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Mihoko Kawamura,
Seiko Ohno,
Nobu Naiki,
Iori Nagaoka,
Kenichi Dochi,
Qi Wang,
Kanae Hasegawa,
Hiromi Kimura,
Akashi Miyamoto,
Yuka Mizusawa, [......],
Naokata Sumitomo,
Hiroya Ushinohama,
Kotaro Oyama,
Nobuyuki Murakoshi,
Kazutaka Aonuma,
Hitoshi Horigome,
Takafumi Honda,
Masao Yoshinaga,
Makoto Ito,
Minoru Horie
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ABSTRACT: Background: The genetic background of catecholaminergic polymorphic ventricular tachycardia (CPVT) has been extensively investigated for the last decade in Western countries, but it remains unstudied in the Asian population. Methods and Results: In 50 Japanese probands from unrelated families who satisfied clinical criteria for CPVT, genetic testing was conducted in all exons on 3 CPVT-related genes: cardiac ryanodine receptor 2 (RYR2), calsequestrin 2 (CASQ2) and inward rectifier potassium channel 2 (KCNJ2), and the clinical features between RYR2-genotyped and -non-genotyped patient groups were compared. Genetic and clinical evaluation was also done in 46 family members. In the genetic screening, 28 (18 novel) RYR2 (56.0%), 1 compound heterozygous CASQ2 (2.0%) and 1 KCNJ2 (2.0%) mutation carriers were identified. In the RYR2 mutation-positive group, the frequency of bidirectional ventricular tachycardia and the use of β-blockers were significantly higher than in the mutation-negative group. In contrast, there was no significant difference in supraventricular arrhythmias between the 2 groups. With regard to disease penetrance, the number of family members of RYR2-genotyped probands with a clinical diagnosis of CPVT was high. Conclusions: Thirty gene mutation carriers were found for 3 genes in 50 probands clinically diagnosed as having CPVT. The penetrance of CPVT phenotype was significantly higher in RYR2 mutation carriers, thus RYR2 gene screening in CPVT patients would be indispensable to prevent unexpected cardiac sudden death of young family members.
Circulation Journal 04/2013; · 3.77 Impact Factor
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ABSTRACT: Background: Mutations in genes encoding the L-type cardiac calcium channel (LTCC) are associated with various types of inherited arrhythmias, including Brugada syndrome (BrS). However, the frequency in Asian populations remains unknown. This study aimed to elucidate disease-causing mutations in LTCC-related genes in Japanese patients diagnosed as BrS or idiopathic ventricular fibrillation (IVF), early repolarization syndrome, short QT syndrome, and compare them with those carrying SCN5A mutations. Methods and Results: We screened CACNA1C and CACNB2b in 312 probands and compared the clinical characteristics between probands with gene mutations in CACNA1C or SCN5A. In results, we identified 6 CACNA1C mutations in 7 unrelated probands and SCN5A mutations in 20 probands. There were no CACNB2b mutation carriers. In topology, half of the mutations were located in the C-terminus. Among 7 CACNA1C mutation carriers, 2 were female and 3 were symptomatic; 2 patients were resuscitated from ventricular fibrillation, and 1 patient had syncope. Compared with SCN5A mutation carriers, there were no significant differences in the ECG characteristics. 2 of 3 symptomatic CACNA1C patients were female, but all female SCN5A mutation carriers remained asymptomatic. Conclusions: We identified 6 CACNA1C mutations in BrS and IVF patients and their phenotypes were varied. Although mutation frequency was not high, screening of LTCC channel genes may be clinically important to prevent unexpected sudden death.
Circulation Journal 04/2013; · 3.77 Impact Factor
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ABSTRACT: Background: Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is a heart muscle disease caused by desmosomal gene mutations, and presents as ventricular tachycardia and sudden cardiac death. Although the mean age at onset or diagnosis of ARVC/D are reported to be around the 30-40s, the age-dependent clinical and genetic differences remain unknown. Methods and Results: A total of 35 consecutive Japanese probands (23 male) who were clinically diagnosed with ARVC/D were enrolled in the present study, and genetic analysis of PKP2, DSP, DSG2, and DSC2 was done. The mean age at the first symptom and at diagnosis was 38.6±14.8 years and 40.5±17.7 years, respectively. Probands in whom the onset was cardiopulmonary arrest were significantly younger (22.3±15.3 years) than those with arrhythmia (41.1±13.2 years) or congestive heart failure (45.7±8.5 years). On genetic screening, 19 mutation carriers were identified. Although there was no age dependence for each gene mutation carrier, carriers with PKP2 premature stop codon developed the disease at a significantly younger age than other mutation carriers. Conclusions: The initial clinical manifestations in some young probands were very severe, and PKP2 mutations with a premature stop codon would be associated with disease onset at a younger age.
Circulation Journal 03/2013; · 3.77 Impact Factor
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Tsukasa Kamakura, Takeru Makiyama,
Kenichi Sasaki,
Yoshinori Yoshida,
Yimin Wuriyanghai,
Jiarong Chen,
Tetsuhisa Hattori,
Seiko Ohno,
Toru Kita,
Minoru Horie,
Shinya Yamanaka,
Takeshi Kimura
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ABSTRACT: Background: In the short- to mid-term, cardiomyocytes generated from human-induced pluripotent stem cells (hiPSC-CMs) have been reported to be less mature than those of adult hearts. However, the maturation process in a long-term culture remains unknown. Methods and Results: A hiPSC clone generated from a healthy control was differentiated into CMs through embryoid body (EB) formation. The ultrastructural characteristics and gene expressions of spontaneously contracting EBs were analyzed through 1-year of culture after cardiac differentiation was initiated. The 14-day-old EBs contained a low number of myofibrils, which lacked alignment, and immature high-density Z-bands lacking A-, H-, I-, and M-bands. Through the long-term culture up to 180 days, the myofibrils became more tightly packed and formed parallel arrays accompanied by the appearance of mature Z-, A-, H-, and I-bands, but not M-bands. Notably, M-bands were finally detected in 360-day-old EBs. The expression levels of the M-band-specific genes in hiPSC-CMs remained lower in comparison with those in the adult heart. Immunocytochemistry indicated increasing number of MLC2v-positive/MLC2a-negative cells with decreasing number of MLC2v/MLC2a double-positive cells, indicating maturing of ventricular-type CMs. Conclusions: The structural maturation process of hiPSC-CMs through 1-year of culture revealed ultrastructural sarcomeric changes accompanied by delayed formation of M-bands. Our study provides new insight into the maturation process of hiPSC-CMs.
Circulation Journal 02/2013; · 3.77 Impact Factor
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Juan Villafañe,
Joseph Atallah,
Michael H Gollob,
Philippe Maury,
Christian Wolpert,
Roman Gebauer,
Hiroshi Watanabe,
Minoru Horie,
Olli Anttonen,
Prince Kannankeril,
Brett Faulknier,
Jorge Bleiz, Takeru Makiyama,
Wataru Shimizu,
Robert Hamilton,
Ming-Lon Young
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ABSTRACT: OBJECTIVES: The purpose of this study was to define the clinical characteristics and long-term follow-up of pediatric patients with short QT syndrome (SQTS). BACKGROUND: SQTS is associated with sudden cardiac death. The clinical characteristics and long-term prognosis in young patients have not been reported. METHODS: This was an international case series involving 15 centers. Patients were analyzed for electrocardiography characteristics, genotype, clinical events, Gollob score, and efficacy of medical or defibrillator (implantable cardioverter-defibrillator [ICD]) therapy. To assess the possible prognostic value of the Gollob score, we devised a modified Gollob score that excluded clinical events from the original score. RESULTS: Twenty-five patients 21 years of age or younger (84% males, median age: 15 years, interquartile range: 9 to 18 years) were followed up for 5.9 years (interquartile range: 4 to 7.1 years). Median corrected QT interval for heart rate was 312 ms (range: 194 to 355 ms). Symptoms occurred in 14 (56%) of 25 patients and included aborted sudden cardiac death in 6 patients (24%) and syncope in 4 patients (16%). Arrhythmias were common and included atrial fibrillation (n = 4), ventricular fibrillation (n = 6), supraventricular tachycardia (n = 1), and polymorphic ventricular tachycardia (n = 1). Sixteen patients (84%) had a familial or personal history of cardiac arrest. A gene mutation associated with SQTS was identified in 5 (24%) of 21 probands. Symptomatic patients had a higher median modified Gollob score (excluding points for clinical events) compared with asymptomatic patients (5 vs. 4, p = 0.044). Ten patients received medical treatment, mainly with quinidine. Eleven of 25 index cases underwent ICD implantation. Two patients had appropriate ICD shocks. Inappropriate ICD shocks were observed in 64% of patients. CONCLUSIONS: SQTS is associated with aborted sudden cardiac death among the pediatric population. Asymptomatic patients with a Gollob score of <5 remained event free, except for an isolated episode of supraventricular tachycardia, over an average 6-year follow-up. A higher modified Gollob score of 5 or more was associated with the likelihood of clinical events. Young SQTS patients have a high rate of inappropriate ICD shocks.
Journal of the American College of Cardiology 01/2013; · 14.16 Impact Factor
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Taisuke Ishikawa,
Naohiko Takahashi,
Seiko Ohno,
Harumizu Sakurada,
Kazufumi Nakamura,
Young Keun On,
Jeong Euy Park, Takeru Makiyama,
Minoru Horie,
Takuro Arimura,
Naomasa Makita,
Akinori Kimura
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ABSTRACT: Background: Brugada syndrome (BrS) is characterized by specific alterations on ECG in the right precordial leads and associated with ventricular arrhythmia that may manifest as syncope or sudden cardiac death. The major causes of BrS are mutations in SCN5A for a large subunit of the sodium channel, Nav1.5, but a mutation in SCN3B for a small subunit of sodium channel, Navβ3, has been recently reported in an American patient. Methods and Results: A total of 181 unrelated BrS patients, 178 Japanese and 3 Koreans, who had no mutations in SCN5A, were examined for mutations in SCN3B by direct sequencing of all exons and adjacent introns. A mutation, Val110Ile, was identified in 3 of 178 (1.7%) Japanese patients, but was not found in 480 Japanese controls. The SCN3B mutation impaired the cytoplasmic trafficking of Nav1.5, the cell surface expression of which was decreased in transfected cells. Whole-cell patch clamp recordings of the transfected cells revealed that the sodium currents were significantly reduced by the SCN3B mutation. Conclusions: The Val110Ile mutation of SCN3B is a relatively common cause of SCN5A-negative BrS in Japan, which has a reduced sodium current because of the loss of cell surface expression of Nav1.5.
Circulation Journal 12/2012; · 3.77 Impact Factor
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Yasuhiro Hamatani,
Naritatsu Saito,
Junichi Tazaki,
Masahiro Natsuaki,
Kentaro Nakai, Takeru Makiyama,
Yasuhiro Sasaki,
Masao Imai,
Shin Watanabe,
Tetsuo Shioi,
Takeshi Kimura,
Kanji Inoue
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ABSTRACT: Percutaneous transcatheter mitral valvuloplasty is the indicated treatment of choice for symptomatic native mitral valve stenosis, but there have been limited reports of successful procedures of balloon valvuloplasty for bioprosthetic mitral valve stenosis. We present the case of a 62-year-old woman suffering from progressive dyspnea due to bioprosthetic mitral valve stenosis. The measured mean pressure gradient across the mitral valve was 30 mmHg and the mitral valve area was 0.73 cm(2). Redoing mitral replacement was considered high risk and was refused by the patient. Percutaneous balloon valvuloplasty was performed with an Inoue balloon catheter inflated to 20 mm. The patient's symptoms immediately improved after the procedure, with no procedure-related complications. The mean pressure gradient across the valve decreased to 19 mmHg, and the mitral valve area increased to 1.21 cm(2) in postprocedural echocardiography. We conducted a literature search and identified 26 cases of balloon valvuloplasty for degenerated bioprosthetic valves. Of these, 14 cases were bioprosthetic mitral valves, and the results were favorable. However, more case reports are required to establish an evidence base for future expert recommendation of balloon valvuloplasty of prosthetic mitral valve. Meanwhile, balloon valvuloplasty will serve a niche role in highly selected patients with prosthetic mitral valve stenosis.
Heart and Vessels 11/2012; · 2.05 Impact Factor
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Hiroshi Watanabe,
Akihiko Nogami,
Kimie Ohkubo,
Hiro Kawata,
Yuka Hayashi,
Taisuke Ishikawa, Takeru Makiyama,
Satomi Nagao,
Nobue Yagihara,
Naofumi Takehara, [......],
Hirotaka Oda,
Masaaki Okabe,
Akinori Kimura,
Koji Maemura,
Ichiro Watanabe,
Shiro Kamakura,
Minoru Horie,
Yoshifusa Aizawa,
Wataru Shimizu,
Naomasa Makita
International journal of cardiology 06/2012; 159(3):238-40. · 7.08 Impact Factor
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Hiromi Kimura,
Jun Zhou,
Mihoko Kawamura,
Hideki Itoh,
Yuka Mizusawa,
Wei-Guang Ding,
Jie Wu,
Seiko Ohno, Takeru Makiyama,
Akashi Miyamoto,
Nobu Naiki,
Qi Wang,
Yu Xie,
Tsugutoshi Suzuki,
Shigeru Tateno,
Yoshihide Nakamura,
Wei-Jin Zang,
Makoto Ito,
Hiroshi Matsuura,
Minoru Horie
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ABSTRACT: Mutations of KCNJ2, the gene encoding the human inward rectifier potassium channel Kir2.1, cause Andersen-Tawil syndrome (ATS), a disease exhibiting ventricular arrhythmia, periodic paralysis, and dysmorphic features. However, some KCNJ2 mutation carriers lack the ATS triad and sometimes share the phenotype of catecholaminergic polymorphic ventricular tachycardia (CPVT). We investigated clinical and biophysical characteristics of KCNJ2 mutation carriers with "atypical ATS."
Mutational analyses of KCNJ2 were performed in 57 unrelated probands showing typical (≥2 ATS features) and atypical (only 1 of the ATS features or CPVT) ATS. We identified 24 mutation carriers. Mutation-positive rates were 75% (15/20) in typical ATS, 71% (5/7) in cardiac phenotype alone, 100% (2/2) in periodic paralysis, and 7% (2/28) in CPVT. We divided all carriers (n=45, including family members) into 2 groups: typical ATS (A) (n=21, 47%) and atypical phenotype (B) (n=24, 53%). Patients in (A) had a longer QUc interval [(A): 695 ± 52 versus (B): 643 ± 35 ms] and higher U-wave amplitude (0.24 ± 0.07 versus 0.18 ± 0.08 mV). C-terminal mutations were more frequent in (A) (85% versus 38%, P<0.05). There were no significant differences in incidences of ventricular tachyarrhythmias. Functional analyses of 4 mutations found in (B) revealed that R82Q, R82W, and G144D exerted strong dominant negative suppression (current reduction by 95%, 97%, and 96%, respectively, versus WT at -50 mV) and T305S moderate suppression (reduction by 89%).
KCNJ2 gene screening in atypical ATS phenotypes is of clinical importance because more than half of mutation carriers express atypical phenotypes, despite their arrhythmia severity.
Circulation Cardiovascular Genetics 05/2012; 5(3):344-53. · 6.11 Impact Factor
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Keiichiro Yamane,
Yoshihiro Kato,
Junichi Tazaki,
Tomohisa Tada, Takeru Makiyama,
Masao Imai,
Toshikazu Jinnai,
Tomoyuki Ikeda,
Ryutaro Shirakawa,
Takeshi Kimura,
Hisanori Horiuchi
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ABSTRACT: Dual antiplatelet therapy (DAPT) with aspirin and clopidogrel is essential after percutaneous coronary intervention (PCI). Clopidogrel is a prodrug and changed into active metabolite by cytochrome p450 enzymes (CYPs), especially CYP2C19. Proton pump inhibitors (PPIs) are used for the prevention of aspirin-induced gastrointestinal bleeding. PPIs are also metabolized by CYP2C19, although the degree of its contribution is dependent on the kind of PPI. Omeprazole, a PPI, has been reported to weaken the antiplatelet effects of clopidogrel. Famotidine, a histamine receptor type 2 (H2) blocker, could also be an alternative to PPIs. The aim of this study was to evaluate the effects of PPIs and an H2 blocker on the antiplatelet function of clopidogrel.
Patients receiving DAPT due to prior PCI, who took either omeprazole or rabeprazole, were enrolled (n=25). The initial PPI was changed to the other PPI as a crossover study. In another study, patients undergoing DAPT without taking PPIs or H2 blockers were enrolled (n=30) and famotidine was added.
Platelet aggregability when taking omeprazole was higher than when taking rabeprazole, evaluated by an optical aggregometer using collagen as a stimulus (p=0.0051) and by the VerifyNow P2Y12 assay (p=0.0060). Platelet aggregability when taking rabeprazole was comparable to that in control patients (n=15). Concomitant use of famotidine had no effect.
Omeprazole significantly reduced the antiplatelet effect of clopidogrel and this effect on clopidogrel was stronger than that of rabeprazole. Concomitant use of famotidine had no effect on the antiplatelet effect of clopidogrel.
Journal of atherosclerosis and thrombosis 04/2012; 19(6):559-69. · 2.69 Impact Factor
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Hiroshi Watanabe,
Akihiko Nogami,
Kimie Ohkubo,
Hiro Kawata,
Yuka Hayashi,
Taisuke Ishikawa, Takeru Makiyama,
Satomi Nagao,
Nobue Yagihara,
Naofumi Takehara, [......],
Hirotaka Oda,
Masaaki Okabe,
Akinori Kimura,
Koji Maemura,
Ichiro Watanabe,
Shiro Kamakura,
Minoru Horie,
Yoshifusa Aizawa,
Wataru Shimizu,
Naomasa Makita
Circulation Arrhythmia and Electrophysiology 04/2012; 5(2):e60-1. · 6.46 Impact Factor
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Naomasa Makita,
Akiko Seki,
Naokata Sumitomo,
Halina Chkourko,
Shigetomo Fukuhara,
Hiroshi Watanabe,
Wataru Shimizu,
Connie R Bezzina,
Can Hasdemir,
Hideo Mugishima, [......],
Estelle Baron,
Minoru Horie,
Nobuhisa Hagiwara,
Arthur A M Wilde,
Vincent Probst,
Hervé Le Marec,
Dan M Roden,
Naoki Mochizuki,
Jean-Jacques Schott,
Mario Delmar
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ABSTRACT: Progressive familial heart block type I (PFHBI) is a hereditary arrhythmia characterized by progressive conduction disturbances in the His-Purkinje system. PFHBI has been linked to genes such as SCN5A that influence cardiac excitability but not to genes that influence cell-to-cell communication. Our goal was to explore whether nucleotide substitutions in genes coding for connexin proteins would associate with clinical cases of PFHBI and if so, to establish a genotype-cell phenotype correlation for that mutation.
We screened 156 probands with PFHBI. In addition to 12 sodium channel mutations, we found a germ line GJA5 (connexin40 [Cx40]) mutation (Q58L) in 1 family. Heterologous expression of Cx40-Q58L in connexin-deficient neuroblastoma cells resulted in marked reduction of junctional conductance (Cx40-wild type [WT], 22.2±1.7 nS, n=14; Cx40-Q58L, 0.56±0.34 nS, n=14; P<0.001) and diffuse localization of immunoreactive proteins in the vicinity of the plasma membrane without formation of gap junctions. Heteromeric cotransfection of Cx40-WT and Cx40-Q58L resulted in homogenous distribution of proteins in the plasma membrane rather than in membrane plaques in ≈50% of cells; well-defined gap junctions were observed in other cells. Junctional conductance values correlated with the distribution of gap junction plaques.
Mutation Cx40-Q58L impairs gap junction formation at cell-cell interfaces. This is the first demonstration of a germ line mutation in a connexin gene that associates with inherited ventricular arrhythmias and emphasizes the importance of Cx40 in normal propagation in the specialized conduction system.
Circulation Arrhythmia and Electrophysiology 02/2012; 5(1):163-72. · 6.46 Impact Factor
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Junichi Tazaki,
Toshikazu Jinnai,
Tomohisa Tada,
Yoshihiro Kato, Takeru Makiyama,
Tomoyuki Ikeda,
Keiichiro Yamane,
Yumiko Naruse,
Kanako Takahashi,
Haruyo Watanabe,
Takeshi Kimura,
Hisanori Horiuchi
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ABSTRACT: Clopidogrel, an essential drug for the prevention of stent thrombosis, is a prodrug activated by CYP enzyme family including CYP2C19. It is known that activity-defective polymorphisms of CYP2C19 (CYP2C19*2 and*3) are associated with reduced clopidogrel efficacy and poor prognosis. Recently, the (13)C-pantoprazole breath test is developed to evaluate the CYP2C19 activity. The aim of this study is to evaluated the efficiency of the CYP2C19 activity test as a predictor of antiplatelet effect of clopidogrel.
The CYP2C19 activity and the antiplatelet effect of clopidogrel were evaluated in 27 healthy volunteers. Change of the carbon isotope ratios ((13)CO(2)/(12)CO(2)) in expiration gas between before and after (13)C-pantoprazole intake was evaluated as delta over baseline (DOB) ratio (‰).
DOB at 30 min was significantly lower in poor metabolizers (PMs) than extensive metabolizers (EMs) and intermediate metabolizers (IMs) (EM vs. PM, p=0.0108; IM vs. PM, p=0.016). The antiplatelet effect of clopidogrel was significantly different in three groups (inhibition of platelet aggregation: p=0.0148, P2Y12 reaction unit: p=0.0241). DOB at 30 min was correlated with the antiplatelet effect of clopidogrel. A cut-off value of DOB at 30 min below 1.0‰ predicted PMs with 96% specificity and 100% sensitivity.
The (13)C-pantoprazole breath test can detect CYP2C19 PMs and predict low responders to clopidogrel rapidly.
Journal of atherosclerosis and thrombosis 12/2011; 19(2):186-93. · 2.69 Impact Factor
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Tetsuhisa Hattori, Takeru Makiyama,
Masaharu Akao,
Eiji Ehara,
Seiko Ohno,
Moritake Iguchi,
Yukiko Nishio,
Kenichi Sasaki,
Hideki Itoh,
Masayuki Yokode,
Toru Kita,
Minoru Horie,
Takeshi Kimura
[show abstract]
[hide abstract]
ABSTRACT: Short-QT syndrome (SQTS) is a recently recognized disorder associated with atrial fibrillation (AF) and sudden death due to ventricular arrhythmias. Mutations in several ion channel genes have been linked to SQTS; however, the mechanism remains unclear. This study describes a novel heterozygous gain-of-function mutation in the inward rectifier potassium channel gene, KCNJ2, identified in SQTS.
We studied an 8-year-old girl with a markedly short-QT interval (QT = 172 ms, QTc = 194 ms) who suffered from paroxysmal AF. Mutational analysis identified a novel heterozygous KCNJ2 mutation, M301K. Functional assays displayed no Kir2.1 currents when M301K channels were expressed alone. However, co-expression of wild-type (WT) with M301K resulted in larger outward currents than the WT at more than -30 mV. These results suggest a gain-of-function type modulation due to decreased inward rectification. Furthermore, we analysed the functional significance of the amino acid charge at M301 (neutral) by changing the residue. As with M301K, in M301R (positive), the homozygous channels were non-functional, whereas the heterozygous channels demonstrated decreased inward rectification. Meanwhile, the currents recorded in M301A (neutral) showed normal inward rectification under both homo- and heterozygous conditions. Heterozygous overexpression of WT and M301K in neonatal rat ventricular myocytes exhibited markedly shorter action potential durations than the WT alone.
In this study, we identified a novel KCNJ2 gain-of-function mutation, M301K, associated with SQTS. Functional assays revealed no functional currents in the homozygous channels, whereas impaired inward rectification demonstrated under the heterozygous condition resulted in larger outward currents, which is a novel mechanism predisposing SQTS.
Cardiovascular research 12/2011; 93(4):666-73. · 5.80 Impact Factor
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Hiroshi Watanabe,
Akihiko Nogami,
Kimie Ohkubo,
Hiro Kawata,
Yuka Hayashi,
Taisuke Ishikawa, Takeru Makiyama,
Satomi Nagao,
Nobue Yagihara,
Naofumi Takehara, [......],
Hirotaka Oda,
Masaaki Okabe,
Akinori Kimura,
Koji Maemura,
Ichiro Watanabe,
Shiro Kamakura,
Minoru Horie,
Yoshifusa Aizawa,
Wataru Shimizu,
Naomasa Makita
[show abstract]
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ABSTRACT: Recently, we and others reported that early repolarization (J wave) is associated with idiopathic ventricular fibrillation. However, its clinical and genetic characteristics are unclear.
This study included 50 patients (44 men; age, 45 ± 17 years) with idiopathic ventricular fibrillation associated with early repolarization, and 250 age- and sex-matched healthy controls. All of the patients had experienced arrhythmia events, and 8 (16%) had a family history of sudden death. Ventricular fibrillation was inducible by programmed electric stimulation in 15 of 29 patients (52%). The heart rate was slower and the PR interval and QRS duration were longer in patients with idiopathic ventricular fibrillation than in controls. We identified nonsynonymous variants in SCN5A (resulting in A226D, L846R, and R367H) in 3 unrelated patients. These variants occur at residues that are highly conserved across mammals. His-ventricular interval was prolonged in all of the patients carrying an SCN5A mutation. Sodium channel blocker challenge resulted in an augmentation of early repolarization or development of ventricular fibrillation in all of 3 patients, but none was diagnosed with Brugada syndrome. In heterologous expression studies, all of the mutant channels failed to generate any currents. Immunostaining revealed a trafficking defect in A226D channels and normal trafficking in R367H and L846R channels.
We found reductions in heart rate and cardiac conduction and loss-of-function mutations in SCN5A in patients with idiopathic ventricular fibrillation associated with early repolarization. These findings support the hypothesis that decreased sodium current enhances ventricular fibrillation susceptibility.
Circulation Arrhythmia and Electrophysiology 12/2011; 4(6):874-81. · 6.46 Impact Factor
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Akashi Miyamoto,
Hideki Hayashi,
Tomohide Yoshino,
Tamiro Kawaguchi,
Atsushi Taniguchi,
Hideki Itoh,
Yoshihisa Sugimoto,
Makoto Itoh, Takeru Makiyama,
Joel Q Xue,
Yoshitaka Murakami,
Minoru Horie
[show abstract]
[hide abstract]
ABSTRACT: Short QT syndrome is one of the underlying disorders associated with ventricular fibrillation. However, the precise prognostic implication of a short QT interval remains unclear.
The purpose of this study was to investigate the prevalence and long-term prognosis in patients with a shorter-than-normal QT interval in a large hospital-based population.
We chose patients with a short Bazett QTc interval from a database consisting of 114,334 patients to determine the clinical characteristics and prognostic value of a short QT interval.
A total of 427 patients (mean age 43.4 ± 22.4 years) had a short QT interval with about a 1.2 times higher male predominance (234 men). The QTc interval was significantly longer in female than in male patients (363.8 ± 6.1 ms vs 357.1 ± 5.8 ms, P <.0001). The age-specific prevalence of patients with short QT interval was biphasic, peaking at young and old age. Atrial fibrillation and early repolarization were complicated with short QT interval in 39 (9.1%) and 26 (6.1%) patients, respectively. The prognosis of 327 patients (182 men; mean age, 46.4 ± 27.3 years) with a short QT interval could be assessed (mean follow-up period, 54.0 ± 62.0 months). During the follow-up, 2 patients, 1 of whom had early repolarization, developed life-threatening events, in contrast to 6 patients who died of noncardiac causes and did not have early repolarization.
The prevalence of a short QT interval showed a slight male preponderance and biphasic age-dependent distribution in both genders. The complication rate of atrial fibrillation was higher in those with a short QT interval than in general populations. The long-term outcome suggested that early repolarization in a short QT interval might be associated with potential risk of lethal arrhythmia.
Heart rhythm: the official journal of the Heart Rhythm Society 08/2011; 9(1):66-74. · 4.56 Impact Factor
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[show abstract]
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ABSTRACT: KCNQ1 gene encodes the delayed rectifier K(+) channel in cardiac muscle, and its mutations cause long QT syndrome type 1 (LQT1). Especially exercise-related cardiac events predominate in LQT1. We previously reported that a KCNQ1 splicing mutation displays LQT1 phenotypes.
We identified novel mutation at the third base of intron 7 (IVS7 +3A>G) in exercise-induced LQT1 patients. Minigene assay in COS7 cells and RT-PCR analysis of patients' lymphocytes demonstrated the presence of exon 7-deficient mRNA in IVS7 +3A>G, as well as c.1032G>A, but not in c.1022C>T. Real-time RT-PCR demonstrated that both IVS7 +3A>G and c.1032G>A carrier expressed significant amounts of exon-skipping mRNAs (18.8% and 44.8% of total KCNQ1 mRNA). Current recordings from Xenopus oocytes injected cRNA by simulating its ratios of exon skipping displayed a significant reduction in currents to 64.8 ± 4.5% for IVS7 +3A>G and to 41.4 ± 9.5% for c.1032G>A carrier, respectively, compared to the condition without splicing error. Computer simulation incorporating these quantitative results revealed the pronounced QT prolongation under beta-adrenergic stimulation in IVS7 +3A>G carrier model.
Here we report a novel splicing mutation IVS7 +3A>G, identified in a family with mild form LQT1 phenotypes, and examined functional outcome in comparison with three other variants around the exon 7-intron 7 junction. In addition to c.1032G>A mutation, IVS7 +3A>G generates exon-skipping mRNAs, and thereby causing LQT1 phenotype. The severity of clinical phenotypes appeared to differ between the two splicing-related mutations and to result from the amount of resultant mRNAs and their functional consequences.
Biochimica et Biophysica Acta 07/2011; 1812(11):1452-9. · 4.66 Impact Factor
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Seiko Ohno,
Dimitar P Zankov,
Wei-Guang Ding,
Hideki Itoh, Takeru Makiyama,
Takahiro Doi,
Satoshi Shizuta,
Tetsuhisa Hattori,
Akashi Miyamoto,
Nobu Naiki,
Jules C Hancox,
Hiroshi Matsuura,
Minoru Horie
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ABSTRACT: Brugada syndrome (BrS) has a significantly higher incidence among the male sex. Among genes coding ion channels and their modulatory proteins, KCNE5 (KCNE1L) is located in the X chromosome and encodes an auxiliary β-subunit for K channels. KCNE5 has been shown to modify the transient outward current (I(to)), which plays a key role in determining the repolarization process in the myocardium. This study investigated whether KCNE5 mutations could be responsible for BrS and other idiopathic ventricular fibrillation (IVF).
In 205 Japanese patients with BrS or IVF who tested negative for SCN5A mutation, we conducted a genetic screen for KCNE5 variants. We identified 2 novel KCNE5 variants: p.Y81H in 3 probands and p.[D92E;E93X] in 1 proband from 4 unrelated families. Y81H was identified in 1 man and 2 women; D92E;E93X was found in a 59-year-old man. All probands received implantable cardioverter-defibrillators. Functional consequences of the KCNE5 variants were determined through biophysical assay using cotransfection with KCND3 or KCNQ1. In the experiments with KCND3, which encodes Kv4.3, I(to) was significantly increased for both KCNE5 variants compared to wild type. In contrast, there were no significant changes in current properties reconstructed by KCNQ1+ wild type KCNE5 and the 2 variants. With the simulation model, both variants demonstrated notch-and-dome or loss-of-dome patterns.
KCNE5 modulates I(to), and its novel variants appeared to cause IVF, especially BrS, in male patients through gain-of-function effects on I(to). Screening for KCNE5 variants is relevant for BrS or IVF.
Circulation Arrhythmia and Electrophysiology 06/2011; 4(3):352-61. · 6.46 Impact Factor
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ABSTRACT: Mutations in KCNJ2, a gene encoding the inward rectifier K(+) channel Kir2.1, are associated with Andersen-Tawil syndrome (ATS), which is characterized by (1) ventricular tachyarrhythmias associated with QT (QU)-interval prolongation, (2) periodic paralysis, and (3) dysmorphic features.
We identified a novel KCNJ2 mutation, S369X, in a 13-year-old boy with prominent QU-interval prolongation and mild periodic paralysis. The mutation results in the truncation at the middle of the cytoplasmic C-terminal domain that eliminates the endoplasmic reticulum (ER)-to-Golgi export signal. Current recordings from Chinese hamster ovary cells transfected with KCNJ2-S369X exhibited significantly smaller K(+) currents compared with KCNJ2 wild type (WT) (1 μg each) (-84 ± 14 versus -542 ± 46 picoamperes per picofarad [pA/pF]; -140 mV; P<0.0001). Coexpression of the WT and S369X subunits did not show a dominant-negative suppression effect but yielded larger currents than those of WT+S369X (-724 ± 98 pA/pF>-[84+542] pA/pF; 1 μg each; -140 mV). Confocal microscopy analysis showed that the fluorescent protein-tagged S369X subunits were predominantly retained in the ER when expressed alone; however, the expression of S369X subunits to the plasma membrane was partially restored when coexpressed with WT. Fluorescence resonance energy transfer analysis demonstrated direct protein-protein interactions between WT and S369X subunits in the intracellular compartment.
The S369X mutation causes a loss of the ER export motif. However, the trafficking deficiency can be partially rescued by directly assembling with the WT protein, resulting in a limited restoration of plasma membrane localization and channel function. This alleviation may explain why our patient presented with a relatively mild ATS phenotype.
Circulation Cardiovascular Genetics 06/2011; 4(3):253-60. · 6.11 Impact Factor
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ABSTRACT: Spontaneous coved ST-segment elevation ≥2 mm followed by a negative T-wave in the right precordial leads (type 1 Brugada ECG) is diagnostic of Brugada syndrome (BS), but there is a false-positive rate.
Computer-processed analysis of a 12-lead ECG database containing 49,286 females and 52,779 males was performed to select patients with a spontaneous type 1 Brugada ECG for an examination of the association of this ECG characteristic with long-term prognosis. There were 185 patients with a spontaneous type 1 Brugada ECG and of these, 16 (15 males; mean age, 46.7±14.0 years) were diagnosed with BS and 15 patients (all males; mean age, 50.1±13.4 years) were undiagnosed. The PQ interval was significantly longer in the diagnosed patients than in the undiagnosed patients (187.4±28.3 ms vs. 161.2±21.5 ms; P=0.0073). The T-wave in lead V(1) was more negative in the diagnosed patients than in the undiagnosed patients (-170.2±174.6 µV vs. -43.2±122.3 µV, P=0.027). Multivariate analysis revealed that a PQ interval ≥170 ms and T-wave amplitude <105 µV in lead V(1) were independent risk stratifiers of life-threatening events. Survival analysis (mean follow-up, 78.6±81.8 months) showed that the PQ interval and a negative T-wave in lead V(1) were significantly associated with poor prognosis.
Analysis of a standard 12-lead ECG can stratify the prognosis of patients with a spontaneous type 1 Brugada ECG.
Circulation Journal 02/2011; 75(4):844-51. · 3.77 Impact Factor
