骨髓间充质干细胞心肌移植后室性心律失常的危险性评估及其机制分析
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摘要
背景
在发达国家心血管疾病是导致死亡的最主要疾病，其中一半是由冠状动脉粥样硬化性心脏病(CHD)引起的。据WHO统计目前每年约有720万人死于CHD，约占全球总死亡人数的1／6。随着发展中国家冠心病发病率的不断增多，形势可能会进一步恶化，越来越多的冠心病患者会出现更为严峻的并发症——心力衰竭，因为流行病学调查发现心衰病人的1年生存率与癌症病人相当或更低，如乳腺癌患者诊断后1年预期生存率为92％，而心衰患者仅有62％。
目前认为冠心病心衰的主要病理生理机制是心肌细胞缺血损伤后功能丧失或死亡致有功能的心肌细胞数绝对减少。由于心肌细胞自身修复和再生能力极低，药物因不能增加心肌细胞数，其改善心功能的作用有限，异体心脏移植虽可解决心衰问题、缓解病人症状，但因供体缺乏和器官排斥等原因限制了其临床运用，因此临床迫切需要有新的治疗途径来解决因心肌细胞丧失而引发的心衰问题。源于胚胎干细胞研究的细胞移植技术就是目前被广泛关注的新的治疗途径。初期研究证实胚胎干细胞移植后能修复或替代损伤的细胞，在恢复心功能方面疗效显著，但因来源短缺和伦理问题影响了其治疗前景。近年成体干细胞的研究进展再度激发了人们对细胞移植治疗的兴趣，大量研究显示成体干细胞移植后确能在一定程度上改善心功能水平。不过由于干细胞研究尚处于初级阶段(at its infancy)，人们对干细胞治疗的安全性尚存疑虑。最近临床研究发现，10名接受骨骼肌成肌
Backgrouds
Cardiovascular disease (CVD) is the leading cause of death in developed countries, of which nearly half is attributable to coronary heart disease (CHD). Globally, CHD accounted for one-sixth of all deaths with the World Health Organization estimating 7.2 million from CHD each year[1-2］ As the morbidity associated with CHD is increasing in developing countries, this situation is expected to become worse.One of the most devastating sequelae of CHD is the development of heart failure since patients with heart failure have 1-year survival rates that are comparable, if not worse, than patients suffering with cancel[3-5]
Heart failure in the context of CHD is characterized patho -physiologically by loss of functioning cardiomyocytes secondary to ischaemic injury[6]. As cardiomyocytes have a very low potential for repair and regeneration, the ability of pharmacological agents to improve cardiac function is limited as these agents do not address the fundamental issue of cell loss. This has led to the search for a new approach in the treatment of patients with heart failure. Currently, there are two therapeutic strategies that overcome the problem of cell loss in heart failure. Heterotropic heart transplantation is able to resolve the problems of heart failure and relieve patients' symptoms, however, this treatment option is severely limited by donor organ availability and problems of
在发达国家心血管疾病是导致死亡的最主要疾病，其中一半是由冠状动脉粥样硬化性心脏病(CHD)引起的。据WHO统计目前每年约有720万人死于CHD，约占全球总死亡人数的1／6。随着发展中国家冠心病发病率的不断增多，形势可能会进一步恶化，越来越多的冠心病患者会出现更为严峻的并发症——心力衰竭，因为流行病学调查发现心衰病人的1年生存率与癌症病人相当或更低，如乳腺癌患者诊断后1年预期生存率为92％，而心衰患者仅有62％。
目前认为冠心病心衰的主要病理生理机制是心肌细胞缺血损伤后功能丧失或死亡致有功能的心肌细胞数绝对减少。由于心肌细胞自身修复和再生能力极低，药物因不能增加心肌细胞数，其改善心功能的作用有限，异体心脏移植虽可解决心衰问题、缓解病人症状，但因供体缺乏和器官排斥等原因限制了其临床运用，因此临床迫切需要有新的治疗途径来解决因心肌细胞丧失而引发的心衰问题。源于胚胎干细胞研究的细胞移植技术就是目前被广泛关注的新的治疗途径。初期研究证实胚胎干细胞移植后能修复或替代损伤的细胞，在恢复心功能方面疗效显著，但因来源短缺和伦理问题影响了其治疗前景。近年成体干细胞的研究进展再度激发了人们对细胞移植治疗的兴趣，大量研究显示成体干细胞移植后确能在一定程度上改善心功能水平。不过由于干细胞研究尚处于初级阶段(at its infancy)，人们对干细胞治疗的安全性尚存疑虑。最近临床研究发现，10名接受骨骼肌成肌
Backgrouds
Cardiovascular disease (CVD) is the leading cause of death in developed countries, of which nearly half is attributable to coronary heart disease (CHD). Globally, CHD accounted for one-sixth of all deaths with the World Health Organization estimating 7.2 million from CHD each year[1-2］ As the morbidity associated with CHD is increasing in developing countries, this situation is expected to become worse.One of the most devastating sequelae of CHD is the development of heart failure since patients with heart failure have 1-year survival rates that are comparable, if not worse, than patients suffering with cancel[3-5]
Heart failure in the context of CHD is characterized patho -physiologically by loss of functioning cardiomyocytes secondary to ischaemic injury[6]. As cardiomyocytes have a very low potential for repair and regeneration, the ability of pharmacological agents to improve cardiac function is limited as these agents do not address the fundamental issue of cell loss. This has led to the search for a new approach in the treatment of patients with heart failure. Currently, there are two therapeutic strategies that overcome the problem of cell loss in heart failure. Heterotropic heart transplantation is able to resolve the problems of heart failure and relieve patients' symptoms, however, this treatment option is severely limited by donor organ availability and problems of
引文
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9．陆再英．心率变异性．见：陈新，主编．临床心律失常学．第1版．北京：人民卫生出版社，2000．249-291．
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1. Min JY, Sullivan MF, Yang Y, et al. Significant improvement of heart function by cotransplantation of human mesenchymal stem cells and fetal??cardiomyocytes in postinfarcted pigs. Ann Thorac Surg, 2002,74:1568-75.
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3. Qayyum MS, Takizawa K, Frantzen M, et al. Mesenchymal stem cell therapy prevents deterioration of left ventricular function in a porcine myocardial infarction model [Abstract]. J Am Coll Cardiol, 2002,39:169A.
4. Smits PC, van Geuns R-J, Poldermans D, et al. Catheter-based intramyocardial injection of autologous skeletal myoblasts as a primary treatment of ischemic heart failure: clinical experience with six-month follow-up. J Am Coll Cardiol, 2003, 42: 2063-9.
5. Menasche P, Hagege AA, Scorsin M, et al. Myoblast transplantation for heart failure. Lancet, 2001, 357:279-80.
6. Menasche P, Hagege AA, Vilquin JT, et al. Autologous skeletal myoblast transplantation for severe postinfarction left ventricular dysfunction. J Am Coll Cardiol, 2003, 41:1078-83.
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1. Menasche P, Hagege AA, Scorsin M, et al. Myoblast transplantation for heart failure. Lancet, 2001, 357: 279-80.
2. Menasche P, Hagege AA, Vilquin JT, et al. Autologous skeletal myoblast transplantation for severe postinfarction left ventricular dysfunction. J Am Coll Cardiol, 2003, 41: 1078-83.3. Smits PC, van Geuns R-J, Poldermans D, et al. Catheter-based intramyocardial injection of autologous skeletal myoblasts as a primary treatment of ischemic heart failure: clinical experience with six-month follow-up. J Am Coll Cardiol, 2003, 42: 2063-9.
4.Robinson SW,Cho PW,Levitsky HI,et al.Arterial delivery of genetically labelled skeletal myoblasts to the murine heart: long-term survival and phenotypic modification of implanted myoblasts. Cell Transplant, 1996,5:77-91.
5.Shintani S,Murohara T,Ikeda H,et al .Mobilization of endothelial progenitor cells in patients with acute myocardial infarction.Circulation,2001,103:2776-9.
6.Asahara T,Masuda H,Takahashi T,et al.Bone marrow origin of endothelial progenitor cells responsible for postnatal vasculogenesis in physiological and pathological neovascularization.Cir Res,1999,85:221-8.
7.Takahashi T,Kalka C,Masuda H,et al.Ischemia- and cytokine- induced mobilization of bone marrow-derived endothelial progenitor cells for neovascularization.Nat Med, 1999,5:434-8.
8.Kawamoto A,Gwon HC,Iwagura H,et al. Therapeutic potential of ex vivo expanded endothelial progenitor cells for myocardial ischemia. Circulation,2001,103:634-7.
9.Kocher AA,Schuster MD,Szabolcs MJ,et al. Neovasculariza -tion of ischemic myocardium by human bone marrow-derived angioblasts??prevents cardiomyocyte apoptosis, reduces remodeling and improves cardiac function. Nat Med,2001,7:430 -6.
10. Leobon B, Garcin I, Menasche P, et al. Myoblasts transplanted into rat infarcted myocardium are functionally isolated from their host. Proc Natl Acad Sci USA 2003;100:7808-11.
11.Daniele Noel, Dan Gazit, Celine Bouquet, et al. Short-Term BMP-2 Expression Is Sufficient for In Vivo Osteochondral Differentiation of Mesenchymal Stem Cells. Stem Cells 2004; 22:74-85.
12. Hui-nam PAK, Mohammed Qayyum, Dave T. Kim, et al. Mesenchymal stem cell injection induces cardiac nerve sprouting and increased tenascin expression in a swine model of myocardial infarction. J Cardiovasc Electrophysiol 2003; 14:841-848.
13. Emerson C. Perin, Hans F.R. Dohmann, Radovan Borojevic, et al. Transendocardial, Autologous Bone Marrow Cell Transplantation for Severe, Chronic Ischemic Heart Failure. Circulation 2003; 107:2294-2302.
14. Nobuyuki Sasaki, Ryo Fukatsu, Kayo Tsuzuki,et al. Advanced Glycation End Products in Alzheimer's Disease and Other Neurodegenerative Diseases. Am J Pathol 1998;153:1149-1155.
15. George Vassilopoulos, Pei-Rong Wang, David W. Russell. Transplanted bone marrow regenerates liver by cell fusion. Nature 2003;422:901-4.16.Donald O, Jan K, Stefano C, et al. Bone marrow cells regenerate infarcted myocardium. Nature,2001,410:701-5.
1. Hui-nam PAK, Mohammed Qayyum, Dave T. Kim, et al. Mesenchymal stem cell injection induces cardiac nerve sprouting and increased tenascin expression in a swine model of myocardial infarction. J Cardiovasc Electrophysiol, 2003, 14: 841-848.
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