Dispersion Of Atrial Effective Refractory Period Research Articles

Regulating the Warburg effect on metabolic stress and myocardial fibrosis remodeling and atrial intracardiac waveform activity induced by atrial fibrillation

Atrial fibrillation (AF) is associated with metabolic stress and induces myocardial fibrosis reconstruction by increasing glycolysis. One goal in the treatment of paroxysmal AF (p-AF) is to improve myocardial fibrosis reconstruction and myocardial metabolic stress caused by the Warburg effect. Adopted male canine that rapid right atrial pacing (RAP) for 6 days to establish a p-AF model. The canines were pre-treated with phenylephrine (PE) or dichloroacetic acid (DCA) before exposure to p-AF or non-p-AF. P-wave duration (Pmax), minimum P-wave duration (Pmin), P wave dispersion (PWD), atrial effective refractory period (AERP) and AERP dispersion (AERPd) were measured in canine atrial cardiomyocytes. Pyruvate dehydrogenase kinase-1 (PDK-1), PDK-4, lactate dehydrogenase A (LDHA), pyruvate dehydrogenase (PDH), citrate synthase (CS), isocitrate dehydrogenase (IDH), and matrix metalloproteinase 9 (MMP-9) were evaluated by western blotting and reverse transcription polymerase chain reaction (RT-PCR), content of adenosine monophosphate (AMP), adenosine triphosphate (ATP), lactic acid and glycogen, and activity of LDHA, PDK-1 and PDK-4 were evaluated by enzyme-linked immunosorbent assay (ELISA), myocardial tissue glycogen content was evaluated by PAS, myocardial fibrosis remodeling was evaluated by hematoxylin and eosin (H&E) and Masson staining. Our findings demonstrated that p-AF increases the Warburg effect-related metabolic stress and myocardial fibrosis remodeling by increasing the expression and activity of PDK-1, PDK-4, and LDHA, content of AMP and lactic acid, and the ratio of AMP/ATP and decreasing the expression of PDH, CS, and IDH, and glycogen content. In addition, p-AF can induce cardiomyocyte fibrosis remodeling and increase MMP-9 expression, and p-AF also increases atrial intracardiac waveform activity by prolonging Pmax, Pmin, PWD, and AERPd and shortening AERP. PDK isoforms agonists (PE) produce a similar p-AF pathological effect and can produce synergistic effects with p-AF, further increasing Warburg effect-related metabolic stress, myocardial fibrosis remodeling, and atrial intracardiac waveform activity. In contrast, the use of PDK-specific inhibitors (DCA) completely reverses these pathophysiological changes induced by p-AF. We demonstrate that p-AF can induce the Warburg effect in canine atrial cardiomyocytes and significantly improve p-AF-induced metabolic stress, myocardial fibrosis remodeling, and atrial intracardiac waveform activity by inhibiting the Warburg effect.

Median nerve stimulation prevents atrial electrical remodelling and inflammation in a canine model with rapid atrial pacing.

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. 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. The effects of MNS on atrial electrical remodelling and AF inducibility might be associated with the cholinergic anti-inflammatory pathway.

NADPH oxidase inhibitor apocynin prevents atrial remodeling in alloxan-induced diabetic rabbits

ObjectivesDiabetes mellitus (DM) is an independent risk factor for atrial fibrillation (AF). The role of the NADPH oxidase (NOX) signaling in the setting of DM and the potential benefits of apocynin on diabetic atrial remodeling remain unknown. MethodsSixty Japanese rabbits were randomized into 3 groups as follows: Control group (Control, n=20), alloxan-induced diabetic group (DM, n=20) and apocynin-treated diabetic group (APO, n=20). Rabbits in the APO group were orally administered apocynin (15mg/kg/day) for 8weeks. Serum malonaldehyde (MDA), superoxide dismutase (SOD) levels, and left atrial tissue NADPH oxidase (NOX) activities were measured. Isolated rabbit hearts were Langendorff perfused. Atrial refractory effective period (AERP), atrial effective refractory period dispersion (AERPD), interatrial conduction time (IACT) and vulnerability to AF were assessed. Atrial interstitial fibrosis was evaluated by Masson's trichrome staining. The protein expression of NF-κB, TGF-β, p38, P-p38, JNK, P-JNK, ERK and P-ERK was measured by Western blot analysis. ResultsThere were no significant differences regarding SBP, DBP, LVEDP and AERP in the three groups. Compared with the Control group, AF inducibility was increased in the DM group (46/450 vs. 5/450, P<0.05), and markedly reduced by apocynin (46/450 vs. 12/450, P<0.05). Apocynin also attenuated atrial structural remodeling in diabetic rabbits. Western-blot analysis indicated that apocynin reduced the DM-induced increased protein expression of TGF-β, NF-κB, P-p38, P-JNK, ERK and P-ERK. ConclusionsApocynin, a NADPH oxidase inhibitor, prevents AF and attenuates atrial remodeling in alloxan-induced diabetic rabbits.

Effect of renal sympathetic denervation on the progression of paroxysmal atrial fibrillation in canines with long-term intermittent atrial pacing.

The aim of the present study was to explore the effect of renal sympathetic denervation (RSD) on the progression of paroxysmal atrial fibrillation (AF) in canines with long-term intermittent atrial pacing. Nineteen beagles were randomly divided into sham-operated group (six dogs), control group (six dogs), and RSD group (seven dogs). Sham-operated group were implanted with pacemakers without pacing; control group were implanted with pacemakers with long-term intermittent atrial pacing; and RSD group underwent catheter-based RSD bilaterally and were simultaneously implanted with pacemakers. Atrial pacing was maintained for 8 h a day and a total of 12 weeks in the control group and RSD group. Echocardiography showed that the left atrial structure and function were significantly improved in the RSD group compared with the control group (P < 0.05). Compared with the control group, the RSD group had fewer incidences of AF and a shorter duration of AF (P < 0.05) after long-term intermittent atrial pacing. In addition to increased atrial effective refractory period (AERP) and AF cycle length, AERP dispersion and P-wave duration and dispersion were significantly decreased in the RSD group compared with the control group (P < 0.05). Atrial morphological evaluation suggested that fibrosis and ultrastructural changes induced by long-term intermittent atrial pacing were markedly suppressed in the RSD dogs compared with controls (P < 0.05). Immunohistochemistry results showed that connexin 43 distribution in RSD mid-myocardial was significantly fewer heterogeneous than that in control mid-myocardial (P < 0.05). Renal denervation inhibits the progression of paroxysmal AF, which might be related to the suppression of atrial electrophysiology and structural heterogeneity.

Association between reversal in the expression of hyperpolarization-activated cyclic nucleotide-gated (HCN) channel and age-related atrial fibrillation.

BackgroundWe compared cardiac electrophysiological indicators and regional expression levels of cardiac hyperpolarization-activated cyclic nucleotide-gated (HCN) channels between adult and aged dogs to identify possible mechanisms of age-related atrial fibrillation.Material/MethodsCorrected sinus node recovery time (SNRTc) and effective refractory period (ERP) of the atrium and pulmonary veins were measured in 10 adult (3–6 years old) and 10 aged dogs (>9 years old). Expression levels of HCN2 and HCN4 channel mRNAs and proteins were measured in the sinoatrial node, atrium, and pulmonary veins by real-time PCR and Western blotting.ResultsAged dogs exhibited a higher induction rate of atrial fibrillation (AF) in response to electrical stimulation, longer AF duration after induction, longer SNRTc, longer right atrial effective refractory period (AERP), shorter left AERP, and increased AERP dispersion compared to adults. Expression levels of HCN2 and HCN4 channel mRNAs and proteins were lower in the sinoatrial node but higher in the atrium and pulmonary veins of aged dogs.ConclusionsChanges in atrial electrophysiological indicators in aged dogs revealed sinoatrial node dysfunction. There was a reversal in the local tissue distribution of HCN2 and HCN4 channel mRNA and protein, a decrease in sinoatrial node expression, and increase in atrial and pulmonary vein expression with age. Changes in atrial electrophysiological characteristics and regional HCN channel expression patterns were associated with the onset and maintenance of age-related atrial fibrillation.

Programmed cell death-1 deficiency results in atrial remodeling in C57BL/6 mice

Deficiency of the programmed cell death-1 (PD-1) gene enhances T-cell activation and increases inflammation levels. It has been reported that atrial fibrillation (AF) is closely related to inflammation. The aim of the present study was to investigate the role of PD-1 deficiency in the pathogenesis of AF. Two groups of mice were used in our experiment: the C57BL/6 and the C57BL/6-PD-(1-/-) group. The expression of the inflammatory cytokines interleukin (IL)-2, -4, -6, -10, -17, interferon-γ and tumor necrosis factor were detected. Furthermore, the levels of atrial myocyte oxidative stress, the atrial effective refractory period (AERP) and the atrial myocardial fibrosis levels were determined. Compared with the C57BL/6 group, we found that the inflammatory cytokines were significantly increased in the PD-1(-/-) group and the levels of atrial myocyte oxidative stress in the PD-1(-/-) group were also higher. The AERP became shorter and the dispersion of AERP was increased in the PD-1(-/-) group. Moreover, the PD-1(-/-) group presented significant atrial myocardial fibrosis but the C57BL/6 group did not. Our findings strongly suggest that the higher levels of inflammatory cytokines and atrial myocyte oxidative stress were present in the PD-1(-/-) mice and resulted in atrial electricity and structural remodeling. Due to the atrial remodeling, the PD-1(-/-) mice were more likely to develop AF.

Inflammation abnormalities and inducibility of atrial fibrillation after epicardial ganglionated plexi ablation

Epicardial ganglionated plexi (GP) ablation can prevent atrial fibrillation inducibility. However, the long-term effects of GP ablation on atrial fibrillation have not been elucidated. Thirteen adult dogs of either sex, weighing 13-17kg, were randomly assigned to a sham-operated group (n=6) or a GP ablation group (n=7). After right thoracotomy, the atrial effective refractory period (AERP) was measured and atrial fibrillation was induced by right atrial rapid burst pacing. Atrial fibrillation and AERP were remeasured after anterior right and inferior right GP ablation in the GP ablation group. The animals were allowed to recover for 8 weeks, after which atrial fibrillation and AERP were measured again. Concentrations of C-reactive protein, tumour necrosis factor-alpha (TNF-α) and interleukin-6 were measured in the blood and atrial tissues. After 8 weeks, atrial fibrillation was induced in all animals in the GP ablation group. AERP and dispersion of AERP (dAERP; maximum AERP minus minimum AERP) were increased after GP ablation but AERP recovered after 8 weeks. There were no significant differences in the concentrations of C-reactive protein, TNF-α or interleukin-6 in venous blood between the two groups and the concentration of C-reactive protein in the atrium did not change before and after GP ablation. However, the concentrations of TNF-α and interleukin-6 in the atrium increased significantly 8 weeks after GP ablation (P<0.05). Increased concentrations of TNF-α and interleukin-6 in the atrium after GP ablation provide a new causative factor in terms of atrial fibrillation vulnerability.

CSPE Young Investigator Award Session

CSPE Young Investigator Award Session

E0032 Role of atrial substrate remodelling in inducibility of atrial fibrillation after epicardial ganglionic plexi ablation

ObjectiveInvestigating the long-term effect of ganglionated plexi (GP) ablation on atrial fibrillation (AF) after GP ablation.Methods13 dogs were randomly divided into sham-operated group and GP ablation group. All animals underwent...

Changes in Atrial Effective Refractory Period and I KACh After Vagal Stimulation Plus Rapid Pacing in the Pulmonary Vein

Recent studies have shown that rapid atrial pacing causes atrial electrical remodeling. However, the influence of the vagus nerve on atrial electrical remodeling is not clear. This study involved 24 dogs divided into three groups. In the control group, the inducibility of atrial fibrillation (AF) during vagal stimulation (VS(1)) was investigated. In the pacing group, the atrial effective refractory period (AERP) was determined before and after pacing in the left superior pulmonary vein (LSPV). In the vagal stimulation (VS) plus pacing group, the LSPV was subjected to rapid electrical pacing after vagal stimulation (VS(2)), and the AERP was measured both before VS(2) and after pacing. The I(KACh) density was measured in LSPV and atrial myocardial cells in the three groups using the patch-clamp technique. The duration of induced AF was greater in the pacing group than in the control or VS-plus-pacing group. In the pacing group, the AERP was markedly shortened and the AERP dispersion (dAERP) was significantly increased (P< .05). However, there was no significant change in AERP in the VS-plus-pacing group, though the dAERP increased significantly (P< .05). The I(KACh) density was increased in LSPV and atrial myocardial cells after pacing. However, there was no significant change in I(KACh) density after VS(2) plus pacing. Although shortening of the AERP may play a fundamental role, it is not in itself responsible for cholinergically induced AF. Rapid pacing in the LSPV increased the I(KACh). However, VS before rapid pacing partly protected the atria against electrical remodeling.

Effects of spironolactone on electrical and structural remodeling of atrium in congestive heart failure dogs

Renin-angiotensin-aldosterone system has been demonstrated to be associated with both congestive heart failure (CHF) and atrial fibrillation (AF). This study investigated the effects of spironolactone, a kind of aldosterone antagonist, on atrial electrical remodeling and fibrosis in CHF dogs induced by chronic rapid ventricular pacing. Twenty one dogs were randomly divided into sham-operated group, control group, and spironolactone group. In control group and spironolactone group, dogs were ventricular paced at 220 beats per minute for 6 weeks. Additionally, spironolactone at 15 mg x kg(-1) x d(-1) was given to dogs 1 week before rapid ventricular pacing until pacing stopped. Transthoracic and transoesophageal echocardiographic examinations were performed to detect structural and functional changes of the atrium. Swan2 Ganz floating catheters were used to measure hemadynamics variances. Atrial effective refractory period (AERP), AERP dispersion (AERPd), intra- and inter-atrium conduction time (CT) and intra-atrium conduction velocity (CV) were determined. The inducibility and duration of AF were also measured in all groups. Finally, atrial fibrosis was quantified with Masson staining. AERP did not change significantly after dogs were ventricular paced for 6 weeks. However, AERPd, intra- and inter-atrium CT increased significantly, and CV decreased apparently, which was negatively correlated to the atrial fibrosis (r = -0.74, P < 0.05). Simultaneously, left atriums were enlarged and cardiac hemadynamics worsened in pacing dogs. Although spironolactone could not affect cardiac hemadynamics effectively, it can obviously improve left atrial ejection fraction (P < 0.05). Spironolactone treatment did not alter AERP duration, but this medicine dramatically decreased AERPd (P < 0.05), shortened intra- and inter-atrium conduction time (P < 0.05), and increased atrium CV. Moreover, spironolactone decreased the inducibility and duration of AF (P < 0.05), as well as atrial fibrosis (P < 0.01) induced by chronic rapid ventricular pacing. Spironolactone contributes to AF prevention in congestive heart failure dogs induced by chronic rapid ventricular pacing, which is related to atrial fibrosis reduction and independent of hemadynamics.

Difference between electrical remodelling after pulmonary veins and right atrium appendage pacing

Pulmonary veins (PVs) are important sources of paroxysmal atrial fibrillation (AF). Rapid atrial pacing changes atrial electrophysiology, and facilitates the induction and maintenance of AF. The purpose of our study was to evaluate the changes in atrial effective refractory period (AERP) proprieties and in ionic currents in PVs myocytes from dogs subjected to rapid atrial pacing in PVs and right atrial appendage (RAA) and to relate these changes to the ability to induce AF. Twelve mongrel dogs in normal sinus rhythm were paced from the superior left PVs or RAA at 500 bpm for 4 h. Electrophysiological studies were conducted to determine the changes in AERP, dispersion, and rhythm. Ionic currents were evaluated using patch clamp technique in single PVs myocytes in sham-operated dogs, and the results were compared with those from PVs and RAA pacing groups. The presence of rapid atrial pacing was associated with a marked shortening in AERP in both PVs and RAA pacing group with a marked increase in AERP dispersion in PVs pacing. Both L-type calcium current (I(Ca,L)) and the transient outward current (I(to)) were reduced in both groups with an increased significance in PVs pacing group. The density of I(Ca,L) was decreased significantly from (-6.03 +/- 0.63) pA/pF in the control group to (-3.21 +/- 0.34) pA/pF in the PVs pacing group and (-4.75 +/- 0.41) pA/pF in the RAA pacing group (n = 6, P < 0.05), whereas the density of I(to) was decreased significantly from (8.45 +/- 0.71) pA/pF in the control group to (5.21 +/- 0.763) pA/pF in the PVs pacing group and (6.84 +/- 0.69) pA/pF in the RAA pacing group (n = 6, P < 0.05). Our findings provide likely ionic mechanisms of shortened repolarization in induced atrial tachycardia with a decrease in I(Ca,L) and I(to) densities, which is the likely mechanism for a decrease in action potential duration rate adaptation in the canine rapid pacing model more pronounced in the PVs pacing group underlying the crucial role of PVs in initiating AF.

Effects of Cilazapril on atrial electrical, structural and functional remodeling in atrial fibrillation dogs

Background and purpose The effects of angiotensin-converting enzyme inhibitor on long-term atrial electrophysiologic and structural remodeling are still unclear. The purpose of this study is to investigate the effects of Cilazapril on atrial electrical, structural, and functional remodeling in atrial fibrillation (AF) dogs induced by chronic rapid atrial pacing. Methods Twenty dogs were randomly divided into sham-operated group (n = 6), control group (n = 7), and Cilazapril group (n = 7). One thin silicon plaque containing 4 pairs of electrodes was sutured to each atrium. A pacemaker was implanted in a subcutaneous pocket and attached to a screw-in epicardial lead in the right atrial appendage. The dogs in control group and Cilazapril group were paced at 400 beats per minute for 6 weeks. The dogs in Cilazapril group received Cilazapril (0.5 mg•kg −1•d −1) 1 week before rapid atrial pacing until pacing stop. Before and after 6-week rapid atrial pacing, atrial effective refractory period (AERP) at 8 sites, AERP dispersion, intraatrium conduction time, inducibility, and duration of AF were measured. Transthoracic and transesophageal echocardiographic examinations included left atrium (LA) maximal volume, LA minimal volume, LA ejection fraction, left atrial appendage (LAA) maximal volume, LAA minimal volume, LAA ejection fraction, LAA maximal forward flow velocity, and LAA minimal backward flow velocity were performed. Atrial collagen volume fraction was analyzed by Masson staining. Results After 6-week rapid atrial pacing, although there was no significant difference in AERP shortening and AERP rate adaptation reduction between the control group and the Cilazapril group, the inducibility and duration of AF were found to be dramatically lower in the Cilazapril group than those in the control group (AF inducibility, 65.7% vs 95.7%, P < .05; AF duration, 531.5 ± 301.2 vs 1432.2 ± 526.5 s, P < .01).The post-tachycardia intraatrium conduction times after 6 weeks with Cilazapril were significantly shorter than those in the control group. Cliazapril could partially prevent AERP dispersion increase induced by chronic rapid atrial pacing. Compared with the control group, the LA and LAA volumes were significantly smaller; LA ejection fraction, LAA ejection fraction, LAA maximal forward flow velocity, and LAA minimal backward flow velocity were dramatically higher in the Cilazapril group. The Cilazapril group had a significantly lower percentage of interstitial fibrosis than the control group. Conclusions Cilazapril can suppress structural and functional remodeling and prevent the induction and promotion of AF in chronic rapid atrial pacing dogs.

Verapamil suppresses the inhomogeneity of electrical remodeling in a canine long-term rapid atrial stimulation model.

Verapamil is known to suppress shortening of the atrial effective refractory period (AERP) during relatively short-term atrial pacing, although the effect of a long-term stimulation model is unclear. The effect of verapamil on electrical remodeling was evaluated in a canine rapid atrial stimulation model. The right atrial appendage (RAA) was continuously paced (400 beats/min) for 2 weeks. Four pairs of electrodes were sutured at four atrial sites; the RAA, right atrium close to the inferior vena cava, Bachmann's bundle, and LA. AERP, AERP dispersion (AERPd), conduction time, and inducibility of AF were evaluated during the pacing phase and the recovery phase. The same protocol was performed under the administration of verapamil. In five control dogs, the AERP shortening was inhomogeneous and the shortening of the AERP was most prominent in the LA. AERPd increased during the rapid pacing phase by 5 +/- 2 ms, but recovered quickly in the recovery phase. The max AERPd was 46 +/- 4 ms in the control group and was larger than that in the verapamil group (31 +/- 3 ms, P = 0.001). At the LA site, the shortening of the AERP was decreased by verapamil administration (-19 +/- 3 vs -5 +/- 2 ms, P = 0.04). However, the AF inducibility was not significantly different between the two groups. The effect of verapamil on electrical remodeling was inhomogeneous, depending on the anatomic portion. As a result, AERPd widening during the rapid pacing phase was suppressed by verapamil, while the AF inducibility was unchanged.

Experimental study of the effect of the vagus nerve on atrial electrical remodeling

Recent studies have shown that rapid atrial activation causes atrial electrical remodeling (AER), which recovers quickly following withdrawal of stimulation. The underlying mechanisms, however, are incompletely understood. The purpose of the present study, therefore, was to characterize the effect of the vagus on AER as well as define possible mechanisms of the phenomenon. Eight dogs were used in the study for 3 consecutive protocols. In the first, the dogs were subjected to atrial pacing at 800 ppm for 7 hours. Every hour, pacing was interrupted for a short time and atrial effective refractory period (AERP) was measured at 6 sites. The rapid atrial pacing was then discontinued and the electrophysiological study was repeated every hour for another 7 hours. Time-domain parameters of heart rate variability (HRV) were also computed 1 hour before pacing as well as each of 7 hours after the rapid atrial pacing protocol. The second program was performed two weeks after the first; 0.04 mg/kg of atropine was administered intravenously 30 min before pacing, and then 0.007 mg/kg was added at each hour. Parameters of HRV were not evaluated. Finally, the 8 dogs were subjected to the third protocol 2 weeks after completion of the second; 0.2 mg/kg of propranolol was given intravenously 30 min before pacing, and 0.04mg/kg was added at each hour. The dispersion of AERP (dAERP) was calculated as, maximum AERP minus minimum AERP. There was a prompt decrease in AERP as the result of pacing ( P<.05), but dAERP did not change significantly. The AERP recovered quickly, and dAERP increased from 21 ±5.3ms to 40 ± 7.4ms ( P<.05) after cessation of pacing. At the same time, the parameters of HRV increased ( P<.05) after cessation of pacing. The AERP increased from 128 ± 12 ms to 135 ± 12 ms and from 127 ± 12 ms to 142 ± 14 ms ( P<.05) after vagal and autonomic blockade. However, AERP decreased during pacing ( P<.05) with vagal or autonomic blockade, but dAERP did not change significantly during or after pacing. These results suggest that vagal and autonomic blockade can not prevent AER, but a high vagal tone is associated with a high dAERP during recovery from AER, indicating that the vagus and sympathetic have a synergistic effect on the refractory period.

Effect of pilsicainide on atrial electrophysiologic properties in the canine rapid atrial stimulation model.

The heterogeneous process of atrial electrical remodeling (AER) in the canine rapid atrial stimulation model has been previously reported although it has been reported that a sodium channel blocker might suppress the shortening of the atrial effective refractory period (AERP), its effect on long-term electrical remodeling is unknown. In the present study, the effect of pilsicainide on AER was evaluated. The right atrial appendage (RAA) was paced at 400 beats/min for 2 weeks. In the RAA, Bachmann's bundle (BB), the right atrium near the inferior vena cava (IVC) and in the left atrium (LA), AERP, AERP dispersion (AERPd) and the inducibility of atrial fibrillation (AF) were evaluated at several time points of the pacing phase and the recovery phase (1 week). The same protocol was performed during the administration of pilsicainide (4.5 mg/kg per day) and the parameters were compared with the controls. In the control dogs, the AERP was significantly shortened by rapid pacing at all atrial sites studied and the AERP shortening (DeltaAERP) was larger at the RAA and LA sites (p<0.03). However, pilsicainide decreased these DeltaAERPs at all 4 atrial sites. AERPd was increased during the pacing phase whereas it was decreased during the recovery phase in the control dogs. In contrast, this pacing-induced AERPd was attenuated by the administration of pilsicainide. The AF inducibility was highest at the LA site in both groups, and the inducibility was lower in the pilsicainide group than the control group at all atrial sites. During the rapid pacing phase, the ventricular heart rate was significantly lower in the pilsicainide group than the control because of intra-atrial conduction block. In a canine rapid right atrial stimulation model, pilsicainide suppressed the shortening of the AERP at all atrial sites, possibly through the improvement of the hemodynamics as well as the action of the Na - Ca exchanger.

Role of dispersion of atrial refractoriness in the recurrence of clinical atrial fibrillation; a manifestation of atrial electrical remodelling in humans?

The mechanism of atrial fibrillation recurrence following cardioversion is unknown, although experimental studies have indicated that changes in dispersion of atrial refractoriness may play a role. The aims of this study were to assess (1) if dispersion of atrial refractoriness is relevant to atrial fibrillation recurrence and (2) if dispersion of refractoriness is part of the atrial electrical remodelling process in humans. Thirty-seven consecutive patients underwent internal cardioversion (CV1) of persistent atrial fibrillation. Patients were monitored by daily transtelephonic recordings following discharge and if there was spontaneous atrial fibrillation recurrence they were rapidly admitted for repeat cardioversion (CV2). We used the 5th percentile of 100 consecutive atrial fibrillation cycle lengths (AFCL(P5)) and the atrial effective refractory period (AERP) as measures of atrial refractoriness at four different atrial sites. Dispersion of AFCL(P5)at CV1 was significantly higher in those who had subsequent recurrence of atrial fibrillation than in those who remained in sinus rhythm for at least 1 month after cardioversion (35+/-17 ms vs 9+/-13 ms;P<0.02). Dispersion of AFCL(P5)measured at CV2 was significantly lower than that measured in the same patients at CV1 (19+/-8 ms vs 35+/-11 ms;P=0.02). i.e. dispersion of AFCL(P5)had reduced following a period of sinus rhythm. In contrast, there was no difference in dispersion of AERP between the recurrers and non-recurrers. Dispersion of AERP between CV1 and CV2 did not change following a period of sinus rhythm. Dispersion of AFCL is relevant to atrial fibrillation recurrence and may represent a manifestation of atrial electrical remodelling in humans. Treatment directed at AFCL dispersion may be useful in the suppression of atrial fibrillation recurrence following cardioversion.

Inhomogeneity in the appearance of electrical remodeling during chronic rapid atrial pacing: evaluation of the dispersion of atrial effective refractoriness.

In the present study, the long-term process of progression of electrical remodeling at various atrial sites, which is not well understood, was compared while monitoring continuously the electrophysiologic parameters at multirecording sites in canine atria during continuous atrial burst pacing. A rapid pacing device was implanted in 5 dogs, and continuous atrial burst pacing (400 beats/min) was delivered at the right atrial appendage (RAA). Four pairs of epicardial wire electrodes were sutured on (1) the RAA, (2) Bachmann's bundle (BB), (3) the right atrium close to the inferior vena cava (IVC), and (4) the left atrium (LA). The distal ends of those wires were exteriorized posteriorly and used for pacing and recording. The atrial effective refractory period (AERP), AERP dispersion (AERPd), atrial conduction time (CT) and inducibility of atrial fibrillation (AF) were evaluated during burst pacing for 14 days and during the subsequent 7 days' recovery. The AERP at the LA pacing site was shorter than that at the other sites on day 0. The AERP shortening was greater in the RAA and LA sites than in the BB and IVC sites. The AERPd increased during pacing and reached the maximum level on day 3, and then decreased during the recovery phase. Prolongation of CT tended to be longer between the RAAand IVC sites than that between the other sites. The incidence of AF induction became higher in accordance with the time course of the rapid pacing phase. There was another peak of AF induction on days 7-10. In a canine chronic rapid atrial stimulation model, the progression of electrical remodeling (ie, the shortening of the AERP and the prolongation of the CT) was not homogeneous in both atria, the AERPd showed a temporal increase between days 3 and 7 and matched the increase in AF inducibility at the LA pacing site, the increase in the AERPd was mainly caused by more rapid AERP shortening at the RAA or LA sites, and the LA site always showed a shorter AERP than the other atrial sites in the control state and during the rapid pacing phase, whereas AF inducibility was higher at the LA site than the other sites.

Effect of verapamil on long-term tachycardia-induced atrial electrical remodeling.

The effect of verapamil on long-term tachycardia-induced atrial electrical remodeling has not been reported. Forty-eight dogs were randomly divided into verapamil and control groups. The dogs in the verapamil group received verapamil 120 mg every day, those in the control group did not receive verapamil. Atrial effective refractory period (AERP), inducibility of atrial fibrillation (AF), and duration of AF were assessed before and after complete atrioventricular junction ablation with 1-day, 1-week, or 6-week rapid atrial pacing (780 bpm). AERP shortening, AERP dispersion, AERP maladaptation, and inducibility of AF after 1-day pacing was significantly attenuated by verapamil. However, verapamil did not have any significant effect on these parameters in the dogs with 1-week or 6-week pacing. Verapamil did not have any significant effect on the conduction velocity in the dogs with 1-day, 1-week, or 6-week pacing. Before rapid atrial pacing, verapamil significantly prolonged the duration of AF. In the dogs with 1-day pacing, the duration of AF measured immediately after termination of pacing was similar between the control and verapamil groups. However, in the dogs with 1-week or 6-week pacing, the duration of AF after pacing was significantly longer in the verapamil group. Verapamil cannot prevent long-term (1 and 6 weeks, respectively) tachycardia-induced changes of atrial electrophysiological properties. Furthermore, verapamil increases the duration of AF in the dogs either before or after long-term rapid atrial pacing.

Electrophysiologic Properties of the Atrium in Patients with Chronic and Paroxysmal Atrial Fibrillation

Background:Atrial fibrillation (AF) causes electrical remodeling of the atrium that plays an important role in increasing atrial vulnerability and the perpetuation of AF. The regional variation and heterogeneities of AFinduced electrical remodeling in patients with AF remain unclear. The purpose of present study was to test the hypothesis that regional heterogeneity of the atrial electrical properties including sinus node dysfunction is more apparent in patients with chronic AF than in patients with paroxysmal AF. Methods:The study group consisted of chronic AF (CAF, n=19), paroxysmal AF (PAF, n=19) and control group (CON, n=13). Monophasic action potential duration 90% (MAPD90) and atrial effective refractory period (AERP) were measured at 9 different sites in the right atrium using MAP catheter. Dispersion of MAPD90 and AERP were calculated from the difference between the maximum and minimum value at 9 sites, respectively. Intra-atrial conduction time (IACT) was calculated from the distance between the earliest activation and the latest one of the electrograms by 20-pole steerable catheter with 2-mm interelectrode distance which was positioned along the tricuspid annulus anterior to the crista terminalis. To evaluate sinus node function, post shock sinus node recovery time (PSRT) was measured. A rate corrected PSRT (PSRTc) was calculated from the difference between PSRT and basic sinus cycle length. Results:MAPD90 significantly shortened in patients with CAF (227.0±32.6 ms) compared with PAF (246.8±38.3 ms, p<0.05) and CON (239.1±39.3 ms, p<0.05), but AERP was not significantly different among 3 groups. The regional changes and dispersion of MAPD90 and AERP in patients with CAF did not differ from those of PAF and CON. IACT was prolonged in CAF group (73.8±22.5 ms) compared with PAF (58.2±8.0 ms, p<0.05) and CON groups (51.6±12.3 ms, p<0.05). IACT in CAF group (73.8±22.5 ms) was significantly prolonged compared with CON groups (51.6±12.3 ms, p<0.05) and was longer than that of PAF groups (58.2±8.0 ms) without statistical significance. PSRTc was longer in CAF group (758.3±525.8 ms) than in PAF group (209.5±125.0 ms, p<0.05). Conclusion: Electrical changes defined as shortened MAPD 90, prolonged IACT and PSRTc were more apparent in 논문접수일:1999년 11월 22일 심사완료일:2000년 2월 17일 교신저자:김영훈, 136-705 서울 성북구 안암동 5가 126-1 고려대학교 의과대학 내과학교실 전화:(02) 920-5445·전송:(02) 927-1478 E-mail:yhkmd@unitel.co.kr