Abstract 449: Late Sodium Currents Generated by Mutation N1325S in Sodium Channel Gene SCN5A Cause Heart Failure
Electrophysiological remodeling of ion channels is well-known in heart failure. Increased late sodium currents and abnormalities of the calcium handling were reported in animal models for heart failure and human patients. However, the cause-consequence relationship between electrophysiological remodeling and heart failure is unknown. In this study, we demonstrate that the late sodium current is the direct cause of heart failure. We studied two models of transgenic mice: one with transgenic overexpresison of the wild type cardiac sodium channel gene SCN5A in the heart (TG-WT L10) and the other with overexpression of mutant SCN5A with LQT3-mutation N1325S (TG-LQT3 L12). Both TG-WT L10 and TG-LQT3 L12 have the similar number of copies of the transgene. RT-PCR and Western blot analyses showed that TG-WT L10 mice had slighter higher expression of SCN5A than TG-LQT3 L12. However, the late sodium current was detected in TG-LQT3 mice, but not in TG-WT mice. We detected a significant increase and prolonged decay in calcium transient signals that possibly indicate abnormal [Ca2+]i homeostasis in TG-LQT3 mice, but not in TG-WT mice. Age-dependent apoptosis of cardiomyocytes was detected in TG-LQT3 hearts, but not in TG-WT hearts. Echocardiography showed dilated cardiomyopathy in surviving TG-LQT3 mice in the later adult stages (8–12 months), but not in TG-WT mice. Fractional shortening(%) was significantly reduced in TG-LQT3 mice (24.9±13) compared to TG-WT (58.4±4.4, p<0.005) or non-transgenic mice (60±15.6, p<0.005). LVEDS was significantly increased and IVSS was significantly decreased in TG-LQT3 mice compared to TG-WT or non-transgenic mice (p<0.01). Cross-sectionals of the hearts further showed dilated chambers and thin walls along with myocardial fibrosis. We propose that the late sodium currents lead to increased intracellular [Ca2+] and increased cardiac apoptosis, which results in dilated cardiomyopathy and heart failure. In conclusion, our genetic results demonstrate that late sodium currents directly cause heart failure.