Elevated Angiopoietin-2 Level in Patients With Continuous-Flow Left Ventricular Assist Devices Leads to Altered Angiogenesis and Is Associated With Higher Nonsurgical Bleeding
BACKGROUND:Nonsurgical bleeding is the most common adverse event in patients with continuous-flow left ventricular assist devices (LVADs) and is caused by arteriovenous malformations. We hypothesized that deregulation of an angiogenic factor, angiopoietin-2 (Ang-2), in patients with LVADs leads to i...
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| Veröffentlicht in: | Circulation (New York, N.Y.) N.Y.), 2016-07, Vol.134 (2), p.141-152 |
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| creator | Tabit, Corey E Chen, Phetcharat Kim, Gene H Fedson, Savitri E Sayer, Gabriel Coplan, Mitchell J Jeevanandam, Valluvan Uriel, Nir Liao, James K |
| description | BACKGROUND:Nonsurgical bleeding is the most common adverse event in patients with continuous-flow left ventricular assist devices (LVADs) and is caused by arteriovenous malformations. We hypothesized that deregulation of an angiogenic factor, angiopoietin-2 (Ang-2), in patients with LVADs leads to increased angiogenesis and higher nonsurgical bleeding.
METHODS:Ang-2 and thrombin levels were measured by ELISA and Western blotting, respectively, in blood samples from 101 patients with heart failure, LVAD, or orthotopic heart transplantation. Ang-2 expression in endothelial biopsy was quantified by immunofluorescence. Angiogenesis was determined by in vitro tube formation from serum from each patient with or without Ang-2–blocking antibody. Ang-2 gene expression was measured by reverse transcription–polymerase chain reaction in endothelial cells incubated with plasma from each patient with or without the thrombin receptor blocker vorapaxar.
RESULTS:Compared with patients with heart failure or those with orthotopic heart transplantation, serum levels and endothelial expression of Ang-2 were higher in LVAD patients (P=0.001 and P |
| doi_str_mv | 10.1161/CIRCULATIONAHA.115.019692 |
| format | Article |
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METHODS:Ang-2 and thrombin levels were measured by ELISA and Western blotting, respectively, in blood samples from 101 patients with heart failure, LVAD, or orthotopic heart transplantation. Ang-2 expression in endothelial biopsy was quantified by immunofluorescence. Angiogenesis was determined by in vitro tube formation from serum from each patient with or without Ang-2–blocking antibody. Ang-2 gene expression was measured by reverse transcription–polymerase chain reaction in endothelial cells incubated with plasma from each patient with or without the thrombin receptor blocker vorapaxar.
RESULTS:Compared with patients with heart failure or those with orthotopic heart transplantation, serum levels and endothelial expression of Ang-2 were higher in LVAD patients (P=0.001 and P<0.001, respectively). This corresponded to an increased angiogenic potential of serum from patients with LVADs (P<0.001), which was normalized with Ang-2 blockade. Furthermore, plasma from LVAD patients contained higher amounts of thrombin (P=0.003), which was associated with activation of the contact coagulation system. Plasma from LVAD patients induced more Ang-2 gene expression in endothelial cells (P<0.001), which was reduced with thrombin receptor blockade (P=0.013). LVAD patients with Ang-2 levels above the mean (12.32 ng/mL) had more nonsurgical bleeding events compared with patients with Ang-2 levels below the mean (P=0.003).
CONCLUSIONS:Our findings indicate that thrombin-induced Ang-2 expression in LVAD patients leads to increased angiogenesis in vitro and may be associated with higher nonsurgical bleeding events. Ang-2 therefore may contribute to arteriovenous malformation formation and subsequent bleeding in LVAD patients.</description><identifier>ISSN: 0009-7322</identifier><identifier>EISSN: 1524-4539</identifier><identifier>DOI: 10.1161/CIRCULATIONAHA.115.019692</identifier><identifier>PMID: 27354285</identifier><language>eng</language><publisher>United States: by the American College of Cardiology Foundation and the American Heart Association, Inc</publisher><subject>Aged ; Angiopoietin-2 - biosynthesis ; Angiopoietin-2 - blood ; Angiopoietin-2 - genetics ; Arteriovenous Malformations - complications ; Biomarkers ; Cross-Sectional Studies ; Endothelial Cells - metabolism ; Female ; Heart-Assist Devices ; Hemorrhage - etiology ; Human Umbilical Vein Endothelial Cells ; Humans ; Male ; Middle Aged ; Neovascularization, Pathologic - blood ; Neovascularization, Pathologic - etiology ; Neovascularization, Pathologic - physiopathology ; Thrombin - pharmacology</subject><ispartof>Circulation (New York, N.Y.), 2016-07, Vol.134 (2), p.141-152</ispartof><rights>2016 by the American College of Cardiology Foundation and the American Heart Association, Inc.</rights><rights>2016 American Heart Association, Inc.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4222-69a5a1b70317b8ac5269a6732e9b21a8ea0c613b24088aafc1215358d077a4da3</citedby><cites>FETCH-LOGICAL-c4222-69a5a1b70317b8ac5269a6732e9b21a8ea0c613b24088aafc1215358d077a4da3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,3674,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/27354285$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Tabit, Corey E</creatorcontrib><creatorcontrib>Chen, Phetcharat</creatorcontrib><creatorcontrib>Kim, Gene H</creatorcontrib><creatorcontrib>Fedson, Savitri E</creatorcontrib><creatorcontrib>Sayer, Gabriel</creatorcontrib><creatorcontrib>Coplan, Mitchell J</creatorcontrib><creatorcontrib>Jeevanandam, Valluvan</creatorcontrib><creatorcontrib>Uriel, Nir</creatorcontrib><creatorcontrib>Liao, James K</creatorcontrib><title>Elevated Angiopoietin-2 Level in Patients With Continuous-Flow Left Ventricular Assist Devices Leads to Altered Angiogenesis and Is Associated With Higher Nonsurgical Bleeding</title><title>Circulation (New York, N.Y.)</title><addtitle>Circulation</addtitle><description>BACKGROUND:Nonsurgical bleeding is the most common adverse event in patients with continuous-flow left ventricular assist devices (LVADs) and is caused by arteriovenous malformations. We hypothesized that deregulation of an angiogenic factor, angiopoietin-2 (Ang-2), in patients with LVADs leads to increased angiogenesis and higher nonsurgical bleeding.
METHODS:Ang-2 and thrombin levels were measured by ELISA and Western blotting, respectively, in blood samples from 101 patients with heart failure, LVAD, or orthotopic heart transplantation. Ang-2 expression in endothelial biopsy was quantified by immunofluorescence. Angiogenesis was determined by in vitro tube formation from serum from each patient with or without Ang-2–blocking antibody. Ang-2 gene expression was measured by reverse transcription–polymerase chain reaction in endothelial cells incubated with plasma from each patient with or without the thrombin receptor blocker vorapaxar.
RESULTS:Compared with patients with heart failure or those with orthotopic heart transplantation, serum levels and endothelial expression of Ang-2 were higher in LVAD patients (P=0.001 and P<0.001, respectively). This corresponded to an increased angiogenic potential of serum from patients with LVADs (P<0.001), which was normalized with Ang-2 blockade. Furthermore, plasma from LVAD patients contained higher amounts of thrombin (P=0.003), which was associated with activation of the contact coagulation system. Plasma from LVAD patients induced more Ang-2 gene expression in endothelial cells (P<0.001), which was reduced with thrombin receptor blockade (P=0.013). LVAD patients with Ang-2 levels above the mean (12.32 ng/mL) had more nonsurgical bleeding events compared with patients with Ang-2 levels below the mean (P=0.003).
CONCLUSIONS:Our findings indicate that thrombin-induced Ang-2 expression in LVAD patients leads to increased angiogenesis in vitro and may be associated with higher nonsurgical bleeding events. Ang-2 therefore may contribute to arteriovenous malformation formation and subsequent bleeding in LVAD patients.</description><subject>Aged</subject><subject>Angiopoietin-2 - biosynthesis</subject><subject>Angiopoietin-2 - blood</subject><subject>Angiopoietin-2 - genetics</subject><subject>Arteriovenous Malformations - complications</subject><subject>Biomarkers</subject><subject>Cross-Sectional Studies</subject><subject>Endothelial Cells - metabolism</subject><subject>Female</subject><subject>Heart-Assist Devices</subject><subject>Hemorrhage - etiology</subject><subject>Human Umbilical Vein Endothelial Cells</subject><subject>Humans</subject><subject>Male</subject><subject>Middle Aged</subject><subject>Neovascularization, Pathologic - blood</subject><subject>Neovascularization, Pathologic - etiology</subject><subject>Neovascularization, Pathologic - physiopathology</subject><subject>Thrombin - pharmacology</subject><issn>0009-7322</issn><issn>1524-4539</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNUctuEzEUtRCIhsIvILNjM60f43ksWAxDSyJFLUItLEcez83E4NjB9iTiq_jFOk2L1F1Xls_D5_oehD5QckZpQc_bxff2dtncLK6vmnmTMHFGaF3U7AWaUcHyLBe8folmhJA6KzljJ-hNCL_SteCleI1OWMlFzioxQ_8uDOxkhAE3dtRu6zREbTOGl7ADg7XF32TUYGPAP3Vc49bZxE9uCtmlcfskW0X8I_Feq8lIj5sQdIj4C-y0gpB4OQQcHW5MBP8YM4KFJMPSDngRDh6n9P0U9yFzPa7B4ytnw-RHraTBnw3AoO34Fr1aSRPg3cN5im4vL27aeba8_rpom2WmcsZYVtRSSNqXhNOyr6QSLCFFWgXUPaOyAklUQXnPclJVUq4UZVRwUQ2kLGU-SH6KPh7f3Xr3Z4IQu40OCoyRFtLnO1oRXtY8r0SS1kep8i4ED6tu6_VG-r8dJd2hr-5pXwkT3bGv5H3_EDP1Gxj-Ox8LSoJPR8HeHRYYfptpD75bgzRx_YyAO-4BqGE</recordid><startdate>20160712</startdate><enddate>20160712</enddate><creator>Tabit, Corey E</creator><creator>Chen, Phetcharat</creator><creator>Kim, Gene H</creator><creator>Fedson, Savitri E</creator><creator>Sayer, Gabriel</creator><creator>Coplan, Mitchell J</creator><creator>Jeevanandam, Valluvan</creator><creator>Uriel, Nir</creator><creator>Liao, James K</creator><general>by the American College of Cardiology Foundation and the American Heart Association, Inc</general><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>20160712</creationdate><title>Elevated Angiopoietin-2 Level in Patients With Continuous-Flow Left Ventricular Assist Devices Leads to Altered Angiogenesis and Is Associated With Higher Nonsurgical Bleeding</title><author>Tabit, Corey E ; Chen, Phetcharat ; Kim, Gene H ; Fedson, Savitri E ; Sayer, Gabriel ; Coplan, Mitchell J ; Jeevanandam, Valluvan ; Uriel, Nir ; Liao, James K</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4222-69a5a1b70317b8ac5269a6732e9b21a8ea0c613b24088aafc1215358d077a4da3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>Aged</topic><topic>Angiopoietin-2 - biosynthesis</topic><topic>Angiopoietin-2 - blood</topic><topic>Angiopoietin-2 - genetics</topic><topic>Arteriovenous Malformations - complications</topic><topic>Biomarkers</topic><topic>Cross-Sectional Studies</topic><topic>Endothelial Cells - metabolism</topic><topic>Female</topic><topic>Heart-Assist Devices</topic><topic>Hemorrhage - etiology</topic><topic>Human Umbilical Vein Endothelial Cells</topic><topic>Humans</topic><topic>Male</topic><topic>Middle Aged</topic><topic>Neovascularization, Pathologic - blood</topic><topic>Neovascularization, Pathologic - etiology</topic><topic>Neovascularization, Pathologic - physiopathology</topic><topic>Thrombin - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Tabit, Corey E</creatorcontrib><creatorcontrib>Chen, Phetcharat</creatorcontrib><creatorcontrib>Kim, Gene H</creatorcontrib><creatorcontrib>Fedson, Savitri E</creatorcontrib><creatorcontrib>Sayer, Gabriel</creatorcontrib><creatorcontrib>Coplan, Mitchell J</creatorcontrib><creatorcontrib>Jeevanandam, Valluvan</creatorcontrib><creatorcontrib>Uriel, Nir</creatorcontrib><creatorcontrib>Liao, James K</creatorcontrib><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 (New York, N.Y.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Tabit, Corey E</au><au>Chen, Phetcharat</au><au>Kim, Gene H</au><au>Fedson, Savitri E</au><au>Sayer, Gabriel</au><au>Coplan, Mitchell J</au><au>Jeevanandam, Valluvan</au><au>Uriel, Nir</au><au>Liao, James K</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Elevated Angiopoietin-2 Level in Patients With Continuous-Flow Left Ventricular Assist Devices Leads to Altered Angiogenesis and Is Associated With Higher Nonsurgical Bleeding</atitle><jtitle>Circulation (New York, N.Y.)</jtitle><addtitle>Circulation</addtitle><date>2016-07-12</date><risdate>2016</risdate><volume>134</volume><issue>2</issue><spage>141</spage><epage>152</epage><pages>141-152</pages><issn>0009-7322</issn><eissn>1524-4539</eissn><abstract>BACKGROUND:Nonsurgical bleeding is the most common adverse event in patients with continuous-flow left ventricular assist devices (LVADs) and is caused by arteriovenous malformations. We hypothesized that deregulation of an angiogenic factor, angiopoietin-2 (Ang-2), in patients with LVADs leads to increased angiogenesis and higher nonsurgical bleeding.
METHODS:Ang-2 and thrombin levels were measured by ELISA and Western blotting, respectively, in blood samples from 101 patients with heart failure, LVAD, or orthotopic heart transplantation. Ang-2 expression in endothelial biopsy was quantified by immunofluorescence. Angiogenesis was determined by in vitro tube formation from serum from each patient with or without Ang-2–blocking antibody. Ang-2 gene expression was measured by reverse transcription–polymerase chain reaction in endothelial cells incubated with plasma from each patient with or without the thrombin receptor blocker vorapaxar.
RESULTS:Compared with patients with heart failure or those with orthotopic heart transplantation, serum levels and endothelial expression of Ang-2 were higher in LVAD patients (P=0.001 and P<0.001, respectively). This corresponded to an increased angiogenic potential of serum from patients with LVADs (P<0.001), which was normalized with Ang-2 blockade. Furthermore, plasma from LVAD patients contained higher amounts of thrombin (P=0.003), which was associated with activation of the contact coagulation system. Plasma from LVAD patients induced more Ang-2 gene expression in endothelial cells (P<0.001), which was reduced with thrombin receptor blockade (P=0.013). LVAD patients with Ang-2 levels above the mean (12.32 ng/mL) had more nonsurgical bleeding events compared with patients with Ang-2 levels below the mean (P=0.003).
CONCLUSIONS:Our findings indicate that thrombin-induced Ang-2 expression in LVAD patients leads to increased angiogenesis in vitro and may be associated with higher nonsurgical bleeding events. Ang-2 therefore may contribute to arteriovenous malformation formation and subsequent bleeding in LVAD patients.</abstract><cop>United States</cop><pub>by the American College of Cardiology Foundation and the American Heart Association, Inc</pub><pmid>27354285</pmid><doi>10.1161/CIRCULATIONAHA.115.019692</doi><tpages>12</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Aged Angiopoietin-2 - biosynthesis Angiopoietin-2 - blood Angiopoietin-2 - genetics Arteriovenous Malformations - complications Biomarkers Cross-Sectional Studies Endothelial Cells - metabolism Female Heart-Assist Devices Hemorrhage - etiology Human Umbilical Vein Endothelial Cells Humans Male Middle Aged Neovascularization, Pathologic - blood Neovascularization, Pathologic - etiology Neovascularization, Pathologic - physiopathology Thrombin - pharmacology |
| title | Elevated Angiopoietin-2 Level in Patients With Continuous-Flow Left Ventricular Assist Devices Leads to Altered Angiogenesis and Is Associated With Higher Nonsurgical Bleeding |
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