【作者】 尹晨；

【导师】 刘苏；

【作者基本信息】 河北医科大学 ， 外科学， 2012， 硕士

【摘要】 目的：观察和分析单独的大剂量辛伐他汀药物在临床中对治疗肺动脉高压的作用及效果。肺动脉高压(pulmonary arterial hypertension, PAH)是一种合并于其他心肺血管疾病（如先天性心脏病、风湿性心脏病、冠心病以及慢性阻塞性肺疾病COPD等）的恶性并发症，约70%的患者集中于年轻人群中，并最终死于难以纠正的右心衰竭。尤其对于需要进行手术治疗的心脏病合并肺动脉高压的患者，围手术期的死亡率和住院时间明显高于非合并肺动脉高压者。肺动脉高压病理学机制复杂，涉及包括骨态样蛋白受体-Ⅱ（BMPR-II）、 Activin样激酶型-1、5-羟色胺转运因子（5-HTT）的遗传机制，以及前列环素、内皮素、内皮细胞功能异常、一氧化氮（NO）通路、5-羟色胺（5-HT）、炎症、血栓等改变的分子细胞机制。经过多年的研究，近年PAH治疗有了极大进展，包括基础治疗、针对发病机制的新型药物治疗、介入及外科手术治疗以及其他治疗。临床上治疗肺动脉高压的药物和方法包括一氧化氮（NO）的吸入、前列环素（依前列素、前列素E1、贝前列环素）、磷酸二酯酶抑制剂（西地那非）、内皮素受体拮抗剂（波生坦）等。最新近的研究还包括血管活性肠肽，对血小板活化和平滑肌细胞增殖的抑制，并表现出显著地肺血管扩张作用。与此同时，生长因子的抑制因子也是新的抗肺动脉高压研究方向之一。基因治疗仍处于研究启蒙阶段，可能成为有效控制PAH以此带来广泛的治疗前景-将PAH小鼠模型的内皮素前体细胞转染一氧化氮合酶，使PAH小鼠的右室压力降低、生存时间延长。总之，肺动脉高压治疗研究进展发展较快，临床医师在治疗用药中应考虑各方面因素，包括心肺血流动力学、有无心衰及药物相互间作用与不良反应。病人心肺功能分级量化对选择药物及药物疗效也有重要影响。但是，上述的药物和治疗方法都存在较严重的副作用及明显的经济因素。他汀类药物是一种羟甲基戊二酰辅酶A（HMG-CoA）还原酶的抑制剂，其通过对内源性胆固醇合成限速酶(HMG-CoA)还原酶竞争性的抑制来阻断细胞内羟甲基戊酸的代谢，使细胞内胆固醇的合成减少，亦反馈性的刺激细胞膜表面(主要为肝细胞)低密度脂蛋白(low densitylipoprotein，LDL)受体数量和活性增加、使血清胆固醇清除增加、水平降低。他汀类药物还可以抑制肝细胞合成载脂蛋白B-100，减少富含甘油三酯及脂蛋白的合成和分泌，是目前最为有效和最经典的降脂药物，并广泛的应用于临床高脂血症的治疗。近年对他汀类药物的研究发现，这类药物更具有独立于降脂作用的多重心血管保护作用，其剂量依赖性的抑制平滑肌细胞迁移和增殖以及血小板性血栓形成，可浓度依赖性地使一氧化氮合成酶（nitricoxide synthase，NOS）表达上调，逆转肺血管重构，还具有抗炎、抗氧化、稳定斑块、减少神经内分泌的激活、抗凝、抗血小板、改善血管内皮功能和抑制血管内皮炎症等作用。近年来国内外的临床研究表现出他汀类药物的多重心血管保护作用，包括他汀类药物和西地那非的联合临床观察。更从副作用、治疗方法方式和价格上都较目前临床现有的治疗方法有其优越性。本实验预从他汀类药物单独的对肺动脉高压作用进行临床观察，以得到新的研究结果和对PAH的治疗方法。方法：选择50例临床上已经确诊的先天性心脏病合并肺动脉高压的，年龄≥17周岁，未应用过他汀类药物的术前患者为研究对象，给予辛伐他汀（舒降之，默沙东公司，规格40mg/片）80mg/日连续应用一周，观察处理前后平均肺动脉压力（mPAP）、动脉血氧分压（PaO2）、动脉血氧饱和度（SaO2）、右室收缩末期内径（RVSD）、右室前壁厚度（RVAW）及主肺动脉内径（PA），同时监测肝功能的变化情况。肺动脉压力应用心脏超声测量，动脉血气分析应用大型血气分析仪测量。采用SPSS13.0统计软件，各结果以xˉ±s表示，组间比较应用独立样本t检验，试验前后结果应用配对t检验，P＜0.05为差异有统计学意义。结果：从总体数据来看，被观察对象经过一周的用药处理前后肺动脉平均压力（mPAP）、动脉血氧分压（PaO2）及动脉血氧饱和度（SaO2）变化幅度均较小，在50例受试者中主要观察指标mPAP处理前为（33.63±7.924）mmHg，处理后为（33.35±7.851）mmHg；PaO2处理前为（91.75±8.126）mmHg，处理后为（92.53±6.762）mmHg；SaO2处理前为（96.10±2.587）mmHg，处理后为（92.53±2.082）mmHg，并没有得到大幅的变化，而实际数值中约有26%的患者mPAP没有任何改变，更有14%的患者mPAP没有被降低反而出现小幅度升高；在PaO2的观察数据中亦有20%者没有发生改变；而对SaO2来说这种数据所占的比例更大达到30%。但将处理前后数据给予配对t检验后的结果显示四组观察指标的P值均小于0.05，存在统计学意义（结果详细见附表）。但在预实验阶段，在对右室收缩末期内径（RVSD）、右室前壁厚度（RVAW）及主肺动脉内径（PA）的观察中发现上述三项指标没有出现改变，所以在后期的临床试验观察中未再进一步统计，其中所导致的结果可能与药物作用时间有直接的相关性。如想得到辛伐他汀是否与RVSD、RVAW和PA存在相关性仍需要延长临床观察时间。对患者病种的分析中，因为房间隔缺损和室间隔缺损所造成的肺动脉高压的血流动力学存在明显的差别，本实验只进行了病种自身的比较，亦未进行病种之间药物作用效果的对比。结论：单独的辛伐他汀针对临床中先天性心脏病合并的肺动脉高压的治疗存在一定作用，由于观察时间较短部分受试对象的部分观察指标并没有得到改善。另外也证明了辛伐他汀在需要迅速降低肺动脉高压的患者中并不能提倡应用，辛伐他汀可能作为轻中度肺动脉高压患者的一种长期治疗方案，或作为更有效的降肺动脉压力药物的辅助用药。更多还原

【Abstract】 Objective: Observe and analyse the role and effect of the individually largesimvastatin drug to cure pulmonary arterial hypertension in clinical.Pulmonary arterial hypertension (PAH) is a malignant complication mergedin some cardiovascular diseases such as congenital heart disease, rheumaticheart disease, coronary heart disease and chronic obstructive pulmonarydisease (COPD), etc. About70%of the patients focus on young people anddied of the hardly corrected right heart failure finally. Especially the patientsof cardiac disease merged pulmonary hypertension who need the surgicaltreatment, the mortality of the peroperative and hospital is obviously higherthan the non pulmonary hypertension patients. The pathology mechanism ofthe PAH is complex, involve the change of molecylar and cellular mechanismincluding the Bone state kind protein receptors-II (BMPR-II), the Activinsample kinase type-1,5-serotonin transporter factor (5-HTT) geneticmechanism and Prostacyclin, Endothelin, Endothelial function abnormal,Nitric oxide access,5-Hydroxytryptamine(5-HT), inflammation, blood clots orelse. After years’ research, there have been significant progress abouttreatment of the PAH in recent years, including basic therapy, new drugstherapy according to the pathogenesis, intervention cure,surgery and others.The drugs and methods for clinical therapy of the pulmonary arterialhypertension include nitric oxide (NO) of inhaled, Prostacycline (Epopros-tenol, Prostaglandin E1, Beraprost), Phosphodiesterase inhibitors (SildenafilCitrate), Endothelin receptor antagonists (Bosentan),etc. The latest researchesinclude vascular active bowel peptide which could inhibite platelet activationand smooth muscle cells’ proliferation and show a significantly expandfunction to the pulmonary vascular. At the same time, the growth factors’ inhibitory factor is a new research direction which resists the pulmonaryarterial hypertension. The Gene therapy still at the research of enlighteningstage, it may become an effective treatment which could control the PAH andbring an extensive prospect. Meanwhile the endothelin of progenitor cells ofthe PAH mouse model transfects nitric oxide synthase, made the PAH mices’right ventricular pressure reduced and the survival time to extend. In a word,the research development of treatment of the pulmonary arterial hypertensionis faster. The clinical doctors should consider various factors in the drugs’treatment include the cardiopulmonary hemodynamics, with or without heartfailure, drugs interactions and adverse reactions. The patient’s heart-lungfunction classification is important to choose drugs and evaluate the effect ofmedicines. But these drugs and treatment methods have more serious sideeffects and obvious economic factors. Statins is a HMG-CoA reductaseinhibitors. It through to endogenous cholesterol synthesis speed limit enzyme(HMG-CoA) reduction enzyme inhibition of competitive to block cell methyleacid is metabolism, so that the synthesis of cholesterol in cells reduce, also thestimulation of feedback on the cell membrane surface which of mainly for theliver cell, low density lipoprotein (low density lipoprotein, LDL) receptornumber and activity increase, make serum cholesterol levels drop, increase ofclear. Statins can also hold-up the liver cell synthesis apolipoprotein B-100,reduce the rich in triglyceride and lipoprotein synthesis and secretion, it is themost effective and most classic cholesterol drugs and widely used in clinicalhyperlipidemia treatment. In recent years, about the statins’s researches foundthat the drugs are more independent of cholesterol in the role of the multiplecardiovascular protective effect, it could inhibite smooth muscle cellproliferation and migration and platelet sex thrombosis with dose dependent. Itcould activate the nitric oxide synthase (NOS) with concentration dependenceand down-regulate reversal pulmonary vascular reconstruction, but also it hasanti-inflammatory, resistance to oxidation stability, patch, reduceneuroendocrine activation, anticoagulation, antiplatelet, improve endothelialfunction and inhibit endothelial function inflammation. At home and abroad clinical studies have showed statins with multiple cardiovascular protectiveeffect in recent years, include statins and sildenafil united clinical observations.It has advantages on side effects which to cure and price compared tocurrently existed clinical treatments. The experiment get the new researchresults and the treatment method to cure the PAH from clinical observations ofthe statins on pulmonary hypertension alone.Methods: The research objects were50cases diagnosed congenital heartdisease with pulmonary hypertension in clinical, older than17years, not usedstatins preoperative. Simvastatin (comfortable drop, Merck company,40mg/specification of)80mg/day application for a week, mean PulmonaryArtery Pressure (mPAP), Artery blood oxygen partial pressure (PaO2), Bloodoxygen saturation (SaO2), Right ventricular end systolic diameter (RVSD),Right ventricular anterior wall (RVAW) and Pulmonary artery diameter(PA)were observed before and after processing. At the same time the change of theliver function was monitored. The Pulmonary artery pressure use heartultrasound measurement, the arterial blood gas analysis apply the large bloodgas analyze measurement. The statistical software SPSS13.0, each sets’ resultsshowed by xˉ±s. Need the independent sample t-test to contrast betweengroups which of the disease types. Before and after test result applies thematching t test, when the P＜0.05is the discrepancy which shows thestatistical significance. But in the experimental stage, we make the observationwhich are the right ventricular end-diastolic inner diameter(RVSD), the rightventricular wall (RVAW) and the main pulmonary artery (PA) diameter tohave no change. So it has not further statistics in later of the clinical trialobservation. These may have a direct correlation about the time that the drugaffect. We need more time of the clinical trial observation if we want to takethe correlation between the simvastatin and the RVSD, RVAW and PAwhether or not. On the analysis of the disease types in patients, because theyhave obviously different factors which cause the pulmonary hypertension inthe haemodynamics between the atrial septal defect (ASD) and ventricularseptal defect(VSD). The experiment of us only made the comparative of the disease variety itself, we did’t have the consequence of the drug’s effectcontrast between the twoes.Results: From the overall data,changes of mean Pulmonary Artery Pressure(mPAP), Artery blood oxygen partial pressure (PaO2), and Blood oxygensaturation (SaO2) were smaller range after a week drug used before and aftertreatment.The primary outcome of the participants’(50cases) mPAP(33.63±7.924mmHg) before treatment and (33.35±7.851mmHg) after cure,PaO2(91.75±8.126mmHg) before and after is (92.53±6.762mmHg), SaO2(96.10±2.587mmHg) before cure and after is (92.53±2.082mmHg), there wasno dramatical change. While values about26%of patients’ mPAP had almostno change actually. More than14%of patients’ mPAP did not reduce but risedsmall. About20%of patients’ PaO2also had not change, and that was morefor SaO2about30%. But matching t test results before and after processingshowed that the observation index of four groups P-value was less than0.05,and there was statistical significance (The result detailed to see the forms).Conclusion: Simvastatin separated to the clinical congenital heart diseasecombined of pulmonary hypertension treatment exists certain effect. Becauseobservation was in a relatively short time test, the outcome part of subjectswas no perfect. Another proof could’t advocate applications of simvastatin inpatients who need to be reduced pulmonary hypertension quickly. Andsimvastatin can be used to patients with mild-moderate donor pulmonaryarterial hypertension as a long-term treatment, or a more effective lowpulmonary artery pressure drug as an auxiliary one.更多还原