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Early afterdepolarizations promote transmural reentry in ischemic human ventricles with reduced repolarization reserve
Acute ischemia is a major cause of sudden arrhythmic death, further promoted by potassium current blockers. Macro-reentry around the ischemic region and early afterdepolarizations (EADs) caused by electrotonic current have been suggested as potential mechanisms in animal and isolated cell studies. H...
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Published in: | Progress in biophysics and molecular biology 2016-01, Vol.120 (1-3), p.236-248 |
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description | Acute ischemia is a major cause of sudden arrhythmic death, further promoted by potassium current blockers. Macro-reentry around the ischemic region and early afterdepolarizations (EADs) caused by electrotonic current have been suggested as potential mechanisms in animal and isolated cell studies. However, ventricular and human-specific arrhythmia mechanisms and their modulation by repolarization reserve remain unclear. The goal of this paper is to unravel multiscale mechanisms underlying the modulation of arrhythmic risk by potassium current (IKr) block in human ventricles with acute regional ischemia.
A human ventricular biophysically-detailed model, with acute regional ischemia is constructed by integrating experimental knowledge on the electrophysiological ionic alterations caused by coronary occlusion. Arrhythmic risk is evaluated by determining the vulnerable window (VW) for reentry following ectopy at the ischemic border zone. Macro-reentry around the ischemic region is the main reentrant mechanism in the ischemic human ventricle with increased repolarization reserve due to the ATP-sensitive potassium current (IK(ATP)) activation. Prolongation of refractoriness by 4% caused by 30% IKr reduction counteracts the establishment of macro-reentry and reduces the VW for reentry (by 23.5%). However, a further decrease in repolarization reserve (50% IKr reduction) is less anti-arrhythmic despite further prolongation of refractoriness. This is due to the establishment of transmural reentry enabled by electrotonically-triggered EADs in the ischemic border zone. EADs are produced by L-type calcium current (ICaL) reactivation due to prolonged low amplitude electrotonic current injected during the repolarization phase.
Electrotonically-triggered EADs are identified as a potential mechanism facilitating intramural reentry in a regionally-ischemic human ventricles model with reduced repolarization reserve. |
doi_str_mv | 10.1016/j.pbiomolbio.2016.01.008 |
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A human ventricular biophysically-detailed model, with acute regional ischemia is constructed by integrating experimental knowledge on the electrophysiological ionic alterations caused by coronary occlusion. Arrhythmic risk is evaluated by determining the vulnerable window (VW) for reentry following ectopy at the ischemic border zone. Macro-reentry around the ischemic region is the main reentrant mechanism in the ischemic human ventricle with increased repolarization reserve due to the ATP-sensitive potassium current (IK(ATP)) activation. Prolongation of refractoriness by 4% caused by 30% IKr reduction counteracts the establishment of macro-reentry and reduces the VW for reentry (by 23.5%). However, a further decrease in repolarization reserve (50% IKr reduction) is less anti-arrhythmic despite further prolongation of refractoriness. This is due to the establishment of transmural reentry enabled by electrotonically-triggered EADs in the ischemic border zone. EADs are produced by L-type calcium current (ICaL) reactivation due to prolonged low amplitude electrotonic current injected during the repolarization phase.
Electrotonically-triggered EADs are identified as a potential mechanism facilitating intramural reentry in a regionally-ischemic human ventricles model with reduced repolarization reserve.</description><identifier>ISSN: 0079-6107</identifier><identifier>EISSN: 1873-1732</identifier><identifier>DOI: 10.1016/j.pbiomolbio.2016.01.008</identifier><identifier>PMID: 26850675</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>Acute Disease ; Animals ; Calcium Channels, L-Type - metabolism ; Computer-based model ; Heart Ventricles - pathology ; Heart Ventricles - physiopathology ; Humans ; Ischemic heart disease ; Membrane Potentials ; Models, Anatomic ; Myocardial Ischemia - metabolism ; Myocardial Ischemia - pathology ; Myocardial Ischemia - physiopathology ; Potassium channels ; Repolarization ; Time Factors ; Ventricular arrhythmia</subject><ispartof>Progress in biophysics and molecular biology, 2016-01, Vol.120 (1-3), p.236-248</ispartof><rights>2016 The Authors</rights><rights>Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.</rights><rights>2016 The Authors 2016</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c479t-30820bd6984dee2c3bdabd31179fe99fa416a8c645e4f3e8fb1844fcd0521ccc3</citedby><cites>FETCH-LOGICAL-c479t-30820bd6984dee2c3bdabd31179fe99fa416a8c645e4f3e8fb1844fcd0521ccc3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26850675$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Dutta, Sara</creatorcontrib><creatorcontrib>Mincholé, Ana</creatorcontrib><creatorcontrib>Zacur, Ernesto</creatorcontrib><creatorcontrib>Quinn, T. Alexander</creatorcontrib><creatorcontrib>Taggart, Peter</creatorcontrib><creatorcontrib>Rodriguez, Blanca</creatorcontrib><title>Early afterdepolarizations promote transmural reentry in ischemic human ventricles with reduced repolarization reserve</title><title>Progress in biophysics and molecular biology</title><addtitle>Prog Biophys Mol Biol</addtitle><description>Acute ischemia is a major cause of sudden arrhythmic death, further promoted by potassium current blockers. Macro-reentry around the ischemic region and early afterdepolarizations (EADs) caused by electrotonic current have been suggested as potential mechanisms in animal and isolated cell studies. However, ventricular and human-specific arrhythmia mechanisms and their modulation by repolarization reserve remain unclear. The goal of this paper is to unravel multiscale mechanisms underlying the modulation of arrhythmic risk by potassium current (IKr) block in human ventricles with acute regional ischemia.
A human ventricular biophysically-detailed model, with acute regional ischemia is constructed by integrating experimental knowledge on the electrophysiological ionic alterations caused by coronary occlusion. Arrhythmic risk is evaluated by determining the vulnerable window (VW) for reentry following ectopy at the ischemic border zone. Macro-reentry around the ischemic region is the main reentrant mechanism in the ischemic human ventricle with increased repolarization reserve due to the ATP-sensitive potassium current (IK(ATP)) activation. Prolongation of refractoriness by 4% caused by 30% IKr reduction counteracts the establishment of macro-reentry and reduces the VW for reentry (by 23.5%). However, a further decrease in repolarization reserve (50% IKr reduction) is less anti-arrhythmic despite further prolongation of refractoriness. This is due to the establishment of transmural reentry enabled by electrotonically-triggered EADs in the ischemic border zone. EADs are produced by L-type calcium current (ICaL) reactivation due to prolonged low amplitude electrotonic current injected during the repolarization phase.
Electrotonically-triggered EADs are identified as a potential mechanism facilitating intramural reentry in a regionally-ischemic human ventricles model with reduced repolarization reserve.</description><subject>Acute Disease</subject><subject>Animals</subject><subject>Calcium Channels, L-Type - metabolism</subject><subject>Computer-based model</subject><subject>Heart Ventricles - pathology</subject><subject>Heart Ventricles - physiopathology</subject><subject>Humans</subject><subject>Ischemic heart disease</subject><subject>Membrane Potentials</subject><subject>Models, Anatomic</subject><subject>Myocardial Ischemia - metabolism</subject><subject>Myocardial Ischemia - pathology</subject><subject>Myocardial Ischemia - physiopathology</subject><subject>Potassium channels</subject><subject>Repolarization</subject><subject>Time Factors</subject><subject>Ventricular arrhythmia</subject><issn>0079-6107</issn><issn>1873-1732</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><recordid>eNqFUU1v1DAQtRCIbgt_AfnIJenYTmLnggRV-ZAqcYGz5dgT1qskDnYStP31eLWllBOXGY3nzXvjeYRQBiUD1lwfyrnzYQxDjiXPLyWwEkA9IzumpCiYFPw52QHItmgYyAtymdIBADiTzUtywRtVQyPrHdluTRyO1PQLRodzGEz092bxYUp0jlliQbpEM6VxjWagEXFa4pH6ifpk9zh6S_fraCa6nRreDpjoL7_sM9KtFl3OT0lzmTBu-Iq86M2Q8PVDviLfP95-u_lc3H399OXm_V1hK9kuhQDFoXNNqyqHyK3onOmcYEy2PbZtbyrWGGWbqsaqF6j6jqmq6q2DmjNrrbgi786889qN6OxpSTPoOfrRxKMOxut_O5Pf6x9h05XijAuRCd4-EMTwc8W06DF_HIfBTBjWpJmUDbRV3bIMVWeojSGliP2jDAN9sk0f9F_b9Mk2DUxn2_Lom6drPg7-8SkDPpwBmI-1eYw6WY9TPrCPaBftgv-_ym_YRrTF</recordid><startdate>201601</startdate><enddate>201601</enddate><creator>Dutta, Sara</creator><creator>Mincholé, Ana</creator><creator>Zacur, Ernesto</creator><creator>Quinn, T. Alexander</creator><creator>Taggart, Peter</creator><creator>Rodriguez, Blanca</creator><general>Elsevier Ltd</general><general>Pergamon Press</general><scope>6I.</scope><scope>AAFTH</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>7X8</scope><scope>5PM</scope></search><sort><creationdate>201601</creationdate><title>Early afterdepolarizations promote transmural reentry in ischemic human ventricles with reduced repolarization reserve</title><author>Dutta, Sara ; Mincholé, Ana ; Zacur, Ernesto ; Quinn, T. Alexander ; Taggart, Peter ; Rodriguez, Blanca</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c479t-30820bd6984dee2c3bdabd31179fe99fa416a8c645e4f3e8fb1844fcd0521ccc3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>Acute Disease</topic><topic>Animals</topic><topic>Calcium Channels, L-Type - metabolism</topic><topic>Computer-based model</topic><topic>Heart Ventricles - pathology</topic><topic>Heart Ventricles - physiopathology</topic><topic>Humans</topic><topic>Ischemic heart disease</topic><topic>Membrane Potentials</topic><topic>Models, Anatomic</topic><topic>Myocardial Ischemia - metabolism</topic><topic>Myocardial Ischemia - pathology</topic><topic>Myocardial Ischemia - physiopathology</topic><topic>Potassium channels</topic><topic>Repolarization</topic><topic>Time Factors</topic><topic>Ventricular arrhythmia</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Dutta, Sara</creatorcontrib><creatorcontrib>Mincholé, Ana</creatorcontrib><creatorcontrib>Zacur, Ernesto</creatorcontrib><creatorcontrib>Quinn, T. Alexander</creatorcontrib><creatorcontrib>Taggart, Peter</creatorcontrib><creatorcontrib>Rodriguez, Blanca</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><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><collection>PubMed Central (Full Participant titles)</collection><jtitle>Progress in biophysics and molecular biology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Dutta, Sara</au><au>Mincholé, Ana</au><au>Zacur, Ernesto</au><au>Quinn, T. Alexander</au><au>Taggart, Peter</au><au>Rodriguez, Blanca</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Early afterdepolarizations promote transmural reentry in ischemic human ventricles with reduced repolarization reserve</atitle><jtitle>Progress in biophysics and molecular biology</jtitle><addtitle>Prog Biophys Mol Biol</addtitle><date>2016-01</date><risdate>2016</risdate><volume>120</volume><issue>1-3</issue><spage>236</spage><epage>248</epage><pages>236-248</pages><issn>0079-6107</issn><eissn>1873-1732</eissn><abstract>Acute ischemia is a major cause of sudden arrhythmic death, further promoted by potassium current blockers. Macro-reentry around the ischemic region and early afterdepolarizations (EADs) caused by electrotonic current have been suggested as potential mechanisms in animal and isolated cell studies. However, ventricular and human-specific arrhythmia mechanisms and their modulation by repolarization reserve remain unclear. The goal of this paper is to unravel multiscale mechanisms underlying the modulation of arrhythmic risk by potassium current (IKr) block in human ventricles with acute regional ischemia.
A human ventricular biophysically-detailed model, with acute regional ischemia is constructed by integrating experimental knowledge on the electrophysiological ionic alterations caused by coronary occlusion. Arrhythmic risk is evaluated by determining the vulnerable window (VW) for reentry following ectopy at the ischemic border zone. Macro-reentry around the ischemic region is the main reentrant mechanism in the ischemic human ventricle with increased repolarization reserve due to the ATP-sensitive potassium current (IK(ATP)) activation. Prolongation of refractoriness by 4% caused by 30% IKr reduction counteracts the establishment of macro-reentry and reduces the VW for reentry (by 23.5%). However, a further decrease in repolarization reserve (50% IKr reduction) is less anti-arrhythmic despite further prolongation of refractoriness. This is due to the establishment of transmural reentry enabled by electrotonically-triggered EADs in the ischemic border zone. EADs are produced by L-type calcium current (ICaL) reactivation due to prolonged low amplitude electrotonic current injected during the repolarization phase.
Electrotonically-triggered EADs are identified as a potential mechanism facilitating intramural reentry in a regionally-ischemic human ventricles model with reduced repolarization reserve.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>26850675</pmid><doi>10.1016/j.pbiomolbio.2016.01.008</doi><tpages>13</tpages><oa>free_for_read</oa></addata></record> |
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subjects | Acute Disease Animals Calcium Channels, L-Type - metabolism Computer-based model Heart Ventricles - pathology Heart Ventricles - physiopathology Humans Ischemic heart disease Membrane Potentials Models, Anatomic Myocardial Ischemia - metabolism Myocardial Ischemia - pathology Myocardial Ischemia - physiopathology Potassium channels Repolarization Time Factors Ventricular arrhythmia |
title | Early afterdepolarizations promote transmural reentry in ischemic human ventricles with reduced repolarization reserve |
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