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. 2008 Oct 24;103(9):1001-8.
doi: 10.1161/CIRCRESAHA.107.168997. Epub 2008 Jul 3.

Connexin40 imparts conduction heterogeneity to atrial tissue

David E Leaf  1 , Jonathan E Feig, Carolina Vasquez, Pamela L Riva, Cindy Yu, Joshua M Lader, Andrianos Kontogeorgis, Elvera L Baron, Nicholas S Peters, Edward A Fisher, David E Gutstein, Gregory E Morley
Affiliations

Connexin40 imparts conduction heterogeneity to atrial tissue

David E Leaf et al. Circ Res. .

Abstract

Impulse propagation in cardiac tissue is a complex process in which intercellular coupling through gap junction channels is a critical component. Connexin40 (Cx40) is an abundant gap junction protein that is expressed in atrial myocytes. Alterations in the expression of Cx40 have been implicated in atrial arrhythmogenesis. The purpose of the current study was to assess the role of Cx40 in atrial impulse propagation. High-resolution optical mapping was used to study conduction in the right and left atrial appendages of isolated Langendorff-perfused murine hearts. Wild-type (Cx40(+/+)), heterozygous (Cx40(+/-)), and knockout (Cx40(-/-)) mice, both adult and embryonic, were studied to assess the effects of reduced Cx40 expression on sinus node function and conduction velocity at different pacing cycle lengths (100 and 60 ms). In both adult and late-stage embryonic Cx40(+/+) mice, heterogeneity in CV was found between the right and left atrial appendages. Either partial (Cx40(+/-)) or complete (Cx40(-/-)) deletion of Cx40 was associated with the loss of conduction heterogeneity in both adult and embryonic mice. Additionally, sinus node impulse initiation was found to be ectopic in Cx40(-/-) mice at 15.5 days postcoitus, whereas Cx40(+/+) mice showed normal activation occurring near the crista terminalis. Our findings suggest that Cx40 plays an essential role in establishing interatrial conduction velocity heterogeneity in the murine model. Additionally, we describe for the first time a developmental requirement for Cx40 in normal sinus node impulse initiation at 15.5 days postcoitus.

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Figures

Figure 1
Figure 1
Pacing sites, conduction patterns, and single pixel recordings from the left atrial appendage. A, Schematic of the atria showing the pacing sites on the RAA and LAA and the imaged area (box). B, Brightfield image of the LAA of a Cx40+/+ mouse. C, Optical map showing LAA pattern of activation. Red indicates earlier times of electric activation, whereas blue indicates later times. Bar=1 mm. D, Pixels were considered activated when their optical action potential (AP) amplitude reached 50% of the maximum value. E, Single pixel recordings (sites 1 to 7 of C) showing propagation of action potentials. ST=sulcus terminalis.
Figure 2
Figure 2
Activation maps and conduction velocities from right and left atrial appendages in adult mice. A–F, Representative activation maps recorded from the RAA and LAA showing chamber-specific heterogeneity in activation times of the Cx40+/+ and the lack of heterogeneity in the Cx40+/− and Cx40−/− mice. Bar=1 mm. G, Average CVs in the RAA and LAA of Cx40+/+ (n=22), Cx40+/− (n=9), and Cx40−/− (n=18). *P<0.05.
Figure 3
Figure 3
Cx40 and Cx43 mRNA and protein levels. A, Cx40 mRNA expression in Cx40+/+ (n=6) and Cx40+/− (n=5) adult mice showing heterogeneity in the Cx40+/+ mice and the lack of heterogeneity in the Cx40+/− mice. B, Cx43 mRNA expression in Cx40+/+ (n=6), Cx40+/− (n=5), and Cx40−/− (n=5) mice showing no inter-/intragenotype differences in expression. C, Cx40 distribution in the RAA (top) and LAA (bottom) of Cx40+/+ adult mice labeled for Cx40 (red). Bar=50 µm. D, Cx43 distribution in the atrial appendages of Cx40+/+ adult mice, RAA (top left) and LAA (top right), and Cx40−/− adult mice, RAA (bottom left), and LAA (bottom right) labeled for Cx43 (green). Propidium iodide (PI), a nucleic acid binding dye, is indicated in red. Bar=50 µm. E–F, Western blot and bar graph quantifying Cx40 protein expression in the RAA and LAA of Cx40+/+ (n=6) and Cx40+/− (n=6) adult mice. GAPDH levels served as loading controls. *P<0.05. NS=not significant.
Figure 4
Figure 4
Activation maps and conduction velocities from embryonic mice during normal sinus rhythm. A–F, Representative activation maps recorded from the right (RA) and left atria (LA) showing heterogeneity of activation times in the Cx40+/+ and the lack of heterogeneity in the Cx40+/− and Cx40−/− mice. Bar=0.5 mm. G, Representative pseudoelectrocardiogram showing normal sinus rhythm. A=atrial depolarization; V=ventricular depolarization. Bar=200 ms. H, Average CVs in the RA and LA of Cx40+/+ (n=11), Cx40+/− (n=5), and Cx40−/− (n=5). Significantly faster CVs were recorded in the RA compared with LA of Cx40+/+ hearts only (P=0.01).
Figure 5
Figure 5
Impulse initiation in Cx40-deficient embryonic mice. A–D, Representative dF/dt activity maps for Cx40+/+ mice at 13.5 dpc (A), Cx40−/− mice at 13.5 dpc (B), Cx40+/+ mice at 15.5 dpc (C), and Cx40−/− mice at 15.5 dpc. Bar=0.5 mm. E–H, Schematic showing normal sinus node activation originating near the crista terminalis in (E) Cx40+/+ mice at 13.5 dpc (n=8), (F) Cx40−/− mice at 13.5 dpc (n=14), and (G) Cx40+/+ mice at 15.5 dpc (n=6) and originating ectopically in (H) Cx40−/− mice at 15.5 dpc (n=10). SVC=superior vena cava; IVC=inferior vena cava; CT=crista terminalis; SAN=sinoatrial node.
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References

    1. Kleber AG, Fast VG, Rohr S. Continuous and discontinuous propagation. In: Zipes DP, Jalife J, editors. Cardiac Electrophysiology: From Cell to Bedside. Philadelphia: WB Saunders Co; 2000. pp. 205–213.
    1. Moreno AP. Biophysical properties of homomeric and heteromultimeric channels formed by cardiac connexins. Cardiovasc Res. 2004;62:276–286. - PubMed
    1. Saffitz JE, Lerner DL, Yamada KA. Gap junction distribution and regulation in the heart. In: Zipes DP, Jalife J, editors. Cardiac Electrophysiology: From Cell to Bedside. Vol IV. Philadelphia: WB Saunders; 2004. pp. 181–191.
    1. Jalife J, Morley GE, Vaidya D. Connexins and impulse propagation in the mouse heart. J Cardiovasc Electrophysiol. 1999;10:1649–1663. - PubMed
    1. Luke RA, Saffitz JE. Remodeling of ventricular conduction pathways in healed canine infarct border zones. J Clin Invest. 1991;87:1594–1602. - PMC - PubMed

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