Effects of a random-frequency stimulation on the dispersion of repolarization in single ventricular myocytes

Cardiac function is primarily regulated by beating frequency and by duration of the myocardial repolarization, which are finely controlled by many physiological mechanisms and also known to be stochastically variable over consecutive beats (Batchvarov et al., 2002). Such variability is present already at the cellular level both in the firing rate of single sinoatrial-node cells (Wilders&Jongsma, 1993) and in the action potential duration (APD) of single ventricular myocytes paced at a fixed cycle-length (Zaniboni et al., 2000). Using the patch clamp whole-cell technique, we paced rat ventricular myocytes through brief depolarizing current pulses delivered at a cycle length which was randomply variable within a certain range, chosen as a given percentage (R%) of a central value of 250 ms. The aim was to study the effect of an intrinsically random pacemaker on the beat-to-beat repolarization variability, monitoring the coefficient of variability of APD (CVAPD) as a function of R%. We found that the intrinsic CVAPD (1.2%) remains fairly constant as R% is kept less than 4%. As R% is risen above this value, this is reflected in a proportional rise of CVAPD. Also we found that the partial block of the calcium current ICaL (10 M Nifedipine) shifted the CVAPD (+0.5%) as well as the partial block of the potassium current ITO (5mM 4-AP) produced an equivalent shift in the opposite direction. We conclude that, at a cellular level, (i) intrinsic APD variability buffers small changes in pacing frequency, (ii) that larger changes can contribute to the APD dispersion, and (iii) that ionic currents active during action potential plateau are likely to mediate the interplay between pacing-rate variability and dispersion of repolarization.