Effects of Acetylcholine on Electrical Remodeling of Human Atrial Fibers

Autonomic nervous system activation can result in significant changes of atrial electrophysiology and facilitate induction of atrial fibrillation. By recording influence of different concentrations of acetylcholine （ACh） on atrial fibers （AF）, we investigated the role of the increased vagal tone in electrical remodeling in atrial fibrillation. Parameters of action potentials and force contraction （Fc） in atrial fibers were recorded by using standard intracellular microelectrode technique and force transducer. It was found that： （1） ACh at 0.1 μmol/L had no significant influence on spontaneous action potentials （SAPs） and Fc （n=6, P0.05）; ACh at both 1.0 and 10.0 μmol/L shortened action potential duration （APD） and Fc of human AF from right atrium （n=6, P0.05）; there was no significant difference in shortening APD between 10.0 and 1.0 μmol/L of ACh; （2） ACh at 0.1 μmol/L had no significant desensitization （n=6, P0.05）, but ACh at 1.0 and 10.0 μmol/L had desensitization （n=6, P0.05） to SAPs and Fc. The desensitization of ACh on APD in AF was concentration- and time-dependent. It was shown that APD was longer than the control along with extending time of continuous Tyrode＇s solution perfusion after desensitization. It is concluded that ACh changes the electrophysiological characteristics of human AF, indicating that increased vagal tone plays a role in the development of a vulnerable substrate for atrial electrical remodeling in atrial fibrillation.

CT-1-CP-induced Ventricular Electrical Remodeling in Mice

The chronic effects of carboxyl-terminal polypeptide of Cardiotrophin-1（CT-1-CP） on ventricular electrical remodeling were investigated. CT-1-CP, which contains 16 amino acids in sequence of the C-terminal of Cardiotrophin-1, was selected and synthesized, and then administered to Kunming mice（aged 5 weeks） by intraperitoneal injection（500 ng·g^-1·day^-1）（4 groups, n=10 and female： male=1：1 in each group） for 1, 2, 3 and 4 weeks, respectively. The control group（n=10, female：male=1：1） was injected by physiological saline for 4 weeks. The epicardial monophasic action potential（MAP） was recorded by using a contact-type MAP electrode placed vertically on the left ventricular（LV） epicardium surface, and the electrocardiogram（ECG） signal in lead Ⅱ was monitored synchronously. ECG intervals（RR, PR, QRS and QT） and the amplitude of MAP（Am）, the maximum upstroke velocity（Vmax）, as well as action potential durations（APDs） at different repolarization levels（APD30, APD50, APD70, and APD90） of MAP were determined and analyzed in detail. There were no significant differences in RR and P intervals between CT-1-CP-treated groups and control group, but the PR segment and the QRS complex were greater in the former than in the latter（F=2.681 and 5.462 respectively, P〈0.05）. Though QT interval and the corrected QT interval（QTc） were shorter in CT-1-CP-treated groups than in control group, the QT dispersion（QTd） of them was greater in the latter than in the former（F=3.090, P〈0.05） and increased with the time. The ECG monitoring synchronously with the MAP showed that the compression of MAP electrode on the left ventricular epicardium induced performance similar to myocardium ischemia. As compared with those before chest-opening, the PR segment and QT intervals remained basically unchanged in control group, but prolonged significantly in all CT-1-CP-treated groups and the prolongation of QT intervals increased gradually along with the time of exposure to CT-1-CP. The QRS complex had no significant change in control group, one-week and three-week CT-1-CP-treated groups, but prolonged significantly in two-week and four-week CT-1-CP-treated groups. Interestingly, the QTd after chest-opening was significantly greater than that before chest-opening in control group（t=5.242, P〈0.01）, but decreased along with the time in CT-1-CP-treated groups. The mean MAP amplitude, Vmax and APD were greater in CT-1-CP-treated groups than those in control group, and became more obvious along with the time. The APD in four CT-1-CP-treat groups was prolonged mainly in middle to final repolarization phase. The difference among these groups became significant in middle phase（APD50）（F=6.076, P〈0.01） and increased furthermore in late and final phases（APD70： F=10.054; APD90： F=18.691, P〈0.01） along with the time of injection of CT-1-CP. The chronic action of CT-1-CP might induce the adapting alteration in cardiac conductivity and ventricular repolarization. The amplitude and the Vmax of the anterior LV epicardial MAP increased obviously, and the APD prolonged mainly in late and final phase of repolarization.

Autonomic mechanism for chronic atrial electrical remodeling induced by rapid atrial pacing in ambulatory danines

Objetives The mechanism for changes in the electrophysiological properties of the atria during rapid pacing induced atrial fibrillation(AF) is not well understood.We aimed to investigate the contribution of intrinsic cardiac autonomic nervous system(ICANS) in chronic atrial electrical remodeling and AF induced by rapid atrial pacing for 4 weeks. Methods Twelve adult mongrel dogs weighing 15 to 20 kg were assigned to two groups;group 1(experimental group,n= 7) and group 2(control group,n =5).All dogs were anesthetized with propofol and mechanically ventilated via endotracheal tubes.The chest was entered via bilateral mini-thoracotomy at the fourth intercostals space.Bipolar pacing electrode was sutured to the right atrial appendage.Four-electrode catheters(Biosense-Webster,Diamond Bar,CA) were secured to allow recording at the right and left atriaum.All tracings from the electrode catheters were amplified and digitally recorded using a computer-based Bard Laboratory System (CR Bard Inc,Billerica,MA).Electrograms were filtered at 50 to 500 Hz.Continuous rapid pacing(600 bpm, 2×threshold[TH]) was performed at the right atrial appendage. Ganglionated Plexi(GP) was localized by applying high frequency stimulation(HFS;20 Hz,0.1ms duration, 0.5 to 4.5 V)with a bipolar stimulation-ablation probe electrode (AtriCure,West Chester,OH).Group1 underwent ablation of bilateral GP and ligament of Marshall followed by 4-week pacing.Group 2 underwent sham operaton without ablation of GP and ligament of Marshall followed by 4-week pacing.The effective refractory period(ERP) and window of vulnerability(WOV) were measured at 2×TH before(baseline) and every week after GP ablation.WOV was defined as the difference between the longest and the shortest coupling interval of the premature stimulus that induced AF.GP consist of the anterior right ganglionated plexi(ARGP) located in the fat pad at the right superior pulmonary vein(RSPV)-atrial junction;the inferior right ganglionated plexi(IRGP) located at the inferior vena cava/right atrial junction;the superior left ganglionated plexi(SLGP) at the left superior pulmonary vein(LSPV) /left atrial junction and the inferior left ganglionated plexi(ILGP) at the left inferior pulmonary vein (LIPV)/left atrial junction.Results Immediately after ablation, the ERP in Group 1 became markedly longer and started to shorten gradually during the first 2 weeks,then stabilized at the 4th week.Compared to Group2,the ERP of Group1 was significantly longer in the first 3 weeks(P【 0.05),but no obvious difference at the 4th week in either the right or left atrium(P】0.05).In Group 1,AF could not be induced(WOV=0)in the first 3 weeks after ablation, and at the 4th week,AF was induced in 2 of 7 dogs.In Group2,WOV progressively widened during the 4-week period. AF could not be induced in 5 of 7 dogs in Group 1 and 1 of 5 dogs in Group 2 during the 4-week pacing period. Conclusions The intrinsic cardiac autonomic nervous system (ICANS) plays an important role in the early stage of atrial electrical remodeling induced by rapid atrial pacing.On the other hand,with time passing by,its effect on the formation of AF decreases gradually,which suggests that ICANS may account for a non-dominant factor in the late stage of the rapid pacing-induced chronic atrial fibrillation.

Effects of Losartan on acute atrial electrical remodeling

Background Atrial electrical remodeling (AER) contributes to the maintainance of atrial fibrillation (AF). This study was to compare the effects of Losartan with those of Diltiazem on tachycardia-induced acute AER in rabbits Methods Twenty-one rabbits paced with maximal atrial capture rate for 3 hours in the right atrium (RA) were randomly divided into saline group, Diltiazem group and Losartan group After autonomic blockage, we measured atrial effective refractory period (AERP), AERP rate adapting feature, AERP dispersion and RA conduction time at basic cycle lengths (BCLs) of 200 ms and 150 ms at baseline, 0 5 hour, 1 hour, 2 and 3 hours after rapid atrial pacing Results In the saline group, there was a prompt decrease in AERP as a result of rapid atrial pacing, and AERP 200 and AERP 150 were shortened sharply within 0 5 hour of pacing (30 2±10 5 ms and 24 1±9 1 ms, respectively) The AERP did not change dramatically in the Diltiazem and Losartan groups In the saline group, the value of (AERP 200 -AERP 150 )/50 ms in high RA was 0 17±0 08 at baseline and became significantly smaller at 0 5 hour (0 08±0 06), 1 hour (0 09±0 06), 2 hours (0 08±0 04) and 3 hours (0 09±0.05) (all P <0 05), suggesting a reduction of rate adaptation of AERP The value of (AERP 200-AERP 150)/50 ms in high RA did not change during the 3 hours of pacing in both Diltiazem and Losartan groups In the saline group, AERP dispersion increased significantly at 2 and 3 hours ( P <0 05) However, Diltiazem could not prevent the increase of AERP dispersion at 3 hours ( P <0 05) During Losartan infusion, the AERP dispersion was no longer increased after rapid atrial pacing There was no significant difference in RA conduction time among the three groups Conclusion Like calcium antagonist Diltiazem, Losartan could prevent AERP shortening and preserve rate adaptation of AERP after rapid atrial pacing Losartan is more effective than Diltiazem in inhibiting the increase of AERP dispersion

Electrical remodeling in human atrial fibrillation

Atrial fibrillation is the most common clinically important cardiac arrhythmia accounting for 20% to 25% of strokes and is a common cause of congestive heart failure.1,2 With the aging population and changing demographics,atrial fibrillation has become an epidemic affecting 2.66 million people in the United States.The prevalence of atrial fibrillation is estimated to increase by 5 fold to 12 million by 2050.3 The diagnosis and treatment of atrial fibrillation represent a significant health care burden of $15.7 billion per year.4 Treatment of atrial fibrillation using antiarrhythmic drugs has been disappointing,while radiofrequency ablation approaches have limitations,including unclear long-term efficacy.Innovation in treatment is needed and pursuit of novel modalities of therapy requires fundamental knowledge in the molecular mechanisms that lead to atrial fibrillation,including electrical remodeling in atrial fibrillation.

Effects of Amiodarone plus Losartan on Electrical Remodeling in Rapid Atrial Pacing in Rabbits

Objectives To investigate the electrical remodeling and the effects of amiodarone and losartan on electrical remodeling in rapid atrial pacing on rabbit model. Methods 40 normal rabbits were randomly divided into 4 groups ： the saline group （control group）, amiodarone group, losartan group, anti ＋ los group. All rabbits were raised drugs in a week. The atrial effective refractory period （AERP） was measured. Then, take a rapid atrial pacing （600 bpm） and the AERP was measured after 0.5, 1, 2, 4, 6 and 8 hours pacing and 30 minutes after the termination of rapid pacing. Results （1） In control group, after 8 hours rapid pacing, AERP200 and AERP150 were significantly shortened 16. 11% ± 3.1% （ P 〈 0. 01 ） and 9. 99 % ± 4. 2% （ P 〈 0. 01 ）. And the degree of AERP shortening induced by rapid pacing was greater at basic cycle lengths of 200 ms （BCL200） than that at BCL150. The AERP of amiodarone, losartan group and ami ＋ los group were not shortened during rapid pacing. （2） In the control group, after the termination of rapid pacing, the AERP gradually increased. The AERP at all of the BCLS examined recovered to almost the 95.78% and 96. 76% of baseline values within the first 10 minutes and recovered to almost the 99.07% and 99.39% of baseline values within the first 30 minutes. Conclusions Short-term atrial rapid pacing can induce the atrial electrical remodeling. Amiodarone and losartan can prevent the electrical remodeling.

Changes of Expression of Stretch-activated Potassium Channel TREK-1 mRNA and Protein in Hypertrophic Myocardium

The expression of stretch activated potassium channel TREK-1 mRNA and protein of hypertrophic myocardium was measured. Using a model of hypertrophy induced by coarctation of abdominal aorta in male Wistar rats, the expression of TREK-1 mRNA and protein was detected by using semi quantitative RT-PCR and Western blot respectively. At 4th and 8th week after constriction of the abdominal aorta , rats developed significant left ventricular hypertrophy. As compared to sham-operated group, stretch-activated potassium channel TREK-1 mRNA was strongly expressed and protein was up regulated in operation groups （P〈0.05）. It was concluded that the expression of TREK-1 was up-regulated in hypertrophic myocardium induced by chronic pressure overload in Wistar rats.

Effect of cyclosporine-A on electrophysiological properties of atria in tachycardia-induced atrial fibrillation

Objective To investigate the effects of ciyelosporine-A(CsA).a calcinenrin(CAN)inhibitor,on electrophysiological propertiesof atria in canine tachycardia-induced model of AF.Methods Eighteen healthy adult mongrel canines weighing 17.0 to 23.2 kg(rangedfrom 2 to 4 years old)were randomized to 3 groups,Sham group(no pacemaker was implanted),atrial tachypacing group(ATP group)each group at baseline and after 8 weeks' tachypacing.Measurements included atrial effective refractory period(AERP),conductionvelocity(CV),wave length(WE),atrial fibrillation load and rate-adaptability. Results After 8 weeks' atrial tachypacing,ATP andCsA groups showed significant longer duration of the P wave,shorter AERP,decreased adaptation of AERE slower CV,shorter Wland longer AF duration compared to the shamg roup (all P＜0.05).AERP of the CsA group was longer than that of ATP group (P＜0.05),but there were no differences in rate-adaptability,CV,incidence of induced AF and AF duration between CsA group and ATP group.Conclusions Our results suggest that calcineurin pathway intervention by CsA have a positive effect on tachycardia-inducedelectrical remodeling of atria,but can not prevent or reverse AF.

Effect of nifekalant on acute electrical remodelling in rapid atrial pacing canine model

Background Nifekalant may prevent atrial fibrillation （AF） and possibly be useful in treatment of atrial tachyarrhythmia in patients with severe heart failure. This study investigated the electophysiologic effect of nifekalant on the acute atrial remodeling in rapid atrial pacing （RAP） model of canine. Methods Twelve mongrel dogs subjected to rapid stimulation （400 beats/min） at left atrial appendage （LAA） for 24 hours, were randomized into the control group （rapid pacing only, n=6） and the nifekalant group （intravenous nifekalant therapy immediately after RAP, n=6）. Atrial electrophysiological parameters were measured in right atrium, coronary sinus, LAA, posterior wall of left atrium （PWLA） and left superior pulmonary vein （LSPV）, before and after the RAP. Results In the control group, the effective refractory periods （ERP） were shortened greatly at all sites, paced dogs had substantially shorter ERPs in the high right atrium, LAA, and LSPV, but fewer changes in the PWLA, the coefficient variation of ERP （COV ERP） was increased significantly. After rapid atrial stimulation, the inducibility of AF increased significantly [induction number： pre-RAP vs post-RAP, 1.00 ± 0.89 vs 8.17 ± 2.79, P〈0.01; duration of AF： pre-RAP vs post-RAP, （450.34± 362.59） ms vs （9975.77±4376.99） ms, P〈0.01]. In the nifekalant group, although the ERPs were prolonged at all sites compared with those in pre-RAP state, only the value at LSPV differed significantly from that in pre-RAP state [pre-RAP vs post-RAP, （102.50±5.24） ms vs （132.51 ±5.20） ms, P〈0.01]; the COV ERP did not change statistically in this group. The inducibility of AF slightly increased but insignificantly after pacing [induction number： pre-RAP vs post-RAP, 0.83 ±0.75 vs 1.67±0.82, P=0.19; duration of AF： pre-RAP vs post-RAP, （378.67±317.88） ms vs （1124.08± 1109.77） ms, P=0.06]. Conduction time values did not alter significantly in either of the two groups after RAP. Condusions In canine RAP model, nifekalant inhibited ERP shortening and ERP heterogeneity increasing, decreased AF induction. Nifekalant can reverse acute electrical remodeling effect in this model.

Automatic modulation of refractoriness of His Purkinje system during atrioventricular nodal reentrant tachycardia

Objective To illustrate the automatic modulation of refractoriness of His Purkinje system during atrioventricular nodal reentrant tachycardia (AVNRT) and to discuss the possible mechanisms Methods Programmed electrical stimulations were performed in high right atrium (HRA) in 8 patients with AVNRT before ablation to induce tachycardia and electrocardiagraphic recordings were done synchronically when AVNRT appeared Results All the patients had 2∶1 atrioventricular (A V) conduction when AVNRT began, 2 of whom were blocked below His bundle, 5 above His bundle and 1 unclear After a duration of 14 03±10 03 s of 2∶1 A V conduction, 1∶1 A V conduction with bundle banch block appeared, 3 of which were right bundle branch block (RBBB), 3 left bundle branch block (LBBB), and 2 with both Bundle branch block disappeared after a duration of 6 87±11 26 s Conclusion Effective refractory period (ERP) of His Purkinje system at the beginning of AVNRT was modulated automatically within less than 30-60?s and thus facilitated nodal ventricular conduction The mechanism of this is electrical remodeling

Expression levels of ionic channels in atrial myocytes are changeable by ambient high hydrostatic pressure stimulation

Background Atrial fibrillation （AF） is the most common arrhythmia encountered in clinical practice and hy- pertension has been well established to be the most common medical condition associated with AF. The present study aimed to explore the expression of ionic channels in atrial myocytes, the main mechanisms of atrial electrical remodeling, under ambient pressure stimulation. Methods A resealable device that could provide and maintain a certain pressure was designed and used. Subconfluent cells were maintained in a pressure culture device which placed in a carbon dioxide incubator for 24 h. The pressure gradient was set to 0 mmHg, 20 mmHg and 40 mmHg. The mRNA and protein levels of the calcium channel, potassium channel and sodium channel were assayed using real-time PCR, and Western blot respectively. Results We found that mRNA and protein expression of Cav1.2 and protein expression of Cav3.1, Kv11.1 and Kv4.3 are significantly decreased after pressure stimulation. Pressure stimulation up-regulated the mRNA and protein expression of Kv1.5 and Kir2.1 but could not regulate mRNA or protein expression of Nay1.5. Conclusions Our results represent a potential pathogenic mechanism of hypertension involved in atrial electrical remodeling and provide enlightening insights to the prevention and treatment of AF.