Shortening Of Effective Refractory Period Research Articles

Risk of Malignant Arrhythmias in Initially Symptomatic Patients With Wolff-Parkinson-White Syndrome

Background— The available amount of detailed long-term data in patients with Wolff-Parkinson-White syndrome is limited, and no prospective electrophysiological studies looking at predictors of malignant arrhythmia are available. Methods and Results— Among 8575 symptomatic Wolff-Parkinson-White patients with atrioventricular reentrant tachycardia referred for electrophysiological test, 369 (mean age, 23±12.5 years) declined catheter ablation and were followed up. The primary end point of the study was to evaluate over a 5-year follow-up the predictors and characteristics of patients who develop malignant arrhythmias. After a mean follow-up of 42.1±10 months, malignant arrhythmias developed in 29 patients (mean age, 13.9±5.6 years; 26 male), resulting in presyncope/syncope (25 patients), hemodynamic collapse (3 patients), or cardiac arrest caused by ventricular fibrillation (1 patient). Of the remaining 340 patients, 168 (mean age, 34.2±9.0 years) remained asymptomatic up to 5 years, and 172 (mean age, 13.6±5.1 years) had benign recurrence, including sustained atrioventricular reentrant tachycardia (132 patients) or atrial fibrillation (40 patients). Compared with the group with no malignant arrhythmias, the group with malignant arrhythmias showed shorter accessory-pathway effective refractory period ( P <0.001) and more often exhibited multiple accessory pathways ( P <0.001), and atrioventricular reentrant tachycardia triggering sustained pre-excited atrial fibrillation was more frequently inducible ( P <0.001). Multivariable analysis demonstrated that short accessory-pathway effective refractory period ( P <0.001) and atrioventricular reentrant tachycardia triggering sustained pre-excited atrial fibrillation ( P <0.001) were independent predictors of malignant arrhythmias. Conclusions— Symptomatic patients with Wolff-Parkinson-White syndrome generally have a good outcome, and predictors of malignant arrhythmias are similar to those reported for asymptomatic patients with ventricular pre-excitation.

Disease modification by autonomic nerve stimulation

v 4 o m p p r One of the arrhythmogenic mechanisms in the pathophysiology of atrial fibrillation (AF) is autonomic influence. The activation of cardiac autonomic nerves results in electrophysiological changes, causing shortening of the atrial effective refractory period and action potential duration, and spatial heterogeneity of refractoriness. Such conditions favor the initiation and maintenance of atrial tachyarrhythmias such as AF. Coumel et al reported that vagus nerve might be associated with paroxysmal AF. Studies using heart rate variability analysis have confirmed that paroxysmal AF occurrence is associated with a primary increase in adrenergic tone followed by a marked modulation toward vagal predominance. Recently, direct recording of intrinsic cardiac nerve activities in ambulatory animals revealed that the nerve activities are invariable triggers of paroxysmal AF. Neural remodeling in atrial tachyarrhythmias has been introduced by several studies. Sympathetic hyperinnervation and nerve sprouting were observed in a canine AF model. Increased atrial sympathetic innervation has also been found in patients with persistent AF. In this issue of HeartRhythm, Yu et al demonstrate the ffects of low-level superior vena cava (SVC) stimulation n neural remodeling and AF inducibility in an acute canine odel of atrial tachyarrhythmia. They placed a 10-pole ircular catheter in the SVC just below the entrance of the nnominate vein. High-frequency stimulation (20 Hz, 0.1 s of pulse duration) was applied for 3 hours with a voltage hat was 50% lower than the threshold. They found that ow-level SVC stimulation restored the neural activities at he anterior right ganglionated plexus to the baseline level nd suppressed AF inducibility.

Cardioprotective effect of dipeptidyl peptidase-4 inhibitor during ischemia–reperfusion injury

BackgroundDipeptidyl peptidase-4 (DPP-4) inhibitor is a new anti-diabetic drug for type-2 diabetes mellitus patients. Despite its benefits on glycemic control, the effects of DPP-4 inhibitor on the heart during ischemia–reperfusion (I/R) periods are not known. We investigated the effect of DPP-4 inhibitor on cardiac electrophysiology and infarct size in a clinically relevant I/R model in swine and its underlying cardioprotective mechanism. MethodsFourteen pigs were randomized to receive either DPP-4 inhibitor (vildagliptin) 50mg or normal saline intravenously prior to a 90-min left anterior descending artery occlusion, followed by a 120-min reperfusion period. The hemodynamic, cardiac electrophysiological and arrhythmic parameters, and the infarct size were determined before and during I/R. Rat cardiac mitochondria were used to study the protective effects of DPP-4 inhibitor on cardiac mitochondrial dysfunction caused by severe oxidative stress induced by H2O2 to mimic the I/R condition. ResultsCompared to the saline group, DPP-4 inhibitor attenuated the shortening of the effective refractory period (ERP), decreased the number of PVCs, increased the ventricular fibrillation threshold (VFT) during the ischemic period, and also decreased the infarct size. In cardiac mitochondria, DPP-4 inhibitor decreased the reactive oxygen species (ROS) production and prevented cardiac mitochondrial depolarization caused by severe oxidative stress. ConclusionsDuring I/R, DPP-4 inhibitor stabilized the cardiac electrophysiology by preventing the ERP shortening, decreasing the number of PVCs, increasing the VFT, and decreasing the infarct size. This cardioprotective effect could be due to its prevention of cardiac mitochondrial dysfunction caused by severe oxidative stress during I/R.

Fish Oil for Secondary Prevention of Atrial Fibrillation

Several epidemiological and large randomized, clinical trials carried out in the general population and in patients with cardiovascular disease have reported a significantly lower incidence of sudden cardiac death (presumably arrhythmic) with high dietary fish consumption or omega-3 polyunsaturated fatty acid (PUFA) supplements.1 This has prompted interest in exploring the antiarrhythmic potential of PUFAs in patients at particularly high risk of sudden arrhythmic death (ie, patients with internal cardioverter-defibrillators for secondary prevention), but the results were unexpectedly disappointing: the meta-analysis of the controlled studies failed to show any benefit from treatment with PUFAs.2 At about the same time, a proof-of-concept open-label study demonstrated a remarkable 65% reduction in the occurrence of atrial fibrillation (AF) after coronary artery bypass grafting surgery,3 and the search for antiarrhythmic activity of PUFAs in atrial tachyarrhythmias has begun. Article see p 1100 Various animal models of AF, including atrial pacing, simultaneous atrioventricular pacing, vagal stimulation, cardiac surgery and sterile pericarditis, and congestive heart failure induced by ventricular tachypacing or intracoronary infusion of doxorubicin, have been used to demonstrate the effects of PUFAs on electric and structural atrial remodeling.4 In these experiments, treatment with PUFAs prevented significant shortening of the atrial effective refractory period associated with AF, reduced inducibility of AF and duration of induced AF, and attenuated atrial fibrosis although a difference in response was noted in some models (eg, lack of effect in atrial tachypacing was reported).5 Results in the clinical arena have been less consistent. Although an early open-label and a larger observational study reported a reduction in the incidence of postoperative AF,3 3 subsequent trials with a more rigorous design (double-blind, placebo-controlled) did not reproduce these results.6 Similarly, in several epidemiological analyses, high dietary-fish consumption conferred no benefit on the prevention of AF in the …

703 Biatrial ganglionated plexus ablation decreases atrial fibrillation susceptibility in a canine chronic rapid atrial pacing model

703 Biatrial ganglionated plexus ablation decreases atrial fibrillation susceptibility in a canine chronic rapid atrial pacing model

Chronic sympathetic activation promotes downregulation of β-adrenoceptor-mediated effects in the guinea pig heart independently of structural remodeling and systolic dysfunction

It is uncertain if downregulation of β-adrenoceptor signaling pathway is promoted by an enhanced adrenergic tone at an early stage of cardiac disease, or it develops secondary to detrimental local myocardial changes in advanced heart failure. We examined the integrity of β-adrenoceptor signaling pathway upon chronic infusion of isoproterenol, a β-adrenoceptor agonist, at a dose producing no structural left ventricular (LV) remodeling and systolic dysfunction. Subcutaneous isoproterenol infusion (400μgkg(-1)h(-1) over 16days) to guinea pigs using osmotic minipumps produced no change in cardiac weights, LV internal dimensions, myocyte cross-sectional area, extent of interstitial fibrosis, and basal contractile function. Isolated, perfused heart preparations from isoproterenol-treated guinea pigs exhibited attenuated responsiveness to acute β-adrenoceptor stimulation, as evidenced by reduced LV developed pressure increase, less shortening of LV epicardial monophasic action potential and effective refractory period, and less myocardial cyclic adenosine monophosphate elevation, in response to isoproterenol exposure, when compared to saline-treated controls. Pharmacological responses to forskolin, an activator of the adenylate cyclase catalytic subunit, were well preserved in isoproterenol-treated hearts. Downregulation of β-adrenoceptor-mediated effects upon chronic isoproterenol infusion was associated with markedly reduced stimulatory G-protein α-subunit (G(sα)) myocardial expression levels. No change in expression levels of β-adrenoceptors, G-protein-coupled receptor kinase 2, inhibitory G-protein α-subunit (G(iα2)), and Ca(v)1.2 and K(v)7.1 ion channels was determined in isoproterenol-treated hearts. We therefore conclude that sustained adrenergic overstimulation may promote downregulation of myocardial β-adrenoceptor-mediated effects independently of structural LV remodeling and systolic failure, an effect attributed to β-adrenoceptor uncoupling from adenylate cyclase due to reduced G(sα)-protein expression.

Combined blockade of early and late activated atrial potassium currents suppresses atrial fibrillation in a pig model of obstructive apnea

Negative tracheal pressure (NTP) during tracheal obstruction in obstructive apnea increases vagal tone and causes pronounced shortening of the atrial effective refractory period (AERP), thereby perpetuating atrial fibrillation (AF). The role of different atrial potassium channels under those conditions has not been investigated. The purpose of this study was to evaluate the atrial effects of blockade of the late activated potassium current (I(Kr)) by sotalol, of blockade of the early activated potassium currents (I(Kur)/I(to)) by AVE0118, and of the multichannel blocker amiodarone during tracheal occlusions with applied NTP. Twenty-one pigs were anesthetized, and an endotracheal tube was placed to apply NTP (up to -100 mbar) comparable to clinically observed obstructive sleep apnea for 2 minutes. Right AERP and AF inducibility were measured transvenously by a monophasic action potential recording and stimulation catheter. Tracheal occlusion with applied NTP caused pronounced AERP shortening. AF was inducible during all NTP maneuvers. Blockade of I(Kr) by sotalol, blockade of I(Kur)/I(to) by AVE0118, and amiodarone did not affect NTP-induced AERP shortening, although they prolonged the AERP during normal breathing. Atropine given after amiodarone completely inhibited NTP-induced AERP shortening. The combined blockade of I(Kr) and I(Kur)/I(to) by sotalol plus AVE0118, however, attenuated NTP-induced AERP shortening and AF inducibility independent of the order of administration. The atrial proarrhythmic effect of NTP simulating obstructive apneas is difficult to inhibit by class III antiarrhythmic drugs. Neither amiodarone nor blockade of I(Kr) or I(Kur)/I(to) attenuated NTP-induced AERP shortening. However, the combined blockade of I(Kur)/I(to) and I(Kr) suppressed NTP-induced AERP shortening.

Targeted nonviral gene-based inhibition of Gαi/o-mediated vagal signaling in the posterior left atrium decreases vagal-induced atrial fibrillation

Pharmacologic and ablative therapies for atrial fibrillation (AF) have suboptimal efficacy. Newer gene-based approaches that target specific mechanisms underlying AF are likely to be more efficacious in treating AF. Parasympathetic signaling appears to be an important contributor to AF substrate. The purpose of this study was to develop a nonviral gene-based strategy to selectively inhibit vagal signaling in the left atrium and thereby suppress vagal-induced AF. In eight dogs, plasmid DNA vectors (minigenes) expressing Gα(i) C-terminal peptide (Gα(i)ctp) was injected in the posterior left atrium either alone or in combination with minigene expressing Gα(o)ctp, followed by electroporation. In five control dogs, minigene expressing scrambled peptide (Gα(R)ctp) was injected. Vagal- and carbachol-induced left atrial effective refractory periods (ERPs), AF inducibility, and Gα(i/o)ctp expression were assessed 3 days following minigene delivery. Vagal stimulation- and carbachol-induced effective refractory period shortening and AF inducibility were significantly attenuated in atria receiving a Gα(i2)ctp-expressing minigene and were nearly eliminated in atria receiving both Gα(i2)ctp- and Gα(o1)ctp-expressing minigenes. Inhibition of both G(i) and G(o) proteins is necessary to abrogate vagal-induced AF in the left atrium and can be achieved via constitutive expression of Gα(i/o)ctps expressed by nonviral plasmid vectors delivered to the posterior left atrium.

Electroanatomic Properties of the Pulmonary Veins: Slowed Conduction, Low Voltage and Altered Refractoriness in AF Patients

Rapid PV activity is critical in initiating and maintaining AF. The underlying substrate responsible for this remains uncertain. We sought to identify if patients with paroxysmal (PAF) and persistent atrial fibrillation (PeAF) have an abnormal substrate within the pulmonary veins (PVs). Thirty-nine patients with AF (21 PAF, 18 PeAF) were compared with 15 age-matched controls with left-sided accessory pathways (AVRT). High-density 3D electroanatomic maps of the PVs were created. PV voltage, conduction, PV muscle sleeve length, effective refractory periods (ERPs) of the PVs, posterior left atrium (PLA), left atrial appendage (LAA) and distal coronary sinus (CSd), and signal complexity were assessed. Compared with controls, the PVs of AF patients had (1) lower mean-voltage and a higher % low-voltage; (2) shorter PV muscle sleeves; (3) slower conduction; (4) shorter ERP; and (5) more prevalent complex signals. Compared with the PAF group, the PeAF group had (1) higher % low voltage; (2) slower conduction; and (3) more complex signals. In PAF patients, the PLA and LAA ERPs were longer than controls and the PV ERP was shorter than controls; in PeAF patients PLA and LAA ERPs were reduced, but to a lesser extent than in the PVs. AF induction occurred during PV ERP testing in both AF groups, but not controls. PAF and PeAF patients demonstrate electrical and electroanatomic remodeling of the PVs compared to control patients without prior AF. Some of these changes were more marked in PeAF.

The influence of the neuropeptide galanin on the contractility and the effective refractory period of guinea-pig heart papillary muscle under normoxic and hypoxic conditions.

The aim of this study was to discover the effects of galanin, a neuropeptide comprising 29 amino acids capable of activating inward-rectifier K+ channels (IK1) in cardiomyocytes, on the force of contraction (Fc), velocity of contraction (+dF/dt), velocity of relaxation (-dF/dt) and effective refractory period (ERP) of guinea-pig heart. The influence of galanin on the time-course of hypoxia-induced disturbances in contractility and ERP was also examined. Experiments were performed on the isolated right ventricle papillary muscle of guinea-pig heart. In the concentration range 0.001-0.01 microM, galanin had no significant effect on the measured parameters. At 0.03 and 0.1 microM, galanin exerted a positive inotropic action and prolonged ERP. Further increasing the concentration led to a negative inotropic action and significant shortening of ERP. Although simulated hypoxia induced a significant drop in Fc, +dF/dt and -dF/dt, and a significant shortening of ERP, recovery of all the measured parameters was complete after 10 min reperfusion. In the presence of 0.03 and 0.1 microM galanin the effect of hypoxia on the contractility of papillary muscle was more profound and reperfusion did not result in complete recovery. In contrast, addition of 1 microM galanin to the hypoxic solution significantly protected the muscle and recovery of the tissues during reperfusion was rapid and complete (in 5 min). One can conclude that galanin at lower concentrations induced a positive inotropic action and a prolongation of ERP, but increased the sensitivity of heart muscle to hypoxia. At higher concentrations however, galanin exerted a negative inotropic action but protected the muscle against hypoxia-induced disturbances in contractility.

Functional mathematical model of dual pathway AV nodal conduction

Dual atrioventricular (AV) nodal pathway physiology is described as two different wave fronts that propagate from the atria to the His bundle: one with a longer effective refractory period [fast pathway (FP)] and a second with a shorter effective refractory period [slow pathway (SP)]. By using His electrogram alternance, we have developed a mathematical model of AV conduction that incorporates dual AV nodal pathway physiology. Experiments were performed on five rabbit atrial-AV nodal preparations to develop and test the presented model. His electrogram alternances from the inferior margin of the His bundle were used to identify fast and slow wave front propagations. The ability to predict AV conduction time and the interaction between FP and SP wave fronts have been analyzed during regular and irregular atrial rhythms (e.g., atrial fibrillation). In addition, the role of dual AV nodal pathway wave fronts in the generation of Wenckebach periodicities has been illustrated. Finally, AV node ablative modifications have been evaluated. The model accurately reproduced interactions between FP and SP during regular and irregular atrial pacing protocols. In all experiments, specificity and sensitivity higher than 85% were obtained in the prediction of the pathway responsible for conduction. It has been shown that, during atrial fibrillation, the SP ablation significantly increased the mean HH interval (204 ± 39 vs. 274 ± 50 ms, P < 0.05), whereas FP ablation did not produce significant slowing of ventricular rate. The presented mathematical model can help in understanding some of the intriguing AV node mechanisms and should be considered as a step forward in the studies of AV nodal conduction.

A Sodium Channel Blocker, Pilsicainide, Produces Atrial Post-Repolarization Refractoriness through the Reduction of Sodium Channel Availability

Atrial fibrillation (AF) is the most common tachyarrhythmia. Shortening of atrial action potential duration (APD) and effective refractory period (ERP) is one of the crucial factors in the occurrence and maintenance of AF. ERP is usually shorter than APD, but ERP can be prolonged beyond action potential repolarization in some situations. It is termed as post-repolarization refractoriness (PRR) that is thought to be one of main anti-arrhythmic mechanisms of class I sodium channel blockers (SCBs). Most of anti-arrhythmic agents, including SCBs, have multi-channel blocking effects. It is unknown whether atrial PRR with SCBs is associated with the reduction of sodium channel availability. We therefore explored the relationship between the reduction of sodium channel availability with a pure SCB (pilsicainide or tetrodotoxin) and atrial PRR using the left atrial appendage from male guinea pigs (each group, n = 3~10). Employing a standard microelectrode technique, we evaluated APD measured at 90% repolarization (APD(90)) and the sodium channel availability, judged from the maximal rate of rise of action potential (Vmax). At a 500-msec basic cycle length (BCL), pilsicainide prolonged atrial ERP assessed by a single extra-stimulus in response to the decrement of the Vmax in a dose-dependent manner without affecting APD(90). Furthermore, pilsicainide increased the ERP and decreased the Vmax in a rate-dependent manner without APD(90) prolongation at a shorter BCL (200 msec). Importantly, tetrodotoxin reproduced the effects of pilsicainide on atrial ERP, APD(90), and Vmax. These results indicate that SCBs produce atrial PRR through the reduction of sodium channel availability.

Functional Properties of the Superior Vena Cava (SVC)‐Aorta Ganglionated Plexus: Evidence Suggesting an Autonomic Basis for Rapid SVC Firing

the mechanism underlying spontaneous rapid superior vena cava (SVC) firing that initiates atrial fibrillation (AF) remains poorly understood. We investigated the role of the SVC-aorta-ganglionated plexus (SVC-Ao-GP) in AF initiated by rapid firing from the SVC. in 42 dogs, a circular catheter was positioned above the SVC-atrial junction. Multielectrode catheters were sutured on atria, atrial appendages and pulmonary veins. The effective refractory period (ERP) and window of vulnerability (WOV) for AF were measured at all sites in the baseline state, during cervical vagosympathetic trunk stimulation and during SVC-Ao-GP stimulation, before and after SVC-Ao-GP ablation. AF inducibility was also assessed by delivering high-frequency stimulation (HFS) within myocardial refractory period to the SVC before and after SVC-Ao-GP ablation. HFS applied to the SVC-Ao-GP slowed the sinus rate and/or atrioventricular conduction. HFS of the SVC-Ao-GP induced more significant shortening of ERP and a greater increase in WOV at the SVC than other sites. Ablation of the SVC-Ao-GP significantly increased the baseline ERP and decreased the baseline WOV only at the SVC. AF induced at the SVC by HFS during refractoriness was eliminated by ablation of the SVC-Ao-GP but was not altered by ablation of the 4 major atrial GP. Direct injection of acetylcholine into the SVC-Ao-GP initiated rapid firing from the SVC in every case. the SVC-Ao-GP preferentially modulates the electrophysiological function of the SVC sleeves and may contribute to rapid firing from the SVC.

Low‐Level Vagosympathetic Nerve Stimulation Inhibits Atrial Fibrillation Inducibility: Direct Evidence by Neural Recordings from Intrinsic Cardiac Ganglia

We hypothesized that low-level vagosympathetic stimulation (LL-VNS) can suppress atrial fibrillation (AF) by inhibiting the activity of the intrinsic cardiac autonomic nervous system (ICANS). Wire electrodes inserted into both vagosympathetic trunks allowed LL-VNS at 10% or 50% below the voltage required to slow the sinus rate or atrioventricular conduction. Multielectrode catheters were attached to atria, atrial appendages and all pulmonary veins. Electrical stimulation at the anterior right and superior left ganglionated plexi (ARGP, SLGP) was used to simulate a hyperactive state of the ICANS. Effective refractory period (ERP) and window of vulnerability (WOV) for AF were determined at baseline and during ARGP+SLGP stimulation in the presence or absence of LL-VNS. Neural activity was recorded from the ARGP or SLGP. ARGP+SLGP stimulation induced shortening of ERP, increase of ERP dispersion and increase of AF inducibility (WOV), all of which were suppressed by LL-VNS (10% or 50% below threshold) at all tested sites. Sham LL-VNS failed to induce these changes. The effects of LL-VNS were mediated by inhibition of the ICANS, as evidenced by (1) LL-VNS suppression of the ability of the ARGP stimulation to slow the sinus rate, (2) the frequency and amplitude of the neural activity recorded from the ARGP or SLGP was markedly suppressed by LL-VNS, and (3) the spatial gradient of the ERP and WOV from the PV-atrial junction toward the atrial appendage was eliminated by LL-VNS. LL-VNS suppressed AF inducibility by inhibiting the neural activity of major GP within the ICANS.

Mechanisms of hypokalemia‐induced ventricular arrhythmogenicity

Hypokalemia is a common biochemical finding in cardiac patients and may represent a side effect of diuretic therapy or result from endogenous activation of renin-angiotensin system and high adrenergic tone. Hypokalemia is independent risk factor contributing to reduced survival of cardiac patients and increased incidence of arrhythmic death. Animal studies demonstrate that hypokalemia-induced arrhythmogenicity is attributed to prolonged ventricular repolarization, slowed conduction, and abnormal pacemaker activity. The prolongation of ventricular repolarization in hypokalemic setting is caused by inhibition of outward potassium currents and often associated with increased propensity for early afterdepolarizations. Slowed conduction is attributed to membrane hyperpolarization and increased excitation threshold. Abnormal pacemaker activity is attributed to increased slope of diastolic depolarization in Purkinje fibers, as well as delayed afterdepolarizations caused by Ca2+ overload secondary to inhibition of Na+--K+ pump and stimulation of the reverse mode of the Na+--Ca2+ exchange. Hypokalemia effect on repolarization is not uniform at distinct ventricular sites thereby contributing to amplified spatial repolarization gradients which promote unidirectional conduction block. In hypokalemic heart preparations, the prolongation of action potential may be associated with shortening of effective refractory period, thus increasing the propensity for ventricular re-excitation over late phase of repolarization. Shortened refractoriness and slowed conduction contribute to reduced excitation wavelength thereby facilitating re-entry. The interplay of triggering factors (early and delayed afterdepolarizations, oscillatory prepotentials in Purkinje fibers) and a favorable electrophysiological substrate (unidirectional conduction block, reduced excitation wavelength, increased critical interval for ventricular re-excitation) may account for the mechanism of life-threatening tachyarrhythmias in hypokalemic patients.

Predicting recurrence of atrial fibrillation after electrical cardioversion: gauging atrial damage

This editorial refers to ‘Clinical and serological predictors for the recurrence of atrial fibrillation after electrical cardioversion’ by S.K. Kim et al ., Europace 2009;11:1632–8. Atrial fibrillation (AF) is the most common sustained arrhythmia encountered in clinical practice, and is associated with substantial mortality and morbidity due to stroke and heart failure.1 It frequently progresses relentlessly, and recurrent paroxysmal AF often evolves to persistent or permanent forms. The notion that ‘AF begets AF’2 has been used to explain the self-perpetuating nature of the disease. As AF persists, it promotes atrial electrophysiological changes including shortening of the atrial effective refractory period, increased dispersion of refractoriness, and slowing of the conduction velocity, which in turn facilitate AF maintenance as well as its recurrence. In addition, atrial structural remodelling, particularly atrial fibrosis, has recently been shown to play an important role in the development of AF.3 Although prompt cardioversion or an ablation procedure can reduce the likelihood of AF recurrence, a substantial proportion of patients continue to have the recurrent arrhythmia afterwards. In these patients, pre-existing changes in the atria provide a milieu for AF to …

Abnormal Action Potential Duration Restitution Property in the Right Ventricular Outflow Tract in Brugada Syndrome

Although patients with Brugada syndrome (BS) are at risk of ventricular fibrillation (VF) and ensuing death, the action potential duration (APD) restitution properties of the right ventricular outflow tract (RVOT) in patients with BS remain undetermined. Endocardial monophasic action potentials (MAPs) were obtained from 16 patients with BS and 17 control patients. MAPs were recorded from the RVOT in all patients. The MAP duration at 90% repolarization (MAPD(90)), effective refractory period (ERP), and maximum slope of the APD restitution curve were obtained. VF was induced with up to 3 extrastimuli from the RV apex or RVOT. There was no difference in MAPD(90) between the 2 groups, but the ERP was significantly shorter in patients with BS than in control patients (210.7+/-10.5 vs 223.8+/-13.4 ms, P=0.008). MAPD at the shortest diastolic interval was significantly shorter in patients with BS than in control patients (149.9+/-19.9 vs 179.8+/-13.7 ms, P<0.001). The maximum slope of the APD restitution curve was steeper in patients with BS than in control patients (2.90+/-1.29 vs 1.38+/-0.41, P<0.001). The shorter ERP, shorter MAPD at the shortest diastolic interval and steeply sloped APD restitution curve in the RVOT appear to be related to the inducibility of VF in patients with BS.

Effects of Potassium Channel Blockers on Changes in Refractoriness of Atrial Cardiomyocytes Induced by Stretch

Shortening of the effective refractory period (ERP) is regarded as one of the key mechanisms of atrial fibrillation (AF). Stretch is an important predisposing factor in the pathogenesis of AF. However, effective methods to counteract alteration of ERP induced by stretch still need to be explored. Although potassium channels play important roles in cardiac repolarization and refractoriness, the effects of potassium channel blockers on the alteration of repolarization and refractoriness induced by stretch are still unknown. Action potential duration (APD) and ERP were recorded using the standard intracellular microelectrode technique in the left atrial appendage cardiomyocytes of guinea pigs. Stretch accelerated repolarization of atrial cardiomyocytes and also shortened the ERP (P < 0.05). Dofetilide, a rapid delayed rectifying potassium ion channel (I(Kr)) blocker; 4-AP, a transient outward potassium ion channel (I(to)) blocker; and BaCl(2), an inward rectifying potassium ion channel (I(K1)) blocker could counteract the shortening of APD and ERP (P < 0.01). Glibenclamide, an ATP-sensitive potassium ion channel (I(KATP)) blocker; 293-B, a slow delayed rectifying potassium channel (I(Ks)) blocker; and DPO-1, an ultra-rapid delayed rectifying potassium ion channel (I(Kur)) blocker all had no effect on APD and ERP (P > 0.05). Stretch could accelerate repolarization of atrial cardiomyocytes and shorten their ERP, and the I(to), I(Kr), and I(K1) blockers could counteract the effects of stretch.

Asymptomatic Ventricular Preexcitation

Background— Sudden cardiac death can be the first clinical presentation of asymptomatic ventricular preexcitation. Methods and Results— From 1995 to 2005, we prospectively collected clinical and electrophysiological data among 293 adults with asymptomatic ventricular preexcitation (61.4% males; median age, 36 years; interquartile range [IQR], 28 to 47.5). After electrophysiological testing, patients were prospectively followed, taking no drugs. The primary end point of the study was the occurrence of a first arrhythmic event. Predictors of arrhythmic events were analyzed by univariate and multivariate Cox models. Over a median follow-up of 67 months (minimum to maximum, 8 to 90), after electrophysiological testing, 262 patients (median age, 37 years; IQR, 30 to 48) did not experience arrhythmic events, remaining totally asymptomatic, whereas 31 patients (median age, 25 years; IQR, 22 to 29; median follow-up, 27 months; minimum to maximum, 8 to 55) had a first arrhythmic event, which was potentially life-threatening in 17 of them (median age, 24 years; IQR, 20 to 28.5; median follow-up, 25 months; minimum to maximum, 9 to 55). Potentially life-threatening tachyarrhythmias resulted in resuscitated cardiac arrest (1 patient), presyncope (7 patients) syncope (4 patients), or dizziness (5 patients). In multivariate analysis age ( P =0.004), inducibility ( P =0.001) and anterograde effective refractory period of the accessory pathway ≤250 ms ( P =0.001) predicted potentially life-threatening arrhythmias. Conclusions— These results indicate that prognosis of adults who present with asymptomatic ventricular preexcitation is good, and the risk of a significant event is small. Short anterograde effective refractory period of the accessory pathway and inducibility at baseline are independent predictors of potentially life-threatening arrhythmic events, and the risk decreases with increasing age.

Induction of heat shock proteins prevents the arrhythmogenic substrate for atrial fibrillation

Atrial fibrillation (AF) is the commonest arrhythmia. Studies have shown that atrial tachypacing (artificial persistent AF) causes electrical remodelling. This is characterised by the shortening of the atrial effective refractory period (ERP), in which reduction in L-type Ca2+ channel current plays an essential part. Atrial fibrosis, a feature of structural remodelling, is induced by continuous infusion of angiotensin II, and has been associated with conduction delay in atria, which promotes AF. Acute atrial ischaemia, frequently observed during development of acute coronary syndrome, has been associated with atrial conduction heterogeneity, which also promotes AF. Induction of heat shock proteins (Hsp72 and Hsp27) by hyperthermia and/or geranylgeranylacetone has demonstrated to protect the heart against such atrial remodelling. The potent protective role of Hsp72 and Hsp27 against clinical AF in patients who underwent open heart surgery has been shown. Taken together, interventions that induce heat shock responses (including induction of Hsp72 and Hsp27) may prevent newly developed AF and delay the progression of paroxysmal AF to persistent AF.