Increased Levels of 25 Hydroxyvitamin D and 1,25-Dihydroxyvitamin D After Rosuvastatin Treatment: A Novel Pleiotropic Effect of Statins?

Objectives  Low levels of 25-hydroxyvitamin D are associated with higher risk of cardiovascular morbidity and mortality. Large trials demonstrated that statins significantly decrease cardiovascular morbidity and mortality. 7-dehydrocholesterol is the precursor of both cholesterol and vitamin D. The aim of this study was to investigate the possible effect of rosuvastatin on vitamin D metabolism. Methods  The study was performed in a prospective cohort design. The study group consisted of 91 hyperlipidemic patients who had not been treated with lipid lowering medications. Lipid parameters, 25 hydroxyvitamin-D, 1,25-dihydroxyvitamin D, and bone alkaline phosphatase were obtained at baseline and after 8 weeks of rosuvastatin treatment. Results  None of the subjects withdrew from the study because of the adverse effects. The mean age was 59.9 ± 12.5 years. The majority of the patients were male (55, 60%). Seventeen patients were diabetic, and 43 patients had systemic hypertension. There was a significant increase in 25-hydroxyvitamin D, from mean 14.0 (range 3.7– 67) to mean 36.3 (range 3.8 –117) ng/ml (p < 0.001), and also an increase of 1,25-dihydroxyvitamin D from mean 22.9 ± 11.2 to 26.6 ± 9.3 pg/dl (p = 0.023). Bone alkaline phosphatase decreased after 8 weeks of rosuvastatin treatment, mean 17.7 (range 2.6–214) to mean 9.5 (range 2.3–19.1) u/l (p < 0.001) rosuvastatin treatment. Conclusion  This study has shown an effect of rosuvastatin on vitamin D metabolism, with an increase in both 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D. This may be an important pleiotropic effect whereby rosuvastatin reduces mortality in patients with coronary artery disease. Further studies are needed to clarify the relationship between statins and vitamin D metabolism.     

Rosuvastatin prevents endothelial cell death and reduces atherosclerotic lesion formation in ApoE-deficient mice

Accumulating evidence suggests that statins have beneficial effects which are independent of their lipid-lowering actions, on vascular cells. Here, we investigated whether the HMG-CoA reductase inhibitor rosuvastatin can inhibit atherosclerotic lesion development with favorable effects on endothelial cells in ApoE-deficient mice. Rosuvastatin rapidly phosphorylated Akt and endothelial nitric oxide synthase (eNOS) in human endothelial cells. Endothelial cell death induced by serum starvation was significantly inhibited by rosuvastatin (percent cell death; 45.9 ± 2.4% vs. 37.3 ± 1.1%, p < 0.05). Eight-week-old ApoE-deficient mice were orally administered vehicle or rosuvastatin at a dose of 20 mg/kg/day for 24 weeks. There was no significant difference in cholesterol profile. Rosuvastatin preserved endothelial lining at the aortic root (CD31-positive luminal side; 63.8 ± 2.8% vs. 81.7 ± 3.9%, p < 0.05). En face Sudan IV staining of aorta revealed that rosuvastatin significantly decreased the atherosclerotic area (21.9 ± 2.9% vs. 11.9 ± 1.9%, p < 0.05). Lipid deposition at the atherosclerotic area was also suppressed by rosuvastatin with more stabilized morphologic features as determined by oil red O staining (3.4 ± 0.4% vs. 1.7 ± 0.4%, p < 0.05). Our findings indicate that rosuvastatin protects endothelial cells from death with phosphorylation of Akt and eNOS. These effects may contribute, at least in part, to the anti-atherosclerotic effects of rosuvastatin.     

经皮冠状动脉介入术前他汀治疗预防围手术期患者心肌梗死效果的Meta分析

目的 系统评价经皮冠状动脉介入术(PCI)术前使用他汀治疗预防围手术期冠心病患者心肌梗死的有效性.方法 计算机检索CNKI、CBM、MEDLINE和The Cochrane Library,收集PCI术前他汀治疗对心血管事件影响的随机对照试验,检索时限均从1990年1月至2011年5月.由2位评价者按照纳入和排除标准筛选文献、提取资料并进行方法学质量评价,然后采用RevMan 5.0软件进行Meta分析.结果 最终纳入10个随机对照试验,共3 012例冠心病患者.Meta分析结果显示:在围手术期,对照组1 498例中有207例发生心肌梗死,他汀治疗组1514例中有98例发生心肌梗死,两组差异有统计学意义[ OR=0.43,95％ CI (0.34,0.56),P＜0.000 01];对照组有226例发生主要心脏不良事件,他汀治疗组103例发生主要心脏不良事件,两组差异有统计学意义[OR=0.41,95％CI (0.32,0.53),P＜ 0.000 01].结论 与安慰剂治疗相比,PCI术前应用他汀类药物可明显降低围手术期冠心病患者心肌梗死发生率和主要心脏不良事件.受纳入研究数量和质量所限,上述结论尚需开展更多高质量大样本研究验证.     

Association of statin use with a pathologic complete response to neoadjuvant chemoradiation for rectal cancer

PURPOSE: To assess whether 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, or statins, might enhance the efficacy of neoadjuvant chemoradiation in rectal cancer. METHODS AND MATERIALS: Between 1996 and 2001, 358 patients with clinically resectable, nonmetastatic rectal cancer underwent surgery at Memorial Sloan-Kettering Cancer Center after neoadjuvant chemoradiation for either locally advanced tumors or low-lying tumors that would require abdominoperineal resection. We excluded 9 patients for radiation therapy dose <45 Gy or if statin use was unknown, leaving 349 evaluable patients. Median radiation therapy dose was 50.4 Gy (range, 45-55.8 Gy), and 308 patients (88%) received 5-fluorouracil-based chemotherapy. Medication use, comorbid illnesses, clinical stage as assessed by digital rectal examination and ultrasound, and type of chemotherapy were analyzed for associations with pathologic complete response (pCR), defined as no microscopic evidence of tumor. Fisher's exact test was used for categoric variables, Mantel-Haenszel test for ordered categoric variables, and logistic regression for multivariate analysis. RESULTS: Thirty-three patients (9%) used a statin, with no differences in clinical stage according to digital rectal examination or ultrasound compared with the other 324 patients. At the time of surgery, 23 nonstatin patients (7%) were found to have metastatic disease, compared with 0% for statin patients. The unadjusted pCR rates with and without statin use were 30% and 17%, respectively (p = 0.10). Variables significant univariately at the p = 0.15 level were entered into a multivariate model, as were nonsteroidal anti-inflammatory drugs (NSAIDs), which were strongly associated with statin use. The odds ratio for statin use on pCR was 4.2 (95% confidence interval, 1.7-12.1; p = 0.003) after adjusting for NSAID use, clinical stage, and type of chemotherapy. CONCLUSION: In multivariate analysis, statin use is associated with an improved pCR rate after neoadjuvant chemoradiation for rectal cancer. The low prevalence of statin use limits the power to detect a significant difference at a type I error threshold of p = 0.05 in this analysis. Although no definitive conclusions can be drawn on the basis of this retrospective study, the unusually high incidence of pCR after chemoradiation suggests that the use of statins in the treatment of rectal cancer warrants further evaluation.     

Genetic Variants Associated With Increased Plasma Levels of Triglycerides,via Effects on the Lipoprotein Lipase Pathway,Increase Risk of Acute Pancreatitis

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中国糖尿病合并动脉粥样硬化性心血管疾病患者他汀类药物的应用现状调查

目的了解中国糖尿病合并动脉粥样硬化性心血管疾病(CVD)患者他汀类药物的应用现状。方法借助1项国际多中心大规模临床试验在中国实施之际,于2007年6～12月在10个城市的39家三级医院对符合标准的高危动脉粥样硬化性CVD患者进行调查,利用电子问卷采集临床资料,对他汀类药物的使用情况进行统计描述和分析。结果调查4429例糖尿病合并动脉粥样硬化性CVD患者,年龄50～80岁,平均(64±8)岁,66.2%为男性,3345例(75.5%)合并冠心病,2053例(46.4%)合并心肌梗死,1976例(44.6%)合并缺血性脑卒中,3181例(71.8%)合并高血压。仅1952例(44.1%)患者在服用他汀类药物,其中1411例(72.3%)患者末在确诊糖尿病后立即开始服用他汀,而451例(23.1%)患者未在确诊CVD后即开始服用他汀。辛伐他汀(20mg≤且40mg)和阿托伐他汀(10mg≤且20mg)为最常用剂量,分别占63.5%(489/770)和61.0%(428/702)。结论目前中国糖尿病合并动脉粥样硬化性CVD患者他汀类药物的使用明显不足,应加强对医师的培训和对患者的健康宣教,努力缩小临床实践与循证医学证据和指南推荐之间的差距。     

他汀类与低分子肝素钙治疗急性冠脉综合征临床疗效观察

目的:观察急性冠脉综合征(ACS)早期应用他汀类与低分子肝素钙治疗的临床疗效。方法:将80例ACS患者按入院顺序分为两组:2002年8月~2003年10月40例设为对照组,给予抗血小板药物,β受体阻滞剂,硝酸酯类、ACEI类治疗。2004年3月~2005年5月40例设为治疗组,在对照组基础上加用他汀类:辛伐他汀20mg,1次/d,抗凝药物:低分子肝素钙(速碧林)5000IU,皮下注射,2次/d。随访6个月,观察两组临床疗效、心电图改变、心血管事件发生情况。结果:加用他汀类与低分子肝素钙治疗ACS,临床症状有效率为87.5%,对照组为57.5%。心电图改善有效率为85%,对照组为62.5%(P<0.05),且随诊6个月中,非致死性心梗、心力衰竭、复发性心绞痛、需再次住院治疗与需做经皮腔内冠脉成形术或冠脉旁路移植术(PTCA/CABG)病例均较对照组明显降低。结论:ACS早期给予他汀类与低分子肝素钙治疗显著提高临床疗效。     

普伐他汀对心力衰竭血浆脑钠素及心功能的研究

目的探讨在慢性心力衰竭患者普伐他汀治疗对血浆脑钠素水平和心功能的影响及其关系。方法56例慢性心力衰竭患者随机分为常规治疗组（26例）和普伐他汀治疗组（30例），剂量为、10rag，每晚1次，疗程8周，测定左室舒张末内径、左室射血分数、血浆BNP浓度和总胆固醇在治疗前后的变化。结果普伐他汀治疗8周后，血浆BNP浓度由（218．6±64．2）pg／mL降至（149．4±50．1）pg／mL（P〈0．01）；LVEF由（34．4±3.4）％升至（45．4±4．9）％（P〈0．05），LVDd由（65．5±5．1）mm降至（45．4±4．9）mm，改善程度明显好于对照组；普伐他汀治疗前后，患者血浆BNP降低值与LVEF增加存在良好的负相关（r=-0．71，P〈0．01），而与LVDd减小呈正相关（r=0．79，P〈0．01）。结论普伐他汀能明显改善慢性心力衰竭患者的血流动力学，抑制神经内分泌的过度激活，改善心功能；血浆BNP可作为评价他汀类药物治疗CHF疗效的监测指标之一。     

洛伐他汀对人肾小球系膜细胞胰岛素样生长因子-1表达的影响

目的：观察HMG-CoA还原酶抑制剂洛伐他汀对人肾小球系膜细胞胰岛素样生长因子-1(IGF-1)表达及纤维连接蛋白、层连蛋白和Ⅳ型胶原分泌的影响。方法：分别于体外低糖(5．6mmol／L)和高糖(30mmol／L)环境中培养人胎肾小球系膜细胞．用RT-PCR法检测系膜细胞IGF-1 mRNA表达水平,用酶免和放免法测定细胞上清液中纤维连接蛋白、层黏连蛋白和Ⅳ型胶原含量。分别在培养液中加入洛伐他汀或／和西拉普利,观察不同刺激时间和药物浓度对上述基质蛋白指标的影响。选择刺激时间48h和刺激浓度10μmol／L,观察单用或联用洛伐他汀和西拉普利对系膜细胞IGF-1 mRNA表达的影响。结果：高糖环境下肾小球系膜细胞过度增殖,细胞上清液中纤维连接蛋白、层黏连蛋白和Ⅳ型胶原含量增加,IGF-1 mRNA表达明显增加。洛伐他汀和西拉普利均可明显抑制系膜细胞增殖,降低细胞上清液中基质蛋白浓度,IGF-1 mRNA表达亦显著下降。洛伐他汀对IGF-1 mRNA表达的抑制作用略强于西拉普利,但两者联用未显示更强的抑制效果。结论：高糖可刺激人肾小球系膜细胞IGF-1高表达,并增加基质蛋白的分泌,洛伐他汀与西拉普利类似,均可一定程度逆转上述现象,提示他汀类药物可能有益于早期糖尿病肾病的防治。