年龄对阿托伐他汀改善缺血性心肌病患者左室重构、功能及心肌能量消耗的影响
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摘要
研究背景
他汀类药物(Statins)是一种有效的降脂药物,可显著降低冠心病的发病率及死亡率,广泛应用于冠心病的一级及二级预防。近年来研究表明他汀类药物具有降脂外的多效性,包括改善内皮功能,抗炎症作用,促进内皮祖细胞动员,抗氧化作用以及抑制心脏病理性重构作用等。这些作用被认为是改善心力衰竭预后的基础。两个小样本、前瞻性研究结果提示阿托伐他汀及辛伐他汀可改善心力衰竭患者的心功能及预后。然而,UNIVERSAL研究提示瑞舒伐他汀不能改善心衰患者的心室重构及心功能。两个大型的临床研究CORONA及GISSI-HF的结果否定了他汀类药物改善预后的结论,因此,他汀对缺血性心肌病(ischemic cardiomyopathy, ICM)患者的心室重构、心功能及预后的作用尚无定论.
目前多数学者认为他汀的种类,剂量及研究人群差异可能是造成研究结果不同的主要原因。一项荟萃分析发现阿托伐他汀可显著改善心衰患者心功能及临床预后,而瑞舒伐他汀则未能起到该作用,提示种类可能影响他汀的作用有效。近期有一项随机研究发现,与小剂量阿托伐他汀比较,大剂量阿托伐他汀可显著改善ICM患者的心室舒张功能及心肌能量代谢。有学者认为他汀的多效性多数在体外研究、非老年患者或者正常人中证实,而两个大型研究中的研究对象大多为老年人群,因而年龄可能影响他汀的有效性。
尽管他汀在心衰治疗中的作用机制目前也不完全清楚,然而越来越多的证据表明,阿托伐他汀可显著地促进骨髓中内皮祖细胞(circulating endothelial progenitor cells, cEPCs)动员及改善内皮功能,晚期心衰患者cEPCs水平明显降低；ICM患者外周血内皮祖细胞存在选择性功能受损,因此,此作用可能有助于ICM患者改善心室重构,心功能、心肌能量消耗及临床预后。然而,衰老相关的内皮功能受损以及cEPCs的功能受损及数量的下降,可能影响他汀对老年ICM患者心血管系统的修复作用。与此同时,衰老可显著影响老年患者心脏结构、心脏功能及心肌能量代谢等方面,主要表现为心肌肥厚,心肌功能减退以及心肌能量代谢障碍。衰老相关的心脏改变可能导致他汀难以逆转老年ICM患者心室重构,心功能下降及能力代谢障碍。
ICM患者具有较高血栓事件发生率。ICM患者血小板活化相关因子易于被炎症因子激活,进而促进血小板聚集而形成血栓,最终导致心律失常及临床事件的发生。研究表明他汀具有抗炎及抗氧化等作用,可减低炎症及氧化应激对血小板活化相关因子的激活作用,可能有助于改善ICM患者的临床预后。。
近年来研究提示外周血循环内皮微颗粒(circulating endothelial-derived microparticles, cEMP)可作为评价心衰患者内皮功能及临床预后的实验指标。本研究组及其他研究者发现标准心脏多普勒超声检测的心脏能量消耗(Myocardial energy expenditure, MEE)是衡量心肌生物能量消耗的有效指标,在心力衰竭人群中,MEE变化值与左室射血分数(Left ventricular ejection fraction, LVEF)变化值的呈负相关,提示MEE可作为评价能量代谢及心功能的有效指标。目前国内外很少有研究探讨年龄对阿托伐他汀促进ICM患者EPCs动员和改善内皮功功能,心室重构、功能及MEE的影响,也少有研究观察不同剂量阿托伐他汀对前列环素及血小板活化相关因子的作用。
目的探讨年龄对阿托伐他汀促进cEPCs动员和降低cEMPs以及改善心室重构、心脏收缩功能及心脏能量消耗的影响,同时观察不同剂量阿托伐他汀对前列环素及血小板活化相关因子的作用
一、研究对象与方法：
1、病例选择：入选标准(1)明确的冠心病证据：心绞痛或心肌梗塞,经选择性冠状动脉造影检查证实前降支、回旋支及右冠状动脉,存在一支或一支以上血管狭窄≥50%,选择性冠状动脉造影方法及判断标准采用Judkins法,常规投照体位行左、右冠状动脉造影,并由造影机图像处理系统对冠脉狭窄定量分析；(2)左室舒张末内径>50mm.(3)慢性充血性心力衰竭,左室射血分数<45%,纽约心功能Ⅱ-Ⅳ的ICM患者；(4)排除了冠心病合并室间隔缺损、重度二尖瓣反流、室壁瘤及心律失常所致的充血性心力衰竭或其他病因导致的大心脏及心力衰竭患者。排除标准已诊断明确的急慢性炎症、血管炎、有其它部位活动感染、癌症、肝病、甲状腺疾病、他汀类药物过敏或肌溶解史、自身免疫性疾病、脑卒中、肾功能衰竭、肺部疾病及预期寿命≤1年患者。
2、病例与分组选择我院心内科住院确诊的ICM患者157例；按患者入院的后按照年龄分为老年组及非老年组,再随机将两组患者随机分为4组：阿托伐他汀(辉瑞)10mg/天非老年组40例、40mg/天非老年组40例、10mg/天老年组38例及40mg/天非老年组39例。在随访期间,10mg非老年组、40mg非老年组、10mg老年组及40mg老年组分别有4例,3例,4例及2例患者因失访或者根据医师专业判断退出本研究。所有患者均随访1年,记录不良反应及心血管事件的发生。
3、一般实验室指标检测：研究开始时及研究结束时,采用自动生化分析仪进行检测血总胆固醇(TC)、甘油三酯(TG)、低密度脂蛋白胆固醇(LDL-C)、高密度脂蛋白胆固醇(HDL-C)、血清尿酸(UA)、肝功能及肌酸激酶(CK)水平等。
4、外周血内皮祖细胞检测：本研究采用乙酰化低密度脂蛋白(Dil-acLDL)及豆凝血素I(FITC-UEA-1)双染色法对cEPCs进行鉴定。研究开始时及研究结束时,使用流式细胞仪检测外周血内皮祖细胞水平,本研究定义外周血CD34+KDR+双阳性单核细胞为cEPCs,以100000个单个核细胞中CD34+KDR+阳性细胞数百分率为静脉血cEPCs水平。
5、外周血内皮微颗粒的检测：外周血内皮细胞微颗粒使用流式细胞仪进行检测,cEMPs浓度定义为大小<1.0μm且CD31阳性CD42b阴性的微颗粒浓度。
6、炎症因子水平测定：血清超敏C-反应蛋白水平(hs-CRP)使用免疫透射浊度法进行测定,血清氧化低密度脂蛋白水平(ox-LDL)用酶联免疫吸附试验双抗体夹心法进行测定。
7、脑钠肽(BNP),血管内皮生长因子水平(VEGF)及基质金属蛋白酶-9(MMP-9)测定：采用BIOSITE Triage Meter型检测仪检测BNP浓度,VEGF及MMP-9浓度检测均采用酶联免疫吸附试验双抗体夹心法进行测定。
8、血小板活化因子测定：分别在研究开始及结束时,采用放射免疫检测的方法,检测血清血小板活化因子(PAF)、6-酮-前列素F1α(6-Keto-PGF1α)及血栓素B2(TXB2)水平。
9、心脏彩超心功能测定：应用美国GE Logig7彩色多普勒超声诊断仪进行检测,分别于研究前后两次进行检测,以美国超声学会推荐的标准平面测定主要指标有左房内径(LA),右室内径(RV)、收缩末期内径(LVIDs)、舒张末期内径(LVIDd)E峰、A峰及射血分数(LVEF)等。
10、心肌能量消耗的测定：应用美国GE Logig7彩色多普勒超声诊断仪进行检测,分别于研究前后两次进行检测,室壁厚度(PWTs)、舒张末室间隔厚度(IVSTd)、收缩末后壁厚度(PWTs)、舒张末后壁厚度(PWTd)、左室每搏输出量(LVSV)、左室射血时间(LVET)等指标。各项指标连续检测3个心动周期,取其平均值为最终结果。按相关参考公式计算心肌能量消耗的各项指标左室收缩末圆周室壁应力(cESS),心肌能量消耗(MEE)及左心室质量指数(LVMI)等。
11、统计学方法：所有资料均采用SPSS17.0软件包进行统计学分析。计量资料进行正态性检验及Levene方差齐性检验,正态资料以平均数±标准差表示,计数资料以百分数表示。四组间计量资料比较采用单变量ANOVA检验方法,方差不齐时使用Welch方差检验,两两比较采用Bonferroni法。计数资料的比较采用Pearson卡方检验或Fisher确切概率方法。相关趋势的变量进行Pearson简单直线相关分析；对缺失数据处理为直接删除缺失数。采用双侧P<0.05为有统计学差异。
二、研究结果
1、基线资料比较四研究组间在性别、家族史、体重指数、体表面积(BSA)、心率(HR)、收缩压(SBP)、高血压病史、糖尿病病史、吸烟史、药物及冠脉支架使用方面无显著差异。四研究组间年龄方面10mg非老年组(53.78+7.14岁)及40mg非老年组(54.76±7.43岁)均显著低于10mg老年组(72.68±5.19岁)及40mg老年组(72.32±4.33岁),差异有统计学意义(F=105.072,P=0.000)；在舒张压方面,10mg及40mg非老年组显著高于10mg及40mg老年组,差异有统计学意义(F=11.367,P=0.000)。
2、血脂及炎症因子水平变化研究开始时,四组间在血清TC、TG、LDL-C、 HDL-C、oxLDL及hsCRP浓度方面无显著差异,研究结束时,与10mg非老年组及10mg老年组相比,40mg非老年组及40mg老年组的TC、TG、LDL-C、oxLDL及hsCRP浓度显著性下降(P<0.01)。
3、cEMPs及cEPCs的测定结果四组间cEMPs基线水平无显著性差异；四组间cEPCs基线水平有统计学差异(P=0.001)：10mg非老年组及40mg非老年组cEPCs的水平均显著高于10mg老年组及40mg老年组。研究结束时,与10mg非老年组,10mg老年组及40mg老年组比较,40mg非老年组cEMPs水平显著下降,差异有统计意义(P<0.001),相反,40mg非老年组cEPCs水平显著性上升(P=0.011)。
4、VEGF测定结果治疗开始时,10mg非老年组及40mg非老年组cEPCs的水平均显著高于10mg老年组及40mmg老年组(P<0.05),四组组内治疗前后比较VEGF水平无显著性差异(P>0.05)。
5、BNP及MMP-9测定结果四组间BNP及MMP-9基线水平无显著差异(P>0.05),治疗结束时,与10mg非老年组,10mmg老年组及40mg老年组比较,40mg非老年组BNP及MMP-9水平显著下降,差异有统计意义(P<0.05)。
6、血小板活化因子水平变化研究开始时四组间在血小板、TXB2、PAF、6-Keto-PGF1α及TXB2/6-Keto-PGF1α比例等方面无显著性差异(P>0.05)。研究结束时,与1Omg非老年组及10mg老年组比较,40mg非老年组及40mg老年组血清TXB2, PAF及TXB2/6-Keto-PGF1α水平显著降低(P<0.05),6-Keto-PGF1α水平显著升高,差异有显著性(P<0.05)。
7、心室结构指标测定结果四组间在基线LVIDs, LVIDd, LVM, LVMI值无显著性差异(P>0.05),治疗结束时,与10mg非老年组,10mg老年组及40mg老年组比较,40mg非老年组LVIDs及LVIDd显著性下降(P<0.05)；与1Omg老年组对比,40mg非老年组的LVM(P=0.002)及LVMI(P=0.011)水平显著下降,差异有统计学意义,虽然与10mg非老年组及40mg老年组对比无显著性差异,但40mg非老年组LVM及LVMI均有下降趋势,P值接近0.05。
8、LVEF测定结果研究开始时,四研究组间LVEF水平无显著性差异(P>0.05)。研究结束时,与其他3组相比,40mg非老年组LVEF显著性改善,差异有统计意义(P<0.05)。
9、心肌能量消耗的测定结果研究开始时,四组间cESS, MEE及每分钟心肌能量消耗(mMEE)水平无显著性差异(P>0.05)。治疗结束时,与1Omg非老年组,10mg老年组及40mg老年组比较,40mg非老年组cESS.MEE及mMEE水平显著性下降,差异有统计意义(P<0.05)
10、随访期间结果：四研究组间药物使用情况无显著性差异(P>0.05)；随访期间,10mg非老年组、40mg非老年组、10mg老年组及40mg老年组分别有4例,3例,4例及2例患者退出本研究。四组间心血管事件发生率无显著性差异：10mg非老年组有3例患者因心功能恶化及1例因冠心病心绞痛发作住院治疗,40mg非老年组2例患者因心功能恶化住院治,10mg老年组有3例患者因心功能恶化及2例因脑梗塞住院治疗,40mg老年组有3例因心功能恶化、1例因冠心病心绞痛及1例因脑梗塞住院治疗。四研究组均无横纹肌溶解症及药物性肝炎的病例发生,四研究组间在肌痛、肌炎及胃肠道症状等不良反应方面无显著差异(P>0.05)
11、直线相关性分析结果：40mg非老年组治疗前后直线相关性分析提示：cEPCs差值与cEMPs差值呈负相关(r=-0.435,P=0.007)；LVEF差值与cEMPs差值及mMEE呈负相关(r=-0.372, P=0.023)及(r=-0.422, P=0,相反与cEPCs差值呈正相关(r=0.471,P=0.003)。
结论：
1.与老年组相比,大剂量阿托伐他汀(40mg/天)在非老年ICM患者人群(小于65岁)中能够显著地升高外周血内皮祖细胞水平及降低外周血内皮微颗粒。阿托伐他汀不能增加ICM患者外周血VEGF浓度；
2.只有40mg.非老年治疗组ICM患者的左室重构、左室收缩功能及心脏能量消耗得到显著改善；MMP-9及BNP在40mg非老年组中下降显著；更高效率地促进内皮祖细胞动员以及改善内皮细胞功能,可能有助于阿托伐他汀改善心功能、左室重构及心肌能量消耗；
3.大剂量阿托伐他汀(40mg/天)可显著降低ICM患者TXB2、PAF TXB2/6-Keto-PGF1α比例水平,并可显著升高患者血清PGI2水平,降低患者血小板活化水平,该效应不受患者年龄影响。
Background
Statins are effective cholesterol lowering agents, and commonly prescribed for the primary and secondary prevention against coronary heart disease (CHD), because they can reduce CHD incidence and motality obviously. Statins have been shown to possess several favorable effects, including improving endothelial function, anti-inflammation, anti-oxidant effect and reversing pathologic myocardial remodeling. All these effects mentioned above may contribute to prevent the progression of chronic heart failure (CHF), and it is confirmed by several small endpoint studies. However, recently, the result from universal study has indicated rosuvastatin could not improve ventricular remodeling and heart function in patients with CHF. Furthermore, the conclusions from two large-scale controlled studies are disappointing. Both studies showed that CHF patients have not gained any benefit from statin therapy in improving clinical outcomes. Hence, it is a matter of debate that whether statins can improve ventricular remodeling, heart function and clinical prognosis in patients with CHF.
Most of experts have the opinion that the different type and dose of statins administration and different populations in these studies may contribute to these controversial results. The result from one meta-analysis showed that statins improved ventricular remodeling, heart function and clinical pronosis in patients with CHF, but not in patients treated with rosuvastatin. Rencently, one randomized study demonstrates that compared to the low dose of atorvastatin, the high dose of atorvastatin might make ventricular remodeling and heart function improved in in patients with ICM. Notably, almost all the favorable effects of statin therapy have been verified by using in vitro techniques, or in younger patients and healthy control, whereas the majority of patients enrolled in these two studies were advanced age (>65years) with multiple comorbidities. Therefore, age might affect the efficacy of statin in patients with ICM.
Although it is still unclear that the exact mechanism of statins works in the treatment of CHF, a growing body of evidences displays that statin can increase mobilization of EPCs from bone marrow and impore endothelial function. Advanced stages of heart failure were shown to be related with reduced levels of cEPCs, and impaired functions of progenitor cells in the peripheral blood in patient with ICM. Hence, this effect might make contribution to improve ventricular remodeling, heart function and clinical pronosis in patients with CHF. However, the age-related changes in cEPCs number and dysfunction and endothelial dysfunction may lead to the impairment of statins repair mechanisms in the aging cardiovascular system. At the same time, Aging plays a negative role on cardiac structure, function and myocardial energy expendicture, including cardiac hyperotrophy, function degeneration and imbalance of myocardial energy expendicture. This aged-related change makes it difficult that statins reverse myocardial remodeling, function degeneration and imbalance of myocardial energy expendicture.
A high incidence of thrombotic complications has been associated with patients with ICM. The platelet-related factors is prone to be activated by inflammatory factors, then the activated platelets were accumulated and enhanced the forming of thrombosis, which at last lead to the incidences of cardiacarrhythmia and clinical events. Statins have been shown to possess positive effects, including anti-inflammation, anti-oxidant effect, which may inhibit the platelet-related factor activated. This effect may contribute to the improvement of clinical prognosis.
The presence of increased levels of circulating endothelial-derived microparticles (cEMP) have been documented in various pathological conditions including coronary syndromes, in which they reflect endothelial dysfunction and are associated with a poor clinical outcome.Our group and other researchers have found that myocardial energy expenditure derived from standard echocardiographic measurements were considered as an effective indicator for myocardial bioenergetics. In patients with heart failure, the absolute change of MEE is inversely correlated with that of LVEF, indicating that MEE might be an effective index for assessing engegy metabolism and heart function.
There were few data to investigated the influence of aging on the effect of atorvastatin improving cEPCs mobilization、endothelial function、left ventricular remodeling、LVEF and MEE in Patients with ICM, and to compare the effect of different dose of atorvastatin on serum prostacyclin and platelet activation.
Objective This study was designed to compare the efficacy of atorvastatin therapy in the mobilization of EPCs, the improvement of endothelial dysfunction, left ventricular remodeling, LVEF and MEE in young and elderly patients with ICM, and to investigate the effect of different dose of atorvastatin on serum prostacyclin and platelet activation.
Subjects and Method
Subjects we included patients with ICM (required to have angiographic evidence of coronary artery disease or a previous MI at least3months prior to inclusion into the study), LVEF<45%, LV end-diastolic dimension>50mm and NYHA class Ⅱ-Ⅳ. The exclusion criteria included individuals with previous statin-induced myopathy or a hypersensitivity reaction, acute infection, chronic inflammatory disease, autoimmune disease, thyroid disease, liver disease, acute or chronic heart failure due to other cardiovascular diseases other than ICM, stroke within3months, renal failure, lung disease and a life expectancy less than1year.
Groups157ICM patients in Cardiovascular Department were assigned into this study from March2007to March2011. In accordance with the hospitalization order, Young (
他汀类药物(Statins)是一种有效的降脂药物,可显著降低冠心病的发病率及死亡率,广泛应用于冠心病的一级及二级预防。近年来研究表明他汀类药物具有降脂外的多效性,包括改善内皮功能,抗炎症作用,促进内皮祖细胞动员,抗氧化作用以及抑制心脏病理性重构作用等。这些作用被认为是改善心力衰竭预后的基础。两个小样本、前瞻性研究结果提示阿托伐他汀及辛伐他汀可改善心力衰竭患者的心功能及预后。然而,UNIVERSAL研究提示瑞舒伐他汀不能改善心衰患者的心室重构及心功能。两个大型的临床研究CORONA及GISSI-HF的结果否定了他汀类药物改善预后的结论,因此,他汀对缺血性心肌病(ischemic cardiomyopathy, ICM)患者的心室重构、心功能及预后的作用尚无定论.
目前多数学者认为他汀的种类,剂量及研究人群差异可能是造成研究结果不同的主要原因。一项荟萃分析发现阿托伐他汀可显著改善心衰患者心功能及临床预后,而瑞舒伐他汀则未能起到该作用,提示种类可能影响他汀的作用有效。近期有一项随机研究发现,与小剂量阿托伐他汀比较,大剂量阿托伐他汀可显著改善ICM患者的心室舒张功能及心肌能量代谢。有学者认为他汀的多效性多数在体外研究、非老年患者或者正常人中证实,而两个大型研究中的研究对象大多为老年人群,因而年龄可能影响他汀的有效性。
尽管他汀在心衰治疗中的作用机制目前也不完全清楚,然而越来越多的证据表明,阿托伐他汀可显著地促进骨髓中内皮祖细胞(circulating endothelial progenitor cells, cEPCs)动员及改善内皮功能,晚期心衰患者cEPCs水平明显降低；ICM患者外周血内皮祖细胞存在选择性功能受损,因此,此作用可能有助于ICM患者改善心室重构,心功能、心肌能量消耗及临床预后。然而,衰老相关的内皮功能受损以及cEPCs的功能受损及数量的下降,可能影响他汀对老年ICM患者心血管系统的修复作用。与此同时,衰老可显著影响老年患者心脏结构、心脏功能及心肌能量代谢等方面,主要表现为心肌肥厚,心肌功能减退以及心肌能量代谢障碍。衰老相关的心脏改变可能导致他汀难以逆转老年ICM患者心室重构,心功能下降及能力代谢障碍。
ICM患者具有较高血栓事件发生率。ICM患者血小板活化相关因子易于被炎症因子激活,进而促进血小板聚集而形成血栓,最终导致心律失常及临床事件的发生。研究表明他汀具有抗炎及抗氧化等作用,可减低炎症及氧化应激对血小板活化相关因子的激活作用,可能有助于改善ICM患者的临床预后。。
近年来研究提示外周血循环内皮微颗粒(circulating endothelial-derived microparticles, cEMP)可作为评价心衰患者内皮功能及临床预后的实验指标。本研究组及其他研究者发现标准心脏多普勒超声检测的心脏能量消耗(Myocardial energy expenditure, MEE)是衡量心肌生物能量消耗的有效指标,在心力衰竭人群中,MEE变化值与左室射血分数(Left ventricular ejection fraction, LVEF)变化值的呈负相关,提示MEE可作为评价能量代谢及心功能的有效指标。目前国内外很少有研究探讨年龄对阿托伐他汀促进ICM患者EPCs动员和改善内皮功功能,心室重构、功能及MEE的影响,也少有研究观察不同剂量阿托伐他汀对前列环素及血小板活化相关因子的作用。
目的探讨年龄对阿托伐他汀促进cEPCs动员和降低cEMPs以及改善心室重构、心脏收缩功能及心脏能量消耗的影响,同时观察不同剂量阿托伐他汀对前列环素及血小板活化相关因子的作用
一、研究对象与方法：
1、病例选择：入选标准(1)明确的冠心病证据：心绞痛或心肌梗塞,经选择性冠状动脉造影检查证实前降支、回旋支及右冠状动脉,存在一支或一支以上血管狭窄≥50%,选择性冠状动脉造影方法及判断标准采用Judkins法,常规投照体位行左、右冠状动脉造影,并由造影机图像处理系统对冠脉狭窄定量分析；(2)左室舒张末内径>50mm.(3)慢性充血性心力衰竭,左室射血分数<45%,纽约心功能Ⅱ-Ⅳ的ICM患者；(4)排除了冠心病合并室间隔缺损、重度二尖瓣反流、室壁瘤及心律失常所致的充血性心力衰竭或其他病因导致的大心脏及心力衰竭患者。排除标准已诊断明确的急慢性炎症、血管炎、有其它部位活动感染、癌症、肝病、甲状腺疾病、他汀类药物过敏或肌溶解史、自身免疫性疾病、脑卒中、肾功能衰竭、肺部疾病及预期寿命≤1年患者。
2、病例与分组选择我院心内科住院确诊的ICM患者157例；按患者入院的后按照年龄分为老年组及非老年组,再随机将两组患者随机分为4组：阿托伐他汀(辉瑞)10mg/天非老年组40例、40mg/天非老年组40例、10mg/天老年组38例及40mg/天非老年组39例。在随访期间,10mg非老年组、40mg非老年组、10mg老年组及40mg老年组分别有4例,3例,4例及2例患者因失访或者根据医师专业判断退出本研究。所有患者均随访1年,记录不良反应及心血管事件的发生。
3、一般实验室指标检测：研究开始时及研究结束时,采用自动生化分析仪进行检测血总胆固醇(TC)、甘油三酯(TG)、低密度脂蛋白胆固醇(LDL-C)、高密度脂蛋白胆固醇(HDL-C)、血清尿酸(UA)、肝功能及肌酸激酶(CK)水平等。
4、外周血内皮祖细胞检测：本研究采用乙酰化低密度脂蛋白(Dil-acLDL)及豆凝血素I(FITC-UEA-1)双染色法对cEPCs进行鉴定。研究开始时及研究结束时,使用流式细胞仪检测外周血内皮祖细胞水平,本研究定义外周血CD34+KDR+双阳性单核细胞为cEPCs,以100000个单个核细胞中CD34+KDR+阳性细胞数百分率为静脉血cEPCs水平。
5、外周血内皮微颗粒的检测：外周血内皮细胞微颗粒使用流式细胞仪进行检测,cEMPs浓度定义为大小<1.0μm且CD31阳性CD42b阴性的微颗粒浓度。
6、炎症因子水平测定：血清超敏C-反应蛋白水平(hs-CRP)使用免疫透射浊度法进行测定,血清氧化低密度脂蛋白水平(ox-LDL)用酶联免疫吸附试验双抗体夹心法进行测定。
7、脑钠肽(BNP),血管内皮生长因子水平(VEGF)及基质金属蛋白酶-9(MMP-9)测定：采用BIOSITE Triage Meter型检测仪检测BNP浓度,VEGF及MMP-9浓度检测均采用酶联免疫吸附试验双抗体夹心法进行测定。
8、血小板活化因子测定：分别在研究开始及结束时,采用放射免疫检测的方法,检测血清血小板活化因子(PAF)、6-酮-前列素F1α(6-Keto-PGF1α)及血栓素B2(TXB2)水平。
9、心脏彩超心功能测定：应用美国GE Logig7彩色多普勒超声诊断仪进行检测,分别于研究前后两次进行检测,以美国超声学会推荐的标准平面测定主要指标有左房内径(LA),右室内径(RV)、收缩末期内径(LVIDs)、舒张末期内径(LVIDd)E峰、A峰及射血分数(LVEF)等。
10、心肌能量消耗的测定：应用美国GE Logig7彩色多普勒超声诊断仪进行检测,分别于研究前后两次进行检测,室壁厚度(PWTs)、舒张末室间隔厚度(IVSTd)、收缩末后壁厚度(PWTs)、舒张末后壁厚度(PWTd)、左室每搏输出量(LVSV)、左室射血时间(LVET)等指标。各项指标连续检测3个心动周期,取其平均值为最终结果。按相关参考公式计算心肌能量消耗的各项指标左室收缩末圆周室壁应力(cESS),心肌能量消耗(MEE)及左心室质量指数(LVMI)等。
11、统计学方法：所有资料均采用SPSS17.0软件包进行统计学分析。计量资料进行正态性检验及Levene方差齐性检验,正态资料以平均数±标准差表示,计数资料以百分数表示。四组间计量资料比较采用单变量ANOVA检验方法,方差不齐时使用Welch方差检验,两两比较采用Bonferroni法。计数资料的比较采用Pearson卡方检验或Fisher确切概率方法。相关趋势的变量进行Pearson简单直线相关分析；对缺失数据处理为直接删除缺失数。采用双侧P<0.05为有统计学差异。
二、研究结果
1、基线资料比较四研究组间在性别、家族史、体重指数、体表面积(BSA)、心率(HR)、收缩压(SBP)、高血压病史、糖尿病病史、吸烟史、药物及冠脉支架使用方面无显著差异。四研究组间年龄方面10mg非老年组(53.78+7.14岁)及40mg非老年组(54.76±7.43岁)均显著低于10mg老年组(72.68±5.19岁)及40mg老年组(72.32±4.33岁),差异有统计学意义(F=105.072,P=0.000)；在舒张压方面,10mg及40mg非老年组显著高于10mg及40mg老年组,差异有统计学意义(F=11.367,P=0.000)。
2、血脂及炎症因子水平变化研究开始时,四组间在血清TC、TG、LDL-C、 HDL-C、oxLDL及hsCRP浓度方面无显著差异,研究结束时,与10mg非老年组及10mg老年组相比,40mg非老年组及40mg老年组的TC、TG、LDL-C、oxLDL及hsCRP浓度显著性下降(P<0.01)。
3、cEMPs及cEPCs的测定结果四组间cEMPs基线水平无显著性差异；四组间cEPCs基线水平有统计学差异(P=0.001)：10mg非老年组及40mg非老年组cEPCs的水平均显著高于10mg老年组及40mg老年组。研究结束时,与10mg非老年组,10mg老年组及40mg老年组比较,40mg非老年组cEMPs水平显著下降,差异有统计意义(P<0.001),相反,40mg非老年组cEPCs水平显著性上升(P=0.011)。
4、VEGF测定结果治疗开始时,10mg非老年组及40mg非老年组cEPCs的水平均显著高于10mg老年组及40mmg老年组(P<0.05),四组组内治疗前后比较VEGF水平无显著性差异(P>0.05)。
5、BNP及MMP-9测定结果四组间BNP及MMP-9基线水平无显著差异(P>0.05),治疗结束时,与10mg非老年组,10mmg老年组及40mg老年组比较,40mg非老年组BNP及MMP-9水平显著下降,差异有统计意义(P<0.05)。
6、血小板活化因子水平变化研究开始时四组间在血小板、TXB2、PAF、6-Keto-PGF1α及TXB2/6-Keto-PGF1α比例等方面无显著性差异(P>0.05)。研究结束时,与1Omg非老年组及10mg老年组比较,40mg非老年组及40mg老年组血清TXB2, PAF及TXB2/6-Keto-PGF1α水平显著降低(P<0.05),6-Keto-PGF1α水平显著升高,差异有显著性(P<0.05)。
7、心室结构指标测定结果四组间在基线LVIDs, LVIDd, LVM, LVMI值无显著性差异(P>0.05),治疗结束时,与10mg非老年组,10mg老年组及40mg老年组比较,40mg非老年组LVIDs及LVIDd显著性下降(P<0.05)；与1Omg老年组对比,40mg非老年组的LVM(P=0.002)及LVMI(P=0.011)水平显著下降,差异有统计学意义,虽然与10mg非老年组及40mg老年组对比无显著性差异,但40mg非老年组LVM及LVMI均有下降趋势,P值接近0.05。
8、LVEF测定结果研究开始时,四研究组间LVEF水平无显著性差异(P>0.05)。研究结束时,与其他3组相比,40mg非老年组LVEF显著性改善,差异有统计意义(P<0.05)。
9、心肌能量消耗的测定结果研究开始时,四组间cESS, MEE及每分钟心肌能量消耗(mMEE)水平无显著性差异(P>0.05)。治疗结束时,与1Omg非老年组,10mg老年组及40mg老年组比较,40mg非老年组cESS.MEE及mMEE水平显著性下降,差异有统计意义(P<0.05)
10、随访期间结果：四研究组间药物使用情况无显著性差异(P>0.05)；随访期间,10mg非老年组、40mg非老年组、10mg老年组及40mg老年组分别有4例,3例,4例及2例患者退出本研究。四组间心血管事件发生率无显著性差异：10mg非老年组有3例患者因心功能恶化及1例因冠心病心绞痛发作住院治疗,40mg非老年组2例患者因心功能恶化住院治,10mg老年组有3例患者因心功能恶化及2例因脑梗塞住院治疗,40mg老年组有3例因心功能恶化、1例因冠心病心绞痛及1例因脑梗塞住院治疗。四研究组均无横纹肌溶解症及药物性肝炎的病例发生,四研究组间在肌痛、肌炎及胃肠道症状等不良反应方面无显著差异(P>0.05)
11、直线相关性分析结果：40mg非老年组治疗前后直线相关性分析提示：cEPCs差值与cEMPs差值呈负相关(r=-0.435,P=0.007)；LVEF差值与cEMPs差值及mMEE呈负相关(r=-0.372, P=0.023)及(r=-0.422, P=0,相反与cEPCs差值呈正相关(r=0.471,P=0.003)。
结论：
1.与老年组相比,大剂量阿托伐他汀(40mg/天)在非老年ICM患者人群(小于65岁)中能够显著地升高外周血内皮祖细胞水平及降低外周血内皮微颗粒。阿托伐他汀不能增加ICM患者外周血VEGF浓度；
2.只有40mg.非老年治疗组ICM患者的左室重构、左室收缩功能及心脏能量消耗得到显著改善；MMP-9及BNP在40mg非老年组中下降显著；更高效率地促进内皮祖细胞动员以及改善内皮细胞功能,可能有助于阿托伐他汀改善心功能、左室重构及心肌能量消耗；
3.大剂量阿托伐他汀(40mg/天)可显著降低ICM患者TXB2、PAF TXB2/6-Keto-PGF1α比例水平,并可显著升高患者血清PGI2水平,降低患者血小板活化水平,该效应不受患者年龄影响。
Background
Statins are effective cholesterol lowering agents, and commonly prescribed for the primary and secondary prevention against coronary heart disease (CHD), because they can reduce CHD incidence and motality obviously. Statins have been shown to possess several favorable effects, including improving endothelial function, anti-inflammation, anti-oxidant effect and reversing pathologic myocardial remodeling. All these effects mentioned above may contribute to prevent the progression of chronic heart failure (CHF), and it is confirmed by several small endpoint studies. However, recently, the result from universal study has indicated rosuvastatin could not improve ventricular remodeling and heart function in patients with CHF. Furthermore, the conclusions from two large-scale controlled studies are disappointing. Both studies showed that CHF patients have not gained any benefit from statin therapy in improving clinical outcomes. Hence, it is a matter of debate that whether statins can improve ventricular remodeling, heart function and clinical prognosis in patients with CHF.
Most of experts have the opinion that the different type and dose of statins administration and different populations in these studies may contribute to these controversial results. The result from one meta-analysis showed that statins improved ventricular remodeling, heart function and clinical pronosis in patients with CHF, but not in patients treated with rosuvastatin. Rencently, one randomized study demonstrates that compared to the low dose of atorvastatin, the high dose of atorvastatin might make ventricular remodeling and heart function improved in in patients with ICM. Notably, almost all the favorable effects of statin therapy have been verified by using in vitro techniques, or in younger patients and healthy control, whereas the majority of patients enrolled in these two studies were advanced age (>65years) with multiple comorbidities. Therefore, age might affect the efficacy of statin in patients with ICM.
Although it is still unclear that the exact mechanism of statins works in the treatment of CHF, a growing body of evidences displays that statin can increase mobilization of EPCs from bone marrow and impore endothelial function. Advanced stages of heart failure were shown to be related with reduced levels of cEPCs, and impaired functions of progenitor cells in the peripheral blood in patient with ICM. Hence, this effect might make contribution to improve ventricular remodeling, heart function and clinical pronosis in patients with CHF. However, the age-related changes in cEPCs number and dysfunction and endothelial dysfunction may lead to the impairment of statins repair mechanisms in the aging cardiovascular system. At the same time, Aging plays a negative role on cardiac structure, function and myocardial energy expendicture, including cardiac hyperotrophy, function degeneration and imbalance of myocardial energy expendicture. This aged-related change makes it difficult that statins reverse myocardial remodeling, function degeneration and imbalance of myocardial energy expendicture.
A high incidence of thrombotic complications has been associated with patients with ICM. The platelet-related factors is prone to be activated by inflammatory factors, then the activated platelets were accumulated and enhanced the forming of thrombosis, which at last lead to the incidences of cardiacarrhythmia and clinical events. Statins have been shown to possess positive effects, including anti-inflammation, anti-oxidant effect, which may inhibit the platelet-related factor activated. This effect may contribute to the improvement of clinical prognosis.
The presence of increased levels of circulating endothelial-derived microparticles (cEMP) have been documented in various pathological conditions including coronary syndromes, in which they reflect endothelial dysfunction and are associated with a poor clinical outcome.Our group and other researchers have found that myocardial energy expenditure derived from standard echocardiographic measurements were considered as an effective indicator for myocardial bioenergetics. In patients with heart failure, the absolute change of MEE is inversely correlated with that of LVEF, indicating that MEE might be an effective index for assessing engegy metabolism and heart function.
There were few data to investigated the influence of aging on the effect of atorvastatin improving cEPCs mobilization、endothelial function、left ventricular remodeling、LVEF and MEE in Patients with ICM, and to compare the effect of different dose of atorvastatin on serum prostacyclin and platelet activation.
Objective This study was designed to compare the efficacy of atorvastatin therapy in the mobilization of EPCs, the improvement of endothelial dysfunction, left ventricular remodeling, LVEF and MEE in young and elderly patients with ICM, and to investigate the effect of different dose of atorvastatin on serum prostacyclin and platelet activation.
Subjects and Method
Subjects we included patients with ICM (required to have angiographic evidence of coronary artery disease or a previous MI at least3months prior to inclusion into the study), LVEF<45%, LV end-diastolic dimension>50mm and NYHA class Ⅱ-Ⅳ. The exclusion criteria included individuals with previous statin-induced myopathy or a hypersensitivity reaction, acute infection, chronic inflammatory disease, autoimmune disease, thyroid disease, liver disease, acute or chronic heart failure due to other cardiovascular diseases other than ICM, stroke within3months, renal failure, lung disease and a life expectancy less than1year.
Groups157ICM patients in Cardiovascular Department were assigned into this study from March2007to March2011. In accordance with the hospitalization order, Young (
引文
[1]Ramasubbu K, Estep J, White DL, et al. Experimental and clinical basis for the use of statins in patients with ischemic and nonischemic cardiomyopathy [J].Am Coll Cardiol.2008; 51:415-426.
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[2]Mozaffarian D, Nye R, Levy WC. Statin therapy is associated with lower mortality among patients with severe heart failure [J].Am J Cardiol 2004;93:1124-1129
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