【作者】 符韶鹏；

【导师】 胡盛寿； 周建业； 郑哲；

【作者基本信息】 中国协和医科大学 ， 心血管外科， 2009， 博士

【摘要】 第一部分表面涂层提高左心辅助装置血液相容性的基础研究左室辅助装置(Left ventricle assist device,LVAD)在临床上应用多年,取得了显著的疗效,但仍然有很多待解决的问题,其主要的危险事件包括感染、出血、血栓栓塞、神经系统并发症、泵失灵等,其中血栓栓塞是一种严重并发症,发生率最高可达30%以上。因此解决左心辅助装置的抗凝问题是当务之急。结构改进、计算流体设计、新材料应用是解决这个问题的三个有效途径。而表面涂层改性在不改变材料形状的同时能改变材料的表面特性,本研究就是从表面涂层改性入于做了两方面内容,一是评价氮化锆(ZrN)涂层的血液相容性,二是比较三种涂层材料的血液相容性。氮化锆是一种新的涂层技术在工业方面应用较多,具备坚固、耐磨损、耐腐蚀的特点,而且在口腔科的应用表现出抗菌、组织相容性佳的特点。这些特点都符合用于左心辅助装置的要求,然而其血液相容性目前尚不知晓,故本文评价了其血液相容性以探讨其在左心辅助装置中应用的可行性。2-Methacryloyloxyethylphosphorylcholine(MPC)也是一种新的涂层材料,医学领域应用较广泛,本文以钻石样碳膜(DLC)和氧化钛膜(TiO)两种已知的能有效改善抗凝特性的涂层材料为对照,评价MPC在左心辅助装置的应用前景。本研究通过体外和体内植入来测试ZrN涂层血液相容性,以氮化钛涂层做为对照材料。体外测试包括蛋白吸附、血小板粘附、动态凝血时间测定等;体内测试将材料植入狗的右心房观察血栓形成情况。并通过材料表面特征检测、接触角的测量、表面能的计算来进一步分析其机制。体外测试结果显示,ZrN涂层对纤维蛋白原吸附更少、粘附的血小板更少、动态凝血时间更长;体内植入狗的右心房10日后未发现肉眼血栓。这些结果表明ZrN涂层具备良好的血液相容性。通过表面能和界面能的计算表明其良好的血液相容性与其较低的界面能有关。三种材料的对比测试中,体外测试结果显示,MPC吸收的纤维蛋白原最少、粘附的血小板最少、具备最长的动态凝血时间;体内植入狗的右心房15日后MPC表面无血栓形成。这些结果表明MPC材料具备最好的血液相容性。而DLC和TiO涂层也能提高钛合金材料的血液相容性。结论:与TiN涂层相比,ZrN涂层表现出更好的血液相容性,这与其较低的界面能有关;MPC涂层显示出优于DLC和TiO涂层的血液相容性。本研究结果表明ZrN涂层和MPC涂层可能成为用于左心辅助装置的新涂层材料,为进一步的实际应用打下了基础。第二部分提高女性冠脉旁路移植术疗效的注册登记研究目的:不停跳冠脉旁路移植术(off-pump)正有挑战传统的冠脉搭桥手术(on-pump)地位之势。大多数研究结果表明off-pump技术的近期效果要优于on-pump技术,尤其是对于那些重症、高危的患者。而女性患者的手术死亡率通常要高于男性,分析其原因主要是由于女性术前的病情要比男性要重,高危因素较多,已有的研究表明off-pump技术使女性在围术期更多的获益,但我们并不清楚其远期效果。故本研究的目的是观察off-pump技术是否能使女性在远期疗效方面受益。方法:我们对阜外医院1999-2005年5359例行单纯冠脉搭桥手术的病人进行了研究,早期观察终点为院内死亡,统计方法采用logistic回归分析。长期随访研究5288人,平均随访57.96±23.46个月。观察的终点事件包括全因死亡和MACCE事件(包括心源性死亡、主要的心血管事件和脑血管事件)。统计方法采用Cox回归模型,并进行了Propensity scores倾向评分,研究了冠脉搭桥的手术方式和性别是否是影响患者远期预后的因素。结果:对于基线水平的分析表明女性患者年龄更高,有更高的二尖瓣返流、高血压、高血脂、糖尿病的发生率,术中更多的输血,而完全再血管化指数(搭桥支数/冠脉病变支数,ICOR)则要显著低于男性(1.1859:1.2454,P＜0.0001),而且女性应用off-pump的病人其ICOR还要低于on-pump的病人(1.0544:1.2962,P＜0.0001)。女性早期死亡率明显高于男性(矫正后的OR值为2.285;p=0.0037),off-pump使女性受益更多,在off-pump组,男女死亡风险无统计学差异(OR=1.914,P=0.1562)。而在on-pump组,女性死亡风险是男性的2.572倍(P=0.0110)。远期随访结果,以全因死亡为观察终点事件,在off-pump组和on-pump组女性远期死亡的风险分别是男性的0.642倍(P=0.1876)和0.823倍(P=0.4239),但无统计学差异。这表明无论是男性还是女性off-pump和on-pump获得了同样的远期生存率。然而在以MACCE事件为观察终点事件的时候我们有了新的发现。在on-pump组,女性远期发生MACCE事件的风险与男性一致(HR=1.085,P=0.4569);但在off-pump组,女性则倾向于发生更多的MACCE事件,是男性的1.297倍(P=0.0364),具有统计学意义。这表明off-pump技术在远期给女性带来了更多的MACCE事件。结论:尽管以往的研究表明off-pump技术使女性在早期更多的受益,而且我们的研究也发现off-pump并不增加晚期的死亡率,但这并不意味着可以对女性患者采用更多的off-pump技术。因为我们对晚期MACCE事件的观察表明off-pump给女性带来了更多的不良事件发生率,其主要原因可能是由于过低的再血管化率。因此我们对女性患者行搭桥手术的时候要慎重选择术式,并应进行更多的研究去甄别出哪些亚组更适于采用off-pump技术。更多还原

【Abstract】 Long-term and short-term support with a left ventricular assist device resulted in substantial improvement in survival in patients with severe heart failure.Despite the substantial survival benefit,the morbidity and mortality associated with the use of the left ventricular assist device were considerable.The adverse events such as infection,bleeding, thromboembolic events,stroke,mechanical failure,etc.remain major challenges for left ventricular assist device that are used in contact with blood.In particular,bleeding and thromboembolic events were major factors in the early survival rate of patients.The rate of thromboembolic events was more than 30%percent in the early reports.Therefore,there is still a great need for improving hemocompatibility of left ventricular assist device.Surface modification is a very effective way to improve blood compatibility of a material as well as maintain its required bulk properties. The surface modification for improving blood compatibility is the direction of the present research.The aim of the present investigation was to evaluate whether ZrN films show sufficient hemocompatibility,and to find out which kind of material is the most effective surface mofidication among Titanium oxide films（TiO）,diamond-like carbon（DLC） and 2-Methacryloyloxyethyl phosphorylcholine（MPC）.Because of their biocompatibility and extremely wear resistant,zirconium nitride（ZrN） films are usually used for industrial products and dental implants.Previous in vitro studies have shown that Ti implant surfaces coated with TiN or ZrN reduce bacterial colonization compared with other clinically used implant surfaces.All above characters of ZrN films indicate their suitability as materials for implants and biomedical devices with direct blood contact,such as blood pumps.The morphology,chemical compound of composition and crystal structure were characterized by scanning electron microscopy（SEM）,X-ray diffraction（XRD） and X-ray photoelectron spectroscopy（XPS）.Surface energy and interface tension were calculated by contact angle measurements.Comprehensive evaluation of the hemocompatibility of ZrN films included clotting time,platelet adhesion and activation,protein adsorption,and in vivo experiment.The adsorption of fibrinogen to the surface was assessed using Iodo-Gen method labeling with ¹²⁵I,whereas,platelet attachment was studied by SEM and quantified using stereological techniques.Titanium nitride（TiN） coating on the same substrates was adopted as reference material for comparison.In vitro and in vivo experiments proved that ZrN films have excellent hemocompatibility. Interface tension of ZrN with blood and plasma proteins was significantly lower than that of TiN.DLC,Tio and MPC are very effective surface modification to improve blood compatibility of a material.However,no imformation could be obtained about their comparative study.The aim of the present investigation was to find out which kind of material is the most effective surface mofidication among TiO,DLC and MPC.Comparative evaluation of the hemocompatibility of three kinds of film included clotting time,platelet adhesion and activation, protein adsorption,and in vivo experiment.In vitro and in vivo experiments proved that MPC films have excellent hemocompatibility,and DLC,TiO film show sufficient hemocompatibility,too.Conclusion:ZrN,DLC,TiO,MPC all show sufficient hemocompatibility.It is suggested that the significantly lower interface tension between ZrN films and plasma proteins give them their improved hemocompatibility.Among the three kinds of films,MPC film offer hemocompatibility significantly superior to that of DLC and TiO films.The results of the present study provide the basic imfromation for the future’ s use of surface modification for improving hemocompatibility of left ventricle assist device. Background:Off-pump coronary artery bypass graft surgery（OPCAB） is associated with lower early mortality and benefits women disproportionately. The objective of this study was to assess the impact of off-pump techniques on sex differences in late outcomes.Methods:We reviewed a clinical database of consecutive patients who underwent isolated coronary artery bypass graft surgery（CABG） at FuWai Hospital from 1999 to 2005.Logistic regression analysis and proportional hazards modeling were used to investigate whether sex or surgery type were associated with early mortality and late outcomes（mortality,major cardiac and cerebral event）.Results:Female sex was associated with higher rates of early death （adjusted odds ratio,2.285;p=0.0037）,and OPCAB benefited women disproportionately for early mortality.Odds ratio of death for women versus men was 2.572（p=0.0110） in the conventional CABG on cardiopulmonary bypass group;odds ratio of death for women versus men was 1.914（p=0.1562） in the OPCAB group.Analysis of late outcomes indicated that OPCAB and cardiopulmonary bypass resulted in similar survival,regardless of sex.The women versus men hazard ratio of late mortality after CABG on cardiopulmonary bypass and OPCAB for women was 0.823（p=0.4239） and 0.642（p=0.1876）, respectively.Women treated with OPCAB were less likely to be free from major cardiac and cerebral events than men treated with OPCAB.The women versus men hazard ratio of major cardiac and cerebral events after CABG on cardiopulmonary bypass and OPCAB for women was 1.085（p=0.4569） and 1.297 （p=0.0364）,respectively.Conclusions:Compared with men,women are a highrisk group and benefit from off-pump operation in terms of early mortality after CABG.Conversely, during follow-up,women have high adjusted risks of major cardiac and cerebral events after OPCAB.更多还原