An autoantibody profile detects Brugada syndrome and identifies abnormally expressed myocardial proteins
Abstract Aims Brugada syndrome (BrS) is characterized by a unique electrocardiogram (ECG) pattern and life-threatening arrhythmias. However, the Type 1 Brugada ECG pattern is often transient, and a genetic cause is only identified in
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| Veröffentlicht in: | European heart journal 2020-08, Vol.41 (30), p.2878-2890 |
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| creator | Chatterjee, Diptendu Pieroni, Maurizio Fatah, Meena Charpentier, Flavien Cunningham, Kristopher S Spears, Danna A Chatterjee, Dipashree Suna, Gonca Bos, J Martjin Ackerman, Michael J Schulze-Bahr, Eric Dittmann, Sven Notarstefano, Pasquale G Bolognese, Leonardo Duru, Firat Saguner, Ardan M Hamilton, Robert M |
| description | Abstract
Aims
Brugada syndrome (BrS) is characterized by a unique electrocardiogram (ECG) pattern and life-threatening arrhythmias. However, the Type 1 Brugada ECG pattern is often transient, and a genetic cause is only identified in |
| doi_str_mv | 10.1093/eurheartj/ehaa383 |
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Aims
Brugada syndrome (BrS) is characterized by a unique electrocardiogram (ECG) pattern and life-threatening arrhythmias. However, the Type 1 Brugada ECG pattern is often transient, and a genetic cause is only identified in <25% of patients. We sought to identify an additional biomarker for this rare condition. As myocardial inflammation may be present in BrS, we evaluated whether myocardial autoantibodies can be detected in these patients.
Methods and results
For antibody (Ab) discovery, normal human ventricular myocardial proteins were solubilized and separated by isoelectric focusing (IEF) and molecular weight on two-dimensional (2D) gels and used to discover Abs by plating with sera from patients with BrS and control subjects. Target proteins were identified by mass spectrometry (MS). Brugada syndrome subjects were defined based on a consensus clinical scoring system. We assessed discovery and validation cohorts by 2D gels, western blots, and ELISA. We performed immunohistochemistry on myocardium from BrS subjects (vs. control). All (3/3) 2D gels exposed to sera from BrS patients demonstrated specific Abs to four proteins, confirmed by MS to be α-cardiac actin, α-skeletal actin, keratin, and connexin-43, vs. 0/8 control subjects. All (18/18) BrS subjects from our validation cohorts demonstrated the same Abs, confirmed by western blots, vs. 0/24 additional controls. ELISA optical densities for all Abs were elevated in all BrS subjects compared to controls. In myocardium obtained from BrS subjects, each protein, as well as SCN5A, demonstrated abnormal protein expression in aggregates.
Conclusion
A biomarker profile of autoantibodies against four cardiac proteins, namely α-cardiac actin, α-skeletal actin, keratin, and connexin-43, can be identified from sera of BrS patients and is highly sensitive and specific, irrespective of genetic cause for BrS. The four involved proteins, along with the SCN5A-encoded Nav1.5 alpha subunit are expressed abnormally in the myocardium of patients with BrS.</description><identifier>ISSN: 0195-668X</identifier><identifier>ISSN: 1522-9645</identifier><identifier>EISSN: 1522-9645</identifier><identifier>DOI: 10.1093/eurheartj/ehaa383</identifier><identifier>PMID: 32533187</identifier><language>eng</language><publisher>England: Oxford University Press</publisher><subject>Arrhythmias, Cardiac ; Autoantibodies ; Brugada Syndrome - diagnosis ; Electrocardiography ; Heart Ventricles ; Humans</subject><ispartof>European heart journal, 2020-08, Vol.41 (30), p.2878-2890</ispartof><rights>Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com. 2020</rights><rights>Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c268t-756889105a375655274922e03abc56ee00aacdd7023d0763d035af5731eaf5253</citedby><cites>FETCH-LOGICAL-c268t-756889105a375655274922e03abc56ee00aacdd7023d0763d035af5731eaf5253</cites><orcidid>0000-0002-4024-2974 ; 0000-0002-2495-711X ; 0000-0002-5199-7870 ; 0000-0003-0740-0464 ; 0000-0001-8093-1371 ; 0000-0002-2513-1627 ; 0000-0001-6884-2501 ; 0000-0002-6502-8333 ; 0000-0002-5344-1278 ; 0000-0002-6830-4292 ; 0000-0002-4748-0158 ; 0000-0002-0595-8942 ; 0000-0003-1896-0803 ; 0000-0002-5057-0998</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,1584,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32533187$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Chatterjee, Diptendu</creatorcontrib><creatorcontrib>Pieroni, Maurizio</creatorcontrib><creatorcontrib>Fatah, Meena</creatorcontrib><creatorcontrib>Charpentier, Flavien</creatorcontrib><creatorcontrib>Cunningham, Kristopher S</creatorcontrib><creatorcontrib>Spears, Danna A</creatorcontrib><creatorcontrib>Chatterjee, Dipashree</creatorcontrib><creatorcontrib>Suna, Gonca</creatorcontrib><creatorcontrib>Bos, J Martjin</creatorcontrib><creatorcontrib>Ackerman, Michael J</creatorcontrib><creatorcontrib>Schulze-Bahr, Eric</creatorcontrib><creatorcontrib>Dittmann, Sven</creatorcontrib><creatorcontrib>Notarstefano, Pasquale G</creatorcontrib><creatorcontrib>Bolognese, Leonardo</creatorcontrib><creatorcontrib>Duru, Firat</creatorcontrib><creatorcontrib>Saguner, Ardan M</creatorcontrib><creatorcontrib>Hamilton, Robert M</creatorcontrib><title>An autoantibody profile detects Brugada syndrome and identifies abnormally expressed myocardial proteins</title><title>European heart journal</title><addtitle>Eur Heart J</addtitle><description>Abstract
Aims
Brugada syndrome (BrS) is characterized by a unique electrocardiogram (ECG) pattern and life-threatening arrhythmias. However, the Type 1 Brugada ECG pattern is often transient, and a genetic cause is only identified in <25% of patients. We sought to identify an additional biomarker for this rare condition. As myocardial inflammation may be present in BrS, we evaluated whether myocardial autoantibodies can be detected in these patients.
Methods and results
For antibody (Ab) discovery, normal human ventricular myocardial proteins were solubilized and separated by isoelectric focusing (IEF) and molecular weight on two-dimensional (2D) gels and used to discover Abs by plating with sera from patients with BrS and control subjects. Target proteins were identified by mass spectrometry (MS). Brugada syndrome subjects were defined based on a consensus clinical scoring system. We assessed discovery and validation cohorts by 2D gels, western blots, and ELISA. We performed immunohistochemistry on myocardium from BrS subjects (vs. control). All (3/3) 2D gels exposed to sera from BrS patients demonstrated specific Abs to four proteins, confirmed by MS to be α-cardiac actin, α-skeletal actin, keratin, and connexin-43, vs. 0/8 control subjects. All (18/18) BrS subjects from our validation cohorts demonstrated the same Abs, confirmed by western blots, vs. 0/24 additional controls. ELISA optical densities for all Abs were elevated in all BrS subjects compared to controls. In myocardium obtained from BrS subjects, each protein, as well as SCN5A, demonstrated abnormal protein expression in aggregates.
Conclusion
A biomarker profile of autoantibodies against four cardiac proteins, namely α-cardiac actin, α-skeletal actin, keratin, and connexin-43, can be identified from sera of BrS patients and is highly sensitive and specific, irrespective of genetic cause for BrS. The four involved proteins, along with the SCN5A-encoded Nav1.5 alpha subunit are expressed abnormally in the myocardium of patients with BrS.</description><subject>Arrhythmias, Cardiac</subject><subject>Autoantibodies</subject><subject>Brugada Syndrome - diagnosis</subject><subject>Electrocardiography</subject><subject>Heart Ventricles</subject><subject>Humans</subject><issn>0195-668X</issn><issn>1522-9645</issn><issn>1522-9645</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkEtPwzAQhC0EoqXwA7ggHzkQ6kftJMdS8ZIqcQGJW7SJNzRVEgc7kci_x1VLz1x29jAzq_0IuebsnrNUznFwGwTXb-e4AZCJPCFTroSIUr1Qp2TKeKoirZPPCbnwfssYSzTX52QihZKSJ_GUbJYthaG30PZVbs1IO2fLqkZqsMei9_TBDV9ggPqxNc42SKE1tDIY_GWFnkLeWtdAXY8UfzqH3qOhzWgLcKaCetfXY9X6S3JWQu3x6qAz8vH0-L56idZvz6-r5ToqhE76KFY6SVLOFMiwKiXiRSoEMgl5oTQiYwCFMTET0rBYhyEVlCqWHIOEt2bkdt8bDn8P6PusqXyBdQ0t2sFnYsFFmsQ8AJgRvrcWznrvsMw6VzXgxoyzbAc4OwLODoBD5uZQP-QNmmPij2gw3O0Nduj-0fcLV1aLuA</recordid><startdate>20200807</startdate><enddate>20200807</enddate><creator>Chatterjee, Diptendu</creator><creator>Pieroni, Maurizio</creator><creator>Fatah, Meena</creator><creator>Charpentier, Flavien</creator><creator>Cunningham, Kristopher S</creator><creator>Spears, Danna A</creator><creator>Chatterjee, Dipashree</creator><creator>Suna, Gonca</creator><creator>Bos, J Martjin</creator><creator>Ackerman, Michael J</creator><creator>Schulze-Bahr, Eric</creator><creator>Dittmann, Sven</creator><creator>Notarstefano, Pasquale G</creator><creator>Bolognese, Leonardo</creator><creator>Duru, Firat</creator><creator>Saguner, Ardan M</creator><creator>Hamilton, Robert M</creator><general>Oxford University Press</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><orcidid>https://orcid.org/0000-0002-4024-2974</orcidid><orcidid>https://orcid.org/0000-0002-2495-711X</orcidid><orcidid>https://orcid.org/0000-0002-5199-7870</orcidid><orcidid>https://orcid.org/0000-0003-0740-0464</orcidid><orcidid>https://orcid.org/0000-0001-8093-1371</orcidid><orcidid>https://orcid.org/0000-0002-2513-1627</orcidid><orcidid>https://orcid.org/0000-0001-6884-2501</orcidid><orcidid>https://orcid.org/0000-0002-6502-8333</orcidid><orcidid>https://orcid.org/0000-0002-5344-1278</orcidid><orcidid>https://orcid.org/0000-0002-6830-4292</orcidid><orcidid>https://orcid.org/0000-0002-4748-0158</orcidid><orcidid>https://orcid.org/0000-0002-0595-8942</orcidid><orcidid>https://orcid.org/0000-0003-1896-0803</orcidid><orcidid>https://orcid.org/0000-0002-5057-0998</orcidid></search><sort><creationdate>20200807</creationdate><title>An autoantibody profile detects Brugada syndrome and identifies abnormally expressed myocardial proteins</title><author>Chatterjee, Diptendu ; Pieroni, Maurizio ; Fatah, Meena ; Charpentier, Flavien ; Cunningham, Kristopher S ; Spears, Danna A ; Chatterjee, Dipashree ; Suna, Gonca ; Bos, J Martjin ; Ackerman, Michael J ; Schulze-Bahr, Eric ; Dittmann, Sven ; Notarstefano, Pasquale G ; Bolognese, Leonardo ; Duru, Firat ; Saguner, Ardan M ; Hamilton, Robert M</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c268t-756889105a375655274922e03abc56ee00aacdd7023d0763d035af5731eaf5253</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Arrhythmias, Cardiac</topic><topic>Autoantibodies</topic><topic>Brugada Syndrome - diagnosis</topic><topic>Electrocardiography</topic><topic>Heart Ventricles</topic><topic>Humans</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Chatterjee, Diptendu</creatorcontrib><creatorcontrib>Pieroni, Maurizio</creatorcontrib><creatorcontrib>Fatah, Meena</creatorcontrib><creatorcontrib>Charpentier, Flavien</creatorcontrib><creatorcontrib>Cunningham, Kristopher S</creatorcontrib><creatorcontrib>Spears, Danna A</creatorcontrib><creatorcontrib>Chatterjee, Dipashree</creatorcontrib><creatorcontrib>Suna, Gonca</creatorcontrib><creatorcontrib>Bos, J Martjin</creatorcontrib><creatorcontrib>Ackerman, Michael J</creatorcontrib><creatorcontrib>Schulze-Bahr, Eric</creatorcontrib><creatorcontrib>Dittmann, Sven</creatorcontrib><creatorcontrib>Notarstefano, Pasquale G</creatorcontrib><creatorcontrib>Bolognese, Leonardo</creatorcontrib><creatorcontrib>Duru, Firat</creatorcontrib><creatorcontrib>Saguner, Ardan M</creatorcontrib><creatorcontrib>Hamilton, Robert M</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>European heart journal</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Chatterjee, Diptendu</au><au>Pieroni, Maurizio</au><au>Fatah, Meena</au><au>Charpentier, Flavien</au><au>Cunningham, Kristopher S</au><au>Spears, Danna A</au><au>Chatterjee, Dipashree</au><au>Suna, Gonca</au><au>Bos, J Martjin</au><au>Ackerman, Michael J</au><au>Schulze-Bahr, Eric</au><au>Dittmann, Sven</au><au>Notarstefano, Pasquale G</au><au>Bolognese, Leonardo</au><au>Duru, Firat</au><au>Saguner, Ardan M</au><au>Hamilton, Robert M</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>An autoantibody profile detects Brugada syndrome and identifies abnormally expressed myocardial proteins</atitle><jtitle>European heart journal</jtitle><addtitle>Eur Heart J</addtitle><date>2020-08-07</date><risdate>2020</risdate><volume>41</volume><issue>30</issue><spage>2878</spage><epage>2890</epage><pages>2878-2890</pages><issn>0195-668X</issn><issn>1522-9645</issn><eissn>1522-9645</eissn><abstract>Abstract
Aims
Brugada syndrome (BrS) is characterized by a unique electrocardiogram (ECG) pattern and life-threatening arrhythmias. However, the Type 1 Brugada ECG pattern is often transient, and a genetic cause is only identified in <25% of patients. We sought to identify an additional biomarker for this rare condition. As myocardial inflammation may be present in BrS, we evaluated whether myocardial autoantibodies can be detected in these patients.
Methods and results
For antibody (Ab) discovery, normal human ventricular myocardial proteins were solubilized and separated by isoelectric focusing (IEF) and molecular weight on two-dimensional (2D) gels and used to discover Abs by plating with sera from patients with BrS and control subjects. Target proteins were identified by mass spectrometry (MS). Brugada syndrome subjects were defined based on a consensus clinical scoring system. We assessed discovery and validation cohorts by 2D gels, western blots, and ELISA. We performed immunohistochemistry on myocardium from BrS subjects (vs. control). All (3/3) 2D gels exposed to sera from BrS patients demonstrated specific Abs to four proteins, confirmed by MS to be α-cardiac actin, α-skeletal actin, keratin, and connexin-43, vs. 0/8 control subjects. All (18/18) BrS subjects from our validation cohorts demonstrated the same Abs, confirmed by western blots, vs. 0/24 additional controls. ELISA optical densities for all Abs were elevated in all BrS subjects compared to controls. In myocardium obtained from BrS subjects, each protein, as well as SCN5A, demonstrated abnormal protein expression in aggregates.
Conclusion
A biomarker profile of autoantibodies against four cardiac proteins, namely α-cardiac actin, α-skeletal actin, keratin, and connexin-43, can be identified from sera of BrS patients and is highly sensitive and specific, irrespective of genetic cause for BrS. The four involved proteins, along with the SCN5A-encoded Nav1.5 alpha subunit are expressed abnormally in the myocardium of patients with BrS.</abstract><cop>England</cop><pub>Oxford University Press</pub><pmid>32533187</pmid><doi>10.1093/eurheartj/ehaa383</doi><tpages>13</tpages><orcidid>https://orcid.org/0000-0002-4024-2974</orcidid><orcidid>https://orcid.org/0000-0002-2495-711X</orcidid><orcidid>https://orcid.org/0000-0002-5199-7870</orcidid><orcidid>https://orcid.org/0000-0003-0740-0464</orcidid><orcidid>https://orcid.org/0000-0001-8093-1371</orcidid><orcidid>https://orcid.org/0000-0002-2513-1627</orcidid><orcidid>https://orcid.org/0000-0001-6884-2501</orcidid><orcidid>https://orcid.org/0000-0002-6502-8333</orcidid><orcidid>https://orcid.org/0000-0002-5344-1278</orcidid><orcidid>https://orcid.org/0000-0002-6830-4292</orcidid><orcidid>https://orcid.org/0000-0002-4748-0158</orcidid><orcidid>https://orcid.org/0000-0002-0595-8942</orcidid><orcidid>https://orcid.org/0000-0003-1896-0803</orcidid><orcidid>https://orcid.org/0000-0002-5057-0998</orcidid></addata></record> |
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| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Oxford University Press Journals All Titles (1996-Current); Alma/SFX Local Collection |
| subjects | Arrhythmias, Cardiac Autoantibodies Brugada Syndrome - diagnosis Electrocardiography Heart Ventricles Humans |
| title | An autoantibody profile detects Brugada syndrome and identifies abnormally expressed myocardial proteins |
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