Chronically elevated branched chain amino acid levels are pro-arrhythmic
Abstract Aims Cardiac arrhythmias comprise a major health and economic burden and are associated with significant morbidity and mortality, including cardiac failure, stroke, and sudden cardiac death (SCD). Development of efficient preventive and therapeutic strategies is hampered by incomplete knowl...
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Veröffentlicht in: | Cardiovascular research 2022-06, Vol.118 (7), p.1742-1757 |
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creator | Portero, Vincent Nicol, Thomas Podliesna, Svitlana Marchal, Gerard A Baartscheer, Antonius Casini, Simona Tadros, Rafik Treur, Jorien L Tanck, Michael W T Cox, I Jane Probert, Fay Hough, Tertius A Falcone, Sara Beekman, Leander Müller-Nurasyid, Martina Kastenmüller, Gabi Gieger, Christian Peters, Annette Kääb, Stefan Sinner, Moritz F Blease, Andrew Verkerk, Arie O Bezzina, Connie R Potter, Paul K Remme, Carol Ann |
description | Abstract
Aims
Cardiac arrhythmias comprise a major health and economic burden and are associated with significant morbidity and mortality, including cardiac failure, stroke, and sudden cardiac death (SCD). Development of efficient preventive and therapeutic strategies is hampered by incomplete knowledge of disease mechanisms and pathways. Our aim is to identify novel mechanisms underlying cardiac arrhythmia and SCD using an unbiased approach.
Methods and results
We employed a phenotype-driven N-ethyl-N-nitrosourea mutagenesis screen and identified a mouse line with a high incidence of sudden death at young age (6–9 weeks) in the absence of prior symptoms. Affected mice were found to be homozygous for the nonsense mutation Bcat2p.Q300*/p.Q300* in the Bcat2 gene encoding branched chain amino acid transaminase 2. At the age of 4–5 weeks, Bcat2p.Q300*/p.Q300* mice displayed drastic increase of plasma levels of branch chain amino acids (BCAAs—leucine, isoleucine, valine) due to the incomplete catabolism of BCAAs, in addition to inducible arrhythmias ex vivo as well as cardiac conduction and repolarization disturbances. In line with these findings, plasma BCAA levels were positively correlated to electrocardiogram indices of conduction and repolarization in the German community-based KORA F4 Study. Isolated cardiomyocytes from Bcat2p.Q300*/p.Q300* mice revealed action potential (AP) prolongation, pro-arrhythmic events (early and late afterdepolarizations, triggered APs), and dysregulated calcium homeostasis. Incubation of human pluripotent stem cell-derived cardiomyocytes with elevated concentration of BCAAs induced similar calcium dysregulation and pro-arrhythmic events which were prevented by rapamycin, demonstrating the crucial involvement of mTOR pathway activation.
Conclusions
Our findings identify for the first time a causative link between elevated BCAAs and arrhythmia, which has implications for arrhythmogenesis in conditions associated with BCAA metabolism dysregulation such as diabetes, metabolic syndrome, and heart failure.
Graphical Abstract
Graphical Abstract |
doi_str_mv | 10.1093/cvr/cvab207 |
format | Article |
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Aims
Cardiac arrhythmias comprise a major health and economic burden and are associated with significant morbidity and mortality, including cardiac failure, stroke, and sudden cardiac death (SCD). Development of efficient preventive and therapeutic strategies is hampered by incomplete knowledge of disease mechanisms and pathways. Our aim is to identify novel mechanisms underlying cardiac arrhythmia and SCD using an unbiased approach.
Methods and results
We employed a phenotype-driven N-ethyl-N-nitrosourea mutagenesis screen and identified a mouse line with a high incidence of sudden death at young age (6–9 weeks) in the absence of prior symptoms. Affected mice were found to be homozygous for the nonsense mutation Bcat2p.Q300*/p.Q300* in the Bcat2 gene encoding branched chain amino acid transaminase 2. At the age of 4–5 weeks, Bcat2p.Q300*/p.Q300* mice displayed drastic increase of plasma levels of branch chain amino acids (BCAAs—leucine, isoleucine, valine) due to the incomplete catabolism of BCAAs, in addition to inducible arrhythmias ex vivo as well as cardiac conduction and repolarization disturbances. In line with these findings, plasma BCAA levels were positively correlated to electrocardiogram indices of conduction and repolarization in the German community-based KORA F4 Study. Isolated cardiomyocytes from Bcat2p.Q300*/p.Q300* mice revealed action potential (AP) prolongation, pro-arrhythmic events (early and late afterdepolarizations, triggered APs), and dysregulated calcium homeostasis. Incubation of human pluripotent stem cell-derived cardiomyocytes with elevated concentration of BCAAs induced similar calcium dysregulation and pro-arrhythmic events which were prevented by rapamycin, demonstrating the crucial involvement of mTOR pathway activation.
Conclusions
Our findings identify for the first time a causative link between elevated BCAAs and arrhythmia, which has implications for arrhythmogenesis in conditions associated with BCAA metabolism dysregulation such as diabetes, metabolic syndrome, and heart failure.
Graphical Abstract
Graphical Abstract</description><identifier>ISSN: 0008-6363</identifier><identifier>EISSN: 1755-3245</identifier><identifier>DOI: 10.1093/cvr/cvab207</identifier><identifier>PMID: 34142125</identifier><language>eng</language><publisher>England: Oxford University Press</publisher><subject>Amino Acids, Branched-Chain - metabolism ; Animals ; Calcium ; Heart Failure ; Humans ; Mice ; Myocytes, Cardiac - metabolism ; Original ; Sirolimus</subject><ispartof>Cardiovascular research, 2022-06, Vol.118 (7), p.1742-1757</ispartof><rights>The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology. 2021</rights><rights>The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c379t-99b0c3f352d44335e8ffe481cf4835d16696064eae1991f7ac43ce13237403b83</citedby><cites>FETCH-LOGICAL-c379t-99b0c3f352d44335e8ffe481cf4835d16696064eae1991f7ac43ce13237403b83</cites><orcidid>0000-0002-6660-796X ; 0000-0003-2140-834X ; 0000-0002-7221-859X ; 0000-0002-9636-9026 ; 0000-0002-2672-2779 ; 0000-0002-9828-7235 ; 0000-0001-5784-7016 ; 0000-0001-9828-4459 ; 0000-0003-4370-3390 ; 0000-0002-1472-0258 ; 0000-0003-2689-2361 ; 0000-0001-8824-3581 ; 0000-0003-0774-9674 ; 0000-0003-3793-5910 ; 0000-0001-6645-0985 ; 0000-0002-0633-3514 ; 0000-0003-0095-0084 ; 0000-0002-8580-2023 ; 0000-0002-7353-0235 ; 0000-0002-2368-7322 ; 0000-0001-6986-9554</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,315,781,785,886,1585,27929,27930</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34142125$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Portero, Vincent</creatorcontrib><creatorcontrib>Nicol, Thomas</creatorcontrib><creatorcontrib>Podliesna, Svitlana</creatorcontrib><creatorcontrib>Marchal, Gerard A</creatorcontrib><creatorcontrib>Baartscheer, Antonius</creatorcontrib><creatorcontrib>Casini, Simona</creatorcontrib><creatorcontrib>Tadros, Rafik</creatorcontrib><creatorcontrib>Treur, Jorien L</creatorcontrib><creatorcontrib>Tanck, Michael W T</creatorcontrib><creatorcontrib>Cox, I Jane</creatorcontrib><creatorcontrib>Probert, Fay</creatorcontrib><creatorcontrib>Hough, Tertius A</creatorcontrib><creatorcontrib>Falcone, Sara</creatorcontrib><creatorcontrib>Beekman, Leander</creatorcontrib><creatorcontrib>Müller-Nurasyid, Martina</creatorcontrib><creatorcontrib>Kastenmüller, Gabi</creatorcontrib><creatorcontrib>Gieger, Christian</creatorcontrib><creatorcontrib>Peters, Annette</creatorcontrib><creatorcontrib>Kääb, Stefan</creatorcontrib><creatorcontrib>Sinner, Moritz F</creatorcontrib><creatorcontrib>Blease, Andrew</creatorcontrib><creatorcontrib>Verkerk, Arie O</creatorcontrib><creatorcontrib>Bezzina, Connie R</creatorcontrib><creatorcontrib>Potter, Paul K</creatorcontrib><creatorcontrib>Remme, Carol Ann</creatorcontrib><title>Chronically elevated branched chain amino acid levels are pro-arrhythmic</title><title>Cardiovascular research</title><addtitle>Cardiovasc Res</addtitle><description>Abstract
Aims
Cardiac arrhythmias comprise a major health and economic burden and are associated with significant morbidity and mortality, including cardiac failure, stroke, and sudden cardiac death (SCD). Development of efficient preventive and therapeutic strategies is hampered by incomplete knowledge of disease mechanisms and pathways. Our aim is to identify novel mechanisms underlying cardiac arrhythmia and SCD using an unbiased approach.
Methods and results
We employed a phenotype-driven N-ethyl-N-nitrosourea mutagenesis screen and identified a mouse line with a high incidence of sudden death at young age (6–9 weeks) in the absence of prior symptoms. Affected mice were found to be homozygous for the nonsense mutation Bcat2p.Q300*/p.Q300* in the Bcat2 gene encoding branched chain amino acid transaminase 2. At the age of 4–5 weeks, Bcat2p.Q300*/p.Q300* mice displayed drastic increase of plasma levels of branch chain amino acids (BCAAs—leucine, isoleucine, valine) due to the incomplete catabolism of BCAAs, in addition to inducible arrhythmias ex vivo as well as cardiac conduction and repolarization disturbances. In line with these findings, plasma BCAA levels were positively correlated to electrocardiogram indices of conduction and repolarization in the German community-based KORA F4 Study. Isolated cardiomyocytes from Bcat2p.Q300*/p.Q300* mice revealed action potential (AP) prolongation, pro-arrhythmic events (early and late afterdepolarizations, triggered APs), and dysregulated calcium homeostasis. Incubation of human pluripotent stem cell-derived cardiomyocytes with elevated concentration of BCAAs induced similar calcium dysregulation and pro-arrhythmic events which were prevented by rapamycin, demonstrating the crucial involvement of mTOR pathway activation.
Conclusions
Our findings identify for the first time a causative link between elevated BCAAs and arrhythmia, which has implications for arrhythmogenesis in conditions associated with BCAA metabolism dysregulation such as diabetes, metabolic syndrome, and heart failure.
Graphical Abstract
Graphical Abstract</description><subject>Amino Acids, Branched-Chain - metabolism</subject><subject>Animals</subject><subject>Calcium</subject><subject>Heart Failure</subject><subject>Humans</subject><subject>Mice</subject><subject>Myocytes, Cardiac - metabolism</subject><subject>Original</subject><subject>Sirolimus</subject><issn>0008-6363</issn><issn>1755-3245</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><sourceid>TOX</sourceid><sourceid>EIF</sourceid><recordid>eNp9kEFLxDAQRoMo7rp68i49eZFq0kna5iLIoq6w4EXPYZqmNtI2Je0W9t8b2XXRi4cwGebNG_gIuWT0llEJd3ry4WGR0OyIzFkmRAwJF8dkTinN4xRSmJGzYfgMrRAZPyUz4IwnLBFzslrW3nVWY9NsI9OYCUdTRoXHTtfho2u0XYSt7VyE2pZRIEwzROhN1HsXo_f1dqxbq8_JSYXNYC72dUHenx7flqt4_fr8snxYxxoyOcZSFlRDBSIpOQcQJq8qw3OmK56DKFmaypSm3KBhUrIqQ81BGwYJZJxCkcOC3O-8_aZoTalNN3psVO9ti36rHFr1d9LZWn24ScmECSbTILjZCbR3w-BNddhlVH0HqkKgah9ooK9-nzuwPwkG4HoHuE3_r-kLwhWAww</recordid><startdate>20220622</startdate><enddate>20220622</enddate><creator>Portero, Vincent</creator><creator>Nicol, Thomas</creator><creator>Podliesna, Svitlana</creator><creator>Marchal, Gerard A</creator><creator>Baartscheer, Antonius</creator><creator>Casini, Simona</creator><creator>Tadros, Rafik</creator><creator>Treur, Jorien L</creator><creator>Tanck, Michael W T</creator><creator>Cox, I Jane</creator><creator>Probert, Fay</creator><creator>Hough, Tertius A</creator><creator>Falcone, Sara</creator><creator>Beekman, Leander</creator><creator>Müller-Nurasyid, Martina</creator><creator>Kastenmüller, Gabi</creator><creator>Gieger, Christian</creator><creator>Peters, Annette</creator><creator>Kääb, Stefan</creator><creator>Sinner, Moritz F</creator><creator>Blease, Andrew</creator><creator>Verkerk, Arie O</creator><creator>Bezzina, Connie R</creator><creator>Potter, Paul K</creator><creator>Remme, Carol Ann</creator><general>Oxford University Press</general><scope>TOX</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-6660-796X</orcidid><orcidid>https://orcid.org/0000-0003-2140-834X</orcidid><orcidid>https://orcid.org/0000-0002-7221-859X</orcidid><orcidid>https://orcid.org/0000-0002-9636-9026</orcidid><orcidid>https://orcid.org/0000-0002-2672-2779</orcidid><orcidid>https://orcid.org/0000-0002-9828-7235</orcidid><orcidid>https://orcid.org/0000-0001-5784-7016</orcidid><orcidid>https://orcid.org/0000-0001-9828-4459</orcidid><orcidid>https://orcid.org/0000-0003-4370-3390</orcidid><orcidid>https://orcid.org/0000-0002-1472-0258</orcidid><orcidid>https://orcid.org/0000-0003-2689-2361</orcidid><orcidid>https://orcid.org/0000-0001-8824-3581</orcidid><orcidid>https://orcid.org/0000-0003-0774-9674</orcidid><orcidid>https://orcid.org/0000-0003-3793-5910</orcidid><orcidid>https://orcid.org/0000-0001-6645-0985</orcidid><orcidid>https://orcid.org/0000-0002-0633-3514</orcidid><orcidid>https://orcid.org/0000-0003-0095-0084</orcidid><orcidid>https://orcid.org/0000-0002-8580-2023</orcidid><orcidid>https://orcid.org/0000-0002-7353-0235</orcidid><orcidid>https://orcid.org/0000-0002-2368-7322</orcidid><orcidid>https://orcid.org/0000-0001-6986-9554</orcidid></search><sort><creationdate>20220622</creationdate><title>Chronically elevated branched chain amino acid levels are pro-arrhythmic</title><author>Portero, Vincent ; Nicol, Thomas ; Podliesna, Svitlana ; Marchal, Gerard A ; Baartscheer, Antonius ; Casini, Simona ; Tadros, Rafik ; Treur, Jorien L ; Tanck, Michael W T ; Cox, I Jane ; Probert, Fay ; Hough, Tertius A ; Falcone, Sara ; Beekman, Leander ; Müller-Nurasyid, Martina ; Kastenmüller, Gabi ; Gieger, Christian ; Peters, Annette ; Kääb, Stefan ; Sinner, Moritz F ; Blease, Andrew ; Verkerk, Arie O ; Bezzina, Connie R ; Potter, Paul K ; Remme, Carol Ann</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c379t-99b0c3f352d44335e8ffe481cf4835d16696064eae1991f7ac43ce13237403b83</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>Amino Acids, Branched-Chain - metabolism</topic><topic>Animals</topic><topic>Calcium</topic><topic>Heart Failure</topic><topic>Humans</topic><topic>Mice</topic><topic>Myocytes, Cardiac - metabolism</topic><topic>Original</topic><topic>Sirolimus</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Portero, Vincent</creatorcontrib><creatorcontrib>Nicol, Thomas</creatorcontrib><creatorcontrib>Podliesna, Svitlana</creatorcontrib><creatorcontrib>Marchal, Gerard A</creatorcontrib><creatorcontrib>Baartscheer, Antonius</creatorcontrib><creatorcontrib>Casini, Simona</creatorcontrib><creatorcontrib>Tadros, Rafik</creatorcontrib><creatorcontrib>Treur, Jorien L</creatorcontrib><creatorcontrib>Tanck, Michael W T</creatorcontrib><creatorcontrib>Cox, I Jane</creatorcontrib><creatorcontrib>Probert, Fay</creatorcontrib><creatorcontrib>Hough, Tertius A</creatorcontrib><creatorcontrib>Falcone, Sara</creatorcontrib><creatorcontrib>Beekman, Leander</creatorcontrib><creatorcontrib>Müller-Nurasyid, Martina</creatorcontrib><creatorcontrib>Kastenmüller, Gabi</creatorcontrib><creatorcontrib>Gieger, Christian</creatorcontrib><creatorcontrib>Peters, Annette</creatorcontrib><creatorcontrib>Kääb, Stefan</creatorcontrib><creatorcontrib>Sinner, Moritz F</creatorcontrib><creatorcontrib>Blease, Andrew</creatorcontrib><creatorcontrib>Verkerk, Arie O</creatorcontrib><creatorcontrib>Bezzina, Connie R</creatorcontrib><creatorcontrib>Potter, Paul K</creatorcontrib><creatorcontrib>Remme, Carol Ann</creatorcontrib><collection>Access via Oxford University Press (Open Access Collection)</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Cardiovascular research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Portero, Vincent</au><au>Nicol, Thomas</au><au>Podliesna, Svitlana</au><au>Marchal, Gerard A</au><au>Baartscheer, Antonius</au><au>Casini, Simona</au><au>Tadros, Rafik</au><au>Treur, Jorien L</au><au>Tanck, Michael W T</au><au>Cox, I Jane</au><au>Probert, Fay</au><au>Hough, Tertius A</au><au>Falcone, Sara</au><au>Beekman, Leander</au><au>Müller-Nurasyid, Martina</au><au>Kastenmüller, Gabi</au><au>Gieger, Christian</au><au>Peters, Annette</au><au>Kääb, Stefan</au><au>Sinner, Moritz F</au><au>Blease, Andrew</au><au>Verkerk, Arie O</au><au>Bezzina, Connie R</au><au>Potter, Paul K</au><au>Remme, Carol Ann</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Chronically elevated branched chain amino acid levels are pro-arrhythmic</atitle><jtitle>Cardiovascular research</jtitle><addtitle>Cardiovasc Res</addtitle><date>2022-06-22</date><risdate>2022</risdate><volume>118</volume><issue>7</issue><spage>1742</spage><epage>1757</epage><pages>1742-1757</pages><issn>0008-6363</issn><eissn>1755-3245</eissn><abstract>Abstract
Aims
Cardiac arrhythmias comprise a major health and economic burden and are associated with significant morbidity and mortality, including cardiac failure, stroke, and sudden cardiac death (SCD). Development of efficient preventive and therapeutic strategies is hampered by incomplete knowledge of disease mechanisms and pathways. Our aim is to identify novel mechanisms underlying cardiac arrhythmia and SCD using an unbiased approach.
Methods and results
We employed a phenotype-driven N-ethyl-N-nitrosourea mutagenesis screen and identified a mouse line with a high incidence of sudden death at young age (6–9 weeks) in the absence of prior symptoms. Affected mice were found to be homozygous for the nonsense mutation Bcat2p.Q300*/p.Q300* in the Bcat2 gene encoding branched chain amino acid transaminase 2. At the age of 4–5 weeks, Bcat2p.Q300*/p.Q300* mice displayed drastic increase of plasma levels of branch chain amino acids (BCAAs—leucine, isoleucine, valine) due to the incomplete catabolism of BCAAs, in addition to inducible arrhythmias ex vivo as well as cardiac conduction and repolarization disturbances. In line with these findings, plasma BCAA levels were positively correlated to electrocardiogram indices of conduction and repolarization in the German community-based KORA F4 Study. Isolated cardiomyocytes from Bcat2p.Q300*/p.Q300* mice revealed action potential (AP) prolongation, pro-arrhythmic events (early and late afterdepolarizations, triggered APs), and dysregulated calcium homeostasis. Incubation of human pluripotent stem cell-derived cardiomyocytes with elevated concentration of BCAAs induced similar calcium dysregulation and pro-arrhythmic events which were prevented by rapamycin, demonstrating the crucial involvement of mTOR pathway activation.
Conclusions
Our findings identify for the first time a causative link between elevated BCAAs and arrhythmia, which has implications for arrhythmogenesis in conditions associated with BCAA metabolism dysregulation such as diabetes, metabolic syndrome, and heart failure.
Graphical Abstract
Graphical Abstract</abstract><cop>England</cop><pub>Oxford University Press</pub><pmid>34142125</pmid><doi>10.1093/cvr/cvab207</doi><tpages>16</tpages><orcidid>https://orcid.org/0000-0002-6660-796X</orcidid><orcidid>https://orcid.org/0000-0003-2140-834X</orcidid><orcidid>https://orcid.org/0000-0002-7221-859X</orcidid><orcidid>https://orcid.org/0000-0002-9636-9026</orcidid><orcidid>https://orcid.org/0000-0002-2672-2779</orcidid><orcidid>https://orcid.org/0000-0002-9828-7235</orcidid><orcidid>https://orcid.org/0000-0001-5784-7016</orcidid><orcidid>https://orcid.org/0000-0001-9828-4459</orcidid><orcidid>https://orcid.org/0000-0003-4370-3390</orcidid><orcidid>https://orcid.org/0000-0002-1472-0258</orcidid><orcidid>https://orcid.org/0000-0003-2689-2361</orcidid><orcidid>https://orcid.org/0000-0001-8824-3581</orcidid><orcidid>https://orcid.org/0000-0003-0774-9674</orcidid><orcidid>https://orcid.org/0000-0003-3793-5910</orcidid><orcidid>https://orcid.org/0000-0001-6645-0985</orcidid><orcidid>https://orcid.org/0000-0002-0633-3514</orcidid><orcidid>https://orcid.org/0000-0003-0095-0084</orcidid><orcidid>https://orcid.org/0000-0002-8580-2023</orcidid><orcidid>https://orcid.org/0000-0002-7353-0235</orcidid><orcidid>https://orcid.org/0000-0002-2368-7322</orcidid><orcidid>https://orcid.org/0000-0001-6986-9554</orcidid><oa>free_for_read</oa></addata></record> |
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source | MEDLINE; Oxford University Press Journals All Titles (1996-Current); EZB-FREE-00999 freely available EZB journals; Alma/SFX Local Collection |
subjects | Amino Acids, Branched-Chain - metabolism Animals Calcium Heart Failure Humans Mice Myocytes, Cardiac - metabolism Original Sirolimus |
title | Chronically elevated branched chain amino acid levels are pro-arrhythmic |
url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-11T16%3A42%3A40IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-oup_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Chronically%20elevated%20branched%20chain%20amino%20acid%20levels%20are%20pro-arrhythmic&rft.jtitle=Cardiovascular%20research&rft.au=Portero,%20Vincent&rft.date=2022-06-22&rft.volume=118&rft.issue=7&rft.spage=1742&rft.epage=1757&rft.pages=1742-1757&rft.issn=0008-6363&rft.eissn=1755-3245&rft_id=info:doi/10.1093/cvr/cvab207&rft_dat=%3Coup_pubme%3E10.1093/cvr/cvab207%3C/oup_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_id=info:pmid/34142125&rft_oup_id=10.1093/cvr/cvab207&rfr_iscdi=true |