Abstract 569: Selective Elimination of IKs and IKr in Transgenic Rabbit Models of LQT1 and LQT2
LQT1 and LQT2, the two most common inherited long QT syndromes are associated with sudden cardiac death due to due torsades the pointes (TdP). We have created two lines of transgenic rabbits overexpressing pore mutants of the human KvLQT1 (KCNQ1) and HERG (KCNH2) in the heart. Both animal models have prolonged QT interval, however, only LQT2 rabbits suffer from TdP and sudden cardiac death. To investigate the differences in the cellular phenotypes we investigated the whole cell current of acute isolated apical ventricular myocytes from LQT1 and LQT2 rabbit models using patch-clamp techniques by depolarizing to potentials between −30 to +30 mV from a holding potential of −40 mV (room temperature). IKr and IKs were defined as currents sensitive to E-4031 (5 μM) and chromanol 293B (30μM) respectively. Our preliminary data revealed that IKs was selectively abolished in 8 out of 8 LQT1 cardiomyocytes, while IKr was spared (Figure 1⇓). By contrast, IKr was selectively abolished in 13 out of 14 LQT2 cardiomyocytes while IKs was spared. The selective elimination of IKr resulted in a significant increase in the duration of action potential (APD90) from 357±48.68ms (n=13) in control to 533.14±54.22ms (n=14) in LQT2 cardiomyoctes (P<0.05), while the elimination of Iks slightly prolonged the APD90 to 423.37± 52.31 (n=8) (P=NS). In conclusion, expression of the pore mutants resulted in specific inhibition of IKs in LQT1 and IKr in LQT2 rabbits, and established these models as unique genetic counterparts of the human LQT1 and LQT2 syndrome. These models will enable detailed analyses of the electrical remodeling in LQTS.