Downregulation of connexin40 and increased prevalence of atrial arrhythmias in transgenic mice with cardiac-restricted overexpression of tumor necrosis factor

Abstract

Sawaya SE, Rajawat YS, Rami TG, Szalai G, Price RL, Sivasubramanian N, Mann DL, Khoury DS. Downregulation of connexin40 and increased prevalence of atrial arrhythmias in transgenic mice with cardiac-restricted overexpression of tumor necrosis factor.

Mathematical modeling mechanisms of arrhythmias in transgenic mouse heart overexpressing TNF-α

“…Western blot analysis and immunohistochemistry studies in mouse hearts overexpressing TNF-␣ do not show decreased Cx43 expression in ventricles (25,55). Immunohistochemical studies, however, show that, while in WT mice Cx43 is primarily located in the intercalated discs of cardiac myocytes, in TG mice, with cardiac-specific overexpression of TNF-␣, Cx43 is dispersed throughout the sarcolemma and in intercalated disks (55).…”

“…Conduction between ventricular myocytes depends on the excitability of cardiomyocytes and the expression and distribution of connexin43 (Cx43), which is the predominant connexin type in the mouse ventricles (55). Western blot analysis and immunohistochemistry studies in mouse hearts overexpressing TNF-␣ do not show decreased Cx43 expression in ventricles (25,55).…”

“…Western blot analysis and immunohistochemistry studies in mouse hearts overexpressing TNF-␣ do not show decreased Cx43 expression in ventricles (25,55). Immunohistochemical studies, however, show that, while in WT mice Cx43 is primarily located in the intercalated discs of cardiac myocytes, in TG mice, with cardiac-specific overexpression of TNF-␣, Cx43 is dispersed throughout the sarcolemma and in intercalated disks (55). According to Peters et al (48) disturbed Cx43 gap junction distribution correlates with the location of reentrant circuits in the epicardial border zone of healing canine infarcts that cause ventricular tachycardia, which points to disorganization of Cx43 in TG mice as a possible cause for a decrease in conduction velocity.…”

Inflammation and C-Reactive Protein in Atrial Fibrillation: Cause or Effect?

“…Irregular production of these proteins might alter intercellular communication, reducing conduction within the atrial myocardium and creating an arrhythmogenic substrate for AF. 46 This concept was supported by Sawaya and coworkers, 47 who achieved the downregulation of connexin 40 (but not of connexin 43) in 8 transgenic mice by means of targeted overexpression of tumor necrosis factor in the pericardium.…”

Inflammation of left atrial epicardial adipose tissue is associated with paroxysmal atrial fibrillation

“…A previous study assessed inflammation of EAT that was harvested from patients undergoing cardiac surgery, and showed that it represented an important local source of the inflammatory mediators tumor necrosis factor-a and interleukin-6 [21,22], which might have direct arrhythmogenic effects on atrial tissue and be associated with AF pathogenesis [23]. Moreover, lone AF and rapid acute pacing were recently reported to provoke significant changes in atrial adipogenesis and to promote adipocyte differentiation and adipose tissue expansion [24].…”