Early afterdepolarizations promote transmural reentry in ischemic human ventricles with reduced repolarization reserve

Sara Dutta; Ana Mincholé; Ernesto Zacur; T. Alexander Quinn; Peter Taggart; Blanca Rodriguez

doi:10.1016/j.pbiomolbio.2016.01.008

Early afterdepolarizations promote transmural reentry in ischemic human ventricles with reduced repolarization reserve

Sara Dutta, Ana Mincholé, Ernesto Zacur, T. Alexander Quinn, Peter Taggart, Blanca Rodriguez

Medicine

Producción científica: Contribución a una revista › Artículo › revisión exhaustiva

69 Citas (Scopus)

Resumen

Aims: 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 (I_Kr) block in human ventricles with acute regional ischemia. Methods and results: 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 (I_K(ATP)) activation. Prolongation of refractoriness by 4% caused by 30% I_Kr reduction counteracts the establishment of macro-reentry and reduces the VW for reentry (by 23.5%). However, a further decrease in repolarization reserve (50% I_Kr 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 (I_CaL) reactivation due to prolonged low amplitude electrotonic current injected during the repolarization phase. Conclusions: Electrotonically-triggered EADs are identified as a potential mechanism facilitating intramural reentry in a regionally-ischemic human ventricles model with reduced repolarization reserve.

Idioma original	English
Páginas (desde-hasta)	236-248
Número de páginas	13
Publicación	Progress in Biophysics and Molecular Biology
Volumen	120
N.º	1-3
DOI	https://doi.org/10.1016/j.pbiomolbio.2016.01.008
Estado	Published - ene. 1 2016

Nota bibliográfica

Funding Information:
This work was supported by a Wellcome Trust Fellowship in Basic Biomedical Sciences [grant number 100246/Z/12/Z to B.R.], an Engineering Physical Sciences Research Council doctoral scholarship to S.D. [EPSRC ref: EP/G03706X/1 ], the Canadian Institutes of Health Research [ MOP 142424 to T.A.Q.] and the Nova Scotia Health Research Foundation [ MED-EST-2014-9582 to T.A.Q], and a Marie Skłodowska-Curie Individual Fellowship from the H2020 EU Framework Programme for Research and Innovation [Proposal No: 655020-DTI4micro-MSCA-IF-EF-ST to E.Z.].

Publisher Copyright:
© 2016 The Authors.

ASJC Scopus Subject Areas

Biophysics
Molecular Biology

PubMed: MeSH publication types

Journal Article
Research Support, Non-U.S. Gov't

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title = "Early afterdepolarizations promote transmural reentry in ischemic human ventricles with reduced repolarization reserve",

abstract = "Aims: 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. Methods and results: 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. Conclusions: Electrotonically-triggered EADs are identified as a potential mechanism facilitating intramural reentry in a regionally-ischemic human ventricles model with reduced repolarization reserve.",

author = "Sara Dutta and Ana Minchol{\'e} and Ernesto Zacur and Quinn, {T. Alexander} and Peter Taggart and Blanca Rodriguez",

note = "Funding Information: This work was supported by a Wellcome Trust Fellowship in Basic Biomedical Sciences [grant number 100246/Z/12/Z to B.R.], an Engineering Physical Sciences Research Council doctoral scholarship to S.D. [EPSRC ref: EP/G03706X/1 ], the Canadian Institutes of Health Research [ MOP 142424 to T.A.Q.] and the Nova Scotia Health Research Foundation [ MED-EST-2014-9582 to T.A.Q], and a Marie Sk{\l}odowska-Curie Individual Fellowship from the H2020 EU Framework Programme for Research and Innovation [Proposal No: 655020-DTI4micro-MSCA-IF-EF-ST to E.Z.]. Publisher Copyright: {\textcopyright} 2016 The Authors.",

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doi = "10.1016/j.pbiomolbio.2016.01.008",

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T1 - Early afterdepolarizations promote transmural reentry in ischemic human ventricles with reduced repolarization reserve

AU - Dutta, Sara

AU - Mincholé, Ana

AU - Zacur, Ernesto

AU - Quinn, T. Alexander

AU - Taggart, Peter

AU - Rodriguez, Blanca

N1 - Funding Information: This work was supported by a Wellcome Trust Fellowship in Basic Biomedical Sciences [grant number 100246/Z/12/Z to B.R.], an Engineering Physical Sciences Research Council doctoral scholarship to S.D. [EPSRC ref: EP/G03706X/1 ], the Canadian Institutes of Health Research [ MOP 142424 to T.A.Q.] and the Nova Scotia Health Research Foundation [ MED-EST-2014-9582 to T.A.Q], and a Marie Skłodowska-Curie Individual Fellowship from the H2020 EU Framework Programme for Research and Innovation [Proposal No: 655020-DTI4micro-MSCA-IF-EF-ST to E.Z.]. Publisher Copyright: © 2016 The Authors.

PY - 2016/1/1

Y1 - 2016/1/1

N2 - Aims: 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. Methods and results: 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. Conclusions: Electrotonically-triggered EADs are identified as a potential mechanism facilitating intramural reentry in a regionally-ischemic human ventricles model with reduced repolarization reserve.

AB - Aims: 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. Methods and results: 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. Conclusions: Electrotonically-triggered EADs are identified as a potential mechanism facilitating intramural reentry in a regionally-ischemic human ventricles model with reduced repolarization reserve.

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Early afterdepolarizations promote transmural reentry in ischemic human ventricles with reduced repolarization reserve

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