Abstract
Increased myofilament Ca2+ sensitivity is associated with an increased susceptibility for arrhythmias, as previously demonstrated in mice expressing Ca2+ sensitizing troponin T (TnT-I79N) mutations and after acute application of the Ca2+ sensitizer EMD57033. We hypothesized that the arrhythmia risk is increased due to altered regulation of connexin43 (Cx43), subsequently leading to a slowing of cardiac conduction.Methods: Fast (longitudinal) and slow (lateral) conduction velocity (CV) was calculated using epi-fluorescence maps from isolated hearts by plotting local CVs against orientation. Phosphorylated Cx43 (P1, P2) from these hearts migrated slower in SDS PAGE and at least three distinct bands could be separated (P0,P1,P2).Results: The lateral CV, but not the longitudinal CV, was significantly reduced in TnT-I79N mice compared to control (16.9±0.8 cm/s (n = 11) vs. 21.5±1.4 cm/s (n = 11) respectively, p<0.05). As a direct consequence the anisotropy of conduction (fast/slow) was increased in TnT-I79N hearts (to 3.2±0.2 vs 2.3±0.1 in control). This change in CV was associated with decreased Cx43 phosphorylation (un-phosphorylated P0-Cx43 increased to 146±20% of control, p<0.05). Blebbistatin, a Ca2+ desensitizer and contractile uncoupler, prevented ventricular arrhythmias in TnT-I79N hearts. Strikingly, blebbistatin also prevented the increase in anisotropy and the decrease in Cx43 phosphorylation, while it had no effect in control hearts. Conversely, acutely increasing Ca2+ sensitivity with EMD decreased Cx43 phosphorylation (P0-Cx43 491± 147%, n = 4, p< 0.05) and rapidly slowed lateral conduction velocity (to 18.2±1.3 vs 22.9±1.1 cm/s in control, p<0.05) thereby increasing anisotropy (to 2.64±0.1 vs 2.17±0.07 in control) and rendered control hearts susceptible to arrhythmia induction.Conclusion: These data suggest that decreased Cx43 phosphorylation and increased conduction anisotropy is at least in part responsible for the increased arrhythmia susceptibility associated with myofilament Ca2+ sensitization.
Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
