40mg与10mg阿托伐他汀对缺血性心肌病患者外周血循环内皮微颗粒、内皮祖细胞、心肌能量消耗及左室功能影响的比较
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摘要
研究背景
他汀作为抗动脉粥样硬化药物,能明显降低冠心病患者心血管事件的发生率,已广泛应用于冠心病患者的二级预防,虽然他汀在心力衰竭患者中应用的安全性已被CORONA and UNIVERSE研究所证实,但目前他汀对缺血性心肌病患者(ischemic cardiomyopathy, ICM)心功能的影响尚无定论,小样本、前瞻性临床研究显示,阿托伐他汀及辛伐他汀可改善CHF患者预后。然而,随后一些研究显示,瑞舒伐他汀不能改善缺血性及非缺血性、收缩性HF患者的预后。目前针对他汀治疗HF患者研究结论不一致,部分原因可能是各研究他汀使用种类、剂量、及研究人群不一致。并且,一些临床试验虽然显示他汀可能改善CHF患者左室功能,但其机制目前仍不完全清楚。
目前研究显示,外周血循环EPCs(circulating EPCs, cEPCs)不仅与多种心血管危险因素及血管功能相关,并且能预测冠脉疾病患者未来心血管事件及动脉粥样硬化疾病的进展。近来研究显示,晚期心衰患者cEPCs水平降低,缺血性心肌病Ischemic cardiomyopathy, ICM)患者存在骨髓及外周血祖细胞选择性功能受损。内皮细胞在受到炎症刺激时能释放微颗粒,外周血循环内皮微颗粒(circulating endothelial-derived microparticles, cEMP)水平升高能见于包括冠脉疾病在内的多种病理状态,能反映内皮功能受损及不良的临床预后,稳定细胞膜降低EPMs释放被认为是血管疾病治疗的一个靶点。
基质金属蛋白酶(matrix metalloproteinase, MMP)存在于心肌细胞,能降解所有的心脏基质成分,是心肌基质重塑的推动力量[1-3]。MMP-9能降解凝胶,在左室重塑过程中,MMP-9的重要作用已被多个研究所证实[4-7],MMP-9的缺失能减少心肌梗塞后心室扩大的程度,因此MMP-9可能是心肌梗塞后可供选择的治疗靶点[6,14-16]。
左室肥厚、重塑将导致心肌能量代谢失衡。目前认为,标准心脏多普勒超声检测的心肌能量消耗(Myocardial energy expenditure, MEE)是衡量心肌生物能量消耗的有效指标,并且MEE与充血性心力衰竭患者,特别是与LVEF降低的患者心功能密切相关,既往研究证实,在CHF患者,降低的LVEF与升高的MEE独立相关。
目前很少有研究探讨他汀的降脂外作用及不同剂量他汀对cEPCs、cEPMs、MEE及左室功能的影响,因此本研究拟在ICM患者中比较40mg与10mg阿托伐他汀对cEPCs、cEPMs、MEE及左室功能的影响,并探讨阿托伐他汀对ICM的作用机制。
第一部分40mg与10mmg阿托伐他汀对缺血性心肌病患者oxLDL、hsCRP、外周血循环内皮微颗粒及内皮祖细胞影响的比较
目的比较40mg与10mg阿托伐他汀对ICM患者oxLDL、hsCRP、外周血循cEMPs及cEPCs的影响,并探讨阿托伐他汀对ICM患者可能作用机制。
方法选择2007年3月至2010年6月在我院心内科住院确诊的ICM患者100例,患者随机分为2组：阿托伐他汀(辉瑞)10mg/天治疗组及40mg/天治疗组,同期门诊健康体检者非冠心病100例为对照组。随访期1年,所有研究对象在研究初始及随访结束时两次行肌酶、肝功能、血脂、血清尿酸、oxLDL、hsCRP、外周血cEMPs及cEPCs,并记录两组患者阿托伐他汀不良反应的发生率。
结果随访结束时,10mg/天阿托伐他汀治疗组及对照组均失访3例,40mg/天阿托伐他汀治疗组失访2例,在随访期间,10mg阿托伐他汀治疗组有2例患者因腔隙性牛脑梗塞及3例患者因心功能恶化住院治疗,40mmg阿托伐他汀治疗组有1例患者因腔隙性脑梗塞及2例患者因心功能恶化住院治疗。两研究组间在心血管事件发生率方面差异无显著性。两研究组均无横纹肌溶解症及药物性肝炎的病例出现,40mg阿托伐他汀组不良反应无明显增多；研究前后,两研究组在CK及ALT方面比较,差异均无显著性。研究开始时,两研究组间在血脂、血清oxLDL、hsCRP、BNP、MMP-9、cEMPs、cEPCs、MEE、心功能、纤维蛋白原、尿酸、ALT、CK、高血压、糖尿病、吸烟、体重指数、年龄、性别、家族史、药物及冠脉支架使用方面,差异均无显著性；两研究组在随访期间药物使用方面比较,差异无显著性,P>0.05；两研究组间心脏彩超结果比较,差异无显著性,P>0.05。研究结束时,与10mmg阿托伐他汀治疗组比较,40mg阿托伐他汀治疗组血清TC(F=11.586,P=0.001)、LDL-C(F=7.459,P=0.008) oxLDL(F=16.106,P=0.000)及hsCRP(F=29.497, P=0.000)水平明显降低,差异有显著性；与10mmg阿托伐他汀治疗组比较,40mg阿托伐他汀治疗组外周血cEMPs(F=24.252,P=0.000)水平明显降低,cEPCs(F=4.969,P=0.028)水平明显升高,差异有显著性。
结论对ICM患者,与10mg阿托伐他汀比较,40mmg阿托伐他汀可能降低患者外周血cEMPs及升高外周血cEPCs水平,阿托伐他汀可能有降脂外的作用。
第二部分40mg与10mg阿托伐他汀对缺血性心肌病患者心肌能量消耗及左室功能影响的比较
目的比较40mg与10mg阿托伐他汀对ICM患者心肌能量消耗(Myocardial energy expenditure, MEE)及左室功能的影响,并探讨阿托伐他汀在ICM中的作用机制。
方法选择2007年3月至2010年6月在我院心内科住院确诊的ICM患者100例,患者随机分为2组：阿托伐他汀(辉瑞)10mg/天治疗组及40mg/天治疗组,同期门诊健康体检者非冠心病100例为对照组。随访期1年,所有实验对象在研究初始及随访结束时两次行BNP(B-type natriuretic peptide),左室收缩末周向室壁应力(Circumferential end-systolic wall stress, cESS), MEE、E/E'及心脏彩超检测。
结果研究结束时,两研究组间在LVMI(F=3.014,P=0.390)方面差异无显著性,但与10mg阿托伐他汀治疗组比较,40mg阿托伐他汀治疗组LVMI有所降低；与10mg阿托伐他汀治疗组比较,40mg阿托伐他汀治疗组MEE(F=5.319,P=0.023)水平明显降低,差异有显著性；与10mg阿托伐他汀治疗组比较,40mg阿托伐他汀治疗组血清BNP水平(F=4.845,P=0.032)及E/E’(F=10.330,P=0.002)明显降低,差异有显著性；两研究组间在LVEF(F=0.385,P=0.536)方面比较,差异无显著性。
结论对ICM患者,与10mg阿托伐他汀比较,40mg阿托伐他汀可能降低患者MEE及E/E'水平,阿托伐他汀可能有降脂外的作用。
第三部分40mg与10mg阿托伐他汀对缺血性心肌病患者血清基质金属蛋白酶-9水平影响的比较
目的比较40mmg与10mmg阿托伐他汀对ICM患者血清基质金属蛋白酶-9(MMP-9)水平影响,并探讨阿托伐他汀在ICM中的作用机制。
方法选择2007年3月至2010年6月在我院心内科住院确诊的ICM患者100例,患者随机分为2组：阿托伐他汀(辉瑞)10mg/天治疗组及40mg/天治疗组,同期门诊健康体检者非冠心病100例为对照组。随访期1年,所有研究对象在研究初始及随访结束时两次行血清MMP-9检测。
结果研究结束时,与10mg阿托伐他汀治疗组比较,40mmg阿托伐他汀治疗组血清MMP-9(F=5.016,P=0.026)水平明显降低,差异有显著性。
结论对ICM患者,与10mg阿托伐他汀比较,40mg阿托伐他汀可能降低患者血清MMP-9水平。
Background
Statins, serving as an anti-atherosclerosis drug, can significantly decrease the rates of cardiovascular events in patients with coronary heart disease (CHD), and were extensively administrated in secondary prevention of CHD. At present, consensus on the possible effects of statins on cardiac function in patients with ischemic cardiomyopathy(ICM) have not been achieved, although the safety of statins in patients with heart failure has been demonstrated by the CORONA and UNIVERSE trials. Small prospective clinical studies using atorvastatin and simvastatin for systolic heart failure (HF) have suggested that statins could be beneficial in patients with congestive heart failure(CHF) Conversely, subsequent studies indicated that rosuvastatin couldn't improve the prognosis in patients with ischemic or nonischemic, systolic HF. The incomplete agreement existing on the role of statins in HF may in part be due to the different class and dose of statins administration and different race in these studies. Several clinical trials administrating statins for CHF have documented an improved LV function, but the mechanisms in patients with CHF are still not completely known.
At present, the level of circulating EPCs(cEPCs) not only correlates with cumulative cardiovascular risk and vascular function7, but also predicts future cardiovascular events and atherosclerotic disease progression in patients with coronary artery disease (CAD). Recently, advanced stages of heart failure were shown to be associated with reduced levels of cEPCs. Study showed ICM was associated with selective impairment of progenitor cell function in the bone marrow and in the peripheral blood.
Endothelial cells could release microparticles after inflammatory stimulation, and 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. Currently, stabilizing cellular membranes to decrease the release of EPMs was considered a target of vascular therapy.
Matrix metalloproteinase(MMPs), which are present in the myocardium and capable of degrading all the matrix components of the heart, are the driving force behind myocardial matrix remodeling. MMP-9is well-known for its ability to degrade gelatins. The particular importance of MMP-9activity during LV remodeling has recently been demonstrated in several studies. Furthermore, MMP-9may be one of the candidates for selective inhibition after myocardial infarction(MI), because the deficiency in MMP-9alone could reduce LV chamber enlargement after infarction.
LV hypertrophy, remodeling would lead to myocardial energy metabolic imbalance. In present, myocardial energy expenditure (MEE) derived from standard echocardiographic measurements was regarded as an effective indicator for myocardial bioenergetics and significantly correlated with cardiac function in CHF patients, especially in CHF patients with reduced LV ejection fraction(LVEF). Previous study demonstrated depressed EF was independently associated with higher MEE and increased MEE could predict cardiac death.
However, currently, there were few data to delineate the effect of different doses statins on cEPCs and cEPMs. Thus, the present study was designed to investigate the differences of40mg versus10mg atorvastatin on cEPCs, cEMPs, MEE and LV function in patients with ICM.
Part one Comparison of40mg versus10mg atorvastatin on oxLDL, hsCRP, circulating endothelial-derived microparticles and endothelial progenitor cells in patients with ischemic cardiomyopathy
Objective This study was designed to investigate the differences of40mg versus lOmg atorvastatin on oxLDL, hsCRP, circulating endothelial-derived microparticles(EMPs) and endothelial progenitor cells(EPCs) in patients with ischemic cardiomyopathy (ICM).
Methods100patients with ICM and100healthy examined people as normal control group were recruited to this study. Patients were randomly divided into two groups:10mg atorvastatin group (n=50) and40mg atorvastatin group (n=50).All subjects were followed up for1year. The levels of serum lipids, oxLDL, hsCRP, circulating EPCs and EMPs were examined in all subjects. The incidences of adverse reactions in two study groups were taken down.
Results3,2and3patients withdrew in lOmg atorvastatin group,40mg atorvastatin group and control group respectively because of moving to other provinces. The incidences of cardiovascular events in10mg atorvastatin group and in40mg atorvastatin group were10.6%(5/47) and6.25%(3/48) during the period of follow-up. There were no significant differences in the rates of cardiovascular events between the two study groups. There was no rhabdomyolysis and drug-induced hepatitis in the two study groups during the follow-up. No excessive episodes of adverse reactions occurred in the40mg atorvastatin group. Subjects did not differ in CK and ALT between the two study groups at the end of study.Subjects did not differ in lipids, oxLDL, hsCRP, cEMPs, cEPCs, MEE, cardiac function, CK, ALT, fibrinogen, urine acid, age, gender, family medical history, index weight, number with hypertension, number with diabetes, number ever smoking, drugs, echocardiographic indices and the rate of stent implanted between the two study groups. At the end of the study, the levels of serum TC(F=11.586,P=0.001), LDL(F=7.459,P=0.008), oxLDL(F=l6.106,P=0.000) and hsCRP(F=29.497,P=0.000) significantly decreased in40mg atorvastatin group in contrast to1Omg atorvastatin group. At the end of the study, the levels of cEMPs(F=24.252,P=0.000) significantly decreased but the levels of cEPCs(F=4.969,P=0.028)significantly increased in40mg atorvastatin group in contrast to10mg atorvastatin group.
Conclusions40mg atorvastatin might decrease the levels of circulating EMPs and increase the number of circulating EPCs in patients with ICM in comparison with lOmg atorvastatin. Furthermore, atorvastatin might have the beyond lipids-decreased effects.
Part two Comparison of40mg versus10mg atorvastatin on myocardial energy expenditure level and left ventricular function in patients with ischemic cardiomyopathy
Objectives The present study was to investigate the differences of40mg versus10mg atorvastatin on myocardial energy expenditure (MEE) and E/E' in patients with ischemic cardiomyopathy (ICM).
Methods100patients with ICM and100healthy examined people as normal control group were recruited to this study. Patients were randomly divided into two groups:10mg atorvastatin group (n=50) and40mg atorvastatin group (n=50).All subjects were followed up for1year. The levels of B-type natriuretic peptide(BNP), circumferential end-systolic wall stress(cESS), MEE, E/E' and echocardiography were examined in all subjects.
Results At the end of this study, the decrease in LVMI(F=3.014,P=0.390)was observed in40mg atorvastatin group in contrast to10mg atorvastatin group although there were no significant differences between the two study groups. At the end of the study, the levels of MEE (F=5.319,P=0.023)significantly decreased in40mg atorvastatin group in contrast to10mg atorvastatin group.At the end of the study, the levels of serum BNP(F=4.845,P=0.032)and E/E'(F=10.330,P=0.002) significantly decreased in40mg atorvastatin group in contrast to10mg atorvastatin group,P<0.05. Subjects did not differ in LVEF(F=0.385,P=0.536) between the two study groups at the end of the study.
Conclusions40mg atorvastatin might significantly decrease the levels of MEE and E/E'obtained from Doppler echocardiography in comparison with10mg atorvastatin in patients with ICM. Moreover the effect might be independent of the decrease of lipids.
Part three Comparison of40mg versus10mg atorvastatin on the levels of serum matrix metalloproteinase-9in patients with ischemic cardiomyopathy
Objectives The present study was to investigate differences of40mg versus10mg atorvastatin on the levels of serum matrix metalloproteinase-9(MMP-9) in patients with ischemic cardiomyopathy (ICM).
Methods100patients with ICM and100healthy examined people as normal control group were recruited to this study. Patients were randomly divided into two groups:10mg atorvastatin group (n=50) and40mg atorvastatin group (n=50).All subjects were followed up for1year. The levels of serum MMP-9were examined in all subjects.
Results At the end of this study, the levels of MMP-9(F=5.016,P=0.026) significantly decreased in40mg atorvastatin group in contrast to10mg atorvastatin group.
Conclusions40mg atorvastatin might significantly decrease the levels of serum MMP-9in comparison with10mg atorvastatin in patients with ICM.
他汀作为抗动脉粥样硬化药物,能明显降低冠心病患者心血管事件的发生率,已广泛应用于冠心病患者的二级预防,虽然他汀在心力衰竭患者中应用的安全性已被CORONA and UNIVERSE研究所证实,但目前他汀对缺血性心肌病患者(ischemic cardiomyopathy, ICM)心功能的影响尚无定论,小样本、前瞻性临床研究显示,阿托伐他汀及辛伐他汀可改善CHF患者预后。然而,随后一些研究显示,瑞舒伐他汀不能改善缺血性及非缺血性、收缩性HF患者的预后。目前针对他汀治疗HF患者研究结论不一致,部分原因可能是各研究他汀使用种类、剂量、及研究人群不一致。并且,一些临床试验虽然显示他汀可能改善CHF患者左室功能,但其机制目前仍不完全清楚。
目前研究显示,外周血循环EPCs(circulating EPCs, cEPCs)不仅与多种心血管危险因素及血管功能相关,并且能预测冠脉疾病患者未来心血管事件及动脉粥样硬化疾病的进展。近来研究显示,晚期心衰患者cEPCs水平降低,缺血性心肌病Ischemic cardiomyopathy, ICM)患者存在骨髓及外周血祖细胞选择性功能受损。内皮细胞在受到炎症刺激时能释放微颗粒,外周血循环内皮微颗粒(circulating endothelial-derived microparticles, cEMP)水平升高能见于包括冠脉疾病在内的多种病理状态,能反映内皮功能受损及不良的临床预后,稳定细胞膜降低EPMs释放被认为是血管疾病治疗的一个靶点。
基质金属蛋白酶(matrix metalloproteinase, MMP)存在于心肌细胞,能降解所有的心脏基质成分,是心肌基质重塑的推动力量[1-3]。MMP-9能降解凝胶,在左室重塑过程中,MMP-9的重要作用已被多个研究所证实[4-7],MMP-9的缺失能减少心肌梗塞后心室扩大的程度,因此MMP-9可能是心肌梗塞后可供选择的治疗靶点[6,14-16]。
左室肥厚、重塑将导致心肌能量代谢失衡。目前认为,标准心脏多普勒超声检测的心肌能量消耗(Myocardial energy expenditure, MEE)是衡量心肌生物能量消耗的有效指标,并且MEE与充血性心力衰竭患者,特别是与LVEF降低的患者心功能密切相关,既往研究证实,在CHF患者,降低的LVEF与升高的MEE独立相关。
目前很少有研究探讨他汀的降脂外作用及不同剂量他汀对cEPCs、cEPMs、MEE及左室功能的影响,因此本研究拟在ICM患者中比较40mg与10mg阿托伐他汀对cEPCs、cEPMs、MEE及左室功能的影响,并探讨阿托伐他汀对ICM的作用机制。
第一部分40mg与10mmg阿托伐他汀对缺血性心肌病患者oxLDL、hsCRP、外周血循环内皮微颗粒及内皮祖细胞影响的比较
目的比较40mg与10mg阿托伐他汀对ICM患者oxLDL、hsCRP、外周血循cEMPs及cEPCs的影响,并探讨阿托伐他汀对ICM患者可能作用机制。
方法选择2007年3月至2010年6月在我院心内科住院确诊的ICM患者100例,患者随机分为2组：阿托伐他汀(辉瑞)10mg/天治疗组及40mg/天治疗组,同期门诊健康体检者非冠心病100例为对照组。随访期1年,所有研究对象在研究初始及随访结束时两次行肌酶、肝功能、血脂、血清尿酸、oxLDL、hsCRP、外周血cEMPs及cEPCs,并记录两组患者阿托伐他汀不良反应的发生率。
结果随访结束时,10mg/天阿托伐他汀治疗组及对照组均失访3例,40mg/天阿托伐他汀治疗组失访2例,在随访期间,10mg阿托伐他汀治疗组有2例患者因腔隙性牛脑梗塞及3例患者因心功能恶化住院治疗,40mmg阿托伐他汀治疗组有1例患者因腔隙性脑梗塞及2例患者因心功能恶化住院治疗。两研究组间在心血管事件发生率方面差异无显著性。两研究组均无横纹肌溶解症及药物性肝炎的病例出现,40mg阿托伐他汀组不良反应无明显增多；研究前后,两研究组在CK及ALT方面比较,差异均无显著性。研究开始时,两研究组间在血脂、血清oxLDL、hsCRP、BNP、MMP-9、cEMPs、cEPCs、MEE、心功能、纤维蛋白原、尿酸、ALT、CK、高血压、糖尿病、吸烟、体重指数、年龄、性别、家族史、药物及冠脉支架使用方面,差异均无显著性；两研究组在随访期间药物使用方面比较,差异无显著性,P>0.05；两研究组间心脏彩超结果比较,差异无显著性,P>0.05。研究结束时,与10mmg阿托伐他汀治疗组比较,40mg阿托伐他汀治疗组血清TC(F=11.586,P=0.001)、LDL-C(F=7.459,P=0.008) oxLDL(F=16.106,P=0.000)及hsCRP(F=29.497, P=0.000)水平明显降低,差异有显著性；与10mmg阿托伐他汀治疗组比较,40mg阿托伐他汀治疗组外周血cEMPs(F=24.252,P=0.000)水平明显降低,cEPCs(F=4.969,P=0.028)水平明显升高,差异有显著性。
结论对ICM患者,与10mg阿托伐他汀比较,40mmg阿托伐他汀可能降低患者外周血cEMPs及升高外周血cEPCs水平,阿托伐他汀可能有降脂外的作用。
第二部分40mg与10mg阿托伐他汀对缺血性心肌病患者心肌能量消耗及左室功能影响的比较
目的比较40mg与10mg阿托伐他汀对ICM患者心肌能量消耗(Myocardial energy expenditure, MEE)及左室功能的影响,并探讨阿托伐他汀在ICM中的作用机制。
方法选择2007年3月至2010年6月在我院心内科住院确诊的ICM患者100例,患者随机分为2组：阿托伐他汀(辉瑞)10mg/天治疗组及40mg/天治疗组,同期门诊健康体检者非冠心病100例为对照组。随访期1年,所有实验对象在研究初始及随访结束时两次行BNP(B-type natriuretic peptide),左室收缩末周向室壁应力(Circumferential end-systolic wall stress, cESS), MEE、E/E'及心脏彩超检测。
结果研究结束时,两研究组间在LVMI(F=3.014,P=0.390)方面差异无显著性,但与10mg阿托伐他汀治疗组比较,40mg阿托伐他汀治疗组LVMI有所降低；与10mg阿托伐他汀治疗组比较,40mg阿托伐他汀治疗组MEE(F=5.319,P=0.023)水平明显降低,差异有显著性；与10mg阿托伐他汀治疗组比较,40mg阿托伐他汀治疗组血清BNP水平(F=4.845,P=0.032)及E/E’(F=10.330,P=0.002)明显降低,差异有显著性；两研究组间在LVEF(F=0.385,P=0.536)方面比较,差异无显著性。
结论对ICM患者,与10mg阿托伐他汀比较,40mg阿托伐他汀可能降低患者MEE及E/E'水平,阿托伐他汀可能有降脂外的作用。
第三部分40mg与10mg阿托伐他汀对缺血性心肌病患者血清基质金属蛋白酶-9水平影响的比较
目的比较40mmg与10mmg阿托伐他汀对ICM患者血清基质金属蛋白酶-9(MMP-9)水平影响,并探讨阿托伐他汀在ICM中的作用机制。
方法选择2007年3月至2010年6月在我院心内科住院确诊的ICM患者100例,患者随机分为2组：阿托伐他汀(辉瑞)10mg/天治疗组及40mg/天治疗组,同期门诊健康体检者非冠心病100例为对照组。随访期1年,所有研究对象在研究初始及随访结束时两次行血清MMP-9检测。
结果研究结束时,与10mg阿托伐他汀治疗组比较,40mmg阿托伐他汀治疗组血清MMP-9(F=5.016,P=0.026)水平明显降低,差异有显著性。
结论对ICM患者,与10mg阿托伐他汀比较,40mg阿托伐他汀可能降低患者血清MMP-9水平。
Background
Statins, serving as an anti-atherosclerosis drug, can significantly decrease the rates of cardiovascular events in patients with coronary heart disease (CHD), and were extensively administrated in secondary prevention of CHD. At present, consensus on the possible effects of statins on cardiac function in patients with ischemic cardiomyopathy(ICM) have not been achieved, although the safety of statins in patients with heart failure has been demonstrated by the CORONA and UNIVERSE trials. Small prospective clinical studies using atorvastatin and simvastatin for systolic heart failure (HF) have suggested that statins could be beneficial in patients with congestive heart failure(CHF) Conversely, subsequent studies indicated that rosuvastatin couldn't improve the prognosis in patients with ischemic or nonischemic, systolic HF. The incomplete agreement existing on the role of statins in HF may in part be due to the different class and dose of statins administration and different race in these studies. Several clinical trials administrating statins for CHF have documented an improved LV function, but the mechanisms in patients with CHF are still not completely known.
At present, the level of circulating EPCs(cEPCs) not only correlates with cumulative cardiovascular risk and vascular function7, but also predicts future cardiovascular events and atherosclerotic disease progression in patients with coronary artery disease (CAD). Recently, advanced stages of heart failure were shown to be associated with reduced levels of cEPCs. Study showed ICM was associated with selective impairment of progenitor cell function in the bone marrow and in the peripheral blood.
Endothelial cells could release microparticles after inflammatory stimulation, and 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. Currently, stabilizing cellular membranes to decrease the release of EPMs was considered a target of vascular therapy.
Matrix metalloproteinase(MMPs), which are present in the myocardium and capable of degrading all the matrix components of the heart, are the driving force behind myocardial matrix remodeling. MMP-9is well-known for its ability to degrade gelatins. The particular importance of MMP-9activity during LV remodeling has recently been demonstrated in several studies. Furthermore, MMP-9may be one of the candidates for selective inhibition after myocardial infarction(MI), because the deficiency in MMP-9alone could reduce LV chamber enlargement after infarction.
LV hypertrophy, remodeling would lead to myocardial energy metabolic imbalance. In present, myocardial energy expenditure (MEE) derived from standard echocardiographic measurements was regarded as an effective indicator for myocardial bioenergetics and significantly correlated with cardiac function in CHF patients, especially in CHF patients with reduced LV ejection fraction(LVEF). Previous study demonstrated depressed EF was independently associated with higher MEE and increased MEE could predict cardiac death.
However, currently, there were few data to delineate the effect of different doses statins on cEPCs and cEPMs. Thus, the present study was designed to investigate the differences of40mg versus10mg atorvastatin on cEPCs, cEMPs, MEE and LV function in patients with ICM.
Part one Comparison of40mg versus10mg atorvastatin on oxLDL, hsCRP, circulating endothelial-derived microparticles and endothelial progenitor cells in patients with ischemic cardiomyopathy
Objective This study was designed to investigate the differences of40mg versus lOmg atorvastatin on oxLDL, hsCRP, circulating endothelial-derived microparticles(EMPs) and endothelial progenitor cells(EPCs) in patients with ischemic cardiomyopathy (ICM).
Methods100patients with ICM and100healthy examined people as normal control group were recruited to this study. Patients were randomly divided into two groups:10mg atorvastatin group (n=50) and40mg atorvastatin group (n=50).All subjects were followed up for1year. The levels of serum lipids, oxLDL, hsCRP, circulating EPCs and EMPs were examined in all subjects. The incidences of adverse reactions in two study groups were taken down.
Results3,2and3patients withdrew in lOmg atorvastatin group,40mg atorvastatin group and control group respectively because of moving to other provinces. The incidences of cardiovascular events in10mg atorvastatin group and in40mg atorvastatin group were10.6%(5/47) and6.25%(3/48) during the period of follow-up. There were no significant differences in the rates of cardiovascular events between the two study groups. There was no rhabdomyolysis and drug-induced hepatitis in the two study groups during the follow-up. No excessive episodes of adverse reactions occurred in the40mg atorvastatin group. Subjects did not differ in CK and ALT between the two study groups at the end of study.Subjects did not differ in lipids, oxLDL, hsCRP, cEMPs, cEPCs, MEE, cardiac function, CK, ALT, fibrinogen, urine acid, age, gender, family medical history, index weight, number with hypertension, number with diabetes, number ever smoking, drugs, echocardiographic indices and the rate of stent implanted between the two study groups. At the end of the study, the levels of serum TC(F=11.586,P=0.001), LDL(F=7.459,P=0.008), oxLDL(F=l6.106,P=0.000) and hsCRP(F=29.497,P=0.000) significantly decreased in40mg atorvastatin group in contrast to1Omg atorvastatin group. At the end of the study, the levels of cEMPs(F=24.252,P=0.000) significantly decreased but the levels of cEPCs(F=4.969,P=0.028)significantly increased in40mg atorvastatin group in contrast to10mg atorvastatin group.
Conclusions40mg atorvastatin might decrease the levels of circulating EMPs and increase the number of circulating EPCs in patients with ICM in comparison with lOmg atorvastatin. Furthermore, atorvastatin might have the beyond lipids-decreased effects.
Part two Comparison of40mg versus10mg atorvastatin on myocardial energy expenditure level and left ventricular function in patients with ischemic cardiomyopathy
Objectives The present study was to investigate the differences of40mg versus10mg atorvastatin on myocardial energy expenditure (MEE) and E/E' in patients with ischemic cardiomyopathy (ICM).
Methods100patients with ICM and100healthy examined people as normal control group were recruited to this study. Patients were randomly divided into two groups:10mg atorvastatin group (n=50) and40mg atorvastatin group (n=50).All subjects were followed up for1year. The levels of B-type natriuretic peptide(BNP), circumferential end-systolic wall stress(cESS), MEE, E/E' and echocardiography were examined in all subjects.
Results At the end of this study, the decrease in LVMI(F=3.014,P=0.390)was observed in40mg atorvastatin group in contrast to10mg atorvastatin group although there were no significant differences between the two study groups. At the end of the study, the levels of MEE (F=5.319,P=0.023)significantly decreased in40mg atorvastatin group in contrast to10mg atorvastatin group.At the end of the study, the levels of serum BNP(F=4.845,P=0.032)and E/E'(F=10.330,P=0.002) significantly decreased in40mg atorvastatin group in contrast to10mg atorvastatin group,P<0.05. Subjects did not differ in LVEF(F=0.385,P=0.536) between the two study groups at the end of the study.
Conclusions40mg atorvastatin might significantly decrease the levels of MEE and E/E'obtained from Doppler echocardiography in comparison with10mg atorvastatin in patients with ICM. Moreover the effect might be independent of the decrease of lipids.
Part three Comparison of40mg versus10mg atorvastatin on the levels of serum matrix metalloproteinase-9in patients with ischemic cardiomyopathy
Objectives The present study was to investigate differences of40mg versus10mg atorvastatin on the levels of serum matrix metalloproteinase-9(MMP-9) in patients with ischemic cardiomyopathy (ICM).
Methods100patients with ICM and100healthy examined people as normal control group were recruited to this study. Patients were randomly divided into two groups:10mg atorvastatin group (n=50) and40mg atorvastatin group (n=50).All subjects were followed up for1year. The levels of serum MMP-9were examined in all subjects.
Results At the end of this study, the levels of MMP-9(F=5.016,P=0.026) significantly decreased in40mg atorvastatin group in contrast to10mg atorvastatin group.
Conclusions40mg atorvastatin might significantly decrease the levels of serum MMP-9in comparison with10mg atorvastatin in patients with ICM.
引文
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