A regional reduction in Ito and IKaCh in the murine posterior left atrial myocardium is associated with action potential prolongation and increased ectopic activity

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@article{f5f6b2da4c074af2ba459134aa10b0e1,
title = "A regional reduction in Ito and IKaCh in the murine posterior left atrial myocardium is associated with action potential prolongation and increased ectopic activity",
abstract = "BACKGROUND: The left atrial posterior wall (LAPW) is potentially an important area for the development and maintenance of atrial fibrillation. We assessed whether there are regional electrical differences throughout the murine left atrial myocardium that could underlie regional differences in arrhythmia susceptibility.METHODS: We used high-resolution optical mapping and sharp microelectrode recordings to quantify regional differences in electrical activation and repolarisation within the intact, superfused murine left atrium and quantified regional ion channel mRNA expression by Taqman Low Density Array. We also performed selected cellular electrophysiology experiments to validate regional differences in ion channel function.RESULTS: Spontaneous ectopic activity was observed during sustained 1Hz pacing in 10/19 intact LA and this was abolished following resection of LAPW (0/19 resected LA, P<0.001). The source of the ectopic activity was the LAPW myocardium, distinct from the pulmonary vein sleeve and LAA, determined by optical mapping. Overall, LAPW action potentials (APs) were ca. 40% longer than the LAA and this region displayed more APD heterogeneity. mRNA expression of Kcna4, Kcnj3 and Kcnj5 was lower in the LAPW myocardium than in the LAA. Cardiomyocytes isolated from the LAPW had decreased Ito and a reduced IKACh current density at both positive and negative test potentials.CONCLUSIONS: The murine LAPW myocardium has a different electrical phenotype and ion channel mRNA expression profile compared with other regions of the LA, and this is associated with increased ectopic activity. If similar regional electrical differences are present in the human LA, then the LAPW may be a potential future target for treatment of atrial fibrillation.",
author = "Holmes, {Andrew P} and Yu, {Ting Y} and Samantha Tull and Fahima Syeda and Kuhlmann, {Stefan M} and Sian-Marie O'Brien and Pushpa Patel and Brain, {Keith L} and Davor Pavlovic and Brown, {Nigel A} and Larissa Fabritz and Paulus Kirchhof",
year = "2016",
month = may,
day = "5",
doi = "10.1371/journal.pone.0154077",
language = "English",
volume = "11",
journal = "PLoSONE",
issn = "1932-6203",
publisher = "Public Library of Science (PLOS)",
number = "5",

}

RIS

TY - JOUR

T1 - A regional reduction in Ito and IKaCh in the murine posterior left atrial myocardium is associated with action potential prolongation and increased ectopic activity

AU - Holmes, Andrew P

AU - Yu, Ting Y

AU - Tull, Samantha

AU - Syeda, Fahima

AU - Kuhlmann, Stefan M

AU - O'Brien, Sian-Marie

AU - Patel, Pushpa

AU - Brain, Keith L

AU - Pavlovic, Davor

AU - Brown, Nigel A

AU - Fabritz, Larissa

AU - Kirchhof, Paulus

PY - 2016/5/5

Y1 - 2016/5/5

N2 - BACKGROUND: The left atrial posterior wall (LAPW) is potentially an important area for the development and maintenance of atrial fibrillation. We assessed whether there are regional electrical differences throughout the murine left atrial myocardium that could underlie regional differences in arrhythmia susceptibility.METHODS: We used high-resolution optical mapping and sharp microelectrode recordings to quantify regional differences in electrical activation and repolarisation within the intact, superfused murine left atrium and quantified regional ion channel mRNA expression by Taqman Low Density Array. We also performed selected cellular electrophysiology experiments to validate regional differences in ion channel function.RESULTS: Spontaneous ectopic activity was observed during sustained 1Hz pacing in 10/19 intact LA and this was abolished following resection of LAPW (0/19 resected LA, P<0.001). The source of the ectopic activity was the LAPW myocardium, distinct from the pulmonary vein sleeve and LAA, determined by optical mapping. Overall, LAPW action potentials (APs) were ca. 40% longer than the LAA and this region displayed more APD heterogeneity. mRNA expression of Kcna4, Kcnj3 and Kcnj5 was lower in the LAPW myocardium than in the LAA. Cardiomyocytes isolated from the LAPW had decreased Ito and a reduced IKACh current density at both positive and negative test potentials.CONCLUSIONS: The murine LAPW myocardium has a different electrical phenotype and ion channel mRNA expression profile compared with other regions of the LA, and this is associated with increased ectopic activity. If similar regional electrical differences are present in the human LA, then the LAPW may be a potential future target for treatment of atrial fibrillation.

AB - BACKGROUND: The left atrial posterior wall (LAPW) is potentially an important area for the development and maintenance of atrial fibrillation. We assessed whether there are regional electrical differences throughout the murine left atrial myocardium that could underlie regional differences in arrhythmia susceptibility.METHODS: We used high-resolution optical mapping and sharp microelectrode recordings to quantify regional differences in electrical activation and repolarisation within the intact, superfused murine left atrium and quantified regional ion channel mRNA expression by Taqman Low Density Array. We also performed selected cellular electrophysiology experiments to validate regional differences in ion channel function.RESULTS: Spontaneous ectopic activity was observed during sustained 1Hz pacing in 10/19 intact LA and this was abolished following resection of LAPW (0/19 resected LA, P<0.001). The source of the ectopic activity was the LAPW myocardium, distinct from the pulmonary vein sleeve and LAA, determined by optical mapping. Overall, LAPW action potentials (APs) were ca. 40% longer than the LAA and this region displayed more APD heterogeneity. mRNA expression of Kcna4, Kcnj3 and Kcnj5 was lower in the LAPW myocardium than in the LAA. Cardiomyocytes isolated from the LAPW had decreased Ito and a reduced IKACh current density at both positive and negative test potentials.CONCLUSIONS: The murine LAPW myocardium has a different electrical phenotype and ion channel mRNA expression profile compared with other regions of the LA, and this is associated with increased ectopic activity. If similar regional electrical differences are present in the human LA, then the LAPW may be a potential future target for treatment of atrial fibrillation.

U2 - 10.1371/journal.pone.0154077

DO - 10.1371/journal.pone.0154077

M3 - Article

C2 - 27149380

VL - 11

JO - PLoSONE

JF - PLoSONE

SN - 1932-6203

IS - 5

M1 - e0154077

ER -