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Biomedical subjects

Shiro Kamakura

Publications and source records attributed to Shiro Kamakura.

At least 55 records · Page 3Linked to original sources
PubMed2004

Classification and mechanism of Torsade de Pointes initiation in patients with congenital long QT syndrome.

AIMS: To examine the initiating mode of Torsade de Pointes (TdP) in patients with congenital long QT syndrome (LQTS). METHODS AND RESULTS: We evaluated 111 episodes of TdP recorded on the electrocardiograms of 24 patients with congenital LQTS, and clarified the initiating mode, the three consecutive preceding RR intervals defined as C(2), C(1), and C(0), the timing of initiating premature ventricular contraction (PVC) and the cycle length (CL) of TdP. Three different initiating patterns were observed: (1) a "short-long-short" sequence (SLS) pattern (23 patients, 72 TdP, 65%) defined as one or more short-long cardiac cycles followed by an initiating short-coupled PVC (C(1)>C(2) and C(0)), (2) an "increased sinus rate" (ISR) pattern (8 patients, 28 TdP, 25%) defined as a gradual increase in sinus rate with or without T-wave alternans (C(2)>/=C(1)>/=C(0)), and (3) a "changed depolarization" (CD) pattern (5 patients, 11 TdP, 10%) defined as a sudden long-coupled PVC or fusion beat followed by short-coupled PVC. The C(0) was shorter in ISR than SLS and CD (mean C(0): 488 vs. 587 and 603 ms, respectively; P<0.05). Therefore, the initiating PVC appeared near the T-wave peak of the last beat before onset in ISR, while it occurred after the T-wave peak in SLS and CD. The CL of TdP was shorter in ISR than in SLS (256 vs. 295 ms, P<0.05). CONCLUSIONS: Our data show the existence of three predominant initiating modes of TdP in patients with congenital LQTS and suggests a differential mechanism of initiation of TdP for each mode.

Adolescent↗
PubMed2004

Diagnostic value of epinephrine test for genotyping LQT1, LQT2, and LQT3 forms of congenital long QT syndrome.

OBJECTIVES: The aim of this study was to test the hypothesis that epinephrine test may have diagnostic value for genotyping LQT1, LQT2, and LQT3 forms of congenital long QT syndrome (LQTS). BACKGROUND: A differential response of dynamic QT interval to epinephrine infusion between LQT1, LQT2, and LQT3 syndromes has been reported, indicating the potential diagnostic value of the epinephrine test for genotyping the three forms. METHODS: The responses of 12-lead ECG parameters to epinephrine were retrospectively examined in 15 LQT1, 10 LQT2, 8 LQT3, and 10 healthy volunteers to select the best ECG criteria for separating the four groups. The epinephrine test then was prospectively conducted in 42 probands clinically affected with LQTS, their 67 family members, and 10 new volunteers. The best criteria were applied in a blinded fashion to prospectively separate a different group of 31 LQT1, 23 LQT2, 6 LQT3, and 30 Control patients (10 genotype-negative LQT1, 10 genotype-negative LQT2 family members, and 10 volunteers). RESULTS: The sensitivity (penetrance) by ECG diagnostic criteria was lower in LQT1 (68%) than in LQT2 (83%) or LQT3 (83%) before epinephrine and was improved with steady-state epinephrine in LQT1 (87%) and LQT2 (91%) but not in LQT3 (83%), without the expense of specificity (100%). The sensitivity and specificity to differentiate LQT1 from LQT2 were 97% and 96%, those from LQT3 were 97% and 100%, and those from Control were 97% and 100%, respectively, when Delta mean corrected Q-Tend >/=35 ms at steady state was used. The sensitivity and specificity to differentiate LQT2 from LQT3 or Control were 100% and 100%, respectively, when Delta mean corrected Q-Tend >/=80 ms at peak was used. CONCLUSIONS: Epinephrine infusion is a powerful test to predict the genotype of LQT1, LQT2, and LQT3 syndromes as well as to improve the clinical diagnosis of genotype-positive patients, especially those with LQT1 syndrome.

Adolescent↗
PubMed2004

Excessive increase in QT interval and dispersion of repolarization predict recurrent ventricular tachyarrhythmia after amiodarone.

Although chronic amiodarone has been proven to be effective to suppress ventricular tachycardia (VT) and ventricular fibrillation (VF), how we predict the recurrence of VT/VF after chronic amiodarone remains unknown. This study evaluated the predictive value of the QT interval, spatial, and transmural dispersions of repolarization (SDR and TDR) for further arrhythmic events after chronic amiodarone. Eighty-seven leads body surface ECGs were recorded before (pre) and one month after (post) chronic oral amiodarone in 50 patients with sustained monomorphic VT associated with organic heart disease. The Q-Tend (QTe), the Q-Tpeak (QTp), and the interval between Tpeak and Tend (Tp-e) as an index of TDR were measured automatically from 87-lead ECG, corrected Bazett's method (QTce, QTcp, Tcp-e), and averaged among all 87 leads. As an index of SDR, the maximum (max) minus minimum (min) QTce (max-min QTce) and standard deviation of QTce (SD-QTce) was obtained among 87 leads. All patients were prospectively followed (15 +/- 10 months) after starting amiodarone, and 20 patients had arrhythmic events. The univariate analysis revealed that post max QTce, post SD-QTce, post max-min QTce, and post mean Tcp-e from 87-lead but not from 12-lead ECG were the significant predictors for further arrhythmic events. ROC analysis indicated the post max-min QTce > or = 106 ms as the best predictor of events (hazard ratio = 10.4, 95%, CI 2.7 to 40.5, P = 0.0008). Excessive QT prolongation associated with increased spatial and transmural dispersions of repolarization predict the recurrence of VT/VF after amiodarone treatment.

Amiodarone↗
PubMed2004

Functional characterization of four naturally occurring variants of human pregnane X receptor (PXR): one variant causes dramatic loss of both DNA binding activity and the transactivation of the CYP3A4 promoter/enhancer region.

Metabolism of administered drugs is determined by expression and activity of many drug-metabolizing enzymes, such as the cytochrome P450 (P450s) family members. Pregnane X receptor (PXR) is a master transcriptional regulator of many drug/xenobiotic-metabolizing enzymes, including P450s and drug transporters. In this study, we describe the functional analysis of four naturally occurring human PXR (hPXR) variants (R98C, R148Q, R381W, and I403V) that we have recently identified. By a reporter gene assay using the CYP3A4 promoter/enhancer reporter in COS-7 or HepG2 cells, it was found that the R98C variant failed to transactivate the CYP3A4 reporter. The R381W and I403V variants also showed varying degrees of reduction in transactivation, depending on the dose of PXR activators, rifampicin, clotrimazole, and paclitaxel. The transcriptional activities of the R148Q variant were not significantly different from that of the wild-type hPXR. The electrophoretic mobility shift assay revealed that only the R98C variant lacked DNA binding. Furthermore, the cellular localization of the hPXR proteins was analyzed. All four variants as well as the wild-type hPXR localized exclusively to the nucleus, regardless of the presence or absence of rifampicin. These data suggest that the R98C, R381W, and I403V hPXR variants, especially R98C, may influence the expression of drug-metabolizing enzymes and transporters, which are transactivated by PXR.

Amino Acid Sequence↗
PubMed2004

Fourteen novel single nucleotide polymorphisms in the SLC22A2 gene encoding human organic cation transporter (OCT2).

Thirty-three genetic variations including fourteen novel ones were found in the SLC22A2 gene from 116 Japanese individuals. The novel variations were as follows: 596C>T (MPJ6_OC2003), 602C>T (MPJ6_OC2004), IVS5+20A>G (MPJ6_OC2010), IVS5-84_-83insG (MPJ6_OC2013), IVS6+30T>C (MPJ6_OC2014), IVS6+146G>T (MPJ6_OC2016), IVS6+179G>T (MPJ6_OC2017), IVS6-16delT (MPJ6_OC2018), 1920G>A (MPJ6_OC2022), 2153G>A (MPJ6_OC2026), 2157C>T (MPJ6_OC2028), 2306T>C (MPJ6_OC2031), 2342+5T>C (the last nucleotide number of mRNA+the position in the 3'-flanking region; MPJ6_OC2032) and 2342+127T>C (MPJ6_OC2033). Six variations were located in the exons, four of which were in the 3'-untranslated region (3'-UTR) of exon 11; six were in the introns; and two were in the 3'-flanking region. The frequencies were 0.802 for IVS5-84_-83insG, 0.013 for 602C>T, 0.009 for 596C>T, and 0.004 for the other 11 variations. Among them, 596C>T and 602C>T resulted in amino acid substitutions (Thr199Ile and Thr201Met, respectively).

Amino Acid Substitution↗
PubMed2004

Seven novel single nucleotide polymorphisms in the human SLC22A1 gene encoding organic cation transporter 1 (OCT1).

Twenty genetic variations, including seven novel ones, were found in the human SLC22A1 gene, which encodes organic cation transporter 1, from 116 Japanese individuals. The novel variations were as follows: -94C>A in the 5'-untranslated region (A of the translation start codon is numbered +1 in the cDNA sequence; MPJ6_OC1001), 350C>T (MPJ6_OC1004), IVS1-35T>C (MPJ6_OC1006), 561G>A (MPJ6_OC1010), IVS6+75C>G (MPJ6_OC1014), IVS8+108A>G (MPJ6_OC1017), and 1671_1673delATG (MPJ6_OC1020). The frequencies were 0.082 for IVS1-35T>C, 0.022 for IVS6+75C>G, 0.009 for 561G>A, and 0.004 for the other 4 variations. Among them, 350C>T resulted in the amino acid substitution Pro117Leu, which is located in the large extracellular loop between transmembrane domains 1 and 2. Also, we detected the four previously reported nonsynonymous variations, 123C>G (Phe41Leu), 480C>G (Phe160Leu), 1022C>T (Pro341Leu), and 1222A>G (Met408Val) with frequencies of 0.004, 0.086, 0.168, and 0.810, respectively.

Genetic Variation↗
PubMed2004

Novel nonsynonymous single nucleotide polymorphisms in the CYP2D6 gene.

Cytochrome P450 (CYP) 2D6 is an important drug-metabolizing enzyme, and its gene is known to be highly polymorphic. Here, we report five novel nonsynonymous single nucleotide polymorphisms (SNPs), and 65 other sequence variations detected from the gene coding for cytochrome P450 (CYP) 2D6 in 254 Japanese subjects. Two of the novel nonsynonymous SNPs were associated with the *10 key SNP, C100T. Among the 65 variations, 23 were novel, including 12 SNPs in 5'-flanking, 1 in 5'-untranslated, and 10 in intronic regions. The nonsynonymous SNPs in the CYP2D6 gene were as follows: 73 C>T (Arg25Trp, exon 1), 972 C>T (Ala90Val, exon 2), 1611 T>A (Phe120Ile, exon 3), 1720 A>C (Glu156Ala, exon 3), 3172 A>C (Glu334Ala, exon 7). The SNPs, 73C>T, 972 C>T, 1611 T>A, 1720 A>C and 3172 A>C were linked with *10, *1, *10, *1 and *2, respectively.

Amino Acid Substitution↗
PubMed2004

Genetic variations of the AHR gene encoding aryl hydrocarbon receptor in a Japanese population.

Aryl hydrocarbon receptor (AhR), encoded by the AHR gene, is a transcriptional factor that induces various drug metabolizing enzymes in response to diverse endogenous and exogenous ligands. In order to identify genetic variations of the AHR gene, genomic DNA from 242 Japanese individuals was sequenced. We identified 32 single nucleotide variations, including 25 novel ones [7 were in the coding exons, 7 in the introns, 1 in the 5'-untranslated region (UTR), 5 in the 3'-UTR, 2 in the 5'-flanking region, and 3 in the 3'-flanking region] and a GGGGC repeat polymorphism (a novel microsatellite marker) in the promoter region. The novel nonsynonymous variations were 50A>C (Lys17Thr), 1202A>G (Lys401Arg), 1459A>G (Asn487Asp), and 1541T>C (Ile514Thr). The allele frequencies were 0.010 for 1459A>G (Asn487Asp) and 0.002 for the other 3 variations. Also detected in this analysis was the known nonsynonymous single nucleotide polymorphism 1661G>A (Arg554Lys) at a 0.444 frequency.

Asian People↗
PubMed2004

Single nucleotide polymorphisms and haplotype frequencies of UGT2B4 and UGT2B7 in a Japanese population.

Both UDP-glucuronosyltransferase 2B4 (UGT2B4) and UGT2B7 are expressed mainly in the human liver and have several overlapping substrates; e.g., catechol estrogens, bile acids, codeine, and carvedilol. To identify novel single nucleotide polymorphisms (SNPs) and haplotypes in a Japanese population, the enhancer/promoter regions, all the exons, and the surrounding intronic regions of UGT2B4 and UGT2B7 were sequenced from 136 Japanese individuals. We found 16 and 21 polymorphisms, including 10 and 4 novel ones in UGT2B4 and UGT2B7, respectively. The novel nonsynonymous SNPs were 1364A>G (K455R) and 1531T>C (C511R) in UGT2B4 and 1192G> A (D398N) in UGT2B7. From linkage disequilibrium analysis, several SNPs in UGT2B7 were found to be highly linked with each other. No close linkage between the SNPs in UGT2B4 and UGT2B7 was observed, indicating that each gene is located within an independent haplotype block. Thus, haplotype analysis was separately performed for the two genes. In UGT2B4, we unambiguously determined 8 haplotypes and inferred an additional 12 haplotypes using an expectation-maximization-based program. In UGT2B7, five haplotypes were unambiguously assigned and an additional eight haplotypes were inferred. The haplotype structure of UGT2B7 was more diverse than that of UGT2B4 in terms of the number of frequent SNPs. In addition, ethnic differences in the UGT2B4(*)2 and UGT2B7(*)2 haplotypes between the Japanese and the Caucasian and/or African populations were found. Our findings provide fundamental and useful information for genotyping UGT2B4 and UGT2B7 in the Japanese, and probably other populations.

Asian People↗
PubMed2003

Six novel nonsynonymous CYP1A2 gene polymorphisms: catalytic activities of the naturally occurring variant enzymes.

Six novel nonsynonymous nucleotide alterations were found in the cytochrome P450 1A2 gene in a Japanese population, which resulted in the following amino acid substitutions: T83M, E168Q, F186L, S212C, G299A, and T438I. These individuals were heterozygous for the amino acid substitutions. The potential functional alterations caused by the amino acid substitutions were characterized by a cDNA-mediated expression system using Chinese hamster V79 cells. Among the six CYP1A2 variants, F186L showed the most profound and statistically significant reduction in O-deethylation of phenacetin and 7-ethoxyresorufin. Kinetic analyses performed for the ethoxyresorufin O-deethylation revealed that the Vmax of the F186L variant was approximately 5% of that of the CYP1A2 wild type, despite a 5-fold lower Km value of the variant, the consequence of which was reduced enzymatic activity toward the substrate. Thus, for the first time, phenylalanine at residue 186 is suggested to be a critical amino acid for catalytic activity.

Amino Acid Sequence↗
PubMed2003

Epinephrine unmasks latent mutation carriers with LQT1 form of congenital long-QT syndrome.

OBJECTIVES: This study was designed to test the hypothesis that epinephrine infusion may be a provocative test able to unmask nonpenetrant KCNQ1 mutation carriers. BACKGROUND: The LQT1 form of congenital long QT syndrome is associated with high vulnerability to sympathetic stimulation and appears with incomplete penetrance. METHODS: The 12-lead electrocardiographic parameters before and after epinephrine infusion were compared among 19 mutation carriers with a baseline corrected QT interval (QTc) of > or =460 ms (Group I), 15 mutation carriers with a QTc of <460 ms (Group II), 12 nonmutation carriers (Group III), and 15 controls (Group IV). RESULTS: The mean corrected Q-Tend (QTce), Q-Tpeak (QTcp), and Tpeak-end (Tcp-e) intervals among 12-leads before epinephrine were significantly larger in Group I than in the other three groups. Epinephrine (0.1 microg/kg/min) increased significantly the mean QTce, QTcp, Tcp-e, and the dispersion of QTcp in Groups I and II, but not in Groups III and IV. The sensitivity and specificity of QTce measurements to identify mutation carriers were 59% (20/34) and 100% (27/27), respectively, before epinephrine, and the sensitivity was substantially improved to 91% (31/34) without the expense of specificity (100%, 27/27) after epinephrine. The mean QTce, QTcp, and Tcp-e before and after epinephrine were significantly larger in 15 symptomatic than in 19 asymptomatic mutation carriers in Groups I and II, and the prolongation of the mean QTce with epinephrine was significantly larger in symptomatic patients. CONCLUSIONS: Epinephrine challenge is a powerful test to establish electrocardiographic diagnosis in silent LQT1 mutation carriers, thus allowing implementation of prophylactic measures aimed at reducing sudden cardiac death.

Adolescent↗
PubMed2003

Exercise stress test amplifies genotype-phenotype correlation in the LQT1 and LQT2 forms of the long-QT syndrome.

BACKGROUND: Experimental studies suggest that the interval between peak and end of T wave (Tpe) in transmural ECGs reflects transmural dispersion of repolarization (TDR), which is amplified by beta-adrenergic stimulation in the LQT1 model. In 82 patients with genetically identified long-QT syndrome (LQTS) and 33 control subjects, we examined T-wave morphology and various parameters for repolarization in 12-lead ECGs including corrected QT (QTc; QT/R-R(1/2)) and corrected Tpe (Tpec; Tpe/R-R(1/2)) before and during exercise stress tests. METHODS AND RESULTS: Under baseline conditions, LQT1 (n=51) showed 3 cardinal T-wave patterns (broad-based, normal-appearing, late-onset) and LQT2 (n=31) 3 patterns (broad-based, bifid with a small or large notch). The QTc and Tpec were 510+/-68 ms and 143+/-53 ms in LQT1 and 520+/-61 ms and 195+/-69 ms in LQT2, respectively, which were both significantly larger than those in control subjects (402+/-36 ms and 99+/-36 ms). Both QTc and Tpec were significantly prolonged during exercise in LQT1 (599+/-54 ms and 215+/-46 ms) with morphological change into a broad-based T-wave pattern. In contrast, exercise produced a prominent notch on the descending limb of the T wave, with no significant changes in the QTc and Tpec (502+/-82 ms and 163+/-86 ms: n=19) in LQT2. CONCLUSIONS: Tpe interval increases during exercise in LQT1 but not in LQT2, which may partially account for the finding that fatal cardiac events in LQT1 are more often associated with exercise.

Adolescent↗
PubMed2003

Single nucleotide polymorphisms and haplotype frequencies of CYP3A5 in a Japanese population.

In order to identify single nucleotide polymorphisms (SNPs) and haplotype frequencies of CYP3A5 in a Japanese population, we sequenced the proximal promoter region, all exons, and the surrounding intronic regions using genomic DNA from 187 Japanese subjects. Thirteen SNPs, including seven novel ones: 13108T>C, 16025A>G, 16903A>G, 16993C>G, 27448C>A, 29782A>G, and 31551T>C (A of the translational start codon of GenBank Accession # NG_000004.2 is numbered 1 according to the CYP Allele Nomenclature), were identified. The most common SNP was 6986A>G (key SNP for CYP3A5*3), with a 0.759 frequency. Two novel SNPs, 29782A>G (I456V) and 31551T>C (I488T), as well as 12952T>C (*5 marker) were found, but these alterations were always associated with the *3A marker SNPs, 6986A>G and 31611C>T. Using these 13 SNPs, haplotype analysis was performed and five novel *1 haplotypes (subtypes) (*1e to *1i) and six novel *3 haplotypes (subtypes) (*3d to *3i) were identified. Our findings suggest that CYP3A5*3 is the major defective allele and that other functional exonic SNPs are rare in the Japanese.

Adult↗
PubMed2003

Directions of atrial excitation wavefront influenced antegrade conduction of manifest accessory atrioventricular pathway: a case report.

We report a case of left accessory atrioventricular pathway (AP) which antegrade conduction was manifest during pacing from the anterior site of the atrial insertion, but absent during pacing from the posterior site. Infusion of adenosine triphosphate during pacing from the posterior site induced a conduction block of atrioventricular node without affecting the persistent antegrade conduction block of the AP. These findings suggested that the different response of the AP according to the directional change of atrial conduction was not due to a "linking" phenomenon, but may relate to the impedance mismatch because of an oblique fashion of the pathway.

Cardiac Pacing, Artificial↗
PubMed2003

Ventricular tachycardia associated with bidirectional reentrant circuit around the tricuspid annulus in arrhythmogenic right ventricular dysplasia.

This case report describes two distinct morphological ventricular tachycardias (VTs) associated with bidirectional reentrant circuit around the tricuspid annulus in a 32-year-old patient with arrhythmogenic right ventricular dysplasia. Multiple radiofrequency linear ablation could abolish both VTs, and this patient has been clinically free from symptoms of VTs at 1-year follow-up.

Adult↗
PubMed2003

Haplotype analysis of ABCB1/MDR1 blocks in a Japanese population reveals genotype-dependent renal clearance of irinotecan.

We performed comprehensive haplotyping of ABCB1/MDR1 gene blocks using 49 genetic polymorphisms, including seven novel ones, obtained from 145 Japanese subjects. The ABCB1/MDR1 gene was divided into four blocks (Blocks -1, 1, 2, and 3) based on linkage disequilibrium analysis of polymorphisms. Using an expectation-maximization based program, 1, 2, 8, and 3 haplotype groups (3, 12, 32, and 18 haplotypes) were identified in Blocks -1, 1, 2, and 3, respectively. Within Block 2, haplotype groups *1, *2, *4, *6, and *8 reported by Kim and colleagues (Clin Pharmacol Ther 2001; 70:189-199) were found, and additional three groups (*9 to *11) were newly defined. We analyzed the association of haplotypes with the renal clearance of irinotecan and its metabolites in 49 Japanese cancer patients given irinotecan intravenously. There was a significant association of the *2 haplotype in Block 2, which includes 1236C>T, 2677G>T and 3435C>T, with a reduced renal clearance of those compounds. Moreover, tendencies of reduced and increased renal clearance were also observed with *1f in Block 2 and *1b in Block 3, respectively. These findings suggest that the P-glycoprotein encoded by ABCB1/MDR1 in the proximal tubules plays a substantial role in renal exclusion of drugs and, moreover, that block-haplotyping is valuable for pharmacogenetic studies.

ATP-Binding Cassette Transporters↗