pinacidil mimics SQTS via increasing potassium outward currents, thereby facilitating inducibility of ventricular fibrillation. Quinidine demonstrates superior antiarrhythmic properties in the treatment of ventricular fibrillation in this model as compared with sotalol and flecainide because of its effects on refractoriness, PRR, and by reducing dispersion of repolarization.