Background Febuxostat,a novel nonpurine selective inhibitor of xanthine oxidase(XO),may be used in the prevention and management of atrial fibrillation(AF).The purpose of this study was to evaluate the effects of febu...Background Febuxostat,a novel nonpurine selective inhibitor of xanthine oxidase(XO),may be used in the prevention and management of atrial fibrillation(AF).The purpose of this study was to evaluate the effects of febuxostat on atrial remodeling in a rabbit model of AF induced by rapid atrial pacing(RAP)and the mechanisms by which it acts.Methods Twenty-four rabbits were randomly divided into four groups:sham-operated group(Group S),RAP group(Group P),RAP with 5 mg/kg per day febuxostat group(Group LFP),and RAP with 10 mg/kg per day febuxostat group(Group HFP).All rabbits except those in Group S were subjected to RAP at 600 beats/min for four weeks.The effects of febuxostat on atrial electrical and structural remodeling,markers of inflammation and oxidative stress,and signaling pathways involved in the left atrium were examined.Results Shortened atrial effective refractory period(AERP),increased AF inducibility,decreased mRNA levels of Cav1.2 and Kv4.3,and left atrial enlargement and dysfunction were observed in Group P,and these changes were suppressed in the groups treated with febuxostat.Prominent atrial fibrosis was observed in Group P,as were increased levels of TGF-β1,Collagen I,andα-SMA and decreased levels of Smad7 and eNOS.Treatment with febuxostat attenuated these differences.Changes in inflammatory and oxidative stress markers induced by RAP were consistent with the protective effects of febuxostat.Conclusions This study is the first to find that febuxostat can inhibit atrial electrical and structural remodeling of AF by suppressing XO and inhibiting the TGF-β1/Smad signaling pathway.展开更多
Objective: To establish a rabbit atrial fibrillation model with rapid atrial pacing (RAP) and investigate its ultrastructural changes and expressions of L-type calcium channel subunits and potassium channel Kv4. 3. Me...Objective: To establish a rabbit atrial fibrillation model with rapid atrial pacing (RAP) and investigate its ultrastructural changes and expressions of L-type calcium channel subunits and potassium channel Kv4. 3. Methods: Thirty-six rabbits were performed electrical stimulation through bipolar endo-cardial led by surgical technique. 600 beat per min from 0 to 48 h. Atrial ultrastructure was observed by transmission electron microscope (TEM) after different pacing times. mRNA were measured by reverse transcription-polymera.se chain reaction (RT-PCR). Results: Atrial ultrastructure had alteration after 3 hours' pacing, such as mitochondria vacuolization, myofilament lysis and glucogen aggregation. The mRNA of the Ca2+ channel β1 and α1 subunits began to decrease after pacing of 6 h. which were paralleled with the change of Kv4. 3 mRNA. But the auxiliary subunit α2 were not affected. Conclusion: Ultrastructural changes and mRNA levels of L-type calcium channel subunits and potassium channel Kv4. 3 are decreased after RAP. with a mechanism of transcriptional down-regulation of underlying ion channels due to calcium overloading after RAP.展开更多
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 ...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.展开更多
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 gr...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.展开更多
目的研究丹参酮ⅡA磺酸钠(TSN)对家兔在体心房单相动作电位(AMAP)及短期快速心房起搏时电重构的影响,探讨其防治房颤的可能机制。方法家兔24只,随机分为对照组与TSN组各12只。将电极经颈内静脉置入右心房记录AMAP,观察基础状态下、给药...目的研究丹参酮ⅡA磺酸钠(TSN)对家兔在体心房单相动作电位(AMAP)及短期快速心房起搏时电重构的影响,探讨其防治房颤的可能机制。方法家兔24只,随机分为对照组与TSN组各12只。将电极经颈内静脉置入右心房记录AMAP,观察基础状态下、给药后0.5 h及以600次.m in-1心房快速起搏后0.5 h、8 h AMAP及其频率适应性的变化。结果与起搏前相比对照组AERP200 m s在起搏后0.5h缩短21.2 m s,起博后8h缩短21.6m s(P<0.05),且心房肌的频率适应性丧失。TSN在基础状态下对AMAPA、AMAPD无明显影响,但使AERP200 m s由(105.9±3.8)m s延长至(114.7±7.2)m s(P<0.05)。起搏后TSN组维持原有的心房肌频率适应性。结论快速心房起搏使心房肌的频率适应性丧失而致电重构,TSN能通过抑制L-型钙通道减轻短期快速心房起搏所致电重构。展开更多
基金supported by the Beijing Natural Science Foundation(Z141100002114050)
文摘Background Febuxostat,a novel nonpurine selective inhibitor of xanthine oxidase(XO),may be used in the prevention and management of atrial fibrillation(AF).The purpose of this study was to evaluate the effects of febuxostat on atrial remodeling in a rabbit model of AF induced by rapid atrial pacing(RAP)and the mechanisms by which it acts.Methods Twenty-four rabbits were randomly divided into four groups:sham-operated group(Group S),RAP group(Group P),RAP with 5 mg/kg per day febuxostat group(Group LFP),and RAP with 10 mg/kg per day febuxostat group(Group HFP).All rabbits except those in Group S were subjected to RAP at 600 beats/min for four weeks.The effects of febuxostat on atrial electrical and structural remodeling,markers of inflammation and oxidative stress,and signaling pathways involved in the left atrium were examined.Results Shortened atrial effective refractory period(AERP),increased AF inducibility,decreased mRNA levels of Cav1.2 and Kv4.3,and left atrial enlargement and dysfunction were observed in Group P,and these changes were suppressed in the groups treated with febuxostat.Prominent atrial fibrosis was observed in Group P,as were increased levels of TGF-β1,Collagen I,andα-SMA and decreased levels of Smad7 and eNOS.Treatment with febuxostat attenuated these differences.Changes in inflammatory and oxidative stress markers induced by RAP were consistent with the protective effects of febuxostat.Conclusions This study is the first to find that febuxostat can inhibit atrial electrical and structural remodeling of AF by suppressing XO and inhibiting the TGF-β1/Smad signaling pathway.
基金Supported by National Natural Science Foundation of China (No.30370583)
文摘Objective: To establish a rabbit atrial fibrillation model with rapid atrial pacing (RAP) and investigate its ultrastructural changes and expressions of L-type calcium channel subunits and potassium channel Kv4. 3. Methods: Thirty-six rabbits were performed electrical stimulation through bipolar endo-cardial led by surgical technique. 600 beat per min from 0 to 48 h. Atrial ultrastructure was observed by transmission electron microscope (TEM) after different pacing times. mRNA were measured by reverse transcription-polymera.se chain reaction (RT-PCR). Results: Atrial ultrastructure had alteration after 3 hours' pacing, such as mitochondria vacuolization, myofilament lysis and glucogen aggregation. The mRNA of the Ca2+ channel β1 and α1 subunits began to decrease after pacing of 6 h. which were paralleled with the change of Kv4. 3 mRNA. But the auxiliary subunit α2 were not affected. Conclusion: Ultrastructural changes and mRNA levels of L-type calcium channel subunits and potassium channel Kv4. 3 are decreased after RAP. with a mechanism of transcriptional down-regulation of underlying ion channels due to calcium overloading after RAP.
文摘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.
文摘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.
文摘目的研究丹参酮ⅡA磺酸钠(TSN)对家兔在体心房单相动作电位(AMAP)及短期快速心房起搏时电重构的影响,探讨其防治房颤的可能机制。方法家兔24只,随机分为对照组与TSN组各12只。将电极经颈内静脉置入右心房记录AMAP,观察基础状态下、给药后0.5 h及以600次.m in-1心房快速起搏后0.5 h、8 h AMAP及其频率适应性的变化。结果与起搏前相比对照组AERP200 m s在起搏后0.5h缩短21.2 m s,起博后8h缩短21.6m s(P<0.05),且心房肌的频率适应性丧失。TSN在基础状态下对AMAPA、AMAPD无明显影响,但使AERP200 m s由(105.9±3.8)m s延长至(114.7±7.2)m s(P<0.05)。起搏后TSN组维持原有的心房肌频率适应性。结论快速心房起搏使心房肌的频率适应性丧失而致电重构,TSN能通过抑制L-型钙通道减轻短期快速心房起搏所致电重构。
