五聚素3对慢性心房颤动患者心房肌细胞K_(Ach)的影响
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摘要
心房颤动(atrial fibrillation, AF)是最常见的心律失常之一。流行病学调查显示AF的发生率有逐年增高的趋势,并且随着年龄的增长发生率显著增加,器质性心脏病患者AF的发生率高达40%。AF能引起血流动力学异常及明显增加血栓栓塞等并发症(如脑卒中等)的发生率,从而显著增加致残率、致死率。到目前为止,AF的治疗多数仍是以防治并发症为目标,不能从根本上终止AF的发生,发展。究其原因主要是AF的发生机制尚未阐明。近年来,随着对AF发生机制研究的逐步深入,学者们已经发现离子通道重构是参与AF发生和维持的重要因素。AF时心房肌细胞产生快速的电活动,可引起离子通道在功能和结构上发生重大的变化,可以认为离子通道的变化是AF的结果,而离子通道发生改变后又为AF的维持创造了条件。随着分子生物学技术的广泛应用,越来越多的学者开始从分子水平上研究AF发生及维持的机制。
近年来,随着学者们对离子通道与AF发生及维持机制等方面的深入研究,人们发现许多离子通道如钠离子通道,钾离子通道,钙离子通道,氯离子通道等与AF的发生都存在着密切的关系。研究证明,KAch具有内向整流特点,并且只存在心房肌细胞膜上,其参与AP的复极和静息电位的形成,所以KAch与AF的关系备受学者们的关注。另据文献报道AF患者心房肌细胞有KAch变化,阻止KAch的变化可防止AF的发生,因此近年来AF患者KAch通道成为研究AF发生及维持机制的热点。
近年来的研究显示,炎症与AF有着非常密切的关系,因此炎症在AF始发及维持中起到的作用越来越引起人们重视。关于炎症及AF的关系最早是1997年由Bruins等首次报道,其在研究中发现了CRP和IL-6在AF发生时有明显升高的变化。随后又有学者进一步证明了CRP与AF的关系,同时还发现其它炎症因子如IL-8、TNF-α等也与AF的发生和发展有关。以往的研究不仅确立了炎症反应在AF发病过程中的地位,更进一步说明了炎症可能是AF发生的独立因素,是导致AF的原因。
PTX3是近年人们发现一种新的炎症标记物,并已证实其在冠心病、急性冠脉综合征、不稳定型心绞痛时水平有明显升高,且与不稳定型心绞痛危险分层有关。但目前对PTX3在AF发生和维持中的作用所知甚少,为此,本文就PTX3对AF患者心房肌细胞KAch的影响进行研究和探讨,在实验中对慢性AF患者心房肌细胞KAch通道的电流变化、蛋白表达和mRNA表达进行观察,并用PTX3进行干预,旨在探讨PTX3在AF发生和维持中的作用,为进一步揭示炎症与AF的关系,并最终为防止AF的发生和寻找治疗AF更为有效的方法提供实验依据。
目的：探讨PTX3在AF发生和维持中的作用及机制,从而进一步揭示炎症与AF的关系,并最终为防止AF的发生和寻找治疗AF更为显著的方法提供实验依据。
方法：
1研究对象：根据《赫尔辛基宣言》精神,所有患者术前均经伦理委员会讨论,并已征得患者及其家属知情同意。选择行心脏外科手术患者22例, AF组11例,男6例,女5例,年龄41.5±4.3岁,心功能Ⅱ级9例,Ⅲ级2例,入选患者无其它心律失常病史且AF持续时间大于1年。SR组11例,男5例,女6例,年龄40.7±5.3岁,心功能Ⅱ级8例,Ⅲ级3例,入选患者无心律失常病史。两组均记录年龄、性别、心功能NYHA分级、心电图、超声心动图及有关实验室检查。甲状腺机能亢进,扩张性心肌病、慢性肺源性心脏病、感染的急性期、肥胖、风湿性疾病、血液和造血系统疾病、内分泌和代谢性疾病、严重肝肾功能不全、近期应用抗生素、阿斯匹林(术前7天停用除外)、ACEI和ARB、他汀类调脂药物等均不列入本研究范围之内。
2标本采集：心脏手术中建立体外循环,于心脏停跳前获取右心耳100mg,除去血液和脂肪组织。
3心房肌细胞分离
4实验分组：将心房肌细胞分组：SR组,AF组,再将AF组分成8份,4份做成膜片,其中3份在灌注液中加入8μg/mL、10μg/mL、12μg/mL三种不同浓度的PTX3各1ml,作用20min,用膜片钳技术测定IKAch密度。在另外4份中,有3份分别加入以上不同浓度的PTX3各1ml,与余下的1份和SR组一起放入恒温箱中,作用1h,用PCR法和WB法观察KAch基因和蛋白的变化。
结果：AF组的Kir3.4mRNA表达、GIRK4表达及IKAch密度明显低于SR组,小剂量组的Kir3.4mRNA表达、GIRK4表达及IKAch密度低于AF组,中剂量组的Kir3.4mRNA表达、GIRK4表达及IKAch密度低于小剂量组,大剂量组的Kir3.4mRNA表达、GIRK4表达及IKAch密度低于中剂量组,统计学均有显著差异。
结论：
1 KAch参与了AF的病理过程。
2 PTX3通过影响慢性AF患者心房肌细胞Kir3.4mRNA和GIRK4表达,进而使IKAch密度降低,推测其可能导致AF发生和维持。
3 PTX3可能通过促进AF炎症反应的发生从而引起心房重构。
4推测炎症可能是AF发生和维持的原因。
Atrial fibrillation (AF) is one of the commonest clinical arrhythmia. According to epidemic disease survey, AF's morbidity has been an increasing trend for the past few years, the older people are, the higher the morbidity is; people of organic cardiopathy even have a morbidity up to 40%. Not only would AF seriously influence life quality in paroxysmal clinical symptoms, but also the comparative high incidence of its thromboembolism would cause obvious increase of cripple and death. Thus, it has been a focus of people to pay attention to probing into its pathogenesis and preventive treatment.
With the research of ion channal on the occurrence and maintenance of AF recently,scientists have found a series of ion channals (such as Na+ Channal,K+ channal,Ca2+ channal,CL- channal) related with the occurence of AF closely.KAch only exist in atrium myocytes,so the relation between KAch and AF has been increasingly valued by scientists. Lots of reports have indicated that some changes of KAch appeared in atrium myocytes of AF patients,and stop the changes can prevent the occurrence of AF.Therefore,the research of the relationship between KAch and AF has become a hot topic.
In the past years,it has been found that inflammation reaction have all relationship with occurrence and maintenance of AF, while relation between inflammation and AF has been increasingly valued by people. Obviously increase changes of CRP and IL-6 when AF occurred were reported by Bruins etc in 1997 for the first time, soon afterwards scholars further proved that AF's occurrence and development had relation with not only CRP but also other inflammatory factors as IL-8, TNF-αetc; on one hand, all the experimental results have established position of inflammation in AF, on the other hand, they have indicated that inflammation is a potential independent factor and reason for occurrence of AF.
Recently, a kind of new inflammation marker-PTX3 has been found, whose level has been proved obviously rising in coronary heart disease, acute coronary syndrome and has relation with danger layering of Unstable angina pectoris. Relativity between plasma PTX3 level and acute coronary syndrome in cardiovascular system obviously exceed that between CRP and acute coronary syndrome. However, PTX3's function in AF's occurrence and development have been rarely known at present, thus, PTX3 of cardiac atrium myocytes for AF patients are studied in the thesis, aiming to reveal their functions in AF and offer experimental basis for inflammation and AF theory.
Purpose:To discuss the function and mechanism of PTX3 in AF's occurrence and maintenance and to offer experimental grounds for further prompting relation between inflammation and AF, prevent occurrence of AF and cure it positively.
Method:
1 Research object:According to Declaration of Helsinki,22 patients suffering cardiac surgical operation are selected after gaining preoperational discussion of Ethics Committee and permission of patients and family members, 11 in AF group,6 men and 5 women with age of 41.5±4.3 years,9 patients haveⅡdegree heart function,2 patients haveⅢdegree heart function, no additional arrhythmia medical history,AF time is over 1 year.11 in SR group,5 men and 6 women with age of 40.7±5.3 years.8 patients have II degree heart function,3 patients haveⅢdegree heart function, no arrhythmia medical history. Age, gender, heart function NYHA grade, electrocardiogram, ultrasonic cardiogram and related laboratory examination are all recorded in the two groups. Hyperthyroidism, dilated cardiomyopathy, chronic pulmonary heart disease, acute infection, fat, rheumatic disease, blood and hemopoietic system disease, internal secretion and metabolic disease, serious liver dysfunction, recent application of antibiotics, aspirin (exclusive of disuse 7 days before operation), ACEI and ARB, statins adjustment lipid deugs are all not listed in this research scope.
2 Sample collection:Extracorporeal circulation should be established in the cardiac surgery and 100mg auricula dextra before cardiac arrest should be acquired, removing blood and adipose tissue.
3 Separation of cardiac atrium myocytes.
4 In separation of cardiac atrium myocytes, firstly, becomes the AF component 8, in 4, some 3 join separately concertration on 8μg/mL, 10μg/mL, 12μg/mL PTX3 each 1ml, with in addition 1 and the SR group together puts in the thermostat, affects 1h, observes the KAch gene and protein change by PCR method and WB method; After another 4 make the patch,3 join the different concertration PTX3 each 1ml in the perfusate, affects 20min, determines the IKAch density by the patch clamp technique.
Results:1.Contents of Kir3.4mRNA and GIRK4and IKAch density in AF group are obviously lower than SR group, while Kir3.4mRNA and GIRK4 contents and IKAch density of the small dose group is lower than AF group, those of the middle dose group are lower than the small dose group, and those of the large dose group are lower than the middle dose group, significant differences in statistics also exist in all groups.
Conclusions:
1. KAch participates in the process of AF pathology.
2. PTX3 reduce the density of IKAch by influencing expression of Kir3.4mRNA and GIRK4 protein. Speculated that it make chronic AF occur and maintain.
3. PTX3 maybe cause restructure of atrium by promoting inflammation reaction of chronic AF patients.
4. Speculated that inflammation maybe the reason of AF occurrence and maintain reasons.
近年来,随着学者们对离子通道与AF发生及维持机制等方面的深入研究,人们发现许多离子通道如钠离子通道,钾离子通道,钙离子通道,氯离子通道等与AF的发生都存在着密切的关系。研究证明,KAch具有内向整流特点,并且只存在心房肌细胞膜上,其参与AP的复极和静息电位的形成,所以KAch与AF的关系备受学者们的关注。另据文献报道AF患者心房肌细胞有KAch变化,阻止KAch的变化可防止AF的发生,因此近年来AF患者KAch通道成为研究AF发生及维持机制的热点。
近年来的研究显示,炎症与AF有着非常密切的关系,因此炎症在AF始发及维持中起到的作用越来越引起人们重视。关于炎症及AF的关系最早是1997年由Bruins等首次报道,其在研究中发现了CRP和IL-6在AF发生时有明显升高的变化。随后又有学者进一步证明了CRP与AF的关系,同时还发现其它炎症因子如IL-8、TNF-α等也与AF的发生和发展有关。以往的研究不仅确立了炎症反应在AF发病过程中的地位,更进一步说明了炎症可能是AF发生的独立因素,是导致AF的原因。
PTX3是近年人们发现一种新的炎症标记物,并已证实其在冠心病、急性冠脉综合征、不稳定型心绞痛时水平有明显升高,且与不稳定型心绞痛危险分层有关。但目前对PTX3在AF发生和维持中的作用所知甚少,为此,本文就PTX3对AF患者心房肌细胞KAch的影响进行研究和探讨,在实验中对慢性AF患者心房肌细胞KAch通道的电流变化、蛋白表达和mRNA表达进行观察,并用PTX3进行干预,旨在探讨PTX3在AF发生和维持中的作用,为进一步揭示炎症与AF的关系,并最终为防止AF的发生和寻找治疗AF更为有效的方法提供实验依据。
目的：探讨PTX3在AF发生和维持中的作用及机制,从而进一步揭示炎症与AF的关系,并最终为防止AF的发生和寻找治疗AF更为显著的方法提供实验依据。
方法：
1研究对象：根据《赫尔辛基宣言》精神,所有患者术前均经伦理委员会讨论,并已征得患者及其家属知情同意。选择行心脏外科手术患者22例, AF组11例,男6例,女5例,年龄41.5±4.3岁,心功能Ⅱ级9例,Ⅲ级2例,入选患者无其它心律失常病史且AF持续时间大于1年。SR组11例,男5例,女6例,年龄40.7±5.3岁,心功能Ⅱ级8例,Ⅲ级3例,入选患者无心律失常病史。两组均记录年龄、性别、心功能NYHA分级、心电图、超声心动图及有关实验室检查。甲状腺机能亢进,扩张性心肌病、慢性肺源性心脏病、感染的急性期、肥胖、风湿性疾病、血液和造血系统疾病、内分泌和代谢性疾病、严重肝肾功能不全、近期应用抗生素、阿斯匹林(术前7天停用除外)、ACEI和ARB、他汀类调脂药物等均不列入本研究范围之内。
2标本采集：心脏手术中建立体外循环,于心脏停跳前获取右心耳100mg,除去血液和脂肪组织。
3心房肌细胞分离
4实验分组：将心房肌细胞分组：SR组,AF组,再将AF组分成8份,4份做成膜片,其中3份在灌注液中加入8μg/mL、10μg/mL、12μg/mL三种不同浓度的PTX3各1ml,作用20min,用膜片钳技术测定IKAch密度。在另外4份中,有3份分别加入以上不同浓度的PTX3各1ml,与余下的1份和SR组一起放入恒温箱中,作用1h,用PCR法和WB法观察KAch基因和蛋白的变化。
结果：AF组的Kir3.4mRNA表达、GIRK4表达及IKAch密度明显低于SR组,小剂量组的Kir3.4mRNA表达、GIRK4表达及IKAch密度低于AF组,中剂量组的Kir3.4mRNA表达、GIRK4表达及IKAch密度低于小剂量组,大剂量组的Kir3.4mRNA表达、GIRK4表达及IKAch密度低于中剂量组,统计学均有显著差异。
结论：
1 KAch参与了AF的病理过程。
2 PTX3通过影响慢性AF患者心房肌细胞Kir3.4mRNA和GIRK4表达,进而使IKAch密度降低,推测其可能导致AF发生和维持。
3 PTX3可能通过促进AF炎症反应的发生从而引起心房重构。
4推测炎症可能是AF发生和维持的原因。
Atrial fibrillation (AF) is one of the commonest clinical arrhythmia. According to epidemic disease survey, AF's morbidity has been an increasing trend for the past few years, the older people are, the higher the morbidity is; people of organic cardiopathy even have a morbidity up to 40%. Not only would AF seriously influence life quality in paroxysmal clinical symptoms, but also the comparative high incidence of its thromboembolism would cause obvious increase of cripple and death. Thus, it has been a focus of people to pay attention to probing into its pathogenesis and preventive treatment.
With the research of ion channal on the occurrence and maintenance of AF recently,scientists have found a series of ion channals (such as Na+ Channal,K+ channal,Ca2+ channal,CL- channal) related with the occurence of AF closely.KAch only exist in atrium myocytes,so the relation between KAch and AF has been increasingly valued by scientists. Lots of reports have indicated that some changes of KAch appeared in atrium myocytes of AF patients,and stop the changes can prevent the occurrence of AF.Therefore,the research of the relationship between KAch and AF has become a hot topic.
In the past years,it has been found that inflammation reaction have all relationship with occurrence and maintenance of AF, while relation between inflammation and AF has been increasingly valued by people. Obviously increase changes of CRP and IL-6 when AF occurred were reported by Bruins etc in 1997 for the first time, soon afterwards scholars further proved that AF's occurrence and development had relation with not only CRP but also other inflammatory factors as IL-8, TNF-αetc; on one hand, all the experimental results have established position of inflammation in AF, on the other hand, they have indicated that inflammation is a potential independent factor and reason for occurrence of AF.
Recently, a kind of new inflammation marker-PTX3 has been found, whose level has been proved obviously rising in coronary heart disease, acute coronary syndrome and has relation with danger layering of Unstable angina pectoris. Relativity between plasma PTX3 level and acute coronary syndrome in cardiovascular system obviously exceed that between CRP and acute coronary syndrome. However, PTX3's function in AF's occurrence and development have been rarely known at present, thus, PTX3 of cardiac atrium myocytes for AF patients are studied in the thesis, aiming to reveal their functions in AF and offer experimental basis for inflammation and AF theory.
Purpose:To discuss the function and mechanism of PTX3 in AF's occurrence and maintenance and to offer experimental grounds for further prompting relation between inflammation and AF, prevent occurrence of AF and cure it positively.
Method:
1 Research object:According to Declaration of Helsinki,22 patients suffering cardiac surgical operation are selected after gaining preoperational discussion of Ethics Committee and permission of patients and family members, 11 in AF group,6 men and 5 women with age of 41.5±4.3 years,9 patients haveⅡdegree heart function,2 patients haveⅢdegree heart function, no additional arrhythmia medical history,AF time is over 1 year.11 in SR group,5 men and 6 women with age of 40.7±5.3 years.8 patients have II degree heart function,3 patients haveⅢdegree heart function, no arrhythmia medical history. Age, gender, heart function NYHA grade, electrocardiogram, ultrasonic cardiogram and related laboratory examination are all recorded in the two groups. Hyperthyroidism, dilated cardiomyopathy, chronic pulmonary heart disease, acute infection, fat, rheumatic disease, blood and hemopoietic system disease, internal secretion and metabolic disease, serious liver dysfunction, recent application of antibiotics, aspirin (exclusive of disuse 7 days before operation), ACEI and ARB, statins adjustment lipid deugs are all not listed in this research scope.
2 Sample collection:Extracorporeal circulation should be established in the cardiac surgery and 100mg auricula dextra before cardiac arrest should be acquired, removing blood and adipose tissue.
3 Separation of cardiac atrium myocytes.
4 In separation of cardiac atrium myocytes, firstly, becomes the AF component 8, in 4, some 3 join separately concertration on 8μg/mL, 10μg/mL, 12μg/mL PTX3 each 1ml, with in addition 1 and the SR group together puts in the thermostat, affects 1h, observes the KAch gene and protein change by PCR method and WB method; After another 4 make the patch,3 join the different concertration PTX3 each 1ml in the perfusate, affects 20min, determines the IKAch density by the patch clamp technique.
Results:1.Contents of Kir3.4mRNA and GIRK4and IKAch density in AF group are obviously lower than SR group, while Kir3.4mRNA and GIRK4 contents and IKAch density of the small dose group is lower than AF group, those of the middle dose group are lower than the small dose group, and those of the large dose group are lower than the middle dose group, significant differences in statistics also exist in all groups.
Conclusions:
1. KAch participates in the process of AF pathology.
2. PTX3 reduce the density of IKAch by influencing expression of Kir3.4mRNA and GIRK4 protein. Speculated that it make chronic AF occur and maintain.
3. PTX3 maybe cause restructure of atrium by promoting inflammation reaction of chronic AF patients.
4. Speculated that inflammation maybe the reason of AF occurrence and maintain reasons.
引文
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[18]张标等.慢性房颤患者心房肌细胞乙酰胆碱敏感钾通道的研究[J].中国病理生理杂志,2010,22(4)：678-682.
[19]刘杰,邓建新,潘秉兴,等KCNE2对Kv4.3通道功能的调节作用.南方医科大学学报,2006,26(12)：1754-1756.
[20]Bosch RF,Scherer CR,Rub N,etal.Molecular mechanism of early electrical remodeling transcriptional downregulation of ion channel subunits reduces I(Ca.L)andI(to) in rapid atrial pacing in rabbits[J].J Am Coll Cardiol,2003,41(5):858-869.
[21]许春萱,张建成,黄丛新,等.心房颤动患者瞬时外向钾电流重构的分子基础[J].中国心律失常杂志,2002,6(4)：228-230.
[22]黄兵,陈雷,吴学仁,等.慢性房颤患者右心房细胞电压依赖性钾电流变化的研究[J].中国病理生理学杂志,2005,21(1)：7-80.
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[24]王春,谷天祥,张玉海,等.风湿性心脏病合并慢性心房颤动右心耳Kv1.5钾通道mRNA和蛋白表达的研究[J].中国医科大学学报,2008,37(4)：516-518.
[25]邓玉莲,高峰,许春萱,等.心房颤动患者心房组织延迟整流钾通道基因表达的研究[J].中华心律失常学杂志,2005,9(6)：445.
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[46]张光伟,谷天祥,王春,等.H202对人心房肌细胞IKur和ICaL的浓度依赖性双向影响[J].生理学报,2008,60(6)：695-703.
[47]Norata GD,Garlanda C,Catapano AL, et al.The long pentraxin PTX3:A modulator of the immunoinflammatory reponse in atherosclerosis and cardiovascular diseases[J].Trends Cardiovasc Med,2010,20(2):35-40.
[48]Souza DG,Amaral FA, Fagundes CT, et al. The long pentraxin PTX3 is crucial for tissue inflammation after intestinal ischemia and reperfusion in mice [J]. Am J pathol,2009,174(4):1309-1318.
[49]尚晓斌,黄学成,等.心房颤动患者血浆B型利纳肽水平和内皮素-1水平的变化及临床意义[J].内科,2008,3(4)：521-523.
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[52]Swartz MF, Fink GW, Lutz CJ, et al. Left versus right atrial difference in dominant frequency, K+ channel transcrips, and fibrosis in patients developing atrial fibrillation after cardiac surgery[J].Heart Rhythm,2009,6(10): 1415-1422.
[53]Gomez R,Caballero R,Barana A, et al. Nitric oxide increase cardiac IK, by nitrosylation of cysteine 76 of Kir 2.1 channals[J].Circ Res,2009, 105(4):383-392.
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[17]戴芝银等.慢性房颤患者心房肌细胞KAch通道Kir3.4基因和蛋白表达变化及机制[J].山东医药,2010；50(5)：2.
[18]张标等.慢性房颤患者心房肌细胞乙酰胆碱敏感钾通道的研究[J].中国病理生理杂志,2010,22(4)：678-682.
[19]刘杰,邓建新,潘秉兴,等KCNE2对Kv4.3通道功能的调节作用.南方医科大学学报,2006,26(12)：1754-1756.
[20]Bosch RF,Scherer CR,Rub N,etal.Molecular mechanism of early electrical remodeling transcriptional downregulation of ion channel subunits reduces I(Ca.L)andI(to) in rapid atrial pacing in rabbits[J].J Am Coll Cardiol,2003,41(5):858-869.
[21]许春萱,张建成,黄丛新,等.心房颤动患者瞬时外向钾电流重构的分子基础[J].中国心律失常杂志,2002,6(4)：228-230.
[22]黄兵,陈雷,吴学仁,等.慢性房颤患者右心房细胞电压依赖性钾电流变化的研究[J].中国病理生理学杂志,2005,21(1)：7-80.
[23]Van Wagoner DR,PondAL,McCarthy PM,et al.Outward K+ currents densities and Kvl.5 expression are reduced in chronic human atrial fibrillation[J].Circ Res,1997,80:772-781.
[24]王春,谷天祥,张玉海,等.风湿性心脏病合并慢性心房颤动右心耳Kv1.5钾通道mRNA和蛋白表达的研究[J].中国医科大学学报,2008,37(4)：516-518.
[25]邓玉莲,高峰,许春萱,等.心房颤动患者心房组织延迟整流钾通道基因表达的研究[J].中华心律失常学杂志,2005,9(6)：445.
[26]Chen YH, Xu SJ,Bendahhou S, et al. KCNQ1 gain of function mutation in familial at rial fibrillation[J]. Science,2003,299 (5604):251-254.
[27]曾治宇,浦介麟,谭琛,等.心房颤动患者KCNQ1, KCNE1和KCNE4基因单核苷酸多态性研究.中华心血管病杂志,2005,33(11)：987-991.
[28]Ma KJ,Li N,Teng SY,et al.Modulation of KCNQ1 current by at rial fibrillation associated KCNE4 (145E/D) gene polymorphism[J]. Chin Med J,2007,120(2):150-154.
[29]Lundby A,Ravn LS,Svendsen J H,et al.KCNQ1 mutation Q147R is associated wit h at rial fibrillation and prolonged QT interval [J].Heart Rhyt hm,2007,4(12):1542-1551.
[30]Brundel BJ,van Gelder IC,Henning RH,etal.Gene expression of proteins influencing the calcium homeostas is in patients with persistent and paroxysmal atrial fibrillation[J].Cardiovasc Res,1999,42:443-446.
[31]LY Chen,JD Ballew,KJ Herron,et al.A Common Polymorphism in SCN5A is Associated with Lone Atrial Fibrillation[J].Clin Pharmacol Ther,2007,81(1):35-41.
[32]Leistad E, Aksnes G, Verburg E, et al. Atrial contractile dysfunction after short-term atrial fibrillation is reduced by verapamil but increased by BAY K8644[J]. Circulation,1996,93:1747-1755.
[33]Morilo CA, Klein GJ, Jones DL, et al. Chronic rap id atrial pacing: struc-tural, functional, and electrophysiological characteristics of a new model of sustained atrial fibrillation[J]. Circulation,1995,91:1588-1595.
[34]GrammerJB,ZengX,BoschRF,etal.AtrialL-type Ca2+ channel,beta-a-drenore ceptor,and 5-hydroxytryptamine type 4 receptor mRNAs in human atrial fibrillation[J].Basic Res Cardiol,2001,96(1):82-7.
[35]刘元生,郭林娜,郭继鸿.钙离子通道基因mRNA表达在心房颤动发生机制中的作用[J].临床心血管病杂志,2009,25(3)：170-3.
[36]史昀青,杨成,丁文军,等.L及T型钙离子通道α1亚基在风湿性房颤心房组织中的表达变化[J].中国分子心脏病学杂志,2010,10(1)：11-5.
[37]赵庆彦,黄从新,等.迷走神经对心房颤动影响的离子通道基础[J].《中国心脏起搏与心电生理杂志》,2005,19(2)：147-149.
[38]张建成,黄从新,邓玉莲,等.心房颤动患者L型钙通道电流改变的分子基础[J].中华心血管病杂志,2002,30：460-463.
[39]van Wagoner DR, Pond AL, LamorgeseM, et al. Atrial L2Type Ca2+ currents and human atrial fibrillation. Circ Res,1999,85:428-436.
[40]李妙龄等.持续性心房颤动患者心房肌细胞L型钙通道电流变化的研究[J].中华心血管病杂志,2006,4：389-391.
[41]吴书林,陈纯波,林秋雄.心房颤动患者心房组织血管紧张素Ⅱ受体表达及血管紧张素转换酶抑制剂干预的初步研究[J].中华心律失常杂志, 2005,9(2)：115-118.
[42]魏立业,夏岳,戚国庆,等.氯沙坦对家兔快速心房起搏心房电重构及L-型钙通道的影响[J].临床心血管病杂志,2009,25(1)：49-51.
[43]GuillemareE,MarionA,NisatoD, et al.Inhibitory effectsofdrone-darone on muscarinic K+ current in guinea pig atrial cells[J]. JCardiovasc Pharmacol, 2000,36:802.
[44]Watanabe Y,Hara Y,Tamagawa M, et al.Pirmenol inhibitsmusca-rinic acet- ylholine receptor-operated KTcurrent in the guinea pig heart[J]. Eur J Pharmacol,1997,338:71.
[45]张园,邱健.PTX3对LPS诱导内皮细胞表达TF的影响[J].中国微循环,2005,9(6)：393-399.
[46]张光伟,谷天祥,王春,等.H202对人心房肌细胞IKur和ICaL的浓度依赖性双向影响[J].生理学报,2008,60(6)：695-703.
[47]Norata GD,Garlanda C,Catapano AL, et al.The long pentraxin PTX3:A modulator of the immunoinflammatory reponse in atherosclerosis and cardiovascular diseases[J].Trends Cardiovasc Med,2010,20(2):35-40.
[48]Souza DG,Amaral FA, Fagundes CT, et al. The long pentraxin PTX3 is crucial for tissue inflammation after intestinal ischemia and reperfusion in mice [J]. Am J pathol,2009,174(4):1309-1318.
[49]尚晓斌,黄学成,等.心房颤动患者血浆B型利纳肽水平和内皮素-1水平的变化及临床意义[J].内科,2008,3(4)：521-523.
[50]安得英,刘铭,王恒大,等.心房颤动患者心房肌组织中内皮素系统的基因表达[J].临床心血管病杂志,2004,20(8)476-478.
[51]Udyavar AR, Chen YC,Chen YJ, et al. Endothelin-1 modulates the arrhy- thmogenic activity of pulmonary veins [J]. J Cardiovasc Electrophysiol. 2008,19(3):285-292.
[52]Swartz MF, Fink GW, Lutz CJ, et al. Left versus right atrial difference in dominant frequency, K+ channel transcrips, and fibrosis in patients developing atrial fibrillation after cardiac surgery[J].Heart Rhythm,2009,6(10): 1415-1422.
[53]Gomez R,Caballero R,Barana A, et al. Nitric oxide increase cardiac IK, by nitrosylation of cysteine 76 of Kir 2.1 channals[J].Circ Res,2009, 105(4):383-392.
[54]Gomez R,Nunez L,Vaguero M,et al. Nitric oxide inhibits Kv3.4 and human cardiac transient outward potassium current(Ito) [J]. Circ Res, 2008,80(3):375-384.
[55]Caouette D,Dongmo C,Berube J,et al. Hydrogen peroxide modulates the Kv1.5 channel expressed in a mammalian cell line[J]. Naunyn schmiede-bergs Arch pharmacol,2003,368(6):479-483.
[56]FearonIM,PalmerAC, BalmforthAJ, et al. Hypoxic and redox inhibition of the human cardiac L-type Ca2+ channel[J].Adv Exp Med Biol,2000, 475:209-218.
[57]盛力,李悦,氧化应激与心房颤动时的心房结构重构[J].中国心脏起搏与心电生理杂志,2007,21(5)：459-461.