The higher frequency components（HFC ; 200 Hz or more）hidden within the QRS complex（QRS）may reflect small local abnormalities of cardiac excitation. Until now, the clinical significance of HFC has been a mysterious subject for cardiologists. However, the appearance of HFC may capture depolarization abnormalities at the millimeter level in the cardiac ventricles. This could provide new information from electrocardiograms. Our group has studied the frequency analysis of QRS for 20 years. In this manuscript, I review our research, which I believe will be beneficial for young researchers in this field. In this review I discuss the development of frequency analysis, discuss the clinical application of the wavelet transform, and explore the genesis of HFC using a computer simulation.

Mutations in the coding sequence of SCN5A have been associated with various arrhythmias. However, it is unknown whether variants in the promoter and transcription regulatory regions of SCN5A modulate the risk of arrhythmias. We resequenced the promoter region of SCN5A in 1288 patients with various arrhythmia syndromes. We also resequenced the conserved noncoding sequences（CNS）in intron 1. We identified novel 26 variants in 29 patients. We performed luciferase-reporter assay to elucidate the functional change caused by the rare variants. Six variants revealed decreased promoter activity compared with wild-type sequence. ChIP-Seq analyses revealed that the majority of the promoter variants are located at the regions bound by the transcription factors or active histone marks. We also identified a rare variant in CNS28 in patients with atrial fibrillation. CNS28 includes 3 binding sites for TEF1, a muscle-specific transcription factor, and the variant was predicted to disrupt one of these binding sites. This variant was associated with decreased promoter activity. Variants in the promoter and the transcription regulatory region of SCN5A were identified in the patients with various arrhythmias, which supported the hypothesis that altered SCN5A transcription levels modulate susceptibility to arrhythmias.

Calmodulin is a ubiquitous Ca2+ sensor molecule encoded by the three unique genes, CALM1–3. Recently, mutations in CALM1–3 have been reported to be associated with severe arrhythmias including long-QT syndrome（LQTS）. However, the underlying mechanism through which heterozygous calmodulin mutations lead to severe LQTS remains unknown, particularly in human cardiomyocytes. We aimed to establish an LQTS disease model associated with a CALM2 mutation（LQT15）using human induced pluripotent stem cells（hiPSCs）and to assess mutant allele-specific ablation by genome editing for the treatment of LQT15. We generated LQT15-hiPSCs from a 12-year-old boy with LQTS carrying a CALM2-N98S mutation and differentiated these hiPSCs into cardiomyocytes（LQT15-hiPSC-CMs）. In addition, we performed mutant allele-specific knockout using a CRISPR-Cas9 system. Electrophysiological properties of hiPSC-CMs were analyzed by the patch-clamp technique. Electrophysiological analyses revealed that LQT15-hiPSC-CMs exhibited significantly lower beating rates, prolonged action potential durations（APD）, and impaired inactivation of LTCC currents compared with control. Ablation of the mutant allele rescued the electrophysiological abnormalities of LQT15-hiPSC-CMs. These results indicate that the mutant allele caused dominant-negative suppression of LTCC inactivation, resulting in prolonged APD. We successfully recapitulated the disease phenotypes of LQT15 and revealed the pathophysiological mechanism in CALM2-N98S hiPSC model. Additionally, allele-specific ablation using the latest genome-editing technology provided important insights into a promising therapeutic approach for inherited cardiac diseases.

The effect of right ventricular septal pacing on cardiac function has been not well clarified. In this study, we evaluated the short-term effectiveness of right ventricular septal pacing. BNP（brain natriuretic peptide）and CTR（cardio-thoracic ratio）, the index of cardiac failure, were improved. The percentage of pacing was not correlated, but paced QRS interval was correlated with BNP and significantly wider in patients with other cardiac diseases.These results suggest that right ventricular septal pacing could improve the prognosis of cardiac failure and it was not correlated with percentage of pacing, and that paced QRS interval is involved in other cardiac diseases.

A 58-year-old-male received radiofrequency catheter ablation（RFCA）for symptomatic manifest WPW syndrome. The morphology of delta wave showed negative / QS pattern in the lead V₁, suggesting septal accessory pathway. Both antegrade and retrograde conduction of the accessory pathway demonstrated the earliest activation at the right mid-septum near the His bundle. Although the accessory pathway disappeared immediately after careful RFCA at this site, temporally atrioventricular block occurred. The accessory pathway recurred after discontinuing the RFCA. The cryoablation was performed in the second ablation session. The accessory pathway was eliminated radically without any atrioventricular conduction disturbance by cryoablation at the same position（the right parahissian mid-septum）as in the first ablation session.