Nonlinear effects in subthreshold virtual electrode polarization

Introduction of the virtual electrode polarization (VEP) theory suggested solutions to several century-old puzzles of heart electrophysiology including explanation of the mechanisms of stimulation and defibrillation. Bidomain theory predicts that VEPs should exist at any stimulus strength. Although the presence of VEPs for strong suprathreshold pulses has been well documented, their existence at subthreshold strengths during diastole remains controversial. We studied cardiac membrane polarization produced by subthreshold stimuli in 1) rabbit ventricular muscle using high-resolution fluorescent imaging with the voltage-sensitive dye pyridinium 4-{2-[6-(dibutylamino)-2-naphthalenyl]-ethenyl}-1-(3-sulfopropyl)hydroxide (di-4-ANEPPS) and 2) an active bidomain model with Luo-Rudy ion channel kinetics. Both in vitro and in numero models show that the common dog-bone-shaped VEP is present at any stimulus strength during both systole and diastole. Diastolic subthreshold VEPs exhibited nonlinear properties that were expressed in time-dependent asymmetric reversal of membrane polarization with respect to stimulus polarity. The bidomain model reveals that this asymmetry is due to nonlinear properties of the inward rectifier potassium current. Our results suggest that active ion channel kinetics modulate the transmembrane polarization pattern that is predicted by the linear bidomain model of cardiac syncytium.