Mechanistic investigation of Ca2+ alternans in human heart failure and its modulation by fibroblasts
Heart failure (HF) is characterized, among other factors, by a progressive loss of contractile function and by the formation of an arrhythmogenic substrate, both aspects partially related to intracellular Ca2+ cycling disorders. In failing hearts both electrophysiological and structural remodeling,...
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| Veröffentlicht in: | PloS one 2019-06, Vol.14 (6), p.e0217993-e0217993 |
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| creator | Mora, Maria T Gomez, Juan F Morley, Gregory Ferrero, Jose M Trenor, Beatriz |
| description | Heart failure (HF) is characterized, among other factors, by a progressive loss of contractile function and by the formation of an arrhythmogenic substrate, both aspects partially related to intracellular Ca2+ cycling disorders. In failing hearts both electrophysiological and structural remodeling, including fibroblast proliferation, contribute to changes in Ca2+ handling which promote the appearance of Ca2+ alternans (Ca-alt). Ca-alt in turn give rise to repolarization alternans, which promote dispersion of repolarization and contribute to reentrant activity. The computational analysis of the incidence of Ca2+ and/or repolarization alternans under HF conditions in the presence of fibroblasts could provide a better understanding of the mechanisms leading to HF arrhythmias and contractile function disorders.
The goal of the present study was to investigate in silico the mechanisms leading to the formation of Ca-alt in failing human ventricular myocytes and tissues with disperse fibroblast distributions. The contribution of ionic currents variability to alternans formation at the cellular level was analyzed and the results show that in normal ventricular tissue, altered Ca2+ dynamics lead to Ca-alt, which precede APD alternans and can be aggravated by the presence of fibroblasts. Electrophysiological remodeling of failing tissue alone is sufficient to develop alternans. The incidence of alternans is reduced when fibroblasts are present in failing tissue due to significantly depressed Ca2+ transients. The analysis of the underlying ionic mechanisms suggests that Ca-alt are driven by Ca2+-handling protein and Ca2+ cycling dysfunctions in the junctional sarcoplasmic reticulum and that their contribution to alternans occurrence depends on the cardiac remodeling conditions and on myocyte-fibroblast interactions.
It can thus be concluded that fibroblasts modulate the formation of Ca-alt in human ventricular tissue subjected to heart failure-related electrophysiological remodeling. Pharmacological therapies should thus consider the extent of both the electrophysiological and structural remodeling present in the failing heart. |
| doi_str_mv | 10.1371/journal.pone.0217993 |
| format | Article |
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The goal of the present study was to investigate in silico the mechanisms leading to the formation of Ca-alt in failing human ventricular myocytes and tissues with disperse fibroblast distributions. The contribution of ionic currents variability to alternans formation at the cellular level was analyzed and the results show that in normal ventricular tissue, altered Ca2+ dynamics lead to Ca-alt, which precede APD alternans and can be aggravated by the presence of fibroblasts. Electrophysiological remodeling of failing tissue alone is sufficient to develop alternans. The incidence of alternans is reduced when fibroblasts are present in failing tissue due to significantly depressed Ca2+ transients. The analysis of the underlying ionic mechanisms suggests that Ca-alt are driven by Ca2+-handling protein and Ca2+ cycling dysfunctions in the junctional sarcoplasmic reticulum and that their contribution to alternans occurrence depends on the cardiac remodeling conditions and on myocyte-fibroblast interactions.
It can thus be concluded that fibroblasts modulate the formation of Ca-alt in human ventricular tissue subjected to heart failure-related electrophysiological remodeling. Pharmacological therapies should thus consider the extent of both the electrophysiological and structural remodeling present in the failing heart.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0217993</identifier><identifier>PMID: 31211790</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Action Potentials ; Arrhythmias, Cardiac - genetics ; Arrhythmias, Cardiac - metabolism ; Arrhythmias, Cardiac - pathology ; Biology and Life Sciences ; Calcium (intracellular) ; Calcium - metabolism ; Calcium ions ; Calcium Signaling - genetics ; Calcium signalling ; Cardiac arrhythmia ; Cardiac muscle ; Cell Proliferation - genetics ; Computer applications ; Congestive heart failure ; Cycles ; Disorders ; Dispersion ; Electrophysiological Phenomena ; Fibroblasts ; Fibroblasts - metabolism ; Fibroblasts - pathology ; Heart ; Heart failure ; Heart Failure - metabolism ; Heart Failure - physiopathology ; Heart Ventricles - metabolism ; Heart Ventricles - pathology ; Humans ; Incidence ; Medicine and Health Sciences ; Models, Cardiovascular ; Muscle contraction ; Myocytes ; Myocytes, Cardiac - metabolism ; Pharmacology ; Proteins ; Research and Analysis Methods ; Sarcoplasmic reticulum ; Sarcoplasmic Reticulum - metabolism ; Sarcoplasmic Reticulum - pathology ; Studies ; Substrates ; Tissues ; Ventricle</subject><ispartof>PloS one, 2019-06, Vol.14 (6), p.e0217993-e0217993</ispartof><rights>2019 Mora et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2019 Mora et al 2019 Mora et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c456t-5fdb23fbd9180fa49d647c24061a99e757ec5e8206226da9038ada69dbe436433</citedby><cites>FETCH-LOGICAL-c456t-5fdb23fbd9180fa49d647c24061a99e757ec5e8206226da9038ada69dbe436433</cites><orcidid>0000-0002-8069-2486</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6581251/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6581251/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,315,728,781,785,865,886,2103,2929,23870,27928,27929,53795,53797</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31211790$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Tolkacheva, Elena G.</contributor><creatorcontrib>Mora, Maria T</creatorcontrib><creatorcontrib>Gomez, Juan F</creatorcontrib><creatorcontrib>Morley, Gregory</creatorcontrib><creatorcontrib>Ferrero, Jose M</creatorcontrib><creatorcontrib>Trenor, Beatriz</creatorcontrib><title>Mechanistic investigation of Ca2+ alternans in human heart failure and its modulation by fibroblasts</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Heart failure (HF) is characterized, among other factors, by a progressive loss of contractile function and by the formation of an arrhythmogenic substrate, both aspects partially related to intracellular Ca2+ cycling disorders. In failing hearts both electrophysiological and structural remodeling, including fibroblast proliferation, contribute to changes in Ca2+ handling which promote the appearance of Ca2+ alternans (Ca-alt). Ca-alt in turn give rise to repolarization alternans, which promote dispersion of repolarization and contribute to reentrant activity. The computational analysis of the incidence of Ca2+ and/or repolarization alternans under HF conditions in the presence of fibroblasts could provide a better understanding of the mechanisms leading to HF arrhythmias and contractile function disorders.
The goal of the present study was to investigate in silico the mechanisms leading to the formation of Ca-alt in failing human ventricular myocytes and tissues with disperse fibroblast distributions. The contribution of ionic currents variability to alternans formation at the cellular level was analyzed and the results show that in normal ventricular tissue, altered Ca2+ dynamics lead to Ca-alt, which precede APD alternans and can be aggravated by the presence of fibroblasts. Electrophysiological remodeling of failing tissue alone is sufficient to develop alternans. The incidence of alternans is reduced when fibroblasts are present in failing tissue due to significantly depressed Ca2+ transients. The analysis of the underlying ionic mechanisms suggests that Ca-alt are driven by Ca2+-handling protein and Ca2+ cycling dysfunctions in the junctional sarcoplasmic reticulum and that their contribution to alternans occurrence depends on the cardiac remodeling conditions and on myocyte-fibroblast interactions.
It can thus be concluded that fibroblasts modulate the formation of Ca-alt in human ventricular tissue subjected to heart failure-related electrophysiological remodeling. Pharmacological therapies should thus consider the extent of both the electrophysiological and structural remodeling present in the failing heart.</description><subject>Action Potentials</subject><subject>Arrhythmias, Cardiac - genetics</subject><subject>Arrhythmias, Cardiac - metabolism</subject><subject>Arrhythmias, Cardiac - pathology</subject><subject>Biology and Life Sciences</subject><subject>Calcium (intracellular)</subject><subject>Calcium - metabolism</subject><subject>Calcium ions</subject><subject>Calcium Signaling - genetics</subject><subject>Calcium signalling</subject><subject>Cardiac arrhythmia</subject><subject>Cardiac muscle</subject><subject>Cell Proliferation - genetics</subject><subject>Computer applications</subject><subject>Congestive heart failure</subject><subject>Cycles</subject><subject>Disorders</subject><subject>Dispersion</subject><subject>Electrophysiological Phenomena</subject><subject>Fibroblasts</subject><subject>Fibroblasts - metabolism</subject><subject>Fibroblasts - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Mora, Maria T</au><au>Gomez, Juan F</au><au>Morley, Gregory</au><au>Ferrero, Jose M</au><au>Trenor, Beatriz</au><au>Tolkacheva, Elena G.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Mechanistic investigation of Ca2+ alternans in human heart failure and its modulation by fibroblasts</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2019-06-18</date><risdate>2019</risdate><volume>14</volume><issue>6</issue><spage>e0217993</spage><epage>e0217993</epage><pages>e0217993-e0217993</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Heart failure (HF) is characterized, among other factors, by a progressive loss of contractile function and by the formation of an arrhythmogenic substrate, both aspects partially related to intracellular Ca2+ cycling disorders. In failing hearts both electrophysiological and structural remodeling, including fibroblast proliferation, contribute to changes in Ca2+ handling which promote the appearance of Ca2+ alternans (Ca-alt). Ca-alt in turn give rise to repolarization alternans, which promote dispersion of repolarization and contribute to reentrant activity. The computational analysis of the incidence of Ca2+ and/or repolarization alternans under HF conditions in the presence of fibroblasts could provide a better understanding of the mechanisms leading to HF arrhythmias and contractile function disorders.
The goal of the present study was to investigate in silico the mechanisms leading to the formation of Ca-alt in failing human ventricular myocytes and tissues with disperse fibroblast distributions. The contribution of ionic currents variability to alternans formation at the cellular level was analyzed and the results show that in normal ventricular tissue, altered Ca2+ dynamics lead to Ca-alt, which precede APD alternans and can be aggravated by the presence of fibroblasts. Electrophysiological remodeling of failing tissue alone is sufficient to develop alternans. The incidence of alternans is reduced when fibroblasts are present in failing tissue due to significantly depressed Ca2+ transients. The analysis of the underlying ionic mechanisms suggests that Ca-alt are driven by Ca2+-handling protein and Ca2+ cycling dysfunctions in the junctional sarcoplasmic reticulum and that their contribution to alternans occurrence depends on the cardiac remodeling conditions and on myocyte-fibroblast interactions.
It can thus be concluded that fibroblasts modulate the formation of Ca-alt in human ventricular tissue subjected to heart failure-related electrophysiological remodeling. Pharmacological therapies should thus consider the extent of both the electrophysiological and structural remodeling present in the failing heart.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>31211790</pmid><doi>10.1371/journal.pone.0217993</doi><orcidid>https://orcid.org/0000-0002-8069-2486</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Action Potentials Arrhythmias, Cardiac - genetics Arrhythmias, Cardiac - metabolism Arrhythmias, Cardiac - pathology Biology and Life Sciences Calcium (intracellular) Calcium - metabolism Calcium ions Calcium Signaling - genetics Calcium signalling Cardiac arrhythmia Cardiac muscle Cell Proliferation - genetics Computer applications Congestive heart failure Cycles Disorders Dispersion Electrophysiological Phenomena Fibroblasts Fibroblasts - metabolism Fibroblasts - pathology Heart Heart failure Heart Failure - metabolism Heart Failure - physiopathology Heart Ventricles - metabolism Heart Ventricles - pathology Humans Incidence Medicine and Health Sciences Models, Cardiovascular Muscle contraction Myocytes Myocytes, Cardiac - metabolism Pharmacology Proteins Research and Analysis Methods Sarcoplasmic reticulum Sarcoplasmic Reticulum - metabolism Sarcoplasmic Reticulum - pathology Studies Substrates Tissues Ventricle |
| title | Mechanistic investigation of Ca2+ alternans in human heart failure and its modulation by fibroblasts |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-16T20%3A01%3A54IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Mechanistic%20investigation%20of%20Ca2+%20alternans%20in%20human%20heart%20failure%20and%20its%20modulation%20by%20fibroblasts&rft.jtitle=PloS%20one&rft.au=Mora,%20Maria%20T&rft.date=2019-06-18&rft.volume=14&rft.issue=6&rft.spage=e0217993&rft.epage=e0217993&rft.pages=e0217993-e0217993&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0217993&rft_dat=%3Cproquest_plos_%3E2243499552%3C/proquest_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2242776109&rft_id=info:pmid/31211790&rft_doaj_id=oai_doaj_org_article_5afef8d64cf147aea55c12fba4d22975&rfr_iscdi=true |