TLR4 pathway induces proarrhythmogenic slow conduction by impaired depolarisation

Abstract Background Cardiac inflammation driven by the Toll-Like-Receptor 4 (TLR4) is correlated to increased risk of arrhythmia. arrhythmogenesis and formation re-entry tachycardia highly dependent on conduction velocity (CV) action potential (AP) duration (APD). As TLR4 induced APD shortening has been shown, we analyze in this study for first time effect conductance disturbances a LPS septic mouse model. Methods Systemic activation mice was achieved intraperitoneal injection 3.5 hours prior experiments. In vivo electrophysiological investigation (EPI) performed using an octapolar transvenous catheter placed right heart. Ex experiments were Langendorff-perfused hearts. AP propagation measured optical voltage mapping (OVM) with sensitive dye Di-4-ANEPPS. For analysis including RMP, intracellular electrical recordings sharp microelectrodes. Wildtype after compared wildtype vehicle (NaCl) or ubiquitous knockout (TLR4−/−) application. Results EPI showed tendency more atrial fibrillation (+LPS 5/6, +NaCl 2/6, p=0.2). Ventricular stimulation evoked ventricular every treated WT but less controls 6/6, 1/6, p=0.01). OVM decreased CV both atria ventricle treatment (atria: +LPS: 43.1±3.1cm/s, n=5; +NaCl: 72.6±9.8cm/s, n=10, p=0.04; ventricle: 50.2±2.2cm/s, n=6; 67.7±5.0cm/s, p=0.02). upstroke slightly (max.dV/dt: 123.1±4.8V/s, n=22; 158.5±5.3V/s, n=39, p=0.04) reduced 91.8±3.6V/s, n=27; 140.7±6.3V/s, n=35, p<0.0001). RMP depolarised (+LPS: −70.1±1.9mV, −81.1±1.2mV, p=0.004) explaining slowing voltage-dependent Na+ channel inactivation. unaffected −75.1±1.1mV, n=44; −76.3±0.9mV, n=55, p=0.83). Therefore currents isolated cardiomyocytes whole cell patch clamp revealing maximum current density lowered −20.6±1.7 pA/pF, n=16, 27.1±2.6 p=0.03). did not affect EPI, CV, TLR4−/− mice. Conclusion Herein report impaired cardiac depolarisation short term vivo. Pro arrhythmogenic mechanisms differ Increased inactivates leading reduction CV. slow caused channels. This different might be important novel antiarrhythmic antiinflammatory applications. Funding Acknowledgement Type funding sources: Public grant(s) – National budget only. Main source(s): GEROK-grant, University Bonn