Generation of reentrant arrhythmias by dominant-negative inhibition of connexin43 in rat cultured myocyte monolayers

Takuo Nakagami, Hideo Tanaka, Ping Dai, Shien Fong Lin, Takuji Tanabe, Hiroki Mani, Katsuji Fujiwara, Hiroaki Matsubara, Tetsuro Takamatsu

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

Aims: Alteration of connexin43 (Cx43)-mediated intercellular communication is known to promote susceptibility to ventricular tachyarrhythmias. However, the precise mechanism of the altered Cx43 responsible for arrhythmogenesis remains unclear. We sought to understand changes in impulse propagation of ventricular myocytes under dominant-negative (DN) inhibition of Cx43 in the development of arrhythmias. Methods and results: Intercellular communication was inhibited in confluent monolayers of neonatal rat cultured myocytes by an adenoviral vector-mediated gene transfer for DNCx43-fused red fluorescence protein (RFP). A high-resolution, macro-zoom fluorescence imaging system was used to visualize both the fluo4- and RFP-fluorescence intensities as measures of Ca2+ transient propagation and distribution of DNCx43 inhibition, respectively, in the myocyte monolayers. DNCx43 inhibition of the monolayers resulted in not only a significant slowing of Ca2+ transient propagation velocity, but also a preferential emergence of spiral-wave reentrant arrhythmias elicited by rapid pacing. Detailed observations on the development of spiral waves revealed that the gene-transferred myocyte monolayers exhibited regional slowing of propagation and subsequent generation of wave break, resulting in reentrant arrhythmias. Furthermore, DNCx43-RFP-transferred monolayers showed higher fluorescence intensity of RFP at the break point than at the surrounding myocardium, indicating a culprit role of DNCx43 inhibition in the genesis of spiral reentry. Conclusion: The present results indicate that regional heterogeneity in gap-junctional communication promotes, in addition to slowing of conduction velocity, susceptibility to reentrant tachyarrhythmias.

Original languageEnglish (US)
Pages (from-to)70-79
Number of pages10
JournalCardiovascular research
Volume79
Issue number1
DOIs
StatePublished - Jul 1 2008

Fingerprint

Connexin 43
Muscle Cells
Cardiac Arrhythmias
Fluorescence
Tachycardia
Proteins
Optical Imaging
Genes
Inhibition (Psychology)
Myocardium
Communication

Keywords

  • Arrhythmia (mechanisms)
  • Connexin43
  • Dominant-negative mutation
  • Myocytes
  • Spiral wave

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Generation of reentrant arrhythmias by dominant-negative inhibition of connexin43 in rat cultured myocyte monolayers. / Nakagami, Takuo; Tanaka, Hideo; Dai, Ping; Lin, Shien Fong; Tanabe, Takuji; Mani, Hiroki; Fujiwara, Katsuji; Matsubara, Hiroaki; Takamatsu, Tetsuro.

In: Cardiovascular research, Vol. 79, No. 1, 01.07.2008, p. 70-79.

Research output: Contribution to journalArticle

Nakagami, T, Tanaka, H, Dai, P, Lin, SF, Tanabe, T, Mani, H, Fujiwara, K, Matsubara, H & Takamatsu, T 2008, 'Generation of reentrant arrhythmias by dominant-negative inhibition of connexin43 in rat cultured myocyte monolayers', Cardiovascular research, vol. 79, no. 1, pp. 70-79. https://doi.org/10.1093/cvr/cvn084
Nakagami, Takuo ; Tanaka, Hideo ; Dai, Ping ; Lin, Shien Fong ; Tanabe, Takuji ; Mani, Hiroki ; Fujiwara, Katsuji ; Matsubara, Hiroaki ; Takamatsu, Tetsuro. / Generation of reentrant arrhythmias by dominant-negative inhibition of connexin43 in rat cultured myocyte monolayers. In: Cardiovascular research. 2008 ; Vol. 79, No. 1. pp. 70-79.
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AU - Dai, Ping

AU - Lin, Shien Fong

AU - Tanabe, Takuji

AU - Mani, Hiroki

AU - Fujiwara, Katsuji

AU - Matsubara, Hiroaki

AU - Takamatsu, Tetsuro

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AB - Aims: Alteration of connexin43 (Cx43)-mediated intercellular communication is known to promote susceptibility to ventricular tachyarrhythmias. However, the precise mechanism of the altered Cx43 responsible for arrhythmogenesis remains unclear. We sought to understand changes in impulse propagation of ventricular myocytes under dominant-negative (DN) inhibition of Cx43 in the development of arrhythmias. Methods and results: Intercellular communication was inhibited in confluent monolayers of neonatal rat cultured myocytes by an adenoviral vector-mediated gene transfer for DNCx43-fused red fluorescence protein (RFP). A high-resolution, macro-zoom fluorescence imaging system was used to visualize both the fluo4- and RFP-fluorescence intensities as measures of Ca2+ transient propagation and distribution of DNCx43 inhibition, respectively, in the myocyte monolayers. DNCx43 inhibition of the monolayers resulted in not only a significant slowing of Ca2+ transient propagation velocity, but also a preferential emergence of spiral-wave reentrant arrhythmias elicited by rapid pacing. Detailed observations on the development of spiral waves revealed that the gene-transferred myocyte monolayers exhibited regional slowing of propagation and subsequent generation of wave break, resulting in reentrant arrhythmias. Furthermore, DNCx43-RFP-transferred monolayers showed higher fluorescence intensity of RFP at the break point than at the surrounding myocardium, indicating a culprit role of DNCx43 inhibition in the genesis of spiral reentry. Conclusion: The present results indicate that regional heterogeneity in gap-junctional communication promotes, in addition to slowing of conduction velocity, susceptibility to reentrant tachyarrhythmias.

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