Beat-to-beat repolarization variability in ventricular myocytes and its suppression by electrical coupling

Single ventricular myocytes paced at a constant rate and held at a constant temperature exhibit beat-to-beat variations in action potential duration ( APD). In this study we sought to quantify this variability, assess its mech anism, and determine its responsiveness to electrotonic interactions with a nother myocyte. Interbeat APD(90) (90% repolarization) of single cells was normally distributed. We thus quantified APD(90) variability as the coeffic ient of variability, CV = (SD/meanAPD(90)) x 100. The mean +/- SD of the CV in normal solution was 2.3 +/- 0.9 (132 cells). Extracellular TTX (13 mu M ) and intracellular EGTA (14 mM) both significantly reduced the CV by 44 an d 26%, respectively. When applied in combination the CV fell by 54%. In con trast, inhibition of the rapid delayed rectifier current with L-691,121 (10 0 nM) increased the CV by 300%. The CV was also significantly reduced by 35 % when two normal myocytes were electrically connected with a junctional re sistance (R-j) of 100 M Ohm. Electrical coupling (R-j = 100 M Ohm) of a nor mal myocyte to one producing early afterdepolarization (EAD) completely blo cked EAD formation. These results indicate that beat-to-beat APD variabilit y is likely mediated by stochastic behavior of ion channels and that electr otonic interactions act to limit temporal dispersion of refractoriness, a m ajor contributor to arrhythmogenesis.