RESUMEN
LQTS (long QT syndrome) is caused by mutations in cardiac ion channel genes; however, the prevalence of LQTS in the general population is not well known. In the present study, we prospectively estimated the prevalence of LQTS and analysed the associated mutation carriers in Japanese children. ECGs were recorded from 7961 Japanese school children (4044 males; mean age, 9.9+/-3.0 years). ECGs were examined again for children who had prolonged QTc (corrected QT) intervals in the initial ECGs, and their QT intervals were measured manually. An LQTS score was determined according to Schwartz's criteria, and ion channel genes were analysed. In vitro characterization of the identified mutants was performed by heterologous expression experiments. Three subjects were assigned to a high probability of LQTS (3.5< or = LQTS score), and eight subjects to an intermediate probability (1.0< LQTS score < or =3.0). Genetic analysis of these II subjects identified three KCNH2 mutations (M124T, 547-553 del GGCGGCG and 2311-2332 del/ins TC). In contrast, no mutations were identified in the 15 subjects with a low probability of LQTS. Electrophysiological studies showed that both the M124T and the 547-553 del GGCGGCG KCNH2 did not suppress the wild-type KCNH2 channel in a dominant-negative manner. These results demonstrate that, in a random sample of healthy Japanese children, the prevalence of a high probability of LQTS is 0.038% (three in 7961), and that LQTS mutation carriers can be identified in at least 0.038% (one in 2653). Furthermore, large-scale genetic studies will be needed to clarify the real prevalence of LQTS by gene-carrier status, as it may have been underestimated in the present study.
Asunto(s)
Heterocigoto , Síndrome de QT Prolongado/genética , Mutación , Adolescente , Niño , Análisis Mutacional de ADN/métodos , Canal de Potasio ERG1 , Electrocardiografía , Métodos Epidemiológicos , Canales de Potasio Éter-A-Go-Go/genética , Femenino , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Japón/epidemiología , Síndrome de QT Prolongado/diagnóstico , Síndrome de QT Prolongado/epidemiología , Masculino , Polimorfismo GenéticoRESUMEN
OBJECTIVE: To identify the ankyrin-B gene mutations that cause long QT syndrome (LQTS) and determine the prevalence of such mutations in Japanese patients with LQTS. METHODS: We conducted a search for ankyrin-B gene mutation in 78 unrelated patients with LQTS (28 males and 50 females, aged 2 to 89 years). With informed consent from all the subjects and/or their parents, genomic DNA was purified from the white blood cells of the patients and amplified using polymerase chain reaction (PCR). Single-strand conformational polymorphism (SSCP) analysis of the amplified DNA was performed to screen for mutations and aberrant SSCP products were isolated and sequenced by dye terminator cycle sequencing method using an automated fluorescent sequencer. PCR and restriction fragment length polymorphism (PCR-RFLP) analysis was carried out to further confirm the missense mutations by comparison with samples from 150 normal healthy individuals. RESULTS: We identified a T to A transition mutation at position 4,603 in exon 40, resulting in the substitution of arginine for a tryptophan at amino acid residue 1,535 (W1535R) in the regulatory domain of 220-kD ankyrin-B, which is a highly conserved domain shared by different species. CONCLUSION: This novel missense mutation in the ankyrin-B gene may be a cause of type 4 LQTS. Ankyrin-B gene mutation might not play the major role in LQTS in Japanese.
Asunto(s)
Ancirinas/genética , Síndrome de QT Prolongado/genética , Mutación Missense , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Sustitución de Aminoácidos , Secuencia de Bases , Niño , Preescolar , Exones , Femenino , Humanos , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , Mutación PuntualRESUMEN
A 36-year-old woman was admitted for recurring chest pain and hemoptysis. Blood pressure in the right and left arms was equal, and no murmurs or bruits were heard. Body temperature was normal on admission and remained within the normal range during the hospital stay. C-reactive protein was slightly elevated (2.3 mg/dL) and lupus anticoagulant was positive. Angiography showed no abnormality of the aorta or its branches, but the left pulmonary artery showed occlusion at the proximal portion. Computed tomography (CT) revealed segmental wall thickening of the thoracic aorta. Fluorine-18-fluorodeoxyglucose positron emission tomography (18FDG PET) showed high uptake in the proximal portion of the left pulmonary artery and in the thoracic aorta with wall thickening on CT. Based on these findings, a diagnosis of Takayasu's arteritis associated with antiphospholipid syndrome was made and high-dose steroid therapy (prednisolone 30 mg/day) was started. Two months later, the C-reactive protein level had decreased from 2.3 mg/dL to 1.1 mg/dL, and both the focal wall thickening and (18)FDG uptake of the thoracic aorta were decreased. 18FDG PET was useful for evaluating the efficacy of the steroid therapy in addition to making a diagnosis of Takayasu's arteritis associated with antiphospholipid syndrome.
Asunto(s)
Síndrome Antifosfolípido/complicaciones , Fluorodesoxiglucosa F18 , Tomografía de Emisión de Positrones , Radiofármacos , Arteritis de Takayasu/diagnóstico por imagen , Adulto , Antiinflamatorios/administración & dosificación , Femenino , Humanos , Prednisolona/administración & dosificación , Arteritis de Takayasu/tratamiento farmacológico , Tomografía Computarizada por Rayos XRESUMEN
STUDY OBJECTIVE: To assess the effects of fenofibrate therapy on concentrations of plasma ubiquinol-10 and ubiquinone-10-the reduced and oxidized forms, respectively, of coenzyme Q(10). DESIGN: Prospective, open-label, non-controlled study. SETTING: University clinic and laboratory. PATIENTS: Eighteen patients with hyperlipidemia and type 2 diabetes mellitus. INTERVENTION: Patients received fenofibrate 150 mg/day for 12 weeks. MEASUREMENTS AND MAIN RESULTS: Metabolic parameters were assessed 4, 8, and 12 weeks after the start of fenofibrate treatment. Plasma ubiquinol-10 and ubiquinone-10 levels were measured by reverse-phase high-performance liquid chromatography. At 4, 8, and 12 weeks, significant reductions in fasting triglyceride levels and significant increases in high-density lipoprotein cholesterol levels were noted. Total cholesterol, low-density lipoprotein cholesterol, fasting plasma glucose, and adiponectin levels, however, did not change significantly. Plasma ubiquinol-10 concentrations significantly increased after 8 and 12 weeks (p<0.05 for both), whereas ubiquinone-10 concentrations tended to decrease, especially at 12 weeks. CONCLUSION: Our findings suggest that fenofibrate may help produce energy or prevent oxidation by increasing plasma ubiquinol-10 concentration; this effect may protect against the development and progression of atherosclerosis. In addition, treatment with fenofibrate demonstrated a favorable effect on serum lipid parameters.
Asunto(s)
Diabetes Mellitus Tipo 2/fisiopatología , Fenofibrato/farmacología , Hiperlipidemias/tratamiento farmacológico , Ubiquinona/análogos & derivados , Coenzimas , Progresión de la Enfermedad , Femenino , Fenofibrato/sangre , Humanos , Hiperlipidemias/fisiopatología , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Ubiquinona/sangre , Ubiquinona/efectos de los fármacosRESUMEN
It has been demonstrated previously that clinical phenotypes of HCM (hypertrophic cardiomyopathy) caused by mutations in the cardiac MyBP-C (myosin-binding protein C) gene show late onset, low penetrance and favourable clinical course. However, we have encountered severe phenotypes in several carriers of the MyBP-C gene mutations. The aim of the present study was to screen novel MyBP-C gene mutations in patients with HCM and to investigate the genetic differences in affected subjects with severe phenotypes. The MyBP-C gene was screened in 292 Japanese probands with HCM, and a novel c.2067+1G-->A mutation was present in 15 subjects in five families. Clinical phenotypes of carriers of the c.2067+1G-->A mutation were compared with those of a previously identified Arg820Gln (Arg820-->Gln) mutation in the MyBP-C gene. The disease penetrance in subjects aged > or =30 years was 90% in carriers of the c.2067+1G-->A mutation and 61% in carriers of the Arg820Gln mutation. Sudden death occurred in four subjects from three families with the c.2067+1G-->A mutation and in two subjects from one family with the Arg820Gln mutation. Two carriers of the c.2067+1G-->A mutation had substantial hypertrophy (maximal wall thickness > or =30 mm). In contrast, two carriers of the Arg820Gln mutation had end-stage HCM. In conclusion, the c.2067+1G-->A mutation is associated with HCM with substantial hypertrophy and moderate incidence of sudden death, whereas the Arg820Gln mutation is associated with end-stage HCM. These observations may provide important prognostic information regarding the clinical practice of HCM.
Asunto(s)
Cardiomiopatía Hipertrófica/genética , Proteínas Portadoras/genética , Muerte Súbita Cardíaca/etiología , Hipertrofia Ventricular Izquierda/genética , Mutación , Adolescente , Adulto , Anciano , Secuencia de Bases , Cardiomiopatía Hipertrófica/diagnóstico por imagen , Niño , Análisis Mutacional de ADN/métodos , Femenino , Predisposición Genética a la Enfermedad , Genotipo , Heterocigoto , Humanos , Hipertrofia Ventricular Izquierda/diagnóstico por imagen , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , Linaje , Penetrancia , Fenotipo , Reacción en Cadena de la Polimerasa/métodos , Pronóstico , UltrasonografíaRESUMEN
The diagnostic value of various classic electrocardiographic (ECG) voltage criteria for hypertrophic cardiomyopathy (HC) has not been established in a genotyped population. This study aimed to determine the most accurate diagnostic definition of classic ECG voltage criteria for detecting carriers of HC. ECG and echocardiographic findings were analyzed in 161 genotyped subjects (97 genetically affected, 64 unaffected) from 20 families with disease-causing mutations in 4 genes. The diagnostic value of 4 voltage criteria (Cornell, Sokolow-Lyon, Romhilt-Estes, and 12-lead QRS voltage) for detecting carriers of HC was investigated. In all subjects, the Romhilt-Estes (point score > or =4) criterion and 12-lead QRS voltage (> or =240 mm) were most sensitive (37% and 36%, respectively), with high specificity (95% each), resulting in the greatest accuracy (60% and 59%, respectively). Using these criteria, in subjects without echocardiographic evidence of left ventricular hypertrophy, voltage abnormalities were found in 22.6% of carriers and 4.7% of noncarriers (p <0.01). In conclusion, these findings suggest that the Romhilt-Estes and the 12-lead QRS voltage criteria may be the most accurate diagnostic definitions for HC on the basis of molecular genetic diagnoses. Furthermore, this study demonstrated that voltage abnormalities may be found in prehypertrophic carriers. Even when genetic testing becomes widely available, it will be difficult to make genetic diagnoses in all patients with HC because of its genetic heterogeneity. Therefore, understanding the diagnostic value of classic ECG voltage criteria may be important in detecting carriers, including those without left ventricular hypertrophy.
Asunto(s)
Cardiomiopatía Hipertrófica/diagnóstico , Electrocardiografía , Heterogeneidad Genética , Adulto , Factores de Edad , Cardiomiopatía Hipertrófica/genética , Cardiomiopatía Hipertrófica/fisiopatología , ADN/análisis , Femenino , Estudios de Seguimiento , Genotipo , Humanos , Masculino , Mutación , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Troponina I/genética , Troponina T/genéticaRESUMEN
The PHT1 promoter::GUS fusion gene was constructed and introduced into Arabidopsis and rice by Agrobacterium-mediated transformation. Strong beta-glucuronidase (GUS) activity was detected in roots and showed phosphate starvation induction both in Arabidopsis and rice. In contrast, GUS activity in aerial tissues such as those of the leaf and stem was low. In situ GUS staining of root tissue indicated that PHT1 was expressed in root hairs and the outer layer of the main roots, but not in root tips. The PHT1 promoter has a desirable character for biotechnological transgene expression in monocot rice plants.
Asunto(s)
Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Oryza/genética , Oryza/metabolismo , Proteínas de Transporte de Fosfato/genética , Proteínas de Transporte de Fosfato/metabolismo , Raíces de Plantas/genética , Raíces de Plantas/metabolismo , Ingeniería de Proteínas/métodos , Regulación de la Expresión Génica de las Plantas/fisiología , Técnicas de Transferencia de Gen , Plantas Modificadas Genéticamente/metabolismo , Regiones Promotoras Genéticas/genética , Proteínas Recombinantes/metabolismoRESUMEN
We report regression of the abnormal Q waves of an inferior old myocardial infarction after an additional anterior acute myocardial infarction, and demonstrate the scintigraphic correlation and chronological course of this phenomenon. Scintigraphic findings in the present case here may contribute to an interpretation of regression of abnormal Q waves in myocardial infarction.
Asunto(s)
Arritmias Cardíacas/diagnóstico , Electrocardiografía/métodos , Infarto del Miocardio/diagnóstico , Tomografía de Emisión de Positrones/métodos , Talio , Disfunción Ventricular Izquierda/diagnóstico , Anciano , Arritmias Cardíacas/etiología , Humanos , Masculino , Infarto del Miocardio/complicaciones , Radiofármacos , Factores de Tiempo , Disfunción Ventricular Izquierda/complicacionesRESUMEN
A 33-year-old man was admitted for general malaise and vomiting. An electrocardiogram showed a complete atrioventricular block and an echocardiogram showed right atrial dilatation and normal wall motion of left ventricle (LV). Gene analysis showed nonsense mutation in the STA gene, which codes for emerin, and Emery-Dreifuss muscular dystrophy was diagnosed. An endomyocardial biopsy of right ventricle showed mild hypertrophy of myocytes. Myocardial scintigraphic studies with Tc-99m methoxyisobutylisonitrile (MIBI) and I-123-betamethyl-p-iodophenylpentadecanoic acid (BMIPP) scintigrams showed no abnormalities. In contrast, I-123 metaiodobenzylguanidine (MIBG) scintigrams showed a diffuse and severe decrease in accumulation of MIBG in the heart. Six months later, his LV wall motion on echocardiograms developed diffuse hypokinesis. These results suggest that the abnormality on I-123 MIBG myocardial scintigrams may predict LV dysfunction in Emery-Dreifuss muscular dystrophy.
Asunto(s)
3-Yodobencilguanidina , Cardiopatías Congénitas/diagnóstico por imagen , Corazón/diagnóstico por imagen , Corazón/inervación , Distrofia Muscular de Emery-Dreifuss/diagnóstico por imagen , Sistema Nervioso Simpático/anomalías , Sistema Nervioso Simpático/diagnóstico por imagen , Disfunción Ventricular Izquierda/diagnóstico por imagen , Adulto , Humanos , Masculino , Cintigrafía , RadiofármacosRESUMEN
BACKGROUND: Early detection in patients with hypertrophic cardiomyopathy (HCM) is very important. Integrated backscatter (IB) provides a useful noninvasive measure of the acoustic properties of the myocardium, and may detect early myocardial changes. METHODS: Thirty-four carriers who had gene mutations causing HCM were studied. The patients were divided into three groups as follows: (1) 21 patients with wall hypertrophy (Group A), (2) 7 patients with ECG abnormalities but without wall hypertrophy (Group B), and (3) 6 carriers with neither ECG abnormalities nor wall hypertrophy (Group C). All subjects underwent ECG, conventional echocardiography and acoustic densitometry. In addition, we studied subjects < or =20 years old from Groups B and C (Group B-2 and Group C-2, respectively), and compared them with control subjects with no cardiac disorders who were < or =20 years old. RESULTS: In Group A, cyclic variations of integrated backscatter (CV-IB) in the interventricular septum and left ventricular posterior wall were significantly smaller than in Group C. The amplitude of IB in the interventricular septum and left ventricular posterior wall in Group A was significantly higher than those in Group C. Even in Group B, CV-IB in the interventricular septum was significantly smaller than those in Group C. Among patients < or =20 years old, CV-IB in the interventricular septum was significantly smaller in Group B-2 than in control subjects, while that in Group C-2 did not differ from that in control subjects. CONCLUSIONS: Changes in tissue characterization were found in the hearts of HCM gene carriers even in the absence of wall hypertrophy. These results suggest that tissue changes detectable by the acoustic densitometry methods may occur in the hearts of HCM gene carriers without wall hypertrophy, and that they may be detectable at the time of appearance of ECG abnormalities.
Asunto(s)
Cardiomiopatía Hipertrófica/genética , Proteínas Portadoras/genética , Mutación , Miocardio/química , Miocardio/patología , Adolescente , Adulto , Factores de Edad , Cardiomiopatía Hipertrófica/diagnóstico por imagen , Cardiomiopatía Hipertrófica/patología , Niño , Preescolar , Ecocardiografía , Femenino , Predisposición Genética a la Enfermedad , Variación Genética , Genotipo , Humanos , Hipertrofia Ventricular Izquierda/genética , Masculino , Persona de Mediana Edad , Cadenas Pesadas de Miosina/genética , Proyectos de Investigación , Troponina I/genética , Troponina T/genéticaAsunto(s)
Insuficiencia Cardíaca/diagnóstico por imagen , Ventrículos Cardíacos/patología , Disfunción Ventricular Izquierda/diagnóstico por imagen , 3-Yodobencilguanidina , Autopsia , Resultado Fatal , Femenino , Insuficiencia Cardíaca/etiología , Humanos , Persona de Mediana Edad , Cintigrafía , Radiofármacos , Tecnecio Tc 99m SestamibiRESUMEN
BACKGROUND: The STA gene encodes emerin and is one of the genes that is affected in Emery-Dreifuss muscular dystrophy (EDMD). Although it has been reported that EDMD caused by the STA gene mutation is associated with X-linked recessive inheritance, the genotype-phenotype correlations, with special reference to cardiac manifestations, are not well defined. METHODS AND RESULTS: We identified 16 carriers (7 male and 9 female) with a nonsense mutation in exon 6 of the STA gene in 2 EDMD families. Pacemakers were required for treatment of bradyarrhythmias in all 7 male carriers and in 2 of the 9 female carriers. In addition, 2 of the 9 female carriers displayed atrial fibrillation. In these 2 families, 3 males without pacemaker implantation, who were not tested genetically, had died suddenly. In these family members, the majority of carriers with the mutation had not been clinically diagnosed as having EDMD before genetic testing because of extremely mild or nonexistent skeletal myopathy. CONCLUSIONS: EDMD caused by this mutation is characterized by atypical clinical features and incomplete penetrance of the clinical phenotype and may result in serious cardiac complications, including sudden death. Approaches to preventing possible sudden death in carriers with the STA gene mutation require further study.
Asunto(s)
Cardiomiopatías/genética , Codón sin Sentido , Muerte Súbita Cardíaca/etiología , Bloqueo Cardíaco/genética , Proteínas de la Membrana/genética , Timopoyetinas/genética , Adolescente , Adulto , Anciano , Arritmias Cardíacas/genética , Preescolar , Salud de la Familia , Femenino , Atrios Cardíacos/fisiopatología , Heterocigoto , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Distrofia Muscular de Emery-Dreifuss/genética , Proteínas Nucleares , Marcapaso Artificial , Linaje , Penetrancia , FenotipoAsunto(s)
Trombosis Coronaria/diagnóstico , Embolia Pulmonar/diagnóstico , Tomografía Computarizada por Rayos X , Anciano , Trombosis Coronaria/tratamiento farmacológico , Trombosis Coronaria/patología , Atrios Cardíacos/patología , Ventrículos Cardíacos/patología , Heparina/uso terapéutico , Humanos , Masculino , Arteria Pulmonar/patología , Embolia Pulmonar/tratamiento farmacológico , Embolia Pulmonar/patología , Terapia Trombolítica , Activador de Tejido Plasminógeno/uso terapéutico , Resultado del TratamientoRESUMEN
Many secretory and several vacuolar proteins in higher plants contain hydroxylated proline residues. In many cases, hydroxyprolines in proteins are glycosylated with either arabinogalactan or oligoarabinose. We have previously shown that a sporamin precursor is O-glycosylated at the hydroxylated proline 36 residue with an arabinogalactan-type glycan when this protein is expressed in tobacco BY-2 cells (Matsuoka et al., 1995). Taking advantage of the fact that this is the only site of proline hydroxylation and glycosylation in sporamin, we analyzed the amino acid requirement for proline hydroxylation and arabinogalactosylation. We expressed several deletion constructs and many amino acid substitution mutants in tobacco cells and analyzed glycosylation and proline hydroxylation of the expressed sporamins. Hydroxylation of a proline residue requires the five amino acid sequence [AVSTG]-Pro-[AVSTGA]-[GAVPSTC]-[APS or acidic] (where Pro is the modification site) and glycosylation of hydroxyproline (Hyp) requires the seven amino acid sequence [not basic]-[not T]-[neither P, T, nor amide]-Hyp-[neither amide nor P]-[not amide]-[APST], although charged amino acids at the -2 position and basic amide residues at the +1 position relative to the modification site seem to inhibit the elongation of the arabinogalactan side chain. Based on the combination of these two requirements, we concluded that the sequence motif for efficient arabinogalactosylation, including the elongation of the glycan side chain, is [not basic]-[not T]-[AVSG]-Pro-[AVST]-[GAVPSTC]-[APS].
Asunto(s)
Secuencias de Aminoácidos , Hidroxiprolina/metabolismo , Proteínas de Plantas/química , Proteínas de Plantas/metabolismo , Prolina/metabolismo , Células Cultivadas , Secuencia de Consenso , Expresión Génica , Glicosilación , Hidroxilación , Mutación , Proteínas de Plantas/genética , Plantas Modificadas Genéticamente , NicotianaRESUMEN
Brugada syndrome is an inherited cardiac disorder caused by mutations in the SCN5A gene encoding the cardiac sodium channel alpha subunit, which can lead ventricular fibrillation and sudden death. Inattentive use of antiarrhythmic drugs potentially triggers fatal cardiac arrhythmias through further reduction of sodium current (I(Na)). We studied the molecular mechanism underlying a case of Brugada syndrome that showed no response to a class Ic antiarrhythmic drug. Molecular genetic studies of a patient with Brugada syndrome identified a novel mutation in SCN5A, which causes substitution of serine for asparagine (N406S) in S6 of domain I (IS6). The provocation test with pilsicainide, a class Ic antiarrhythmic drug, failed to exacerbate ST-segment elevation in this case. Electrophysiological analyses of the N406S-mutant channel expressed together with the beta1 subunit in HEK293 cells showed that the voltage dependence of activation was positively shifted by 16 mV and that intermediate inactivation was enhanced. Whereas tonic block by pilsicainide was not changed in the N406S channel, use-dependent block by pilsicainide was almost completely abolished, consistent with the clinical findings of the negative provocation test. In contrast, the N406S channel showed stronger use-dependent block by quinidine than the wild-type channel. We demonstrate a novel Brugada mutation N406S, which is associated with the discordant effects on blocking actions of antiarrhythmic drugs as well as the multiple channel gating defects. We emphasis that an antiarrhythmic drug may exert unpredicted effects in patients with channel mutations.
Asunto(s)
Antiarrítmicos/farmacología , Bloqueo de Rama/tratamiento farmacológico , Bloqueo de Rama/genética , Mutación Missense , Bloqueadores de los Canales de Sodio/farmacología , Adulto , Anciano , Electrocardiografía , Femenino , Expresión Génica , Humanos , Inmunohistoquímica , Masculino , Canal de Sodio Activado por Voltaje NAV1.5 , Linaje , Canales de Sodio/efectos de los fármacos , Síndrome , TransfecciónRESUMEN
A 38-year-old Japanese woman was admitted to hospital for further examination of systemic xanthomas. She had a past history of genital bleeding during her third delivery at the age of 21 years. She was diagnosed with Sheehan's syndrome. Her serum total cholesterol and triglyceride concentrations were 500 and 898 mg/dl, respectively. She was also diagnosed as having type III hyperlipoproteinemia on the basis of the presence of a broad-beta-band on agarose gel electrophoresis and extremely high concentrations of very-low-density lipoprotein cholesterol (310 mg/dl). The diagnosis was later confirmed by her apolipoprotein E isoforms (E2/E2) and genotypes (epsilon2/epsilon2). Thyroid and corticosteroid hormone replacement therapy cured the xanthomas, but also elevated her blood pressure. The serum concentration of intermediate-density lipoprotein cholesterol was consistently high, whereas that of low-density lipoprotein cholesterol was relatively low during the follow-up. Coronary atherosclerosis had already developed by the age of 38 years, and progressed significantly over the following 28 years. Severe stenotic lesions were observed in the bilateral renal arteries and carotid arteries, and in the abdominal aorta when she was 66 years old. These findings suggest that the continuous elevation of intermediate-density lipoprotein cholesterol for a long period contributed to the development of the atherosclerotic lesions.
Asunto(s)
Enfermedad de la Arteria Coronaria , Hiperlipoproteinemia Tipo III , Hipopituitarismo , Adulto , Enfermedad de la Arteria Coronaria/sangre , Enfermedad de la Arteria Coronaria/etiología , Femenino , Humanos , Hiperlipoproteinemia Tipo III/sangre , Hiperlipoproteinemia Tipo III/complicaciones , Hiperlipoproteinemia Tipo III/terapia , Hipopituitarismo/sangre , Hipopituitarismo/complicaciones , Hipopituitarismo/terapiaRESUMEN
Brugada syndrome is an inherited cardiac disorder caused by mutations in the SCN5A gene encoding the cardiac sodium channel alpha-subunit, and potentially leads to ventricular fibrillation and sudden death. We report a case of a novel SCN5A mutation associated with Brugada syndrome. A 51-year-old man suffered from recurrent nocturnal syncopal attacks due to polymorphic ventricular tachycardia. His electrocardiogram showed ST-segment elevation in V1-V3 leads, but there was no evidence of structural heart disease. DNA sequence analysis of SCN5A in this patient revealed a missense mutation (R282H) in the S5-pore region of domain I. This mutational change was not present in 100 healthy Japanese controls. In the patient's family, a 36-year-old brother had died suddenly. Genetic analysis identified two other carriers of the R282H mutation, who had ST-segment elevation and slightly increased QRS widths, but they experienced no syncopal episodes or ventricular fibrillation. Electrophysiological investigation of the R282H mutant channel expressed in cultured cells showed a severe reduction in sodium current density and a mild positive shift of activation curve. R282H did not enhance intermediate inactivation. Single-channel conductance of R282H was slightly decreased compared with WT. The electrophysiological characteristics of the R282H channel are suggested to be closely related to the clinical phenotype of Brugada syndrome.
Asunto(s)
Sistema de Conducción Cardíaco/fisiopatología , Mutación Missense , Canales de Sodio/genética , Fibrilación Ventricular/genética , Análisis Mutacional de ADN , Electrofisiología/métodos , Estudios de Seguimiento , Expresión Génica , Marcadores Genéticos , Frecuencia Cardíaca/fisiología , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Canal de Sodio Activado por Voltaje NAV1.5 , Linaje , Reacción en Cadena de la Polimerasa , Canales de Sodio/metabolismo , Síndrome , Fibrilación Ventricular/metabolismo , Fibrilación Ventricular/fisiopatologíaRESUMEN
BACKGROUND: Cholesterol lowering therapy may offset the development of coronary atherosclerosis, and the resulting reduction in coronary ischemia may be observed in the electrocardiogram (ECG). METHODS: A total of 2039 Japanese adults with hypercholesterolemia were divided into two groups (receiving 10-20 mg pravastatin daily or a normal diet) and were followed up for 5 years. ECG studies were performed at entry and every year during the follow-up period. The occurrence of myocardial infarction and the appearance or worsening of ischemic ST changes were assessed in terms of effects on the ECG. RESULTS: Of the 2039 patients registered, 827 were excluded from the study for various reasons. Consequently, a total of 1212 patients were analyzed. There was a lower degree of worsening in the pravastatin group (n=757) than in the normal diet group (n=455) in the primary prevention cohort [11 (1.8%) vs. 16 (4.3%), respectively, P=0.031]. On the other hand, there was no difference in the frequency of worsening between the two groups in the secondary prevention cohort [7 (4.4%) in the pravastatin group vs. 4 (4.9%) in the diet group, P=0.25]. Event-free survival was better in the pravastatin group than in the normal diet group in the primary prevention cohort (P=0.011), but there was no difference between the two groups in the secondary prevention cohort. CONCLUSIONS: These results suggest that pravastatin may reduce the incidence of coronary heart disease and that this effect may be predominantly observed in patients with early atheromatous lesions.
Asunto(s)
Anticolesterolemiantes/uso terapéutico , Enfermedad de la Arteria Coronaria/prevención & control , Electrocardiografía , Hipercolesterolemia/tratamiento farmacológico , Pravastatina/uso terapéutico , Anciano , Colesterol/sangre , LDL-Colesterol/sangre , Enfermedad de la Arteria Coronaria/diagnóstico , Femenino , Humanos , Masculino , Persona de Mediana Edad , RiesgoRESUMEN
Our purpose in this study was to evaluate the new JAS guidelines as a risk assessment tool in Japanese patients with hypercholesterolemia, using the cohort of the Holicos-PAT study. The Holicos-PAT study was designed as a prospective observational study. 2039 patients were followed with or without pravastatin for 5 years. We assessed coronary heart disease (CHD) and cerebrovascular disease (CVD) risks by the patient categories described in the JAS guidelines. In the Holicos-PAT study, the primary endpoints were CHD, and the secondary endpoints were CVD and total mortality. CHD event includes onset and worsening of angina pectoris, performing CABG or PTCA, non-fatal and fatal myocardial infarction, and death from CHD including heart death and sudden death. CVD events are onset or recurrence of cerebral infarction, onset of cerebral hemorrhage, and death from cerebral infarction or hemorrhage. The event rates were calculated by the person-years method, and the differences in event rates between category groups were analyzed by chi-square test. The event rates of CHD in Category A, B1, B2, B3, B4 and C, were 1.1, 4.0, 2.8, 5.7, 18.2 and 38.8 per 1,000 person-years. The rates of CHD events in the higher risk category groups, Category B4 group (p = 0.004 in whole patients) and C group (p < 0.001 in whole patients), were significantly higher than that in the combined category groups A + B1 + B2. The event rates of CVD in Category A, B1, B2, B3, B4 and C, were 2.1, 1.8, 1.8, 0.6, 10.8 and 6.4 per 1,000 person-years. The event rates of CHD in men were significantly higher than those in women, in categories B4 (p < 0.001) and C (p < 0.001). From these results, each category classified by accumulation of risk factors, showed increasing event rates of CHD and CVD. The categories in the JAS guidelines are useful to assess CHD and CVD risk in Japanese patients with hypercholesterolemia. However, the risk evaluation by the JAS guideline categories may underestimate the risk in men and overestimate it in women.
Asunto(s)
Trastornos Cerebrovasculares/epidemiología , Enfermedad Coronaria/epidemiología , Estudios de Cohortes , Humanos , Japón , Medición de RiesgoRESUMEN
BACKGROUND: Some patients with dilated cardiomyopathy (DCM) have mutations of the genes that encode sarcomeric or cytoskeletal proteins of cardiomyocytes, but the prevalence of these mutations in Japan remains unclear. METHODS AND RESULTS: A group of 99 unrelated adult patients with DCM (familial n=27, sporadic n=72) were screened for the following genes: cardiac beta-myosin heavy chain, cardiac myosin-binding protein C (MYBPC3), regulatory and essential myosin light chains, alpha cardiac actin, alpha tropomyosin, cardiac troponin T, cardiac troponin I, cardiac troponin C, dystrophin, and lamin A/C. A mutation (R820Q) in MYBPC3 was found in an aged patient. In addition, dystrophin mutations were identified in 3 male patients (2 with exon 45-48 deletion and 1 with exon 48-52 deletion). The prevalence of dystrophin mutations in male patients with DCM was 4.4% (3 of 68). No mutations involving amino acid changes were identified in the other genes. CONCLUSIONS: Although cases of adult patients with DCM caused by mutations of the genes encoding sarcomeric or cytoskeletal proteins of cardiomyocytes are infrequent in Japan, it may be advisable to screen older DCM patients for MYBPC3 mutations, and male patients with familial DCM for dystrophin mutations.