Abnormal Cardiac Na + Channel Properties and QT Heart Rate Adaptation in Neonatal Ankyrin B Knockout Mice

Abstract

Abstract —The cytoskeleton of the cardiomyocyte has been shown to modulate ion channel function. Cytoskeletal disruption in vitro alters Na + channel kinetics, producing a late Na + current that can prolong repolarization. This study describes the properties of the cardiac Na + channel and cardiac repolarization in neonatal mice lacking ankyrin B , a cytoskeletal “adaptor” protein. Using whole-cell voltage clamp techniques, I Na density was lower in ankyrin B (−/−) ventricular myocytes than in wild-type (WT) myocytes (−307±26 versus −444±39 pA/pF, P <0.01). Ankyrin B (−/−) myocytes exhibited a hyperpolarizing shift in activation and inactivation kinetics compared with WT. Slower recovery from inactivation contributed to the negative shift in steady-state inactivation in ankyrin B (−/−). Single Na + channel mean open time was longer in ankyrin B (−/−) versus WT at test potentials ( V t ) of −40 mV (1.0±0.1 versus 0.61±0.04 ms, P <0.05) and −50 mV (0.8±0.1 versus 0.39±0.05 ms, P <0.05). Ankyrin B (−/−) exhibited late single-channel openings at V t −40 and −50 mV, which were not seen in WT. Late I Na contributed to longer action potential durations measured at 90% repolarization (APD 90 ) at 1 Hz stimulation in ankyrin B (−/−) compared with WT (354±26 versus 274±22 ms, P <0.05). From ECG recordings of neonatal mice, heart rates were slower in ankyrin B (−/−) than in WT (380±14 versus 434±13 bpm, P <0.01). Although the QT interval was similar in ankyrin B (−/−) and WT at physiological heart rates, QT-interval prolongation in response to heart rate deceleration was greater in ankyrin B (−/−). In conclusion, Na + channels in ankyrin B (−/−) display reduced I Na density and abnormal kinetics at the whole-cell and single-channel level that contribute to prolonged APD 90 and abnormal QT-rate adaptation.