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医汇心血管学术 > 肾素血管紧张素系统房颤抑制效应的临床和实验证据

肾素血管紧张素系统房颤抑制效应的临床和实验证据

发表于 2014-10-09 14:37:39
摘要:房颤是常见的心律失常,而且目前治疗仍较困难。旨在维持窦性心律的房颤药物治疗因其疗效欠佳和潜在的副作用而应用受到限制。而致力于改善心房基质进展的治疗新方法引起了人们的兴趣。新近研究表明血管紧张素转换酶抑制剂和血管紧张素受体拮抗剂在改善心房基质重构可能有益,特别是伴有心室肥大和心力衰竭的患者。而对其临床潜在效应和机制目前研究活跃。研究表明,血管紧张素II参与心肌重构并可对心肌产生直接的电生理作用。实验表明ACEI和ARB可以防止心房基质重构和电重构,并可能对心肌离子通道有潜在效应。目前虽缺少它们在房颤患者中前瞻性随机双盲的临床试验而无应用指征,但正在进行中的研究可能在不久的将来使其得以改变。这些令人兴奋的研究将为房颤患者的治疗选择带来重大进步。本文就ACEI和ARB在房颤患者中的临床应用和作用机制综述如下。 关键词:心律失常 心房颤动 肾素血管紧张素系统 药物治疗 引言 随着研究深入,人们对肾素血管紧张素醛固酮系统在房颤的下游效应认识逐步增加。Ang-II是一个八肽化合物,由肝脏合成的485个氨基酸组成的血管紧张素原前体经剪接后形成。研究发现,血管紧张素原的基因多态性与非家族性房颤密切相关,而且ACEI和ARB可预防某些患者房颤复发。 研究表明Ang-II在调节血压、纤维增生和心肌肥大方面有重要作用。心力衰竭患者Ang-II的效应可被增强。早期临床试验已经证明ACEI对心力衰竭患者死亡率和发病率的有益影响。ACEI也可减少陈旧性心肌梗死患者室性心律失常,室性期前收缩的数量和受累患者的数量均有下降。左室功能不全研究(SOLVD)回顾性分析表明ACEI可防止合并症状性CHF的房颤患者复发。其他的研究亦发现ACEI对房颤合并其他危险因素(如高血压伴左室肥厚、急性心肌梗死伴LVEF降低)的患者有预防作用。最近的一项meta分析肾素血管紧张素醛固酮系统对房颤伴左室功能不全患者的明显抑制效应。与先前的综述总结的临床证据一致,ACEI和ARB抗房颤疗效确切,本文更新了新近的临床证据并试图阐明其潜在机制。方法: 在PubMed数据库检索,选定关键词:AF,肾素血管紧张素系统,ACEI,ARB。检索2000-2005年的含有英文摘要文章,并给予适当评价。选定文章的参考文献列表另附文评价。数据资料的提取来自专家审查的原始评论文章。临床证据 ACEI降低新发房颤的发生率 一个回顾性的、纵向队列研究共入选病例800000患者,比较了ACEI与钙拮抗剂治疗高血压患者房颤的发生率。另一项包含10926名患者的队列研究(平均年龄65岁)被平等地分为两组,随访4年ACEI组新发房颤的调整危险比为0.85(95% CI: 0.74–0.97).若干研究比较了ACEI与其他药物(beta-受体阻断剂, 钙离子拮抗剂和利尿剂 )治疗高血压患者,新发房颤的发生率无明显差异。此外,ARBs可明显减少高血压合并房颤心血管疾病发病率、死亡率和中风危险。LIFE研究ARB用于左室肥大患者,而其他临床试验成功评价了ACEI用于更大范围的高血压患者疗效。AF与心肌梗死后患者不良预后明显相关。一项回顾性研究分析了ACEI对房颤发生率的效应,共入选了1577名窦性心律伴LVEF<35%的心肌梗死后患者。ACEI减少房颤的发生率达55%,而对照组房颤的发生率(5.3 to 2.8%)。而且房颤发生率减少并不能用血清K和LV收缩功能的差异来解释,支持ACEI在其中发挥了主要作用。SOLVD研究亚组分析入选了391名LVEF均值<30%患者,给予ACEI治疗平均随访时间2.9±1.0年明显减少了新发房颤的发生(治疗组5.4 vs. 24%对照组)。ACEI预防房颤更有益。另一项SLOVD的回顾性分析评价了192名因房性心律失常住院的其中158名患者,ACEI治疗与再住院率和死亡相对风险降低(RR: 0.87, 95% CI: 0.79–0.96, P<0.007)明显相关。房性心律失常的再住院率降低(RR 0.64, 95% CI:0.48–0.85, P<0.002)。与对照组相比,Val-HeFT事后分析证明给予缬沙坦基上加用ACEI可是更少的CHF窦性心率的患者发展为房颤(5.12 vs. 7.95%, P<0.0002)。 总结,血管紧张素系统抑制剂对高血压伴LV肥大,陈旧性心肌梗死伴左室功能不全,慢性心力衰竭患者可防止房颤发生。这种效应在LV收缩功能不全和充血性心力衰竭的患者最为明显。由于房颤在回顾性研究中并不是预先确定的终点,这些结果需要在前瞻性试验中证实。此外,肾素血管紧张素系统抑制剂对房颤发生率的效应并未在不具备高血压、陈旧性心肌梗死等适应症的患者中得到系统的验证。正在研究中的ACTIVE试验比较伊贝沙坦与对照组的疗效。另外一项正在进行的试验研究厄贝沙坦在阵发性房颤患者的应用。ANTIPAF(血管紧张素II受体拮抗剂在阵发性房颤的应用评价)。ACEI可预防电复律后房颤复发,并且可产生有益的血流动力学效应和提高与房颤相关的慢性心力衰竭患者的最大耗氧需要,还有更好维持转复后窦性心律的趋势(治疗组71%vs.36%对照组 P=n.s)。回顾性分析AFFIRM 试验732名患者被随机分配到节律控制组证明伴有慢性心力衰竭的患者给予ACEI后房颤复发更少。Madrid等前瞻性的研究了电复律后胺碘酮基础上加用伊贝沙坦的疗效,房颤的发生率在伊贝沙坦组降低。类似的,Ueng等研究表明胺碘酮联合ACEI可明显减少转复后房颤复发。这些试验,将抗心律失常与肾素血管紧张素系统抑制剂联合治疗进一步改善了预后,减少了复发,虽然随访时间相对较短。另一个试验电复律后给予ACEI治疗6-12月,证明可以缩短信号平均P波时间,反映了改善了心房传导。 实验证据 ACEI和ARB抗房颤的潜在机制 1.改善血流动力学和降低心房牵张2.抑制AngII诱导的心房纤维化 3.直接介导心房离子通道功能 ACEI降低心房牵张 ACEI血流动力学效应包括体循环动脉血管舒张、增加大动脉顺应性其可降低收缩压。肾素血管紧张素系统抑制剂可降低慢性心力衰竭患者后负荷和收缩期大血管壁压力,提高患者心功能。ACEI还可降低左房压和室壁应力。压力急剧增加可增加心房损害的敏感性,其通过缩短心房不应期,也可能是通过开放压力敏感性离子通道。二尖瓣腱索破裂后心房牵张可改变心房肌电生理特性(如期前收缩的传导明显减慢),类似与实验性CHF相关AF。实验性CHF诱导了明显的心房牵张,并且大多数CHF动物进展为二尖瓣返流。二尖瓣返流减慢了冲动传导,并触发了狗房颤。使羊的主肺动脉短路可逐步使其左房扩大,并改变其电生理特性(动作电位缩短,ICa,L降低),并易患房颤。慢性容量负荷过重的兔子证明了折返和局灶性左房电活动。牵张不仅是CHF患者唯一的房颤基质决定因素。快速起搏诱导CHF恢复后,AF仍可被诱发尽管心房扩张已经逆转恢复。模拟的ACEI血流动力学效应并不能抑制实验性CHF相关AF,然而ACE确实可以抑制AF,表明血流动力学效应不能充分反映ACEI作用。 预防心房纤维化 血管紧张素II可调节心肌成纤维细胞增生。TGF-ß1对心房纤维化可能有特别重要的意义。AngII与AT1受体结合可通过促进TGF-ß1合成刺激纤维组织形成。转基因鼠心肌选择性过度表达TGF-ß1可导致心房纤维化而非心室,并有房颤易患倾向。实验CHF狗模型中,心房肌较心室局部有更高水平的AngII,而且心房TGF-ß1在CHF进展中被激活。心肌特异性ACE过度表达可引起心房增大和AF,与AngII、心房纤维化以及AF有一致联系。实验性CHF,ACEI治疗可抑制心房纤维化并减少AF持续时间。CHF诱导的离子流变化当从实验性CHF回复后逆转恢复但心房纤维化仍持续存在,并伴增加AF持续时间。然而,ACEI可防止心房纤维化和AF进展是不完全的,而一些变化(如细胞死亡、炎性细胞浸润、介质激活)并不能预防。血浆AngII升高之前心房的AngII浓度已增高并增加了快速室性心律诱导CHF,提示心内AngII已经产生。而且局部ACE合成在人类慢性房颤中增加。人类右房标本,AT1和AT2受体在房颤患者中的调节可能存在差异:AT1受体表达下调而AT2受体(具有潜在的抗增生作用)表达上调。其他的研究表明AT1受体在左房表达上调而右房不变并且实验数据证明AT1和AT2受体表达均增加。因此,血管紧张素受体作用在房颤患者中仍不十分清楚。AT1受体拮抗剂结合触发磷脂酰肌醇信号通路,激活丝裂原蛋白激酶并引起细胞肥大。ARBs可通过阻断AT1受体调节心肌血管紧张素II的效应,而且并不影响AT2受体作用的发挥。但是,目前并没有证据表明房颤应用中ARBs优于ACEI。已有证据表明AngII在调节炎症反应的作用,而炎症反应也可能参与房颤的发生。醛固酮拮抗剂可减少高血压心脏病心室纤维化,或许在预防心房纤维化中亦有作用。 ACEIs and ARBs的抗心律失常作用 ACEIs and ARBs可防止经过数小时房性快速心律的狗心房电生理特性变化。然而,尽管AngII注入患者了升高血压,但心房有效不应期、ERP离散度、传导特性或AF诱导性等并无变化。依那普利并不影响7天心快快速起搏引起的心房重构。周心房快速起搏诱导的持续性房颤,伴有未控制的心室率,可导致LV心功能不全。在快速起搏之前1周给予坎地沙坦(10 mg/kg/day)可减少AF持续时间。心房ERP缩短并不受影响,表明这种获益独立于心率依赖性重构。坎地沙坦可减少间质纤维化(药物组7±2 vs. 16±1%对照组, P<0.001),提示抗房颤的有效性是源于其防止心动过速心肌病变诱导的结构重构。 心肌细胞电生理效应 AngII直接的心肌细胞电生理效应仍然存在争议。据报道L型和T型Ca2+离子流由AngII调节。胞内AngII可降低鼠心室肌细胞ICa,L流,然而在田鼠观察到相反的情况。有研究认为AngII通过PKC依赖通路增加ICa,L,其由AngII刺激引起。如阻断ICa,T可预防AF基质进展,肾素血管紧张素系统抑制剂可能是通过防止AngII介导的ICa,T增加而产生有益作用。但是,目前并没有ACEI拮抗1周心房快速起搏性重构获益的证据,相反ICa,拮抗剂米贝拉地尔在同一模型中却有明显作用,并不支持ICa,T抑制介导机制来解释ACEI抑制剂获益。K+离子流的调节也有报道。豚鼠心室肌细胞的快速延迟整流IKr增加与AngII浓度(30 nmol/L)临床相关。Ito通道转录下调正是AF诱导电重构的证据。Kv4.3亚基( -亚基形成的离子通道微孔是瞬时外向K+离子流的基础,即Ito)与AT1受体形成复合物并调节其细胞表面的表达。予AngII刺激结合其受体可导致此复合物内化生成,后者引起Ito-离子流降低。AngII可引起APD延长,而ACEI却可逆转这一变化并促进细胞之间的信息交流。体外试验研究异源表达的K+离子通道亚基表明ARBs的不同效应。氯沙坦可阻断有HERG (与IKr一致)、KvLQT1、minK (IKs) 和hKv1.5亚基(超速延迟整流电流, IKur)转运的离子流。这种药物可延长豚鼠心室APD,然而其降解产物E-3174可缩短APD。坎地沙坦、伊博诺沙坦、伊贝沙坦等均可由hKv1.5, HERG, KvLQT1+mink, and rKv4.3 亚基转运的离子流。但是治疗浓度的伊贝沙坦可阻断rKv4.3和 hKv1.5,在高于治疗浓度范围时可阻断HERG 和 KvLQT1+minK 离子流.总之,这些证据提示肾素血管紧张素系统可影响离子通道,APD和兴奋传导和局灶性折返。另一方面,目前尚不能量化AngII对人心房电生理特性的作用。ARBs可能通过抑制复极K+离子流而对急性心房重构有益。某些ARBs可抑制Kv1.5离子流,后者是心房表达IKur的基础,并且是AF治疗的首要靶点。 结论 ACEIs和ARBs均可减少AF的发生和防止AF相关的并发症。然而,现今尚无充分的前瞻性双盲试验证据,也无可靠的临床证据推荐ACEIs和ARBs单独应用于AF预防。目前,正在进行的临床试验将有助于了解这些药物在AF治疗的作用。一些问题尚待在基础医学水平进一步研究。临床证据表明ACEIs在有高危因素(如心力衰竭、高血压伴LV肥大)的AF患者有益作用。此外,目前仍缺乏房颤基质进展形成后肾素血管紧张素系统抑制效应的实验证据,而且联合ACEI和ARB治疗仍无相关研究。临床上ACEI和ARB的抗心律失常作用可能由其防止心房重构间接发挥作用。直接的调节离子通道作用也可能参与。ACEI和ARB治疗对心房重构变化和电生理的直接作用将有助于阐明临床相关机制的作用。 References 1.Tsai CT, Lai LP, Lin JL, Chiang FT, Hwang JJ, Ritchie MD, Moore JH, Hsu KL, Tseng CD, Liau CS, Tseng YZ. 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