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Inhibition of Coagulation Factor Xa Improves Myocardial Function During CVB3‐Induced Myocarditis
Summary Introduction Myocarditis is induced by coxsackievirus B3 (CVB3). Myocardial inflammation is tied to the activation of coagulation. Coagulation factor (F) Xa, a central player in coagulation, activates matrix metalloproteinases (MMP), which modulate the remodeling. Aims In this study, we inve...
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| Published in: | Cardiovascular therapeutics 2014-06, Vol.32 (3), p.113-119 |
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| container_title | Cardiovascular therapeutics |
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| creator | Malz, Ronny Weithauser, Alice Tschöpe, Carsten Schultheiss, Heinz‐Peter Rauch, Ursula |
| description | Summary
Introduction
Myocarditis is induced by coxsackievirus B3 (CVB3). Myocardial inflammation is tied to the activation of coagulation. Coagulation factor (F) Xa, a central player in coagulation, activates matrix metalloproteinases (MMP), which modulate the remodeling.
Aims
In this study, we investigated the effects of pharmacological FXa inhibition on myocardial function, inflammation, and remodeling during a CVB3‐induced myocarditis.
Methods and Results
Immune cells and matrix proteins were detected by immunohistochemistry. The expression of cytokines was measured by real‐time PCR and the activity of MMP‐2 by zymography. Left ventricular function was analyzed using microconductance pressure catheter. Treatment with the FXa inhibitor fondaparinux led to an improved left ventricular function in CVB3‐induced mice compared to saline‐treated controls (dPdtmax: fondaparinux 4632 ± 499.6 vs. saline 3131 ± 374.0 [mmHg/s], P = 0.0503; SV: fondaparinux 33.19 ± 4.893 vs. saline 19.32 ± 2.236 [μL], P |
| doi_str_mv | 10.1111/1755-5922.12069 |
| format | article |
| fullrecord | <record><control><sourceid>proquest_24P</sourceid><recordid>TN_cdi_proquest_miscellaneous_1518816004</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>3282050231</sourcerecordid><originalsourceid>FETCH-LOGICAL-j3929-5f8fcf3a79a0861045155010219a0bf3635f81d5ac332090cb03d368dbda728b3</originalsourceid><addsrcrecordid>eNpd0b1OwzAQAGALgWgpzGwoEgtLis-Ok3iElEKkIiQEiM1y_oqr_JQ4BnXjEXhGngQ3LR3w4vP50-l0h9Ap4DHYcwkBYy7jhIyBYJ_voeEus7-LwRugI60XGPuY-3CIBsRjlAbAhyiJ6zeVqE41tdMUTtTIuSll_5zKtGta51U6cbVsm49cO_erJpVtpmTpTE2d9mxiWlXPnejlmv58fcd1ZtI828lO6WN0UMhS5yfbe4SepzdP0Z07e7iNo6uZu6CccJcVYZEWVAZc4tAH7DFgDAMmYBNJQX1qBWRMppQSzHGaYJpRP8ySTAYkTOgIXWzq2mbfTa47USmd5mUp67wxWgCDMAQfY8_S83900Zi2tt31CkLGKLfqbKtMUuWZWLaqku1K_E3PArYBn6rMV7t_wGK9HLEev1ivQvTLEdHksQ_oL6OFf70</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1518185539</pqid></control><display><type>article</type><title>Inhibition of Coagulation Factor Xa Improves Myocardial Function During CVB3‐Induced Myocarditis</title><source>Wiley-Blackwell Open Access Collection</source><creator>Malz, Ronny ; Weithauser, Alice ; Tschöpe, Carsten ; Schultheiss, Heinz‐Peter ; Rauch, Ursula</creator><creatorcontrib>Malz, Ronny ; Weithauser, Alice ; Tschöpe, Carsten ; Schultheiss, Heinz‐Peter ; Rauch, Ursula</creatorcontrib><description>Summary
Introduction
Myocarditis is induced by coxsackievirus B3 (CVB3). Myocardial inflammation is tied to the activation of coagulation. Coagulation factor (F) Xa, a central player in coagulation, activates matrix metalloproteinases (MMP), which modulate the remodeling.
Aims
In this study, we investigated the effects of pharmacological FXa inhibition on myocardial function, inflammation, and remodeling during a CVB3‐induced myocarditis.
Methods and Results
Immune cells and matrix proteins were detected by immunohistochemistry. The expression of cytokines was measured by real‐time PCR and the activity of MMP‐2 by zymography. Left ventricular function was analyzed using microconductance pressure catheter. Treatment with the FXa inhibitor fondaparinux led to an improved left ventricular function in CVB3‐induced mice compared to saline‐treated controls (dPdtmax: fondaparinux 4632 ± 499.6 vs. saline 3131 ± 374.0 [mmHg/s], P = 0.0503; SV: fondaparinux 33.19 ± 4.893 vs. saline 19.32 ± 2.236 [μL], P < 0.118; CO: fondaparinux 15124 ± 2183 vs. saline 8088 ± 1035 [μL/min], P < 0.05). Therapy with fondaparinux reduced the activity of MMP‐2 (fondaparinux 1.208 ± 0.1247 vs. saline 1.565 ± 0.05476, P < 0.05). The collagen type I/III ratio as well as the expression of TIMP‐1 was comparable in both infection groups postinfectionem (p.i.), despite an increased infiltration of macrophages into the hearts of mice treated with fondaparinux 8 days p.i. (CD68+: fondaparinux 494.2 ± 64.73 vs. saline 306.9 ± 43.73 [cells/mm2], P < 0.05). Anti‐inflammatory CD206‐positive M2‐type macrophages were increased in the infected hearts after fondaparinux treatment (CD206+: fondaparinux 182.1 ± 18.18 vs. saline 111.6 ± 21.07 [cells/mm2], P < 0.05), whereas CD80‐positive M1‐type macrophages were comparable in both groups.
Conclusion
In conclusion, selective inhibition of FXa improves the left ventricular function during CVB3‐induced myocarditis and seems to be associated with an improved myocardial remodeling.</description><identifier>ISSN: 1755-5914</identifier><identifier>EISSN: 1755-5922</identifier><identifier>DOI: 10.1111/1755-5922.12069</identifier><identifier>PMID: 24533719</identifier><language>eng</language><publisher>England: Hindawi Limited</publisher><subject>Animals ; Coxsackievirus Infections - blood ; Coxsackievirus Infections - drug therapy ; Coxsackievirus Infections - physiopathology ; Coxsackievirus Infections - virology ; Cytokines - genetics ; Cytokines - metabolism ; Disease Models, Animal ; Enterovirus B, Human - pathogenicity ; Factor Xa ; Factor Xa - metabolism ; Factor Xa Inhibitors - pharmacology ; Fondaparinux ; Inflammation ; Inflammation Mediators - metabolism ; Male ; Matrix Metalloproteinase 2 - metabolism ; Mice, Inbred C57BL ; Myocarditis ; Myocarditis - blood ; Myocarditis - drug therapy ; Myocarditis - physiopathology ; Myocarditis - virology ; Polysaccharides - pharmacology ; Remodeling ; RNA, Messenger - metabolism ; Ventricular Function, Left - drug effects ; Ventricular Remodeling - drug effects ; Viral Load</subject><ispartof>Cardiovascular therapeutics, 2014-06, Vol.32 (3), p.113-119</ispartof><rights>2014 John Wiley & Sons Ltd</rights><rights>2014 John Wiley & Sons Ltd.</rights><rights>Copyright © 2014 John Wiley & Sons Ltd</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1111%2F1755-5922.12069$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1111%2F1755-5922.12069$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,776,780,11542,27903,27904,46030,46454</link.rule.ids><linktorsrc>$$Uhttps://onlinelibrary.wiley.com/doi/abs/10.1111%2F1755-5922.12069$$EView_record_in_Wiley-Blackwell$$FView_record_in_$$GWiley-Blackwell</linktorsrc><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24533719$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Malz, Ronny</creatorcontrib><creatorcontrib>Weithauser, Alice</creatorcontrib><creatorcontrib>Tschöpe, Carsten</creatorcontrib><creatorcontrib>Schultheiss, Heinz‐Peter</creatorcontrib><creatorcontrib>Rauch, Ursula</creatorcontrib><title>Inhibition of Coagulation Factor Xa Improves Myocardial Function During CVB3‐Induced Myocarditis</title><title>Cardiovascular therapeutics</title><addtitle>Cardiovasc Ther</addtitle><description>Summary
Introduction
Myocarditis is induced by coxsackievirus B3 (CVB3). Myocardial inflammation is tied to the activation of coagulation. Coagulation factor (F) Xa, a central player in coagulation, activates matrix metalloproteinases (MMP), which modulate the remodeling.
Aims
In this study, we investigated the effects of pharmacological FXa inhibition on myocardial function, inflammation, and remodeling during a CVB3‐induced myocarditis.
Methods and Results
Immune cells and matrix proteins were detected by immunohistochemistry. The expression of cytokines was measured by real‐time PCR and the activity of MMP‐2 by zymography. Left ventricular function was analyzed using microconductance pressure catheter. Treatment with the FXa inhibitor fondaparinux led to an improved left ventricular function in CVB3‐induced mice compared to saline‐treated controls (dPdtmax: fondaparinux 4632 ± 499.6 vs. saline 3131 ± 374.0 [mmHg/s], P = 0.0503; SV: fondaparinux 33.19 ± 4.893 vs. saline 19.32 ± 2.236 [μL], P < 0.118; CO: fondaparinux 15124 ± 2183 vs. saline 8088 ± 1035 [μL/min], P < 0.05). Therapy with fondaparinux reduced the activity of MMP‐2 (fondaparinux 1.208 ± 0.1247 vs. saline 1.565 ± 0.05476, P < 0.05). The collagen type I/III ratio as well as the expression of TIMP‐1 was comparable in both infection groups postinfectionem (p.i.), despite an increased infiltration of macrophages into the hearts of mice treated with fondaparinux 8 days p.i. (CD68+: fondaparinux 494.2 ± 64.73 vs. saline 306.9 ± 43.73 [cells/mm2], P < 0.05). Anti‐inflammatory CD206‐positive M2‐type macrophages were increased in the infected hearts after fondaparinux treatment (CD206+: fondaparinux 182.1 ± 18.18 vs. saline 111.6 ± 21.07 [cells/mm2], P < 0.05), whereas CD80‐positive M1‐type macrophages were comparable in both groups.
Conclusion
In conclusion, selective inhibition of FXa improves the left ventricular function during CVB3‐induced myocarditis and seems to be associated with an improved myocardial remodeling.</description><subject>Animals</subject><subject>Coxsackievirus Infections - blood</subject><subject>Coxsackievirus Infections - drug therapy</subject><subject>Coxsackievirus Infections - physiopathology</subject><subject>Coxsackievirus Infections - virology</subject><subject>Cytokines - genetics</subject><subject>Cytokines - metabolism</subject><subject>Disease Models, Animal</subject><subject>Enterovirus B, Human - pathogenicity</subject><subject>Factor Xa</subject><subject>Factor Xa - metabolism</subject><subject>Factor Xa Inhibitors - pharmacology</subject><subject>Fondaparinux</subject><subject>Inflammation</subject><subject>Inflammation Mediators - metabolism</subject><subject>Male</subject><subject>Matrix Metalloproteinase 2 - metabolism</subject><subject>Mice, Inbred C57BL</subject><subject>Myocarditis</subject><subject>Myocarditis - blood</subject><subject>Myocarditis - drug therapy</subject><subject>Myocarditis - physiopathology</subject><subject>Myocarditis - virology</subject><subject>Polysaccharides - pharmacology</subject><subject>Remodeling</subject><subject>RNA, Messenger - metabolism</subject><subject>Ventricular Function, Left - drug effects</subject><subject>Ventricular Remodeling - drug effects</subject><subject>Viral Load</subject><issn>1755-5914</issn><issn>1755-5922</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><recordid>eNpd0b1OwzAQAGALgWgpzGwoEgtLis-Ok3iElEKkIiQEiM1y_oqr_JQ4BnXjEXhGngQ3LR3w4vP50-l0h9Ap4DHYcwkBYy7jhIyBYJ_voeEus7-LwRugI60XGPuY-3CIBsRjlAbAhyiJ6zeVqE41tdMUTtTIuSll_5zKtGta51U6cbVsm49cO_erJpVtpmTpTE2d9mxiWlXPnejlmv58fcd1ZtI828lO6WN0UMhS5yfbe4SepzdP0Z07e7iNo6uZu6CccJcVYZEWVAZc4tAH7DFgDAMmYBNJQX1qBWRMppQSzHGaYJpRP8ySTAYkTOgIXWzq2mbfTa47USmd5mUp67wxWgCDMAQfY8_S83900Zi2tt31CkLGKLfqbKtMUuWZWLaqku1K_E3PArYBn6rMV7t_wGK9HLEev1ivQvTLEdHksQ_oL6OFf70</recordid><startdate>201406</startdate><enddate>201406</enddate><creator>Malz, Ronny</creator><creator>Weithauser, Alice</creator><creator>Tschöpe, Carsten</creator><creator>Schultheiss, Heinz‐Peter</creator><creator>Rauch, Ursula</creator><general>Hindawi Limited</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>K9.</scope><scope>7X8</scope></search><sort><creationdate>201406</creationdate><title>Inhibition of Coagulation Factor Xa Improves Myocardial Function During CVB3‐Induced Myocarditis</title><author>Malz, Ronny ; Weithauser, Alice ; Tschöpe, Carsten ; Schultheiss, Heinz‐Peter ; Rauch, Ursula</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-j3929-5f8fcf3a79a0861045155010219a0bf3635f81d5ac332090cb03d368dbda728b3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Animals</topic><topic>Coxsackievirus Infections - blood</topic><topic>Coxsackievirus Infections - drug therapy</topic><topic>Coxsackievirus Infections - physiopathology</topic><topic>Coxsackievirus Infections - virology</topic><topic>Cytokines - genetics</topic><topic>Cytokines - metabolism</topic><topic>Disease Models, Animal</topic><topic>Enterovirus B, Human - pathogenicity</topic><topic>Factor Xa</topic><topic>Factor Xa - metabolism</topic><topic>Factor Xa Inhibitors - pharmacology</topic><topic>Fondaparinux</topic><topic>Inflammation</topic><topic>Inflammation Mediators - metabolism</topic><topic>Male</topic><topic>Matrix Metalloproteinase 2 - metabolism</topic><topic>Mice, Inbred C57BL</topic><topic>Myocarditis</topic><topic>Myocarditis - blood</topic><topic>Myocarditis - drug therapy</topic><topic>Myocarditis - physiopathology</topic><topic>Myocarditis - virology</topic><topic>Polysaccharides - pharmacology</topic><topic>Remodeling</topic><topic>RNA, Messenger - metabolism</topic><topic>Ventricular Function, Left - drug effects</topic><topic>Ventricular Remodeling - drug effects</topic><topic>Viral Load</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Malz, Ronny</creatorcontrib><creatorcontrib>Weithauser, Alice</creatorcontrib><creatorcontrib>Tschöpe, Carsten</creatorcontrib><creatorcontrib>Schultheiss, Heinz‐Peter</creatorcontrib><creatorcontrib>Rauch, Ursula</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>MEDLINE - Academic</collection><jtitle>Cardiovascular therapeutics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext_linktorsrc</fulltext></delivery><addata><au>Malz, Ronny</au><au>Weithauser, Alice</au><au>Tschöpe, Carsten</au><au>Schultheiss, Heinz‐Peter</au><au>Rauch, Ursula</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Inhibition of Coagulation Factor Xa Improves Myocardial Function During CVB3‐Induced Myocarditis</atitle><jtitle>Cardiovascular therapeutics</jtitle><addtitle>Cardiovasc Ther</addtitle><date>2014-06</date><risdate>2014</risdate><volume>32</volume><issue>3</issue><spage>113</spage><epage>119</epage><pages>113-119</pages><issn>1755-5914</issn><eissn>1755-5922</eissn><abstract>Summary
Introduction
Myocarditis is induced by coxsackievirus B3 (CVB3). Myocardial inflammation is tied to the activation of coagulation. Coagulation factor (F) Xa, a central player in coagulation, activates matrix metalloproteinases (MMP), which modulate the remodeling.
Aims
In this study, we investigated the effects of pharmacological FXa inhibition on myocardial function, inflammation, and remodeling during a CVB3‐induced myocarditis.
Methods and Results
Immune cells and matrix proteins were detected by immunohistochemistry. The expression of cytokines was measured by real‐time PCR and the activity of MMP‐2 by zymography. Left ventricular function was analyzed using microconductance pressure catheter. Treatment with the FXa inhibitor fondaparinux led to an improved left ventricular function in CVB3‐induced mice compared to saline‐treated controls (dPdtmax: fondaparinux 4632 ± 499.6 vs. saline 3131 ± 374.0 [mmHg/s], P = 0.0503; SV: fondaparinux 33.19 ± 4.893 vs. saline 19.32 ± 2.236 [μL], P < 0.118; CO: fondaparinux 15124 ± 2183 vs. saline 8088 ± 1035 [μL/min], P < 0.05). Therapy with fondaparinux reduced the activity of MMP‐2 (fondaparinux 1.208 ± 0.1247 vs. saline 1.565 ± 0.05476, P < 0.05). The collagen type I/III ratio as well as the expression of TIMP‐1 was comparable in both infection groups postinfectionem (p.i.), despite an increased infiltration of macrophages into the hearts of mice treated with fondaparinux 8 days p.i. (CD68+: fondaparinux 494.2 ± 64.73 vs. saline 306.9 ± 43.73 [cells/mm2], P < 0.05). Anti‐inflammatory CD206‐positive M2‐type macrophages were increased in the infected hearts after fondaparinux treatment (CD206+: fondaparinux 182.1 ± 18.18 vs. saline 111.6 ± 21.07 [cells/mm2], P < 0.05), whereas CD80‐positive M1‐type macrophages were comparable in both groups.
Conclusion
In conclusion, selective inhibition of FXa improves the left ventricular function during CVB3‐induced myocarditis and seems to be associated with an improved myocardial remodeling.</abstract><cop>England</cop><pub>Hindawi Limited</pub><pmid>24533719</pmid><doi>10.1111/1755-5922.12069</doi><tpages>7</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Animals Coxsackievirus Infections - blood Coxsackievirus Infections - drug therapy Coxsackievirus Infections - physiopathology Coxsackievirus Infections - virology Cytokines - genetics Cytokines - metabolism Disease Models, Animal Enterovirus B, Human - pathogenicity Factor Xa Factor Xa - metabolism Factor Xa Inhibitors - pharmacology Fondaparinux Inflammation Inflammation Mediators - metabolism Male Matrix Metalloproteinase 2 - metabolism Mice, Inbred C57BL Myocarditis Myocarditis - blood Myocarditis - drug therapy Myocarditis - physiopathology Myocarditis - virology Polysaccharides - pharmacology Remodeling RNA, Messenger - metabolism Ventricular Function, Left - drug effects Ventricular Remodeling - drug effects Viral Load |
| title | Inhibition of Coagulation Factor Xa Improves Myocardial Function During CVB3‐Induced Myocarditis |
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