炎症在心房颤动发生及维持中的作用机制研究
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摘要
目的心房颤动是临床是上最常见的心律失常,发病率随年龄的增长而增加。房颤时易发生多种并发症,如血栓栓塞、心力衰竭、诱发心肌缺血等,严重威胁人类健康。由于目前房颤发生及维持的机制尚不明确,临床上缺乏有效的治疗手段。许多研究发现炎症与房颤之间存在密切关系。一方面房颤患者常伴随着心肌炎症反应或血清炎症介质的增高,另一方面炎症反应发生时房颤的发生也增多。他汀类药物或激素抑制炎症可明显抑制房颤的发生及发展。但炎症与房颤之间的因果关系尚不明确。明确二者的关系对房颤的预防和治疗具有非常重要的意义,有助于对房颤机制的认识,有助于为房颤寻找更为有效的防治策略。本研究拟建立山羊无菌性心包炎模型和心房快速激动模型,通过这两个不同的始动环节,观察炎症因子的变化以及心房电生理特性的变化,并结合他汀类药物的干预,初步探讨炎症与房颤的因果关系,分析炎症在房颤发生及维持中的作用,研究他汀类药物对房颤的作用及可能机制。
方法1、健康雄性山羊15只,随机分为对照组、心包炎组和他汀干预组。他汀干预组山羊于术前1周开始给予阿托伐他汀60mg 1/日口服,至实验结束。左侧开胸,在左心房缝合含5对银制电极的硅胶电极,在右心房缝合2对电极。心包炎组和他汀干预组山羊制作无菌性心包炎模型。基础状态下、术后24、48、72h及7、14、21d测量左右心房有效不应期(ERP)、ERP频率适应性、左右心房传导速度(CV)、房颤诱发率及持续时间,ELISA法测定血清hs-CRP、IL-6、TNF-α水平。2、健康雄性山羊15只,随机分为对照组、心房刺激组和他汀干预组。他汀干预组山羊于术前1周开始给予阿托伐他汀60mg 1/日口服,至实验结束。左侧开胸,在左心房缝合含5对银制电极的硅胶电极,在右心房缝合2对电极。心房刺激组和他汀干预组山羊给予400～450次/分连续快速刺激。基础状态下、刺激24、48、72h及7、14d测量左右心房有效不应期(ERP)、ERP频率适应性、左右心房传导速度(CV)、房颤诱发率及持续时间,ELISA法测定血清hs-CRP、IL-6、TNF-α水平。
结果
1、(1)心包炎组和他汀干预组山羊血清hs-CRP、IL-6、TNF-α水平在术后明显升高(p＜0.05),48h～72h达到高峰,于术后7d开始逐渐下降,但仍明显高于基础状态(p＜0.05),亦高于对照组(p＜0.05)。他汀干预组山羊血清hs-CRP、IL-6、TNF-α水平在术后24h～48h以后均明显低于心包炎组(p＜0.05),但仍高于对照组(p＜0.05)。(2)心包炎组和他汀干预组山羊左房ERP在术后明显缩短(p＜0.05),至术后72h达到最低值,此后稍有延长但仍明显低于基础状态(p＜0.05)。与对照组相比,心包炎组山羊左房ERP明显缩短(p＜0.05)。与心包炎组比较,他汀干预组山羊术后左房ERP明显延长(p＜0.05)。心包炎组山羊右房ERP在术后24h～72h较对照纽明显缩短(p＜0.05)。(3)各纽山羊心房ERP频率适应性在术后均明显降低(p＜0.05)。术后14d及21d对照组和他汀干预组恢复至正常,而心包炎组仍表现为ERP频率适应性不良,显著低于基础状态(p＜0.05)。心包炎组山羊心房ERP频率适应性与血清hs-CRP呈明显负相关。(4)各组山羊左右心房CV均无显著变化,左房CV稍快于右房CV(p＞0.05)。(5)心包炎组和他汀干预组山羊左房房颤诱发率在术后明显增高(p＜0.05),他汀干预组低于心包炎组(p＞0.05)。各组山羊右房房颤诱发率术后无显著变化。心包炎组和他汀干预组山羊房颤持续时间在术后明显延长(p＜0.05)。他汀干预组房颤持续时间明显短于心包炎组(p＜0.05)。
2、(1)心房刺激组和他汀干预组山羊左房ERP随着刺激时间的延长逐渐缩短,至刺激7d时趋于稳定。他汀干预组山羊左房ERP在刺激48h以后较心房刺激组明显延长(p＜0.05)。心房刺激组和他汀干预组山羊右房ERP之间比较无显著差异。(2)心房刺激组山羊心房ERP频率适应性随着刺激时间的延长逐渐降低,他汀干预组在刺激72h以后显著高于心房刺激组(p＜0.05)。(3)各组山羊左右心房CV均无显著变化。(4)心房刺激组和他汀干预组山羊血清hs-CRP、IL-6、TNF-α水平随着刺激时间的延长不断升高,显著高于对照组(p＜0.05)。他汀干预组山羊血清hs-CRP、IL-6、TNF-α水平于刺激48h以后明显低于心房刺激组山羊(p＜0.05)。(5)心房刺激组和他汀干预组山羊左房房颤诱发率随着刺激时间的延长逐渐增高,显著高于对照组(p＜0.05)。心房刺激组山羊于刺激14d左房房颤诱发率达到100%。他汀干预组山羊左房房颤诱发率于刺激48h及以后明显低于心房刺激组(p＜0.05)。各组山羊右房房颤诱发率在刺激过程中无明显变化(p＞0.05)。心房刺激组和他汀干预组山羊房颤持续时间随着刺激时间的延长逐渐延长(p＜0.05),两组之间比较他汀干预组明显短于心房刺激组(p＜0.05)。
结论
1、山羊无菌性心包炎术后心房电生理特性发生明显改变,表现为心房ERP缩短,ERP频率适应性降低,而CV无明显变化。提示炎症通过缩短心房ERP及ERP频率适应性影响了WL,使心房形成一种“房颤基质”,易于房颤的诱发及维持。心房快速激动后,山羊血清炎症因子水平随着刺激时间的延长逐渐升高,提示心房快速激动导致了炎症反应的发生。推测此时炎症反应又进一步对心房电生理特性产生影响,加重了电重构,并与其共同作用,促进了“房颤引发房颤”,形成恶性循环,最终使房颤趋于稳定。以上提示炎症在房颤的发生及维持中均起到重要的作用,炎症与房颤互为因果,相互促进。
2、组织学观察发现,阿托伐他汀减轻了心房肌的炎症反应。阿托伐他汀可以明显抑制炎症发生后导致的心房电生理特性的改变,也可以一定程度地减轻心房快速激动导致的心房电重构。以上说明阿托伐他汀通过抑制炎症反应,抑制了心房电生理特性的改变,降低了房颤的诱发率及持续时间。提示阿托伐他汀对心脏术后的房颤发生可能有一定的预防作用,并可能有易于预防房颤复发。
Objective Atrial fibrillation(AF) is the most common sustained arrhythmia in clinical practice,and the prevalence of AF is strongly age-dependent.AF is associated with an increased mortality and morbidity from stroke and thromboembolism,heart failure and impaired quality of life.Therefore attention has been directed towards understanding the underlying pathophysiology of this condition,to provide novel insights into improving the therapeutic management of this condition.There are emerging data to support a significant association between inflammation and the development,recurrence and perpetuation of AF. For example,AF patients are always accompanied with an elevation of CRP level, and AF may be induced by the active inflammatory process.In addition,the increasing data supports a reduction in the development of AF by 3-hydroxy-3-methylglutaryl coenzyme A(HMG-CoA) reductase inhibitors (statins) use which provides an anti-inflammatory action.However,the causality of AF and inflammation remains controversial.This study was designed to determine the relationship between AF and inflammation in goat sterile pericarditis model and atrial tachypacing model,to analyze the role of inflammation on the atrial electrophysiological properties,and to assess the effect of atorvastatin on AF.
Methods 1.Fifteen adult male goats were randomly divided into control, pericarditis,and atorvastatin groups.Atorvastatin was administered orally(60 mg/day) beginning 1 week before the operation until the end of the study in atorvastatin group.The chest was opened through the left fourth intercostal space, and pericardial electrodes patches were sutured on the left atrium(LA) and right atrium(RA).The sterile pericarditis model was established in pericarditis and atorvastatin groups.At baseline,24,48,72 hours and 7,14,21 days after the operation,atrial effective refractory period(ERP),ERP rate adaptation, conduction velocity(CV),and duration of induced AF,and hs-CRP,IL-6,TNF-αlevels were measured.2.Fifteen adult male goats were randomly divided into control,atrial tachypacing(ATP),and atorvastatin groups.Atorvastatin was administered orally(60 mg/day) beginning 1 week before ATP until the end of the study in atorvastatin group.All goats were instrumented with epicardial electrodes patches on LA and RA.Goats in ATP and atorvastatin groups were subjected to atrial tachypacing(ATP) at 400～450 bpm.At baseline,24,48,72 hours and 7, 14 days after tachypacing onset,ERP,ERP rate adaptation,CV,and duration of induced AF,and hs-CRP,IL-6,TNF-αlevels were measured.
Results
1.(1) Levels of hs-CRP,IL-6 and TNF-αelevated significantly after the operation in pericarditis and atorvastatin groups(p＜0.05) with a peak elevation of hs-CRP, IL-6 and TNF-αlevels at 48～72 hours after the operation,and were higher than that in control group(p＜0.05).Atorvastatin group had a lower hs-CRP,IL-6 and TNF-αlevels than pericarditis group(p＜0.05).(2) ERP and ERP rate adaptation of pericarditis goats decreased significantly after the operation(p＜0.05).Atorvastatin group had a longer ERP and a higher ERP rate adaptation than pericarditis group (p＜0.05).There was significant negative correlation between ERP and hs-CRP level in pericarditis group.(3) There was no significant change in CV in all groups after the operation.(4) The inducibility of AF in LA and duration of AF in pericarditis and atorvastatin groups increased after the operation(p＜0.05).And pericarditis group had a longer duration of AF than atorvastatin group(p＜0.05). The inducibility of AF in RA unchanged before and after the operation in all groups.
2.(1) ERP of LA in ATP and atorvastatin groups decreased gradually(p＜0.05) and reached a steady state at 7 days.Atorvastatin group had a longer ERP in LA than ATP group since 48 hours after tachypacing onset(p＜0.05).There was no difference in ERP in RA between ATP and atorvastatin group.(2) ERP rate adaptation in ATP group decreased gradually(p＜0.05) and was lower than that in atorvastatin group(p＜0.05).(3) There was no significant change in left and right atrial CV in all groups.(4) Levels of hs-CRP,IL-6 and TNF-αin ATP group elevated gradually(p＜0.05) and was higher than that in control group(p＜0.05). Atorvastatin group had a lower hs-CRP,IL-6 and TNF-αlevels than ATP group (p＜0.05).(5) The inducibility of AF in LA and duration of AF in ATP and atorvastatin groups increased gradually(p＜0.05) and were all higher than that in control group(p＜0.05).The inducibility of AF in LA at 14 days in ATP group was 100%.The inducibility of AF in LA in atorvastatin group was lower than ATP group since 48 hours after tachypacing onset(p＜0.05).The inducibility of AF in RA unchanged in all groups.Atorvastatin group had a shorter AF duration than ATP group(p＜0.05).
Conclusion Inflammation may promote AF by shortening atrial ERP and adaptation of ERP to rate,which might be a potential "substrate".And the elevation of hs-CRP,IL-6,TNF-αinduced by atrial tachyarrhythmia suggests that AF may induce an inflammatory process.Consequently,inflammation resulted from AF will aggravate atrial electrical remodeling further,promote "AF begets AF" together with AF,and ultimately facilitate the perpetuation of AF. Inflammation plays an important role in the initiation and maintenance of AF. Atorvastatin can attenuate AF promotion by inhibiting inflammation both in goat sterile pericarditis model and atrial tachypacing model.This indicates that atorvastatin may prevent AF post-cardiacsurgery and recurrence of AF.
方法1、健康雄性山羊15只,随机分为对照组、心包炎组和他汀干预组。他汀干预组山羊于术前1周开始给予阿托伐他汀60mg 1/日口服,至实验结束。左侧开胸,在左心房缝合含5对银制电极的硅胶电极,在右心房缝合2对电极。心包炎组和他汀干预组山羊制作无菌性心包炎模型。基础状态下、术后24、48、72h及7、14、21d测量左右心房有效不应期(ERP)、ERP频率适应性、左右心房传导速度(CV)、房颤诱发率及持续时间,ELISA法测定血清hs-CRP、IL-6、TNF-α水平。2、健康雄性山羊15只,随机分为对照组、心房刺激组和他汀干预组。他汀干预组山羊于术前1周开始给予阿托伐他汀60mg 1/日口服,至实验结束。左侧开胸,在左心房缝合含5对银制电极的硅胶电极,在右心房缝合2对电极。心房刺激组和他汀干预组山羊给予400～450次/分连续快速刺激。基础状态下、刺激24、48、72h及7、14d测量左右心房有效不应期(ERP)、ERP频率适应性、左右心房传导速度(CV)、房颤诱发率及持续时间,ELISA法测定血清hs-CRP、IL-6、TNF-α水平。
结果
1、(1)心包炎组和他汀干预组山羊血清hs-CRP、IL-6、TNF-α水平在术后明显升高(p＜0.05),48h～72h达到高峰,于术后7d开始逐渐下降,但仍明显高于基础状态(p＜0.05),亦高于对照组(p＜0.05)。他汀干预组山羊血清hs-CRP、IL-6、TNF-α水平在术后24h～48h以后均明显低于心包炎组(p＜0.05),但仍高于对照组(p＜0.05)。(2)心包炎组和他汀干预组山羊左房ERP在术后明显缩短(p＜0.05),至术后72h达到最低值,此后稍有延长但仍明显低于基础状态(p＜0.05)。与对照组相比,心包炎组山羊左房ERP明显缩短(p＜0.05)。与心包炎组比较,他汀干预组山羊术后左房ERP明显延长(p＜0.05)。心包炎组山羊右房ERP在术后24h～72h较对照纽明显缩短(p＜0.05)。(3)各纽山羊心房ERP频率适应性在术后均明显降低(p＜0.05)。术后14d及21d对照组和他汀干预组恢复至正常,而心包炎组仍表现为ERP频率适应性不良,显著低于基础状态(p＜0.05)。心包炎组山羊心房ERP频率适应性与血清hs-CRP呈明显负相关。(4)各组山羊左右心房CV均无显著变化,左房CV稍快于右房CV(p＞0.05)。(5)心包炎组和他汀干预组山羊左房房颤诱发率在术后明显增高(p＜0.05),他汀干预组低于心包炎组(p＞0.05)。各组山羊右房房颤诱发率术后无显著变化。心包炎组和他汀干预组山羊房颤持续时间在术后明显延长(p＜0.05)。他汀干预组房颤持续时间明显短于心包炎组(p＜0.05)。
2、(1)心房刺激组和他汀干预组山羊左房ERP随着刺激时间的延长逐渐缩短,至刺激7d时趋于稳定。他汀干预组山羊左房ERP在刺激48h以后较心房刺激组明显延长(p＜0.05)。心房刺激组和他汀干预组山羊右房ERP之间比较无显著差异。(2)心房刺激组山羊心房ERP频率适应性随着刺激时间的延长逐渐降低,他汀干预组在刺激72h以后显著高于心房刺激组(p＜0.05)。(3)各组山羊左右心房CV均无显著变化。(4)心房刺激组和他汀干预组山羊血清hs-CRP、IL-6、TNF-α水平随着刺激时间的延长不断升高,显著高于对照组(p＜0.05)。他汀干预组山羊血清hs-CRP、IL-6、TNF-α水平于刺激48h以后明显低于心房刺激组山羊(p＜0.05)。(5)心房刺激组和他汀干预组山羊左房房颤诱发率随着刺激时间的延长逐渐增高,显著高于对照组(p＜0.05)。心房刺激组山羊于刺激14d左房房颤诱发率达到100%。他汀干预组山羊左房房颤诱发率于刺激48h及以后明显低于心房刺激组(p＜0.05)。各组山羊右房房颤诱发率在刺激过程中无明显变化(p＞0.05)。心房刺激组和他汀干预组山羊房颤持续时间随着刺激时间的延长逐渐延长(p＜0.05),两组之间比较他汀干预组明显短于心房刺激组(p＜0.05)。
结论
1、山羊无菌性心包炎术后心房电生理特性发生明显改变,表现为心房ERP缩短,ERP频率适应性降低,而CV无明显变化。提示炎症通过缩短心房ERP及ERP频率适应性影响了WL,使心房形成一种“房颤基质”,易于房颤的诱发及维持。心房快速激动后,山羊血清炎症因子水平随着刺激时间的延长逐渐升高,提示心房快速激动导致了炎症反应的发生。推测此时炎症反应又进一步对心房电生理特性产生影响,加重了电重构,并与其共同作用,促进了“房颤引发房颤”,形成恶性循环,最终使房颤趋于稳定。以上提示炎症在房颤的发生及维持中均起到重要的作用,炎症与房颤互为因果,相互促进。
2、组织学观察发现,阿托伐他汀减轻了心房肌的炎症反应。阿托伐他汀可以明显抑制炎症发生后导致的心房电生理特性的改变,也可以一定程度地减轻心房快速激动导致的心房电重构。以上说明阿托伐他汀通过抑制炎症反应,抑制了心房电生理特性的改变,降低了房颤的诱发率及持续时间。提示阿托伐他汀对心脏术后的房颤发生可能有一定的预防作用,并可能有易于预防房颤复发。
Objective Atrial fibrillation(AF) is the most common sustained arrhythmia in clinical practice,and the prevalence of AF is strongly age-dependent.AF is associated with an increased mortality and morbidity from stroke and thromboembolism,heart failure and impaired quality of life.Therefore attention has been directed towards understanding the underlying pathophysiology of this condition,to provide novel insights into improving the therapeutic management of this condition.There are emerging data to support a significant association between inflammation and the development,recurrence and perpetuation of AF. For example,AF patients are always accompanied with an elevation of CRP level, and AF may be induced by the active inflammatory process.In addition,the increasing data supports a reduction in the development of AF by 3-hydroxy-3-methylglutaryl coenzyme A(HMG-CoA) reductase inhibitors (statins) use which provides an anti-inflammatory action.However,the causality of AF and inflammation remains controversial.This study was designed to determine the relationship between AF and inflammation in goat sterile pericarditis model and atrial tachypacing model,to analyze the role of inflammation on the atrial electrophysiological properties,and to assess the effect of atorvastatin on AF.
Methods 1.Fifteen adult male goats were randomly divided into control, pericarditis,and atorvastatin groups.Atorvastatin was administered orally(60 mg/day) beginning 1 week before the operation until the end of the study in atorvastatin group.The chest was opened through the left fourth intercostal space, and pericardial electrodes patches were sutured on the left atrium(LA) and right atrium(RA).The sterile pericarditis model was established in pericarditis and atorvastatin groups.At baseline,24,48,72 hours and 7,14,21 days after the operation,atrial effective refractory period(ERP),ERP rate adaptation, conduction velocity(CV),and duration of induced AF,and hs-CRP,IL-6,TNF-αlevels were measured.2.Fifteen adult male goats were randomly divided into control,atrial tachypacing(ATP),and atorvastatin groups.Atorvastatin was administered orally(60 mg/day) beginning 1 week before ATP until the end of the study in atorvastatin group.All goats were instrumented with epicardial electrodes patches on LA and RA.Goats in ATP and atorvastatin groups were subjected to atrial tachypacing(ATP) at 400～450 bpm.At baseline,24,48,72 hours and 7, 14 days after tachypacing onset,ERP,ERP rate adaptation,CV,and duration of induced AF,and hs-CRP,IL-6,TNF-αlevels were measured.
Results
1.(1) Levels of hs-CRP,IL-6 and TNF-αelevated significantly after the operation in pericarditis and atorvastatin groups(p＜0.05) with a peak elevation of hs-CRP, IL-6 and TNF-αlevels at 48～72 hours after the operation,and were higher than that in control group(p＜0.05).Atorvastatin group had a lower hs-CRP,IL-6 and TNF-αlevels than pericarditis group(p＜0.05).(2) ERP and ERP rate adaptation of pericarditis goats decreased significantly after the operation(p＜0.05).Atorvastatin group had a longer ERP and a higher ERP rate adaptation than pericarditis group (p＜0.05).There was significant negative correlation between ERP and hs-CRP level in pericarditis group.(3) There was no significant change in CV in all groups after the operation.(4) The inducibility of AF in LA and duration of AF in pericarditis and atorvastatin groups increased after the operation(p＜0.05).And pericarditis group had a longer duration of AF than atorvastatin group(p＜0.05). The inducibility of AF in RA unchanged before and after the operation in all groups.
2.(1) ERP of LA in ATP and atorvastatin groups decreased gradually(p＜0.05) and reached a steady state at 7 days.Atorvastatin group had a longer ERP in LA than ATP group since 48 hours after tachypacing onset(p＜0.05).There was no difference in ERP in RA between ATP and atorvastatin group.(2) ERP rate adaptation in ATP group decreased gradually(p＜0.05) and was lower than that in atorvastatin group(p＜0.05).(3) There was no significant change in left and right atrial CV in all groups.(4) Levels of hs-CRP,IL-6 and TNF-αin ATP group elevated gradually(p＜0.05) and was higher than that in control group(p＜0.05). Atorvastatin group had a lower hs-CRP,IL-6 and TNF-αlevels than ATP group (p＜0.05).(5) The inducibility of AF in LA and duration of AF in ATP and atorvastatin groups increased gradually(p＜0.05) and were all higher than that in control group(p＜0.05).The inducibility of AF in LA at 14 days in ATP group was 100%.The inducibility of AF in LA in atorvastatin group was lower than ATP group since 48 hours after tachypacing onset(p＜0.05).The inducibility of AF in RA unchanged in all groups.Atorvastatin group had a shorter AF duration than ATP group(p＜0.05).
Conclusion Inflammation may promote AF by shortening atrial ERP and adaptation of ERP to rate,which might be a potential "substrate".And the elevation of hs-CRP,IL-6,TNF-αinduced by atrial tachyarrhythmia suggests that AF may induce an inflammatory process.Consequently,inflammation resulted from AF will aggravate atrial electrical remodeling further,promote "AF begets AF" together with AF,and ultimately facilitate the perpetuation of AF. Inflammation plays an important role in the initiation and maintenance of AF. Atorvastatin can attenuate AF promotion by inhibiting inflammation both in goat sterile pericarditis model and atrial tachypacing model.This indicates that atorvastatin may prevent AF post-cardiacsurgery and recurrence of AF.
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