第一部分 他汀类药物在非体外循环下冠状动脉旁路移植术围术期应用效果评价的队列研究

目的：

通过观察OPCAB的患者队列，分析围术期他汀类药物治疗对术后早期桥血管通畅率的影响及对其他临床结局的影响。

方法：

本研究共纳入2009年10月至2012年9月于我院行首次单纯OPCAB的患者共582例，均通过冠脉CT获得早期桥血管通畅率。根据术前、术后是否全程连续服用他汀类药物分为两组，连续服用他汀组（Continuous statin group, CS组）398例，中断他汀组（Discontinuous statin group, DS组）184例。运用倾向性评分（Propensity score, PS）的统计学方法，结合倾向性评分逆概率加权（Inverse probability weighting, IPW），对患者人口学特征、冠脉病变情况、术前血脂水平、心功能等相关因素进行逆概率加权调整，消除治疗分组偏倚，均衡队列基线情况。主要研究终点是平均术后5天的桥血管通畅率和住院死亡率。次要研究终点包括术中失血、肝、肾功能等。

结果：

本研究队列未发生院内死亡。经过倾向性评分逆概率加权，两组基线资料无统计学差异。PS加权前，CS组患者的出院LDL水平降至65.35 mg/dL，显著低于DS组（76.57 mg/dL, P=0.038）。PS加权后，CS组LDL水平降至65.02 mg/dL，显著低于DS组（78.56 mg/dL, P<0.001）。CS组的患者术后早期桥血管通畅率为98.4%（桥血管通畅比为1255/1275），DS组为98.0%（桥血管通畅比为583/595，P=0.486）。两组间桥血管通畅率无显著差异，差异在PS加权后仍无统计学意义（98.5% vs 98.0%，P=0.224）。亚组分析表明，在吸烟患者中，CS组的桥血管闭塞率显著低于DS组（CS组为3.6%，DS组为8.1%，OR 0.41；95%CI 0.20-0.86；P<0.05），与非吸烟亚组相比差异显著（P=0.026）。次要终点显示，两组患者在术中失血（438.53 mL vs 480.47 mL，P=0.010），血清肌酐（1.04 mg/dL vs 1.06 mg/dL，P＝0.331）和估测肾小球滤过率（76.28 mL/min/1.73m2 vs 76.13 mL/min /1.73m2，P＝0.90）方面均无显著差异。而CS组的丙氨酸氨基转氨酶异常升高比例为8.9%，显著高于DS组的3.1%（比值比为3.06；95%置信区间, 1.77-5.29，P<0.001），表明CS组肝功能异常比DS组更为普遍。

结论：

在接受OPCAB的患者中，围术期连续服用他汀类药物并没有改善早期桥血管通畅率。连续服用他汀类药物在吸烟患者中可能能够降低桥血管闭塞率。围术期连续使用他汀类药物会增加肝功能异常的风险。

关键词：冠心病；非体外循环下冠状动脉旁路移植术；桥血管通畅率；3-羟基-3-甲基戊二酞辅酶A还原酶抑制剂/ 他汀类药物；围术期 

第二部分 FW-2轴流式左心室辅助装置的临床前大动物实验研究

目的：

根据急性心衰患者的需要研制配套完善的、具有自主知识产权且符合临床使用要求的FW-2轴流式左心室辅助装置（Left ventricular assist device, LVAD），对完善后的LVAD进行临床前大动物在体实验以评价其的安全性和有效性，进行临床应用标准建立。

方法：

1) 根据前期动物实验和临床试验发现的问题，对泵出入口和外连接管道进行了优化设计和改进。

2) 通过七只健康成年小尾寒羊的中短期在体实验，对FW-2轴流式左心辅助装置的血液相容性和血流动力学指标进行了测试。血浆游离血红蛋白通过血浆血红蛋白测试仪（Sigma, St. Louis, MO）进行检测。到达实验终点后对各重要脏器，包括心脏、肺、肾脏、肝脏、脾、脑组织，进行系统地解剖，多点取样送病理科行组织学检查，拆分泵体并对转子、前导叶、后导叶、流入管、流出管进行检查，以评估血栓栓塞和脏器梗死情况。

3) 通过动物实验对配套管道系统进行优化。

结果：

1) 改进了FW-2泵体两端接头形状，消除截流效应。

2) FW-2轴流式左心辅助装置在转速7500 rpm的条件下，输出流量控制在2.0-4.0 L/min之间。该装置的运转可有效地分流心室搏出的血液，通过调节泵的转速能够调节流量，进而调节血流动力学。在FW-2轴流式左心辅助装置12-24天实验周期内，泵体运转正常、稳定，溶血程度轻且稳定，游离血红蛋白小于1.0 g/L，基本未对血液成分造成破坏，主要血清学指标和各脏器功能未见明显异常，泵体本身有少许血栓形成，全身主要脏器未见血栓及出血。病理结果显示：轴流式左心辅助装置安装后动物的心肌、肺、肝、脾、肾脏和脑组织等重要脏器未见血栓栓塞及梗死

3) 示范性左心室辅助装置临床应用技术完成建立。

结论：

1) FW-2轴流式左心室辅助装置的血液相容性能好，在大动物实验中安全、有效，可达到中短期辅助循环的目的。

2) 配套管道在消除截流效应的同时兼顾手术操作。

3) 建立了左心室辅助装置临床应用技术规范。

关键词：左心室辅助装置；FW-2；血液相容性；血栓栓塞；临床前大动物实验 

第三部分 一种新型导电生物材料在改善大鼠心肌梗死后受损心肌电传导性的作用与机制研究

背景

心肌梗死（Myocardial infarction, MI）可导致心肌细胞的坏死，坏死心肌由成纤维细胞和胶原组织替代。而纤维组织不具有导电性，导致MI后心肌异常电信号传导，并使心脏不同步收缩，产生心律失常。组织工程化生物材料已被用于治疗MI。然而，目前应用的生物材料都不具备导电性。可植入的导电生物材料支架可能具有重建梗死区及周围心肌电信号的传导以达到改善心律失常、促使心肌同步收缩和恢复心功能的潜力。这种组织工程化生物支架的生物相容性是可否植入心梗心脏并改善心肌电传导的关键因素。此外，我们还评估了该新型导电生物材料polyAMBA-Gelfoam（PAMB-G）心脏支架的导电性和有效性，支持体外心肌细胞（Cardiomyocyte, CM）的活性和功能恢复，并在大鼠心梗模型中进行外科植入治疗。

方法和结果

3-氨基-4-甲氧基苯甲酸（AMBA）聚合物具有独特的导电聚合物结构，但不具有生物相容性。我们将AMBA与以明胶为主要成分的明胶海绵（Gelfoam）高分子侧链结合，形成了一种新型的导电生物支架（PAMB-G）。循环伏安测试表明，PAMB-G生物支架的导电性是明胶海绵的11倍。PAMB-G生物支架对大鼠新生心肌细胞存活和生长无细胞毒性。钙瞬变分析显示，与明胶海绵相比，在PAMB-G生物支架上生长的心肌细胞具有更快的电传导速度，并可形成自发搏动且同步收缩的心肌细胞群。本研究利用明胶海绵骨架的三维孔隙结构特点，合成三维PAMB-G生物支架，并通过乳鼠心肌细胞种植进行组织工程化PAMB-G心脏支架的体外构建。64极微电极阵列（64-MEA）实验表明，PAMB-G心脏支架中的心肌细胞具有更高的场电位振幅和更快的电传导速度。将组织工程化PAMB-G心脏支架植入大鼠心脏梗死瘢痕区表面，可改善瘢痕组织中及梗死边界区的电信号传导，而单纯明胶海绵植入的心梗心脏则存在延迟的电信号传导并显著降低传导速度。程序电刺激分析表明，与明胶海绵植入组相比，植入PAMB-G支架的心梗大鼠更不容易发生心律失常。在植入PAMB-G导电生物支架4周后，心梗大鼠的左室射血分数（Left ventricular ejection fraction, LVEF）和短轴缩短率（Fraction 

shortening, FS）均得到改善，且种植乳鼠CM组织工程化的PAMB-G组其LVEF和FS值高于无CM种植的PAMB-G组。

结论：

组织工程化PAMB-G生物支架具有良好的生物相容性和导电性，能够改善心肌细胞电传导速度，改善心肌梗死后心功能，为心肌梗死的组织工程疗法提供了一个新的途径。

关键词：组织工程化心肌支架；植入式；生物相容性；电传导；心肌梗死；心功能

part i a cohort study for outcome evaluation of efficacy and safety of perioperative statin therapy on patients undergoing off-pump coronary artery bypass grafting

decreased graft patency after off-pump coronary artery bypass surgery (opcab) are common and lead to substantial increases in cardiac events and clinical outcomes. however, there is paucity of data on the efficacy and safety of perioperative statin therapy for opcab populations.

ives: 
to evaluate the efficacy of perioperative continuation of statin therapy on early graft patency and clinical outcomes among patients undergoing off-pump coronary artery bypass surgery (opcab).

methods: 
a total of 582 patients who were scheduled for first-time isolated opcab in a single-institution database (october 2009- september 2012) were stratified by perioperative continuation of statin therapy (cs group, n=398) or not (ds group, n=184). to account for non-random treatment assignment, inverse probability weighted (ipw) propensity adjustment across 20 preoperative and procedural characteristics was used, resulting in a well-matched cohort. primary outcomes were graft patency at an average of five days after operation and in-hospital mortality. secondary outcomes included intraoperative blood loss, liver and renal functions.

results: 
no in-hospital death occurred in this study. low-density lipoprotein levels of patients on continuous statin treatment were reduced to 65.35 mg/dl (pre-ipw adjustment) and 65.02 mg/dl (post-ipw adjustment). early graft patency rates post opcab were 98.4% (1255 of 1275 grafts) in the cs group and 98.0% (583 of 595 grafts, p=0.486) in the ds group. this lack of significant difference in graft patency between groups also held true following ipw adjustment (98.5% versus 98.0%, p=0.224). subgroup analyses suggested that graft occlusion was less common in cs than in ds group among smoking patients (odds ratio 0.41; 95% confidence interval, 0.20 to 0.86; p<0.05), a difference that was absent in the non-smokers (6.0% versus 4.6%, or 1.34; 95% ci, 0.64 to 2.83), p-interaction = 0.026. secondary outcomes showed a reduction in blood loss during operation (438.53 ml versus 480.47 ml, p=0.010). there was no significant difference in serum creatinine (1.04 mg/dl versus 1.06 mg/dl, p=0.331) and estimated glomerular filtration rate (76.28 ml/min/1.73m2 versus 76.13 ml/min/1.73m2, p=0.90). in the entire cohort, following ipw adjustment, abnormal alanine transaminase elevation was observed in 8.9% of the cs group, and 3.1% in the ds group (odds ratio 3.06; 95% confidence interval, 1.77 to 5.29, p<0.001), indicating that elevated liver function was more prevalent in cs than in ds conditions.

conclusions: 
perioperative continuation of statin therapy did not improve early graft patency among patients undergoing opcab. smoking patients might benefit from perioperative continuation of statin therapy in terms of graft occlusion. perioperative continuation of statin therapy tended to increase the risk of elevated liver function.

key words
coronary artery disease; off-pump coronary artery bypass; graft patency; perioperative statin therapy; hmg-coa reductase inhibitors

part ⅱpreclinical study of fw-2 left ventricular assist device in large animals

ives: to evaluate the hemodynamics and biocompatibility of fw-2 left ventricular assist device (lvad) in sheep model.
methods: the fw-2 lvad, a miniaturized axial rotary blood pump with a diameter of 30 mm and a weight of 180 g, had been developed at fuwai hospital over years. we evaluate the short-term (7 days) efficacy and safety of fw-2 lvad on seven healthy adult sheep by hemodynamic and biochemical tests at day1, 3,5,7, postoperatively. the level of plasma-free hemoglobin was measured by plasma hemoglobin measuring kits (sigma, st. louis, mo). complete necropsy, histological examination and pump inspection were also performed in order to analyse the situation of thromboembolism in the heart, lung, kidney, liver, spleen and brain. 
results: no sheep died during the scheduled study duration of 7 days. all the sheep lived for 8 and 21 days respectively without any major adverse events, such as anorexia, infection, or neurologic disorders, under the mechanical circulatory support of fw-2 lvad. the devices functioned well without any technical problem in all sheep. an average pump speed of 7500 r/min provided the average flow of 2.5 l/min. the average plasma-free hemoglobin concentration was 70 mg/l at postoperative day 3 and then decreased to 30 mg/l at postoperative day 7. histological examination showed no evidence of ischemia or infarction in hearts, lungs, kidneys, livers, spleens or brains.
conclusions: fw-2 lvad functioned well in vivo. it might be a promising device for short-term mechanical circulatory support.

keywords
left ventricular assist device; fw-2; biocompatibility; embolism; preclinical study

part ⅲa novel tissue-engineered conductive scaffold supports cell electrical signaling and improves ventricular function after implantation within myocardial infarction rats
ives: 
myocardial infarction (mi) results in cardiomyocyte necrosis which is replaced by fibroblasts and collagen tissue. the nonconductive nature of the fibrotic tissue causes abnormal electric signal propagation and desynchronizes cardiac contraction, resulting in cardiac arrhythmia. both stable and biodegradable biomaterials have been used to treat myocardial infarction. however, neither type of biomaterial can conduct electrical activity. an implantable conductive biomaterial scaffold may hold such a potential to rebuild electric signaling propagation through the infarct region to synchronize contraction and restore ventricular function. however, biocompatibility of such a tissue-engineered scaffold is the key factor for the successful resynchronization of contraction. besides, we evaluated the conductivity and efficacy of the newly synthesized conductive polyamba (3-amino-4-methoxybenzoic acid)–gelfoam (pamb-g) cardiac scaffold to support cardiomyocyte (cm) viability and function in vitro and to surgically treat mi in vivo.

methods and results: 
amba (3-amino-4-methoxybenzoic acid) has a unique structure as a conductive polymer, but is non-biocompatible. we conjugated amba to sidechain of gelfoam, which was mainly composed of gelatin, creating a novel conductive scaffold (pamb-g). cyclic voltammetry measurement showed that pamb-g scaffold was 11 times more conductive than gelfoam alone. pamb-g scaffold did not show any cytotoxicity regarding rat neonatal cardiomyocyte survival and growth. ca2+ imaging analysis showed that cardiomyocytes grown on pamb-g had higher conductive velocity with synchronized contraction of distinct clusters of spontaneously-beating cardiomyocytes in comparison with gelfoam alone. the backbone of gelfoam made pamb-g a 3-dimensional conductive scaffold thus in vitro construction of tissue-engineered pamb-g cardiac scaffold was performed. 64-electrode microelectrode array (64-mea) measurement showed pamb-g had higher field potential amplitude as well as better conductive velocity. implantation of tissue-engineered pamb-g scaffold onto the scar zone of rat hearts improved electrical impulse propagation across the scarred tissue whereas gelfoam-implanted hearts continued to have delayed propagation patterns and significantly reduced conduction velocity. program electrical stimulation analysis demonstrated that the infarcted heart with pamb-g scaffold had significantly less occurrence of cardiac arrhythmia than those hearts with gelfoam implantation. 
conclusions: 
the pamb-g scaffold was biocompatible and conductive, making it an attractive candidate for a new biomaterial platform for cardiac surgical treatment to preserve synchronous ventricular contraction and improve ventricular function post myocardial infarction.

key words 
tissue-engineered cardiac scaffold; implantable; biocompatible; electric conductivity; myocardial infarction; ventricular function