The Effect of Oligonucleotides to c-myb on Vascular Smooth Muscle Cell Proliferation and Neointima Formation After Porcine Coronary Angioplasty
Proto-oncogenes, including c-myb, are expressed early after vascular injury. The application of antisense oligodeoxynucleotides (AS-ODNs) against these genes inhibits cell proliferation and neointima formation in small animals and in peripheral arteries. The aim of this study was to investigate the...
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| Veröffentlicht in: | Circulation research 1997-04, Vol.80 (4), p.520-531 |
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| creator | Gunn, Julian Holt, Cathy M Francis, Sheila E Shepherd, Lynda Grohmann, Malcolm Newman, Christopher M.H Crossman, David C Cumberland, David C |
| description | Proto-oncogenes, including c-myb, are expressed early after vascular injury. The application of antisense oligodeoxynucleotides (AS-ODNs) against these genes inhibits cell proliferation and neointima formation in small animals and in peripheral arteries. The aim of this study was to investigate the specificity of action of AS-ODN-c-myb in vitro and to assess its effect, when delivered locally, on neointima formation after percutaneous transluminal coronary angioplasty (PTCA) in porcine coronary arteries. AS-ODN-c-myb inhibited the proliferation of vascular smooth muscle cells (VSMCs) in vitro in a dose-dependent manner. There was a corresponding reduction in steady state levels of c-myb mRNA and protein. Expression of another early gene, c-fos, was unaffected. S1 nuclease analysis demonstrated intact full-length AS-ODN-c-myb retrieved from VSMCs in culture after 12 hours. A range of ODNs, related and unrelated to c-myb, with and without a GGGG sequence, inhibited VSMC proliferation. Phosphorothioated AS-ODN-c-myb was 30 times less potent than unphosphorothioated AS-ODN-c-myb. PTCA induced porcine coronary artery neointima formation. c-myb mRNA was maximally induced 18 hours after injury. Unmodified AS-ODN-c-myb, sense-ODN-c-myb, saline, or nothing was delivered immediately after balloon dilatation via a double-skinned porous balloon (Transport, SciMed). Fluorescence-labeled AS-ODN-c-myb was deposited throughout the vessel wall. Mean maximum intima/media cross-sectional area 4 weeks after PTCA was reduced with AS-ODN-c-myb by 79% compared with saline (P |
| doi_str_mv | 10.1161/01.RES.80.4.520 |
| format | Article |
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The application of antisense oligodeoxynucleotides (AS-ODNs) against these genes inhibits cell proliferation and neointima formation in small animals and in peripheral arteries. The aim of this study was to investigate the specificity of action of AS-ODN-c-myb in vitro and to assess its effect, when delivered locally, on neointima formation after percutaneous transluminal coronary angioplasty (PTCA) in porcine coronary arteries. AS-ODN-c-myb inhibited the proliferation of vascular smooth muscle cells (VSMCs) in vitro in a dose-dependent manner. There was a corresponding reduction in steady state levels of c-myb mRNA and protein. Expression of another early gene, c-fos, was unaffected. S1 nuclease analysis demonstrated intact full-length AS-ODN-c-myb retrieved from VSMCs in culture after 12 hours. A range of ODNs, related and unrelated to c-myb, with and without a GGGG sequence, inhibited VSMC proliferation. Phosphorothioated AS-ODN-c-myb was 30 times less potent than unphosphorothioated AS-ODN-c-myb. PTCA induced porcine coronary artery neointima formation. c-myb mRNA was maximally induced 18 hours after injury. Unmodified AS-ODN-c-myb, sense-ODN-c-myb, saline, or nothing was delivered immediately after balloon dilatation via a double-skinned porous balloon (Transport, SciMed). Fluorescence-labeled AS-ODN-c-myb was deposited throughout the vessel wall. Mean maximum intima/media cross-sectional area 4 weeks after PTCA was reduced with AS-ODN-c-myb by 79% compared with saline (P<.05), 82% compared with sense-ODN-c-myb, and 63% compared with nothing (P<.10). Conclusions are as follows(1) c-myb is expressed in VSMCs after vascular injury. (2) AS-ODN-c-myb is retained intact in VSMCs, reducing their proliferation in vitro in dose-dependent fashion, with reduction in c-myb mRNA and protein, whereas sense-ODN-c-myb is not. (3) A range of ODNs can reduce VSMC proliferation by a non-sequence-specific mechanism. (4) Phosphorothioate protection of antisense molecules may reduce their efficacy. (5) Local delivery of unmodified AS-ODN-c-myb via the Transport catheter reduces neointima formation after porcine PTCA. (6) Local delivery of fluid may exacerbate neointimal thickening. (Circ Res. 1997;80:520-531.)</description><identifier>ISSN: 0009-7330</identifier><identifier>EISSN: 1524-4571</identifier><identifier>DOI: 10.1161/01.RES.80.4.520</identifier><identifier>PMID: 9118483</identifier><identifier>CODEN: CIRUAL</identifier><language>eng</language><publisher>Hagerstown, MD: American Heart Association, Inc</publisher><subject>Angioplasty, Balloon - adverse effects ; Angioplasty, Balloon, Coronary - methods ; Animals ; Biological and medical sciences ; Cattle ; Cell Division ; Cell physiology ; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes ; Cells, Cultured ; Coronary Vessels - metabolism ; Coronary Vessels - physiology ; Fluorescent Antibody Technique, Direct ; Fundamental and applied biological sciences. Psychology ; Genes, fos - physiology ; Humans ; Molecular and cellular biology ; Muscle, Smooth, Vascular - metabolism ; Muscle, Smooth, Vascular - physiology ; Oligonucleotides, Antisense - pharmacology ; Oncogenes - physiology ; RNA, Messenger - metabolism ; RNA-Binding Proteins ; Swine</subject><ispartof>Circulation research, 1997-04, Vol.80 (4), p.520-531</ispartof><rights>1997 American Heart Association, Inc.</rights><rights>1997 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4481-da980f731eaf8b66d79eb783c21bf0b99e84b395f02f8d421efe95bef60b0aef3</citedby><cites>FETCH-LOGICAL-c4481-da980f731eaf8b66d79eb783c21bf0b99e84b395f02f8d421efe95bef60b0aef3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,778,782,3676,27907,27908</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=2623585$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/9118483$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Gunn, Julian</creatorcontrib><creatorcontrib>Holt, Cathy M</creatorcontrib><creatorcontrib>Francis, Sheila E</creatorcontrib><creatorcontrib>Shepherd, Lynda</creatorcontrib><creatorcontrib>Grohmann, Malcolm</creatorcontrib><creatorcontrib>Newman, Christopher M.H</creatorcontrib><creatorcontrib>Crossman, David C</creatorcontrib><creatorcontrib>Cumberland, David C</creatorcontrib><title>The Effect of Oligonucleotides to c-myb on Vascular Smooth Muscle Cell Proliferation and Neointima Formation After Porcine Coronary Angioplasty</title><title>Circulation research</title><addtitle>Circ Res</addtitle><description>Proto-oncogenes, including c-myb, are expressed early after vascular injury. The application of antisense oligodeoxynucleotides (AS-ODNs) against these genes inhibits cell proliferation and neointima formation in small animals and in peripheral arteries. The aim of this study was to investigate the specificity of action of AS-ODN-c-myb in vitro and to assess its effect, when delivered locally, on neointima formation after percutaneous transluminal coronary angioplasty (PTCA) in porcine coronary arteries. AS-ODN-c-myb inhibited the proliferation of vascular smooth muscle cells (VSMCs) in vitro in a dose-dependent manner. There was a corresponding reduction in steady state levels of c-myb mRNA and protein. Expression of another early gene, c-fos, was unaffected. S1 nuclease analysis demonstrated intact full-length AS-ODN-c-myb retrieved from VSMCs in culture after 12 hours. A range of ODNs, related and unrelated to c-myb, with and without a GGGG sequence, inhibited VSMC proliferation. Phosphorothioated AS-ODN-c-myb was 30 times less potent than unphosphorothioated AS-ODN-c-myb. PTCA induced porcine coronary artery neointima formation. c-myb mRNA was maximally induced 18 hours after injury. Unmodified AS-ODN-c-myb, sense-ODN-c-myb, saline, or nothing was delivered immediately after balloon dilatation via a double-skinned porous balloon (Transport, SciMed). Fluorescence-labeled AS-ODN-c-myb was deposited throughout the vessel wall. Mean maximum intima/media cross-sectional area 4 weeks after PTCA was reduced with AS-ODN-c-myb by 79% compared with saline (P<.05), 82% compared with sense-ODN-c-myb, and 63% compared with nothing (P<.10). Conclusions are as follows(1) c-myb is expressed in VSMCs after vascular injury. (2) AS-ODN-c-myb is retained intact in VSMCs, reducing their proliferation in vitro in dose-dependent fashion, with reduction in c-myb mRNA and protein, whereas sense-ODN-c-myb is not. (3) A range of ODNs can reduce VSMC proliferation by a non-sequence-specific mechanism. (4) Phosphorothioate protection of antisense molecules may reduce their efficacy. (5) Local delivery of unmodified AS-ODN-c-myb via the Transport catheter reduces neointima formation after porcine PTCA. (6) Local delivery of fluid may exacerbate neointimal thickening. (Circ Res. 1997;80:520-531.)</description><subject>Angioplasty, Balloon - adverse effects</subject><subject>Angioplasty, Balloon, Coronary - methods</subject><subject>Animals</subject><subject>Biological and medical sciences</subject><subject>Cattle</subject><subject>Cell Division</subject><subject>Cell physiology</subject><subject>Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes</subject><subject>Cells, Cultured</subject><subject>Coronary Vessels - metabolism</subject><subject>Coronary Vessels - physiology</subject><subject>Fluorescent Antibody Technique, Direct</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>Genes, fos - physiology</subject><subject>Humans</subject><subject>Molecular and cellular biology</subject><subject>Muscle, Smooth, Vascular - metabolism</subject><subject>Muscle, Smooth, Vascular - physiology</subject><subject>Oligonucleotides, Antisense - pharmacology</subject><subject>Oncogenes - physiology</subject><subject>RNA, Messenger - metabolism</subject><subject>RNA-Binding Proteins</subject><subject>Swine</subject><issn>0009-7330</issn><issn>1524-4571</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1997</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNo9kcFu1DAQhi0EKtvCmROSD4hb0nHsJPZxtdpCpUIrWrhajjPuBpx4ayeq9il4ZYx21cNoNDPfjDT_T8gHBiVjDbsEVv7Y3pcSSlHWFbwiK1ZXohB1y16TFQCoouUc3pLzlH4DMMErdUbOFGNSSL4ifx92SLfOoZ1pcPTWD49hWqzHMA89JjoHaovx0NEw0V8m2cWbSO_HEOYd_bakDNINek_vYvCDw2jmIZNm6ul3DMM0D6OhVyGOx_7azRjpXYh2mPJiiGEy8UDX0-MQ9t6k-fCOvHHGJ3x_yhfk59X2YfO1uLn9cr1Z3xRWCMmK3igJruUMjZNd0_Stwq6V3Fasc9AphVJ0XNUOKid7UTF0qOoOXQMdGHT8gnw-3t3H8LRgmvU4JJs_MROGJelWKsjCyQxeHkEbQ0oRnd7H_FQ8aAb6vwUamM4WaAla6GxB3vh4Or10I_Yv_EnzPP90mmc9jXfRTHZIL1jVVLyWdcbEEXsOPquW_vjlGaPeofHzTmdngQOrCqZUCyJXRQ7G-D-vQqC_</recordid><startdate>199704</startdate><enddate>199704</enddate><creator>Gunn, Julian</creator><creator>Holt, Cathy M</creator><creator>Francis, Sheila E</creator><creator>Shepherd, Lynda</creator><creator>Grohmann, Malcolm</creator><creator>Newman, Christopher M.H</creator><creator>Crossman, David C</creator><creator>Cumberland, David C</creator><general>American Heart Association, Inc</general><general>Lippincott</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>199704</creationdate><title>The Effect of Oligonucleotides to c-myb on Vascular Smooth Muscle Cell Proliferation and Neointima Formation After Porcine Coronary Angioplasty</title><author>Gunn, Julian ; Holt, Cathy M ; Francis, Sheila E ; Shepherd, Lynda ; Grohmann, Malcolm ; Newman, Christopher M.H ; Crossman, David C ; Cumberland, David C</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4481-da980f731eaf8b66d79eb783c21bf0b99e84b395f02f8d421efe95bef60b0aef3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1997</creationdate><topic>Angioplasty, Balloon - adverse effects</topic><topic>Angioplasty, Balloon, Coronary - methods</topic><topic>Animals</topic><topic>Biological and medical sciences</topic><topic>Cattle</topic><topic>Cell Division</topic><topic>Cell physiology</topic><topic>Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes</topic><topic>Cells, Cultured</topic><topic>Coronary Vessels - metabolism</topic><topic>Coronary Vessels - physiology</topic><topic>Fluorescent Antibody Technique, Direct</topic><topic>Fundamental and applied biological sciences. Psychology</topic><topic>Genes, fos - physiology</topic><topic>Humans</topic><topic>Molecular and cellular biology</topic><topic>Muscle, Smooth, Vascular - metabolism</topic><topic>Muscle, Smooth, Vascular - physiology</topic><topic>Oligonucleotides, Antisense - pharmacology</topic><topic>Oncogenes - physiology</topic><topic>RNA, Messenger - metabolism</topic><topic>RNA-Binding Proteins</topic><topic>Swine</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Gunn, Julian</creatorcontrib><creatorcontrib>Holt, Cathy M</creatorcontrib><creatorcontrib>Francis, Sheila E</creatorcontrib><creatorcontrib>Shepherd, Lynda</creatorcontrib><creatorcontrib>Grohmann, Malcolm</creatorcontrib><creatorcontrib>Newman, Christopher M.H</creatorcontrib><creatorcontrib>Crossman, David C</creatorcontrib><creatorcontrib>Cumberland, David C</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Circulation research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Gunn, Julian</au><au>Holt, Cathy M</au><au>Francis, Sheila E</au><au>Shepherd, Lynda</au><au>Grohmann, Malcolm</au><au>Newman, Christopher M.H</au><au>Crossman, David C</au><au>Cumberland, David C</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The Effect of Oligonucleotides to c-myb on Vascular Smooth Muscle Cell Proliferation and Neointima Formation After Porcine Coronary Angioplasty</atitle><jtitle>Circulation research</jtitle><addtitle>Circ Res</addtitle><date>1997-04</date><risdate>1997</risdate><volume>80</volume><issue>4</issue><spage>520</spage><epage>531</epage><pages>520-531</pages><issn>0009-7330</issn><eissn>1524-4571</eissn><coden>CIRUAL</coden><abstract>Proto-oncogenes, including c-myb, are expressed early after vascular injury. The application of antisense oligodeoxynucleotides (AS-ODNs) against these genes inhibits cell proliferation and neointima formation in small animals and in peripheral arteries. The aim of this study was to investigate the specificity of action of AS-ODN-c-myb in vitro and to assess its effect, when delivered locally, on neointima formation after percutaneous transluminal coronary angioplasty (PTCA) in porcine coronary arteries. AS-ODN-c-myb inhibited the proliferation of vascular smooth muscle cells (VSMCs) in vitro in a dose-dependent manner. There was a corresponding reduction in steady state levels of c-myb mRNA and protein. Expression of another early gene, c-fos, was unaffected. S1 nuclease analysis demonstrated intact full-length AS-ODN-c-myb retrieved from VSMCs in culture after 12 hours. A range of ODNs, related and unrelated to c-myb, with and without a GGGG sequence, inhibited VSMC proliferation. Phosphorothioated AS-ODN-c-myb was 30 times less potent than unphosphorothioated AS-ODN-c-myb. PTCA induced porcine coronary artery neointima formation. c-myb mRNA was maximally induced 18 hours after injury. Unmodified AS-ODN-c-myb, sense-ODN-c-myb, saline, or nothing was delivered immediately after balloon dilatation via a double-skinned porous balloon (Transport, SciMed). Fluorescence-labeled AS-ODN-c-myb was deposited throughout the vessel wall. Mean maximum intima/media cross-sectional area 4 weeks after PTCA was reduced with AS-ODN-c-myb by 79% compared with saline (P<.05), 82% compared with sense-ODN-c-myb, and 63% compared with nothing (P<.10). Conclusions are as follows(1) c-myb is expressed in VSMCs after vascular injury. (2) AS-ODN-c-myb is retained intact in VSMCs, reducing their proliferation in vitro in dose-dependent fashion, with reduction in c-myb mRNA and protein, whereas sense-ODN-c-myb is not. (3) A range of ODNs can reduce VSMC proliferation by a non-sequence-specific mechanism. (4) Phosphorothioate protection of antisense molecules may reduce their efficacy. (5) Local delivery of unmodified AS-ODN-c-myb via the Transport catheter reduces neointima formation after porcine PTCA. (6) Local delivery of fluid may exacerbate neointimal thickening. (Circ Res. 1997;80:520-531.)</abstract><cop>Hagerstown, MD</cop><pub>American Heart Association, Inc</pub><pmid>9118483</pmid><doi>10.1161/01.RES.80.4.520</doi><tpages>12</tpages></addata></record> |
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| source | MEDLINE; American Heart Association Journals; Journals@Ovid Complete; EZB-FREE-00999 freely available EZB journals |
| subjects | Angioplasty, Balloon - adverse effects Angioplasty, Balloon, Coronary - methods Animals Biological and medical sciences Cattle Cell Division Cell physiology Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes Cells, Cultured Coronary Vessels - metabolism Coronary Vessels - physiology Fluorescent Antibody Technique, Direct Fundamental and applied biological sciences. Psychology Genes, fos - physiology Humans Molecular and cellular biology Muscle, Smooth, Vascular - metabolism Muscle, Smooth, Vascular - physiology Oligonucleotides, Antisense - pharmacology Oncogenes - physiology RNA, Messenger - metabolism RNA-Binding Proteins Swine |
| title | The Effect of Oligonucleotides to c-myb on Vascular Smooth Muscle Cell Proliferation and Neointima Formation After Porcine Coronary Angioplasty |
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