胺碘酮对心房颤动犬心房结构及基质金属蛋白酶-9表达的影响

目的 观察Ⅲ类抗心律失常药物乙胺碘呋酮(胺碘酮)对长期心房快速起搏诱发心房颤动(房颤)犬心房结构及基质金属蛋白酶-9(MMP-9)表达的影响,探寻胺碘酮对房颤犬心房结构重构的作用机制.方法 20只犬随机分为假手术组(n=6)、对照组(n=7)和胺碘酮组(n=7).对照组和胺碘酮组犬心房快速起搏6周(400次/min),建立房颤犬模型.胺碘酮组犬起搏后口服胺碘酮30 mg/(kg·d),直至起搏结束.超声评价各组犬起搏前后左心房、左心耳结构和功能;测定房颤诱发情况;Masson染色检测心房肌胶原容积分数(CVF);免疫组化法观察心房肌MMP-9蛋白表达情况.结果 胺碘酮能够有效防止心房快速起搏诱发房颤犬左心房、左心耳功能降低,使犬房颤诱发率和平均持续时间显著减少,降低房颤犬心房肌CVF值,有效抑制房颤犬心房肌MMP-9表达增加.结论 胺碘酮能够阻止长期心房快速起搏房颤犬心房结构的改变及心房纤维化,防止房颤犬心房结构重构,减少房颤发生.     

高甲状腺素对心房和肺静脉缝隙连接、电生理特性的影响

目的研究高甲状腺素对心房和肺静脉缝隙连接、电生理特性的影响。方法24只实验兔随机分为正常对照组和甲亢组。测定心房有效不应期(AERP),然后取心房、肺静脉组织,用Western blot和半定量逆转录聚合酶链反应法分别测定连接蛋白43(cx43)及连接蛋白40(Cx40)的蛋白表达和mRNA水平。结果甲亢组的AERP均明显短于对照组(P＜0．01),且AERP的频率适应性较对照组明显下降(P＜0．01)。甲亢组心房及肺静脉的Cx43蛋白和mRNA表达量较对照组明显增加,而Cx40的蛋白表达量低于对照组(P＜0．05)。心房及肺静脉的Cx40 mRNA表达量在两组之间差异无统计学意义。结论高甲状腺素可引起心房电生理重构和心房及肺静脉的缝隙连接重构。     

急性心房压力增高对心房肌电生理性质的影响

目的:探讨急性心房压力增高对心房肌电生理性质的影响及其与房性心律失常的关系。方法:12只杂种成年犬,在阻断自主神经状态下行心外膜电生理检查,分成基础对照组,单纯升压组及胺碘酮 升压组,分别测量心房不同位点的单相动作电位(MAP)及房颤诱发率。结果:与基础对照相比,单纯升压组MAPD90明显延长,MAPD90离散度(△MAPD90)增大,RT离散度(△RT)增大,房颤诱发率增加。胺碘酮 升压组MAPD90延长,但△MAPD90减小,△RT在慢频率起搏时减小,但起搏频率增快时逐渐增大,房颤诱发率虽高于对基础对照,但与单纯升压组相比无统计学差异。结论:1)急性心房压力增高后△RT增大,这可能是此时房颤诱发率增高的电生理基础;2)胺碘酮静脉制剂在房压增高时不能有效降低房颤诱发率,推测与这时△RT在快频率起搏时增大有关。     

替米沙坦联合胺碘酮治疗阵发性房颤临床疗效观察

选取我院内科2012年1月~2013年6月收治的81例阵发性房颤患者。随机分为联合用药组40例和单纯用药组41例。两组患者均服用胺碘酮,联合用药组在此基础上给予替米沙坦,比较两组患者治疗前后房颤发作次数、发作持续时间及左房内径。结果联合用药组患者治疗后房颤发作次数、持续时间明显优于单纯用药组(P<0.05);联合用药组患者治疗后左房内径增大幅度小于单纯用药组(P<0.05)。替米沙坦与胺碘酮联合治疗阵发性房颤,可有效减少心房颤动次数,抑制心房重构,延缓心房扩大速度,治疗效果优于单服胺碘酮。     

胺碘酮联合贝那普利治疗阵发性心房颤动70例临床分析

目的观察胺碘酮联合贝那普利对阵发性房颤的疗效。方法选择我院2008年3月至2010年3月期间阵发性心房纤颤患者145例,随机分为治疗组（胺碘酮＋贝那普利）和对照组（单用胺碘酮）,对照组应用胺碘酮治疗,治疗组在此基础加用贝那普利。结果随访12个月,治疗组窦性心律维持率明显高于对照组（P〈0．05）,左房内径亦有显著性缩小（P〈0．05）。结论贝那普利具有抑制心房电重构和解剖重构,降低房颤复发率及阻止房颤持续的作用,胺碘酮联合贝那普利能更有效地治疗和预防阵发性房颤。     

胺碘酮与厄贝沙坦联用对病态窦房结综合征人工心脏起搏后的疗效

目的观察厄贝沙坦和胺碘酮联用对病态窦房结综合征(病窦综合征)并阵发性心房颤动(房颤)双腔起搏(DDD)起搏后房颤发生率的影响。方法选取病窦综合征并阵发性房颤患者60例,DDD起搏后随机分为胺碘酮组(30例)和厄贝沙坦+胺碘酮组(30例),胺碘酮组治疗方案:DDD起搏后,给予胺碘酮0.2 g,口服1次/d;厄贝沙坦+胺碘酮组在上述方案基础上加厄贝沙坦75~150 mg/d,疗程观察18个月。结果与胺碘酮组比较,厄贝沙坦+胺碘酮组房颤的发生率明显降低(P<0.05),且厄贝沙坦+胺碘酮组窦性心律维持率高于胺碘酮组。结论厄贝沙坦联合胺碘酮对植入DDD型起搏器患者心房颤动的发生有明显的协同抑制作用。     

缬沙坦在预防心房颤动复发中的作用及对心房重构的影响

目的:探讨缬沙坦在房颤转复后预防房颤复发,维持窦性心律的有效性及对心房重构的影响.方法:60例持续性房颤患者(持续超过7天),经药物或电复律后随机分为两组,Ⅰ组30例给予胺碘酮0.2每日1次,Ⅱ组30例给予胺碘酮0.2每日1次,缬沙坦80 mg每日1次,两组均连续服用6个月.于治疗后第1周、2周、1月、2月、4月及6月分别行心电图或动态心电图以检测是否房颤复发;复律次日及6月后做超声心动图检查,观察左心房结构及功能变化.结果:60例均完成治疗,随访6月,心房颤动复发率Ⅰ组33%,Ⅱ组13%,两组间比较有统计学意义(P＜0.05) .Ⅱ组心房颤动转复6月后患者左心房内径缩小,治疗前后比较差异有统计学意义(P＜0.05) ;Ⅰ组患者治疗前后比较差异无统计学意义P＞0.05.结论:缬沙坦与胺碘酮联用于持续性心房颤动复律后维持窦性心律,较单用胺碘酮有效,长期服用缬沙坦可逆转左房扩大,降低左房压,抑制RAS激活,从而抑制心房结构及电重构,防止房颤复发.     

胺碘酮联合缬沙坦、氟伐他汀预防阵发性房颤复发的临床观察

目的：探讨胺碘酮联合缬沙坦、氟伐他汀预防阵发性房颤复发的临床疗效。方法：随机选取阵发性房颤复律后患者85例,分为观察组43例和对照组42例。观察组口服胺碘酮加缬沙坦、氟伐他汀,对照组口服胺碘酮,观察12个月。结果：观察组房颤复发率明显下降并低于对照组有统计学差异（P〈0.05）。观察组左房结构功能改善优于对照组,差异有统计学意义（P〈0.05）,观察组CRP水平在12个月后显著低于对照组（P〈0.01）。结论：胺碘酮联合缬沙坦、氟伐他汀能更有效预防房颤复发。     

阿托伐他汀对心房颤动预防作用及其电生理机制的实验研究

目的探讨阿托伐他汀对心房颤动（房颤）电生理机制的影响。方法 30只新西兰大白兔随机分为对照组、房颤组和阿托伐他汀组,各10只。房颤组和阿托伐他汀组采用快速心房起搏（频率600次/min）制作急性房颤模型,对照组仅植入电极不起搏,阿托伐他汀组起搏前用阿托伐他汀2mg/（kg.d）灌胃7d。观察起搏0,4,8,12,16,20,24h时房颤诱发率、房颤持续时间、心房有效不应期和频率适应性的变化。结果起搏后8,12,16,20,24h房颤组和阿托伐他汀组房颤诱发率高于对照组（P〈0.05）,房颤组高于阿托伐他汀组（P〈0.05）;房颤组和阿托伐他汀组房颤持续时间较对照组延长（P〈0.05）,阿托伐他汀组房颤持续时间的延长较房颤组减少,但差异无统计学意义（P〉0.05）;与对照组比较,起搏4h后房颤组心房有效不应期缩短（P〈0.05）,心房有效不应期频率适应性降低（P〈0.05）,随起搏时间延长呈进行性加重;阿托伐他汀组起搏12h后心房有效不应期高于房颤组（P〈0.05）,起搏8h后心房有效不应期频率适应性的降低较房颤组减少（P〈0.05）。结论阿托伐他汀可有效抑制快速心房起搏兔心房肌的电重构,表现为抑制心房有效不应期缩短和心房有效不应期频率适应性不良,可有效预防房颤发生,但并不影响房颤维持时间。     

快速心室起搏犬心房颤动模型研究

目的建立快速起搏心室致心力衰竭犬房颤模型,研究其电生理及心房结构和功能改变。方法 15只健康杂种犬分两组:对照组6只,实验组9只[240次/min心室起搏(25±3)d]。超声心动图测定起搏前后心房面积、面积缩小分数及左心室功能,利用心内电极测定心房有效不应期、传导速度及房颤诱发情况。结果实验组7只犬完成了实验。快速心室起搏(25±3)d后,犬的收缩末期和舒张末期左、右心房面积显著增大(与起搏前比较,P<0.01),左、右心房面积缩小分数显著减小(左心房:(35.7±1.9)%和(20.7±2.7)%,P<0.01;右心房:(35.0±2.3)%和(18.0±2.3)%,P<0.01),左室射血分数从(65.3±2.1)%降至(31.6±2.8)%(P<0.01)。实验组犬左、右心房有效不应期显著延长,心房内传导速率较对照组减慢。实验组有5只犬诱发出超过30 min的房颤,平均房颤持续时间较对照组显著延长(687±290)s和(13±9)s,P<0.01)。实验组平均房颤持续时间与左、右心房面积及面积缩小分数相关(P<0.05)。结论 快速心室起搏致心衰模型能稳定地诱发出房颤,房颤持续时间与心衰引起的显著心房结构和功能异常相关。     

缝隙连接蛋白Cx32与Cx43在癫痫发病中的作用

目的:探讨缝隙连接蛋白(Cx)与癫痫之间的关系.方法:采用免疫组织化学方法测定氯化锂-匹罗卡品致痫大鼠癫痫发作后不同时间不同脑区Cx32与Cx43免疫阳性表达情况.结果:与对照组比较,致痫组大鼠海马区与皮层区Cx32和Cx43免疫阳性表达在癫痫发作1h后开始增强(Cx32免疫阳性细胞数分别为海马区16.62±4.51和皮层区14.85±3.30,均P＜0.05;Cx43免疫阳性细胞数分别为海马区18.26±4.03和皮层区18.65±4.51,均P＜0.01),24 h达到高峰(Cx32免疫阳性细胞数分别为海马区46.53±9.47和皮层区28.25±8.69,均P＜0.01;Cx43免疫阳性细胞数分别为海马区39.77±7.79和皮层区26.50±6.56,均P＜0.01),此后逐步下降.但至14 d Cx32海马区与皮层区免疫阳性细胞数分别为22.45±6.56和15.92±3.16,仍高于对照组(均P＜0.05),而Cx43在14 d的表达则有所不同:海马区免疫阳性细胞数17.54±3.77仍高于对照组(P＜0.01);皮层区表达则降至正常水平.致痫24 h时海马区Cx32和Cx43免疫阳性表达均明显高于同一时限的皮层区(均P＜0.05).结论:Cx32和Cx43参与了癫痫的发生与发展过程,反映了脑组织中神经元、星形胶质细胞之间的缝隙连接与癫痫发病机制密切相关.     

Enhancement of repopulation haemopoiesis by heterozygous connexin 43 stem cells seeded on wild-type connexin 43 stroma

The present paper analyses the results of competitive blood-cell repopulation experiments in which Cx43-WT (connexin 43 wild-type) host mice, whose own HSCs (haemopoietic stem cells) were deleted, were grafted with fetal liver cells: 50% Gpi-1a (glucose phosphate isomerase-1a)/Cx43-WT cells competing with 50% Gpi-1b/Cx43-WT, 50% Gpi-1b/Cx43-HZ (heterozygous) or 50% Gpi-1b/Cx43-KO (knock-out) cells. The percentages of platelets, granulocytes, red cells, B-cells and T-cells containing Gpi-1b in blood samples obtained from 22 to 186 days after grafting, and the percentages of high-proliferation-potential colony-forming cells containing Gpi-1b at 255 days after grafting, were measured. The results show that, if we wait 4 months so that we measure the percentages of Gpi-1b end-cells formed by initially resting stem cells in the graft, values in HZ mice are greater than those in WT and KO mice by 10% or more. We propose a bipolar influence model for blood formation by grafted HSCs to explain this difference and other features of the data. Influence A is a direct one: for individual HSCs, the combined effect on HSC niching and HSC proliferation of Cx43 is superior to that of the KO allele. Influence B is a demographic one: HZ foundation mice compensate by having more HSCs than WT mice. The net outcome of influences A and B is that HZ is the winner.     

Gene transfer of connexin43 into skeletal muscle

Cellular cardiomyoplasty using skeletal myoblasts may be beneficial for infarct repair. One drawback to skeletal muscle cells is their lack of gap junction expression after differentiation, thus preventing electrical coupling to host cardiomyocytes. We sought to overexpress the gap junction protein connexin43 (Cx43) in differentiated skeletal myotubes, using retroviral, adenoviral, and plasmid-mediated gene transfer. All strategies resulted in overexpression of Cx43 in cultured myotubes, but expression of Cx43 from constitutive viral promoters caused significant death upon differentiation. Dye transfer studies showed that surviving myotubes contained functional gap junctions, however. Retrovirally transfected myoblasts did not express Cx43 after grafting into the heart, possibly due to promoter silencing. Adenovirally transfected myoblasts expressed abundant Cx43 after forming myotubes in cardiac grafts, but grafts showed signs of injury at 1 week and had died by 2 weeks. Interestingly, transfection of already differentiated myotubes with adenoviral Cx43 was nontoxic, implying a window of vulnerability during differentiation. To test this hypothesis, Cx43 was expressed from the muscle creatine kinase (MCK) promoter, which is active only after myocyte differentiation. The MCK promoter resulted in high levels of Cx43 expression in differentiated myotubes but did not cause cell death during differentiation. MCK-Cx43-transfected myoblasts formed viable cardiac grafts and, in some cases, Cx43-expressing myotubes were in close apposition to host cardiomyocytes, possibly allowing electrical coupling. Thus, high levels of Cx43 during skeletal muscle differentiation cause cell death. When, however, expression of Cx43 is delayed until after differentiation, using the MCK promoter, myotubes are viable and express gap junction proteins after grafting in the heart. This strategy may permit electrical coupling of skeletal and cardiac muscle for cardiac repair.     

心室纤颤时心肌缝隙连接蛋白Cx43的变化

目的 观察心室纤颤(室颤)发生后缝隙连接蛋白Cx43的表达以及缝隙连接改造剂ZP123对Cx43表达的影响.方法 按照随机数字表法将30只家猪分为假手术组、模型组和ZP123干预组,每组10只.以80 V电压持续刺激动物5 s诱发室颤;致颤前15 min ZP123组给予ZP123 1μg/kg静脉推注+ZP12310μg·kg-1·h-1微量泵泵入;模型组泵入生理盐水50 ml;假手术组动物不致颤也不补液.室颤持续8 min后开胸取左心室游离壁心肌,用免疫荧光结合激光共聚焦显微镜技术检测Cx43的分布及水平,用蛋白质免疫印迹法(Western blotting)定量检测Cx43蛋白表达.结果 假手术组Cx43荧光信号强,分布均匀;模型组Cx43荧光信号弱,呈不均一分布;ZP123干预组Cx43荧光信号增强,不均一分布减轻.与假手术组比较,模型组心室肌组织Cx43荧光信号面积百分比、积分吸光度(A)值及蛋白表达均明显下降[面积百分比:(0.64±0.36)%比(1.27±0.19)%,积分A值:15 201±2 613比30 634±4 975,Cx43蛋白表达:0.72±0.08比0.97±0.07,均P＜0.05];与模型组比较,ZP123干预组Cx43表达[面积百分比(0.96±0.16)%,积分A值22 100±4 404,Cx43蛋白表达0.82±0.04]均明显升高(均P＜0.05).结论 室颤发生时心肌组织Cx43表达减少;应用ZP123可减少或逆转Cx43的降解.     

室性心动过速时连接蛋白43含量与分布的变化

目的　探讨室性心动过速 (室速 )时心肌细胞连接蛋白 4 3(Cx 4 3)含量和分布的变化。方法　实验用日本大耳白兔 2 0只 ,随机分为对照组、30min室速组、6 0min室速组、12 0min室速组 4组。分别通过心室刺激复制室性心动过速动物模型 ,应用激光共聚焦显微镜技术和荧光免疫组织化学方法对其发生心律失常心肌连接蛋白 4 3的含量和分布进行定量分析。结果　 30min室速组连接蛋白 4 3像素密度较对照组减少 18.4 % (P <0 .0 5 ) ,6 0min室速组减少 38.0 % (P <0 .0 1) ,12 0min室速组减少 5 4 .8% (P <0 .0 1)。对照组各层间心肌细胞连接蛋白 4 3含量比较无显著差异 ,但心律失常后 ,中间层心肌细胞连接蛋白 4 3含量较其他层心肌细胞含量下降更明显 (P <0 .0 5或P <0 .0 1)。结论　室性心动过速时连接蛋白 4 3迅速降解 ,其分布也发生明显的改变 ,各层心肌细胞连接蛋白 4 3的降解程度也明显不均一。     

卡维地洛对连接蛋白43的分布及数量的影响

目的观察卡维地洛对心肌梗死边缘区Cx43分布的影响。方法36只家兔随机分为梗死组，卡维地洛组，假手术组，每组12只。梗死组和卡维地洛组开胸结扎冠状动脉左前降支，假手术组不结扎。所有家兔普通饲料喂养，卡维地洛组另给予卡维地洛5mg·kg^-1·d^-1。12周后观察：（1）共聚焦激光显微镜观察梗死边缘区Cx43的分布，（2）Werstem Blot检查梗死边缘区Cx43的蛋白表达。结果（1）共聚焦激光显微镜下观察心肌梗死组Cx43荧光斑的形态相对粗乱，呈现不均一分布；卡维地洛组Cx43的荧光分布改变较少，不均一分布的程度较心肌梗死组减轻；心梗组的Cx43相对密度显著低于卡维地洛组；[（0．16±0．06）％vs（0．32±0．11）％，P〈0．05]；（2）Werstem Blot检查梗死组Cx43及卡维地洛组较假手术组减少，但卡维地洛组的Cx43表达较心肌梗死组增多[（0．89±0．28）vs（0．67±0．32），P〈0．05]。结论卡维地洛可以引起Cx43的再分布，增加心肌梗死后Cx43蛋白的表达，这可能是其较减少心肌梗死后室性心律失常的原因之一。     

Sepsis up-regulates the expression of connexin 40 in rat aortic endothelium

OBJECTIVE: A distinctive feature of sepsis is a pleiotropic modification of membrane protein expression in the vascular endothelium, associated with diminished endothelium-dependent relaxation (endothelial dysfunction). In cultured endothelial cells, inflammatory stimuli alter expression of connexins (Cx), proteins that make up the gap junctions responsible for intercellular communication. In the present study, we tested whether the polymicrobial sepsis induced by cecal ligation and perforation in the rat alters the expression of the connexins present in the vascular endothelium (i.e., Cx37, Cx40, and Cx43). We also examined a possible association between such changes and endothelial dysfunction in this model. DESIGN: Animal study, with two parallel groups. SETTING: Animal research facility. SUBJECTS: One hundred four male adult Wistar rats. INTERVENTIONS: Rats underwent either cecal ligation and perforation to induce sepsis or a sham operation and were killed after a variable time, mostly 24 hrs. MEASUREMENTS AND MAIN RESULTS: Experiments designed to test for the impact of sepsis on connexin expression disclosed a three-fold increase in Cx40 messenger RNA and protein in the aorta, an effect that peaked at 24 hrs after cecal ligation and perforation, was specific to this connexin (i.e., levels of Cx37 and Cx43 did not vary), and was restricted to the aortic endothelium. Experiments designed to test the permeability of interendothelial gap junctions using the scrape-loading method did not show a change in function in the septic group. Finally, a time-course study was designed to test for a possible association of enhanced Cx40 expression with endothelial dysfunction. Endothelium-dependent relaxation was diminished in rings of aorta when harvested from septic rats before (6 hrs after surgery) but not at the time when enhanced Cx40 expression occurred (12 and 24 hrs). CONCLUSION: In this experimental model, recovery from an early transient dysfunction of the aortic endothelium is associated with an enhanced expression of aortic endothelial Cx40.