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Biomedical subjects

Minoru Horie

Publications and source records attributed to Minoru Horie.

At least 37 records · Page 2Linked to original sources
PubMed2006

Arrhythmogenesis in the short-QT syndrome associated with combined HERG channel gating defects: a simulation study.

BACKGROUND: This study aimed to show the mechanism how the HERG channel gating defects causes life-threatening arrhythmia in the short-QT syndrome, using a simulation model of ventricular action potentials (APs). METHODS AND RESULTS: To evaluate the electrophysiological consequences of the short-QT syndrome at the level of the cardiac AP, the Markov model of wild-type (WT) KCNH2 channel was modified to obtain a model of the KCNH2 channel with the N588K mutation associated with the short-QT syndrome. Two parameters (betai and betabeta) were changed to reconstruct the N588K mutant Markov model, which successfully reproduced the experimental results of voltage-clamp recordings. The WT and mutant models were then integrated into the Luo-Rudy theoretical model of the cardiac ventricular AP. Unexpectedly, 1 parameter change alone, which caused gain of function, could shorten the AP duration (APD) but failed to induce early after-depolarizations (EADs). Only the condition with the combined gating defects could lead to EAD. CONCLUSIONS: Although the gain of function for KCNH2 shortened APD in the short-QT syndrome, this simulation study suggested that arrhythmogenesis was associated not only with gain of function, but also with accelerated deactivation of KCNH2.

Action Potentials↗
PubMed2006

Gender and age effects on ventricular repolarization abnormality in Japanese general carriers of a G643S common single nucleotide polymorphism for the KCNQ1 gene.

BACKGROUND: The KCNQ1 single nucleotide polymorphism (SNP), G643S, is known to be associated with secondary long QT syndrome (LQTS) and to cause a mild reduction in KCNQ1 current. However, the precise incidence and its association with QT intervals remain unknown in the greater cohort of the population in Japan. METHODS AND RESULTS: The genotype was screened at codon 643 of KCNQ1 in 992 residents of a farming community. Eighty-eight individuals (female/male =52/36, 8.9%) were found to have a heterozygous G643S SNP. Matching both gender and age, we randomly selected 243 control (G643G) cases and compared the electrocardiogram parameters in both groups; QT, QTf (QT corrected by Fridericia's formula) intervals, the peak and the end of the T wave (Tpe) interval, and the Tpe/QT ratio. The latter 2 reflect the transmural dispersion of ventricular repolarization (TDR). In G643S carriers, both Tpe and Tpe/QT were significantly longer than in non-carriers, without significant QT prolongation. Both genders showed a tendency for an increase in QTf with aging. In females, both Tpe and Tpe/QT showed a similar significant increase with age, which was not observed in males. CONCLUSIONS: In elderly females, G643S might be an independent risk factor for secondary LQTS by causing a greater TDR.

Adult↗
PubMed2006

Prediction of mortality by high-sensitivity C-reactive protein and brain natriuretic peptide in patients with dilated cardiomyopathy.

BACKGROUND: The prognostic role of serum C-reactive protein (CRP) in chronic heart failure (CHF) patients, especially those with nonischemic dilated cardiomyopathy (DCM), remains unknown. In the present study, whether CRP provides prognostic information in DCM patients was evaluated. METHODS AND RESULTS: Neurohumoral factors and hemodynamics in 84 consecutive DCM patients were measured and these patients were followed up for a mean period of 42 months. During the follow-up period, 23 patients developed cardiac events and 18 patients died of cardiac causes. Using stepwise multivariate Cox proportional hazards regression analyses, log brain natriuretic peptide (BNP) (p = 0.007) and high-sensitivity CRP (hsCRP) > 1 mg/L (p = 0.008) were significant independent predictors of cardiac events. The patients were stratified into 4 groups based on the normal serum concentration of hsCRP (1 mg/L) and median plasma concentration of BNP (110 pg/ml). Survival rates were significantly higher in patients with hsCRP < 1 mg/L and BNP < 110 pg/ml. The hazard ratio of patients with BNP > 110 pg/ml and hsCRP > 1 mg/L was 15.8 (95% confidence interval, 1.9-127.2) compared with those with BNP < 110 pg/ml and hsCRP < 1 mg/L for cardiac death. CONCLUSIONS: Serum hsCRP level is an independent prognostic predictor in patients with DCM and the combination of hsCRP and BNP may be useful for the management of CHF patients with DCM.

C-Reactive Protein↗
PubMed2006

Novel mutation of plakophilin-2 associated with arrhythmogenic right ventricular cardiomyopathy.

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a disease characterized by dilatation and akinesis of the right ventricle, and causes life-threatening ventricular arrhythmia. Mutations of plakophilin-2 (PKP2) have recently been identified as one causative abnormality in ARVC. A case of ARVC with a mutation of PKP2 is reported here. Direct sequencing of the patient's DNA revealed an insertion mutation in exon 8 of PKP2 (1728_1729insGATG). The mutation caused the frameshift and the premature termination of translation (R577DfsX5). This is the first case report of PKP2 mutation found in Japanese ARVC patients.

Adult↗
PubMed2006

Impact of paraoxonase polymorphism (Q192R) on endothelial function in intact coronary circulation.

Paraoxonase-1 (PON1) can protect endothelial function by preventing the oxidation of low-density lipoprotein (LDL) cholesterol and retarding the development of atherosclerosis. We examined whether PON1 polymorphism influences endothelium-dependent coronary vasomotor responses. Sixty-seven patients underwent diagnostic cardiac catheterization, but showed no significant coronary artery stenosis. In all patients, PON1 genotypes (Q/Q, Q/R and R/R) were determined, and provocative testing was performed by the intracoronary administration of graded doses of bradykinin (BK; 0.2, 0.6 and 2.0 mug/min) and acetylcholine (ACh; 3, 10 and 30 mug/min). Coronary blood flow (CBF) was evaluated by a Doppler guide wire. The patients were divided into 2 groups on the basis of ACh testing: one with coronary spastic angina (CSA) and one with non-CSA. The frequencies of the PON1 genotype in the CSA group did not differ significantly from those in the non-CSA group. In the non-CSA group, the patients were subdivided into 2 groups: a group with the Q/Q or Q/R genotypes and a group with the R/R genotype. The vasoconstrictive responses of the epicardial coronary artery to ACh were comparable between the Q/Q + Q/R and R/R groups. Also, the coronary vasodilations induced by BK in the R/R group were similar to those in the QR + QQ group. There were no significant differences in the CBF responses induced by BK or ACh between the Q/Q + Q/R and R/R groups. In conclusion, as estimated by BK and ACh testing, our findings suggest that PON1 genotypes may not play a critical role in the modulation of endothelial vasomotor function in the intact coronary circulation.

Acetylcholine↗
PubMed2005

High risk for bradyarrhythmic complications in patients with Brugada syndrome caused by SCN5A gene mutations.

OBJECTIVES: We carried out a complete screening of the SCN5A gene in 38 Japanese patients with Brugada syndrome to investigate the genotype-phenotype relationship. BACKGROUND: The gene SCN5A encodes the pore-forming alpha-subunit of voltage-gated cardiac sodium (Na) channel, which plays an important role in heart excitation/contraction. Mutations of SCN5A have been identified in 15% of patients with Brugada syndrome. METHODS: In 38 unrelated patients with clinically diagnosed Brugada syndrome, we screened for SCN5A gene mutations using denaturing high-performance liquid chromatography and direct sequencing, and conducted a functional assay for identified mutations using whole-cell patch-clamp in heterologous expression system. RESULTS: Four heterozygous mutations were identified (T187I, D356N, K1578fs/52, and R1623X) in 4 of the 38 patients. All of them had bradyarrhythmic complications: three with sick sinus syndrome (SSS) and the other (D356N) with paroxysmal complete atrioventricular block. SCN5A-linked Brugada patients were associated with a higher incidence of bradyarrhythmia (4 of 4) than non-SCN5A-linked Brugada patients (2 of 34). Families with T187I and K1578fs/52 had widespread penetrance of SSS. Notably, the patient with K1578fs/52, who had been diagnosed as having familial SSS without any clinical signs of Brugada syndrome, showed a Brugada-type ST-segment elevation after intravenous administration of pilsicainide and programmed electrical stimulation-induced ventricular tachycardia. All of the mutations encoded non-functional Na channels, and thus were suggested to cause impulse propagation defect underlying bradyarrhythmias. CONCLUSIONS: Our findings suggest that loss-of-function SCN5A mutations resulting in Brugada syndrome are distinguished by profound bradyarrhythmias.

Adult↗
PubMed2005

Electrocardiographic features in Andersen-Tawil syndrome patients with KCNJ2 mutations: characteristic T-U-wave patterns predict the KCNJ2 genotype.

BACKGROUND: The ECG features of Andersen-Tawil syndrome (ATS) patients with KCNJ2 mutations (ATS1) have not been systematically assessed. This study aimed to define ECG features of KCNJ2 mutation carriers, to determine whether characteristic T-U-wave patterns exist, and to establish whether T-U patterns predict the ATS1 genotype. METHODS AND RESULTS: In phase I, evaluation of T-U morphology in ECGs of 39 KCNJ2 mutation carriers identified characteristic T-U patterns: prolonged terminal T downslope, wide T-U junction, and biphasic and enlarged U waves. In phase II, ATS1 genotype prediction by T-U pattern was evaluated in the next 147 ECGs (57 other KCNJ2 mutation carriers, 61 unaffected family members, and 29 ATS patients without KCNJ2 mutations), with a sensitivity of 84% and specificity of 97%. Characteristic T-U patterns were present in 91% (87/96), in whom an enlarged U wave was predominant (73%). In phase III, QTc, QUc, and T- and U-wave duration/amplitude were compared in the 96 ATS1, 29 non-KCNJ2 ATS, and 75 normal subjects. In ATS1 patients, QUc, U-wave duration and amplitude, and QTc were all increased (P<0.001), but median QTc and interquartile range (IQR) were just 440 ms (IQR, 28 ms) compared with 420 ms (IQR, 20 ms) in normal subjects and 425 ms (IQR, 48 ms) in ATS non-KCNJ2 patients. CONCLUSIONS: In ATS1 patients, gene-specific T-U-wave patterns resulting from decreased IK1 owing to KCNJ2 mutations can aid diagnosis and direct genotyping. The normal QTc, distinct ECG, and other clinical features distinguish ATS1 from long-QT syndrome, and it is best designated as ATS1 rather than LQT7.

Adult↗
PubMed2005

Cellular and ionic mechanism for drug-induced long QT syndrome and effectiveness of verapamil.

OBJECTIVES: We examined the cellular and ionic mechanism for QT prolongation and subsequent Torsade de Pointes (TdP) and the effect of verapamil under conditions mimicking KCNQ1 (I(Ks) gene) defect linked to acquired long QT syndrome (LQTS). BACKGROUND: Agents with an I(Kr)-blocking effect often induce marked QT prolongation in patients with acquired LQTS. Previous reports demonstrated a relationship between subclinical mutations in cardiac K+ channel genes and a risk of drug-induced TdP. METHODS: Transmembrane action potentials from epicardial (EPI), midmyocardial (M), and endocardial (ENDO) cells were simultaneously recorded, together with a transmural electrocardiogram, at a basic cycle length of 2,000 ms in arterially perfused feline left ventricular preparations. RESULTS: The I(Kr) block (E-4031: 1 micromol/l) under control conditions (n = 5) prolonged the QT interval but neither increased transmural dispersion of repolarization (TDR) nor induced arrhythmias. However, the I(Kr) blocker under conditions with I(Ks) suppression by chromanol 293B 10 micromol/l mimicking the KCNQ1 defect (n = 10) preferentially prolonged action potential duration (APD) in EPI rather than M or ENDO, thereby dramatically increasing the QT interval and TDR. Spontaneous or epinephrine-induced early afterdepolarizations (EADs) were observed in EPI, and subsequent TdP occurred only under both I(Ks) and I(Kr) suppression. Verapamil (0.1 to 5.0 micromol/l) dose-dependently abbreviated APD in EPI more than in M and ENDO, thereby significantly decreasing the QT interval, TDR, and suppressing EADs and TdP. CONCLUSIONS: Subclinical I(Ks) dysfunction could be a risk of drug-induced TdP. Verapamil is effective in decreasing the QT interval and TDR and in suppressing EADs, thus preventing TdP in the model of acquired LQTS.

Action Potentials↗
PubMed2005

Dilated cardiomyopathy relieved as a result of beta-blocker therapy: a case report--key points in assessment of prognosis based on MIBG myocardial scintigraphy and BNP levels.

A 48-year-old male patient was admitted to our hospital with dyspnea accompanied by orthopnea. Chest x-rays showed a cardiothoracic ratio of 68% and pulmonary congestion. He was diagnosed with dilated cardiomyopathy. Beta-Blocker (carvedilol) therapy was initiated on Day 22 of the disease using a small initial dose. He was followed up based on BNP levels and MIBG scintigraphy. The H/M ratio and MIBG washout rate were 1.98 and 33.4%, respectively, on Day 20 and 2.15 and 28.1%, respectively, on Day 72. The patient was discharged on Day 72 when congestive heart failure improved. Relatively high BNP levels were observed for 1 month after starting treatment with a beta-blocker. Plasma BNP levels were still as high when his heart failure was improved. BNP is useful as a convenient indicator for the severity of cardiac diseases. MIBG scintigraphy may be used thereafter to evaluate the severity in greater detail and more precisely determine the prognosis.

3-Iodobenzylguanidine↗
PubMed2005

Left ventricular systolic/diastolic function evaluated by quantitative ECG-gated SPECT: comparison with echocardiography and plasma BNP analysis.

OBJECTIVE: The aim of this study was to evaluate the left ventricular (LV) functional parameters calculated using quantitative electrocardiography (ECG)-gated myocardial perfusion single photon emission computed tomography (QGS). In addition to LV systolic parameters, diastolic parameters were compared with those by ultrasound echocardiography (UCG) and also with plasma B-type natriuretic peptide (BNP) concentrations. METHODS: We examined 46 patients with various forms of heart disease. By the QGS data with 16 framing data acquisition using technetium (Tc)-99m methoxyisobutylisonitrile (MIBI) perfusion, we calculated the following parameters: LV end-diastolic volume (EDV), end-systolic volume (ESV), ejection fraction (EF), peak filling rate (PFR), filling rate during the first third of the filling time (1/3FR) and first third filling fraction (1/3FF). By UCG, we measured mitral early to atrial (E/A) wave velocity ratio and pulmonary venous inflow systolic/diastolic (S/D) ratio as diastolic functional parameters. Plasma BNP concentrations were also measured. RESULTS: There was a significant correlation between LVEDV, ESV and EF measured by QGS and UCG (EDV, r = 0.71, p < 0.001; ESV, r = 0.82, p < 0.001; EF, r = 0.75, p < 0.001). The PFR, 1/3FR and 1/3FF obtained by QGS correlated positively with E/A ratio (PFR, r = 0.54, p < 0.001; 1/3FR, r = 0.61, p < 0.001; 1/3FF, r = 0.42, p < 0.01) and negatively with S/D ratio (PFR, r = -0.40, p < 0.01; 1/3FR, r = -0.38, p < 0.05; 1/3FF, r = -0.39, p < 0.01) obtained by UCG. Plasma BNP concentrations in EF < 50% patients were greater than those in EF > or = 50% patients (335.2 +/- 60.2 vs. 101.2 +/- 41.3 pg/ml, p < 0.01, both n = 17). Plasma BNP levels were also compared between higher and lower 1/3FF patients matched for LVEF. Plasma BNP concentrations in 1/3FF < 35% patients were significantly greater than those in 1/3FF > or = 35% patients (312.9 +/- 62.5 vs. 120.5 +/- 32.8 pg/ml, p < 0.05, both n = 14). CONCLUSIONS: The degree of LV systolic and diastolic dysfunctions evaluated by QGS correlated with that by UCG or BNP. The QGS functional parameters offer useful information regarding cardiac failure.

Adolescent↗
PubMed2005

Anomaly of the left atrium in patients with atrial fibrillation detected by ECG-gated multi-slice computed tomography.

We illustrate pulmonary vein anatomy in 2 patients undergoing multi-slice computed tomography (MSCT) scanning prior to atrial fibrillation ablation, including anomaly of the pulmonary vein. The anomalous variations need to be investigated before catheter procedure, because of the anomalous variations. Non-invasive imaging using MSCT could have important clinical implications and provide the physicians useful information on morphological feature in patients with atrial fibrillation before catheter ablation.

Atrial Fibrillation↗
PubMed2005

Double SCN5A mutation underlying asymptomatic Brugada syndrome.

OBJECTIVES: The purpose of this study was to identify risk markers in patients with Brugada syndrome. BACKGROUND: Patients with Brugada syndrome who experience syncope or aborted sudden death are at high risk for recurrent lethal arrhythmias. The prognosis and therapeutic approaches in asymptomatic individuals with a Brugada-type ECG (asymptomatic Brugada syndrome) are controversial. METHODS: We genetically screened 30 asymptomatic probands (29 men and 1 woman; mean age 47.1 years) exhibiting a spontaneous Brugada-type ECG. Family members of patients with Brugada syndrome were excluded from the study. RESULTS: Twenty-nine of 30 patients (96.7%) remained symptom-free for at least 3 years. One patient (case 1) with a family history of sudden death died suddenly during sleep. Ventricular fibrillation was induced by programmed electrical stimulation in 14 of 18 subjects (78%), but none of these 18 subjects developed spontaneous ventricular arrhythmias. Genetic screening failed to identify SCN5A mutations in most cases but demonstrated a novel double missense mutation (K1527R and A1569P) located on the same allele in another asymptomatic subject (case 2). Heterologously expressed mutant Na channels exhibited a negative shift of steady-state inactivation (9.2 mV) and enhanced slow inactivation, suggesting this individual harbors a subclinical channel dysfunction compatible with symptomatic Brugada syndrome. CONCLUSIONS: Asymptomatic individuals with a Brugada-type ECG generally have a better prognosis than their symptomatic counterparts, but a subgroup of these individuals may have a poor prognosis. Severe Na channel dysfunction as a result of SCN5A mutations may not be sufficient to cause symptoms or arrhythmias in patients with Brugada syndrome, suggesting unknown factors or modifier genes influence arrhythmogenesis.

Arrhythmias, Cardiac↗
PubMed2005

In situ Ca2+ dynamics of Purkinje fibers and its interconnection with subjacent ventricular myocytes.

Purkinje fibers play essential roles in impulse propagation to the ventricles, and their functional impairment can become arrhythmogenic. However, little is known about precise spatiotemporal pattern(s) of interconnection between Purkinje-fiber network and the underlying ventricular myocardium within the heart. To address this issue, we simultaneously visualized intracellular Ca(2+) dynamics at Purkinje fibers and subjacent ventricular myocytes in Langendorff-perfused rat hearts using multi-pinhole type, rapid-scanning confocal microscopy. Under recording of electrocardiogram at room temperature spatiotemporal changes in fluo3-fluorescence intensity were visualized on the subendocardial region of the right-ventricular septum. Staining of the heart with either fluo3, acetylthiocholine iodide (ATCHI), or di-4-ANEPPS revealed characteristic structures of Purkinje fibers. During sinus rhythm (about 60 bpm) or atrial pacing (up to 3 Hz) each Purkinje-fiber exhibited spatiotemporally synchronous Ca(2+) transients nearly simultaneously to ventricular excitation. Ca(2+) transients in individual fibers were still synchronized within the Purkinje-fiber network not only under high-K(+) (8 mM) perfusion-induced Purkinje-to-ventricular (P-V) conduction delay, but also under unidirectional, orthodromic P-V block produced by 10-mM K(+) perfusion. While spontaneous, asynchronous intracellular Ca(2+) waves were identified in injured fibers of Purkinje network locally, surrounding fibers still exhibited Ca(2+) transients synchronously to ventricular excitation. In summary, these results are the first demonstration of intracellular Ca(2+) dynamics in the Purkinje-fiber network in situ. The synchronous Ca(2+) transients, preserved even under P-V conduction disturbances or under emergence of Ca(2+) waves, imply a syncytial role of Purkinje fibers as a specialized conduction system, whereas unidirectional block at P-V junctions indicates a substrate for reentrant arrhythmias.

Animals↗
PubMed2005

Regulation of the muscarinic K+ channel by extracellular ATP through membrane phosphatidylinositol 4,5-bisphosphate in guinea-pig atrial myocytes.

1 The present study was designed to examine the functional role of membrane phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P(2)) in the regulation of the muscarinic K(+) channel (I(K,ACh)) by extracellular ATP and adenosine in guinea-pig atrial myocytes, using the whole-cell patch-clamp method. 2 Bath application of ATP in micromolar concentrations typically evoked a transient activation of I(K,ACh); a rapid activation phase was consistently followed by a progressive decline even to the baseline level despite the continued presence of ATP. This progressive decline of I(K,ACh) was significantly attenuated either by blockade of phospholipase C (PLC) with compound 48/80 (100 microM) or by addition of PtdIns(4,5)P(2) (50 microM) to the cell inside, suggesting that depletion of membrane PtdIns(4,5)P(2) via PLC activation is mainly, if not totally, responsible for the progressive decline of I(K,ACh) during the presence of ATP. 3 When atrial myocytes were exposed to wortmannin (50 microM) following ATP (50 microM) application to impair the resynthesis of PtdIns(4,5)P(2), the activation of I(K,ACh) evoked by subsequently applied ATP (50 microM) was greatly reduced. Activation of I(K,ACh) by adenosine (100 microM) was partially reduced by pretreatment of atrial myocytes with ATP (100 microM) and was largely abolished by a further addition of wortmannin (50 microM) in the presence of ATP (100 microM). These results support the view that the activation of I(K,ACh) by ATP and adenosine depends on membrane PtdIns(4,5)P(2) that is subject to reduction by extracellular ATP. 4 The present study thus provides functional evidence to suggest that extracellular ATP activates PLC and thereby depletes membrane PtdIns(4,5)P(2) that is critically involved in the activation process of I(K,ACh) by its agonists ATP and adenosine in guinea-pig atrial myocytes.

Adenosine↗
PubMed2005

Open-state unblock characterizes acute inhibition of I potassium current by amiodarone in guinea pig ventricular myocytes.

INTRODUCTION: The aim of the present study was to investigate the acute action of amiodarone on the slow component of delayed rectifier K+ current (IKs) under basal conditions and during beta-adrenoceptor stimulation in guinea pig ventricular myocytes. METHODS AND RESULTS: Using the whole-cell patch-clamp method, IKs was evoked by depolarizing voltage-clamp steps, during superfusion with the Na+-, K+-, and Ca2+-free solution supplemented with 0.4 microM nisoldipine and 5 microM E-4031. The acute effect of amiodarone was evaluated, within approximately 10 minutes after starting the bath application, by the amplitude of deactivating tail currents at -50 mV. Amiodarone concentration dependently blocked I(Ks) and exerted a more potent effect on IKs when activated by shorter pulse durations; the degree of block by 30 microM amiodarone on IKs activated by 200 ms, 500 ms, and 2000 ms depolarizing pulses to +30 mV was 55.9 +/- 5.8%, 38.6 +/- 6.0%, and 27.1 +/- 4.0% (n = 5 each), respectively. An envelope of tails test conducted at +10, +30, and +60 mV demonstrated that the degree of IKs block by amiodarone was gradually attenuated during membrane depolarization, which can be described by a monoexponential function, thus supporting the presence of open channel unblock. Amiodarone also blocked IKs maximally stimulated by 1 microM isoprenaline, to an extent similar to control, when IKs was activated by pulse durations of < or =2000 ms. CONCLUSION: We propose that amiodarone acutely blocks native IKs with characteristics associated with open channel unblock, and that the protein kinase A-mediated phosphorylation of channel proteins only minimally affects the amiodarone block.

AMP-Activated Protein Kinases↗