Temporal variability of repolarization in rat ventricular myocytes paced with time‐varying frequencies

Adaptation of action potential duration (APD) to pacing cycle length (CL) has been previously characterized in isolated cardiomyocytes for sudden changes in constant CL and for pre-/postmature stimuli following constant pacing trains. However, random fluctuations characterize both physiological sinus rhythm (up to 10% of mean CL) and intrinsic beat-to-beat APD at constant pacing rate. We analysed the beat-to-beat sensitivity of each APD to the preceding CL during constant-sudden, random or linearly changing pacing trains in single patch clamped rat left ventricular myocytes, in the absence of the autonomic and electrotonic effects that modulate rate dependency in the intact heart. Beat-to-beat variability of APD at -60 mV (APD(-60 mV)), quantified as S.D. over 10-beat sequences, increased with corresponding mean APD. When measured as coefficient of variability (CV), APD(-60 mV) variability was inversely proportional to pacing frequency (from 1.2% at 5 Hz to 3.2% at 0.2 Hz). It was increased, at a basic CL (BCL) of 250 ms, by 55% by the L-type calcium current (I(CaL)) blocker nifedipine, and decreased by 23% by the transient-outward potassium current (I(to)) blocker 4-aminopyridine. Variability of APD at BCL of 250 ms prevented the detection of random changes of CL smaller than approximately 5%. Ten per cent random changes in CL were detected as a 40% increase in CV of APD and tended to correlate with it (r = 0.43). Block of I(CaL) depressed this correlation (r = 0.23), whereas block of I(to) significantly increased it (r = 0.67); this was similar with linearly changing CL ramps (ranging +/-10% and +/-20% of 250 ms). We conclude that beat-to-beat APD variability, a major determinant of the propensity for development of arrhythmia in the heart, is present in isolated myocytes, where it is dependent on mean APD and pacing rate. Action potential duration shows a beat-to-beat positive correlation with preceding randomly/linearly changing CL, which can be pharmacologically modulated.