Hiroko Takemasa

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.

Comparison of HERG channel blocking effects of various β‐blockers – implication for clinical strategy

β‐Blockers are widely used in the treatment of cardiovascular diseases. However, their effects on HERG channels at comparable conditions remain to be defined. We investigated the direct acute effects of β‐blockers on HERG current and the molecular basis of drug binding to HERG channels with mutations of putative common binding site (Y652A and F656C). β‐Blockers were selected based on the receptor subtype. Wild‐type, Y652A and F656C mutants of HERG channel were stably expressed in HEK293 cells, and the current was recorded by using whole‐cell patch‐clamp technique (23°C). Carvedilol (nonselective), propranolol (nonselective) and ICI 118551 (β2‐selective) inhibited HERG current in a concentration‐dependent manner (IC50 0.51, 3.9 and 9.2 μM, respectively). The IC50 value for carvedilol was a clinically relevant concentration. High metoprolol (β1‐selective) concentrations were required for blockade (IC50 145 μM), and atenolol (β1‐selective) did not inhibit the HERG current. Inhibition of HERG current by carvedilol, propranolol and ICI 118551 was partially but significantly attenuated in Y652A and F656C mutant channels. Affinities of metoprolol to Y652A and F656C mutant channels were not different compared with the wild‐type. HERG current block by all β‐blockers was not frequency‐dependent. Drug affinities to HERG channels were different in β‐blockers. Our results provide additional strategies for clinical usage of β‐blockers. Atenolol and metoprolol may be preferable for patients with type 1 and 2 long QT syndrome. Carvedilol has a class III antiarrhythmic effect, which may provide the rationale for a favourable clinical outcome compared with other β‐blockers as suggested in the recent COMET (Carvedilol Or Metoprolol European Trial) substudy.

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.

Right ventricular outflow tract endocardial pacing complicated by intercostal muscle twitching.

A recipient of a dual‐chamber pacing system, with a bipolar endocardial lead screwed into the right ventricular outflow tract (RVOT), developed intercostal muscle twitching. No lead perforation was identified. This observation suggests that meticulous attention should be paid to this potential complication when choosing the RVOT as a site of permanent endocardial pacing.

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.