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Local adenovirus-mediated transfer of C-type natriuretic peptide suppresses vascular remodeling in porcine coronary arteries in vivo

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JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY 2000年第4期35卷 1040-1047页

作者： Morishige, K Shimokawa, H Yamawaki, T Miyata, K Eto, Y Kandabashi, T Yogo, K Higo, T Egashira, K Ueno, H Takeshita, A Kyushu Univ Grad Sch Med Sci Dept Cardiovasc Med Higashi Ku Fukuoka 8128582 Japan

OBJECTIVE This study was designed to examine whether or not adenovirus-mediated gene transfer of C-type natriuretic peptide (CNP) can prevent coronary restenotic changes after balloon injury in pigs in vivo. BACKGROUND Gene therapy to prevent restenosis after percutaneous transluminal coronary angioplasty (PTCA) might be useful but requires a method applicable for in vivo gene delivery into the coronary artery as well as the efficient vector encoding a potent antiproliferative substance. We tested whether the adenovirus-mediated gene transfer of CNP by use of an infiltrator angioplasty balloon catheter (IABC) might prevent the coronary restenotic changes after balloon injury. METHODS Balloon angioplasty was performed in the left anterior descending and the left circumflex coronary artery in pigs. Immediately after the balloon injury, adenovirus solution encoding either CNP (AdCACNP) or beta-galactosidase (AdCALacZ) gene was injected with IABC into the balloon-injured coronary segments. Expression of CNP was assessed by immunohistochemical staining and cyclic guanosine 3',5'-monophosphate (cGMP) measurement. Coronary restenotic changes were evaluated by both angiographic and histological examinations. RESULTS CNP was highly expressed in the media and the adventitia of the coronary artery at the AdCACNP-transfected but not at the AdCALacZ-transfected segment. In the AdCALacZ-transfeaed segment, vascular cGMP levels tended to be reduced as compared with the untreated segment, whereas in the AdCACNP-transfected segment, vascular cGMP levels were restored. Angiographic coronary stenosis was significantly less at the AdCACNP-transfected than at the AdCALacZ-transfected segment. Histological examination revealed that this was achieved primarily by the marked inhibition of the geometric remodeling of the coronary artery by the CNP gene transfer. CONCLUSIONS Adenovirus-mediated CNP gene transfer with the IABC system may be a useful gene therapy to prevent restenosis after PT

关键词：腺病毒科/遗传学血管成形术气囊冠状动脉冠状血管造影术冠状动脉循环/遗传学冠心病/遗传学冠心病/病理学冠心病/治疗冠状血管/损伤冠状血管/病理学基因表达调控/生理学基因转移技术利钠肽 C型/遗传学复发猪动物

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Racial heterogeneity in coronary artery vasomotor reactivity: Differences between Japanese and Caucasian patients

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JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY 1999年第6期33卷 1442-1452页

作者： Beltrame, JF Sasayama, S Maseri, A Univ Adelaide Cardiol Unit NW Adelaide Hlth Serv Adelaide SA 5005 Australia Kyoto Univ Hosp Dept Cardiovasc Med Grad Sch Med Kyoto 606 Japan Univ Cattolica Sacro Cuore Cardiol Inst Agostino Gemelli Hosp I-00168 Rome Italy

Japanese investigators have provided a substantial contribution in the understanding of coronary vasomotor reactivity: On occasions, their findings have been at variance with those undertaken on caucasian patients, raising speculation that vasomotor differences between races may exist. In a comparative review of the published literature, we evaluated the vasoreactive differences among Japanese and caucasian patients with variant angina or myocardial infarction. Tn variant angina, Japanese patients appear to have diffusely hyperreactive coronary arteries compared with caucasian people, manifested by their segmental rather than focal spasm, hyperreactive nonspastic vessels and multivessel spasm. These differences may reflect the increased basal tone among Japanese variant angina patients and may relate to controversial differences in endothelial nitric oxide production or autonomic nervous system activity. Provocative vasomotor studies of Japanese patients with a recent myocardial. infarction report a higher incidence of inducible spasm than caucasian studies, an observation recently supported by a controlled study. Furthermore, the hyperreactivity was diffuse, occurring in both non-infarct- and infarct-related vessels. These observations support the existence. of racial coronary vasomotor reactivity differences but require confirmation in further prospectively conducted studies. (C) 1999 by the American College of Cardiology.

关键词：心绞痛变异型/人种学心绞痛变异型/遗传学亚洲大陆世系人群/遗传学自主神经系统/病理生理学冠状动脉循环/遗传学冠状动脉循环/生理学冠状血管痉挛/人种学冠状血管痉挛/遗传学冠状血管痉挛/病理生理学欧洲大陆世系人群/遗传学心肌梗死/人种学心肌梗死/遗传学心肌梗死/病理生理学一氧化氮/生理学血管舒缩系统/病理生理学成年人老年人老年人 80以上女(雌)性人类男(雄)性中年人

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Electromagnetic guidance for catheter-based transendocardial injection: A platform for intramyocardial angiogenesis therapy - Results in normal and ischemic porcine models

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JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY 2000年第4期35卷 1031-1039页

作者： Kornowski, R Leon, MB Fuchs, S Vodovotz, Y Flynn, MA Gordon, DA Pierre, A Kovesdi, I Keiser, JA Epstein, SE Washington Hosp Ctr Cardiovasc Res Fdn Expt Pharmacol & Myocard Revascularizat Program Washington DC 20010 USA Warner Lambert Parke Davis Parke Davis Pharmaceut Res Dept Cardiovasc Therapeut Ann Arbor MI 48105 USA GenVec Inc Rockville MD USA

OBJECTIVES To test the feasibility of myocardial angiogenic gene expression using a novel catheter-based transendocardial injection system. BACKGROUND Angiogenesis has been induced by direct injection of growth factors into ischemic myocardium during open-heart surgery. METHODS Catheter-based. transendocardial injection of angiogenic factors may provide equivalent benefit without need of surgery. A new guidance system for intramyocardial therapy utilizes magnetic fields and catheter-tip sensors to locate a position in space and reconstruct three-dimensional left ventricular (LV) electromechanical maps without using fluoroscopy. A retractable 27G needle was coupled with the guidance system for LV transendocardial injection. In 12 pigs, the catheter was used to inject 0.1 ml of methylene-blue (MB) dye and 8 pigs had myocardial injections of adenoviral vector (1 x 10(10) particles per site) containing the LacZ transgene. Ten pigs underwent catheter-based transendocardial injection and six pigs were injected using transepicardial approach with the gene encoding adenovirus vascular endothelial growth factor-121 (***(121);1 X 10(10) viral particles X 6 sites) and sacrificed at 24 h. Injection sites were identified with ultraviolet light by coinjection of fluorescent beads. RESULTS Overall, 138 of 152 attempted injection MB tracks (91%) were found after sacrifice. Tissue staining was 7.1 +/- 2.1 mm in depth and 2.3 +/- 1.8 mm in width. No animal had pericardial effusion or tamponade. In *** injected animals, gross pathology showed positive staining in injected zones, and histology confirmed positive myocyte staining. Adenovirus vascular endothelial growth factor-121 injected sites showed high levels of VEGF(121) production that was of similar magnitude whether injected using the transendocardial (880.4 +/- 412.2 pg VEGF(121)/mg protein) or transepicardial (838.3 +/- 270 pg VEGF(121)/mg protein) delivery approach (p = 0.62). CONCLUSIONS Using this magnetic guidance

关键词：体表电位图/仪器和设备冠状动脉循环/遗传学心内膜/病理学内皮生长因子/投药和剂量内皮生长因子/遗传学设备设计可行性研究基因转移技术/仪器和设备图像处理计算机辅助/仪器和设备注射淋巴因子/投药和剂量淋巴因子/遗传学心肌缺血/遗传学心肌缺血/病理学心肌缺血/治疗心包/病理学血管内皮生长因子A 血管内皮生长因子类动物

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Genetic determinants of coronary vasomotor tone in humans

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AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY 2001年第4期281卷 H1465-H1468页

作者： Heusch, G Erbel, R Siffert, W Univ Klinikum Essen Abt Pharmakol D-45122 Essen Germany Univ Klinikum Essen Abt Kardiol D-45122 Essen Germany Univ Klinikum Essen Abt Pathophysiol D-45122 Essen Germany

Editorial. Discusses the determinants of coronary vasomotor tone in humans. Number of single nucleotide polymorphisms that comprised human genome; Details of G protein beta-3 subunit gene C825T polymorphism and coronary vasoconstrictor responsiveness; Endothelial nitric oxide synthase polymorphism and coronary spasm; Detection of other polymorphisms that are associated with cardiovascular disease.

关键词：冠状动脉循环/遗传学冠状血管痉挛/遗传学 GTP结合蛋白质类/遗传学一氧化氮合酶/遗传学一氧化氮合酶Ⅲ型多态现象遗传/生理学蛋白质亚型/遗传学血管舒缩系统/生理学人类

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Gene therapy for myocardial angiogenesis

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AMERICAN HEART JOURNAL 1999年第2期138卷 S132-S141页

作者： Losordo, DW Vale, PR Isner, JM Tufts Univ Dept Med Div Cardiovasc Med St Elizabeths Med CtrSch Med Boston MA 02135 USA

In patients in whom antianginal medications fail to provide sufficient symptomatic relief, additional interventions such as angioplasty or bypass surgery may be required. Although both types of intervention have been shown to be effective for various types of patients, a certain group of patients may not be candidates for either intervention because of the diffuse nature of their coronary artery disease. Moreover, there ore many patients in whom recurrent narrowing and/or occlusion of bypass conduits after initially successful surgery has left the patient again symptomatic with no further angioplasty or surgical option. Ischemic muscle represents a promising target for gene therapy with naked plasmid DNA. Intramuscular transfection of genes encoding angiogenic cytokines, particularly those naturally secreted by intact cells, may constitute an alternative treatment strategy for patients with extensive tissue ischemia in whom contemporary therapies (antianginal medications, angioplasty, bypass surgery) have previously failed or are not feasible. This strategy is designed to promote the development of supplemental collateral blood vessels that will constitute endogenous bypass conduits around occluded native arteries, a strategy termed "therapeutic angiogenesis." preclinical animal studies from our laboratory have established that intramuscular gene transfer may be used to successfully accomplish therapeutic angiogenesis. More recently, phase 1 clinical studies from our institution have established that intramuscular gene transfer may be used to safely and successfully accomplish therapeutic angiogenesis in patients with critical limb ischemia, The notion that this concept could be extrapolated to the treatment of chronic myocardial ischemia was demonstrated in our laboratory by administering recombinant human vascular endothelial growth Factor (VEGF) to a porcine model of chronic myocardial ischemia. Recent experiments performed in this same porcine model of myocardia

关键词：侧支循环/遗传学冠状动脉循环/遗传学冠心病/外科学冠状血管/生理学 DNA 疾病模型动物内皮生长因子/遗传学基因疗法缺血/治疗腿/血液供给淋巴因子/遗传学心肌梗死/治疗新生血管化生理性/遗传学质粒蛋白质亚型/遗传学复发转染血管内皮生长因子A 血管内皮生长因子类动物人类

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