Takuo Tsurugi

Coexistence of hERG current block and disruption of protein trafficking in ketoconazole-induced long QT syndrome

Many drugs associated with acquired long QT syndrome (LQTS) directly block human ether‐a‐go‐go‐related gene (hERG) K+ channels. Recently, disrupted trafficking of the hERG channel protein was proposed as a new mechanism underlying LQTS, but whether this defect coexists with the hERG current block remains unclear. This study investigated how ketoconazole, a direct hERG current inhibitor, affects the trafficking of hERG channel protein.

Differential modulation of late sodium current by protein kinase A in R1623Q mutant of LQT3

AIMS In the type 3 long QT syndrome (LQT3), shortening of the QT interval by overdrive pacing is used to prevent life-threatening arrhythmias. However, it is unclear whether accelerated heart rate induced by beta-adrenergic agents produces similar effects on the late sodium current (I(Na)) to those by overdrive pacing therapy. We analyzed the beta-adrenergic-like effects of protein kinase A and fluoride on I(Na) in R1623Q mutant channels. MAIN METHODS cDNA encoding either wild-type (WT) or R1623Q mutant of hNa(v)1.5 was stably transfected into HEK293 cells. I(Na) was recorded using a whole-cell patch-clamp technique at 23 degrees C. KEY FINDINGS In R1623Q channels, 2 mM pCPT-AMP and 120 mM fluoride significantly delayed macroscopic current decay and increased relative amplitude of the late I(Na) in a time-dependent manner. Modulations of peak I(Na) gating kinetics (activation, inactivation, recovery from inactivation) by fluoride were similar in WT and R1623Q channels. The effects of fluoride were almost completely abolished by concomitant dialysis with a protein kinase inhibitor. We also compared the effect of pacing with that of beta-adrenergic stimulation by analyzing the frequency-dependence of the late I(Na). Fluoride augmented frequency-dependent reduction of the late I(Na), which was due to preferential delay of recovery of late I(Na). However, the increase in late I(Na) by fluoride at steady-state was more potent than the frequency-dependent reduction of late I(Na). SIGNIFICANCE Different basic mechanisms participate in the QT interval shortening by pacing and beta-adrenergic stimulation in the LQT3.

Effects of pacing modes on cardiac baroreflex function in permanently paced patients with sinus node dysfunction

Objectives: We compared, in patients with sick sinus syndrome, the effects of various pacing modes on baroreceptor (BR)‐stroke volume (SV) reflex sensitivity, a method we have closely correlated with BR‐heart rate (HR) reflex sensitivity.

Non-Pharmacological Management of Neurocardiogenic Syncope

Neurocardiogenic syncope is a common disorder. It is diagnosed by obtaining a detailed history and performing a head‐up tilt test, with or without drug provocation. Several studies have been performed pertaining to its management. However, no treatment, whether pharmacological or non‐pharmacological, except for counterpressure maneuvers and daily orthostatic tilt training, has been proven effective. Randomized studies of therapies for neurocardiogenic syncope are needed.