Short-Long Heart Rate Variation Increases Dispersion of Action Potential Duration in Long QT Type 2 Transgenic Rabbit Model

The initiation of polymorphic ventricular tachycardia in long QT syndrome type 2 (LQT2) has been associated with a characteristic ECG pattern of short-long RR intervals. We hypothesize that this characteristic pattern increases APD dispersion in LQT2, thereby promoting arrhythmia. We investigated APD dispersion and its dependence on two previous cycle lengths (CLs) in transgenic rabbit models of LQT2, LQT1, and their littermate controls (LMC) using random stimulation protocols. The results show that the short-long RR pattern was associated with a larger APD dispersion in LQT2 but not in LQT1 rabbits. The multivariate analyses of APD as a function of two previous CLs (APD_n = C + α₁CL_n−1 + α₂CL_n−2) showed that α₁ (APD restitution slope) is largest and heterogeneous in LQT2 but uniform in LQT1, enhancing APD dispersion under long CL_n−1 in LQT2. The α₂ (short-term memory) was negative in LQT2 while positive in LQT1, and the spatial pattern of α₁ was inversely correlated to α₂ in LQT2, which explains why a short-long combination causes a larger APD dispersion in LQT2 but not in LQT1 rabbits. In conclusion, short-long RR pattern increased APD dispersion only in LQT2 rabbits through heterogeneous APD restitution and the short-term memory, underscoring the genotype-specific triggering of arrhythmias in LQT syndrome.