Background: Long QT syndrome 3 (LQT3) is caused by SCN5A mutations. Late sodium current (late I Na) inhibitors are current-specific to treat patients with LQT3, but the mechanisms underlying mexiletine (MEX)-sensitive (N1325S and R1623Q) and-insensitive (M1652R) mutations remains to be elucidated. Methods: LQT3 patients with causative mutations were treated with oral MEX following i.v. lidocaine. Whole-cell patch-clamp techniques and molecular remodeling were used to determine the mechanisms underlying the sensitivity to MEX. Results: Intravenous administration of lidocaine followed by MEX orally in LQT patients with N1325S and R1623Q sodium channel mutation shortened QTc interval, abolished arrhythmias, and completely normalized the ECG. In HEK293 cells, the steady-state inactivation curves of the M1652R channels were rightward shifted by 5.6 mV relative to the WT channel. In contrast, the R1623Q mutation caused a leftward shift of the steady-state inactivation curve by 15.2 mV compared with WT channel, and N1325S mutation did not affect steady-state inactivation (n = 5-13, P < 0.05). The extent of the window current was expanded in all three mutant channels compared with WT. All three mutations increased late I Na with the greatest amplitude in the M1652R channel (n = 9-15, P < 0.05). MEX caused a hyperpolarizing shift of the steady-state inactivation and delayed the recovery of all three mutant channels. Furthermore, it suppressed late I Na in N1325S and R1623Q to a greater extent compared to that of M1652R mutant channel. Mutations altered the sensitivity of Na v 1.5 to MEX through allosteric mechanisms by changing the conformation of Na v 1.5 to become more or less favorable for MEX binding. Late I Na inhibitors suppressed late I Na in N1325S and R1623Q to a greater extent than that in the M1652R mutation (n = 4-7, P < 0.05).

Rationale: Glomerulonephritis triggered by a chronically infected graft is increasingly identified because of widely used implanted device. Removal of the aortic graft and sustained antibiotic therapy is the usual approach to maximize the chance of renal recovery, but as this case shows graft removal is not always possible. Patient concerns: A 35-year-old man with intractable and recurrent fever had acute renal failure in sustained antibiotic therapy. Diagnoses: Renal biopsy suggested crescentic glomerulonephritis. 18 fluorodeoxyglucose/positron emission tomography–computed tomography showed increased metabolic activity at the site of aortic graft, reminding that chronic infection of an implanted graft can lead to severe glomerulonephritis. TGFBR2 c.1133G>T mutation was observed in mutation analysis, which was reported to be associated with Loeys–Dietz syndrome. Interventions: Although infection was properly controlled with appropriate antimicrobial treatment, his renal dysfunction did not improve. A short-term inclusion of low-dose corticosteroid significantly benefit without introducing harm. Outcomes: He partly recovered from renal injury. Lessons: In patients with glomerulonephritis triggered by a long-duration infection, low-dose corticosteroid therapy may be considered when renal dysfunction secondary to nephritis does not improve after appropriate antimicrobial treatment.