Abstract
Background: Tumor Necrosis Factor α (TNFα) upregulation during acute inflammatory response has been associated with numerous cardiac effects including modulating Connexin43 and vascular permeability. This may in turn alter cardiac gap junctional (GJ) coupling and extracellular volume (ephaptic coupling) respectively. We hypothesized that acute exposure to pathophysiological TNFα levels can modulate conduction velocity (CV) in the heart by altering electrical coupling: GJ and ephaptic.Methods and Results: Hearts were optically mapped to determine CV from control, TNFα and TNFα + high calcium (2.5 vs. 1.25 mM) treated guinea pig hearts over 90 mins. Transmission electron microscopy was performed to measure changes in intercellular separation in the gap junction-adjacent extracellular nanodomain—perinexus (WP). Cx43 expression and phosphorylation were determined by Western blotting and Cx43 distribution by confocal immunofluorescence. At 90 mins, longitudinal and transverse CV (CVL and CVT, respectively) increased with control Tyrode perfusion but TNFα slowed CVT alone relative to control and anisotropy of conduction increased, but not significantly. TNFα increased WP relative to control at 90 mins, without significantly changing GJ coupling. Increasing extracellular calcium after 30 mins of just TNFα exposure increased CVT within 15 mins. TNFα + high calcium also restored CVT at 90 mins and reduced WP to control values. Interestingly, TNFα + high calcium also improved GJ coupling at 90 mins, which along with reduced WP may have contributed to increasing CV.Conclusions: Elevating extracellular calcium during acute TNFα exposure reduces perinexal expansion, increases ephaptic, and GJ coupling, improves CV and may be a novel method for preventing inflammation induced CV slowing.
Highlights
Myocardial inflammation is associated with many cardiac diseases (Marchant et al, 2012; De Jesus et al, 2015) and modulates several determinants of cardiac function, both mechanical and electrical
Studies have demonstrated a temporal change in the regulation of Cx43 expression by Tumor Necrosis Factor α (TNFα) where an increase in Cx43 mRNA and protein expression was reported at 6 h of TNFα exposure and a decrease at longer durations up to 48 h (Liu et al, 2012)
In hearts perfused with control Tyrode’s solution, both CV—both longitudinal (CVL) and CVT isotropically increased over time
Summary
Myocardial inflammation is associated with many cardiac diseases (Marchant et al, 2012; De Jesus et al, 2015) and modulates several determinants of cardiac function, both mechanical and electrical. Some studies (Celes et al, 2007; Kimura and Nishida, 2010) demonstrated that exposure to TNFα reduces Connexin (Cx43) functional expression, the principle gap junctional protein in cardiac ventricles, while others reported no change (Sawaya et al, 2007). Tumor Necrosis Factor α (TNFα) upregulation during acute inflammatory response has been associated with numerous cardiac effects including modulating Connexin and vascular permeability. This may in turn alter cardiac gap junctional (GJ) coupling and extracellular volume (ephaptic coupling) respectively. We hypothesized that acute exposure to pathophysiological TNFα levels can modulate conduction velocity (CV) in the heart by altering electrical coupling: GJ and ephaptic
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