Radiation therapy impairs endothelium-dependent vasodilation in humans
Identifieur interne : 006D31 ( Istex/Corpus ); précédent : 006D30; suivant : 006D32Radiation therapy impairs endothelium-dependent vasodilation in humans
Auteurs : Joshua A. Beckman ; Avni Thakore ; Barbara H. Kalinowski ; Jay R. Harris ; Mark A. CreagerSource :
- Journal of the American College of Cardiology [ 0735-1097 ] ; 2001.
English descriptors
Abstract
OBJECTIVESThe objective of this study was to test the hypothesis that external-beam radiation induces a chronic impairment of endothelium-dependent vasodilation.BACKGROUNDRadiation therapy is used commonly in the treatment of cancer and is associated with an increased incidence of adverse vascular events related to the field of radiation, including stroke and myocardial infarction. As endothelial injury is central to the pathogenesis of vascular diseases, we hypothesized that radiotherapy induces arterial endothelial dysfunction.METHODSSixteen women with unilateral breast cancer who underwent standard external-beam radiation therapy to the breast and axilla >3 years before enrollment and ten healthy women were studied. Vascular ultrasonography was used to image both the artery exposed to radiation and the contralateral artery. Flow-mediated, endothelium-dependent vasodilation and endothelium-independent vasodilation to nitroglycerin of both axillary arteries were measured.RESULTSEndothelium-dependent vasodilation was significantly impaired in the irradiated axillary arteries compared with the contralateral, nonirradiated arteries (−0.4 ± 0.4% vs. 3.2 ± 0.8%, p < 0.001) and also compared with control subjects’ arteries (−0.4 ± 0.4% vs. 2.5 ± 0.6%, p < 0.001). In contrast, endothelium-independent vasodilation was greater in the arteries that received radiation compared with the contralateral arteries (3.8 ± 0.5% vs. 2.0 ± 0.4%, p < 0.05) and also compared with control arteries (3.8 ± 0.5% vs. 2.5 ± 0.4%, p < 0.05).CONCLUSIONSExternal beam radiation therapy impairs endothelium-dependent vasodilation of conduit arteries, implicating a decrease in the bioavailability of nitric oxide. These abnormalities may contribute to the development of arterial occlusive disease and associated clinical events.
Url:
DOI: 10.1016/S0735-1097(00)01190-6
Links to Exploration step
ISTEX:E8FBCAAB71401269CBDBA928BA64E4206BF9E5F0Le document en format XML
<record><TEI wicri:istexFullTextTei="biblStruct"><teiHeader><fileDesc><titleStmt><title xml:lang="en">Radiation therapy impairs endothelium-dependent vasodilation in humans</title><author><name sortKey="Beckman, Joshua A" sort="Beckman, Joshua A" uniqKey="Beckman J" first="Joshua A" last="Beckman">Joshua A. Beckman</name><affiliation><mods:affiliation>Vascular Medicine Section, Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts, USA</mods:affiliation></affiliation></author><author><name sortKey="Thakore, Avni" sort="Thakore, Avni" uniqKey="Thakore A" first="Avni" last="Thakore">Avni Thakore</name><affiliation><mods:affiliation>Vascular Medicine Section, Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts, USA</mods:affiliation></affiliation></author><author><name sortKey="Kalinowski, Barbara H" sort="Kalinowski, Barbara H" uniqKey="Kalinowski B" first="Barbara H" last="Kalinowski">Barbara H. Kalinowski</name><affiliation><mods:affiliation>Department of Radiation Oncology, Brigham and Women’s Hospital, Boston, Massachusetts, USA</mods:affiliation></affiliation></author><author><name sortKey="Harris, Jay R" sort="Harris, Jay R" uniqKey="Harris J" first="Jay R" last="Harris">Jay R. Harris</name><affiliation><mods:affiliation>Department of Radiation Oncology, Brigham and Women’s Hospital, Boston, Massachusetts, USA</mods:affiliation></affiliation></author><author><name sortKey="Creager, Mark A" sort="Creager, Mark A" uniqKey="Creager M" first="Mark A" last="Creager">Mark A. Creager</name><affiliation><mods:affiliation>Vascular Medicine Section, Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts, USA</mods:affiliation></affiliation><affiliation><mods:affiliation>Reprint requests and correspondence: Dr. Mark A. Creager, Cardiovascular Division, Brigham and Women’s Hospital, 75 Francis Street, Boston, Massachusetts 02115</mods:affiliation></affiliation><affiliation><mods:affiliation>E-mail: mcreager@partners.org</mods:affiliation></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">ISTEX</idno><idno type="RBID">ISTEX:E8FBCAAB71401269CBDBA928BA64E4206BF9E5F0</idno><date when="2001" year="2001">2001</date><idno type="doi">10.1016/S0735-1097(00)01190-6</idno><idno type="url">https://api.istex.fr/document/E8FBCAAB71401269CBDBA928BA64E4206BF9E5F0/fulltext/pdf</idno><idno type="wicri:Area/Istex/Corpus">006D31</idno><idno type="wicri:explorRef" wicri:stream="Istex" wicri:step="Corpus" wicri:corpus="ISTEX">006D31</idno></publicationStmt><sourceDesc><biblStruct><analytic><title level="a" type="main" xml:lang="en">Radiation therapy impairs endothelium-dependent vasodilation in humans</title><author><name sortKey="Beckman, Joshua A" sort="Beckman, Joshua A" uniqKey="Beckman J" first="Joshua A" last="Beckman">Joshua A. Beckman</name><affiliation><mods:affiliation>Vascular Medicine Section, Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts, USA</mods:affiliation></affiliation></author><author><name sortKey="Thakore, Avni" sort="Thakore, Avni" uniqKey="Thakore A" first="Avni" last="Thakore">Avni Thakore</name><affiliation><mods:affiliation>Vascular Medicine Section, Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts, USA</mods:affiliation></affiliation></author><author><name sortKey="Kalinowski, Barbara H" sort="Kalinowski, Barbara H" uniqKey="Kalinowski B" first="Barbara H" last="Kalinowski">Barbara H. Kalinowski</name><affiliation><mods:affiliation>Department of Radiation Oncology, Brigham and Women’s Hospital, Boston, Massachusetts, USA</mods:affiliation></affiliation></author><author><name sortKey="Harris, Jay R" sort="Harris, Jay R" uniqKey="Harris J" first="Jay R" last="Harris">Jay R. Harris</name><affiliation><mods:affiliation>Department of Radiation Oncology, Brigham and Women’s Hospital, Boston, Massachusetts, USA</mods:affiliation></affiliation></author><author><name sortKey="Creager, Mark A" sort="Creager, Mark A" uniqKey="Creager M" first="Mark A" last="Creager">Mark A. Creager</name><affiliation><mods:affiliation>Vascular Medicine Section, Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts, USA</mods:affiliation></affiliation><affiliation><mods:affiliation>Reprint requests and correspondence: Dr. Mark A. Creager, Cardiovascular Division, Brigham and Women’s Hospital, 75 Francis Street, Boston, Massachusetts 02115</mods:affiliation></affiliation><affiliation><mods:affiliation>E-mail: mcreager@partners.org</mods:affiliation></affiliation></author></analytic><monogr></monogr><series><title level="j">Journal of the American College of Cardiology</title><title level="j" type="abbrev">JAC</title><idno type="ISSN">0735-1097</idno><imprint><publisher>ELSEVIER</publisher><date type="published" when="2001">2001</date><biblScope unit="volume">37</biblScope><biblScope unit="issue">3</biblScope><biblScope unit="page" from="761">761</biblScope><biblScope unit="page" to="765">765</biblScope></imprint><idno type="ISSN">0735-1097</idno></series></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0735-1097</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>BP</term><term>LDL</term><term>MI</term></keywords></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">OBJECTIVESThe objective of this study was to test the hypothesis that external-beam radiation induces a chronic impairment of endothelium-dependent vasodilation.BACKGROUNDRadiation therapy is used commonly in the treatment of cancer and is associated with an increased incidence of adverse vascular events related to the field of radiation, including stroke and myocardial infarction. As endothelial injury is central to the pathogenesis of vascular diseases, we hypothesized that radiotherapy induces arterial endothelial dysfunction.METHODSSixteen women with unilateral breast cancer who underwent standard external-beam radiation therapy to the breast and axilla >3 years before enrollment and ten healthy women were studied. Vascular ultrasonography was used to image both the artery exposed to radiation and the contralateral artery. Flow-mediated, endothelium-dependent vasodilation and endothelium-independent vasodilation to nitroglycerin of both axillary arteries were measured.RESULTSEndothelium-dependent vasodilation was significantly impaired in the irradiated axillary arteries compared with the contralateral, nonirradiated arteries (−0.4 ± 0.4% vs. 3.2 ± 0.8%, p < 0.001) and also compared with control subjects’ arteries (−0.4 ± 0.4% vs. 2.5 ± 0.6%, p < 0.001). In contrast, endothelium-independent vasodilation was greater in the arteries that received radiation compared with the contralateral arteries (3.8 ± 0.5% vs. 2.0 ± 0.4%, p < 0.05) and also compared with control arteries (3.8 ± 0.5% vs. 2.5 ± 0.4%, p < 0.05).CONCLUSIONSExternal beam radiation therapy impairs endothelium-dependent vasodilation of conduit arteries, implicating a decrease in the bioavailability of nitric oxide. These abnormalities may contribute to the development of arterial occlusive disease and associated clinical events.</div></front></TEI><istex><corpusName>elsevier</corpusName><keywords><teeft><json:string>vasodilation</json:string><json:string>axillary</json:string><json:string>nitric</json:string><json:string>radiation therapy</json:string><json:string>nonirradiated</json:string><json:string>control subjects</json:string><json:string>contralateral</json:string><json:string>axillary arteries</json:string><json:string>nitric oxide</json:string><json:string>nitroglycerin</json:string><json:string>axillary artery</json:string><json:string>creager</json:string><json:string>nonirradiated arteries</json:string><json:string>baseline</json:string><json:string>radiation exposure</json:string><json:string>contralateral arteries</json:string><json:string>endothelial</json:string><json:string>healthy control subjects</json:string><json:string>standard error</json:string><json:string>myocardial infarction</json:string><json:string>endothelial dysfunction</json:string><json:string>oxide</json:string><json:string>cuff release</json:string><json:string>diabetes mellitus</json:string><json:string>breast cancer</json:string><json:string>error bars</json:string><json:string>american college</json:string><json:string>coll cardiol</json:string><json:string>ultrasound machine</json:string><json:string>cellular apoptosis</json:string><json:string>postmenopausal women</json:string><json:string>reactive hyperemia</json:string><json:string>arterial diameter</json:string><json:string>cardiovascular division</json:string><json:string>density lipoprotein</json:string><json:string>regression analysis</json:string><json:string>vascular function jacc</json:string><json:string>percent increase</json:string><json:string>axillary artery size</json:string><json:string>radiation oncology</json:string><json:string>nonirradiated contralateral arteries</json:string><json:string>endotheliumdependent vasodilation</json:string><json:string>direct comparison</json:string><json:string>nonirradiated axillary arteries</json:string><json:string>cigarette smoking</json:string><json:string>luminal surface</json:string><json:string>blood pressure</json:string></teeft></keywords><author><json:item><name>Joshua A Beckman MD, FACC</name><affiliations><json:string>Vascular Medicine Section, Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts, USA</json:string></affiliations></json:item><json:item><name>Avni Thakore MS</name><affiliations><json:string>Vascular Medicine Section, Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts, USA</json:string></affiliations></json:item><json:item><name>Barbara H Kalinowski RN, MSN</name><affiliations><json:string>Department of Radiation Oncology, Brigham and Women’s Hospital, Boston, Massachusetts, USA</json:string></affiliations></json:item><json:item><name>Jay R Harris MD</name><affiliations><json:string>Department of Radiation Oncology, Brigham and Women’s Hospital, Boston, Massachusetts, USA</json:string></affiliations></json:item><json:item><name>Mark A Creager MD, FACC</name><affiliations><json:string>Vascular Medicine Section, Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts, USA</json:string><json:string>Reprint requests and correspondence: Dr. Mark A. Creager, Cardiovascular Division, Brigham and Women’s Hospital, 75 Francis Street, Boston, Massachusetts 02115</json:string><json:string>E-mail: mcreager@partners.org</json:string></affiliations></json:item></author><subject><json:item><lang><json:string>eng</json:string></lang><value>Clinical study: endothelial function</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>BP : blood pressure</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>LDL : low density lipoprotein</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>MI : myocardial infarction</value></json:item></subject><language><json:string>eng</json:string></language><originalGenre><json:string>Full-length article</json:string></originalGenre><abstract>OBJECTIVESThe objective of this study was to test the hypothesis that external-beam radiation induces a chronic impairment of endothelium-dependent vasodilation.BACKGROUNDRadiation therapy is used commonly in the treatment of cancer and is associated with an increased incidence of adverse vascular events related to the field of radiation, including stroke and myocardial infarction. As endothelial injury is central to the pathogenesis of vascular diseases, we hypothesized that radiotherapy induces arterial endothelial dysfunction.METHODSSixteen women with unilateral breast cancer who underwent standard external-beam radiation therapy to the breast and axilla >3 years before enrollment and ten healthy women were studied. Vascular ultrasonography was used to image both the artery exposed to radiation and the contralateral artery. Flow-mediated, endothelium-dependent vasodilation and endothelium-independent vasodilation to nitroglycerin of both axillary arteries were measured.RESULTSEndothelium-dependent vasodilation was significantly impaired in the irradiated axillary arteries compared with the contralateral, nonirradiated arteries (−0.4 ± 0.4% vs. 3.2 ± 0.8%, p > 0.001) and also compared with control subjects’ arteries (−0.4 ± 0.4% vs. 2.5 ± 0.6%, p > 0.001). In contrast, endothelium-independent vasodilation was greater in the arteries that received radiation compared with the contralateral arteries (3.8 ± 0.5% vs. 2.0 ± 0.4%, p > 0.05) and also compared with control arteries (3.8 ± 0.5% vs. 2.5 ± 0.4%, p > 0.05).CONCLUSIONSExternal beam radiation therapy impairs endothelium-dependent vasodilation of conduit arteries, implicating a decrease in the bioavailability of nitric oxide. These abnormalities may contribute to the development of arterial occlusive disease and associated clinical events.</abstract><qualityIndicators><score>8.088</score><pdfVersion>1.7</pdfVersion><pdfPageSize>586 x 786 pts</pdfPageSize><refBibsNative>true</refBibsNative><keywordCount>4</keywordCount><abstractCharCount>1823</abstractCharCount><pdfWordCount>3160</pdfWordCount><pdfCharCount>21847</pdfCharCount><pdfPageCount>5</pdfPageCount><abstractWordCount>244</abstractWordCount></qualityIndicators><title>Radiation therapy impairs endothelium-dependent vasodilation in humans</title><pii><json:string>S0735-1097(00)01190-6</json:string></pii><genre><json:string>research-article</json:string></genre><host><title>Journal of the American College of Cardiology</title><language><json:string>unknown</json:string></language><publicationDate>2001</publicationDate><issn><json:string>0735-1097</json:string></issn><pii><json:string>S0735-1097(00)X0090-3</json:string></pii><volume>37</volume><issue>3</issue><pages><first>761</first><last>765</last></pages><genre><json:string>journal</json:string></genre></host><categories><wos><json:string>science</json:string><json:string>cardiac & cardiovascular systems</json:string></wos><scienceMetrix><json:string>health sciences</json:string><json:string>clinical medicine</json:string><json:string>cardiovascular system & hematology</json:string></scienceMetrix><inist><json:string>sciences appliquees, technologies et medecines</json:string><json:string>sciences biologiques et medicales</json:string><json:string>sciences medicales</json:string></inist></categories><publicationDate>2001</publicationDate><copyrightDate>2001</copyrightDate><doi><json:string>10.1016/S0735-1097(00)01190-6</json:string></doi><id>E8FBCAAB71401269CBDBA928BA64E4206BF9E5F0</id><score>1</score><fulltext><json:item><extension>pdf</extension><original>true</original><mimetype>application/pdf</mimetype><uri>https://api.istex.fr/document/E8FBCAAB71401269CBDBA928BA64E4206BF9E5F0/fulltext/pdf</uri></json:item><json:item><extension>zip</extension><original>false</original><mimetype>application/zip</mimetype><uri>https://api.istex.fr/document/E8FBCAAB71401269CBDBA928BA64E4206BF9E5F0/fulltext/zip</uri></json:item><istex:fulltextTEI uri="https://api.istex.fr/document/E8FBCAAB71401269CBDBA928BA64E4206BF9E5F0/fulltext/tei"><teiHeader><fileDesc><titleStmt><title level="a" type="main" xml:lang="en">Radiation therapy impairs endothelium-dependent vasodilation in humans</title></titleStmt><publicationStmt><authority>ISTEX</authority><publisher>ELSEVIER</publisher><availability><p>©2001 American College of Cardiology</p></availability><date>2001</date></publicationStmt><notesStmt><note>Supported, in part, by grants from the National Heart, Lung, and Blood Institute, HL-48743 and HL04169-01, Bethesda, Maryland.</note><note type="content">Section title: Clinical study: endothelial function</note><note type="content">Figure 1: Effect of radiation therapy on flow-mediated vasodilation. The individual and mean percent increase in axillary artery size 1 min after cuff release compared with baseline is illustrated. Error bars represent standard error. Flow-mediated vasodilation was significantly impaired in irradiated arteries compared with nonirradiated arteries and arteries in control subjects (p < 0.001).</note><note type="content">Figure 2: Effect of radiation therapy on nitroglycerin-mediated vasodilation. The individual and mean percent increase in axillary artery size after nitroglycerin administration is shown. Error bars represent standard error. Nitroglycerin-mediated vasodilation was significantly greater in irradiated arteries compared with nonirradiated arteries and arteries in control subjects (p < 0.05).</note><note type="content">Figure 3: Inter-arm variation between healthy control subjects. The individual and mean flow-mediated and nitroglycerin-mediated vasodilation in the right and left arms of the control subjects. Error bars represent standard error. There is no significant difference between arms for either flow-mediated or nitroglycerin-mediated vasodilation.</note></notesStmt><sourceDesc><biblStruct type="inbook"><analytic><title level="a" type="main" xml:lang="en">Radiation therapy impairs endothelium-dependent vasodilation in humans</title><author xml:id="author-0000"><persName><forename type="first">Joshua A</forename><surname>Beckman</surname></persName><roleName type="degree">MD, FACC</roleName><affiliation>Vascular Medicine Section, Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts, USA</affiliation></author><author xml:id="author-0001"><persName><forename type="first">Avni</forename><surname>Thakore</surname></persName><roleName type="degree">MS</roleName><affiliation>Vascular Medicine Section, Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts, USA</affiliation></author><author xml:id="author-0002"><persName><forename type="first">Barbara H</forename><surname>Kalinowski</surname></persName><roleName type="degree">RN, MSN</roleName><affiliation>Department of Radiation Oncology, Brigham and Women’s Hospital, Boston, Massachusetts, USA</affiliation></author><author xml:id="author-0003"><persName><forename type="first">Jay R</forename><surname>Harris</surname></persName><roleName type="degree">MD</roleName><affiliation>Department of Radiation Oncology, Brigham and Women’s Hospital, Boston, Massachusetts, USA</affiliation></author><author xml:id="author-0004"><persName><forename type="first">Mark A</forename><surname>Creager</surname></persName><roleName type="degree">MD, FACC</roleName><email>mcreager@partners.org</email><affiliation>Vascular Medicine Section, Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts, USA</affiliation><affiliation>Reprint requests and correspondence: Dr. Mark A. Creager, Cardiovascular Division, Brigham and Women’s Hospital, 75 Francis Street, Boston, Massachusetts 02115</affiliation></author><idno type="istex">E8FBCAAB71401269CBDBA928BA64E4206BF9E5F0</idno><idno type="DOI">10.1016/S0735-1097(00)01190-6</idno><idno type="PII">S0735-1097(00)01190-6</idno></analytic><monogr><title level="j">Journal of the American College of Cardiology</title><title level="j" type="abbrev">JAC</title><idno type="pISSN">0735-1097</idno><idno type="PII">S0735-1097(00)X0090-3</idno><imprint><publisher>ELSEVIER</publisher><date type="published" when="2001"></date><biblScope unit="volume">37</biblScope><biblScope unit="issue">3</biblScope><biblScope unit="page" from="761">761</biblScope><biblScope unit="page" to="765">765</biblScope></imprint></monogr></biblStruct></sourceDesc></fileDesc><profileDesc><creation><date>2001</date></creation><langUsage><language ident="en">en</language></langUsage><abstract xml:lang="en"><p>OBJECTIVESThe objective of this study was to test the hypothesis that external-beam radiation induces a chronic impairment of endothelium-dependent vasodilation.BACKGROUNDRadiation therapy is used commonly in the treatment of cancer and is associated with an increased incidence of adverse vascular events related to the field of radiation, including stroke and myocardial infarction. As endothelial injury is central to the pathogenesis of vascular diseases, we hypothesized that radiotherapy induces arterial endothelial dysfunction.METHODSSixteen women with unilateral breast cancer who underwent standard external-beam radiation therapy to the breast and axilla >3 years before enrollment and ten healthy women were studied. Vascular ultrasonography was used to image both the artery exposed to radiation and the contralateral artery. Flow-mediated, endothelium-dependent vasodilation and endothelium-independent vasodilation to nitroglycerin of both axillary arteries were measured.RESULTSEndothelium-dependent vasodilation was significantly impaired in the irradiated axillary arteries compared with the contralateral, nonirradiated arteries (−0.4 ± 0.4% vs. 3.2 ± 0.8%, p < 0.001) and also compared with control subjects’ arteries (−0.4 ± 0.4% vs. 2.5 ± 0.6%, p < 0.001). In contrast, endothelium-independent vasodilation was greater in the arteries that received radiation compared with the contralateral arteries (3.8 ± 0.5% vs. 2.0 ± 0.4%, p < 0.05) and also compared with control arteries (3.8 ± 0.5% vs. 2.5 ± 0.4%, p < 0.05).CONCLUSIONSExternal beam radiation therapy impairs endothelium-dependent vasodilation of conduit arteries, implicating a decrease in the bioavailability of nitric oxide. These abnormalities may contribute to the development of arterial occlusive disease and associated clinical events.</p></abstract><textClass><keywords scheme="keyword"><list><head>article-category</head><item><term>Clinical study: endothelial function</term></item></list></keywords></textClass><textClass xml:lang="en"><keywords scheme="keyword"><list><head>Abbreviations</head><item><term>BP</term><term>blood pressure</term></item><item><term>LDL</term><term>low density lipoprotein</term></item><item><term>MI</term><term>myocardial infarction</term></item></list></keywords></textClass></profileDesc><revisionDesc><change when="2000-10-06">Modified</change><change when="2001">Published</change></revisionDesc></teiHeader></istex:fulltextTEI><json:item><extension>txt</extension><original>false</original><mimetype>text/plain</mimetype><uri>https://api.istex.fr/document/E8FBCAAB71401269CBDBA928BA64E4206BF9E5F0/fulltext/txt</uri></json:item></fulltext><metadata><istex:metadataXml wicri:clean="Elsevier doc found" wicri:toSee="Elsevier, no converted or simple article"><istex:xmlDeclaration>version="1.0" encoding="utf-8"</istex:xmlDeclaration><istex:docType PUBLIC="-//ES//DTD journal article DTD version 5.1.0//EN//XML" URI="art510.dtd" name="istex:docType"><istex:entity SYSTEM="gr1" NDATA="IMAGE" name="gr1"></istex:entity><istex:entity SYSTEM="gr2" NDATA="IMAGE" name="gr2"></istex:entity><istex:entity SYSTEM="gr3" NDATA="IMAGE" name="gr3"></istex:entity></istex:docType><istex:document><article version="5.1" docsubtype="fla" xml:lang="en"><item-info><jid>JAC</jid><aid>7487</aid><ce:pii>S0735-1097(00)01190-6</ce:pii><ce:doi>10.1016/S0735-1097(00)01190-6</ce:doi><ce:copyright type="society" year="2001">American College of Cardiology</ce:copyright><ce:doctopics><ce:doctopic><ce:text id="tx0010">Clinical study: endothelial function</ce:text></ce:doctopic></ce:doctopics></item-info><ce:floats><ce:figure id="FIG1"><ce:label>Figure 1</ce:label><ce:caption><ce:simple-para id="sp0010">Effect of radiation therapy on flow-mediated vasodilation. The individual and mean percent increase in axillary artery size 1 min after cuff release compared with baseline is illustrated. Error bars represent standard error. Flow-mediated vasodilation was significantly impaired in irradiated arteries compared with nonirradiated arteries and arteries in control subjects (p < 0.001).</ce:simple-para></ce:caption><ce:link id="lk0010" locator="gr1"></ce:link></ce:figure><ce:figure id="FIG2"><ce:label>Figure 2</ce:label><ce:caption><ce:simple-para id="sp0015">Effect of radiation therapy on nitroglycerin-mediated vasodilation. The individual and mean percent increase in axillary artery size after nitroglycerin administration is shown. Error bars represent standard error. Nitroglycerin-mediated vasodilation was significantly greater in irradiated arteries compared with nonirradiated arteries and arteries in control subjects (p < 0.05).</ce:simple-para></ce:caption><ce:link id="lk0015" locator="gr2"></ce:link></ce:figure><ce:figure id="FIG3"><ce:label>Figure 3</ce:label><ce:caption><ce:simple-para id="sp0020">Inter-arm variation between healthy control subjects. The individual and mean flow-mediated and nitroglycerin-mediated vasodilation in the right and left arms of the control subjects. Error bars represent standard error. There is no significant difference between arms for either flow-mediated or nitroglycerin-mediated vasodilation.</ce:simple-para></ce:caption><ce:link id="lk0020" locator="gr3"></ce:link></ce:figure></ce:floats><head><ce:article-footnote><ce:label>☆</ce:label><ce:note-para id="np0010">Supported, in part, by grants from the National Heart, Lung, and Blood Institute, HL-48743 and HL04169-01, Bethesda, Maryland.</ce:note-para></ce:article-footnote><ce:dochead><ce:textfn id="tn0010">Clinical study: endothelial function</ce:textfn></ce:dochead><ce:title>Radiation therapy impairs endothelium-dependent vasodilation in humans</ce:title><ce:author-group><ce:author id="au0010"><ce:given-name>Joshua A</ce:given-name><ce:surname>Beckman</ce:surname><ce:degrees>MD, FACC</ce:degrees><ce:cross-ref refid="AFF1">∗</ce:cross-ref></ce:author><ce:author id="au0015"><ce:given-name>Avni</ce:given-name><ce:surname>Thakore</ce:surname><ce:degrees>MS</ce:degrees><ce:cross-ref refid="AFF1">∗</ce:cross-ref></ce:author><ce:author id="au0020"><ce:given-name>Barbara H</ce:given-name><ce:surname>Kalinowski</ce:surname><ce:degrees>RN, MSN</ce:degrees><ce:cross-ref refid="AFF2">†</ce:cross-ref></ce:author><ce:author id="au0025"><ce:given-name>Jay R</ce:given-name><ce:surname>Harris</ce:surname><ce:degrees>MD</ce:degrees><ce:cross-ref refid="AFF2">†</ce:cross-ref></ce:author><ce:author id="au0030"><ce:given-name>Mark A</ce:given-name><ce:surname>Creager</ce:surname><ce:degrees>MD, FACC</ce:degrees><ce:cross-ref refid="AFF1">∗</ce:cross-ref><ce:cross-ref refid="CORR1">*</ce:cross-ref><ce:e-address>mcreager@partners.org</ce:e-address></ce:author><ce:affiliation id="AFF1"><ce:label>∗</ce:label><ce:textfn id="tn0015">Vascular Medicine Section, Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts, USA</ce:textfn></ce:affiliation><ce:affiliation id="AFF2"><ce:label>†</ce:label><ce:textfn id="tn0020">Department of Radiation Oncology, Brigham and Women’s Hospital, Boston, Massachusetts, USA</ce:textfn></ce:affiliation><ce:correspondence id="CORR1"><ce:label>*</ce:label><ce:text id="tx0015">Reprint requests and correspondence: Dr. Mark A. Creager, Cardiovascular Division, Brigham and Women’s Hospital, 75 Francis Street, Boston, Massachusetts 02115</ce:text></ce:correspondence></ce:author-group><ce:date-received day="19" month="5" year="2000"></ce:date-received><ce:date-revised day="6" month="10" year="2000"></ce:date-revised><ce:date-accepted day="17" month="11" year="2000"></ce:date-accepted><ce:abstract><ce:section-title id="st0010">Abstract</ce:section-title><ce:abstract-sec><ce:simple-para id="sp0025">OBJECTIVES</ce:simple-para><ce:simple-para id="sp0030">The objective of this study was to test the hypothesis that external-beam radiation induces a chronic impairment of endothelium-dependent vasodilation.</ce:simple-para><ce:simple-para id="sp0035">BACKGROUND</ce:simple-para><ce:simple-para id="sp0040">Radiation therapy is used commonly in the treatment of cancer and is associated with an increased incidence of adverse vascular events related to the field of radiation, including stroke and myocardial infarction. As endothelial injury is central to the pathogenesis of vascular diseases, we hypothesized that radiotherapy induces arterial endothelial dysfunction.</ce:simple-para><ce:simple-para id="sp0045">METHODS</ce:simple-para><ce:simple-para id="sp0050">Sixteen women with unilateral breast cancer who underwent standard external-beam radiation therapy to the breast and axilla >3 years before enrollment and ten healthy women were studied. Vascular ultrasonography was used to image both the artery exposed to radiation and the contralateral artery. Flow-mediated, endothelium-dependent vasodilation and endothelium-independent vasodilation to nitroglycerin of both axillary arteries were measured.</ce:simple-para><ce:simple-para id="sp0055">RESULTS</ce:simple-para><ce:simple-para id="sp0060">Endothelium-dependent vasodilation was significantly impaired in the irradiated axillary arteries compared with the contralateral, nonirradiated arteries (−0.4 ± 0.4% vs. 3.2 ± 0.8%, p < 0.001) and also compared with control subjects’ arteries (−0.4 ± 0.4% vs. 2.5 ± 0.6%, p < 0.001). In contrast, endothelium-independent vasodilation was greater in the arteries that received radiation compared with the contralateral arteries (3.8 ± 0.5% vs. 2.0 ± 0.4%, p < 0.05) and also compared with control arteries (3.8 ± 0.5% vs. 2.5 ± 0.4%, p < 0.05).</ce:simple-para><ce:simple-para id="sp0065">CONCLUSIONS</ce:simple-para><ce:simple-para id="sp0070">External beam radiation therapy impairs endothelium-dependent vasodilation of conduit arteries, implicating a decrease in the bioavailability of nitric oxide. These abnormalities may contribute to the development of arterial occlusive disease and associated clinical events.</ce:simple-para></ce:abstract-sec></ce:abstract><ce:keywords class="abr"><ce:section-title id="st0015">Abbreviations</ce:section-title><ce:keyword><ce:text id="tx0020">BP</ce:text><ce:keyword><ce:text id="tx0025">blood pressure</ce:text></ce:keyword></ce:keyword><ce:keyword><ce:text id="tx0030">LDL</ce:text><ce:keyword><ce:text id="tx0035">low density lipoprotein</ce:text></ce:keyword></ce:keyword><ce:keyword><ce:text id="tx0040">MI</ce:text><ce:keyword><ce:text id="tx0045">myocardial infarction</ce:text></ce:keyword></ce:keyword></ce:keywords></head><body><ce:sections><ce:para id="p0010">External-beam radiation therapy is commonly employed as a primary and adjuvant therapeutic modality in patients with neoplasms. Its mechanism of action is thought to involve direct DNA damage, which causes cell death <ce:cross-ref refid="BIB1">(1)</ce:cross-ref>. Despite improving technology and dose delivery, normal “bystander” tissues, including the vasculature, are often affected. Indeed, radiation therapy increases the incidence of arterial occlusive disease years after therapy. The arterial lesions become manifest in the region of previous radiation and can cause clinical events in the cerebrovascular <ce:cross-refs refid="BIB2 BIB3 BIB4 BIB5">(2–5)</ce:cross-refs>, coronary <ce:cross-refs refid="BIB6 BIB7 BIB8">(6–8)</ce:cross-refs> and peripheral circulations <ce:cross-ref refid="BIB9">(9)</ce:cross-ref>.</ce:para><ce:para id="p0015">The mechanism whereby radiation therapy causes arterial stenoses after radiation exposure is unclear, but important consideration must be given to impairment of endothelial-cell function. Decreased bioavailability of endothelium-derived nitric oxide may contribute to vascular injury by facilitating platelet aggregation, increasing the adherence of leukocytes to the endothelial surface and by promoting growth of vascular smooth cells <ce:cross-ref refid="BIB10">(10)</ce:cross-ref>. Abnormalities in endothelium-dependent vasodilation and, by extension, endothelium-derived nitric oxide have been demonstrated to accompany risk factors for atherosclerosis <ce:cross-refs refid="BIB11 BIB12 BIB13 BIB14 BIB15">(11–15)</ce:cross-refs> and may also account for the predisposition to vascular disease in arteries exposed to radiation. Abnormal endothelium-dependent vasodilation has been demonstrated in animal models and humans in vitro and in animals in vivo <ce:cross-refs refid="BIB16 BIB17 BIB18 BIB19">(16–19)</ce:cross-refs> acutely after radiation exposure. There has been no investigation to determine if the effect of radiation therapy on the endothelium persists chronically after radiation exposure, thus providing a substrate for arterial disease.</ce:para><ce:para id="p0020">Accordingly, the purpose of this study was to test the hypothesis that endothelium-dependent vasodilation is impaired in vivo in human arteries exposed to radiation. We used high-resolution ultrasound to measure endothelium-dependent and endothelium-independent vasodilation in the irradiated and contralateral nonirradiated axillary arteries of women who underwent unilateral radiation therapy for breast cancer.</ce:para><ce:section id="s0010"><ce:section-title id="st0020">Methods</ce:section-title><ce:section id="s0015"><ce:section-title id="st0025">Patient selection and recruitment</ce:section-title><ce:para id="p0025">Sixteen postmenopausal women who had received unilateral adjunctive axillary radiotherapy for breast cancer >3 years earlier were eligible for enrollment. Subjects were recruited from the clinic of one of the investigators (J.R.H.). Ten healthy, postmenopausal, age-matched women were also recruited via advertisement and invited to participate in the study. Exclusion criteria included diabetes mellitus, cigarette smoking, total and low density lipoprotein (LDL) cholesterol >75th percentile for age, untreated hypertension, clinical manifestations of atherosclerosis, evidence of recurrent or second malignancy, severe lymphedema or other major medical problem. All subjects underwent pre-enrollment history and physical examination. Each subject provided written, informed consent. This study was approved by the Human Research Committee of Brigham and Women’s Hospital.</ce:para></ce:section><ce:section id="s0020"><ce:section-title id="st0030">Vascular reactivity studies</ce:section-title><ce:para id="p0030">Subjects were studied in a quiet, temperature-controlled, dimly lit room after resting supine for 5 min. High-resolution ultrasonography of the axillary artery was performed using a Toshiba 270 SSA ultrasound machine and 7.5 MHz linear array probe. The axillary artery was imaged longitudinally just distal to the axillary-subclavian junction, with the arm abducted 90° from the body. The transducer position was adjusted to obtain optimal images of the near and far walls of the intima. Baseline images were simultaneously recorded on super VHS videotape. The video output and electrocardiographic signal of the ultrasound machine were connected to a computer equipped with a Data Translation frame-grabber videocard, (Dataviz, Trumbull, Connecticut). The ‘R’ wave on the electrocardiogram was used as a trigger to acquire frames at end-diastole. After baseline image acquisition, a mid-arm sphygmomanometric cuff was inflated to suprasystolic pressure for 5 min. Upon cuff release, reactive hyperemia causes flow to increase through the conduit artery subserving the arm, in this case the axillary artery. Flow-induced, endothelium-dependent vasodilation of the axillary artery was determined via imaging at 1 min after cuff deflation. Flow-mediated vasodilation at this time point is largely nitric oxide mediated and endothelium dependent and can be inhibited by administration of the nitric oxide synthase antagonist, N<ce:sup>G</ce:sup>-monomethyl-L-arginine <ce:cross-ref refid="BIB20">(20)</ce:cross-ref>. Ten minutes after cuff release, the axillary artery was imaged again to re-establish baseline conditions. Then, to determine endothelium-independent vasodilation, subjects received 0.4 mg of nitroglycerin, sublingually. The axillary artery was imaged 3 min later. Axillary artery blood flow velocity was determined via time-velocity integral measurement and is reported as cm/s. At least 15 min after the administration of nitroglycerin and after re-establishment of pre-nitroglycerin heart rate and blood pressure (BP), the procedure was repeated in the contralateral axillary artery. Nitroglycerin was not administered if the systolic BP was below 110 mm Hg.</ce:para></ce:section><ce:section id="s0025"><ce:section-title id="st0035">Image analysis</ce:section-title><ce:para id="p0035">Acquisition and analysis of the stored images were performed using software designed for this purpose (Information Integrity, Inc., Cambridge, Massachusetts). At least four end-diastolic images for each condition (baseline, reactive hyperemia, repeat baseline, nitroglycerin) were selected for analysis. Analysis was performed by one investigator (J.A.B.) who was blinded to subject name, date and presence or absence of radiation exposure. The near and far walls were determined by derivative-based edge detection after identification of the region of the anterior and posterior walls by the investigator. The maximum diameter of the vessel was then determined. Arterial diameter was measured from the vessel-lumen interface on the posterior wall to the vessel-lumen interface of the anterior wall.</ce:para></ce:section><ce:section id="s0030"><ce:section-title id="st0040">Statistical analysis</ce:section-title><ce:para id="p0040">Descriptive statistics are reported as mean ± standard deviation. Vasodilation is reported as mean ± standard error of the mean. Endothelium-dependent and endothelium-independent vasodilation in the axillary artery exposed to radiation therapy were first compared using repeated measures analysis of variance. Post-hoc, endothelium-dependent and endothelium-independent vasodilation in the axillary artery exposed to radiation therapy were compared with that of the contralateral nonirradiated artery using a paired Student <ce:italic>t</ce:italic> test. Comparisons of endothelium-dependent and independent vasodilation of the irradiated arteries of patients to axillary arteries of healthy control subjects were made using an unpaired <ce:italic>t</ce:italic> test. Regression analysis was used to examine the relationship between endothelium-dependent vasodilation and selected subject characteristics. Statistical significance was accepted at the p < 0.05 (95% confidence interval) level.</ce:para></ce:section></ce:section><ce:section id="s0035"><ce:section-title id="st0045">Results</ce:section-title><ce:section id="s0040"><ce:section-title id="st0050">Baseline characteristics</ce:section-title><ce:para id="p0045">Twenty-six postmenopausal women, including 16 subjects with prior radiation therapy and 10 healthy control subjects, were enrolled. By group, the participants were aged 58 ± 10 and 58 ± 4 years, had a mean BP of 90 ± 13 and 91 ± 9 mm Hg, had a total cholesterol of 203 ± 21 and 212 ± 20 mg/dl, and LDL of 121 ± 17 and 116 ± 22 mg/dl for the radiation-therapy subjects and healthy control subjects, respectively. There were no significant between group differences (all p = NS). The average length of time between the last radiation therapy and enrollment was 12 ± 6 years. Nine patients had had chemotherapy. One patient was taking tamoxifen. In the radiation therapy group, three subjects had a history of hypertension; two were taking beta-adrenergic blocking agents, and one patient was taking an angiotensin-converting enzyme inhibitor. They were asked to hold these medications on the study day.</ce:para></ce:section><ce:section id="s0045"><ce:section-title id="st0055">Effect of radiation therapy on endothelium-dependent vasodilation</ce:section-title><ce:para id="p0050">The baseline diameters of the axillary arteries in the subjects who received radiation therapy were 5.3 ± 0.9 mm and 5.7 ± 0.7 mm for the irradiated and nonirradiated contralateral arteries, respectively (p = 0.06). Reactive hyperemia augmented axillary artery flow velocity 240% (from 9.8 cm/s to 23.8 cm/s) in the irradiated arteries and 260% (from 8.2 cm/s to 22.8 cm/s) in the nonirradiated, contralateral arteries. The increase in blood flow velocity was not significantly different in the irradiated and nonirradiated arteries (p = 0.62). Flow-mediated, endothelium-dependent vasodilation was lower in the arteries exposed to radiation therapy than it was in the contralateral arteries and in the arteries of the healthy, control subjects (p = 0.001 by analysis of variance) <ce:cross-ref refid="FIG1">(Fig. 1)</ce:cross-ref>. <ce:float-anchor refid="FIG1"></ce:float-anchor> In a direct comparison between the irradiated arteries and the contralateral arteries, the irradiated arteries did not vasodilate, while the contralateral arteries did (−0.4 ± 0.4% vs. 3.2 ± 0.8%, respectively; p < 0.001).</ce:para><ce:para id="p0055">The baseline diameter of the axillary arteries in the healthy, control subjects was 5.7 ± 0.7 mm, and this was not significantly different from the unexposed (i.e., nonirradiated) axillary arteries of the patients who received radiation therapy (p = 0.75). Flow-mediated vasodilation of the axillary arteries of control subjects averaged 2.5 ± 0.6% and did not differ between arms. Flow-mediated vasodilation was significantly greater in the axillary arteries of control subjects than it was in the arteries of patients exposed to radiation therapy (2.5 ± 0.6% vs. −0.4 ± 0.4%, respectively; p < 0.001) <ce:cross-ref refid="FIG1">(Fig. 1)</ce:cross-ref>. Flow-mediated vasodilation did not differ significantly between the nonirradiated axillary arteries of the subjects who received radiation therapy and the axillary arteries of control subjects (3.2 ± 0.8% vs. 2.5 ± 0.6%, p = 0.51).</ce:para></ce:section><ce:section id="s0050"><ce:section-title id="st0060">Effect of radiation therapy on exposed artery endothelium-independent vasodilation</ce:section-title><ce:para id="p0060">Seven of the patients who had previously received radiation therapy were given nitroglycerin to determine endothelium-independent vasodilation. Of those who did not receive nitroglycerin, eight subjects had systolic BP below 110 mm Hg, and one subject refused nitroglycerin. Endothelium-independent vasodilation was significantly greater in the irradiated arteries compared with the nonirradiated arteries and the arteries of the control subjects (p = 0.048, by analysis of variance). In a direct comparison, endothelium-independent vasodilation was significantly greater in the irradiated arteries compared with the nonirradiated arteries (3.8 ± 0.5% vs. 2.0 ± 0.4%, p < 0.05) <ce:cross-ref refid="FIG2">(Fig. 2)</ce:cross-ref>. <ce:float-anchor refid="FIG2"></ce:float-anchor> The arteries exposed to radiation therapy also had a greater response to nitroglycerin than those of the control subjects (3.8 ± 0.5% vs. 2.5 ± 0.4%, respectively; p < 0.05).</ce:para></ce:section><ce:section id="s0055"><ce:section-title id="st0065">Multivariate analysis</ce:section-title><ce:para id="p0065">Subject age, total and LDL cholesterol, BP, previous administration of chemotherapy and length of time since radiotherapy administration did not affect the flow-mediated and nitroglycerin-mediated vasodilation of irradiated and nonirradiated arteries (all p = NS by regression analysis). There was no significant interaction between the vasodilation and any of the above factors (p = NS). There was no significant difference in flow-mediated vasodilation or nitroglycerin-mediated vasodilation between arms of the control subjects (p > 0.2 for both comparisons) <ce:cross-ref refid="FIG3">(Fig. 3)</ce:cross-ref>. <ce:float-anchor refid="FIG3"></ce:float-anchor></ce:para></ce:section></ce:section><ce:section id="s0060"><ce:section-title id="st0070">Discussion</ce:section-title><ce:para id="p0070">The novel finding of these experiments is that external-beam radiation therapy causes chronic impairment of endothelium-dependent vasodilation in humans in vivo, specific to arteries that received radiation. This observation suggests that endothelial dysfunction may contribute to the increased incidence of arterial occlusive disease that occurs in patients who received radiation therapy.</ce:para><ce:para id="p0075">Radiation modifies endothelial-cell function and reduces its survival. Radiation causes the endothelial release of a neutrophil chemoattractant, up-regulates endothelial expression of cellular adhesion and diapedesis molecules and increases endothelial cell production of platelet derived growth factor <ce:cross-refs refid="BIB21 BIB22 BIB23">(21–23)</ce:cross-refs>. Irradiation of muscular (conduit) arteries results in endothelial cell death, leaving the luminal surface sparsely populated at six weeks. Irregular appearing cells begin to repopulate the luminal surface 6 to 10 weeks later <ce:cross-ref refid="BIB24">(24)</ce:cross-ref>.</ce:para><ce:section id="s0065"><ce:section-title id="st0075">Radiation and endothelium-derived nitric oxide</ce:section-title><ce:para id="p0080">Studies in animals and humans in vitro and animals in vivo suggest that bioavailability of endothelium-derived nitric oxide is diminished shortly after radiation exposure <ce:cross-refs refid="BIB16 BIB17 BIB18 BIB19">(16–19)</ce:cross-refs>. Endothelium-dependent vasorelaxation to acetylcholine and calcium ionophore in irradiated rabbit-ear arteries in vitro is reduced, whereas nitroprusside-induced vasorelaxation is preserved <ce:cross-ref refid="BIB18">(18)</ce:cross-ref>. In rats receiving prostate radiation, in vivo erectile function and the number of nitric oxide synthase-containing nerve fibers per corpus callosum is decreased <ce:cross-ref refid="BIB19">(19)</ce:cross-ref>. In humans, endothelium-dependent vasodilation is impaired in vitro, and tissue endothelial nitric oxide synthase is decreased in carotid arteries four to six weeks after neck irradiation <ce:cross-ref refid="BIB16">(16)</ce:cross-ref>. Our in vivo findings of impaired endothelium-dependent vasodilation in irradiated arteries extend these observations. We observed that endothelium-dependent vasodilation was diminished in irradiated arteries years beyond therapy.</ce:para><ce:para id="p0085">There was a trend toward a smaller baseline diameter of the irradiated axillary arteries compared with the contralateral, nonirradiated axillary arteries and the axillary arteries of the healthy, control subjects. The mechanisms whereby radiation therapy may have reduced arterial diameter are not known, but decreased nitric oxide is a plausible possibility. Normal levels of nitric oxide are known to protect against cellular apoptosis <ce:cross-refs refid="BIB25 BIB26">(25,26)</ce:cross-refs>. The smaller baseline size may reflect increased cellular apoptosis within the vessel as a consequence of decreased nitric oxide bioavailability. Endothelium-derived nitric oxide is also a potent vasodilator and important in the regulation of arterial tone. Thus, chronically diminished constitutive nitric oxide production may result in a persistently smaller resting vessel lumen.</ce:para></ce:section><ce:section id="s0070"><ce:section-title id="st0080">Radiation therapy and endothelium-independent vasodilation</ce:section-title><ce:para id="p0090">Endothelium-independent vasodilation was increased in the irradiated axillary arteries compared with the nonirradiated contralateral arteries and the arteries of control subjects. This finding may reflect the fact that smaller arteries dilate proportionally more than larger arteries when exposed to a vasodilator stimulus <ce:cross-ref refid="BIB27">(27)</ce:cross-ref> or occur as a compensatory response to any nitric oxide donor when endogenous nitric oxide is reduced <ce:cross-ref refid="BIB28">(28)</ce:cross-ref>.</ce:para></ce:section><ce:section id="s0075"><ce:section-title id="st0085">Clinical significance</ce:section-title><ce:para id="p0095">This study demonstrates that exposure to radiation chronically impairs endothelial function. Endothelial dysfunction is a form fruste of atherosclerosis and may account, in part, for stenoses that occur in irradiated arteries, such as the coronary, carotid and subclavian/axillary circulations. Patients who receive mantle or head and neck radiation therapy have an increased rate of myocardial infarction (MI) <ce:cross-refs refid="BIB6 BIB7 BIB8">(6–8)</ce:cross-refs> and stroke <ce:cross-refs refid="BIB2 BIB3 BIB4 BIB5">(2–5)</ce:cross-refs>. In fact, in women under age 60 who receive left chest irradiation, the risk of MI is doubled <ce:cross-ref refid="BIB29">(29)</ce:cross-ref>. For younger patients who survive their cancer, long-term morbidity and mortality is increased by the life-saving radiotherapy. Our study provides evidence that endothelial dysfunction may be a target for therapy to prevent these adverse outcomes.</ce:para></ce:section><ce:section id="s0080"><ce:section-title id="st0090">Conclusions</ce:section-title><ce:para id="p0100">The results of this study enable us to conclude that radiation therapy causes impairment of endothelium-dependent vasodilation in exposed arteries. The findings implicate reduced bioavailability of endothelium-derived nitric oxide as an important mechanism for the subsequent development of arterial occlusions and vascular events in patients receiving radiation therapy.</ce:para></ce:section></ce:section></ce:sections></body><tail><ce:bibliography id="bi0010"><ce:section-title id="st0095">References</ce:section-title><ce:bibliography-sec id="bs0010"><ce:bib-reference id="BIB1"><ce:label>1</ce:label><sb:reference id="rf0010"><sb:contribution><sb:authors><sb:author><ce:given-name>A.S.</ce:given-name><ce:surname>Lichter</ce:surname></sb:author><sb:author><ce:given-name>T.S.</ce:given-name><ce:surname>Lawrence</ce:surname></sb:author></sb:authors><sb:title><sb:maintitle>Recent advances in radiation oncology</sb:maintitle></sb:title></sb:contribution><sb:host><sb:issue><sb:series><sb:title><sb:maintitle>N Engl J Med</sb:maintitle></sb:title><sb:volume-nr>332</sb:volume-nr></sb:series><sb:date>1995</sb:date></sb:issue><sb:pages><sb:first-page>371</sb:first-page><sb:last-page>378</sb:last-page></sb:pages></sb:host></sb:reference></ce:bib-reference><ce:bib-reference id="BIB2"><ce:label>2</ce:label><sb:reference id="rf0015"><sb:contribution><sb:authors><sb:author><ce:given-name>D.I.</ce:given-name><ce:surname>Peterson</ce:surname></sb:author><sb:author><ce:given-name>F.</ce:given-name><ce:surname>Alfonso</ce:surname></sb:author><sb:author><ce:given-name>B.</ce:given-name><ce:surname>Geslani</ce:surname></sb:author></sb:authors><sb:title><sb:maintitle>Cerebral infarction due to radiation accelerated arteriosclerosis</sb:maintitle></sb:title></sb:contribution><sb:host><sb:issue><sb:series><sb:title><sb:maintitle>Bull Clin Neurosci</sb:maintitle></sb:title><sb:volume-nr>52</sb:volume-nr></sb:series><sb:date>1987</sb:date></sb:issue><sb:pages><sb:first-page>43</sb:first-page><sb:last-page>46</sb:last-page></sb:pages></sb:host></sb:reference></ce:bib-reference><ce:bib-reference id="BIB3"><ce:label>3</ce:label><sb:reference id="rf0020"><sb:contribution><sb:authors><sb:author><ce:given-name>J.W.</ce:given-name><ce:surname>Francfort</ce:surname></sb:author><sb:author><ce:given-name>J.F.</ce:given-name><ce:surname>Gallagher</ce:surname></sb:author><sb:author><ce:given-name>E.</ce:given-name><ce:surname>Penman</ce:surname></sb:author><sb:author><ce:given-name>R.M.</ce:given-name><ce:surname>Fairman</ce:surname></sb:author></sb:authors><sb:title><sb:maintitle>Surgery for radiation-induced symptomatic carotid atherosclerosis</sb:maintitle></sb:title></sb:contribution><sb:host><sb:issue><sb:series><sb:title><sb:maintitle>Ann Vasc Surg</sb:maintitle></sb:title><sb:volume-nr>3</sb:volume-nr></sb:series><sb:date>1989</sb:date></sb:issue><sb:pages><sb:first-page>14</sb:first-page><sb:last-page>19</sb:last-page></sb:pages></sb:host></sb:reference></ce:bib-reference><ce:bib-reference id="BIB4"><ce:label>4</ce:label><sb:reference id="rf0025"><sb:contribution><sb:authors><sb:author><ce:given-name>W.G.</ce:given-name><ce:surname>Mitchell</ce:surname></sb:author><sb:author><ce:given-name>L.S.</ce:given-name><ce:surname>Fishman</ce:surname></sb:author><sb:author><ce:given-name>J.H.</ce:given-name><ce:surname>Miller</ce:surname></sb:author><sb:et-al></sb:et-al></sb:authors><sb:title><sb:maintitle>Stroke as a late sequela of cranial irradiation for childhood brain tumors</sb:maintitle></sb:title></sb:contribution><sb:host><sb:issue><sb:series><sb:title><sb:maintitle>J Child Neurol</sb:maintitle></sb:title><sb:volume-nr>6</sb:volume-nr></sb:series><sb:date>1991</sb:date></sb:issue><sb:pages><sb:first-page>128</sb:first-page><sb:last-page>133</sb:last-page></sb:pages></sb:host></sb:reference></ce:bib-reference><ce:bib-reference id="BIB5"><ce:label>5</ce:label><sb:reference id="rf0030"><sb:contribution><sb:authors><sb:author><ce:given-name>J.P.</ce:given-name><ce:surname>Conomy</ce:surname></sb:author><sb:author><ce:given-name>R.W.</ce:given-name><ce:surname>Kellermeyer</ce:surname></sb:author></sb:authors><sb:title><sb:maintitle>Delayed cerebrovascular consequences of therapeutic radiation. A clinicopathologic study of a stroke associated with radiation-related carotid arteriopathy</sb:maintitle></sb:title></sb:contribution><sb:host><sb:issue><sb:series><sb:title><sb:maintitle>Cancer</sb:maintitle></sb:title><sb:volume-nr>36</sb:volume-nr></sb:series><sb:date>1975</sb:date></sb:issue><sb:pages><sb:first-page>1702</sb:first-page><sb:last-page>1708</sb:last-page></sb:pages></sb:host></sb:reference></ce:bib-reference><ce:bib-reference id="BIB6"><ce:label>6</ce:label><sb:reference id="rf0035"><sb:contribution><sb:authors><sb:author><ce:given-name>J.</ce:given-name><ce:surname>Feher</ce:surname></sb:author></sb:authors><sb:title><sb:maintitle>Myocardial infarction following radiation</sb:maintitle></sb:title></sb:contribution><sb:host><sb:issue><sb:series><sb:title><sb:maintitle>Lancet</sb:maintitle></sb:title><sb:volume-nr>2</sb:volume-nr></sb:series><sb:date>1965</sb:date></sb:issue><sb:pages><sb:first-page>643</sb:first-page><sb:last-page>644</sb:last-page></sb:pages></sb:host></sb:reference></ce:bib-reference><ce:bib-reference id="BIB7"><ce:label>7</ce:label><sb:reference id="rf0040"><sb:contribution><sb:authors><sb:author><ce:given-name>G.</ce:given-name><ce:surname>Gyenes</ce:surname></sb:author><sb:author><ce:given-name>L.E.</ce:given-name><ce:surname>Rutqvist</ce:surname></sb:author><sb:author><ce:given-name>A.</ce:given-name><ce:surname>Liedberg</ce:surname></sb:author><sb:author><ce:given-name>T.</ce:given-name><ce:surname>Fornander</ce:surname></sb:author></sb:authors><sb:title><sb:maintitle>Long-term cardiac morbidity and mortality in a randomized trial of pre- and postoperative radiation therapy versus surgery alone in primary breast cancer</sb:maintitle></sb:title></sb:contribution><sb:host><sb:issue><sb:series><sb:title><sb:maintitle>Radiother Oncol</sb:maintitle></sb:title><sb:volume-nr>48</sb:volume-nr></sb:series><sb:date>1998</sb:date></sb:issue><sb:pages><sb:first-page>185</sb:first-page><sb:last-page>190</sb:last-page></sb:pages></sb:host></sb:reference></ce:bib-reference><ce:bib-reference id="BIB8"><ce:label>8</ce:label><sb:reference id="rf0045"><sb:contribution><sb:authors><sb:author><ce:given-name>H.</ce:given-name><ce:surname>Huff</ce:surname></sb:author><sb:author><ce:given-name>E.M.</ce:given-name><ce:surname>Sanders</ce:surname></sb:author></sb:authors><sb:title><sb:maintitle>Coronary-artery occlusion after radiation</sb:maintitle></sb:title></sb:contribution><sb:host><sb:issue><sb:series><sb:title><sb:maintitle>N Engl J Med</sb:maintitle></sb:title><sb:volume-nr>286</sb:volume-nr></sb:series><sb:date>1972</sb:date></sb:issue><sb:pages><sb:first-page>780</sb:first-page></sb:pages></sb:host></sb:reference></ce:bib-reference><ce:bib-reference id="BIB9"><ce:label>9</ce:label><sb:reference id="rf0050"><sb:contribution><sb:authors><sb:author><ce:given-name>M.</ce:given-name><ce:surname>Hasmonai</ce:surname></sb:author><sb:author><ce:given-name>A.</ce:given-name><ce:surname>Elami</ce:surname></sb:author><sb:author><ce:given-name>A.</ce:given-name><ce:surname>Kuten</ce:surname></sb:author><sb:author><ce:given-name>C.</ce:given-name><ce:surname>Lichtig</ce:surname></sb:author><sb:author><ce:given-name>S.</ce:given-name><ce:surname>Torem</ce:surname></sb:author></sb:authors><sb:title><sb:maintitle>Subclavian artery occlusion after radiotherapy for carcinoma of the breast</sb:maintitle></sb:title></sb:contribution><sb:host><sb:issue><sb:series><sb:title><sb:maintitle>Cancer</sb:maintitle></sb:title><sb:volume-nr>61</sb:volume-nr></sb:series><sb:date>1988</sb:date></sb:issue><sb:pages><sb:first-page>2015</sb:first-page><sb:last-page>2018</sb:last-page></sb:pages></sb:host></sb:reference></ce:bib-reference><ce:bib-reference id="BIB10"><ce:label>10</ce:label><sb:reference id="rf0055"><sb:contribution><sb:authors><sb:author><ce:given-name>S.</ce:given-name><ce:surname>Moncada</ce:surname></sb:author><sb:author><ce:given-name>A.</ce:given-name><ce:surname>Higgs</ce:surname></sb:author></sb:authors><sb:title><sb:maintitle>The L-arginine nitric oxide pathway</sb:maintitle></sb:title></sb:contribution><sb:host><sb:issue><sb:series><sb:title><sb:maintitle>N Engl J Med</sb:maintitle></sb:title><sb:volume-nr>329</sb:volume-nr></sb:series><sb:date>1993</sb:date></sb:issue><sb:pages><sb:first-page>2002</sb:first-page><sb:last-page>2012</sb:last-page></sb:pages></sb:host></sb:reference></ce:bib-reference><ce:bib-reference id="BIB11"><ce:label>11</ce:label><sb:reference id="rf0060"><sb:contribution><sb:authors><sb:author><ce:given-name>D.S.</ce:given-name><ce:surname>Celermajer</ce:surname></sb:author><sb:author><ce:given-name>K.E.</ce:given-name><ce:surname>Sorensen</ce:surname></sb:author><sb:author><ce:given-name>D.</ce:given-name><ce:surname>Georgakopoulos</ce:surname></sb:author><sb:et-al></sb:et-al></sb:authors><sb:title><sb:maintitle>Cigarette smoking is associated with dose-related and potentially reversible impairment of endothelium-dependent dilation in healthy young adults</sb:maintitle></sb:title></sb:contribution><sb:host><sb:issue><sb:series><sb:title><sb:maintitle>Circulation</sb:maintitle></sb:title><sb:volume-nr>88</sb:volume-nr></sb:series><sb:date>1993</sb:date></sb:issue><sb:pages><sb:first-page>2149</sb:first-page><sb:last-page>2155</sb:last-page></sb:pages></sb:host></sb:reference></ce:bib-reference><ce:bib-reference id="BIB12"><ce:label>12</ce:label><sb:reference id="rf0065"><sb:contribution><sb:authors><sb:author><ce:given-name>M.</ce:given-name><ce:surname>Gerhard</ce:surname></sb:author><sb:author><ce:given-name>M.A.</ce:given-name><ce:surname>Roddy</ce:surname></sb:author><sb:author><ce:given-name>S.J.</ce:given-name><ce:surname>Creager</ce:surname></sb:author><sb:author><ce:given-name>M.A.</ce:given-name><ce:surname>Creager</ce:surname></sb:author></sb:authors><sb:title><sb:maintitle>Aging progressively impairs endothelium-dependent vasodilation in forearm resistance vessels of humans</sb:maintitle></sb:title></sb:contribution><sb:host><sb:issue><sb:series><sb:title><sb:maintitle>Hypertension</sb:maintitle></sb:title><sb:volume-nr>27</sb:volume-nr></sb:series><sb:date>1996</sb:date></sb:issue><sb:pages><sb:first-page>849</sb:first-page><sb:last-page>853</sb:last-page></sb:pages></sb:host></sb:reference></ce:bib-reference><ce:bib-reference id="BIB13"><ce:label>13</ce:label><sb:reference id="rf0070"><sb:contribution><sb:authors><sb:author><ce:given-name>M.T.</ce:given-name><ce:surname>Johnstone</ce:surname></sb:author><sb:author><ce:given-name>S.J.</ce:given-name><ce:surname>Creager</ce:surname></sb:author><sb:author><ce:given-name>K.M.</ce:given-name><ce:surname>Scales</ce:surname></sb:author><sb:author><ce:given-name>J.A.</ce:given-name><ce:surname>Cusco</ce:surname></sb:author><sb:author><ce:given-name>B.K.</ce:given-name><ce:surname>Lee</ce:surname></sb:author><sb:author><ce:given-name>M.A.</ce:given-name><ce:surname>Creager</ce:surname></sb:author></sb:authors><sb:title><sb:maintitle>Impaired endothelium-dependent vasodilation in patients with insulin-dependent diabetes mellitus</sb:maintitle></sb:title></sb:contribution><sb:host><sb:issue><sb:series><sb:title><sb:maintitle>Circulation</sb:maintitle></sb:title><sb:volume-nr>88</sb:volume-nr></sb:series><sb:date>1993</sb:date></sb:issue><sb:pages><sb:first-page>2510</sb:first-page><sb:last-page>2516</sb:last-page></sb:pages></sb:host></sb:reference></ce:bib-reference><ce:bib-reference id="BIB14"><ce:label>14</ce:label><sb:reference id="rf0075"><sb:contribution><sb:authors><sb:author><ce:given-name>S.B.</ce:given-name><ce:surname>Williams</ce:surname></sb:author><sb:author><ce:given-name>J.A.</ce:given-name><ce:surname>Cusco</ce:surname></sb:author><sb:author><ce:given-name>M.-A.</ce:given-name><ce:surname>Roddy</ce:surname></sb:author><sb:author><ce:given-name>M.T.</ce:given-name><ce:surname>Johnstone</ce:surname></sb:author><sb:author><ce:given-name>M.A.</ce:given-name><ce:surname>Creager</ce:surname></sb:author></sb:authors><sb:title><sb:maintitle>Impaired nitric oxide-mediated vasodilation in patients with noninsulin-dependent diabetes mellitus</sb:maintitle></sb:title></sb:contribution><sb:host><sb:issue><sb:series><sb:title><sb:maintitle>J Am Coll Cardiol</sb:maintitle></sb:title><sb:volume-nr>27</sb:volume-nr></sb:series><sb:date>1996</sb:date></sb:issue><sb:pages><sb:first-page>567</sb:first-page><sb:last-page>574</sb:last-page></sb:pages></sb:host></sb:reference></ce:bib-reference><ce:bib-reference id="BIB15"><ce:label>15</ce:label><sb:reference id="rf0080"><sb:contribution><sb:authors><sb:author><ce:given-name>W.</ce:given-name><ce:surname>Lockette</ce:surname></sb:author><sb:author><ce:given-name>Y.</ce:given-name><ce:surname>Otsuka</ce:surname></sb:author><sb:author><ce:given-name>O.</ce:given-name><ce:surname>Carretero</ce:surname></sb:author></sb:authors><sb:title><sb:maintitle>The loss of endothelium-dependent vascular relaxation in hypertension</sb:maintitle></sb:title></sb:contribution><sb:host><sb:issue><sb:series><sb:title><sb:maintitle>Hypertension</sb:maintitle></sb:title><sb:volume-nr>892</sb:volume-nr></sb:series><sb:date>1986</sb:date></sb:issue><sb:pages><sb:first-page>II61</sb:first-page><sb:last-page>II66</sb:last-page></sb:pages></sb:host></sb:reference></ce:bib-reference><ce:bib-reference id="BIB16"><ce:label>16</ce:label><sb:reference id="rf0085"><sb:contribution><sb:authors><sb:author><ce:given-name>T.</ce:given-name><ce:surname>Sugihara</ce:surname></sb:author><sb:author><ce:given-name>Y.</ce:given-name><ce:surname>Hattori</ce:surname></sb:author><sb:author><ce:given-name>Y.</ce:given-name><ce:surname>Yamamoto</ce:surname></sb:author><sb:et-al></sb:et-al></sb:authors><sb:title><sb:maintitle>Preferential impairment of nitric oxide-mediated endothelium-dependent relaxation in human cervical arteries after irradiation</sb:maintitle></sb:title></sb:contribution><sb:host><sb:issue><sb:series><sb:title><sb:maintitle>Circulation</sb:maintitle></sb:title><sb:volume-nr>100</sb:volume-nr></sb:series><sb:date>1999</sb:date></sb:issue><sb:pages><sb:first-page>635</sb:first-page><sb:last-page>641</sb:last-page></sb:pages></sb:host></sb:reference></ce:bib-reference><ce:bib-reference id="BIB17"><ce:label>17</ce:label><sb:reference id="rf0090"><sb:contribution><sb:authors><sb:author><ce:given-name>K.I.</ce:given-name><ce:surname>Maynard</ce:surname></sb:author><sb:author><ce:given-name>A.L.</ce:given-name><ce:surname>Stewart-Lee</ce:surname></sb:author><sb:author><ce:given-name>P.</ce:given-name><ce:surname>Milner</ce:surname></sb:author><sb:author><ce:given-name>G.</ce:given-name><ce:surname>Burnstock</ce:surname></sb:author></sb:authors><sb:title><sb:maintitle>X-irradiation attenuates relaxant responses in the rabbit ear artery</sb:maintitle></sb:title></sb:contribution><sb:host><sb:issue><sb:series><sb:title><sb:maintitle>Br J Pharmacol</sb:maintitle></sb:title><sb:volume-nr>105</sb:volume-nr></sb:series><sb:date>1992</sb:date></sb:issue><sb:pages><sb:first-page>126</sb:first-page><sb:last-page>128</sb:last-page></sb:pages></sb:host></sb:reference></ce:bib-reference><ce:bib-reference id="BIB18"><ce:label>18</ce:label><sb:reference id="rf0095"><sb:contribution><sb:authors><sb:author><ce:given-name>F.</ce:given-name><ce:surname>Qi</ce:surname></sb:author><sb:author><ce:given-name>T.</ce:given-name><ce:surname>Sugihara</ce:surname></sb:author><sb:author><ce:given-name>Y.</ce:given-name><ce:surname>Hattori</ce:surname></sb:author><sb:author><ce:given-name>Y.</ce:given-name><ce:surname>Yamamoto</ce:surname></sb:author><sb:author><ce:given-name>M.</ce:given-name><ce:surname>Kanno</ce:surname></sb:author><sb:author><ce:given-name>K.</ce:given-name><ce:surname>Abe</ce:surname></sb:author></sb:authors><sb:title><sb:maintitle>Functional and morphological damage of endothelium in rabbit-ear artery following irradiation with cobalt 60</sb:maintitle></sb:title></sb:contribution><sb:host><sb:issue><sb:series><sb:title><sb:maintitle>Br J Pharmacol</sb:maintitle></sb:title><sb:volume-nr>123</sb:volume-nr></sb:series><sb:date>1998</sb:date></sb:issue><sb:pages><sb:first-page>653</sb:first-page><sb:last-page>660</sb:last-page></sb:pages></sb:host></sb:reference></ce:bib-reference><ce:bib-reference id="BIB19"><ce:label>19</ce:label><sb:reference id="rf0100"><sb:contribution><sb:authors><sb:author><ce:given-name>S.</ce:given-name><ce:surname>Carrier</ce:surname></sb:author><sb:author><ce:given-name>H.</ce:given-name><ce:surname>Hricak</ce:surname></sb:author><sb:author><ce:given-name>S.-S.</ce:given-name><ce:surname>Lee</ce:surname></sb:author><sb:et-al></sb:et-al></sb:authors><sb:title><sb:maintitle>Radiation-induced decrease in nitric oxide synthase-containing nerves in the rat penis</sb:maintitle></sb:title></sb:contribution><sb:host><sb:issue><sb:series><sb:title><sb:maintitle>Radiology</sb:maintitle></sb:title><sb:volume-nr>195</sb:volume-nr></sb:series><sb:date>1995</sb:date></sb:issue><sb:pages><sb:first-page>95</sb:first-page><sb:last-page>99</sb:last-page></sb:pages></sb:host></sb:reference></ce:bib-reference><ce:bib-reference id="BIB20"><ce:label>20</ce:label><sb:reference id="rf0105"><sb:contribution><sb:authors><sb:author><ce:given-name>E.H.</ce:given-name><ce:surname>Lieberman</ce:surname></sb:author><sb:author><ce:given-name>M.D.</ce:given-name><ce:surname>Gerhard</ce:surname></sb:author><sb:author><ce:given-name>A.</ce:given-name><ce:surname>Uehata</ce:surname></sb:author><sb:et-al></sb:et-al></sb:authors><sb:title><sb:maintitle>Flow-induced vasodilation of the human brachial artery is impaired in patients <40 years of age with coronary artery disease</sb:maintitle></sb:title></sb:contribution><sb:host><sb:issue><sb:series><sb:title><sb:maintitle>Am J Cardiol</sb:maintitle></sb:title><sb:volume-nr>78</sb:volume-nr></sb:series><sb:date>1993</sb:date></sb:issue><sb:pages><sb:first-page>1210</sb:first-page><sb:last-page>1214</sb:last-page></sb:pages></sb:host></sb:reference></ce:bib-reference><ce:bib-reference id="BIB21"><ce:label>21</ce:label><sb:reference id="rf0110"><sb:contribution><sb:authors><sb:author><ce:given-name>Y.</ce:given-name><ce:surname>Matzner</ce:surname></sb:author><sb:author><ce:given-name>M.</ce:given-name><ce:surname>Cohn</ce:surname></sb:author><sb:author><ce:given-name>E.</ce:given-name><ce:surname>Hyam</ce:surname></sb:author><sb:et-al></sb:et-al></sb:authors><sb:title><sb:maintitle>Generation of lipid neutrophil chemoattractant by irradiated bovine aortic endothelial cells</sb:maintitle></sb:title></sb:contribution><sb:host><sb:issue><sb:series><sb:title><sb:maintitle>J Immunol</sb:maintitle></sb:title><sb:volume-nr>140</sb:volume-nr></sb:series><sb:date>1988</sb:date></sb:issue><sb:pages><sb:first-page>2681</sb:first-page><sb:last-page>2685</sb:last-page></sb:pages></sb:host></sb:reference></ce:bib-reference><ce:bib-reference id="BIB22"><ce:label>22</ce:label><sb:reference id="rf0115"><sb:contribution><sb:authors><sb:author><ce:given-name>J.</ce:given-name><ce:surname>Panes</ce:surname></sb:author><sb:author><ce:given-name>D.C.</ce:given-name><ce:surname>Anderson</ce:surname></sb:author><sb:author><ce:given-name>M.</ce:given-name><ce:surname>Miyasaka</ce:surname></sb:author><sb:author><ce:given-name>D.N.</ce:given-name><ce:surname>Granger</ce:surname></sb:author></sb:authors><sb:title><sb:maintitle>Role of leukocyte-endothelial cell adhesion in radiation-induced microvascular dysfunction in rats</sb:maintitle></sb:title></sb:contribution><sb:host><sb:issue><sb:series><sb:title><sb:maintitle>Gastroenterology</sb:maintitle></sb:title><sb:volume-nr>108</sb:volume-nr></sb:series><sb:date>1995</sb:date></sb:issue><sb:pages><sb:first-page>1761</sb:first-page><sb:last-page>1769</sb:last-page></sb:pages></sb:host></sb:reference></ce:bib-reference><ce:bib-reference id="BIB23"><ce:label>23</ce:label><sb:reference id="rf0120"><sb:contribution><sb:authors><sb:author><ce:given-name>L.</ce:given-name><ce:surname>Witte</ce:surname></sb:author><sb:author><ce:given-name>Z.</ce:given-name><ce:surname>Fuks</ce:surname></sb:author><sb:author><ce:given-name>A.</ce:given-name><ce:surname>Haimovitz-Friedman</ce:surname></sb:author><sb:author><ce:given-name>I.</ce:given-name><ce:surname>Vlodavsky</ce:surname></sb:author><sb:author><ce:given-name>D.S.</ce:given-name><ce:surname>Goodman</ce:surname></sb:author><sb:author><ce:given-name>A.</ce:given-name><ce:surname>Eldor</ce:surname></sb:author></sb:authors><sb:title><sb:maintitle>Effects of irradiation on the release of growth factors from cultured bovine, porcine and human endothelial cells</sb:maintitle></sb:title></sb:contribution><sb:host><sb:issue><sb:series><sb:title><sb:maintitle>Cancer Res</sb:maintitle></sb:title><sb:volume-nr>49</sb:volume-nr></sb:series><sb:date>1989</sb:date></sb:issue><sb:pages><sb:first-page>5066</sb:first-page><sb:last-page>5072</sb:last-page></sb:pages></sb:host></sb:reference></ce:bib-reference><ce:bib-reference id="BIB24"><ce:label>24</ce:label><sb:reference id="rf0125"><sb:contribution><sb:authors><sb:author><ce:given-name>E.W.</ce:given-name><ce:surname>Fonkalsrud</ce:surname></sb:author><sb:author><ce:given-name>M.</ce:given-name><ce:surname>Sanchez</ce:surname></sb:author><sb:author><ce:given-name>R.</ce:given-name><ce:surname>Zerubavel</ce:surname></sb:author><sb:author><ce:given-name>A.</ce:given-name><ce:surname>Mahoney</ce:surname></sb:author></sb:authors><sb:title><sb:maintitle>Serial changes in arterial structure following radiation therapy</sb:maintitle></sb:title></sb:contribution><sb:host><sb:issue><sb:series><sb:title><sb:maintitle>Surg Gynecol Obstet</sb:maintitle></sb:title><sb:volume-nr>145</sb:volume-nr></sb:series><sb:date>1977</sb:date></sb:issue><sb:pages><sb:first-page>395</sb:first-page><sb:last-page>400</sb:last-page></sb:pages></sb:host></sb:reference></ce:bib-reference><ce:bib-reference id="BIB25"><ce:label>25</ce:label><sb:reference id="rf0130"><sb:contribution><sb:authors><sb:author><ce:given-name>Y.M.</ce:given-name><ce:surname>Kim</ce:surname></sb:author><sb:author><ce:given-name>C.A.</ce:given-name><ce:surname>Bombeck</ce:surname></sb:author><sb:author><ce:given-name>T.R.</ce:given-name><ce:surname>Billiar</ce:surname></sb:author></sb:authors><sb:title><sb:maintitle>Nitric oxide as a bifunctional regulator of apoptosis</sb:maintitle></sb:title></sb:contribution><sb:host><sb:issue><sb:series><sb:title><sb:maintitle>Circ Res</sb:maintitle></sb:title><sb:volume-nr>84</sb:volume-nr></sb:series><sb:date>1999</sb:date></sb:issue><sb:pages><sb:first-page>253</sb:first-page><sb:last-page>256</sb:last-page></sb:pages></sb:host></sb:reference></ce:bib-reference><ce:bib-reference id="BIB26"><ce:label>26</ce:label><sb:reference id="rf0135"><sb:contribution><sb:authors><sb:author><ce:given-name>S.</ce:given-name><ce:surname>Dimmeler</ce:surname></sb:author><sb:author><ce:given-name>J.</ce:given-name><ce:surname>Haendeler</ce:surname></sb:author><sb:author><ce:given-name>M.</ce:given-name><ce:surname>Nehls</ce:surname></sb:author><sb:author><ce:given-name>A.M.</ce:given-name><ce:surname>Zeiher</ce:surname></sb:author></sb:authors><sb:title><sb:maintitle>Suppression of apoptosis by nitric oxide via inhibition of interleukin-1beta-converting enzyme (ICE)-like and cysteine protease protein (CPP)-32-like proteases</sb:maintitle></sb:title></sb:contribution><sb:host><sb:issue><sb:series><sb:title><sb:maintitle>J Exp Med</sb:maintitle></sb:title><sb:volume-nr>185</sb:volume-nr></sb:series><sb:date>1997</sb:date></sb:issue><sb:pages><sb:first-page>601</sb:first-page><sb:last-page>607</sb:last-page></sb:pages></sb:host></sb:reference></ce:bib-reference><ce:bib-reference id="BIB27"><ce:label>27</ce:label><sb:reference id="rf0140"><sb:contribution><sb:authors><sb:author><ce:given-name>D.S.</ce:given-name><ce:surname>Celermajer</ce:surname></sb:author><sb:author><ce:given-name>K.E.</ce:given-name><ce:surname>Sorensen</ce:surname></sb:author><sb:author><ce:given-name>V.M.</ce:given-name><ce:surname>Gooch</ce:surname></sb:author><sb:et-al></sb:et-al></sb:authors><sb:title><sb:maintitle>Noninvasive detection of endothelial dysfunction in children and adults at risk of atherosclerosis</sb:maintitle></sb:title></sb:contribution><sb:host><sb:issue><sb:series><sb:title><sb:maintitle>Lancet</sb:maintitle></sb:title><sb:volume-nr>340</sb:volume-nr></sb:series><sb:date>1992</sb:date></sb:issue><sb:pages><sb:first-page>1111</sb:first-page><sb:last-page>1115</sb:last-page></sb:pages></sb:host></sb:reference></ce:bib-reference><ce:bib-reference id="BIB28"><ce:label>28</ce:label><sb:reference id="rf0145"><sb:contribution><sb:authors><sb:author><ce:given-name>A.</ce:given-name><ce:surname>Vials</ce:surname></sb:author><sb:author><ce:given-name>G.</ce:given-name><ce:surname>Burnstock</ce:surname></sb:author></sb:authors><sb:title><sb:maintitle>Effects of nitric oxide synthase inhibitors, L-NG-nitroarginine and L-NG-nitroarginine methyl ester, on responses to vasodilators of the guinea-pig coronary vasculature</sb:maintitle></sb:title></sb:contribution><sb:host><sb:issue><sb:series><sb:title><sb:maintitle>Br J Pharmacol</sb:maintitle></sb:title><sb:volume-nr>107</sb:volume-nr></sb:series><sb:date>1992</sb:date></sb:issue><sb:pages><sb:first-page>604</sb:first-page><sb:last-page>609</sb:last-page></sb:pages></sb:host></sb:reference></ce:bib-reference><ce:bib-reference id="BIB29"><ce:label>29</ce:label><sb:reference id="rf0150"><sb:contribution><sb:authors><sb:author><ce:given-name>L.F.</ce:given-name><ce:surname>Paszat</ce:surname></sb:author><sb:author><ce:given-name>W.J.</ce:given-name><ce:surname>Mackillop</ce:surname></sb:author><sb:author><ce:given-name>P.A.</ce:given-name><ce:surname>Groome</ce:surname></sb:author><sb:author><ce:given-name>C.</ce:given-name><ce:surname>Boyd</ce:surname></sb:author><sb:author><ce:given-name>K.</ce:given-name><ce:surname>Schulze</ce:surname></sb:author><sb:author><ce:given-name>E.</ce:given-name><ce:surname>Holowaty</ce:surname></sb:author></sb:authors><sb:title><sb:maintitle>Mortality from myocardial infarction after adjuvant radiotherapy for breast cancer in the surveillance, epidemiology and end-results cancer registries</sb:maintitle></sb:title></sb:contribution><sb:host><sb:issue><sb:series><sb:title><sb:maintitle>J Clin Oncol</sb:maintitle></sb:title><sb:volume-nr>16</sb:volume-nr></sb:series><sb:date>1998</sb:date></sb:issue><sb:pages><sb:first-page>2625</sb:first-page><sb:last-page>2631</sb:last-page></sb:pages></sb:host></sb:reference></ce:bib-reference></ce:bibliography-sec></ce:bibliography></tail></article></istex:document></istex:metadataXml><mods version="3.6"><titleInfo lang="en"><title>Radiation therapy impairs endothelium-dependent vasodilation in humans</title></titleInfo><titleInfo type="alternative" lang="en" contentType="CDATA"><title>Radiation therapy impairs endothelium-dependent vasodilation in humans</title></titleInfo><name type="personal"><namePart type="given">Joshua A</namePart><namePart type="family">Beckman</namePart><namePart type="termsOfAddress">MD, FACC</namePart><affiliation>Vascular Medicine Section, Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Avni</namePart><namePart type="family">Thakore</namePart><namePart type="termsOfAddress">MS</namePart><affiliation>Vascular Medicine Section, Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Barbara H</namePart><namePart type="family">Kalinowski</namePart><namePart type="termsOfAddress">RN, MSN</namePart><affiliation>Department of Radiation Oncology, Brigham and Women’s Hospital, Boston, Massachusetts, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Jay R</namePart><namePart type="family">Harris</namePart><namePart type="termsOfAddress">MD</namePart><affiliation>Department of Radiation Oncology, Brigham and Women’s Hospital, Boston, Massachusetts, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Mark A</namePart><namePart type="family">Creager</namePart><namePart type="termsOfAddress">MD, FACC</namePart><affiliation>Vascular Medicine Section, Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts, USA</affiliation><affiliation>Reprint requests and correspondence: Dr. Mark A. Creager, Cardiovascular Division, Brigham and Women’s Hospital, 75 Francis Street, Boston, Massachusetts 02115</affiliation><affiliation>E-mail: mcreager@partners.org</affiliation><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="research-article" displayLabel="Full-length article"></genre><originInfo><publisher>ELSEVIER</publisher><dateIssued encoding="w3cdtf">2001</dateIssued><dateModified encoding="w3cdtf">2000-10-06</dateModified><copyrightDate encoding="w3cdtf">2001</copyrightDate></originInfo><language><languageTerm type="code" authority="iso639-2b">eng</languageTerm><languageTerm type="code" authority="rfc3066">en</languageTerm></language><physicalDescription><internetMediaType>text/html</internetMediaType></physicalDescription><abstract lang="en">OBJECTIVESThe objective of this study was to test the hypothesis that external-beam radiation induces a chronic impairment of endothelium-dependent vasodilation.BACKGROUNDRadiation therapy is used commonly in the treatment of cancer and is associated with an increased incidence of adverse vascular events related to the field of radiation, including stroke and myocardial infarction. As endothelial injury is central to the pathogenesis of vascular diseases, we hypothesized that radiotherapy induces arterial endothelial dysfunction.METHODSSixteen women with unilateral breast cancer who underwent standard external-beam radiation therapy to the breast and axilla >3 years before enrollment and ten healthy women were studied. Vascular ultrasonography was used to image both the artery exposed to radiation and the contralateral artery. Flow-mediated, endothelium-dependent vasodilation and endothelium-independent vasodilation to nitroglycerin of both axillary arteries were measured.RESULTSEndothelium-dependent vasodilation was significantly impaired in the irradiated axillary arteries compared with the contralateral, nonirradiated arteries (−0.4 ± 0.4% vs. 3.2 ± 0.8%, p < 0.001) and also compared with control subjects’ arteries (−0.4 ± 0.4% vs. 2.5 ± 0.6%, p < 0.001). In contrast, endothelium-independent vasodilation was greater in the arteries that received radiation compared with the contralateral arteries (3.8 ± 0.5% vs. 2.0 ± 0.4%, p < 0.05) and also compared with control arteries (3.8 ± 0.5% vs. 2.5 ± 0.4%, p < 0.05).CONCLUSIONSExternal beam radiation therapy impairs endothelium-dependent vasodilation of conduit arteries, implicating a decrease in the bioavailability of nitric oxide. These abnormalities may contribute to the development of arterial occlusive disease and associated clinical events.</abstract><note>Supported, in part, by grants from the National Heart, Lung, and Blood Institute, HL-48743 and HL04169-01, Bethesda, Maryland.</note><note type="content">Section title: Clinical study: endothelial function</note><note type="content">Figure 1: Effect of radiation therapy on flow-mediated vasodilation. The individual and mean percent increase in axillary artery size 1 min after cuff release compared with baseline is illustrated. Error bars represent standard error. Flow-mediated vasodilation was significantly impaired in irradiated arteries compared with nonirradiated arteries and arteries in control subjects (p < 0.001).</note><note type="content">Figure 2: Effect of radiation therapy on nitroglycerin-mediated vasodilation. The individual and mean percent increase in axillary artery size after nitroglycerin administration is shown. Error bars represent standard error. Nitroglycerin-mediated vasodilation was significantly greater in irradiated arteries compared with nonirradiated arteries and arteries in control subjects (p < 0.05).</note><note type="content">Figure 3: Inter-arm variation between healthy control subjects. The individual and mean flow-mediated and nitroglycerin-mediated vasodilation in the right and left arms of the control subjects. Error bars represent standard error. There is no significant difference between arms for either flow-mediated or nitroglycerin-mediated vasodilation.</note><subject><genre>article-category</genre><topic>Clinical study: endothelial function</topic></subject><subject lang="en"><genre>Abbreviations</genre><topic>BP : blood pressure</topic><topic>LDL : low density lipoprotein</topic><topic>MI : myocardial infarction</topic></subject><relatedItem type="host"><titleInfo><title>Journal of the American College of Cardiology</title></titleInfo><titleInfo type="abbreviated"><title>JAC</title></titleInfo><genre type="journal">journal</genre><originInfo><dateIssued encoding="w3cdtf">200103</dateIssued></originInfo><identifier type="ISSN">0735-1097</identifier><identifier type="PII">S0735-1097(00)X0090-3</identifier><part><date>200103</date><detail type="volume"><number>37</number><caption>vol.</caption></detail><detail type="issue"><number>3</number><caption>no.</caption></detail><extent unit="issue pages"><start>A1</start><end>A54</end></extent><extent unit="issue pages"><start>691</start><end>974</end></extent><extent unit="pages"><start>761</start><end>765</end></extent></part></relatedItem><identifier type="istex">E8FBCAAB71401269CBDBA928BA64E4206BF9E5F0</identifier><identifier type="DOI">10.1016/S0735-1097(00)01190-6</identifier><identifier type="PII">S0735-1097(00)01190-6</identifier><accessCondition type="use and reproduction" contentType="copyright">©2001 American College of Cardiology</accessCondition><recordInfo><recordContentSource>ELSEVIER</recordContentSource><recordOrigin>American College of Cardiology, ©2001</recordOrigin></recordInfo></mods></metadata><serie></serie></istex></record>Pour manipuler ce document sous Unix (Dilib)
EXPLOR_STEP=$WICRI_ROOT/Wicri/Sante/explor/LymphedemaV1/Data/Istex/Corpus
HfdSelect -h $EXPLOR_STEP/biblio.hfd -nk 006D31 | SxmlIndent | more
Ou
HfdSelect -h $EXPLOR_AREA/Data/Istex/Corpus/biblio.hfd -nk 006D31 | SxmlIndent | more
Pour mettre un lien sur cette page dans le réseau Wicri
{{Explor lien
|wiki= Wicri/Sante
|area= LymphedemaV1
|flux= Istex
|étape= Corpus
|type= RBID
|clé= ISTEX:E8FBCAAB71401269CBDBA928BA64E4206BF9E5F0
|texte= Radiation therapy impairs endothelium-dependent vasodilation in humans
}}
| This area was generated with Dilib version V0.6.31. |  |