心脏震波应用于未获血运重建冠心病患者的疗效和机理研究
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摘要
[背景]作为人类主要疾病负担和首要疾病死因的冠心病(CAD)近年来在中国等发展中国家呈持续增多趋势。现有药物治疗、冠脉介入治疗(PCI)、冠脉旁路移植(CABG)等虽已使CAD的疗效大为改观,但均疗效有限、费用昂贵、技术复杂、并发症凶险,迄今尚无任何方法可根治CAD。中国众多CAD患者未获规范适宜的诊治和健康指导,原因包括：①很多CAD患者因贫困不得不放弃现行血运重建治疗(溶栓、PCI、CABG)。②PCI/CABG等有创操作要求医务人员有较高技术,基层医院尚难普及。③患者合并其他疾病(SSS、出血倾向等)不能耐受手术。④无现行血运重建治疗适应证或治疗失败。⑤患者因心理畏惧,不愿接受PCI/CABG。⑥患者因宗教信仰、民风民俗差异,不愿接受有创治疗或在体内植入异物。相当长的时期内以上原因将限制现行血运重建疗法在中国CAD患者中普遍运用而降低患者获益,迫使医学界寻找新的微创甚至无创、有效、安全、经济、简便的CAD疗法。体外心脏震波治疗(CSWT)为广大CAD患者带来曙光,其在已经完成的体外实验、动物模型和已获血运重建仍心肌缺血CAD患者中应用的结果证实,低能量冲击波靶向释放是促进缺血心肌内毛细血管新生和加速侧支循环建立、改善心肌缺血、无创、安全、有效的CAD新疗法,堪称冠心病治疗的第三把“利剑”。面对中国广大未获血运重建的CAD患者,如能证实CSWT的有效性和安全性,将对我国遏制CAD危害发挥极大的社会效益和经济效益。
[目的]探讨CSWT应用于未获血运重建冠心病患者的疗效、安全性、方法学要点及适应人群；探讨CSWT对血管再生相关细胞因子的影响,分析心肌灌注、心肌代谢与促血管再生细胞因子间的相关性。
[方法]①连续选取2008年10月～2011年1月收住昆明医科大学第一附属医院心内科的冠心病陈旧性心肌梗死(OMI)患者87例(男68例、女19例,平均年龄66.80±8.41岁),病史1～15年,随机单盲分入震波组62例,其中根据震波方案不同分常规震波组(每缺血靶区行9点治疗)32例和扩大震波组(每缺血靶区行25点治疗)30例；假震波组(接受相同震波程序但不释放震波能量)即对照组25例。3月为1疗程,累计9次震波。三组患者入选时、震波治疗后第3、6、12月均行99mTc-甲氧基异丁基异腈(MIBI)/18氟-脱氧葡萄糖(FDG)双核素SPECT心肌灌注/代谢显像寻找缺血心肌及存活心肌,记录加拿大心绞痛分级、纽约心功能分级、西雅图心绞痛量表、硝酸甘油用量、6分钟步行距离、左室射血分数、左室舒张末内径、微伏级T波电交替等,震波组治疗前1天、第3、6、9次震波后次日均采集外周静脉血检测心肌坏死标志物。比较各组间死亡率、再次心梗率、再次住院率、心肌灌注、心肌代谢、心功能等指标的变化。②所有患者治疗前、治疗后第3、6、12月采集空腹外周静脉全血各5ml,2h内常温下离心(3000r/min,15min),取血清置-80℃冰箱储存备用,ELISA法检测外周血eNOS、bFGF、SDF-1、CXCR4等血管再生相关因子的水平。
[结果]结果1：①患者接受CSWT期间均无心绞痛加剧、无心力衰竭、无出血、栓塞、无恶性心律失常(室速、室颤)等,血压、心率、氧饱和度无明显变化。②随访期间震波组患者未再发心梗,常规震波组死亡1例与震波治疗无关、行择期PCI1例,假震波组猝死1例、行CABG1例、因AMI行急诊PCI1例。三组间死亡率、再次心梗率均无显著性差异(P均>0.05)。随访期内26例患者因CAD事件再次住院,常规震波组、扩大震波组和假震波组分别占7、5、14例,两种震波方案间再次住院率的差异无显著性(P>0.05),却均低于假震波组(P均<0.05)。③两种震波方案的4次血清CK、CK-MB、CTNI水平检测均无显著性差异(P均>0.05)。④随访3、6、12月,震波组NYHA分级、CCS心绞痛分级、SAQ评分、6MWT、硝酸甘油用量等指标均较震波前改善(P均<0.05),随访6月时扩大震波组的以上指标均较常规震波组改善(P均<0.05),随访12月时,CCS心绞痛分级、硝酸甘油用量仍较常规震波组改善(P均<0.05)。随访3、6、12月,震波组患者的以上指标均较假震波组明显改善(P均<0.05)。假震波组的以上指标震波前后各观测点两两比较,除12月时6MWT较震波前减少外(P<0.05),其余指标无显著性差异(P均>0.05)。⑤震波组随访第3、6、12月的LVEF均较震波前改善(P均<0.05),随访12月时扩大震波组的LVEF较常规震波组明显改善(P<0.05)。LVEDD于常规震波组、扩大震波组间同期两两比较无显著性差异(P均>0.05)。假震波组的LVEF不同观测点两两比较无显著性差异(P均>0.05)；LVEDD则在随访12月时较基线值增加(P<0.05)。⑥震波组MTWA值、频率阈值(HR)、运动时间、MTWA/HR比值等,随访3、6、12月时均较震波前和假震波组改善(P均<0.05),除运动时间在随访期间连续递增,且随访12月时增加最明显(P<0.05)外,其余指标震波后不同观测点比较无显著性变化(P均>0.05)。假震波组以上指标不同观测点两两比较无显著性差异(P均>0.05)。⑦震波组双核素SPCET检测心肌缺血节段、代谢异常节段、心肌灌注总评分、心肌代谢总评分等指标,震波后12月与震波前、震波后3月比较均明显改善(P均<0.05),与震波后6月比较无显著性差异(P均>0.05)。震波后3、6、12月观察,扩大震波组以上指标均优于常规震波组(P均<0.05)；震波组以上指标在不同观测点均比假震波组改善(P均<0.05)。假震波组随访12月时以上指标均较基线值恶化(P均<0.05)。⑧心肌灌注是否改善与震波疗程无显著性相关(P>0.05)。⑨随访期内震波组患者再次住院的危险因素排序依次为LVEF≤45%、心肌灌注总评分≥34分、MTWA≥32u V、心绞痛分级≥Ⅲ级。
结果2：①三组患者震波前血清eNOS、bFGF、SDF-1、CXCR4水平两两比较无显著性差异(P均>0.05)。随访第3月震波组的以上指标均较震波前改善(P均<0.05),随访第6月震波组的以上指标均较震波前、第3月改善(P均<0.05)。随访第12月常规震波组eNOS、SDF-1、CXCR4均较震波前和随访第3月改善(P均<0.05),与随访第6月比较无显著性差异(P均>0.05),bFGF则较震波前和随访第3、6月有改善(P均<0.05)；扩大震波组bFGF、SDF-1、CXCR4均较震波前和随访第3、6月有改善(P均<0.05),eNOS较震波前和随访第3月改善(P均<0.05),与随访第6月比较无显著性差异(P>0.05)。随访期各观测点两两比较,扩大震波组的以上指标均优于常规震波组(P均<0.05),且震波组随访第3、6、12月以上指标均分别较同期假震波组改善(P均<0.05)。假震波组随访第12月以上指标均较基线值和随访第3、6月降低(P均<0.05)。②震波组心肌灌注总评分与血清eNOS、bFGF、SDF-1、CXCR4水平均呈负相关(常规震波组r值分别为-0.813、-0.847、-0.736、-0.759,扩大震波组r值分别为-0.856、-0.892、-0.775、-0.805,P均<0.001)；震波组心肌代谢总评分均与血清eNOS、bFGF、SDF-1、CXCR4水平呈负相关(常规震波组r值分别为-0.796、-0.839、-0.721、-0.747,扩大震波组r值分别为-0.823、-0.844、-0.751、-0.778,P均<0.001)；由于心肌灌注总评分反应心肌灌注水平,二者呈反比,心肌代谢总评分与心肌代谢水平亦呈反比,结合相关性分析结果震波组心肌灌注和心肌代谢水平均分别与上述4种细胞因子的血清水平正相关,且扩大震波组的相关性强于常规震波组,相关性由强到弱的排序依次为bFGF、eNOS、CXCR4、SDF-1。
[结论]①CSWT无创、安全、有效、易于重复,似为新的促心肌内血管新生疗法。②CSWT治疗早期即使CAD患者心肌缺血症状缓解、心肌灌注及代谢改善、冠脉储备增加、生活质量及运动耐量提高,可抑制心室重构和改善心功能。③CSWT改善心脏变时功能和增加诱发TWA的频率阈值,似可降低CAD患者室性心律失常和SCD风险。④借助99mTc-MIBI/18F-FDG双核素SPECT心肌灌注／代谢显像定位缺血心肌、存活心肌,可提高CSWT治疗靶区定位精度和疗效。⑤CSWT既可应用于已获现行血运重建治疗仍心肌缺血的复杂CAD患者,也可应用于未获血运重建治疗的终末期或非终末期CAD患者。⑥扩大震波范围的25点CSWT方案似可比常规震波9点方案更多改善心肌灌注、心肌代谢及心功能。⑦CSWT治疗似可促进机体高表达eNOS、bFGF、SDF-1及其受体CXCR4,且扩大震波范围较常规震波方案更能持续、有效促进eNOS、bFGF、SDF-1及其受体CXCR4高表达。⑧接受CSWT治疗患者的心肌灌注和心肌代谢水平均分别与eNOS、bFGF、SDF-1、 CXCR4的血清水平正相关,尤以扩大震波范围的患者明显,且相关性由强到弱的排序依次为bFGF、eNOS、CXCR4、SDF-1,提示CSWT的促血管新生作用似由这些细胞因子介导。
Background Coronary Artery Disease (CAD) has become a major global burden of disease and one of the leading causes of death, the mortality rate of CAD in developing countries (including China) shows a rising trend in recent years. Although, current drug therapies, Percutaneous Transluminal Coronary Intervention (PCI) and Coronary Artery Bypass Grafting (CABG) have greatly improved the treatment of coronary artery disease, but due to the limited curative effects, expensive costs, complex technical and dangerous complications, so far there has no radical or fundamental solutions to CAD. A number of patients have not received appropriate diagnosis, treatment and health guidance of CAD patients in China, the reasons as following:①Many CAD patients had to abandon revascularization therapies (thrombolysis therapy, PCI and CABG) because of poverty.②Invasive operations such as PCI/CABG needs the doctor with high technical requirements, grass-roots hospital can not carry on this kind of operations universally.③Combined with other diseases (such as SSS, thrombocytopenia), patients can not withstand surgery.④No indication of Coronary artery revascularization or revascularization surgery failed.⑤Fear of invasive operation, refuse to accept PCI/CABG treatment.⑥Because of the religious beliefs, folk customs, patients can not accept the invasive surgery or implanted foreign object in their body. The above mentioned reasons have constrained standard revascularization treatment of CAD universal application in China and reduced patient benefit from the treatment. This make us to find a new minimally invasive or non-invasive, effective, safe, economic and easy method of CAD treatment. Cardiac Shock Wave Therapy (CSWT) appears, brings twilight for CAD patients, currently it has been confirmed by in-vitro experiment, animal models and CAD patients who have carried the revascularization therapy that low energy of shock wave can promote new capillaries angiogenesis and accelerate the establishment of collateral circulation, thus improved myocardial ischemia, it is a non-invasive, security, effective therapy of CAD, can be called as the third "Sword" of CAD treatment. Face to the CAD patients who have not received revascularization in China, if we can prove the effectiveness and safety of CSWT, it will play a significant social and economic benefits to restrain the hazard of CAD in China.
PARTI A Safety and Efficiency Study of CSWT in CAD Patients Without Coronary Artery Revascularization
Objective To evaluate the effectiveness, safety, methodological outline and indications of CSWT for treatment of CAD patients without coronary artery revascularization.
Methods This study was performed in accordance with the ethics committee of our hospital. The informed written consent was obtained from each patient prior to enrollment. All of the selected87patients had been suffered from Old Myocardial Infarction(68male,19female, mean age was66.80±8.41years) with medical history1-15years, all of the selected patients had been admitted at our institute, the Cardiology Department of the First Affiliated Hospital of Kunming Medical University from October2008to January2011. Sixty-two patients were in the CSWT group by using randomized single-blind method, and divided32cases into the regular treatment group(Group A,9spots treatment of each ischemia target region) according to different shock wave procedure and30cases into the expanding scope treatment group (Group B,25spots treatment of each ischemia target region), and25cases in the fake shock wave group (Group C, treated with the same procedures but without the shock wave energy). In the course for3months,9CSWT procedures were performed totally to all of the patients. We follow-up all patients at3months,6months and12months, Patients of three groups were received the examinations include the technetium-99m sestamibi myocardial perfusion (99mTc-MIBI) and fluorine-18-fluorodeoxyglucose (18F-FDG) myocardial metabolism single photon emission computed tomography (SPECT) to identify the myocardial ischemia and viability segments, Canadian Cardiovascular Society (CCS) angina scale, New York Heart Association (NYHA) class, Seattle Angina Questionnaire (SAQ) scale, nitroglycerin used dosage,6-min walk test (6MWT), Left ventricular ejection fraction (LVEF), left ventricular end diastolic dimension (LVEDD), Microvolt Level T-Wave Alternans (MTWA) and so on to evaluate the effect of CSWT. One day before shock wave therapy and the second day after the3rd,6th and9th times of shock wave therapy to test the serum concentrations of myocardial necrosis markers in CSWT group. Compared the changes of following index, include the mortality rates, rates of myocardial infarction happened again, rehospitalization rates, myocardial perfusion, myocardial metabolism and heart function in different groups.
Results
①During the CSWT, the angina of the patients was not to be worse and no heart failure, no hemorrhage, no embolism, no malignant arrhythmia (ventricular tachycardia/fibrillation) as well as no any obvious changes on blood pressure, heart rate and blood oxygen saturation.
②Patients in CSWT group have no myocardial infarction (MI) occurred during the follow-up. In regular treatment group, one patient died but have nothing to do with the shock wave treatment, one patient carried percutaneous coronary intervention (PCI) with time selecting. In fake shock wave group, one patient died suddenly, one patient carried CABG operation and one patient suffered from AMI received emergency Percutaneous Coronary Intervention (PCI) operation. Compared the mortality and re-myocardial infarction rates of patients in three groups, the difference was no statistical significance (P>0.05). A total of26patients suffered from rehospitalization due to myocardial ischemia related symptoms,7of them in regular treatment group,5in expanding scope treatment group,14in fake shock wave group, compared the rehospitalization rates of regular treatment group and expanding scope treatment group, the difference was no statistical significance (P>0.05). However, the rehospitalization rates of regular treatment group and expanding scope treatment group are lower than fake shock wave group (P<0.05).
③Patients in regular treatment group and expanding scope treatment group, compared serum concentrations of CK, CK-MB, CTNI before and the3rd,6th,9th times after shock wave (SW) treatment respectively, the difference have no statistical significance (P>0.05).
④After the SW treatment, compared the NYHA class, CCS angina scale, SAQ scale,6MWT and nitroglycerin used dosage in follow-up of3months,6months,12months in regular treatment group and expanding scope treatment group with0month respectively, all the above mentioned parameters improved significantly (P<0.05); follow-up to6months, the above mentioned parameters of expanding scope treatment group improved significantly than regular treatment group (P<0.05), CCS angina scale and nitroglycerin used dosage in expanding scope treatment group improved significantly compared with regular treatment group (P<0.05) during12months follow-up. At follow-up of3months,6months,12months, the above mentioned parameters in regular treatment group and expanding scope treatment group improved significantly compared with fake shock wave group (P<0.05). Compared the above mentioned parameters before and after the SW treatment in fake shock wave group, except the6MWT in12months follow-up is less than the data before treatment (P<0.05), the differences of other parameters have no statistical significance (P>0.05).
⑤In regular treatment group and expanding scope treatment group, follow-up to3months,6months,12months, the LVEF significant improved respectively than0month (P<0.05), LVEF of the expanding scope treatment group at12months follow-up improved significantly compared with regular treatment group (P<0.05). The LVEDD in regular treatment group and expanding scope treatment group, compared each two of same time subgroup, the differences have no statistical significance (P>0.05). LVEF in fake shock wave group, compared each two of different observation spot, the differences have no statistical significance (P>0.05). However, follow-up to12months LVEDD in fake shock wave group significant enlarged than0month (P<0.05).
⑥Compared the MTWA, HR, exercise time,MTWA/HR in regular treatment group and expanding scope treatment group, all the parameters improved significantly of3months,6months,12months follow-up than0month(P<0.05), and also improved significantly than the above mentioned parameters in fake shock wave group(P<0.05), during follow-up the exercise time of patients in regular treatment group and expanding scope treatment group have continuous increased significantly, especially for follow-up to12months the exercise time increased obviously (P<0.05), the rest parameters compared with each two of different observation spot, the differences have no statistical significance (P>0.05). The above mentioned parameters in fake shock wave group, compared with each two of different observation spot, the differences have no statistical significance (P>0.05).
⑦Follow-up to12months, the myocardial ischemic segments, dysbolism segments, total radioactive score of perfusion imaging, total radioactive score of metabolism imaging of CSWT group compared with0month,3months respectively, the above mentioned parameters all improved significantly (P<0.05), but compared with follow-up to6months, the differences have no statistical significance (P>0.05). Follow-up to3months,6months,12months, the above mentioned parameters of expanding scope treatment group improved significantly than regular treatment group (P<0.05). The above mentioned parameters of different period of CSWT group compared with fake shock wave group, all the parameters improved significantly (P<0.05). Follow-up to12months the above mentioned parameters of fake shock wave group significant worse than the baseline value (P<0.05).
⑧The myocardial perfusion improved or not have no any obvious relationship with course of treatment of CSWT (P>0.05).
⑨The risk factors of rehospitalization of patients in CSWT group during follow-up are as follows:LVEF≤45%, total radioactive score of perfusion imaging≥34points, MTWA≥32μV, angina pectoris Grade≥Grade Ⅲ(P<0.05).
Conclusions①CSWT is a non-invasive, safe, effective, easy to duplicate, new method to promote myocardial angiogenesis.②CSWT could relieve myocardial ischemia related symptoms in the early stage, improved myocardial perfusion and metabolism, increased the coronary artery reserve, life quality and exercise tolerance increased too, it can restrain cardiac remodeling and improved the heart function.③CSWT can improve the heart chronotropic function and increase the threshold of frequency which causes TWA, it seems could lower the risk of CAD patients occurred ventricular arrhythmia and SCD.④CSWT can exactly located the target ischemic area with some viable myocardial segments by the99m Tc-MIBI myocardial perfusion and18F-FDG myocardial metabolism SPECT, so that it can improved the accuracy and effectiveness of CSWT.⑤CSWT not only can be used for the complex CAD patients who have already received revascularization treatment still have related symptoms of myocardial ischemia, but also it could used for the end-stage or non-end-stage CAD patients who have not received revascularization treatment.⑥It seems that expanding the range of treatment (25points therapy) could obvious improve myocardial perfusion, myocardial metabolism and heart function than the conventional treatment protocols (9points treatment).
PART II Effects of CSWT on The Angiogenesis Related Cytokine of CAD Patients
Objective To explore the effects of CSWT on the angiogenesis related cytokine of CAD Patients, to analysis the correlation between myocardial perfusion, myocardial metabolism and the angiogenesis related cytokine.
Methods A total of87patients with old myocardial infarction (OMI) were enrolled in this study who received treatment in Department of Cardiology,1st Affiliated Hospital of Kunming Medical University from October2008to January2011, including68male and19female, aged from43to80years (66.80±8.41years) with medical history1-15years, the group dividing and treatment protocols are the same with Part Ⅰ. Before the SW treatment (0month) and the follow-up of3months,6months,12months, all patients collected5ml fasting in peripheral venous blood, then centrifugate the blood within2hours (3000r/min,15min), collected serum then stored in-80℃freezer for using. Used ELISA method to test the serum concentration of eNOS, bFGF, SDF-1, CXCR4and so on, to evaluate the level of the angiogenesis related cytokine.
Results
①Before the SW treatment there was no significant difference for each assessing parameter include serum eNOS, bFGF, SDF-1, CXCR4among three groups (P>0.05). Follow-up to3months, the above mentioned parameters of patients in CSWT group compared with0month respectively improved significantly (P<0.05), follow-up to6months, the above mentioned parameters compared with0month and3month of patients in CSWT group improved significantly (P<0.05). Follow-up to12months, eNOS, SDF-1, CXCR4of regular treatment group compared with0month and3months improved significantly (P<0.05), compared with6months the differences have no statistical significance (P>0.05), for bFGF compared with0month,3months and6months improved significantly (P<0.05); and bFGF, SDF-1,CXCR4of expanding scope treatment group compared with0month,3months and6months improved significantly (P<0.05), the eNOS compared with0month and3months improved significantly (P<0.05), compared with6months the difference have no statistical significance (P>0.05). In the following-up, all of the above mentioned parameters of expanding scope treatment group improved significantly compared with the same period of regular treatment group (P<0.05), further more, the above mentioned parameters of CSWT group in the follow-up of3months,6months and12months improved significantly respectively compared with fake shock wave group in the same period (P<0.05).The above mentioned parameters of fake shock wave group at12months follow-up decreased than baseline data and follow-up at3months,6months (P<0.05).
②The total radioactive score of myocardial perfusion of CSWT group has negative correlation with serum concentration of eNOS, bFGF, SDF-1, CXCR4(For regular treatment group:r=-0.813, r=-0.847, r=-0.736, r=-0.759, P<0.001, for expanding scope treatment group:r=-0.856, r=-0.892, r=-0.775, r=- 0.805, P<0.001); the total radioactive score of myocardial metabolism has negative correlation with serum concentration of eNOS, bFGF, SDF-1, CXCR4(For regular treatment group:r=-0.796, r=-0.839, r=-0.721, r=-0.747, P<0.001, for expanding scope treatment group:r=-0.823, r=-0.844, r=-0.751, r=-0.778, P<0.001); The total radioactive score of myocardial perfusion showed the level of myocardial perfusion, these two indicators are in inverse proportion, The total radioactive score of myocardial metabolism is inversely proportional to the level of myocardial metabolism, combined with the related analysis result showed that the myocardial perfusion and myocardial metabolism were positively related with the above mentioned four cytokine, and the degrees of correlation of expanding scope treatment group was stronger than regular treatment group, and the sequence from high to low of the degrees of correlation are bFGF, eNOS, CXCR4, SDF-1.
Conclusions①CSWT can promote the expression of eNOS, bFGF, SDF-1and its receptor CXCR4, and25points expanding the treatment range of CSWT can be more continuously and effectively promote the expression of eNOS, bFGF, SDF-1and its receptor CXCR4than9points regular treatment.②After CSWT, there was a positive correlation of myocardial perfusion and myocardial metabolism with each serum eNOS, bFGF, SDF-1, CXCR4parameters, the degrees of correlation of expanding the treatment range are better than9points regular treatment, and the sequence from high to low are bFGF, eNOS, CXCR4, SDF-1. It point out that effectiveness of angiogenesis by CSWT may due to these above mentioned cytokine.
[目的]探讨CSWT应用于未获血运重建冠心病患者的疗效、安全性、方法学要点及适应人群；探讨CSWT对血管再生相关细胞因子的影响,分析心肌灌注、心肌代谢与促血管再生细胞因子间的相关性。
[方法]①连续选取2008年10月～2011年1月收住昆明医科大学第一附属医院心内科的冠心病陈旧性心肌梗死(OMI)患者87例(男68例、女19例,平均年龄66.80±8.41岁),病史1～15年,随机单盲分入震波组62例,其中根据震波方案不同分常规震波组(每缺血靶区行9点治疗)32例和扩大震波组(每缺血靶区行25点治疗)30例；假震波组(接受相同震波程序但不释放震波能量)即对照组25例。3月为1疗程,累计9次震波。三组患者入选时、震波治疗后第3、6、12月均行99mTc-甲氧基异丁基异腈(MIBI)/18氟-脱氧葡萄糖(FDG)双核素SPECT心肌灌注/代谢显像寻找缺血心肌及存活心肌,记录加拿大心绞痛分级、纽约心功能分级、西雅图心绞痛量表、硝酸甘油用量、6分钟步行距离、左室射血分数、左室舒张末内径、微伏级T波电交替等,震波组治疗前1天、第3、6、9次震波后次日均采集外周静脉血检测心肌坏死标志物。比较各组间死亡率、再次心梗率、再次住院率、心肌灌注、心肌代谢、心功能等指标的变化。②所有患者治疗前、治疗后第3、6、12月采集空腹外周静脉全血各5ml,2h内常温下离心(3000r/min,15min),取血清置-80℃冰箱储存备用,ELISA法检测外周血eNOS、bFGF、SDF-1、CXCR4等血管再生相关因子的水平。
[结果]结果1：①患者接受CSWT期间均无心绞痛加剧、无心力衰竭、无出血、栓塞、无恶性心律失常(室速、室颤)等,血压、心率、氧饱和度无明显变化。②随访期间震波组患者未再发心梗,常规震波组死亡1例与震波治疗无关、行择期PCI1例,假震波组猝死1例、行CABG1例、因AMI行急诊PCI1例。三组间死亡率、再次心梗率均无显著性差异(P均>0.05)。随访期内26例患者因CAD事件再次住院,常规震波组、扩大震波组和假震波组分别占7、5、14例,两种震波方案间再次住院率的差异无显著性(P>0.05),却均低于假震波组(P均<0.05)。③两种震波方案的4次血清CK、CK-MB、CTNI水平检测均无显著性差异(P均>0.05)。④随访3、6、12月,震波组NYHA分级、CCS心绞痛分级、SAQ评分、6MWT、硝酸甘油用量等指标均较震波前改善(P均<0.05),随访6月时扩大震波组的以上指标均较常规震波组改善(P均<0.05),随访12月时,CCS心绞痛分级、硝酸甘油用量仍较常规震波组改善(P均<0.05)。随访3、6、12月,震波组患者的以上指标均较假震波组明显改善(P均<0.05)。假震波组的以上指标震波前后各观测点两两比较,除12月时6MWT较震波前减少外(P<0.05),其余指标无显著性差异(P均>0.05)。⑤震波组随访第3、6、12月的LVEF均较震波前改善(P均<0.05),随访12月时扩大震波组的LVEF较常规震波组明显改善(P<0.05)。LVEDD于常规震波组、扩大震波组间同期两两比较无显著性差异(P均>0.05)。假震波组的LVEF不同观测点两两比较无显著性差异(P均>0.05)；LVEDD则在随访12月时较基线值增加(P<0.05)。⑥震波组MTWA值、频率阈值(HR)、运动时间、MTWA/HR比值等,随访3、6、12月时均较震波前和假震波组改善(P均<0.05),除运动时间在随访期间连续递增,且随访12月时增加最明显(P<0.05)外,其余指标震波后不同观测点比较无显著性变化(P均>0.05)。假震波组以上指标不同观测点两两比较无显著性差异(P均>0.05)。⑦震波组双核素SPCET检测心肌缺血节段、代谢异常节段、心肌灌注总评分、心肌代谢总评分等指标,震波后12月与震波前、震波后3月比较均明显改善(P均<0.05),与震波后6月比较无显著性差异(P均>0.05)。震波后3、6、12月观察,扩大震波组以上指标均优于常规震波组(P均<0.05)；震波组以上指标在不同观测点均比假震波组改善(P均<0.05)。假震波组随访12月时以上指标均较基线值恶化(P均<0.05)。⑧心肌灌注是否改善与震波疗程无显著性相关(P>0.05)。⑨随访期内震波组患者再次住院的危险因素排序依次为LVEF≤45%、心肌灌注总评分≥34分、MTWA≥32u V、心绞痛分级≥Ⅲ级。
结果2：①三组患者震波前血清eNOS、bFGF、SDF-1、CXCR4水平两两比较无显著性差异(P均>0.05)。随访第3月震波组的以上指标均较震波前改善(P均<0.05),随访第6月震波组的以上指标均较震波前、第3月改善(P均<0.05)。随访第12月常规震波组eNOS、SDF-1、CXCR4均较震波前和随访第3月改善(P均<0.05),与随访第6月比较无显著性差异(P均>0.05),bFGF则较震波前和随访第3、6月有改善(P均<0.05)；扩大震波组bFGF、SDF-1、CXCR4均较震波前和随访第3、6月有改善(P均<0.05),eNOS较震波前和随访第3月改善(P均<0.05),与随访第6月比较无显著性差异(P>0.05)。随访期各观测点两两比较,扩大震波组的以上指标均优于常规震波组(P均<0.05),且震波组随访第3、6、12月以上指标均分别较同期假震波组改善(P均<0.05)。假震波组随访第12月以上指标均较基线值和随访第3、6月降低(P均<0.05)。②震波组心肌灌注总评分与血清eNOS、bFGF、SDF-1、CXCR4水平均呈负相关(常规震波组r值分别为-0.813、-0.847、-0.736、-0.759,扩大震波组r值分别为-0.856、-0.892、-0.775、-0.805,P均<0.001)；震波组心肌代谢总评分均与血清eNOS、bFGF、SDF-1、CXCR4水平呈负相关(常规震波组r值分别为-0.796、-0.839、-0.721、-0.747,扩大震波组r值分别为-0.823、-0.844、-0.751、-0.778,P均<0.001)；由于心肌灌注总评分反应心肌灌注水平,二者呈反比,心肌代谢总评分与心肌代谢水平亦呈反比,结合相关性分析结果震波组心肌灌注和心肌代谢水平均分别与上述4种细胞因子的血清水平正相关,且扩大震波组的相关性强于常规震波组,相关性由强到弱的排序依次为bFGF、eNOS、CXCR4、SDF-1。
[结论]①CSWT无创、安全、有效、易于重复,似为新的促心肌内血管新生疗法。②CSWT治疗早期即使CAD患者心肌缺血症状缓解、心肌灌注及代谢改善、冠脉储备增加、生活质量及运动耐量提高,可抑制心室重构和改善心功能。③CSWT改善心脏变时功能和增加诱发TWA的频率阈值,似可降低CAD患者室性心律失常和SCD风险。④借助99mTc-MIBI/18F-FDG双核素SPECT心肌灌注／代谢显像定位缺血心肌、存活心肌,可提高CSWT治疗靶区定位精度和疗效。⑤CSWT既可应用于已获现行血运重建治疗仍心肌缺血的复杂CAD患者,也可应用于未获血运重建治疗的终末期或非终末期CAD患者。⑥扩大震波范围的25点CSWT方案似可比常规震波9点方案更多改善心肌灌注、心肌代谢及心功能。⑦CSWT治疗似可促进机体高表达eNOS、bFGF、SDF-1及其受体CXCR4,且扩大震波范围较常规震波方案更能持续、有效促进eNOS、bFGF、SDF-1及其受体CXCR4高表达。⑧接受CSWT治疗患者的心肌灌注和心肌代谢水平均分别与eNOS、bFGF、SDF-1、 CXCR4的血清水平正相关,尤以扩大震波范围的患者明显,且相关性由强到弱的排序依次为bFGF、eNOS、CXCR4、SDF-1,提示CSWT的促血管新生作用似由这些细胞因子介导。
Background Coronary Artery Disease (CAD) has become a major global burden of disease and one of the leading causes of death, the mortality rate of CAD in developing countries (including China) shows a rising trend in recent years. Although, current drug therapies, Percutaneous Transluminal Coronary Intervention (PCI) and Coronary Artery Bypass Grafting (CABG) have greatly improved the treatment of coronary artery disease, but due to the limited curative effects, expensive costs, complex technical and dangerous complications, so far there has no radical or fundamental solutions to CAD. A number of patients have not received appropriate diagnosis, treatment and health guidance of CAD patients in China, the reasons as following:①Many CAD patients had to abandon revascularization therapies (thrombolysis therapy, PCI and CABG) because of poverty.②Invasive operations such as PCI/CABG needs the doctor with high technical requirements, grass-roots hospital can not carry on this kind of operations universally.③Combined with other diseases (such as SSS, thrombocytopenia), patients can not withstand surgery.④No indication of Coronary artery revascularization or revascularization surgery failed.⑤Fear of invasive operation, refuse to accept PCI/CABG treatment.⑥Because of the religious beliefs, folk customs, patients can not accept the invasive surgery or implanted foreign object in their body. The above mentioned reasons have constrained standard revascularization treatment of CAD universal application in China and reduced patient benefit from the treatment. This make us to find a new minimally invasive or non-invasive, effective, safe, economic and easy method of CAD treatment. Cardiac Shock Wave Therapy (CSWT) appears, brings twilight for CAD patients, currently it has been confirmed by in-vitro experiment, animal models and CAD patients who have carried the revascularization therapy that low energy of shock wave can promote new capillaries angiogenesis and accelerate the establishment of collateral circulation, thus improved myocardial ischemia, it is a non-invasive, security, effective therapy of CAD, can be called as the third "Sword" of CAD treatment. Face to the CAD patients who have not received revascularization in China, if we can prove the effectiveness and safety of CSWT, it will play a significant social and economic benefits to restrain the hazard of CAD in China.
PARTI A Safety and Efficiency Study of CSWT in CAD Patients Without Coronary Artery Revascularization
Objective To evaluate the effectiveness, safety, methodological outline and indications of CSWT for treatment of CAD patients without coronary artery revascularization.
Methods This study was performed in accordance with the ethics committee of our hospital. The informed written consent was obtained from each patient prior to enrollment. All of the selected87patients had been suffered from Old Myocardial Infarction(68male,19female, mean age was66.80±8.41years) with medical history1-15years, all of the selected patients had been admitted at our institute, the Cardiology Department of the First Affiliated Hospital of Kunming Medical University from October2008to January2011. Sixty-two patients were in the CSWT group by using randomized single-blind method, and divided32cases into the regular treatment group(Group A,9spots treatment of each ischemia target region) according to different shock wave procedure and30cases into the expanding scope treatment group (Group B,25spots treatment of each ischemia target region), and25cases in the fake shock wave group (Group C, treated with the same procedures but without the shock wave energy). In the course for3months,9CSWT procedures were performed totally to all of the patients. We follow-up all patients at3months,6months and12months, Patients of three groups were received the examinations include the technetium-99m sestamibi myocardial perfusion (99mTc-MIBI) and fluorine-18-fluorodeoxyglucose (18F-FDG) myocardial metabolism single photon emission computed tomography (SPECT) to identify the myocardial ischemia and viability segments, Canadian Cardiovascular Society (CCS) angina scale, New York Heart Association (NYHA) class, Seattle Angina Questionnaire (SAQ) scale, nitroglycerin used dosage,6-min walk test (6MWT), Left ventricular ejection fraction (LVEF), left ventricular end diastolic dimension (LVEDD), Microvolt Level T-Wave Alternans (MTWA) and so on to evaluate the effect of CSWT. One day before shock wave therapy and the second day after the3rd,6th and9th times of shock wave therapy to test the serum concentrations of myocardial necrosis markers in CSWT group. Compared the changes of following index, include the mortality rates, rates of myocardial infarction happened again, rehospitalization rates, myocardial perfusion, myocardial metabolism and heart function in different groups.
Results
①During the CSWT, the angina of the patients was not to be worse and no heart failure, no hemorrhage, no embolism, no malignant arrhythmia (ventricular tachycardia/fibrillation) as well as no any obvious changes on blood pressure, heart rate and blood oxygen saturation.
②Patients in CSWT group have no myocardial infarction (MI) occurred during the follow-up. In regular treatment group, one patient died but have nothing to do with the shock wave treatment, one patient carried percutaneous coronary intervention (PCI) with time selecting. In fake shock wave group, one patient died suddenly, one patient carried CABG operation and one patient suffered from AMI received emergency Percutaneous Coronary Intervention (PCI) operation. Compared the mortality and re-myocardial infarction rates of patients in three groups, the difference was no statistical significance (P>0.05). A total of26patients suffered from rehospitalization due to myocardial ischemia related symptoms,7of them in regular treatment group,5in expanding scope treatment group,14in fake shock wave group, compared the rehospitalization rates of regular treatment group and expanding scope treatment group, the difference was no statistical significance (P>0.05). However, the rehospitalization rates of regular treatment group and expanding scope treatment group are lower than fake shock wave group (P<0.05).
③Patients in regular treatment group and expanding scope treatment group, compared serum concentrations of CK, CK-MB, CTNI before and the3rd,6th,9th times after shock wave (SW) treatment respectively, the difference have no statistical significance (P>0.05).
④After the SW treatment, compared the NYHA class, CCS angina scale, SAQ scale,6MWT and nitroglycerin used dosage in follow-up of3months,6months,12months in regular treatment group and expanding scope treatment group with0month respectively, all the above mentioned parameters improved significantly (P<0.05); follow-up to6months, the above mentioned parameters of expanding scope treatment group improved significantly than regular treatment group (P<0.05), CCS angina scale and nitroglycerin used dosage in expanding scope treatment group improved significantly compared with regular treatment group (P<0.05) during12months follow-up. At follow-up of3months,6months,12months, the above mentioned parameters in regular treatment group and expanding scope treatment group improved significantly compared with fake shock wave group (P<0.05). Compared the above mentioned parameters before and after the SW treatment in fake shock wave group, except the6MWT in12months follow-up is less than the data before treatment (P<0.05), the differences of other parameters have no statistical significance (P>0.05).
⑤In regular treatment group and expanding scope treatment group, follow-up to3months,6months,12months, the LVEF significant improved respectively than0month (P<0.05), LVEF of the expanding scope treatment group at12months follow-up improved significantly compared with regular treatment group (P<0.05). The LVEDD in regular treatment group and expanding scope treatment group, compared each two of same time subgroup, the differences have no statistical significance (P>0.05). LVEF in fake shock wave group, compared each two of different observation spot, the differences have no statistical significance (P>0.05). However, follow-up to12months LVEDD in fake shock wave group significant enlarged than0month (P<0.05).
⑥Compared the MTWA, HR, exercise time,MTWA/HR in regular treatment group and expanding scope treatment group, all the parameters improved significantly of3months,6months,12months follow-up than0month(P<0.05), and also improved significantly than the above mentioned parameters in fake shock wave group(P<0.05), during follow-up the exercise time of patients in regular treatment group and expanding scope treatment group have continuous increased significantly, especially for follow-up to12months the exercise time increased obviously (P<0.05), the rest parameters compared with each two of different observation spot, the differences have no statistical significance (P>0.05). The above mentioned parameters in fake shock wave group, compared with each two of different observation spot, the differences have no statistical significance (P>0.05).
⑦Follow-up to12months, the myocardial ischemic segments, dysbolism segments, total radioactive score of perfusion imaging, total radioactive score of metabolism imaging of CSWT group compared with0month,3months respectively, the above mentioned parameters all improved significantly (P<0.05), but compared with follow-up to6months, the differences have no statistical significance (P>0.05). Follow-up to3months,6months,12months, the above mentioned parameters of expanding scope treatment group improved significantly than regular treatment group (P<0.05). The above mentioned parameters of different period of CSWT group compared with fake shock wave group, all the parameters improved significantly (P<0.05). Follow-up to12months the above mentioned parameters of fake shock wave group significant worse than the baseline value (P<0.05).
⑧The myocardial perfusion improved or not have no any obvious relationship with course of treatment of CSWT (P>0.05).
⑨The risk factors of rehospitalization of patients in CSWT group during follow-up are as follows:LVEF≤45%, total radioactive score of perfusion imaging≥34points, MTWA≥32μV, angina pectoris Grade≥Grade Ⅲ(P<0.05).
Conclusions①CSWT is a non-invasive, safe, effective, easy to duplicate, new method to promote myocardial angiogenesis.②CSWT could relieve myocardial ischemia related symptoms in the early stage, improved myocardial perfusion and metabolism, increased the coronary artery reserve, life quality and exercise tolerance increased too, it can restrain cardiac remodeling and improved the heart function.③CSWT can improve the heart chronotropic function and increase the threshold of frequency which causes TWA, it seems could lower the risk of CAD patients occurred ventricular arrhythmia and SCD.④CSWT can exactly located the target ischemic area with some viable myocardial segments by the99m Tc-MIBI myocardial perfusion and18F-FDG myocardial metabolism SPECT, so that it can improved the accuracy and effectiveness of CSWT.⑤CSWT not only can be used for the complex CAD patients who have already received revascularization treatment still have related symptoms of myocardial ischemia, but also it could used for the end-stage or non-end-stage CAD patients who have not received revascularization treatment.⑥It seems that expanding the range of treatment (25points therapy) could obvious improve myocardial perfusion, myocardial metabolism and heart function than the conventional treatment protocols (9points treatment).
PART II Effects of CSWT on The Angiogenesis Related Cytokine of CAD Patients
Objective To explore the effects of CSWT on the angiogenesis related cytokine of CAD Patients, to analysis the correlation between myocardial perfusion, myocardial metabolism and the angiogenesis related cytokine.
Methods A total of87patients with old myocardial infarction (OMI) were enrolled in this study who received treatment in Department of Cardiology,1st Affiliated Hospital of Kunming Medical University from October2008to January2011, including68male and19female, aged from43to80years (66.80±8.41years) with medical history1-15years, the group dividing and treatment protocols are the same with Part Ⅰ. Before the SW treatment (0month) and the follow-up of3months,6months,12months, all patients collected5ml fasting in peripheral venous blood, then centrifugate the blood within2hours (3000r/min,15min), collected serum then stored in-80℃freezer for using. Used ELISA method to test the serum concentration of eNOS, bFGF, SDF-1, CXCR4and so on, to evaluate the level of the angiogenesis related cytokine.
Results
①Before the SW treatment there was no significant difference for each assessing parameter include serum eNOS, bFGF, SDF-1, CXCR4among three groups (P>0.05). Follow-up to3months, the above mentioned parameters of patients in CSWT group compared with0month respectively improved significantly (P<0.05), follow-up to6months, the above mentioned parameters compared with0month and3month of patients in CSWT group improved significantly (P<0.05). Follow-up to12months, eNOS, SDF-1, CXCR4of regular treatment group compared with0month and3months improved significantly (P<0.05), compared with6months the differences have no statistical significance (P>0.05), for bFGF compared with0month,3months and6months improved significantly (P<0.05); and bFGF, SDF-1,CXCR4of expanding scope treatment group compared with0month,3months and6months improved significantly (P<0.05), the eNOS compared with0month and3months improved significantly (P<0.05), compared with6months the difference have no statistical significance (P>0.05). In the following-up, all of the above mentioned parameters of expanding scope treatment group improved significantly compared with the same period of regular treatment group (P<0.05), further more, the above mentioned parameters of CSWT group in the follow-up of3months,6months and12months improved significantly respectively compared with fake shock wave group in the same period (P<0.05).The above mentioned parameters of fake shock wave group at12months follow-up decreased than baseline data and follow-up at3months,6months (P<0.05).
②The total radioactive score of myocardial perfusion of CSWT group has negative correlation with serum concentration of eNOS, bFGF, SDF-1, CXCR4(For regular treatment group:r=-0.813, r=-0.847, r=-0.736, r=-0.759, P<0.001, for expanding scope treatment group:r=-0.856, r=-0.892, r=-0.775, r=- 0.805, P<0.001); the total radioactive score of myocardial metabolism has negative correlation with serum concentration of eNOS, bFGF, SDF-1, CXCR4(For regular treatment group:r=-0.796, r=-0.839, r=-0.721, r=-0.747, P<0.001, for expanding scope treatment group:r=-0.823, r=-0.844, r=-0.751, r=-0.778, P<0.001); The total radioactive score of myocardial perfusion showed the level of myocardial perfusion, these two indicators are in inverse proportion, The total radioactive score of myocardial metabolism is inversely proportional to the level of myocardial metabolism, combined with the related analysis result showed that the myocardial perfusion and myocardial metabolism were positively related with the above mentioned four cytokine, and the degrees of correlation of expanding scope treatment group was stronger than regular treatment group, and the sequence from high to low of the degrees of correlation are bFGF, eNOS, CXCR4, SDF-1.
Conclusions①CSWT can promote the expression of eNOS, bFGF, SDF-1and its receptor CXCR4, and25points expanding the treatment range of CSWT can be more continuously and effectively promote the expression of eNOS, bFGF, SDF-1and its receptor CXCR4than9points regular treatment.②After CSWT, there was a positive correlation of myocardial perfusion and myocardial metabolism with each serum eNOS, bFGF, SDF-1, CXCR4parameters, the degrees of correlation of expanding the treatment range are better than9points regular treatment, and the sequence from high to low are bFGF, eNOS, CXCR4, SDF-1. It point out that effectiveness of angiogenesis by CSWT may due to these above mentioned cytokine.
引文
[1]Bonow RO, Smaha LA, Smith SC, et al. World Heart Day 2002:the international burden of cardiovascular disease:responding to the emerging global epidemic [J]. Circulation,2002, 106(13):1602-1605.
[2]Wu Z, Yao C, Zhao D, et al. Sino-MONICA project:a collaborative study on trends and determinants in cardiovascular diseases in China, Ⅰ:morbidity and mortality monitoring [J]. Circulation,2001,103:462-468.
[3]赵冬.冠心病二级预防研究进展／／胡大一,马长生.心脏病学实践2005.北京：人民卫生出版社.2005：3-6.
[4]Murray CJL, Lopez AD. Mortality by cause for eight regions of the world:Global Burden of . Disease Study [J]. Lancet,1997,349:1269-1276.
[5]国家“九五”科技攻关课题协作组.我国人群心血管主要危险因素流行现状及从20世纪80年代初至90年代末的变化趋势[J].中华心血管病杂志,2001,29：74-80.
[6]赵冬,吴兆苏,王薇,等.北京地区1984-1997年急性冠心病事件死亡率变化趋势(中国MONICA方案的研究)[J].中华心血管病杂志,2000,28：14-17.
[7]Mathur A, martin JF. Stem cell and repair of the heart[J]. Lancet,2004,364:183-192.
[8]Rafii S, Lyden D. Therapeutic stem and progenitor cell transplantation for organ vascularization and regeneration [J].Nat Med,2003,9:702-712.
[9]Kimm SS,Sundback CA,Kaihara S,et al.Dynamic-seeding and in-vitro culture of hepatocytes in a flow perfusion system[J].Tissue Eng,2000,6:39-44.
[10]曾哲淳,赵冬,王文化等.北京市40家基层医院高血压防治硬件条件的现状调查[J].中华流行病学杂志,2003,24：1078-1081.
[11]贾妍娜,赵冬,王薇等.北京市不同级别医院医生冠心病临床诊断和处理能力的评价[J].心肺血管病杂志,2008,27(4)：193-196.
[12]Erbel R, Gutersohn A. Cardiac shock wave therapy, a successful workshop at ESC 2003 [DB /OL]. http://www. storzmedical. ch/English/News,2003-09-01.
[13]Mariotto S, Cavalieri E, Amerio E, et al. Extracorporeal shock waves:From lithotripsy to anti-inflammatory action by NO production[J]. Nitric Oxide,2005,(12):89-96.
[14]Gotte G, Amelio E, Russo S, et al. Short-time non-enzymatic nitric oxide synthesis from L-arginine and hydrogen peroxide induced by shock waves treatment[J]. FEBS Lett,2002, 520:153-155.
[15]Uwatoku T, Ito K, Abe K, et al. Extracorporeal cardiac shock wave therapy proves left ventricular remodeling after acute myocardial infarction in pigs[J]. Coron Artery Dis, 2007,18(5):397-404.
[16]郑志远,王海东,许良春,等.体外心脏震波治疗系统治疗冠心病的机理及主要结构和工作原理.中国医疗设备,2010,25(1)：47-49.
[17]Folberth W, KEhler G, Rohwedder A, et al. Pressure distribution and energy flow in the focal region of two different electromagnetic shock wave sources [J]. Journal of Stone Disease, 1992,4(1):108-115.
[18]Gutersohn A,Caspari G, Shock wave upregulate vascular endothelial growth factor mRNA in human umbilical vascular endothelial cells[J].Circulation.,2000,102(suppl):18-23.
[19]Nishida T, Shimokawa H, Oi K,et al. Extracorporeal cardiac shock wave therapy markedly ameliorates ischemia-induced myocardial dysfunction in pigs in vivo[J]. Circulation, 2004,110(19):3055-61.
[20]Fukumoto Y, Ito A, Uwatoku T, et al. Extracorporeal cardiac shock wave therapy ameliorates myocardial ischemia in patients with severe coronary artery disease[J]. Coron Artery Dis, 2006,17:63-70.
[21]Ito K, Fukumoto Y, Shimokawa H. Extracorporeal shock wave therapy as a new and non-invasive angiogenic therapy [J]. Tohoku J Exp Med,2009,219:1-9.
[22]Zimpfer D. angiogenesis in ischemic heart failure Direct epicardial shock wave therapy improves ventricular function and induces [J]. J Thorac Cardiovasc Surg,2009,137:963-970.
[23]Kikuchi Y, Ito K, et al.Double-Blind and Placebo-Controlled Study of the Effectiveness and Safety of Extracorporeal Cardiac Shock Wave Therapy for Severe Angina Pectoris[J]. Circ J, 2010,74(3):589-591.
[24]蔡红雁,王钰,李琳,等.体外心脏震波治疗前后外周血内皮祖细胞数量的变化[J].中国组织工程研究与临床康复,2010,14(49)：9249-9252.
[25]陶四明,郭涛,王钰,等.体外心脏震波重建猪急性心肌梗死后早期心肌微循环的实验研究[J].四川大学学报(医学版)2011,42(2)：222-226.
[26]Wang Y, Guo T, Cai HY, et al. Cardiac Shock Wave Therapy Reduces Angina and Improves Myocardial Function in Patients With Refractory Coronary Artery Disease[J]. Clin Cardiol, 2010,33:693-699.
[27]王钰,郭涛,蔡红雁,等.体外心脏震波治疗冠心病的应用研究[J].中华心血管病杂志,2010,38：711-715.
[28]杨萍,郭涛,彭云珠,等.体外心脏震波治疗冠心病的有效性研究.重庆医学,2011,40(29)：2918-2921.
[29]杨萍,彭云珠,郭涛,等.体外心脏震波治疗冠心病患者的临床研究.重庆医学,2012,41(9)：847-851.
[30]Yusuf S, Reddy S, Ounpuu S, et al. Global burden of cardiovascular disease:Part Ⅱ:variation in cardiovascular disease by specific ethnic groups and geographic regions and prevention strategies [J]. Circulation,2001,104:2855-2864.
[31]中华医学会心血管病学分会,中华心血管病杂志编辑委员会.急性ST段抬高型心肌梗死诊断和治疗指南2010[J].中华心血管病杂志,2010,38(8)：675-687.
[32]Cerqueira MD, Weissman NJ, Dilsizian V, et al. American Heart Association Writing Group on Myocardial Segmentation and Registration for Cardiac Imaging. Standardized myocardial segmentation and nomenclature for tomographic imaging of the heart:a statement for healthcare professionals from the cardiac imaging committee of the Council on Clinical Cardiology of the American Heart Association[J]. J Nucl Cardiol,2002,9:240-245.
[33]方理刚,李隽,陈黎波,等.小剂量腺苷负荷超声心动图试验与双核素心肌显像检测急性心肌梗死后患者存活心肌比较[J].临床心血管病志,2009,25：623-626.
[34]Khattab AA, Brodersen B, Schuermann-Kuchenbrandt D,et al. Extracorporeal cardiac shock wave therapy:first experience in the everyday practice for treatment of chronic refractory angina pectoris[J]. Int J Cardiol,2007,121:84-85.
[35]Verrier RL,Nearing BD. Modified moving average analysis of T-wave alternans to predict ventricular fibrillation with high accuracy [J]. J Appl Physiol,2002,92:541-549.
[36]Verrier RL, Nearing BD, Larovere MT, et al. Ambulatory electrocardiogram-based tracking of T-wave alternans in postmyocardial infarction patients to assess risk of cardic arrest or arrhythmic death[J]. J Cardiovasc Electrophysiol,2003,14:705-711.
[37]杨萍,郭涛,汤亚明,等.微伏级T波电交替对心性猝死高危人群的预测价值.中华心血管病杂志,2008,36(6)：517-522.
[38]Bittner V, Weiner DH, Yusuf S,et al. Prediction of mortality and morbidity with a 6-minute walk test in patients with left ventricular dysfunction. SOLVD Investigtors [J].JAMA, 1993,270 (14):1702-1707.
[39]peters P, Mets T. The 6-minute walk test as an appropriate exercise test in elderly patients with chronic heart failure [J]. J Gerontol A Biol Sci Med Sci,1996,54:M147-151.
[40]Matsunari I, Kanayama S, Yoneyam AT, et al. Electrocardiographic gated dual isotope simultaneous acquisition SPECT using 18F-FDG and 99mTc-sestamibi to assess myocardial viability and function in a single study[J]. Eur J Nucl Med Mol Imaging,2005,32:195-202.
[41]Slartr H, Baxj J, Deboer J, et al. Comparison of 99mTc-sestamibi/18FDG DISA SPECT with PET for the detection of viability in patients with coronary artery disease and left ventricular dysfunction[J]. Eur J Nucl Med Mol Imaging,2005,32:972-979.
[42]Prinz C, Lindner O, Bitter T, et al. Extracorporeal Cardiac Shock Wave Therapy Ameliorates Clinical Symptoms and Improves Regional Myocardial Blood Flow in a Patient with Severe Coronary Artery Disease and Refractory Angina [J]. Case Reports Med,2009,639594,3-10.
[43]Nearing BD, Verrier RL. Progressive increases in complexity of T-wave oscillations herald ischemia-induced ventricular fibrillation[J] Cir Res,2000,91:727-732.
[44]Ikeda T, Saito H, Tanno K, et al. T-wave alternans as a predictor for sudden cardiac death after myocardial infarction[J]. Am J Cardiol,2002,89:79-82.
[45]蒲里津,汤亚明,郭涛,等.在常规运动试验中以时域法微伏级T波电交替筛查冠心病的价值[J].中国循环杂志,2011,26(3)：190-193.
[46]Walker MR, Rosenbaum DS. Repolarization alternans:implications for the mechanism and prevention of sudden cardiac death [J]. Cardiovas Res,2003,57(3):599-614.
[47]Pruvot EJ, Karte RP, Rosenbaum DS, et al. Role of calcium cycling versus restitution in the mechanism of repolarisation alternans[J]. Circ Res,2004,94(8):1083-1090.
[48]MacMurdy KS, Kirk MM, Cooklin M, et al.Gold MR. The effect of selective autonomic blockade on T-wave alternans[J].Circulation,1999,100(Suppl):2683.
[49]Marban E, Kitakaze M, Koretsune Y, et al. Quantification of [Ca2+] in perfused hearts: critical evaluation of the 5F-BAPTA and nuclear magnetic resonance method as applied to the study of ischemia and reperfusion[J]. Circ Res,1990,66:1255-1267.
[50]Kop WJ, Krantz DS, Nearing BD, et al. Effects of acute mental stress and Exercise on T-wave alternans in patients with implantable cardioverter defibrillators and controls[J]. Circulation,2004,109:1-6.
[51]Verrier RL, Nearing BD. Electrophysiologic basis for T-ware alternans as an index of vulnerability to ventricular fibrillation [J]. J Carbiovasc Electrophysiol,1994,5 (6):445-446.
[52]Rosenbaum DS, Jackson LE, Smith JM, et al. Electrical alternans and vulnerability to ventricular arrythmias [J]. N Engl J Med,1994,330 (3):235-241.
[53]Gale NW, Yancopoulos GD. Growth factors acting via endothelial cell specific receptor tyrosine kinases:VEGF's, angiopoietins and ephrins in vascular development[J]. Genes Dev, 1999,13 (78):1055-1066.
[54]Devel L, Rogakos V, David A, et al. Development of selective inhibitors and substrate of matrix metallo proteinase-12 [J]. J Biol Chem,2006,281 (16):11152-11160.
[55]Igarashi J, Miyoshi M, Hashimoto T, et al. Statins induce S1PI receptors and enhance endothelial nitric oxide production in response to high-density lipoproteins[J]. Br J Pharmacol,2007,150 (4):470-479.
[56]Thurston G, Rudge JS, Ioffe E, et al. Angiopoietin-1 protects the adult vascularture against plasma leakage[J]. NatMed,2000,6 (36):460-463.
[57]Hirschi K, Rohovsky S, D'Amore P. PDGF, TGF-β and heterotypic cell-cell interactionsmediate endothelial cell induced recruitment of 10T1/2 cells and their differentiation to a smoothmuscle fate [J]. J CellB iol,1998,141 (846):805-814.
[58]MassaM, Rosti V, Ferrario M, et al. Increased circulating hematopoietic and endothelial p-rogenitor cells in the early phase of acute myocardial infarction [J].Blood,2005,105: 199-206.
[59]Ceradini DJ, Kulkarni AR, Callaghan MJ, et al. Progenitor cell trafficking is regulated by hypoxic gradients through H IF-1 induction of SDF-1 [J]. Nat Med,2004,10:858-864.
[60]Aicher A, Heescher C, Sasak K, et al. Low-energy shock wave for enhancing recrutement of endothelial progenitor cell; a new modality to increase efficacy of cell therapy in chronic hind limb ischemia [J]. Mol Cardiol,2006,10:2819-2823.
[61]Andre Pasternac, Martial G. Bourassa. Pathogenesis of chest pain in patients with cardiomyopathies and normal coronary arteries [J]. Inter.J.Cardiol,1983(3):273-280.
[62]Nurzynska D, Meglio FD, Castaldo C, et al. Shock waves activate in vitro cultured progenitors and precursors of cardiac cell lineages from the human heart [J]. Ultrasound in Med & Biol,2008,34:334-342.
[63]Dvorak P, Hampl A. Basic fibroblast growth factor and its receptors in human embryonic stem cells [J]. Folia Histochem Cytobiol,2005,43(4):203-208.
[64]Fam N P. Verma S, Kutryk M, et al. Clinician Guide to Angiogenesis [J].Circulation,2003, 108(21):2613-2618.
[65]Bottcher R T, Niehrs C. Fibroblast growth factor signaling during early vertebrate development[J]. Endocrine Rev,2005,26(1):63-77.
[66]Fisher AB, Chien S, Barakat AI,et al. Endothelial cellular response to altered shear stress[J]. Am J Physiol,2001,28:L529-L533.
[67]Ichioka S, Shibata M, Kosaki K, et al. Effects of shear stress on wound healing angiogenesis in the rabbit ear chamber[J]. J Surg Res,1997,72:29-35.
[68]Mariotto S.Cavalieri E, Amelio E, et al. Extracorporeal shock waves:from lithotripsy to anti-inflammatory action by NO production[J]. Nitric Oxide,2005,12:89-96.
[69]Anna R, Carcereri A, Amelio E, et al. Nitric oxide mediates anti-inflammatory action of extracorporeal shock waves[J]. FEBS Lett,2005,579:6839-6845.
[70]Oi K, Fukumoto Y, Ito K, et al. Extracorporeal shock wave therapy ameliorates hindlimb ischemiain rabbits[J]. Tohoku J Exp Med,2008,214:151-158.
[71]Ito Y, Ito K, Shiroto T, et al. Cardiac shock wave therapy ameliorates left ventricular remodeling after myocardial ischemia reperfusion injury in pigs in vivo[J]. Coron Artery Dis, 2010,21:304-311.
[72]Fu M, Sun CK, Lin YC, et al. Extracorporeal Shock Wave Therapy Reverses Ischemia-Related Left Ventricular Dysfunction and Remodeling:Molecular-Cellular and Functional Assessment[J].PLoS One,2011;6(9):e24342.
[73]Iwakiri Y, Satoh A, Chatterjee S, et al. Nitric oxide synthase generates nitric oxide locally to regulate compartmentalized protein S-nitrosylation and protein trafficking[J]. Proc Natl Acad Sci,2006,103:19777-19782.
[74]Puddu GM, Cravero E, Arnone G, et al. Molecular aspects of atherogenesis:new insights and unsolved questions[J]. J Biomed Sci,2005,12:839-853.
[75]Yetik- Anacak G, Catravas JD. Nitric oxide and the endothelium:History and impact on cardiovascular disease[J]. Vascul Pharmacol,2006,45:268-276.
[76]Gooch KJ,Dangler CA, Frangos JA,et al. Exogenous, basal, and flow-induced nitric oxide production and endothelial cell proliferation[J] J Cell Physiol,1997,171 (3):252-258.
[77]Duda DG, Fukumura O, Jain RK. Role of eNOS in neovascularization:NO for endothelial progenitor cells[J]. Trends Mol Med,2004,10(4):143-145.
[78]Fulton D, Gratton JP, McCabe TJ, et al. Regulation of endothelium-derived nitric oxide production by the protein kinase Akt[J]. Nature,1999,399(6736):597-601.
[79]Tian J, Hou Y, Lu Q, et al. A novel role for caveolin-1 in regulating endothelial nitric oxide synthase activation in response to H2O2 and shear stress [J]. Free Radic Biol Med, 2010,49(2):159-170.
[80]Aicher A, C Heeschen, C Mildner-Rihm, et al. Essential role of endothelial nitric oxide synthase for mobilization of stem and progenitor cells[J]. Nat Med,2003;9:1370-6.
[81]Cai WJ, Elisabeth K, Luo XG, et al. Expression of endothelial nitric oxide synthase in the vascular wall during arteriogenesis[J]. Mol Cell Biochem,2004,264(1-2):193-200.
[82]Jones SP, Greer JJ, van Haperen R, et al. Endothelial nitric oxide synthase overexpression attenuates congestive heart failure in mice[J]. Proc Natl Acad Sci,2003,100:4891-4896.
[83]Rifkin DB, Moscatelli D. Resent development in the ceil biology of basic fibr oblast growth factor[J]. J Cell Bio 1,1989,109:1.
[84]Damico F M. Angiogenesis and retinal diseases [J]. Arq Bras Oftlmol,2007,70(3):547-553.
[85]Nakajima H, Sakakibara Y, Tambara K. Therapeutic angiogenesis by the controlled release of basic fibroblast growth factor for ischemic limb and heart injury:toward safety and minimal invasiveness [J]. Artif Organs,2004,7(2):58-61.
[86]Koivisto H, Hyvarinen M, Stromberg AM, et al. Cultures of human embryonic stem cells: serum replacement medium or serum-containing media and the effect of basic fibroblast growth factor[J]. Reprod Biomed Online,2004,9(3):330-337.
[87]Hall H. Modified fibrin hydrogel matrices:both,3D-scaffolds and local and controlled release systems to stimulate angiogenesis[J]. Curr Pharm Des,2007, (35):3597-3607.
[88]Gleichmann M, Gillen C, Czardybon M. et al. Cloning and characterization of SDF-1 gamma, a novel chemokine transcript with developmentally regulated expression in the nervous systerm[J]. Eur J Neurosci,2000 Jun; 12(6):1857-66.
[89]Askari AT, Unzek S, Popovic ZB, et al. Effect of stromal-cell-derived factor 1 on stem-cell homing and tissue regeneration in ischaemic cardiomyopathy[J]. Lancet,2003,362 (9385):697-703.
[90]Schober A, Knarren S, Lietz M, et al.Crucial role of Stromal cell derived factor-1alpha in neointima formation after vascular injury in apolipoprotein E-deficient mice[J]. Circulation, 2003,108 (20):2491-2497.
[91]Yamaguchi J, Kusano K. Masuo O, et al. Stromal cell derived factor-1 effects on exvivo expanded endothelial progenitor cell recruitment for ischemic neovascularization [J]. Circulation,2003,107 (9):1322-1328.
[92]Kijow sk i J, BajKrzyworzeka M, Iizasa H, et al. The SDF-1-CXC R4 axis stim ulates VEGF secretion and activates integrins but does not affect proliferation and survival in lymphohematopoietic cells[J]. Stem Cells,2001,19 (5):453-466.
[93]Guleng B. Tateishi K, Ohta M, et al. Blockade of the stromal cell-derived fact or-1/CXCR4 axis attenuates in vivo tumor growth by inhibiting angiogenesis in a vascular endothelial growth factor independent manner[J]. Cancer,2005,65 (13):5864-5871.
[94]Tang Y, Qian K, Zhan g Y, et al. Mobilizing of haematopoiet ic stem cells to ischemic myocardium by plasmid mediated stromal-cell-derived factor-1 (SDF-la) treatment [J]. Regulatory Peptides,2005,125(18):1-8.
[2]Wu Z, Yao C, Zhao D, et al. Sino-MONICA project:a collaborative study on trends and determinants in cardiovascular diseases in China, Ⅰ:morbidity and mortality monitoring [J]. Circulation,2001,103:462-468.
[3]赵冬.冠心病二级预防研究进展／／胡大一,马长生.心脏病学实践2005.北京：人民卫生出版社.2005：3-6.
[4]Murray CJL, Lopez AD. Mortality by cause for eight regions of the world:Global Burden of . Disease Study [J]. Lancet,1997,349:1269-1276.
[5]国家“九五”科技攻关课题协作组.我国人群心血管主要危险因素流行现状及从20世纪80年代初至90年代末的变化趋势[J].中华心血管病杂志,2001,29：74-80.
[6]赵冬,吴兆苏,王薇,等.北京地区1984-1997年急性冠心病事件死亡率变化趋势(中国MONICA方案的研究)[J].中华心血管病杂志,2000,28：14-17.
[7]Mathur A, martin JF. Stem cell and repair of the heart[J]. Lancet,2004,364:183-192.
[8]Rafii S, Lyden D. Therapeutic stem and progenitor cell transplantation for organ vascularization and regeneration [J].Nat Med,2003,9:702-712.
[9]Kimm SS,Sundback CA,Kaihara S,et al.Dynamic-seeding and in-vitro culture of hepatocytes in a flow perfusion system[J].Tissue Eng,2000,6:39-44.
[10]曾哲淳,赵冬,王文化等.北京市40家基层医院高血压防治硬件条件的现状调查[J].中华流行病学杂志,2003,24：1078-1081.
[11]贾妍娜,赵冬,王薇等.北京市不同级别医院医生冠心病临床诊断和处理能力的评价[J].心肺血管病杂志,2008,27(4)：193-196.
[12]Erbel R, Gutersohn A. Cardiac shock wave therapy, a successful workshop at ESC 2003 [DB /OL]. http://www. storzmedical. ch/English/News,2003-09-01.
[13]Mariotto S, Cavalieri E, Amerio E, et al. Extracorporeal shock waves:From lithotripsy to anti-inflammatory action by NO production[J]. Nitric Oxide,2005,(12):89-96.
[14]Gotte G, Amelio E, Russo S, et al. Short-time non-enzymatic nitric oxide synthesis from L-arginine and hydrogen peroxide induced by shock waves treatment[J]. FEBS Lett,2002, 520:153-155.
[15]Uwatoku T, Ito K, Abe K, et al. Extracorporeal cardiac shock wave therapy proves left ventricular remodeling after acute myocardial infarction in pigs[J]. Coron Artery Dis, 2007,18(5):397-404.
[16]郑志远,王海东,许良春,等.体外心脏震波治疗系统治疗冠心病的机理及主要结构和工作原理.中国医疗设备,2010,25(1)：47-49.
[17]Folberth W, KEhler G, Rohwedder A, et al. Pressure distribution and energy flow in the focal region of two different electromagnetic shock wave sources [J]. Journal of Stone Disease, 1992,4(1):108-115.
[18]Gutersohn A,Caspari G, Shock wave upregulate vascular endothelial growth factor mRNA in human umbilical vascular endothelial cells[J].Circulation.,2000,102(suppl):18-23.
[19]Nishida T, Shimokawa H, Oi K,et al. Extracorporeal cardiac shock wave therapy markedly ameliorates ischemia-induced myocardial dysfunction in pigs in vivo[J]. Circulation, 2004,110(19):3055-61.
[20]Fukumoto Y, Ito A, Uwatoku T, et al. Extracorporeal cardiac shock wave therapy ameliorates myocardial ischemia in patients with severe coronary artery disease[J]. Coron Artery Dis, 2006,17:63-70.
[21]Ito K, Fukumoto Y, Shimokawa H. Extracorporeal shock wave therapy as a new and non-invasive angiogenic therapy [J]. Tohoku J Exp Med,2009,219:1-9.
[22]Zimpfer D. angiogenesis in ischemic heart failure Direct epicardial shock wave therapy improves ventricular function and induces [J]. J Thorac Cardiovasc Surg,2009,137:963-970.
[23]Kikuchi Y, Ito K, et al.Double-Blind and Placebo-Controlled Study of the Effectiveness and Safety of Extracorporeal Cardiac Shock Wave Therapy for Severe Angina Pectoris[J]. Circ J, 2010,74(3):589-591.
[24]蔡红雁,王钰,李琳,等.体外心脏震波治疗前后外周血内皮祖细胞数量的变化[J].中国组织工程研究与临床康复,2010,14(49)：9249-9252.
[25]陶四明,郭涛,王钰,等.体外心脏震波重建猪急性心肌梗死后早期心肌微循环的实验研究[J].四川大学学报(医学版)2011,42(2)：222-226.
[26]Wang Y, Guo T, Cai HY, et al. Cardiac Shock Wave Therapy Reduces Angina and Improves Myocardial Function in Patients With Refractory Coronary Artery Disease[J]. Clin Cardiol, 2010,33:693-699.
[27]王钰,郭涛,蔡红雁,等.体外心脏震波治疗冠心病的应用研究[J].中华心血管病杂志,2010,38：711-715.
[28]杨萍,郭涛,彭云珠,等.体外心脏震波治疗冠心病的有效性研究.重庆医学,2011,40(29)：2918-2921.
[29]杨萍,彭云珠,郭涛,等.体外心脏震波治疗冠心病患者的临床研究.重庆医学,2012,41(9)：847-851.
[30]Yusuf S, Reddy S, Ounpuu S, et al. Global burden of cardiovascular disease:Part Ⅱ:variation in cardiovascular disease by specific ethnic groups and geographic regions and prevention strategies [J]. Circulation,2001,104:2855-2864.
[31]中华医学会心血管病学分会,中华心血管病杂志编辑委员会.急性ST段抬高型心肌梗死诊断和治疗指南2010[J].中华心血管病杂志,2010,38(8)：675-687.
[32]Cerqueira MD, Weissman NJ, Dilsizian V, et al. American Heart Association Writing Group on Myocardial Segmentation and Registration for Cardiac Imaging. Standardized myocardial segmentation and nomenclature for tomographic imaging of the heart:a statement for healthcare professionals from the cardiac imaging committee of the Council on Clinical Cardiology of the American Heart Association[J]. J Nucl Cardiol,2002,9:240-245.
[33]方理刚,李隽,陈黎波,等.小剂量腺苷负荷超声心动图试验与双核素心肌显像检测急性心肌梗死后患者存活心肌比较[J].临床心血管病志,2009,25：623-626.
[34]Khattab AA, Brodersen B, Schuermann-Kuchenbrandt D,et al. Extracorporeal cardiac shock wave therapy:first experience in the everyday practice for treatment of chronic refractory angina pectoris[J]. Int J Cardiol,2007,121:84-85.
[35]Verrier RL,Nearing BD. Modified moving average analysis of T-wave alternans to predict ventricular fibrillation with high accuracy [J]. J Appl Physiol,2002,92:541-549.
[36]Verrier RL, Nearing BD, Larovere MT, et al. Ambulatory electrocardiogram-based tracking of T-wave alternans in postmyocardial infarction patients to assess risk of cardic arrest or arrhythmic death[J]. J Cardiovasc Electrophysiol,2003,14:705-711.
[37]杨萍,郭涛,汤亚明,等.微伏级T波电交替对心性猝死高危人群的预测价值.中华心血管病杂志,2008,36(6)：517-522.
[38]Bittner V, Weiner DH, Yusuf S,et al. Prediction of mortality and morbidity with a 6-minute walk test in patients with left ventricular dysfunction. SOLVD Investigtors [J].JAMA, 1993,270 (14):1702-1707.
[39]peters P, Mets T. The 6-minute walk test as an appropriate exercise test in elderly patients with chronic heart failure [J]. J Gerontol A Biol Sci Med Sci,1996,54:M147-151.
[40]Matsunari I, Kanayama S, Yoneyam AT, et al. Electrocardiographic gated dual isotope simultaneous acquisition SPECT using 18F-FDG and 99mTc-sestamibi to assess myocardial viability and function in a single study[J]. Eur J Nucl Med Mol Imaging,2005,32:195-202.
[41]Slartr H, Baxj J, Deboer J, et al. Comparison of 99mTc-sestamibi/18FDG DISA SPECT with PET for the detection of viability in patients with coronary artery disease and left ventricular dysfunction[J]. Eur J Nucl Med Mol Imaging,2005,32:972-979.
[42]Prinz C, Lindner O, Bitter T, et al. Extracorporeal Cardiac Shock Wave Therapy Ameliorates Clinical Symptoms and Improves Regional Myocardial Blood Flow in a Patient with Severe Coronary Artery Disease and Refractory Angina [J]. Case Reports Med,2009,639594,3-10.
[43]Nearing BD, Verrier RL. Progressive increases in complexity of T-wave oscillations herald ischemia-induced ventricular fibrillation[J] Cir Res,2000,91:727-732.
[44]Ikeda T, Saito H, Tanno K, et al. T-wave alternans as a predictor for sudden cardiac death after myocardial infarction[J]. Am J Cardiol,2002,89:79-82.
[45]蒲里津,汤亚明,郭涛,等.在常规运动试验中以时域法微伏级T波电交替筛查冠心病的价值[J].中国循环杂志,2011,26(3)：190-193.
[46]Walker MR, Rosenbaum DS. Repolarization alternans:implications for the mechanism and prevention of sudden cardiac death [J]. Cardiovas Res,2003,57(3):599-614.
[47]Pruvot EJ, Karte RP, Rosenbaum DS, et al. Role of calcium cycling versus restitution in the mechanism of repolarisation alternans[J]. Circ Res,2004,94(8):1083-1090.
[48]MacMurdy KS, Kirk MM, Cooklin M, et al.Gold MR. The effect of selective autonomic blockade on T-wave alternans[J].Circulation,1999,100(Suppl):2683.
[49]Marban E, Kitakaze M, Koretsune Y, et al. Quantification of [Ca2+] in perfused hearts: critical evaluation of the 5F-BAPTA and nuclear magnetic resonance method as applied to the study of ischemia and reperfusion[J]. Circ Res,1990,66:1255-1267.
[50]Kop WJ, Krantz DS, Nearing BD, et al. Effects of acute mental stress and Exercise on T-wave alternans in patients with implantable cardioverter defibrillators and controls[J]. Circulation,2004,109:1-6.
[51]Verrier RL, Nearing BD. Electrophysiologic basis for T-ware alternans as an index of vulnerability to ventricular fibrillation [J]. J Carbiovasc Electrophysiol,1994,5 (6):445-446.
[52]Rosenbaum DS, Jackson LE, Smith JM, et al. Electrical alternans and vulnerability to ventricular arrythmias [J]. N Engl J Med,1994,330 (3):235-241.
[53]Gale NW, Yancopoulos GD. Growth factors acting via endothelial cell specific receptor tyrosine kinases:VEGF's, angiopoietins and ephrins in vascular development[J]. Genes Dev, 1999,13 (78):1055-1066.
[54]Devel L, Rogakos V, David A, et al. Development of selective inhibitors and substrate of matrix metallo proteinase-12 [J]. J Biol Chem,2006,281 (16):11152-11160.
[55]Igarashi J, Miyoshi M, Hashimoto T, et al. Statins induce S1PI receptors and enhance endothelial nitric oxide production in response to high-density lipoproteins[J]. Br J Pharmacol,2007,150 (4):470-479.
[56]Thurston G, Rudge JS, Ioffe E, et al. Angiopoietin-1 protects the adult vascularture against plasma leakage[J]. NatMed,2000,6 (36):460-463.
[57]Hirschi K, Rohovsky S, D'Amore P. PDGF, TGF-β and heterotypic cell-cell interactionsmediate endothelial cell induced recruitment of 10T1/2 cells and their differentiation to a smoothmuscle fate [J]. J CellB iol,1998,141 (846):805-814.
[58]MassaM, Rosti V, Ferrario M, et al. Increased circulating hematopoietic and endothelial p-rogenitor cells in the early phase of acute myocardial infarction [J].Blood,2005,105: 199-206.
[59]Ceradini DJ, Kulkarni AR, Callaghan MJ, et al. Progenitor cell trafficking is regulated by hypoxic gradients through H IF-1 induction of SDF-1 [J]. Nat Med,2004,10:858-864.
[60]Aicher A, Heescher C, Sasak K, et al. Low-energy shock wave for enhancing recrutement of endothelial progenitor cell; a new modality to increase efficacy of cell therapy in chronic hind limb ischemia [J]. Mol Cardiol,2006,10:2819-2823.
[61]Andre Pasternac, Martial G. Bourassa. Pathogenesis of chest pain in patients with cardiomyopathies and normal coronary arteries [J]. Inter.J.Cardiol,1983(3):273-280.
[62]Nurzynska D, Meglio FD, Castaldo C, et al. Shock waves activate in vitro cultured progenitors and precursors of cardiac cell lineages from the human heart [J]. Ultrasound in Med & Biol,2008,34:334-342.
[63]Dvorak P, Hampl A. Basic fibroblast growth factor and its receptors in human embryonic stem cells [J]. Folia Histochem Cytobiol,2005,43(4):203-208.
[64]Fam N P. Verma S, Kutryk M, et al. Clinician Guide to Angiogenesis [J].Circulation,2003, 108(21):2613-2618.
[65]Bottcher R T, Niehrs C. Fibroblast growth factor signaling during early vertebrate development[J]. Endocrine Rev,2005,26(1):63-77.
[66]Fisher AB, Chien S, Barakat AI,et al. Endothelial cellular response to altered shear stress[J]. Am J Physiol,2001,28:L529-L533.
[67]Ichioka S, Shibata M, Kosaki K, et al. Effects of shear stress on wound healing angiogenesis in the rabbit ear chamber[J]. J Surg Res,1997,72:29-35.
[68]Mariotto S.Cavalieri E, Amelio E, et al. Extracorporeal shock waves:from lithotripsy to anti-inflammatory action by NO production[J]. Nitric Oxide,2005,12:89-96.
[69]Anna R, Carcereri A, Amelio E, et al. Nitric oxide mediates anti-inflammatory action of extracorporeal shock waves[J]. FEBS Lett,2005,579:6839-6845.
[70]Oi K, Fukumoto Y, Ito K, et al. Extracorporeal shock wave therapy ameliorates hindlimb ischemiain rabbits[J]. Tohoku J Exp Med,2008,214:151-158.
[71]Ito Y, Ito K, Shiroto T, et al. Cardiac shock wave therapy ameliorates left ventricular remodeling after myocardial ischemia reperfusion injury in pigs in vivo[J]. Coron Artery Dis, 2010,21:304-311.
[72]Fu M, Sun CK, Lin YC, et al. Extracorporeal Shock Wave Therapy Reverses Ischemia-Related Left Ventricular Dysfunction and Remodeling:Molecular-Cellular and Functional Assessment[J].PLoS One,2011;6(9):e24342.
[73]Iwakiri Y, Satoh A, Chatterjee S, et al. Nitric oxide synthase generates nitric oxide locally to regulate compartmentalized protein S-nitrosylation and protein trafficking[J]. Proc Natl Acad Sci,2006,103:19777-19782.
[74]Puddu GM, Cravero E, Arnone G, et al. Molecular aspects of atherogenesis:new insights and unsolved questions[J]. J Biomed Sci,2005,12:839-853.
[75]Yetik- Anacak G, Catravas JD. Nitric oxide and the endothelium:History and impact on cardiovascular disease[J]. Vascul Pharmacol,2006,45:268-276.
[76]Gooch KJ,Dangler CA, Frangos JA,et al. Exogenous, basal, and flow-induced nitric oxide production and endothelial cell proliferation[J] J Cell Physiol,1997,171 (3):252-258.
[77]Duda DG, Fukumura O, Jain RK. Role of eNOS in neovascularization:NO for endothelial progenitor cells[J]. Trends Mol Med,2004,10(4):143-145.
[78]Fulton D, Gratton JP, McCabe TJ, et al. Regulation of endothelium-derived nitric oxide production by the protein kinase Akt[J]. Nature,1999,399(6736):597-601.
[79]Tian J, Hou Y, Lu Q, et al. A novel role for caveolin-1 in regulating endothelial nitric oxide synthase activation in response to H2O2 and shear stress [J]. Free Radic Biol Med, 2010,49(2):159-170.
[80]Aicher A, C Heeschen, C Mildner-Rihm, et al. Essential role of endothelial nitric oxide synthase for mobilization of stem and progenitor cells[J]. Nat Med,2003;9:1370-6.
[81]Cai WJ, Elisabeth K, Luo XG, et al. Expression of endothelial nitric oxide synthase in the vascular wall during arteriogenesis[J]. Mol Cell Biochem,2004,264(1-2):193-200.
[82]Jones SP, Greer JJ, van Haperen R, et al. Endothelial nitric oxide synthase overexpression attenuates congestive heart failure in mice[J]. Proc Natl Acad Sci,2003,100:4891-4896.
[83]Rifkin DB, Moscatelli D. Resent development in the ceil biology of basic fibr oblast growth factor[J]. J Cell Bio 1,1989,109:1.
[84]Damico F M. Angiogenesis and retinal diseases [J]. Arq Bras Oftlmol,2007,70(3):547-553.
[85]Nakajima H, Sakakibara Y, Tambara K. Therapeutic angiogenesis by the controlled release of basic fibroblast growth factor for ischemic limb and heart injury:toward safety and minimal invasiveness [J]. Artif Organs,2004,7(2):58-61.
[86]Koivisto H, Hyvarinen M, Stromberg AM, et al. Cultures of human embryonic stem cells: serum replacement medium or serum-containing media and the effect of basic fibroblast growth factor[J]. Reprod Biomed Online,2004,9(3):330-337.
[87]Hall H. Modified fibrin hydrogel matrices:both,3D-scaffolds and local and controlled release systems to stimulate angiogenesis[J]. Curr Pharm Des,2007, (35):3597-3607.
[88]Gleichmann M, Gillen C, Czardybon M. et al. Cloning and characterization of SDF-1 gamma, a novel chemokine transcript with developmentally regulated expression in the nervous systerm[J]. Eur J Neurosci,2000 Jun; 12(6):1857-66.
[89]Askari AT, Unzek S, Popovic ZB, et al. Effect of stromal-cell-derived factor 1 on stem-cell homing and tissue regeneration in ischaemic cardiomyopathy[J]. Lancet,2003,362 (9385):697-703.
[90]Schober A, Knarren S, Lietz M, et al.Crucial role of Stromal cell derived factor-1alpha in neointima formation after vascular injury in apolipoprotein E-deficient mice[J]. Circulation, 2003,108 (20):2491-2497.
[91]Yamaguchi J, Kusano K. Masuo O, et al. Stromal cell derived factor-1 effects on exvivo expanded endothelial progenitor cell recruitment for ischemic neovascularization [J]. Circulation,2003,107 (9):1322-1328.
[92]Kijow sk i J, BajKrzyworzeka M, Iizasa H, et al. The SDF-1-CXC R4 axis stim ulates VEGF secretion and activates integrins but does not affect proliferation and survival in lymphohematopoietic cells[J]. Stem Cells,2001,19 (5):453-466.
[93]Guleng B. Tateishi K, Ohta M, et al. Blockade of the stromal cell-derived fact or-1/CXCR4 axis attenuates in vivo tumor growth by inhibiting angiogenesis in a vascular endothelial growth factor independent manner[J]. Cancer,2005,65 (13):5864-5871.
[94]Tang Y, Qian K, Zhan g Y, et al. Mobilizing of haematopoiet ic stem cells to ischemic myocardium by plasmid mediated stromal-cell-derived factor-1 (SDF-la) treatment [J]. Regulatory Peptides,2005,125(18):1-8.