摘要
急性心肌梗死（acute myocardial infarction，AMI）直接经皮冠状动脉介入治疗（percutaneous coronary intervention，PCI）已成为短时间内开通梗死相关动脉（infarct-related artery，IRA），恢复冠脉前向血流的重要措施。但仍有10%~30%的患者即使开通IRA后，也未能恢复有效的心肌灌注，即存在着心肌缺血失灌注性微循环障碍（ischemia-non-perfusion-microcirculatory disorder，INP-MCD）和缺血-再灌注损伤性微循环障碍（ischemia-reperfusion injury-microcirculatorydisorder，IRI-MCD）的病理生理过程，两者因果互动，导致心肌损伤恶化加重，临床表现为PCI后的无复流现象。
目前针对心肌INP-MCD/IRI-MCD的处理，主要采用术中和术后发生无复流时，即血管开通后的药物性/机械性治疗手段，即“下游挽救性干预治疗”。如何实现在开通IRA、恢复冠脉前向血流之前，进行药物干预，使梗死相关区域心肌组织微循环作出再灌注适应性调节反应，减轻和预防IRA开通后心肌INP-MCD/IRI-MCD，即运用“上游预防性干预治疗”，是目前国内外介入心脏病学界尚未涉猎的重要领域。
急性下壁心肌梗死（acute inferior myocardial infarction，AIMI）时梗死区的心脏抑制性感受器受到刺激，心迷走、血管迷走张力增高，通常伴有心率慢、血压低、过缓心律失常等不稳定的血流动力学状态，PCI开通血管时易发生再灌注低血压、再灌注过缓/过速心律失常（如房室传导阻滞/室性心动过速），导致主要不良心血管事件发生率增加，当梗死累及后壁、右室时预后更差。另一方面，AMI-PCI中对比剂的应用也相应导致了对比剂肾病（contrast-induced nephropathy，CIN）的发生率增加，恶化老年患者及原有肾病患者的肾功能，增加出血并发症，同时恶化心功能，极大地削弱了PCI的治疗获益并导致不良的短期和长期预后。因此，寻找有效的既可提高AMI-PCI后心肌灌注水平、保护心功能，又可减少或避免CIN的发生、降低围手术期肾损害、提高肾灌注水平、保护肾功能的药物是AMI-PCI中亟待解决的问题。
山莨菪碱是我国从茄科植物唐古特莨菪中分离出的具有多重药理学效应的生物碱，已有研究显示山莨菪碱具有扩张微小血管，调节毛细血管前、后括约肌的舒缩功能，改善微循环灌注的作用，超大剂量应用时也未见严重的毒副作用。我们的前期动物实验和临床研究在国内外率先表明：冠脉内应用山莨菪碱可提高冠脉平均灌注压，在改善冠脉前向血流的同时改善心肌组织灌注，可有效逆转AMI患者直接PCI术后无复流现象。
他汀也具有多重药理学效应，除降脂作用外，还具有改善内皮功能、抗炎、减少氧化应激、扩张冠脉微血管、抑制血栓形成等作用，可为急性冠脉综合征（acute coronary syndrome，ACS）患者带来早期的预防和治疗获益。近来研究表明：PCI围手术期应用他汀治疗可减少无复流的发生，提高心肌灌注水平，同时降低CIN的发生，保护肾功能，并最终降低死亡率。
本研究包括三个部分：前两部分以AIMI患者为研究对象，探讨预防性冠脉内应用不同剂量山莨菪碱联合不同剂量阿托伐他汀对直接PCI术后心肌再灌注和心功能的保护效应；第三部分评价高剂量阿托伐他汀预处理对直接PCI术后CIN的预防及肾功能的保护作用，为临床AMI-PCI的综合心肾预防保护策略提供有价值的临床依据和有效的预防性药物治疗方法。
目的：探讨预防性冠脉内应用山莨菪碱对AIMI-PCI无复流的预防、心肌再灌注的保护效应及其可能的炎症机制。
方法：本研究为单中心前瞻随机对照研究，入选患者为2009年1月至2011年3月发病12小时内行直接PCI治疗的AIMI患者。符合条件的患者随机分为两组：山莨菪碱组，72例，IRA开通前（导丝通过后，球囊扩张前，冠脉有前向血流时）预防性冠脉内给予山莨菪碱1500μg/3ml；生理盐水对照组，71例，IRA开通前冠脉内给予等量生理盐水3ml。全部患者均经桡动脉入径行冠状动脉造影（CAG）检查及PCI治疗。由两位介入心脏病专家对所有量化的冠脉造影组织灌注指标进行判定，包括初始TIMI血流、术后TIMI血流、TIMI心肌灌注分级（TMPG）。应用指引导管在山莨菪碱给药前、给药后1min、5min、10min测定冠脉收缩压、舒张压、平均压。术前及术后每4小时查一次心肌坏死标记物，以CK-MB及cTnI峰值水平间接评估心肌梗死面积。术前及术后24h各查一次炎症反应标记物（hs-CRP、IL-6、P-selectin及ICAM-1）。入院时及术后90min各查心电图一次，以ST段回落（STR）程度作为反映术后心肌再灌注水平的间接指标，并把两组完全STR（术后90min时较比入院时ST段抬高之和下降≥70%）的比例定义为本研究的主要终点。随访术后30天及6个月的主要不良心血管事件（心源性死亡+复发心肌梗死+靶血管血运重建，MACEs）。应用重复测量方差分析描述山莨菪碱组冠脉收缩压、舒张压、平均压及心率随时间的变化。应用多变量Logistic回归分析探讨有助于完全STR的相关可能因素。双侧p值小于0.05认为差异有统计学意义，全部统计学分析均在SPSS16.0统计软件的辅助下完成。
结果：两组患者基线临床资料无统计学差异。PCI术前，两组TIMI血流分级相似；术后，山莨菪碱组TIMI3级及TMPG3级的比例均显著高于生理盐水对照组（TIMI3级：91.7%vs.77.5%, p=0.03；TMPG3级：80.6%vs.60.6%, p=0.01）。山莨菪碱组心电图上ST段明显回落，Σ STE从10.0±4.2mm下降到5.8±1.7mm，两组完全STR的比例有显著差别（69.4%vs.50.7%, p=0.03）。术前两组过缓心律失常发生率无显著差异；再灌注后，山莨菪碱组有4例患者（5.6%）发生再灌注性过缓心律失常（二度房室传导阻滞2例，一度房室传导阻滞2例）；而对照组有42例患者（59.2%）发生再灌注性过缓心律失常（三度房室传导阻滞10例，二度房室传导阻滞17例，一度房室传导阻滞和窦性心动过缓共15例，3例患者需植入临时起搏器）。多变量Logistic回归分析显示：冠脉舒张压降低（p<0.0001, OR=1.298,95%CI=1.155-1.457）及心率减慢（p=0.002, OR=1.251,95%CI=1.087-1.440）是造成不完全STR的独立危险因素，而预防性冠脉内应用山莨菪碱则为完全STR的保护性因素（p <0.0001, OR=0.059,95%CI=0.014-0.255）。PCI术前两组血清hs-CRP、IL-6、P-selectin及ICAM-1的水平无显著性差异；术后24h时，两组炎症反应标记物水平均升高，但山莨菪碱组炎症反应标记物的水平显著低于对照组（p <0.0001）。随访30天时对照组有1例患者发生再次心肌梗死，1例患者需要靶血管血运重建。随访6个月时山莨菪碱组和对照组各有1例和5例患者出现MACE（p=0.21）。
结论：
1预防性冠脉内应用山莨菪碱可增加AIMI患者的前向冠脉血流压力，同时调节疏浚IRA开通前INP-MCD，提高AIMI-PCI开通IRA后区域心肌灌注水平，减少IRI-MCD损伤与无复流的发生；
2预防性冠脉内应用山莨菪碱可降低IRA开通前INP-MCD状态下的炎症递质水平，有助于保护和改善AIMI-PCI开通IRA后区域心肌微循环；
3预防性冠脉内应用山莨菪碱对AIMI-PCI的微循环保护效应可挽救更多濒死存活心肌数量，缩小梗死面积，阻抑心室重构，保护心室功能；
4预防性冠脉内应用山莨菪碱在防治围AIMI-PCI中的INP-MCD/IRI-MCD上具有较好的可行性和安全性。
目的：应用2×2析因设计交叉对比研究评价预防性冠脉内给予不同剂量山莨菪碱联合不同剂量阿托伐他汀对AIMI-PCI冠脉微循环灌注改善作用的量效关系，探讨其在AIMI-PCI中预防和逆转无复流的协同效应及其可能的炎症机制。
方法：本研究为单中心、前瞻、随机、对照、2×2析因设计交叉对比研究，入选患者为2011年4月至2012年11月AIMI发病12小时内行直接PCI治疗的患者112例。符合条件的患者以1:1的比例随机接受不同的给药方法：A组（阿托伐他汀20mg联合山莨菪碱1500μg，n=28）；B组（阿托伐他汀20mg联合山莨菪碱3000μg，n=28）；C组（阿托伐他汀80mg联合山莨菪碱1500μg，n=28）；D组（阿托伐他汀80mg联合山莨菪碱3000μg，n=28）。所有患者均经桡动脉入径行CAG检查和PCI治疗。由两位介入心脏病专家对量化的冠脉造影组织灌注指标进行判定，包括术前TIMI血流、术后TIMI血流、TIMI心肌灌注分级（TMPG），并以各组直接PCI术后TMPG3级的比例作为本研究的主要终点。通过指引导管直接测定山莨菪碱给药前及给药后1min、5min、10min的冠脉收缩压、舒张压及平均压。术前及术后每4小时查一次心肌坏死标记物，以CK-MB及cTnI峰值水平间接评估心肌梗死面积。术前及术后24h各查一次炎症反应标记物（hs-CRP、IL-6、P-selectin及ICAM-1）。入院时及术后90min各查心电图一次，记录各组完全ST段回落（STR）的情况（完全STR定义为术后90min时较比入院时ST段抬高之和下降≥70%）。监测术后1个月的肝功能，以此评价阿托伐他汀的安全性。随访术后30天及6个月的主要不良心血管事件（心源性死亡+复发心肌梗死+靶血管血运重建）。应用多变量Logistic回归分析探讨有助于直接PCI术后达TMPG3级的相关可能因素。以CK-MB峰值及左室射血分数（LVEF）为观察目标，应用析因设计方差分析阐明两种药物各自的主效应及是否存在交互作用。双侧p值小于0.05认为差异有统计学意义，全部统计学分析均在SPSS16.0统计软件的辅助下完成。
结果：四组患者基线临床资料无统计学差异。PCI术前四组TIMI血流分级相似；术后D组TMPG3级的比例显著高于其它组（p=0.011），TIMI3级及完全STR的比例均有高于其它各组的趋势，但尚未达到统计学差别（p值分别为0.073和0.051）。D组CK-MB、cTnI峰值最低，术后三天的LVEF最高。山莨菪碱联合阿托伐他汀具有降低CK-MB峰值水平的协同效应，且具有统计学意义（p=0.001）；而仅具有升高LVEF的协同效应趋势，尚不具有统计学意义（p=0.284）。四组患者术前过缓心律失常发生率无显著性差异；给予山莨菪碱后血压和心率适度升高，除B组1例患者出现房性早搏外，术中术后均未见严重的过缓/过速型心律失常发生。多变量Logistic回归分析显示：血栓积分3-4分（p=0.041, OR=3.492,95%CI=1.055-11.553）、冠脉舒张压降低（p=0.049, OR=1.085,95%CI=1.000-1.177）为直接PCI术后心肌灌注不良（表现为TMPG <3级）的独立危险因素，而预防性冠脉内应用山莨菪碱3000μg则为保护性因素（p=0.038, OR=0.183,95%CI=0.037-0.912）。PCI术前四组血清hs-CRP、IL-6、P-selectin及ICAM-1的水平无显著性差异；术后24h时，四组炎症反应标记物水平均升高，但D组炎症反应标记物水平显著低于其它三组（p <0.05）。各组患者随访30天及6个月的MACE发生率无显著差别。
结论：
1预防性冠脉内应用山莨菪碱联合阿托伐他汀不同剂量药物组合呈现出不同临床效果的量效关系。高剂量的山莨菪碱（3000μg）联合高剂量阿托伐他汀（80mg）的药物组合较其它组合可更有效地改善AIMI-PCI
的心肌灌注水平，减少无复流的发生，缩小梗死面积。提示两者具有协同效应，且临床可行，无严重不良反应；
2预防性冠脉内应用山莨菪碱联合阿托伐他汀可更显著地降低IRA开通前INP-MCD状态下的炎症递质水平，有助于保护和改善AIMI-PCI开通IRA后区域心肌微循环，且与两者的剂量相关，可能是两者协同改善AIMI-PCI心肌微循环灌注的重要机制；
3预防性冠脉内应用山莨菪碱联合阿托伐他汀可更有效地保护围AIMI-PCI的心肌微循环状态，增加心肌存活数量，缩小梗死面积，阻抑心室重构，保护心室功能并改善临床预后。
目的：在急性ST段抬高性心肌梗死（STEMI）行直接经皮冠状动脉介入治疗（PCI）的患者中，探讨高剂量阿托伐他汀预处理是否可降低PCI术后对比剂肾病（CIN）的发生率，保护肾功能。
方法：本研究为单中心、随机、对照、前瞻性研究，入选患者为2009年1月1日至2011年12月31日就诊于河北医科大学第二医院的急性STEMI发病12小时内行直接PCI治疗的患者，排除当前或之前3个月内接受他汀治疗、肝肾功能不全及透析治疗的患者。符合条件的患者以1:1的比例随机分为两组：阿托伐他汀组（在急诊室，患者口服阿托伐他汀负荷量80mg，之后转运至导管室行紧急冠状动脉造影检查和PCI治疗，术后以20mg/天长期维持，n=78）和对照组（负荷量药物为安慰剂，余同试验组，n=83）。PCI成功定义为经定量冠脉影像分析判定TIMI血流3级，残余狭窄小于20%。介入治疗中均使用非离子型对比剂（Ultravist370，iodine370mg/ml）。全部患者均于术前至术后12小时接受静脉水化治疗（生理盐水，静点速率为1ml/kg/h）。患者入院24小时内行超声心动图检查以评价左室功能。以两组CIN的发生率作为本研究的主要终点事件。CIN定义为排除其它引起肾损伤的病因后，经血管内注射碘对比剂后72小时内发生的急性肾损伤，一般的量化标准为血清肌酐（SCr）水平升高0.5mg/dl（44.2μmol/L）或较基础值升高25%以上。测定入院时、术后24h、48h、72h的SCr浓度及入院时、暴露于对比剂后24h的血清胱抑素C浓度。以术后1个月内谷丙转氨酶的变化评价阿托伐他汀的安全性。应用重复测量方差分析对比两组SCr随时间变化的过程。应用多变量Logistic回归分析探讨与CIN风险降低相关的可能因素。双侧p值小于0.05认为差异有统计学意义，全部统计学分析均在SPSS16.0统计软件的辅助下完成。
结果：阿托伐他汀组与对照组无复流的发生率分别为7.7%和10.8%(p=0.69)，对比剂用量分别为100.0±25.9和103.6±26.2ml (p=0.38)。与对照组相比，阿托伐他汀组术后SCr水平明显更低(93.4±17.1vs112.6±23.3μmol/L at48h and84.2±14.2vs95.3±17.7μmol/L at72h, bothp <0.0001)，峰值血清胱抑素C水平明显更低(0.51±0.14vs0.61±0.13mg/L, p <0.0001)。阿托伐他汀组与对照组CIN的发生率分别为2.6%和15.7%(p=0.01)。术后1个月内谷丙转氨酶升高超过正常高限3倍以上的比例两组分别为3.85%和1.20%，无统计学差别（p=0.57）。多变量Logistic回归分析显示：峰值CK-MB水平(OR=1.013,95%CI=1.002-1.024, p=0.024)和对比剂用量(OR=1.035,95%CI=1.001-1.070, p=0.043)为导致CIN发生的危险因素，而术前高剂量阿托伐他汀预处理为术后CIN风险降低的保护性因素(OR=0.084,95%CI=0.015-0.462, p=0.004)。
结论：对于急性STEMI行直接PCI治疗的患者，术前高剂量阿托伐他汀预处理可降低术后CIN的发生，保护肾功能。
Primary percutaneous coronary intervention (PCI) has become animportant strategy for the opening of the infarct-related artery (IRA) and therestoration of the coronary blood supply within a short period in acutemyocardial infarction (AMI). But still10%to30%of patients present thateven after the opening of the IRA, it also fails to restore effective myocardialperfusion, which means existence of no-perfusion-microcirculatorydisorder (NP-MCD) and ischemia-reperfusion injury-microcirculatorydisorder (IRI-MCD). This causal interaction of the above twopathophysiologic processes leads to the deterioration of myocardial injury,which indicates no-reflow phenomenon after PCI in clinical settings.
At present, for the treatment of myocardial NP-MCD/IRI-MCD, themain strategy is “downstream salvage intervention”, that is thepharmaceutical/mechanical intervention during and after PCI. How to adopt“upstream prevention intervention”, referring to the pharmaceuticalintervention before the opening of the IRA and the restoration of the coronaryblood supply, thereby achieve the accommodation of myocardialmicrocirculation in the infarct-related region to the change of reperfusion,relieve and prevent myocardial NP-MCD/IRI-MCD after the opening of theIRA, is an important topic currently uninvolved in interventional cardiology athome and abroad.
Anisodamine, an alkaloid with multiple pharmacological effects, isisolated from the Solanaceae tanguticum Belladonna in China. It has beenshown that anisodamine has abilities in the expansion of microvessels,regulation of systolic and diastolic functions of the capillary sphincters andimprovement of microcirculatory perfusion. In addition, large dose of anisodamine is safe without serious side effects. Our previous animalexperiments and clinical studies showed first at home and abroad that:intracoronary administration of anisodamine could effectively reverse theno-reflow phenomenon by increasing coronary perfusion pressure, improvingcoronary blood flow and myocardial perfusion in AMI treated with primaryPCI.
Acute inferior myocardial infarction (AIMI) is usually associated withunstable hemodynamic states such as hypotension, bradycardia, high vagustone and so on. Therefore, the circulatory collapse, reperfusion injury andserious arrhythmias like severe atrioventricular block in addition to no-reflowphenomenon possibly happen during primary PCI. As a result, major adversecardiovascular events increase, which severely influences the clinicalprognosis. After comprehensive analysis of the features of AIMI andanisodamine, it is speculated that: anisodamine, a drug withmulti-pharmacological effects, is especially suitable for AIMI.
The benefits of statins in acute coronary syndromes (ACS) are seen early,before substantial lipid lowering has occurred. This suggests that pleiotropiceffects of statins, not lipid-lowering effects, are responsible for these earlybenefits. These pleiotropic effects may include improvement in endothelialfunction, anti-inflammatory effects, decrease in oxidative stress, vasodilationof coronary microvessels, and inhibition of thrombogenic response.
The growing number of interventional procedures requiring contrastmedia has triggered a parallel increase of contrast-induced nephropathy (CIN).CIN is the third leading cause of hospital-acquired acute renal failure inadmitted patients; it greatly decreases the efficacy of PCI and results inadverse short-and long-term outcomes.
This study consists of three parts: part I and II, regarding AIMI as studypopulation, explore the protective effects of preventively intracoronaryadministration of different doses of anisodamine combined with differentdoses of atorvastatin on myocardial reperfusion and cardiac function after PCI;the third part, evaluate the preventive and protective effects of high-dose atorvastatin pretreatment on CIN following PCI, all of which will providevaluable references for the comprehensive heart-kidney protections duringAMI-PCI in clinical settings.
Objectives: To investigate whether preventively intracoronaryadministration of anisodamine before the opening of the infarct-related artery(IRA) can reduce/avoid no-reflow phenomenon and improve myocardialreperfusion and heart function in acute inferior myocardial infarction (AIMI)treated with primary percutaneous coronary intervention (PCI).
Methods: It was a single-center prospective randomized controlled studywhich enrolled patients suffering from AIMI within12hours undergoingprimary PCI from September2009to June2012. Eligible patients wererandomly divided into two groups: anisodamine group,72cases, preventivelyintracoronary administration of anisodamine1500μg/3ml before the openingof the IRA; control group,71cases, intracoronary administration of saline3ml.All patients underwent coronary angiography (CAG) and/or PCI bytransradial artery approach. All quantitative coronary angiography tissueperfusion indexes [including the initial thrombolysis in myocardial infarction(TIMI), postoperative TIMI, corrected TIMI frame count (CTFC) and TIMImyocardial perfusion grade (TMPG)] were judged by two interventionalcardiologists. Coronary systolic, diastolic and mean pressures were measuredby invasive catheterization before and1min,5min,10min after anisodamineadministration. Myocardial infarct size was estimated by peak levels ofcreatine kinase-MB (CK-MB) and troponin I (cTnI) which were determinedbefore and every4hours after the procedure. Electrocardiography wasrecorded both on admission and at90min after PCI. A decrease in the sum ofST-segment elevation by≥70%was categorized as complete ST-segmentresolution (STR) and used as an indirect measure of myocardial reperfusion and the primary end point of this study. Major adverse cardiovascular events(cardiac death+recurrent MI+target vessel revascularization, MACEs) wereevaluated during the hospital stay and30d after discharge. Repeated measuresanalysis of variance was applied to describe the changes of coronary systolic,diastolic and mean pressures and heart rate over time in anisodamine group.Multivariate logistic regression analysis was used to explore the possiblefactors associated with complete STR. P values (2-sided) of less than0.05were considered statistically significant. All calculations were computed withthe aid of SPSS statistical software (version16.0).
Results: After PCI, the proportion of TIMI3in anisodamine group washigher than that in control group (91.7%vs.77.5%, p=0.03), so was theTMPG3(80.6%vs.60.6%, p=0.01). ST segments were significantlyresolved, from10.0±4.2mm to5.8±1.7mm in anisodamine group. Thepercentage of complete STR was statistically different (69.4%vs.50.7%, p=0.03). After intracoronary administration of anisodamine, the coronary bloodpressure and heart rate increased moderately, and there was not any severebradyarrhythmia and tachyarrhythmia. Multivariate Logistic regressionanalysis showed that: low coronary diastolic pressure (p <0.0001, OR=1.298,95%CI=1.155-1.457) and slow heart rate (p=0.002, OR=1.251,95%CI=1.087-1.440) were independent risk factors of incomplete STR, whileanisodamine administration was a protective factor for complete STR (p <0.0001, OR=0.059,95%CI=0.014-0.255). During hospital stay, there wasone patient developing recurrent MI and another patient needing target vesselrevascularization in control group. At the end of30-day follow up, one MACEand5MACEs occurred in anisodamine group and control group respectively(p=0.21).
Conclusions:
1Preventively intracoronary administration of anisodamine can increasecoronary antegrade blood pressure, regulate and drege INP-MCD, improvemyocardial perfusion and alleviate IRI-MCD as well as no reflow;
2Anisodamine can decrease the level of inflammatory mediators, protect and improve myocardial microcirculation;
3Anisodamine can save more viable myocardium, reduce infarct size,inhibit ventricular remodeling and protect cardiac function;
4Anisodamine has a better feasibility and safety against theINP-MCD/IRI-MCD.
Objectives: In acute inferior myocardial infarction (AIMI), many drugsused to improve myocardial microcirculation disorder will significantly reduceblood pressure and coronary perfusion pressure, aggravate bradyarrhythmiaand the hemodynamic states of the whole body, which greatly limits theapplication of these drugs in clinical settings. This study was to assess theefect of various anisodamine (3000μg vs.1500μg) and atorvastatin (80mg vs.20mg) regimens on prevention of no-reflow and amelioration of myocardialreperfusion in patients with AIMI undergoing primary percutaneous coronaryintervention (PCI).
Methods: From September2009to June2012, consecutive patients(n=112) with AIMI presented within12hours of symptom onset undergoingprimary PCI were enrolled into this single-center open-label randomizedcontrolled study. Eligible patients were randomly assigned in a1:1ratio toreceive different regimens: Group A (atorvastatin20mg and anisodamine1500μg, n=28); Group B (atorvastatin20mg and anisodamine3000μg, n=28);Group C (atorvastatin80mg and anisodamine1500μg, n=28); Group D(atorvastatin80mg and anisodamine3000μg, n=28). Patients underwentcoronary angiography (CAG) and PCI by transradial artery access. All the angiographic results [initial thrombolysis in myocardial infarction (TIMI),final TIMI/corrected TIMI frame count (CTFC)/TIMI myocardial perfusiongrade (TMPG)] were evaluated by two cardiologists blinded to the clinicalstatus of the patient and the treatment modality. The incidence of TMPG3after the procedure was defined as the primary end point of this study.Coronary systolic, diastolic and mean pressures were determined by invasivecatheterization before and1min,5min,10min after anisodamineadministration. Myocardial infarct size was estimated by peak levels ofcreatine kinase-MB (CK-MB) and troponin I (cTnI) which were determinedbefore and every4hours after the procedure. Electrocardiography wasrecorded both on admission and at90min after PCI. Complete ST-segmentresolution (STR) was defined as a decrease in the sum of ST-segmentelevation by≥70%. The hepatic function was observed within1month of theprocedure to justify the safety of atorvastatin. Major adverse cardiovascularevents (cardiac death+recurrent MI+target vessel revascularization, MACEs)were evaluated during the hospital stay and30days after discharge.Multivariate Logistic regression analysis was used to explore the possiblefactors associated with the optimal myocardial reperfusion (TMPG3). Forpeak CK-MB and left ventricular ejection fraction (LVEF), factorial designanalysis of variance was applied to elucidate the main effects and interactionsof the two drugs. P values (2-sided) of less than0.05were consideredstatistically significant. All calculations were computed with the aid of SPSSstatistical software (version16.0).
Results: After PCI, the proportion of TMPG3was significantly higher ingroup D than that in other groups (p=0.011); the proportions of postoperativeTIMI3and complete STR were the highest in group D, but no statisticaldifferences were achieved, only a trend (p=0.073and0.051respectively).The peak CK-MB and cTnI were the lowest and LVEF three days after theprocedure was highest in group D. Targeting the peak CK-MB, anisodaminecombined with atorvastatin had the synergistic effect in reducing the peakCK-MB level, with statistical significance (p=0.001); while targeting LVEF, anisodamine combined with atorvastatin only had the trend of synergisticeffect in elevating LVEF, without statistical significance (p=0.284).Anisodamine elevated blood pressure and heart rate moderately, except thatone case appeared atrial premature beat in group B, no other severebradyarrhythmia and tachyarrhythmia were observed during and after theprocedure. The follow up during hospitalization and30days after dischargedid not differ among these four groups. Multivariate Logistic regressionanalysis displayed: thrombus score3/4(p=0.041, OR=3.492,95%CI=1.055-11.553) and low coronary diastolic pressure before anisodamine (p=0.049, OR=1.085,95%CI=1.000-1.177) were the independent risk factorsfor poor myocardial reperfusion (expressed as TMPG <3), while anisodamine3000μg before PCI was protective for optimal myocardial reperfusion after theprocedure (p=0.038, OR=0.183,95%CI=0.037-0.912).
Conclusions:
1Preventively intracoronary administration of different doses ofanisodamine combined with different doses of atorvastatin has dose-effectrelationship. High dose of anisodamine (3000μg) combined with high-dose ofatorvastatin (80mg) can be more effective in the improvement of myocardialperfusion, decrease of the incidence of no-reflow and reduction of infarct size,which suggests that these two drugs have a synergistic effect;
2Anisodamine combined with atorvastatin can significantly decreaseinflammatory mediators, protect and improve myocardial microcirculationwith dose-related effect, which may be one of the important mechanisms ofthe improvement of myocardial microcirculatory perfusion;
3Anisodamine combined with atorvastatin can effectively protectmyocardial microcirculation, increase the number of viable myocardium,reduce infarct size, inhibit ventricular remodeling, protect cardiac function andimprove clinical prognosis.
Objectives: To investigate whether preprocedural high-dose atorvastatindecreases the incidence of contrast-induced nephropathy (CIN) and protectsthe renal function in acute ST-segment elevation myocardial infarction(STEMI) undergoing primary percutaneous coronary intervention (PCI).
Methods: This randomized controlled study was conducted at the SecondHospital of Hebei Medical University between January1,2009and December31,2011. We enrolled all consecutive patients with acute STEMI presentedwithin12h of symptom onset undergoing primary PCI (door-to-balloon≤1.5h). Patients in current or previous (within3months) statin treatment, with ahistory of renal and hepatic dysfunction and in dialytic treatment wereexcluded. Eligible patients were randomly assigned in a1:1ratio to receiveatorvastatin (in the emergency room, atorvastatin load80mg p.o. wasadministered to patients who were then immediately transferred to cathlab toundergo coronary angiography and PCI. After the procedure, all patients hadlong-term atorvastatin treatment20mg/day. n=78) or placebo (all theprotocols were same as the atorvastatin group except that the atorvastatin loadwas replaced by placebo80mg p.o. n=83). PCI success was defined as TIMI(Thrombolysis in Myocardial Infarction) grade3flow after procedure andresidual stenosis to <20%by quantitative coronary analysis. The nonioniccontrast (Ultravist370, iodine370mg/ml) was used in all patients.Intravenous hydration was administered to all patients with isotonic saline(0.9%) at a rate of1ml/kg/h before the procedure and for12h after theprocedure. Left ventricular function was evaluated by echocardiography in allpatients within24h of admission. Investigators involved in this study were allblinded to the randomized treatment. CIN was defined as an increase in serumcreatinine (SCr) of>0.5mg/dl (>44.2μmol/l) or25%above baseline. SCr concentration was measured upon admission and every day for the following3days after PCI. Serum cystatin C was tested upon admission and24h afterexposure to the contrast medium. The hepatic function was observed within1month of the procedure to justify the safety of atorvastatin. The primary endpoint was the incidence of CIN. Repeated-measures analysis of variance wasapplied to describe the changes of SCr over time between2groups.Multivariate Logistic regression analysis was used to explore the possiblefactors associated with the decreased risk of CIN. A p value <0.05(2-tailed)was considered statistically significant. All calculations were computed withthe aid of SPSS statistical software (version16.0).
Results: During the procedure, the incidence of no-reflow was7.7versus10.8%(p=0.69) and the contrast volume was100.0±25.9versus103.6±26.2ml (p=0.38). Compared with the control group, the postprocedural SCrwas significantly lower (93.4±17.1vs112.6±23.3μmol/L at48h and84.2±14.2vs95.3±17.7μmol/L at72h, both p <0.0001) and peak serum cystatin Cwas lower (0.51±0.14vs0.61±0.13mg/L, p <0.0001) in the atorvastatingroup. Finally,2.6%of patients in the atorvastatin group developed CINversus15.7%of those in the control group (p=0.01). Multivariate Logisticregression analysis showed that: peak CK-MB (OR=1.013,95%CI=1.002–1.024, p=0.024) and contrast volume (OR=1.035,95%CI=1.001–1.070, p=0.043) were risk factors of CIN, and atorvastatinpretreatment was independently associated with a decreased risk of CIN (OR=0.084,95%CI=0.015–0.462, p=0.004). The proportion of alanineaminotransferase (ALT)>3×upper limit of normal value (ULN) within1month of the procedure was3.85versus1.20%(atorvastatin group vs. controlgroup, p=0.57), without statistical significance.
Conclusions: Preprocedural high-dose atorvastatin load in the emergencyroom prevents CIN and protects the renal function in patients with acuteSTEMI undergoing primary PCI. These results lend further support for the early use of high-dose statins as adjuvant pharmacologic therapy in primaryPCI.
引文
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