Abstract 157: Toll like Receptor 4 Activation Promotes Cardiac Arrhythmias By Decreasing The Transient Outward Potassium Current (ito) Through An Irf3 dependent And Myd88 independent Pathway

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Abstract

Cardiac arrhythmias are one of the main causes of death worldwide. Several studies have shown that inflammation plays a key role in different cardiac diseases and Toll like receptors (TLR’s) play an important role in cardiac complications. In the present study, we investigated whether the activation of TLR4 induces cardiac electrical remodeling and arrhythmias. Also the signaling pathway involved in these phenomena was studied. Action potentials, the presence of cardiac arrhythmias and transient outward K+ current (Ito) were recorded in Wistar rat’s hearts after 24 h exposure to the TLR4 agonist ultrapure Lipopolysaccharide (LPS - 1μg/ml). TLR4 stimulation in vitro promotes a cardiac electrical remodeling that leads to cardiac action potential prolongation which evokes arrhythmic events such as delayed after depolarization (DAD's) and triggered activity. The perfusion of LPS (1μg/ml) during 30 minutes did not modify Ito. Conversely, after 24 h of LPS incubation Ito was reduced, with no changes in the biophysical properties of the current. Major changes in Ca2+ cycling were not observed in ventricular myocytes after 24 h exposure to LPS; however, extrasystolic activity was present in a considerable number of cells (25%). Neither the blockade of Interleulink-1 receptor-associated kinase 4 nor nuclear factor kappa B (NF-kB) prevented the LPS effect on Ito. However, interferon regulatory factor 3 (IRF3) inhibition prevented the effect of TLR4 activation on Ito. Activation of TLR4 induced extrasystolic activity, longer AP duration and evoked DAD's and triggered activity because of a reduction in Ito. The mechanism involved is MyD88-independent and IRF3-dependent.

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