A Mechanism And Efficiency Evaluation Of Cardiac Shock Wave Therapy(CSWT) In Patients Without Coronary Artery Revascularization

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 RevascularizationObjective 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.Results①During 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 PatientsObjective 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.Results①Before 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.