Search

Atrial fibrillation (AF) is the most common arrhythmia of the heart in industrialized countries. Its generation and the transitory behavior of paroxysmal AF are still not well understood. In this work we examine the interaction of two activation sources via an isthmus as possible cause for the initiation of fibrillation episodes. For this study, the electrophysiological model of Bueno-Orovio, Cherry and Fenton is adapted to atrial electrophysiology, both for physiological and electrophysiologically remodeled conditions due to AF. We show that the interaction of the pacemakers, combined with the geometrical constraints of the isthmus, can produce fibrillatory-type irregularities, which we quantify by the loss of spatial phase coherence in the transmembrane voltage. Transitions to irregular behavior occur when the frequencies of the pacemakers exceed certain thresholds, suggesting that AF episodes are initiated by frequency changes of the activating sources (sinus node, ectopic focus).

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.

Summary Postictal refractoriness checked by paired stimulations of the limbic structures was demonstrated to fail in rats

Anti-atrial fibrillatory, proarrhythmic and cardiodepressive profiles of dronedarone were analyzed using the halothane-anesthetized beagle dogs (n = 4) to create a standard protocol for clarifying both efficacy and adverse effects of anti-atrial fibrillatory drugs. Intravenous administration of dronedarone hydrochloride in doses of 0.3 and 3 mg/kg over 30 s attained the peak plasma concentrations of 61 and 1248 ng/mL, respectively, reflecting sub- to supra-therapeutic ones. The low dose decreased the left ventricular contraction and mean blood pressure, which were enhanced at the high dose. The high dose also decreased the heart rate and cardiac output, but increased the total peripheral resistance and left ventricular end-diastolic pressure, showing its potent cardiodepressive profile. Moreover, the high dose delayed the atrioventricular nodal and intraventricular conductions in addition to the ventricular repolarization, suggesting its inhibitory action on the Ca2+, Na+ and K+ channels in the in situ heart, respectively. The high dose also prolonged the effective refractory period 1.9 times greater in the atrium than in the ventricle, explaining its clinically demonstrated efficacy against the atrial arrhythmias. Dronedarone significantly prolonged the Tpeak–Tend in a dose-related manner with a tendency to prolong the terminal repolarization period and J–Tpeakc, indicating considerable risk to induce torsade de pointes. No significant change was detected in the P-wave duration by either dose, indicating the lack of effect on the atrial Na+ channel in vivo. The current experimental protocol and the results of dronedarone can be used as a guide for safety pharmacological evaluation of new anti-atrial fibrillatory drugs.

Background: The substrate location and underlying electrophysiological mechanisms that contribute to the characteristic ECG pattern of Brugada syndrome (BrS) are still debated. Using noninvasive electrocardiographical imaging, we studied whole heart conduction and repolarization patterns during ajmaline challenge in BrS individuals. Methods and Results: A total of 13 participants (mean age, 44±12 years; 8 men), 11 concealed patients with type I BrS and 2 healthy controls, underwent an ajmaline infusion with electrocardiographical imaging and ECG recordings. Electrocardiographical imaging activation recovery intervals and activation timings across the right ventricle (RV) body, outflow tract (RVOT), and left ventricle were calculated and analyzed at baseline and when type I BrS pattern manifested after ajmaline infusion. Peak J-ST point elevation was calculated from the surface ECG and compared with the electrocardiographical imaging–derived parameters at the same time point. After ajmaline infusion, the RVOT had the greatest increase in conduction delay (5.4±2.8 versus 2.0±2.8 versus 1.1±1.6 ms; P =0.007) and activation recovery intervals prolongation (69±32 versus 39±29 versus 21±12 ms; P =0.0005) compared with RV or left ventricle. In controls, there was minimal change in J-ST point elevation, conduction delay, or activation recovery intervals at all sites with ajmaline. In patients with BrS, conduction delay in RVOT, but not RV or left ventricle, correlated to the degree of J-ST point elevation (Pearson R , 0.81; P Conclusions: Magnitude of ST (J point) elevation in the type I BrS pattern is attributed to degree of conduction delay in the RVOT and not prolongation in repolarization time.

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia and a major cause of morbidity and mortality. Traditional antiarrhythmic agents used for restoration of sinus rhythm have limited efficacy in long-term AF and they may possess ventricular proarrhythmic adverse effects, especially in patients with structural heart disease. The acetylcholine receptor-activated potassium channel (I

Background The mechanisms of atrial fibrillation ( AF ) induced by obstructive sleep apnea ( OSA ) are not completely understood. This study investigated the roles of the intrinsic and extrinsic cardiac autonomic nervous system in OSA ‐induced AF and provided noninvasive autonomic nervous modulation for the suppression of OSA ‐induced AF by using low‐level transcutaneous electrical stimulation ( LL ‐ TS ) of the auricular branch of the vagus nerve at the tragus. Methods and Results Eighteen dogs received tracheostomy under general anesthesia and were randomly divided into 3 groups: the OSA group ( OSA was simulated via clamping of the endotracheal tube at end expiration for 1.5 minutes every 10 minutes, n=6), the LL ‐ TS + OSA group (simulated OSA plus LL ‐ TS , at 80% of the slowing sinus rate, n=6), and the control group (sham surgery without stimulation, n=6). The effective refractory period was significantly shortened after 1 hour of simulated OSA , and the window of vulnerability and plasma norepinephrine levels were both markedly increased in the OSA group. OSA dramatically increased the neural function and activity of the intrinsic and extrinsic cardiac autonomic nervous system , including the superior left ganglionated plexus, the left stellate ganglion, and the left renal sympathetic nerve. OSA also significantly upregulated the expression levels of c‐fos and nerve growth factor in the superior left ganglionated plexus and the left stellate ganglion . However, LL ‐ TS markedly improved these parameters. Conclusions These findings suggest that the intrinsic and extrinsic cardiac autonomic nervous system plays crucial roles in the acute stage of OSA ‐induced AF . Noninvasive LL ‐ TS suppressed shortening of atrial refractoriness and autonomic remodeling, which prevented OSA ‐induced AF .

The effects of background noise on speech‐evoked cortical auditory evoked potentials (CAEPs) can provide insight into the physiology of the auditory system. The purpose of this study was to determine background noise effects on neural coding of different phonemes within a syllable. CAEPs were recorded from 15 young normal‐hearing adults in response to speech signals /s/, /ɑ/, and /sɑ/. Signals were presented at varying signal‐to‐noise ratios (SNRs). The effects of SNR and context (in isolation or within syllable) were analyzed for both phonemes. For all three stimuli, latencies generally decreased and amplitudes generally increased as SNR improved, and context effects were not present; however, the amplitude of the /ɑ/ response was the exception, showing no SNR effect and a significant context effect. Differential coding of /s/ and /ɑ/ likely result from level and timing differences. Neural refractoriness may result in the lack of a robust SNR effect on amplitude in the syllable context. The stable amplitude across SNRs in response to the vowel in /sɑ/ suggests the combined effects of (1) acoustic characteristics of the syllable and noise at poor SNRs and (2) refractory effects resulting from phoneme timing at good SNRs. Results provide insights into the coding of multiple‐onset speech syllables in varying levels of background noise and, together with behavioral measures, may help to improve our understanding of speech‐perception‐in‐noise difficulties.

The exact mechanisms underlying the loss of skeletal muscle bulk and power with normal human aging are not well established. Recording of muscle velocity recovery cycles (MVRCs) is an in-vivo neurophysiologic technique we employed to assess the impact of age on sarcolemmal excitability.MVRC recordings were obtained from tibialis anterior (n = 74) and rectus femoris (n = 32) muscles in 74 healthy subjects (18-84 years, median age 35 years, interquartile range 29-55 years).Increasing age was linearly associated with longer muscle relative refractory period (MRRP) and reduced early supernormality (ESN) in both tibialis anterior (MRRP: rThe results are consistent with progressive depolarization of the resting sarcolemmal potential with normal aging. This may be an important mechanism in explaining age-related muscle decline. Muscle Nerve 57: 981-988, 2018.

Aims Antazoline is a first-generation antihistamine with antiarrhythmic properties. This study examines potential electrophysiological effects of antazoline in short-QT-syndrome (SQTS) and long-QT-syndrome (LQTS). Methods and results Sixty-five rabbit hearts were Langendorff-perfused. Action potential duration at 90% of repolarization (APD90), QT-interval, spatial dispersion (DISP), and effective refractory period (ERP) were measured. The IK, ATP-opener pinacidil (1 µM, n = 14) reduced APD90 (-14 ms, P

Background: In human and veterinary medicine, monophasic action potential (MAP) analysis and determination of local refractory periods by contact electrode technique gives valuable information about local cardiac electrophysiological properties. It is used to investigate dysrhythmias and the impact of drugs on the myocardium. Precise measurement of total MAP duration is difficult, therefore the MAP duration is usually determined at a repolarization level of 90% (APD90). Until now, no studies are published about the feasibility of this technique in the standing non-sedated horse. In 6 healthy Warmblood horses, on two different days, an 8F quadripolar contact catheter was passed through a jugular introducer sheath and placed under ultrasound guidance at the level of the intervenous tubercle or right atrial free wall (RA), and in the right ventricular apex (RV) to record the MAP. The MAP amplitude and APD90 were measured at a resting sinus rhythm (heart rate of 30-42 bpm) and at pacing cycle lengths (PCL) of 1000 and 600 ms. The effective refractory period (ERP) was determined at PCL of 1000 and 600 ms. Results: The overall mean (+/- SD) APD90 (rest), APD90 (1000) and APD90 (600) were 263 +/- 39 ms, 262 +/- 41 ms, 236 +/- 47 ms for the RA and 467 +/- 23 ms, 412 +/- 38 ms, 322 +/- 29 ms for the RV. The mean ERP1000 and ERP600 were 273 +/- 24 ms and 256 +/- 22 ms for the RA and 386 +/- 40 ms and 293 +/- 30 ms for the RV. The measurement variability for the amplitude, APD90 and ERP measurements in the RA ranged between 36 and 44, 9-22 and 7-8%, respectively. The measurement variability for the amplitude, APD90 and ERP measurements in the RV ranged between 49 and 66, 6-7 and 10-12%, respectively. Conclusions: RA and RV MAP duration and ERP can be obtained by a contact electrode in standing non-sedated horses. The measurement variability varies with catheter location.

Aims This study aims to determine the degree and mechanisms of endo-epicardial dissociation of electrical activity during atrial fibrillation (AF) and endo-epicardial differences in atrial electrophysiology at different stages of atrial remodelling. Methods and results Simultaneous high-density endo-epicardial mapping of AF was performed on left atrial free walls of goats with acute AF, after 3 weeks, and after 6 months of AF (all n = 7). Endo-epicardial activation time differences and differences in the direction of conduction vectors were calculated, endocardial and epicardial effective refractory periods (ERP) were determined, and fractionation of electrograms was quantified. Histograms of endo-epicardial activation time differences and differences in the direction of conduction vectors revealed two distinct populations, i.e. dissociated and non-dissociated activity. Dyssynchronous activity (dissociated in time) increased from 17 +/- 7% during acute AF to 39 +/- 17% after 3 weeks, and 68 +/- 13% after 6 months of AF. Dissociation was more pronounced in thicker parts of the atrial wall (thick: 49.3 +/- 21.4%, thin: 42.2 +/- 19.0%, P

Background Moderate exercise training has been shown to decrease sudden cardiac death post myocardial infarction. However, the effects of intensive exercise are still controversial. Methods and Results Fourteen myocardial‐infarcted rats were divided into sedentary (n=8) and intensive training groups (n=6) and 18 sham control rats to sedentary (n=10) and intensive training groups (n=8). Heart rate variability was obtained at weeks 1 and 8. The inducibility of ventricular tachycardia/fibrillation was assessed in a Langendorff system. Fast Fourier transforms were applied on the recorded ventricular tachycardia/fibrillations. Training reduces low to high frequency ratio of heart rate variability at week 8 compared with that at week 1 ( P P P P ECG findings revealed an exercise‐induced ventricular fibrillation transition from a narrow, single‐peak spectrum at 17 Hz in sedentary controls to a broader range of peaks ranging from 13 to 22 Hz in the intensive training controls. Conclusions Intensive exercise in infarcted rats leads to reduced ventricular fibrillation propensity and is associated with normalization of refractoriness and intrinsic spatiotemporal electrical variations.

Amitriptyline has been reported to induce long QT syndrome in addition to Brugada syndrome. We qualitatively and quantitatively analyzed the potential of amitriptyline to induce these lethal syndromes by using the halothane-anesthetized dogs (n = 6). Amitriptyline was intravenously administered in doses of 0.1, 1 and 10 mg/kg over 10 min every 20 min, which would provide approximately 1, 10 and 100 times higher plasma concentrations than a therapeutic one, respectively. The low dose hardly altered any of the cardiovascular variables. The middle dose increased the heart rate, cardiac output and left ventricular contractility, but decreased the total peripheral vascular resistance and left ventricular end-diastolic pressure, whereas it did not alter any of the electrocardiographic variables. The high dose decreased the mean blood pressure and left ventricular contractility; suppressed atrioventricular nodal and intraventricular conduction; shortened the repolarization period without altering the J–T peak c and T peak–T end; and prolonged the effective refractory period, providing post-repolarization refractoriness in addition to the enhancement of the middle dose-induced cardiovascular effects. Thus, amitriptyline at up to 100 times its therapeutic concentration may not be associated with the onset of long QT syndrome, but may induce Brugada syndrome.

Background Diagnosis of short QT syndrome ( SQTS ) remains difficult in case of borderline QT values as often found in normal populations. Whether some shortening of refractory periods ( RP ) may help in differentiating SQTS from normal subjects is unknown. Methods and Results Atrial and right ventricular RP at the apex and right ventricular outflow tract as determined during standard electrophysiological study were compared between 16 SQTS patients ( QT c 324±24 ms) and 15 controls with similar clinical characteristics ( QT c 417±32 ms). Atrial RP were significantly shorter in SQTS compared with controls at 600‐ and 500‐ms basic cycle lengths. Baseline ventricular RP were significantly shorter in SQTS patients than in controls, both at the apex and right ventricular outflow tract and for any cycle length. Differences remained significant for RP of any subsequent extrastimulus at any cycle length and any pacing site. A cut‐off value of baseline RP SQTS . Conclusions Patients with SQTS have shorter ventricular RP than controls, both at baseline during various cycle lengths and after premature extrastimuli. A cut‐off value of 200 ms at the right ventricular outflow tract during 600‐ and 500‐ms basic cycle length may help in detecting true SQTS from normal subjects with borderline QT values.

Background We hypothesized that, compared with propofol, desflurane prolongs the antegrade accessory pathway effective refractory period (APERP) in children undergoing radiofrequency catheter ablation for Wolff-Parkinson-White (WPW) syndrome. Methods In this randomized crossover study, children aged 4.1−16.1 years undergoing radiofrequency catheter ablation for WPW syndrome were randomly divided into four groups according to the concentration of desflurane and anesthetics used in the first and the second electrophysiological studies (EPS). After induction of general anesthesia with propofol and tracheal intubation, they received one of the following regimens: 0.5 minimum alveolar concentration (MAC) desflurane (first EPS) and propofol (second EPS) (Des0.5-Prop group, n = 8); propofol (first EPS) and 0.5 MAC desflurane (second EPS) (Prop-Des0.5 group, n = 9); 1 MAC desflurane (first EPS) and propofol (second EPS) (Des1.0-Prop group, n = 10); propofol (first EPS) and 1 MAC desflurane (second EPS) (Prop-Des1.0 group, n = 9). Radiofrequency catheter ablation was performed upon completion of EPS. Sample size was determined to detect a difference in the APERP. Results Desflurane at 1.0 MAC significantly prolonged the APERP compared with propofol, but did not affect the sinoatrial conduction time, atrio-His interval or atrioventricular node effective refractory period. Supraventricular tachycardia was induced in all children receiving propofol, but not induced in 1 and 4 children receiving 0.5 MAC and 1.0 MAC desflurane, respectively. Conclusion Desflurane enhances the refractoriness and may block the electrical conduction of the atrioventricular accessory pathway, and is therefore not suitable for use in children undergoing radiofrequency catheter ablation for WPW syndrome.

What is the central question of this study? Does sensory input from peripheral mechanoreceptors determine the specific neural control of eccentric contractions? How corticospinal excitability (i.e. muscle responses to motor cortex stimulation) is affected by muscle length has never been investigated during eccentric contractions. What is the main finding and its importance? Muscle length does not influence corticospinal excitability during concentric and isometric maximal contractions, but does during eccentric maximal contractions. This indicates that neural control in eccentric contractions differs from that in concentric and isometric contractions. Neural control of eccentric contractions differs from that of concentric and isometric contractions, but no previous study has compared responses to motor cortex stimulations at long muscle lengths during such contraction types. In this study, we compared the effect of muscle length on corticospinal excitability between maximal concentric, isometric and eccentric contractions of the knee extensors. Twelve men performed 12 maximal concentric, isometric and eccentric voluntary contractions (36 contractions in total), separated by a 5 min rest between contraction types. The 12 contractions for the same contraction type were performed every 10 s, and transcranial magnetic stimulations (first eight contractions) and electrical femoral nerve stimulations (last four contractions) were superimposed alternately at 75 and 100 deg of knee flexion. Average motor evoked potential amplitude, normalized to the maximal M wave amplitude (MEP/M) and cortical silent period duration were calculated for each angle and compared among the contraction types. The MEP/M was lower (-23 and -28%, respectively) during eccentric than both concentric and isometric contractions at 75 deg, but similar between contraction types at 100 deg (P 0.05). The cortical silent period duration was shorter (-12 and -10%, respectively) during eccentric than both concentric and isometric contractions at 75 deg, but longer (+11 and +9%, respectively) during eccentric contractions at 100 deg (P 0.05). These results show that corticospinal excitability during eccentric contractions is angle dependent such that cortical inhibitory processes are greater with no alteration of corticospinal excitability at 100 deg, whereas this control is reversed at 75 deg.

Background Although atrial fibrillation ( AF ) is the most common abnormal heart rhythm and its prevalence continues to rise, there is a marked paucity of effective and safe antiarrhythmic drugs for AF . This study was done to test whether combined use of dofetilide and mexiletine exhibits not only a synergistic effect on AF suppression but also a safer profile in drug‐induced ventricular proarrhythmias. Methods and Results The effects of dofetilide plus mexiletine on atrial effective refractory period ( ERP ), AF inducibility, QT , and QT ‐related ventricular arrhythmias were studied using the isolated arterially perfused rabbit atrial and ventricular wedge preparations. Dofetilide or mexiletine alone mildly to moderately prolonged atrial ERP , but their combined use produced a markedly rate‐dependent increase in atrial ERP . Dofetilide (3 nmol/L) plus mexiletine (10 μmol/L) increased the ERP by 28.2% from 72.2±5.7 to 92.8±5.9 ms (n=9, P P AF inducibility. On the other hand, dofetilide at 10 nmol/L produced marked QT and T p‐e prolongation, steeper QT ‐ BCL and T p‐e ‐ BCL slopes, and induced early afterdepolarizations and torsade de pointes in the ventricular wedges. Mexiletine at 10 μmol/L reduced dofetilide‐induced QT and T p‐e prolongation, QT ‐ BCL and T p‐e ‐ BCL slopes, and abolished early afterdepolarizations and torsade de pointes. Conclusions In rabbits, combined use of dofetilide and mexiletine not only synergistically increases atrial ERP and effectively suppresses AF inducibility, but also markedly reduces QT liability and torsade de pointes risk posed by dofetilide alone.

Introduction: The gain-of-function mutations that underlie sodium channel myotonia(SCM) and paramyotonia congenita(PMC) produce differing clinical phenotypes. We used muscle velocity recovery cycles (MVRCs) to investigate membrane properties. Methods: MVRCs and responses to trains of stimuli were compared in patients with SCM (n=9), PMC (N=8), and normal controls (n=26). Results: The muscle relative refractory period was reduced in SCM, consistent with faster recovery of the mutant sodium channels from inactivation. Both SCM and PMC showed an increased early supernormality, and increased mean supernormality following multiple conditioning stimuli, consistent with slowed sodium channel inactivation. Trains of fast impulses caused a loss of amplitude in PMC, after which only half of the muscle fibres recovered, suggesting that the remainder stayed depolarized by persistent sodium currents. Discussion: The differing effects of mutations on sodium channel function can be demonstrated in human subjects in vivo using this technique. This article is protected by copyright. All rights reserved.

Axonal excitability measures give insight into the biophysical properties of peripheral nerve axons. In this study we applied these techniques to the study of facial palsy.Thirty patients with established facial palsy due to unresolved Bell's palsy or herpes zoster (6 months duration), tumor invasion of the facial nerve, or traumatic facial nerve injury were assessed using facial nerve excitability techniques.Full recordings were obtained in 23 patients (15 unrecovered Bell's palsy or herpes zoster, 5 trauma, 3 tumor-related). Compared with normal controls, the facial palsy group demonstrated changes in stimulus response properties, threshold electrotonus, refractoriness, superexcitability, and I/V slope. Depolarizing threshold electrotonus distinguished between viral and non-viral etiologies on subgroup analysis.In this cross-sectional study, established facial palsy demonstrated findings similar to those seen in studies of regenerated axons. The improved understanding of underlying axonal characteristics offered by the technique may guide future treatment. Muscle Nerve 57: 268-272, 2018.

The contractile function of skeletal muscle declines during intense or prolonged physical exercise, that is, fatigue develops. Skeletal muscle fibers fatigue acutely during highly intense exercise when they have to rely on anaerobic metabolism. Early stages of fatigue involve impaired myofibrillar function, whereas decreased Ca(2+) release from the sarcoplasmic reticulum (SR) becomes more important in later stages. SR Ca(2+) release can also become reduced with more prolonged, lower intensity exercise, and it is then related to glycogen depletion. Increased reactive oxygen/nitrogen species can cause long-lasting impairments in SR Ca(2+) release resulting in a prolonged force depression after exercise. In this article, we discuss molecular and cellular mechanisms of the above fatigue-induced changes, with special focus on multiple mechanisms to decrease SR Ca(2+) release to avoid energy depletion and preserve muscle fiber integrity. We also discuss fatigue-related effects of exercise-induced Ca(2+) fluxes over the sarcolemma and between the cytoplasm and mitochondria.

Aims The primary goal in the treatment of symptomatic atrial fibrillation/flutter (AF) is to restore sinus rhythm by cardioversion. Electrical shocks are highly effective, but have to be applied under analgo-sedation and can further harm the heart. In order to develop a novel pain-free and less harmful approach, we explored herein the optogenetic cardioversion by light-induced depolarization. Methods and results Hearts from mice expressing Channelrhodopsin-2 (ChR2) and the AF-promoting loss-of-function Connexin 40 Ala96Ser mutation were explanted and perfused with low K+ Tyrode's solution and an atrial KATP-channel activator. This new protocol shortened atrial refractoriness as well as slowed atrial conduction and thereby enabled the induction of sustained AF. AF episodes could be terminated by epicardial illumination of the atria with focussed blue light (470 nm, 0.4 mW/mm2) with an efficacy of ∼97% (n = 17 hearts). In > 80% of cases, light directly terminated the AF episode with onset of illumination. Because similar illumination intensity was able to locally inhibit atrial activity, we propose that a light-induced block of electrical activity is responsible for reliable AF termination. The success rate was strongly depending on the illuminated area, applied light intensity and duration of illumination. Importantly, we were also able to demonstrate optogenetic termination of AF in vivo, using epicardial illumination through the open chest (n = 3 hearts). To point towards a translational potential, we systemically injected an adeno-associated virus to express ChR2 in wild type hearts. After 6-8 months, we found robust ChR2 expression in the atria, enabling light-mediated AF termination in six of seven mice tested. Conclusion We provide the first evidence for optogenetic termination of atrial tachyarrhythmia in intact hearts from transgenic as well as wild type mice ex and in vivo. Thus, this report could lay the foundation for the development of implantable devices for pain-free termination of AF.

Sensory organs are thought to sample the environment rhythmically thereby providing periodic perceptual input. Whisking and sniffing are governed by oscillators which impose rhythms on the motor-control of sensory acquisition and consequently on sensory input. Saccadic eye movements are the main visual sampling mechanism in primates, and were suggested to constitute part of such a rhythmic exploration system. In this study we characterized saccadic rhythmicity, and examined whether it is consistent with autonomous oscillatory generator or with self-paced generation. Eye movements were tracked while observers were either free-viewing a movie or fixating a static stimulus. We inspected the temporal dynamics of exploratory and fixational saccades and quantified their first-order and high-order dependencies. Data were analyzed using methods derived from spike-train analysis, and tested against mathematical models and simulations. The findings show that saccade timings are explained by first-order dependencies, specifically by their refractory period. Saccade-timings are inconsistent with an autonomous pace-maker but are consistent with a “self-paced” generator, where each saccade is a link in a chain of neural processes that depend on the outcome of the saccade itself. We propose a mathematical model parsimoniously capturing various facets of saccade-timings, and suggest a possible neural mechanism producing the observed dynamics.

The I(f) channel inhibitor ivabradine is recommended for treatment of heart failure but also affects potassium currents and thereby prolongs ventricular repolarization. The aim of this study was to examine the electrophysiological effects of ivabradine on digitalis-induced ventricular arrhythmias. Thirteen rabbit hearts were isolated and Langendorff-perfused. After obtaining baseline data, the digitalis glycoside ouabain was infused (0.2 μM). Monophasic action potentials and ECG showed a significant abbreviation of QT interval (-34 ms, p < 0.05) and action potential duration (APD90 ; -27 ms, p < 0.05). The shortening of ventricular repolarization was accompanied by a reduction in effective refractory period (ERP; -27 ms, p < 0.05). Thereafter, hearts were additionally treated with ivabradine (5 μM). Of note, this did not exert significant effects on QT interval (-4 ms, p = ns) or APD90 (-15 ms, p = ns) but resulted in an increase in ERP (+17 ms, p < 0.05). This led to a significant increase in post-repolarization refractoriness (PRR, +32 ms, p < 0.01) as compared with sole ouabain treatment. Under baseline conditions, ventricular fibrillation (VF) was inducible by a standardized pacing protocol including programmed stimulation and burst stimulation in four of 13 hearts (31%; 15 episodes). After application of 0.2 μM ouabain, eight of 13 hearts were inducible (62%, 49 episodes). Additional infusion of 5 μM ivabradine led to a significant suppression of VF. Only four episodes could be induced in two of 13 hearts (15%). In this study, ivabradine reduced digitalis-induced ventricular arrhythmias. Ivabradine did not affect ventricular repolarization in the presence of digitalis treatment but demonstrated potent anti-arrhythmic properties based on an increase in both ERP and PRR. The study further characterizes the beneficial electrophysiological profile of ivabradine.

Changes in nerve conduction velocity following an impulse (i.e. velocity recovery cycles) reflect after-potentials, and can provide an indication of altered nerve membrane properties. This study used microneurography to assess the effects of ischaemia on single human sympathetic fibres innervating the dorsum of the foot. It was found that velocity recovery cycles can distinguish whether a sympathetic nerve fibre is depolarized or not. The method may be used to detect membrane depolarization of sympathetic nerve fibres in human patients when autonomic neuropathy is suspected.The aim of this study was to determine whether velocity recovery cycles (VRCs) could detect the effects of ischaemia on sympathetic nerve fibres. VRCs of human sympathetic nerve fibres of the superficial peroneal nerve innervating the dorsum of the foot were recorded by microneurography in seven healthy volunteers. Sympathetic nerve fibres were identified by studying their response to manoeuvres increasing sympathetic outflow and by measuring activity-dependent slowing at 2 Hz stimulation. VRCs were assessed at rest, during 30 min of induced limb ischaemia and during 20 min of recovery after ischaemia. From each VRC was measured the relative refractory period (RRP), the supernormality and the time to peak supernormality (SN@). During ischaemia, RRP increased from the baseline value of 37.4 ± 8.7 ms (mean ± SEM) to 67.1 ± 12.1 ms (P 0.01) and SN@ increased from 68.6 ± 9.8 ms to 133.8 ± 11.0 ms (P 0.005). The difference between SN@ and RRP separated ischaemic from non-ischaemic sympathetic nerve fibres. It is concluded that these sympathetic nerve fibres are sensitive to ischaemia, and that VRCs provide a method to study changes of axonal membrane potential of human sympathetic nerve fibres in vivo.

Refractory period (RP) plays a central role in neural signaling. Because it limits an excitable membrane's recovery time from a previous excitation, it can restrict information transmission. Classically, RP means the recovery time from an action potential (spike), and its impact to encoding has been mostly studied in spiking neurons. However, many sensory neurons do not communicate with spikes but convey information by graded potential changes. In these systems, RP can arise as an intrinsic property of their quantal micro/nanodomain sampling events, as recently revealed for quantum bumps (single photon responses) in microvillar photoreceptors. Whilst RP is directly unobservable and hard to measure, masked by the graded macroscopic response that integrates numerous quantal events, modeling can uncover its role in encoding. Here, we investigate computationally how RP can affect encoding of graded neural responses. Simulations in a simple stochastic process model for a fly photoreceptor elucidate how RP can profoundly contribute to nonlinear gain control to achieve a large dynamic range. [Abstract copyright: © 2017 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.]

In heart failure (HF), dysregulated cardiac ryanodine receptors (RyR2) contribute to the generation of diastolic Ca2+ waves (DCWs), thereby predisposing adrenergically stressed failing hearts to life-threatening arrhythmias. However, the specific cellular, subcellular, and molecular defects that account for cardiac arrhythmia in HF remain to be elucidated. Patch-clamp techniques and confocal Ca2+ imaging were applied to study spatially defined Ca2+ handling in ventricular myocytes isolated from normal (control) and failing canine hearts. Based on their activation time upon electrical stimulation, Ca2+ release sites were categorized as coupled, located in close proximity to the sarcolemmal Ca2+ channels, and uncoupled, the Ca2+ channel-free non-junctional Ca2+ release units. In control myocytes, stimulation of β-adrenergic receptors with isoproterenol (Iso) resulted in a preferential increase in Ca2+ spark rate at uncoupled sites. This site-specific effect of Iso was eliminated by the phosphatase inhibitor okadaic acid, which caused similar facilitation of Ca2+ sparks at coupled and uncoupled sites. Iso-challenged HF myocytes exhibited increased predisposition to DCWs compared to control myocytes. In addition, the overall frequency of Ca2+ sparks was increased in HF cells due to preferential stimulation of coupled sites. Furthermore, coupled sites exhibited accelerated recovery from functional refractoriness in HF myocytes compared to control myocytes. Spatially resolved subcellular Ca2+ mapping revealed that DCWs predominantly originated from coupled sites. Inhibition of CaMK∏ suppressed DCWs and prevented preferential stimulation of coupled sites in Iso-challenged HF myocytes. These results suggest that CaMK∏-(and phosphatase)-dependent dysregulation of junctional Ca2+ release sites contributes to Ca2+-dependent arrhythmogenesis in HF.

Na+ channel blockers flecainide and quinidine can increase propensity to ventricular tachyarrhythmia, whereas lidocaine and mexiletine are recognized as safe antiarrhythmics. Clinically, ventricular fibrillation is often precipitated by transient tachycardia that reduces action potential duration, suggesting that a critical shortening of the excitation wavelength (EW) may contribute to the arrhythmic substrate. This study examined whether different INa blockers can produce contrasting effects on the rate adaptation of the EW, which would explain the difference in their safety profile. In perfused guinea-pig hearts, effective refractory periods (ERP), conduction times, and EW values were determined over a wide range of cardiac pacing intervals. All INa blockers tested were found to flatten the slope of ERP restitution, indicating antiarrhythmic tendency. However, with flecainide and quinidine, the beneficial changes in ERP were reversed owing to the use-dependent conduction slowing, thereby leading to significantly steepened restitution of the EW. In contrast, lidocaine and mexiletine had no effect on ventricular conduction, and therefore reduced the slope of the EW restitution, as expected from their effect on ERP. These findings suggest that the slope of the EW restitution is an important electrophysiological determinant which can discriminate INa blockers with proarrhythmic and antiarrhythmic profile.

Supplemental Digital Content is available in the text., Background Evidence has emerged that small-conductance Ca2+-activated K+ (SK) channels constitute a new target for treatment of atrial fibrillation (AF). SK channels are predominantly expressed in the atria as compared with the ventricles. Various marketed antiarrhythmic drugs are limited by ventricular adverse effects and efficacy loss as AF progresses. Methods and Results A total of 43 pigs were used for the studies. AF reversion in conscious long-term tachypaced pigs: Pigs were subjected to atrial tachypacing (7 Hz) until they developed sustained AF that could not be reverted by vernakalant 4 mg/kg (18.8±3.3 days of atrial tachypacing). When the SK channel inhibitor AP14145 was tested in these animals, vernakalant-resistant AF was reverted to sinus rhythm, and reinduction of AF by burst pacing (50 Hz) was prevented in 8 of 8 pigs. Effects on refractory period and AF duration in open chest pigs: The effects of AP14145 and vernakalant on the effective refractory periods and acute burst pacing-induced AF were examined in anaesthetized open chest pigs. Both vernakalant and AP14145 significantly prolonged atrial refractoriness and reduced AF duration without affecting the ventricular refractoriness or blood pressure in pigs subjected to 7 days atrial tachypacing, as well as in sham-operated control pigs. Conclusions SK currents play a role in porcine atrial repolarization, and pharmacological inhibition of these with AP14145 demonstrates antiarrhythmic effects in a vernakalant-resistant porcine model of AF. These results suggest SK channel blockers as potentially interesting anti-AF drugs.

Introduction The antihistaminic antazoline (ANT) was reported to be highly effective and safe for rapid conversion of atrial fibrillation (AF). We therefore analyzed underlying mechanisms in an experimental whole-heart model. Methods and Results Isolated and retrogradely perfused rabbit hearts underwent a standardized protocol employing atrial burst pacing induced AF in 5 of 20 hearts under baseline conditions (7 episodes). Thereafter, a combination of acetylcholine and isoproterenol was employed to enhance AF occurrence. Two monophasic action potential recordings on the left- and two on the right atrial epicardium showed a decrease of atrial action potential duration (aAPD, -25ms, p

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.

Aims The aim of this study was to investigate the role of gap junctions in atrial fibrillation (AF) by analysing the effects of a gap junction enhancer and blocker on AF vulnerability and electrophysiological properties of isolated hearts. Methods and results The acute atrial stretch model of AF in the isolated rabbit heart was used. Sustained AF (SAF) was induced by a burst of high-frequency stimulation of the Bachmann's bundle. The effective refractory period (ERP) was measured, and the total conduction time (TCT) and the pattern of conduction of the anterior surface of the left atrium were monitored by using an optical mapping system. The effect of enhancing gap junction function by 100–1000 nM rotigaptide (ZP123) and block by 30 μM carbenoxolone on these parameters was measured. SAF inducibility was increased with an elevation of intra-atrial pressure. Enhanced gap junction conductance induced by treatment with 100–1000 nM rotigaptide reduced SAF inducibility, and the gap junction blocker carbenoxolone increased SAF inducibility. In the absence of gap junction enhancer or blocker, normal conduction was observed at 0 cmH2O. When intra-atrial pressure was raised to 12 cmH2O, the conduction pattern was changed to a heterogeneous zig-zag pattern and TCT was prolonged. Conduction pattern was not affected by either agent. Rotigaptide shortened TCT, whereas carbenoxolone prolonged TCT. ERP was significantly shortened with an increase in intra-atrial pressure, but ERP was unaffected by either agent. Conclusion Gap junction modulators changed AF inducibility through their effects on atrial conduction, not by altering ERP.

Background The therapeutic mechanisms of deep brain stimulations (DBS) are not fully understood. Axonal block induced by high frequency stimulation (HFS) has been suggested as one possible underlying mechanism of DBS. Objective To investigate the mechanism of the generation of HFS-induced axonal block. Methods High frequency pulse trains were applied to the fiber tracts of alveus and Schaffer collaterals in the hippocampal CA1 neurons in anaesthetized rats at 50, 100 and 200 Hz. The amplitude changes of antidromic-evoked population spikes (APS) were measured to determine the degree of axonal block. The amplitude ratio of paired-pulse evoked APS was used to assess the changes of refractory period. Results There were two distinct recovery stages of axonal block following the termination of HFS. One frequency-dependent faster phase followed by another frequency-independent slower phase. Experiments with specially designed temporal patterns of stimulation showed that HFS produced an extension of the duration of axonal refractory period thereby causing a fast recovery phase of the axonal block. Thus, prolonged gaps inserted within HFS trains could eliminate the axonal block and induced large population spikes and even epileptiform activity in the upstream or downstream regions. Conclusions Extension of refractory period plays an important role on HFS induced axonal block. Stimulation pattern with properly designed pauses could be beneficial for different requirements of excitation or inhibition in DBS therapies.

Introduction: High intensity cutaneous stimulus transiently suppresses tonic voluntary muscle activity resulting in cutaneous silent period (CSP). Aim: The aim of our study was to evaluate the normal values of an onset latency L1, a late latency L2 and a duration of CSP after stimulating sensory fibres of the median nerve. Material and Methods: This prospective study was performed at the Neurology Department, Clinical Center of Sarajevo University in period from January 1st 2013 to December 1st 2013. In our study we examined 61 subjects. The group included our relatives, coworkers and friends. The informed consent from testing subjects was obtained. Results: The origin of silent period is stimulation of small A-delta nerve fibres. The pre-synaptic or post-synaptic interruption of the electrical volley to motor neurons is discussed. Median values of muscle activity suppression in healthy female is 55.0 ms (45.0-74.0) and 59.0 ms (52.0-67) male subjects. There is a correlation between the onset latency L1and the late L2 latency (p‹0.03). In the on-going study it seems that delay of L1 and shorter muscle activity suppression might provide a sign of small nerve fibres involvement. Conclusion: The use of CSP improves the value of neurophysiology examination.

Aims Emerging evidences indicate that SCN10A /NaV1.8 is associated with cardiac conduction and atrial fibrillation, but the exact role of NaV1.8 in cardiac electrophysiology remains poorly understood. The present study was designed to investigate the effects of blocking NaV1.8 channels in cardiac ganglionated plexi (GP) on modulating cardiac conduction and atrial fibrillation inducibility in the canine model. Methods and results Thirteen mongrel dogs were randomly enrolled. Right cervical vagus nerve stimulation (VNS) was applied to determine its effects on the sinus rate, ventricular rate during atrial fibrillation, PR interval, atrial effective refractory period, and the cumulative window of vulnerability. The NaV1.8 blocker A-803467 (1 μmol/0.5 mL per GP, n = 7) or 5% DMSO/95% polyethylene glycol (0.5 mL per GP, n = 6, control) was injected into the anterior right GP and the inferior right GP. The effects of VNS on the sinus rate, ventricular rate, PR interval, atrial effective refractory period, and the cumulative window of vulnerability were significantly eliminated at 10, 35, and 90 min after A-803467 injection. In separate experiments ( n = 8), A-803467 blunted the slowing of sinus rate with increasing stimulation voltage of the anterior right GP at 10 min after local injection. Conclusions Blockade of NaV1.8 channels suppresses the effects of VNS on cardiac conduction and atrial fibrillation inducibility, most likely by inhibiting the neural activity of the cardiac GP.

Aims Studies have shown that stellate ganglion nerve activity has association with atrial electrical remodelling and atrial fibrillation (AF) inducibility, while median nerve stimulation (MNS) decreases cardiac sympathetic drive. In this study, we tested the hypothesis that MNS suppresses atrial electrical remodelling and AF vulnerability. Methods and results The atrial effective refractory period (AERP) and AF inducibility at baseline and after 3 h of rapid atrial pacing were determined in dogs undergoing MNS (n = 7), MNS+ application of methyllycaconitine (n = 7) or sham procedure (n = 6). Then, the levels of tumour necrosis factor-alpha (TNF-a), interleukin-6 (IL-6), and acetylcholine (Ach) in the plasma and atrial tissues were measured. The control dogs (n = 4) were assigned to measure atrial inflammation cytokines. Short-term rapid atrial pacing induced shortening of the AERP, an increase in AERP dispersion, and an increase AF vulnerability in the sham dogs, which were all suppressed by MNS. Levels of TNF-a and IL-6 were higher, and Ach levels were lower in the left and the right atrium in the sham dogs than in the MNS dogs. Methyllycaconitine blunted the effects of MNS on the AERP, AERP dispersion, the AF vulnerability, and TNF-a and IL-6 levels in the atrium, but had no impact on the levels of Ach. Conclusions The effects of MNS on atrial electrical remodelling and AF inducibility might be associated with the cholinergic anti-inflammatory pathway.

To understand the strategies used by the brain to analyze complex environments, we must first characterize how the features of sensory stimuli are encoded in the spiking of neuronal populations. Characterizing a population code requires identifying the temporal precision of spiking and the extent to which spiking is correlated, both between cells and over time. In this study, we characterize the population code for speech in the gerbil inferior colliculus (IC), the hub of the auditory system where inputs from parallel brainstem pathways are integrated for transmission to the cortex. We find that IC spike trains can carry information about speech with sub-millisecond precision, and, consequently, that the temporal correlations imposed by refractoriness can play a significant role in shaping spike patterns. We also find that, in contrast to most other brain areas, the noise correlations between IC cells are extremely weak, indicating that spiking in the population is conditionally independent. These results demonstrate that the problem of understanding the population coding of speech can be reduced to the problem of understanding the stimulus-driven spiking of individual cells, suggesting that a comprehensive model of the subcortical processing of speech may be attainable in the near future.

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.

Summary Background Ranolazine is evaluated for antiarrhythmic therapy of atrial fibrillation (AF). The electrophysiologic mechanisms of ranolazine in combination with class III drugs were studied in an isolated whole-heart model of stretch-related AF. Methods and Results Thirty rabbits were fed with amiodarone (50 mg/kg/day, n = 10), dronedarone (50 mg/kg/day, n = 10), or placebo (n = 10) for 6 weeks. Subsequently, in isolated hearts, AF was induced by high-rate atrial pacing and acute atrial dilatation. In placebo-treated hearts, d,l-sotalol (50 μM) was acutely administered. Ranolazine (10 μM) was additionally infused in all groups. Chronic amiodarone (+26 ± 7 ms, P

ObjectiveThe 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.MethodsDomestic 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.ResultsOver a range of ERPs from 75 to 250 ms, the probability of AF was correlated with increasing tissue area (range, 19.5-105 cm2) and decreasing ERP. Logistic regression analysis identified shorter ERP (P

Exaggerated dispersion of repolarization is likely to play a role in both the initiation and the maintenance of malignant ventricular arrhythmias. It was proposed that the inter-lead QT interval differences within a 12-lead ECG termed 'QT dispersion' might reflect regional differences in myocardial refractoriness, and that this might predict cardiac dysrhythmias.The study aimed to perform a meta-analysis of the relevant available publications.A MEDLINE search from 1990 to 2012 at PubMed (NLM) was performed. An all-fields search for index terms 'QT dispersion' and 'anxiety' was done. Case-control studies and surveys were included in the analysis provided they encompassed physically healthy subjects who had been evaluated for anxiety disorders with validated inventories. Outcome measures were either crude or heart rate-corrected QT dispersions.Five studies were included in the analysis, which encompassed 580 patients with calculated mean age of 36.8 years (standard error = 5.5). The values of crude and heart rate-corrected QT dispersions across the studies were statistically significantly higher in the patients with anxiety disorders. Crude values of QT dispersion were available in 164 patients with anxiety and in 273 controls. Summarized standardized difference in the means (random effect model) was equal to 1.472 (95% confidence interval: 1.034-1.911). Heart rate-corrected QT dispersion values were available in 193 patients with anxiety and in 282 controls, and the summarized standardized difference in the means was equal to 3.299 (95% confidence interval: 1.215-5.384).High anxiety is associated with increased QT dispersion, which may predispose to cardiac arrhythmias.

G protein-coupled inwardly rectifying K⁺ channels (GIRK) are important in the regulation of heart rate and atrial electrophysiology. GIRK channels are activated by G protein-coupled receptors, including muscarinic M₂ receptors and adenosine A₁ receptors. The aim of this study was to characterize and compare the electrophysiological effects of acetylcholine (ACh) and adenosine on GIRK channels in rat atria. Action potential duration at 90% repolarization (APD₉₀), effective refractory period (ERP), and resting membrane potential (RMP) were investigated in isolated rat atria by intracellular recordings. Both the adenosine analog N6-cyclopentyladenosine (CPA) and ACh profoundly shortened APD₉₀ and ERP and hyperpolarized the RMP. No additive or synergistic effect of CPA and ACh coapplication was observed. To antagonize GIRK channel activation, the specific inhibitor rTertiapin Q (TTQ) was applied. The coapplication of TTQ reversed the CPA and ACh-induced effects. When TTQ was applied without exogenous receptor activator, both APD₉₀ and ERP were prolonged and RMP was depolarized, confirming a basal activity of the GIRK current. The results reveal that activation of A₁ and M₂ receptors has a profound and equal effect on the electrophysiology in rat atrium. This effect is to a major extent mediated through GIRK channels. Furthermore, these results support the notion that atrial GIRK currents from healthy hearts have a basal component and additional activation can be mediated via at least 2 different receptor mechanisms.

Background— Myocardial infarction (MI) is associated with the development of atrial fibrillation (AF). We aimed to characterize the atrial abnormalities because of MI and determine the role of ischemia to the AF substrate. Methods and Results— Forty-four sheep were studied. MI was induced by occlusion of the left circumflex artery (LCX) or left anterior descending artery (LAD). Excluding 11 with fatal arrhythmias, equal groups of animals (LCX; LAD; and sham-operated) underwent sequential electrophysiology study for 45 minutes to determine atrial effective refractory periods, conduction velocity, conduction heterogeneity index, and AF inducibility. Postmortem evaluation was performed with 2,3,5 triphenyl tetrazolium chloride staining. MI resulted in greater left ventricular dysfunction ( P P P P P P P P P P P P Conclusions— Left ventricular infarction, which is known to result in atrial stretch, hemodynamic change, and neurohumoral activation, contributes partially to the atrial abnormalities in MI. Atrial ischemia/infarction results in greater atrial electrophysiological changes and propensity for AF forming the dominant substrate for AF in MI.