Gender-related differences of ventricular repolarization in LQT2 rabbit model

To explore the cellular mechanism responsible for the gender-related differences of ventricular tachyarrhythmias in long QT syndromes (LQTS), we observed the characteristics of pre-existing electrophysiological heterogeneity and dynamics of ventricular repolarization in different gender of LQT2 rabbit models. The intracellular floating microelectrodes technique was used to record transmembrane action potentials simultaneously from epicardial and endocardial sites of the arterially perfused rabbit left ventricular wedge preparation; in the mean time, the electrocardiogram (ECG) was also recorded. The wedge preparations were placed in a small tissue bath and arterially perfused with normal Tyrode's solution (control group), 100 mumol/L dl-sotalol Tyrode's solution (LQT2 model group), and 100 mumol/L dl-sotalol plus 3.0 mmol/L KCl Tyrode's solution (LQT2 model plus hypokalemia group), buffered with 95% O2 and 5% CO2 [(36.0+/-1) degrees C]. Double diastolic threshold currents were delivered with basic cycle length (BCL) 2 000, 1 000 and 500 ms (S1), respectively, to record transmembrane action potentials and transmural ECG. Each driving train of S1 is with 20 beats. To determine action potential duration restitution (APDR) curves, the S1-S2 programmed stimuli were used. The tissue was paced at 1 000 ms and 500 ms cycle length (S1) for eight beats, followed by a single premature stimulus (S2). The S1-S2 coupling interval was progressively shortened with 10 ms decrements until the S2 failed to capture. The results showed that female rabbits exhibited significantly longer transmural dispersion of repolarization (TDR) and steeper maximal slopes of APDR curves than that in male rabbits at same pacing rates (P<0.05), and which were pacing rate-dependent. In the condition of dl-sotalol plus hypokalemia, the TDR and the maximal slopes of APDR curves were significantly increased in comparison with that in the control group (P<0.01). At a BCL of 1 000 ms of seven experiments, one female showed torsade de pointes (TdP) in the LQT2 model group; five females and two males showed TdP in LQT2 model plus hypokalemia group, showing significant gender-related differences (P<0.05). The present findings suggest that the pre-existing electrophysiological and dynamic heterogeneity in the LQT2 model shows an obvious gender-related difference and pacing rate-dependence. Both increased TDR and steepness of APDR in female rabbits are possibly the major factors which prompt the TdP generation in female LQT2 rabbits more easily than in male rabbits.