Triggered firing and atrial fibrillation in transgenic mice with selective atrial fibrosis induced by over expression of TGF-β1

Eue Keun Choi, Po Cheng Chang, Young Soo Lee, Shien Fong Lin, Wuqiang Zhu, Mitsunori Maruyama, Michael C. Fishbein, Zhenhui Chen, Michael von der Rubart-Lohe, Loren J. Field, Peng Sheng Chen

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

Background: Calcium transient triggered firing (CTTF) is induced by large intracellular calcium (Cai) transient and short action potential duration (APD). We hypothesized that CTTF underlies the mechanisms of early afterdepolarization (EAD) and spontaneous recurrent atrial fibrillation (AF) in transgenic (Tx) mice with overexpression of transforming growth factor β1 (TGF-β1). Methods and Results: MHC-TGFcys 33ser Tx mice develop atrial fibrosis because of elevated levels of TGF-β1. We studied membrane potential and Cai transients of isolated superfused atria from Tx and wild-type (Wt) littermates. Short APD and persistently elevated Cai transients promoted spontaneous repetitive EADs, triggered activity and spontaneous AF after cessation of burst pacing in Tx but not Wt atria (39% vs. 0%, P=0.008). We were able to map optically 4 episodes of spontaneous AF re-initiation. All first and second beats of spontaneous AF originated from the right atrium (4/4, 100%), which is more severely fibrotic than the left atrium. Ryanodine and thapsigargin inhibited spontaneous re-initiation of AF in all 7 Tx atria tested. Western blotting showed no significant changes of calsequestrin or sarco/endoplasmic reticulum Ca 2+-ATPase 2a. Conclusions: Spontaneous AF may occur in the Tx atrium because of CTTF, characterized by APD shortening, prolonged Cai transient, EAD and triggered activity. Inhibition of Ca 2+release from the sarcoplasmic reticulum suppressed spontaneous AF. Our results indicate that CTTF is an important arrhythmogenic mechanism in TGF-β1 Tx atria.

Original languageEnglish (US)
Pages (from-to)1354-1362
Number of pages9
JournalCirculation Journal
Volume76
Issue number6
DOIs
StatePublished - Jun 2012

Fingerprint

Transforming Growth Factors
Atrial Fibrillation
Transgenic Mice
Fibrosis
Calcium
Action Potentials
Heart Atria
Calsequestrin
Ryanodine
Thapsigargin
Sarcoplasmic Reticulum
Endoplasmic Reticulum
Membrane Potentials
Adenosine Triphosphatases
Western Blotting

Keywords

  • Arrhythmia
  • Atrial fibrillation
  • Ca2+ triggers
  • Optical mapping
  • Transgenic mice models

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Triggered firing and atrial fibrillation in transgenic mice with selective atrial fibrosis induced by over expression of TGF-β1. / Choi, Eue Keun; Chang, Po Cheng; Lee, Young Soo; Lin, Shien Fong; Zhu, Wuqiang; Maruyama, Mitsunori; Fishbein, Michael C.; Chen, Zhenhui; von der Rubart-Lohe, Michael; Field, Loren J.; Chen, Peng Sheng.

In: Circulation Journal, Vol. 76, No. 6, 06.2012, p. 1354-1362.

Research output: Contribution to journalArticle

Choi, Eue Keun ; Chang, Po Cheng ; Lee, Young Soo ; Lin, Shien Fong ; Zhu, Wuqiang ; Maruyama, Mitsunori ; Fishbein, Michael C. ; Chen, Zhenhui ; von der Rubart-Lohe, Michael ; Field, Loren J. ; Chen, Peng Sheng. / Triggered firing and atrial fibrillation in transgenic mice with selective atrial fibrosis induced by over expression of TGF-β1. In: Circulation Journal. 2012 ; Vol. 76, No. 6. pp. 1354-1362.
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title = "Triggered firing and atrial fibrillation in transgenic mice with selective atrial fibrosis induced by over expression of TGF-β1",
abstract = "Background: Calcium transient triggered firing (CTTF) is induced by large intracellular calcium (Cai) transient and short action potential duration (APD). We hypothesized that CTTF underlies the mechanisms of early afterdepolarization (EAD) and spontaneous recurrent atrial fibrillation (AF) in transgenic (Tx) mice with overexpression of transforming growth factor β1 (TGF-β1). Methods and Results: MHC-TGFcys 33ser Tx mice develop atrial fibrosis because of elevated levels of TGF-β1. We studied membrane potential and Cai transients of isolated superfused atria from Tx and wild-type (Wt) littermates. Short APD and persistently elevated Cai transients promoted spontaneous repetitive EADs, triggered activity and spontaneous AF after cessation of burst pacing in Tx but not Wt atria (39{\%} vs. 0{\%}, P=0.008). We were able to map optically 4 episodes of spontaneous AF re-initiation. All first and second beats of spontaneous AF originated from the right atrium (4/4, 100{\%}), which is more severely fibrotic than the left atrium. Ryanodine and thapsigargin inhibited spontaneous re-initiation of AF in all 7 Tx atria tested. Western blotting showed no significant changes of calsequestrin or sarco/endoplasmic reticulum Ca 2+-ATPase 2a. Conclusions: Spontaneous AF may occur in the Tx atrium because of CTTF, characterized by APD shortening, prolonged Cai transient, EAD and triggered activity. Inhibition of Ca 2+release from the sarcoplasmic reticulum suppressed spontaneous AF. Our results indicate that CTTF is an important arrhythmogenic mechanism in TGF-β1 Tx atria.",
keywords = "Arrhythmia, Atrial fibrillation, Ca2+ triggers, Optical mapping, Transgenic mice models",
author = "Choi, {Eue Keun} and Chang, {Po Cheng} and Lee, {Young Soo} and Lin, {Shien Fong} and Wuqiang Zhu and Mitsunori Maruyama and Fishbein, {Michael C.} and Zhenhui Chen and {von der Rubart-Lohe}, Michael and Field, {Loren J.} and Chen, {Peng Sheng}",
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T1 - Triggered firing and atrial fibrillation in transgenic mice with selective atrial fibrosis induced by over expression of TGF-β1

AU - Choi, Eue Keun

AU - Chang, Po Cheng

AU - Lee, Young Soo

AU - Lin, Shien Fong

AU - Zhu, Wuqiang

AU - Maruyama, Mitsunori

AU - Fishbein, Michael C.

AU - Chen, Zhenhui

AU - von der Rubart-Lohe, Michael

AU - Field, Loren J.

AU - Chen, Peng Sheng

PY - 2012/6

Y1 - 2012/6

N2 - Background: Calcium transient triggered firing (CTTF) is induced by large intracellular calcium (Cai) transient and short action potential duration (APD). We hypothesized that CTTF underlies the mechanisms of early afterdepolarization (EAD) and spontaneous recurrent atrial fibrillation (AF) in transgenic (Tx) mice with overexpression of transforming growth factor β1 (TGF-β1). Methods and Results: MHC-TGFcys 33ser Tx mice develop atrial fibrosis because of elevated levels of TGF-β1. We studied membrane potential and Cai transients of isolated superfused atria from Tx and wild-type (Wt) littermates. Short APD and persistently elevated Cai transients promoted spontaneous repetitive EADs, triggered activity and spontaneous AF after cessation of burst pacing in Tx but not Wt atria (39% vs. 0%, P=0.008). We were able to map optically 4 episodes of spontaneous AF re-initiation. All first and second beats of spontaneous AF originated from the right atrium (4/4, 100%), which is more severely fibrotic than the left atrium. Ryanodine and thapsigargin inhibited spontaneous re-initiation of AF in all 7 Tx atria tested. Western blotting showed no significant changes of calsequestrin or sarco/endoplasmic reticulum Ca 2+-ATPase 2a. Conclusions: Spontaneous AF may occur in the Tx atrium because of CTTF, characterized by APD shortening, prolonged Cai transient, EAD and triggered activity. Inhibition of Ca 2+release from the sarcoplasmic reticulum suppressed spontaneous AF. Our results indicate that CTTF is an important arrhythmogenic mechanism in TGF-β1 Tx atria.

AB - Background: Calcium transient triggered firing (CTTF) is induced by large intracellular calcium (Cai) transient and short action potential duration (APD). We hypothesized that CTTF underlies the mechanisms of early afterdepolarization (EAD) and spontaneous recurrent atrial fibrillation (AF) in transgenic (Tx) mice with overexpression of transforming growth factor β1 (TGF-β1). Methods and Results: MHC-TGFcys 33ser Tx mice develop atrial fibrosis because of elevated levels of TGF-β1. We studied membrane potential and Cai transients of isolated superfused atria from Tx and wild-type (Wt) littermates. Short APD and persistently elevated Cai transients promoted spontaneous repetitive EADs, triggered activity and spontaneous AF after cessation of burst pacing in Tx but not Wt atria (39% vs. 0%, P=0.008). We were able to map optically 4 episodes of spontaneous AF re-initiation. All first and second beats of spontaneous AF originated from the right atrium (4/4, 100%), which is more severely fibrotic than the left atrium. Ryanodine and thapsigargin inhibited spontaneous re-initiation of AF in all 7 Tx atria tested. Western blotting showed no significant changes of calsequestrin or sarco/endoplasmic reticulum Ca 2+-ATPase 2a. Conclusions: Spontaneous AF may occur in the Tx atrium because of CTTF, characterized by APD shortening, prolonged Cai transient, EAD and triggered activity. Inhibition of Ca 2+release from the sarcoplasmic reticulum suppressed spontaneous AF. Our results indicate that CTTF is an important arrhythmogenic mechanism in TGF-β1 Tx atria.

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KW - Ca2+ triggers

KW - Optical mapping

KW - Transgenic mice models

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