Atrial Vulnerability Research Articles

Comparative effects of thiopental and propofol on atrial vulnerability: electrophysiological study in a porcine model including acute alcoholic intoxication

Atrial tachyarrhythmias (AT) frequently complicate the perioperative period. Alcohol intoxication is a recognized causative factor for dysrrhythmias. We studied the effects of propofol and thiopental on atrial electrophysiology and vulnerability to AT in a closed-chest porcine model in which AT are facilitated by ethanol. Thirty-eight pigs were randomly assigned to thiopental (T-group, n=19) or propofol (P-group n=19). All animals were assigned to undergo a right atrial electrical stimulation protocol (RASP) at baseline. Thirty pigs were assigned to undergo additional RASP during ethanol infusion, while the remaining eight were assigned to undergo additional RASP during saline infusion (control group). We analysed effective refractory period (ERP), and intra-atrial conduction interval (ICI) (between atrial sites 4 cm apart), at several cycle lengths (CL). There were no significant differences at baseline. During ethanol infusion, propofol produced a greater rate-dependent decrease in excitability, manifested by a longer minimum paced CL with 1:1 atrial capture: 145 (11) vs 164 (27) ms in the T- and P-group, respectively (P=0.01). Propofol was associated with a greater rate-related slowing in conduction: difference between ICI at CL of 300 ms and ICI at minimum CL: 30 ms in P-group and 22 ms in T-group (P<0.03). In the P-group we observed a longer duration of induced arrhythmias (145 (131) vs 74 (91) s, P<0.03) and a higher proportion with atrial flutter (AFl) (76 vs 19%, P<0.001). Propofol in this model was more arrhythmogenic than thiopental, as manifested by a longer duration of induced arrhythmias, particularly AFI.

Relation between history of paroxysmal atrial fibrillation and electrophysiological abnormalities of atrial muscle.

Although electrophysiological abnormalities of atrial muscle have been evaluated in patients with paroxysmal atrial fibrillation (PAF), no prior study has determined the contribution of the patient's history of PAF to electrophysiological abnormalities. The study population consisted of 108 patients (71 men; mean age, 57 +/- 14 years) with symptomatic and idiopathic PAF who underwent electrophysiological study. Before electrophysiological study, histories of frequency, number of PAF episodes per month, and duration, a time interval from the first episode of PAF to electrophysiological study, were examined. At electrophysiological study, endocardial electrograms from 12 right atrial sites were recorded during sinus rhythm, and the right atrial effective refractory period was determined. Longest duration of atrial electrograms, maximal number of fragmented deflections, and number of abnormal atrial electrograms recorded at the right atrial sites were significantly greater in the frequent group (> 1 PAF episode per month, n = 57) than in the infrequent group (< 1 PAF episode per month, n = 51) (98 +/- 18 ms vs 88 +/- 16 ms, P < 0.005; 8.7 +/- 2.6 vs 7.5 +/- 2.6, P < 0.05; and 2.2 +/- 2.2 vs 1.4 +/- 1.6, P < 0.05, respectively). Indices of atrial vulnerability were also greater in the frequent group. Duration of PAF history was significantly correlated with longest duration r = 0.52, P < 0.0001), maximal number of fragmented deflections r = 0.51, P < 0.0001), and number of abnormal atrial electrograms r = 0.58, P < 0.0001). More frequent episodes and longer history of PAF significantly increased the electrophysiological abnormalities of the atrial muscle, suggesting that PAF results in gradual electrical remodeling of the atrial muscle.

Association of human connexin40 gene polymorphisms with atrial vulnerability as a risk factor for idiopathic atrial fibrillation.

Alterations in distribution, density, and properties of cardiac gap junctions, which mediate electrical coupling of cardiomyocytes, are considered potentially arrhythmogenic. We recently reported 2 linked polymorphisms within regulatory regions of the gene for the atrial gap junction protein connexin40 (Cx40) at nucleotides -44 (G-->A) and +71 (A-->G), which were associated with familial atrial standstill. The present study examined whether these Cx40 polymorphisms were associated with increased atrial vulnerability in vivo and arrhythmia susceptibility. In 30 subjects without structural heart disease, of whom 14 had documented sporadic paroxysmal atrial fibrillation (AF) and 16 had no AF history, inducibility of AF was assessed using an increasingly aggressive atrial stimulation protocol. Coefficient of spatial dispersion of refractoriness (CD) was calculated. CD was defined as the SD of 12 local mean fibrillatory intervals recorded at right atrial sites, expressed as a percentage of the overall mean fibrillatory interval. Cx40 genotypes were determined by direct DNA sequencing. Subjects were stratified according to normal or increased CD with a cutoff value of 3.0, because CD >3.0 was previously shown to be strongly associated with enhanced atrial vulnerability. The prevalence of the minor Cx40 allele (-44A) and -44AA genotype was significantly higher in subjects with increased dispersion (n=13) compared with those with CD < or =3.0 (n=17; P=0.00046 and P=0.025; odds ratios of 6.7 and 7.4) and a control population (n=253; P=0.00002 and P=3.90x10(-7)). Carriers of -44AA genotype had a significantly higher CD compared with those with -44GG genotype (6.37+/-1.21 versus 2.38+/-0.39, P=0.018), whereas heterozygotes had intermediate values (3.95+/-1.38, NS). All subjects with increased CD had a history of idiopathic AF compared with only 1 subject with normal CD. The -44A allele and -44AA genotype were significantly more frequent in subjects with prior AF than in those without (P=0.0019 and P=0.031; odds ratios 5.3 and 6.2). This study provides strong evidence linking Cx40 polymorphisms to enhanced atrial vulnerability and increased risk of AF. The full text of this article is available online at http://circres.ahajournals.org.

Increased P wave dispersion after the radiofrequency catheter ablation in overt pre-excitation patients: the role of atrial vulnerability

The pathogenesis of paroxysmal atrial fibrillation (PAF) in patients with overt pre-excitation and effect of elimination of accessory pathways on the appearance of AF are still controversial. We demonstrated the increased P max and P wave dispersion (PWD) reflecting more inhomogeneous and prolonged atrial conduction in patients with Wolff–Parkinson–White (WPW) syndrome and PAF attacks. One-hundred and fifty-one patients who underwent radiofrequency (RF) catheter ablation due to paroxysmal tachycardia medicated by accessory pathway were enrolled in this study. The patients were classified into two groups according to the presence of previous PAF attacks. We compared the clinical characteristics, echocardiograhic findings, P max and PWD values measured after normalization of PR intervals and disappearance of pre-excitation after ablation in overt pre-excitation patients. Although the differences in age, left atrial diameter and left ventricular ejection fraction (LVEF) were not significant in both groups, P maximum (130.0±8.4 vs. 122.3±8.7 ms, p=0.002) and P wave dispersion values measured after ablation (50.3±7.2 vs. 35.7±6.1 ms, p=0.001) were significantly higher in patients with previous PAF attacks. Accessory pathway (AP) antegrade and retrograde effective refractory period (ERP) values were shorter (276±27.3 vs. 321.0±48.7, p=0.001; 263.4±41.3 vs. 299.7±38.2, p=0.002, respectively) in patients with PAF attack when compared to those without PAF attacks. Higher P wave dispersion values in patients with previous PAF attacks suggest the important role of inhomogenous and discontinuous propagation of sinus impulses. Therefore, we concluded that not only the accessory pathway but also inhomogenous propagation of sinus impulses may play an important role in occurrence of AF in patients with pre-excitation.

On the atrial response to focal discharges in man.

Triggers and vulnerability are key factors for the occurrence of atrial fibrillation (AF). The aim of this study was to assess spatial dispersion of atrial refractoriness and vulnerability in response to both focal discharges as well as programmed electrical stimulation in patients undergoing ablation of atrial arrhythmogenic foci. Twenty-nine patients were studied, and 12 right atrial unipolar electrograms were recorded. Inducibility of AF was assessed by a pacing protocol that started with one extrastimulus, followed by more aggressive pacing until AF was obtained. Mean fibrillatory intervals were used to assess the local refractoriness of each recording site. Spatial dispersion of refractoriness was calculated as the coefficient of dispersion (CD value: standard deviation of the mean of all local mean fibrillatory intervals as a percentage of the overall mean fibrillatory interval). Based on our previous study, a CD value </= 3.0 was defined as normal, whereas a CD value >3.0 was considered enhanced spatial dispersion of refractoriness. Fifteen of 29 patients had normal dispersion of refractoriness (mean CD value 1.65 +/- 0.43), and AF was inducible with burst pacing only. These patients had focal discharges causing rapid atrial tachycardia with a focal activation pattern. Activation mapping of focal activity was possible in 14 of 15 patients. Focal triggering of AF occurred in only 1 of 15 patients. Fourteen of 29 patients had enhanced dispersion (mean CD value 4.2 +/- 0.72). AF was inducible with a single extrastimulus in 11 of 14 patients (P < 0.001). Focal triggering of AF occurred in all 14 patients. Spatial dispersion of atrial refractoriness determines whether focal atrial discharges trigger AF with disorganized activity or, alternatively, only rapid atrial tachycardia.

Abnormal right atrial electrograms predict the transition to chronic atrial fibrillation in paced patients with sick sinus syndrome.

Although pacing therapy for sick sinus syndrome (SSS) is established, the risk of developing chronic atrial fibrillation (CAF) makes pacing therapy infeasible in some patients. We evaluated whether electrophysiological characteristics of atrial muscle can serve as predictors of the transition to CAF after pacemaker implantation in patients with SSS. Eighty-nine patients with SSS underwent electrophysiological study before pacing therapy. Catheter mapping of 12 right atrial sites was performed during sinus rhythm during electrophysiological. An abnormal atrial electrogram was defined as having a duration of 100 ms or longer, or eight or more fragmented deflections, or both. Right atrial extrastimulation was also performed for atrial vulnerability. After electrophysiological study, all patients underwent pacemaker implantation and were followed up. During the follow-up period of 85 +/- 50 months, development of CAF was observed in 12 patients (group A). The remaining 77 patients remained in sinus rhythm (group B). There were significantly more abnormal atrial electrograms in group A than group B (2.7 +/- 2.3 vs 0.8 +/- 1.2; P < 0.001). The distribution of abnormal atrial electrograms was also greater in group A; patients in group A had more abnormal atrial electrograms than patients in group B in both the high and middle right atrium (P < 0.005 and P < 0.01, respectively). Kaplan-Meier analysis showed that almost 50% of the paced patients with abnormal atrial electrograms (n = 42) developed CAF (P < 0.005). Our data suggest that the existence of abnormal atrial electrograms is predictive of the transition to CAF in paced patients with SSS.

Effects of intravenous nifekalant, a class III antiarrhythmic drug, on atrial vulnerability parameters in patients with paroxysmal atrial fibrillation.

Nifekalant, a class III antiarrhythmic drug, has been shown to suppress ventricular tachyarrhythmias, but its effects on AF are unclear. The aim of this study was to clarify the effects of nifekalant on the atrial vulnerability parameters in patients with paroxysmal AF. The study included 18 patients with paroxysmal AF who underwent electrophysiological study before and after intravenous infusion of nifekalant. The atrial electrophysiological parameters including the atrial effective refractory period (AERP), maximum intraatrial conduction delay, and wavelength index, calculated as the ratio of AERP to the maximum conduction delay, were quantitatively measured at baseline and during nifekalant infusion. The mean AERP was significantly prolonged from 214 +/- 27 ms at baseline to 242 +/- 39 ms after nifekalant (P < 0.001). Although earlier studies have shown that nifekalant does not affect the atrial conduction time, the mean maximum conduction delay of the study patients was significantly prolonged from 59 +/- 19 ms at baseline to 72 +/- 28 ms after nifekalant (P = 0.015). There was no significant difference in the wavelength index at baseline (4.1 +/- 1.7) and after nifekalant (4.1 +/- 2.5). However, when the differences of AERP and wavelength index were defined as each parameter during nifekalant infusion minus that at baseline, the difference of AERP showed a direct positive correlation with that of the wavelength index (P = 0.013). In conclusion, nifekalant may be effective in the prevention of AF due to prolongation of the AERP. However, in those patients who have a lesser degree of prolongation of the AERP by nifekalant, the wavelength index tended to be decreased, suggesting that the drug might augment the propensity for AF.

Evaluation of atrial vulnerability by P wave signal averaged electrocardiogram in patients with Brugada syndrome

Evaluation of atrial vulnerability by P wave signal averaged electrocardiogram in patients with Brugada syndrome

Diadenosine-5-phosphate exerts A1-receptor-mediated proarrhythmic effects in rabbit atrial myocardium.

(1) Diadenosine polyphosphates have been described to be present in the myocardium and exert purinergic- and nonreceptor-mediated effects. Since the electrophysiological properties of atrial myocardium are effectively regulated by A(1) receptors, we investigated the effect of diadenosine pentaphosphate (Ap(5)A) in rabbit myocardium. (2) Parameters of supraventricular electrophysiology and atrial vulnerability were measured in Langendorff-perfused rabbit hearts. Muscarinic potassium current (I(K(ACh/Ado))) and ATP-sensitive potassium current (I(K(ATP))) were measured by using the whole-cell voltage clamp method. (3) Ap(5)A prolonged the cycle length of spontaneously beating Langendorff perfused hearts from 225+/-14 (control) to 1823+/-400 ms (Ap(5)A 50 micro M; n=6; P<0.05). This effect was paralleled by higher degree of atrio-ventricular block. Atrial effective refractory period (AERP) in control hearts was 84+/-14 ms (n=6). Ap(5)A>/=1 micro M reduced AERP (100 micro M, 58+/-11 ms; n=6). (4) Extrastimuli delivered to hearts perfused with Ap(5)A- or adenosine (>/= micro M)-induced atrial fibrillation, the incidence of which correlated to the concentration added to the perfusate. The selective A(1)-receptor antagonist CPX (20 micro M) inhibited the Ap(5)A- and adenosine-induced decrease of AERP. Atrial fibrillation was no longer observed in the presence of CPX. (5) The described Ap(5)A-induced effects in the multicellular preparation were enhanced by dipyridamole (10 micro M), which is a cellular adenosine uptake inhibitor. Dipyridamole-induced enhancement was inhibited by CPX. (6) Ap(5)A (</=1 mM) did neither induce I(K(Ado)) nor I(K(ATP)). No effect on activated I(K(Ado/ATP)) was observed in myocytes superfused with Ap(5)A. However, effluents from Langendorff hearts perfused with Ap(5)A 100 micro M activated I(K(Ado)) by using A(1) receptors. (7) Ap(5)A did not activate A(1) receptors in rabbit atrial myocytes. The Ap(5)A induced A(1)-receptor-mediated effects on supraventricular electrophysiology and vulnerability suggest that in the multicellular preparation Ap(5)A is hydrolyzed to yield adenosine, which acts via A(1) receptors. An influence on atrial electrophysiology or a facilitation of atrial fibrillation under conditions resulting in increased interstitial Ap(5)A concentrations might be of physiological/pathophysiological relevance.

Comparative study of atrial vulnerability in patients with unexplained ischemic stroke or lone atrial paroxysmal fibrillation

Strokes have a high prevalence, with a high rate of recurrence, and about 30–40% remain of unknown cause. Some patients might have asymptomatic paroxysmal atrial fibrillation (AF) which remains the main cause of embolic events. A latent atrial arrhythmogenic substrate may induce recurrent arrhythmias, including functional abnormalities such as nonuniform refractoriness and/or anatomic abnormalities such as atrial septum aneurysm (ASA) and patent foramen ovale (PFO). In 175 patients divided into three groups (Group I: 103 patients with unexplained ischemic stroke, Group II: 48 patients with paroxysmal AF and Group III or control group: 24 patients explored for another cause), such an atrial arrhythmogenic substrate was assessed by electrophysiological study. Groups I and II had a similar high rate of inducible atrial arrhythmias compared to control group III where no arrhythmia was induced. An induced atrial arrhythmia was observed in more than 50% of patients of Group I and in more than 70% of patients of Group II without any significant difference according to age. However, in 26 young patients of Group I who had a transesophageal echocardiography, both a high rate (46%) of ASA and/or PFO and a frequent latent atrial vulnerability (LAV) were observed, compared to older patients where an atrial septum abnormality was observed in only 21% of cases. Thus, among patients with stroke of unknown cause, a high percentage of them might have asymptomatic atrial paroxysmal arrhythmia. The predictive value of the electrophysiological study for spontaneous arrhythmias and recurrence of stroke remains to be demonstrated.

Vulnérabilité atriale : un nouveau protocole par stimulation bigéminée

Introduction. – There is little information available on the events that mediate short term remodeling. In a bigeminy atrial-pacing protocol, we sought to evaluate the electrophysiological consequences of an irregular short-long cycle length atrial pacing. Methods and results. – This study included 22 consecutive patients with documented arrhythmias and 10 control subjects. After evaluating the effective and functional refractory periods, bigeminy atrial pacing was performed for 5 min. During bigeminy pacing, in 12 AF patients and in none of the control subjects, AF was started lasting longer than 1 minute (Group I). Short salvos of AF occurred in five patients and three controls (Group II) and no arrhythmia occurred in five patients and seven controls (Group III). Sensitivity, specificity, negative and positive predictive values of sustained AF induced by bigeminy pacing were 54%, 100%, 50% and 100%, respectively. Atrial refractory periods measured immediately after termination of 5 minutes of bigeminy pacing were shorter than during baseline. The degree of shortening was similar in AF patients and in controls. The loco-regional conduction did not change after the bigeminy protocol. Conclusion. – This study demonstrates that atrial bigeminy pacing unmasks latent atrial vulnerability.

Occurrence of atrial fibrillation after flutter ablation: the significance of intra-atrial conduction and atrial vulnerability

Atrial vulnerability and intra-atrial conduction delay are important substrates for paroxysmal atrial fibrillation (AFib); however, their significance is unknown in patients undergoing atrial flutter ablation. Antegrade (high right atrium to coronary sinus: HRA-CS) and retrograde (CS-HRA) intra-atrial conduction times and AFib inducibility were assessed in 61 patients undergoing ablation for type I atrial flutter. Twenty-three patients had structural heart disease and 18 AFib before the procedure. After 16 ± 12 months of follow-up 17 patients experienced AFib, 5 of which progressed into chronic AFib. During the study, AFib was easily inducible in 14 patients, 7 of which developed AFib ( P = .03). Patients with post- ablation AFib were older (59 ± 11 vs. 44 ± 15 years, P = .001), had longer intra-atrial conduction times before (98 ± 17 ms vs. 68 ± 20 ms, P < .001) and after ablation (91 ± 19 ms vs. 73 ± 21 ms, P = .01) than those without AFib. Discriminant analysis revealed that only age, previous AFib and inta-atrial conduction delay (>90ms) were independent predictors of postablation AFib. Patients without a history of AFib and with normal intra-atrial conduction had a 3% risk of AFib, while patients with both factors had a 90% risk of AFib after ablation. Intra-atrial conduction delay is an important electrophysiological factor predicting atrial fibrillation after successful flutter ablation.

Effects of flecainide on the electrophysiological properties of atrial vulnerability in humans.

The aims of this study were to evaluate the changes in the electrophysiological characteristics of the right atrium after the administration of flecainide and to clarify whether flecainide has a selective effect on human atrial tissue. Electrophysiological measurements were made in 38 patients, before and after intravenous administration of flecainide (2 mg/kg per 10 min). The effective refractory period of the right atrium (ERP-A), maximum conduction delay (Max.CD), repetitive atrial firing zone (RAFZ), fragmented atrial activity zone (FAAZ), and conduction delay zone (CDZ) were studied in the patients who were divided into 2 groups based on whether repetitive atrial firing (RAF) was induced in the baseline study. Flecainide significantly prolonged the ERP-A (202+/-22 to 238+/-33 ms, p<0.001) and shortened Max.CD (77+/-17 to 63+/-32 ms, p<0.05) in the patients with RAF, but not in those without RAF in the baseline study. After flecainide administration, there were significant reductions in the RAFZ (43+/-22 to 13+/-19 ms, p<0.0001), FAAZ (51+/-22 to 28+/-26 ms, p<0.001) and CDZ (70+/-21 to 48+/-30 ms, p<0.01) in the patients with RAF. However, atrial fibrillation (AF) was induced by stimulation after flecainide in 2 patients without RAF in the baseline study. There was a significant negative correlation between the ERP-A in the baseline study and the change in the ERP-A upon flecainide administration (r=0.45, p<0.01). Flecainide may preferentially activate the substrate for AF and RAF, but that action is mainly based on the electrophysiological characteristics found in the baseline study.

Bigeminy Pacing: A New Protocol to Unmask Atrial Vulnerability

One of the most exciting developments in our understanding of atrial fibrillation (AF) mechanisms has been the recognition that "AF begets AF" in a process termed atrial remodeling. Little information is available about the events that mediate short-term remodeling. In a bigeminy atrial pacing protocol that produces a continuous extrasystole-postextrasystole cycle length, we sought to evaluate the electrophysiologic consequences of irregular atrial pacing. This study included 22 consecutive patients with documented paroxysmal AF and 10 control subjects. After evaluating the effective refractory period (ERP) and functional refractory period (FRP), bigeminy atrial pacing was performed for 5 minutes. The S1-S2 coupling interval during bigeminy pacing was programmed to a mean value of 275 +/- 45 msec, i.e., 45 msec longer than the basic ERP measured at 100 beats/min. During bigeminy pacing, AF that lasted longer than 1 minute occurred in 12 AF patients and in none of the control subjects (group I). Short salvos of AF occurred in 5 patients and 3 controls (group II). No arrhythmia occurred in 5 patients and 7 controls (group III). Sensitivity, specificity, and negative and positive predictive values of sustained AF induced by bigeminy pacing were 54%, 100%, 50%, and 100%, respectively. No differences were observed between different pacing rates during bigeminy, the premature coupling interval S1-S2, or the conduction parameters S2-A2 and A2. Group I had the shortest basic ERP (222 +/- 38 msec) and group III the longest ERP (242 +/- 21 msec, P < 0.05); group II was intermediate. Atrial ERPs and FRPs measured immediately after termination of 5 minutes of bigeminy pacing were shorter than during baseline. The degree of shortening was similar in AF patients and in controls. The locoregional conduction delay A2 did not change after the bigeminy protocol. This study demonstrates that atrial bigeminy pacing highly increases atrial vulnerability. This protocol appears interesting because its sensitivity and specificity are higher than those of the conventional extrastimulation test. This makes it attractive for routine diagnosis of undocumented paroxysmal AF. Because it may induce atrial arrhythmias independently of the classic mechanisms of wavelength shortening, this study emphasizes the need for new modalities in the prevention of atrial arrhythmias.

Age-Related Changes in the Electrophysiologic Properties of the Atrium in Patients with no History of Atrial Fibrillation

Although atrial fibrillation is a common arrhythmia, especially in the elderly, little is known about age-related changes in the electrophysiologic properties of the atrium. The aim of this study was to analyze the effect of aging on atrial vulnerability to atrial fibrillation. An electrophysiologic study was performed in 45 patients with no history of atrial fibrillation, Wolff-Parkinson-White syndrome, structural heart disease, or conditions with potential effects on cardiac hemodynamic or electrophysiologic function (15 females; mean age, 52 +/- 18 years; range, 14 to 84 years). The following atrial excitability parameters were assessed: spontaneous or paced (A1) and extrastimulated (A2) atrial electrogram widths, percent maximum atrial fragmentation (A2/A1 x 100), effective refractory period, wavelength index (ERP/A2), and inducibility of atrial fibrillation. Atrial fibrillation was induced in 9 patients. Percent maximum atrial fragmentation was greater (176 +/- 36 vs 137 +/- 26%, P < 0.001) and wavelength index was shorter (2.4 +/- 0.4 vs 3.2 +/- 0.9, P < 0.01) in the patients with than without inducible atrial fibrillation. However, age was similar in patients with and without inducible atrial fibrillation (47 +/- 11 vs 53 +/- 19 years, P = 0.36). Percent maximum atrial fragmentation and effective refractory period directly correlated with age (r = 0.32, P < 0.05 and r = 0.45, P < 0.001, respectively). On the other hand, wavelength index (3.1 +/- 0.9) did not correlate with age (r = -0.05, P = 0.77). This study suggests that the mechanism triggering atrial fibrillation may be very well different between older and younger patients with atrial fibrillation, because younger patients have no marked substrate for atrial fibrillation.

Atrial fibrillation and atrial vulnerability in patients with Brugada syndrome

ObjectivesWe sought to study atrial vulnerability in patients with Brugada syndrome. BackgroundAtrial fibrillation (AF) often occurs in patients with Brugada syndrome, but atrial vulnerability in Brugada syndrome has not been evaluated. MethodsThe patient group consisted of 18 patients with Brugada syndrome. The control group consisted of 12 age- and gender-matched subjects who had neither organic heart disease nor AF episodes. The incidence and clinical characteristics of AF were evaluated in all 18 patients with Brugada syndrome, and an electrophysiologic study was performed in all 12 control subjects and in 14 of the 18 patients with Brugada syndrome. The atrial effective refractory period of the right atrium (RA-ERP), intra-atrial conduction time (conduction time from the stimulus at the right atrium to atrial deflection at the distal portion of the coronary sinus), duration of local atrial potential, and repetitive atrial firing (occurrence of two or more premature atrial complexes after atrial stimulation) were studied. ResultsSpontaneous AF occurred in 7 of the 18 patients with Brugada syndrome but in none of the control subjects. The RA-ERP was not different between the two groups. The intra-atrial conduction time was increased in the Brugada syndrome group versus the control group (168.4 ± 17.5 vs. 131.8 ± 13.0 ms, p < 0.001). The duration of atrial potential at the RA-ERP was prolonged in the Brugada syndrome group versus the control group (80.3 ± 18.0 vs. 59.3 ± 9.2 ms, p < 0.001). Repetitive atrial firing was induced in nine patients with Brugada syndrome and in six control subjects. Atrial fibrillation was induced in eight patients with Brugada syndrome but in none of the control subjects. In patients with Brugada syndrome without spontaneous AF, the intra-atrial conduction time and duration of atrial potential were also increased. ConclusionsAtrial vulnerability is increased in patients with Brugada syndrome. Abnormal atrial conduction may be an electrophysiologic basis for induction of AF in patients with Brugada syndrome.

Induction of atrial fibrillation in mice by rapid transesophageal atrial pacing.

Atrial fibrillation (AF) as an "indicator arrhythmia" for enhanced atrial vulnerability in mouse hearts has not yet been systematically examined. We therefore evaluated a transesophageal rapid atrial stimulation protocol for the induction of AF in C57Bl/6 mice. 40 C57Bl/6 mice (19 female and 21 male; 5.2 +/- 2.1 months; 18 - 27 g) were examined by closed chest transesophageal atrial stimulation. Baseline ECG and electrophysiological parameters, AF-inducing stimulation cycle length (CL) and AF duration were analyzed. The surface ECG demonstrated a significantly faster heart rate in female mice (R-R: 138.7 +/- 19.9 ms versus 150.5 +/- 15.7 ms, P < 0.05). AF was inducible in 90 % of the population and not inducible in 4 mice, all female (21 % in this subgroup). Mean induction CL was 27.4 +/- 7.3 ms. Mean AF duration was 26.9 +/- 42.6 s before spontaneous termination. In a subgroup of 4 female and 4 male mice (mean age 7.5 months), successive testing of AF induction showed a range of higher susceptibility to AF at stimulus amplitudes of 3.0 - 4.0 mA and stimulation CLs between 15 - 25 ms. AF induction was observed to be constantly reproducible in the individual animals. No correlation to pacing stimulus length and amplitude was found. This study demonstrates that it is possible to reproducibly induce self-terminating AF and supraventricular arrhythmias in mice by transesophageal atrial burst stimulation. The presented method allowing serial testings of the same animal can be a useful tool in further investigations with transgenic mice and might be helpful in the characterization of underlying genetic or molecular mechanisms of AF.

Patent Foramen Ovale and Recurrent Stroke

Clinical management of patients with acute stroke and the approach used for secondary prevention depends upon clarification of pathogenesis. Although most strokes are a consequence of cerebrovascular disease, ≈15% to 20% of ischemic (nonhemorrhagic) strokes have been attributed to cardiogenic embolism.1 In practice, determination of the stroke mechanism is fraught with uncertainty, particularly when the possibility of thromboembolism emanating from atherosclerotic lesions in the aorta or cervical arteries is considered. When cardiogenic embolism is suspected, cardiac ultrasound is the principal method used to identify the potential source. The finding of left atrial enlargement has been shown to bear a significant relationship to the risk of stroke in a multivariate analysis of population-based data from the Framingham Heart Study2. The most frequent confounding variable is atrial fibrillation, occurring in >2 million patients in North America and in over half of all patients with cardiogenic embolism. Criteria for selection of patients with acute ischemic stroke for transesophageal echocardiography (TEE) to search for a potential cardiac source of embolism are controversial, particularly because cardiogenic embolism is often an uncertain diagnosis that is inferred merely on the basis of the finding of potential cardiac source. Even after extensive investigation, ≈40% of ischemic stroke patients have no clearly identifiable pathogenesis (cryptogenic stroke).3 In one study, 62% of patients younger than 60 years of age without an obvious source of cerebral infarction and 23% of those with arterial lesions had potential sources of cardiogenic embolism identified by TEE ( P =0.0007 for the difference).4 See p 2625 Among the cardiac anomalies detected by TEE that have been implicated as risk factors for stroke are patent foramen ovale (PFO) and atrial septal aneurysm (ASA).5,6⇓ The foramen ovale, a remnant of the fetal circulation, remains patent through adulthood in ≈1 in 4 …

Downregulation of immunodetectable atrial connexin40 in a canine model of chronic left ventricular myocardial infarction: implications to atrial fibrillation.

The substrate(s) for atrial fibrillation associated with chronic left ventricular myocardial infarction remain poorly defined. Since atrial connexin40 has a rapid turnover rate and may cause atrial fibrillation, we hypothesized that chronic left ventricular myocardial infarction downregulates atrial Connexin40 and increases atrial fibrillation vulnerability. The left anterior descending coronary artery was occluded distal to the first diagonal branch in five dogs and studied 7 weeks later. Five dogs with no left anterior descending coronary artery occlusion served as control. Vulnerability to atrial fibrillation was tested by burst atrial stimulation (50 milliseconds for 3 seconds). Atrial fibrillation was induced in all myocardial infarction dogs, lasting from 20 seconds to several minutes. In contrast, only rapid repetitive activity and short-lasting atrial fibrillation (< 5 seconds) could be induced in control dogs. The mean refractory periods of epicardial RA and LA appendages were not significantly different in the two groups. Mean left ventricular myocardial infarction size was 17 +/- 4% of the left ventricle. Histologic analyses showed no signs of atrial ischemic injury or interstitial fibrosis in either group. Atrial myocyte diameter measured at the level of the nuclei of longitudinally sectioned myocytes was not significantly different in the two groups (10.1 +/- 1.2 microm vs. 10.2 +/- 1.2 microm; P = 0.3). Atrial Connexin40 (both left and right atria) in the left ventricular myocardial infarction group was highly heterogeneous and had significantly smaller total area stained than in the control (0.48 +/- 0.09% vs. 0.82 +/- 0.13%; P < 0.01). Chronic left ventricular myocardial infarction downregulates immunodetectable atrial Connexin40, a property that might contribute to the increased atrial fibrillation vulnerability in this model.

Dynamic nature of atrial fibrillation substrate during development and reversal of heart failure in dogs.

Clinical atrial fibrillation (AF) often results from pathologies that cause atrial structural remodeling. The reversibility of arrhythmogenic structural remodeling on removal of the underlying stimulus has not been studied systematically. Chronically instrumented dogs were subjected to 4 to 6 weeks of ventricular tachypacing (VTP; 220 to 240 bpm) to induce congestive heart failure (CHF), followed by a 5-week recovery period leading to hemodynamic normalization at 5-week recovery (Wk5(rec)). The duration of burst pacing-induced AF under ketamine/diazepam/isoflurane anesthesia increased progressively during VTP and recovered toward baseline during the recovery period, paralleling changes in atrial dimensions. However, even at full recovery, sustained AF could still be induced under relatively vagotonic morphine/chloralose anesthesia. Wk5(rec) dogs showed no recovery of CHF-induced atrial fibrosis (3.1+/-0.3% for controls versus 10.7+/-1.0% for CHF and 12.0+/-0.8% for Wk5(rec) dogs) or local conduction abnormalities (conduction heterogeneity index 1.8+/-0.1 in controls versus 2.3+/-0.1 in CHF and 2.2+/-0.2 in Wk5(rec) dogs). One week of atrial tachypacing failed to affect the right atrial effective refractory period significantly in CHF dogs but caused highly significant effective refractory period reductions and atrial vulnerability increases in Wk5(rec) dogs. Reversal of CHF is followed by normalized atrial function and decreased duration of AF; however, fibrosis and conduction abnormalities are not reversible, and a substrate that can support prolonged AF remains. Early intervention to prevent fixed structural abnormalities may be important in patients with conditions that predispose to the arrhythmia.