Nobuhisa Hagiwara

The SCN5A R1623Q mutation is one of the most common genetic variants associated with severe congenital long QT syndrome 3 (LQT3) in fetal and neonatal patients. To investigate the properties of the R1623Q mutation, we established an induced pluripotent stem cell (iPSC) cardiomyocyte (CM) model from a patient with LQTS harboring a heterozygous R1623Q mutation. The properties and pharmacological responses of iPSC-CMs were characterized using a multi-electrode array system. The biophysical characteristic analysis revealed that R1623Q increased open probability and persistent currents of sodium channel, indicating a gain-of-function mutation. In the pharmacological study, mexiletine shortened FPDcF in R1623Q-iPSC-CMs, which exhibited prolonged field potential duration corrected by Fridericia’s formula (FPDcF, analogous to QTcF). Meanwhile, E4031, a specific inhibitor of human ether-a-go-go-related gene (hERG) channel, significantly increased the frequency of arrhythmia-like early after depolarization (EAD) events. These characteristics partly reflect the patient phenotypes. To further analyze the effect of neonatal isoform, which is predominantly expressed in the fetal period, on the R1623Q mutant properties, we transfected adult form and neonatal isoform SCN5A of control and R1623Q mutant SCN5A genes to 293T cells. Whole-cell automated patch-clamp recordings revealed that R1623Q increased persistent Na⁺ currents, indicating a gain-of-function mutation. Our findings demonstrate the utility of LQT3-associated R1623Q mutation-harboring iPSC-CMs for assessing pharmacological responses to therapeutic drugs and improving treatment efficacy. Furthermore, developmental switching of neonatal/adult Nav1.5 isoforms may be involved in the pathological mechanisms underlying severe long QT syndrome in fetuses and neonates.

Introduction: Peripheral artery disease (PAD) occurs at an advanced stage of atherosclerosis and its comorbidities are associated with poor prognoses. Malnutrition is related to the severity of atherosclerosis in patients with cardiovascular disease and it predicts mortality. The Controlling Nutritional Status (CONUT) score is calculated from serum albumin concentration, peripheral lymphocyte count and total cholesterol concentration, and it robustly represents the nutritional status of hospitalized patients. This study aimed to determine the prognostic value of the CONUT score in patients with peripheral artery disease (PAD) who were undergoing endovascular therapy (EVT). METHODS and RESULTS: This study included 628 PAD patients who underwent EVT between 2013 and 2017 and were assigned to low (CONUT score 0: n = 81), mild (CONUT score 1–2: n = 250), moderate (CONUT score 3–4: n = 169), and high (CONUT score ≥ 5: n = 128) risk groups. The study’s primary endpoint was any death. Patients in the groups with higher CONUT scores were more likely to have chronic kidney disease (p < 0.001), impaired left ventricular ejection fractions (p < 0.001), and critical limb ischemia (p < 0.001) on admission. During follow-up, 95 patients (15%) died. Kaplan–Meier analyses revealed that the patients with higher CONUT scores had lower survival rates (p < 0.001; log-rank trend test). Multivariate Cox regression analyses showed that following adjustments for the confounding factors, a higher CONUT score was significantly associated with any death (hazard ratio, 1.15; 95% confidence interval, 1.03–1.30). CONCLUSION: The simple index CONUT score at the time of EVT may predict long-term mortality in PAD patients.