Satoru Komura

Function, subcellular localization and assembly of a novel mutation of KCNJ2 in Andersen's syndrome.

Andersens syndrome (AS) (which is characterized by periodic paralysis, cardiac arrhythmias and dysmorphic features), a hereditary disease, and missense mutations of KCNJ2 (which encodes an inward rectifying potassium channel) have been reported recently. We performed clinical and molecular analyses of a patient with AS, and found a novel mutation (G215D) of KCNJ2. Twelve-lead electrocardiography revealed a long QT interval and frequent premature ventricular contractions, and polymorphic ventricular tachycardia was induced by programmed electrical stimulation. Use of a conventional whole-cell patch-clamp system with COS7 cells demonstrated that the G215D mutant was non-functional, and that co-expression of wild type (WT)- and mutant-KCNJ2 shows a dominant negative effect on both inward and outward currents. We performed confocal laser scanning microscopy to assess the cellular trafficking of WT- and mutant-KCNJ2 subunits tagged with yellow fluorescent protein (YFP) and cyan fluorescent protein (CFP), respectively. Tagging with the YFP did not affect the channel function of WT-KCNJ2 and both proteins showed similar plasma membrane fluorescence patterns. Furthermore, the result of fluorescence resonance energy transfer (FRET) studies at the plasma membrane region suggested that both YFP-tagged WT- and CFP-tagged mutant-KCNJ2 combine to construct a hetero-multimer of the potassium channel. In conclusion, the G215D mutant of KCNJ2 is distributed normally in the plasma membrane, but exhibits a dominant-negative effect and reduces the Kir2.1 current, presumably due to hetero-multimer construction.

Thyroid hormone regulates mRNA expression and currents of ion channels in rat atrium.

Atrial fibrillation is one of the common arrhythmias associated with hyperthyroidism. This study examined the effects of thyroid hormone (T3) on mRNA expression and currents of major ionic channels determining the action potential duration (APD) in the rat atrium using the RNase protection assay and the whole-cell patch-clamp technique, respectively. T3 increased the Kv1.5 mRNA expression and decreased the L-type calcium channel mRNA expression, while the Kv4.2 mRNA expression did not change. APD was shorter in hyperthyroid than in euthyroid myocytes. The ultrarapid delayed rectifier potassium currents were remarkably increased in hyperthyroid than in euthyroid myocytes, whereas the transient outward potassium currents were unchanged. L-type calcium currents were decreased in hyperthyroid than in euthyroid myocytes. T3 shifted the current-voltage relationship for calcium currents negatively. In conclusion, T3 increased the outward currents and decreased the inward currents. The resultant changes of ionic currents shortened APD, providing a substrate for atrial fibrillation.

Relationship between dominant prolongation of the filtered QRS duration in the right precordial leads and clinical characteristics in Brugada syndrome.

Background: Electrical abnormalities in the RVOT may be involved in Brugada syndrome.

Suppression of Electrical Storm by Biventricular Pacing in a Patient with Idiopathic Dilated Cardiomyopathy and Ventricular Tachycardia

TANABE, Y., et al. : Suppression of Electrical Storm by Biventricular Pacing in a Patient with Idiopathic Dilated Cardiomyopathy and Ventricular Tachycardia. This study presents a patient with idiopathic dilated cardiomyopathy who had suffered from multiple ICD shocks. Amiodarone and a β‐blocker failed to suppress ventricular tachycardia. His ECG showed a very wide QRS complex with an intraventricular conduction delay, so biventricular (BV) pacing was attempted. The BV pacing successfully prevented the multiple ICD shocks accompanied with an improvement in left ventricular systolic function and physical activity.(PACE 2003; 26[Pt. I]:101–102)

Variable Electrocardiographic Effects of Short‐Term Quinidine Sulfate Administration in Brugada Syndrome

Quinidine, a class I antiarrhythmic agent with blocking property of transient outward current, is a possible candidate for the suppression of ventricular fibrillation in patients with Brugada syndrome; although there is a concern that its ability to these effects may be proarrhythmic. Therefore, we evaluated the effect of quinidine sulfate on ST‐segment elevation in Brugada syndrome. In 8 patients with Brugada syndrome, the magnitude of ST‐elevation at the J‐point (STJ), and the ST‐segment configuration in leads V1–V3, were compared before and on day 2 after the initiation of quinidine administration. In 3 patients, quinidine attenuated STJ by ≥0.1 mV. Of these 3 patients, ST‐segment elevation was normalized in 2 patients, while the ST‐segment configuration was unchanged in another. In another 3 patients, quinidine augmented STJ by ≥0.1 mV without any change of ST‐segment configuration, and the augmentation was returned to baseline after the discontinuation of quinidine. Quinidine exhibited no effect on the ST‐segment in the remaining 2 patients. The favorable effects of quinidine on the ST‐segment tended to be more pronounced in patients with prominent ST‐elevation at baseline. In 1 patient, quinidine was effective in eliminating both ST‐segment elevation and repetitive tachyarrhythmia episodes. In conclusion, the effects of quinidine on ST‐segment elevation were variable. Quinidine may potentially augment the ST‐segment elevation in some patients with Brugada syndrome.

Inducibility of atrial fibrillation depends not on inflammation but on atrial structural remodeling in rat experimental autoimmune myocarditis

INTRODUCTION There is increasing evidence to support a link between inflammation and atrial fibrillation (AF). However, the role of inflammation on new-onset AF is still to be elucidated. METHODS Rats underwent induction of experimental autoimmune myocarditis (EAM). Atrial structural change was evaluated by echocardiography and histological analysis. Electrophysiological data and the in vivo atrial response to burst atrial pacing were evaluated in the acute (2 weeks after EAM induction) and chronic phases (8 weeks after induction). In addition, atrial pacing after 2, 4, and 6 h after lipopolysaccharide (LPS) infusion, when the expression of gap junctions was modified, were challenged with young healthy rats. RESULTS AF was induced in 11 of 15 chronic phase EAM rats but not in either acute phase EAM rats or LPS infusion rats (P<.01). Echocardiography showed dilatation of both atrium and ventricle and a decrease in the ejection fraction in the chronic phase. Histology revealed severe inflammatory lesions only in the acute phase. Interstitial atrial fibrosis as well as the area of atrial myocyte increased in the chronic phase but not in the acute phase. CONCLUSIONS AF could be induced in the chronic phase of myocarditis rats, but not in the acute phase of myocarditis rats or in rats with LPS infusion. Acute inflammation per se did not increase the occurrence of AF induction. Atrial structural remodeling caused by inflammation and hemodynamic effects is necessary to induce AF.

Life-Threatening Serotonin Syndrome in a Patient With Chronic Heart Failure and CYP2D6*1/*5

We report a case of serotonin syndrome that occurred in a patient with chronic heart failure associated with a panic disorder. The 39-year-old Japanese man had been treated with paroxetine at 20 mg/d for 1 1/2 years. He presented with rhabdomyolysis, renal failure, fulminant liver failure, cardiac conduction disturbance, and disseminated intravascular coagulation, as well as conventional symptoms of serotonin syndrome including alterations in cognition (disorientation, confusion) and behavior (restlessness), autonomic nervous system dysfunction (fever, shivering), and abnormal neuromuscular activity (ataxia, hyperreflexia, myoclonus). All medications prescribed before hospital admission were discontinued. After 24 hours of continuous venovenous hemofiltration, diuresis resumed and renal and liver function improved rapidly. Disorientation, restlessness, hyperreflexia, and myoclonus abated slowly over the next 72 hours. The patients anxiety subsided more slowly, and he recovered completely 1 week later. The plasma concentration of paroxetine was elevated far above the upper limit of the therapeutic range. The patient had cytochrome P-450 (CYP) 2D6*1/*5, a heterozygosity of an inactivated allele of CYP2D6, which metabolizes paroxetine. The patient was determined to be an intermediate metabolizer who was potentially vulnerable to paroxetine, a major inhibitor of CYP2D6. Heart failure is often accompanied by psychiatric disorders. A wide range of drugs commonly prescribed for these conditions, including beta-blockers, antiarrhythmics, and antidepressants, are metabolized by CYP2D6. Genetic screening for CYP2D6 in patients with these conditions may prevent life-threatening drug intoxication.

Effect of Dl-Sotalol on Mortality and Recurrence of Ventricular Tachyarrhythmias:Ischemic Compared to Nonischemic Cardiomyopathy

Objective: We compared the effectiveness of sotalol on mortality and the recurrence of ventricular tachyarrhythmia (VTA) between idiopathic dilated cardiomyopathy (IDCM) and coronary artery disease (CAD).

Genomic and Non-Genomic Regulation of L-Type Calcium Channels in Rat Ventricle by Thyroid Hormone

Hyperthyroidism is associated with low exercise tolerance despite high cardiac output and sometimes with the development of heart failure. L-type calcium channels may play a role in the mechanism, but this has not been fully understood. We examined the effects of thyroid hormone on gene expression and function of L-type calcium channels in rat ventricles by the ribonuclease protection assay and whole-cell patch-clamp technique, respectively. The effects of bisoprolol, beta-blocking agent, on the regulation of calcium channel by thyroid hormone was also studied. In hyperthyroid animals, the mRNA of the calcium channel alpha1c subunit was reduced on day 4, compared with that in euthyroid animals, and remained low on day 8. Bisoprolol did not affect the thyroid hormone mediated decrease in alpha1c subunit mRNA. While L-type calcium current was greater in hyperthyroid than euthyroid myocytes on day 4, it was smaller on day 8. In addition, the isoproterenol-induced increase in calcium current in euthyroid rats was attenuated in hyperthyroid rats. Acetylcholine decreased calcium current in hyperthyroid myocytes, but not in euthyroid myocytes. In conclusion, L-type calcium current was increased by thyroid hormone in rat ventricular myocytes by the activation of the adenylate cyclase cascade, despite a decreased calcium channel gene expression. These genomic and non-genomic modifications may play an important role in the association of high cardiac output with low exercise tolerance, and in the development of heart failure in hyperthyroidism.

A post-QRS potential in Brugada syndrome: its relation to electrocardiographic pattern and possible genesis.

To the Editor: Brugada syndrome (BS) has been established as a clinical entity of idiopathic ventricular fibrillation (VF) and is characterized by the peculiar electrocardiographic (ECG) pattern in V1 and/or V2 ([1][1]). The characteristic ECG patterns, coved- or saddleback-type ST-segment elevation