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1.
Cancer Genet ; 228-229: 1-4, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30553462

RESUMO

Li-Fraumeni syndrome is an autosomal-dominant disorder caused by germline mutations in the tumour suppressor gene TP53. Here we report the case of a family whose index case was a woman diagnosed with bilateral breast cancer at the age of 18 and who had a non-informative result after BRCA1 and BRCA2 testing. After extending the study through multigene panel testing, two clinically relevant variants in the TP53 and BRIP1 genes, respectively, were found. Afterwards, the patient developed a glioblastoma. Both tumours were consistent with Li-Fraumeni syndrome. Thanks to the possibility of studying different genes related with hereditary breast and ovarian cancer, it was possible to find out the gene variant that caused the early onset cancers in the patient. Furthermore, genetic counselling was provided to the index case and her family.


Assuntos
Neoplasias da Mama/diagnóstico , Neoplasias da Mama/genética , Códon sem Sentido , Proteínas de Grupos de Complementação da Anemia de Fanconi/genética , Genes p53 , Testes Genéticos/métodos , RNA Helicases/genética , Adolescente , Idade de Início , Neoplasias da Mama/patologia , Feminino , Humanos , Masculino , Linhagem
2.
Eur J Med Genet ; 61(6): 355-361, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29409816

RESUMO

RAD51C and RAD51D have been defined as susceptibility genes for hereditary breast and ovarian cancer syndrome in several studies. In the present study, a mutation analysis of these genes was performed on non BRCA1/2 families. RAD51C and RAD51D genes were analyzed in 141 and 77 families, respectively. The analysis included direct sequencing and multiple ligation probe analysis. The RAD51C pathogenic variant c.404G > A was identified in a breast and ovarian cancer family (0.7%), while the RAD51D pathogenic variant c.694C > T was described in an ovarian cancer family (1.3%). Moreover, three unknown clinical significance variants were detected: c.307T > G in RAD51C, and c.413A > G and c.715C > T in RAD51D. No large genomic rearrangements (LGRs) were found. RAD51D carriers suffered from premenopausal ovarian tumors. These results increase our knowledge about the RAD51C and RAD51D mutation spectrum and support the notion that these genes should be included in the gene panel testing performed on patients with hereditary breast and ovarian cancer syndrome.


Assuntos
Análise Mutacional de DNA , Proteínas de Ligação a DNA/genética , Síndrome Hereditária de Câncer de Mama e Ovário/genética , Mutação , Estudos de Casos e Controles , Feminino , Genes BRCA1 , Genes BRCA2 , Triagem de Portadores Genéticos , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Linhagem , Fenótipo , Pré-Menopausa , Espanha
3.
Fam Cancer ; 16(4): 477-489, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28477318

RESUMO

This is the first study performed in Murcia (south-eastern Spain) in which 592 families with hereditary breast and ovarian cancer were identified thanks to Genetic Counselling Units from this area over 6 years. Diagnostic performance was 18.1% and 194 different genetic variants were obtained. Variants with uncertain significance accounted for only 5.6% of the total number of reports, so our population has been well characterised. In BRCA1 gene, two novel variants were found (c.1859delT and c.3205C > T) and the most frequently detected mutations were c.68_69delAG, c.212 + 1G > A, c.5123C > A, c.211A > G and c.1918C > T, which together represented 56.67% of total pathogenic mutations. In BRCA2 gene, four recurrent variants were described (deletion of entire exon 2, c.9117G > A, c.3264dupT and c.3455T > G) representing 43.5% of the mutations in this gene. Mutation c.68_69delAG and deletion of entire exon 2 in BRCA1 and BRCA2 genes respectively were the most prevalent variants in our population. Regarding the genotype-phenotype relation, mutation c.212 + 1G > A appeared in an important percentage of breast and ovarian cancer cases, c.5123C > A in bilateral breast cancer and c.9117G > A in bilateral breast cancer and ovarian cancer. With respect to clinical-pathological characteristic, BRCA1/BRCA2 mutation carriers showed earlier onset age of breast tumour and higher risk of developing contra lateral breast cancer than non-informative cases. Moreover, association between either molecular subtype triple negative breast cancer or ovarian cancer and BRCA1 carriers was obtained.


Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/genética , Mutação , Neoplasias Ovarianas/genética , Idade de Início , Neoplasias da Mama/patologia , Éxons , Feminino , Predisposição Genética para Doença , Variação Genética , Síndrome Hereditária de Câncer de Mama e Ovário/genética , Síndrome Hereditária de Câncer de Mama e Ovário/patologia , Heterozigoto , Humanos , Masculino , Neoplasias Ovarianas/patologia , Linhagem , Espanha
4.
Mol Med Rep ; 13(6): 4677-80, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-27082542

RESUMO

Brugada syndrome (BS) is an electrical disease, inherited in an autosomal dominant manner. BS is caused by mutations in up to 13 different genes. SCN5A is the gene most frequently mutated in BS, although this presents an incomplete penetrance. The present case study investigated the SCN5A gene in a family exhibiting BS. Direct sequencing of the SCN5A gene was performed to identify mutations and a familial investigation was performed. A novel variant was identified in the voltage­sensing domain of the SCN5A protein. This familial investigation revealed one novel asymptomatic carrier in the family. Genetic investigations are useful to classify individuals who require more frequent clinical monitoring and to stratify the risk of developing the disease.


Assuntos
Síndrome de Brugada/genética , Mutação de Sentido Incorreto , Canal de Sódio Disparado por Voltagem NAV1.5/genética , Mutação Puntual , Adulto , Síndrome de Brugada/patologia , Análise Mutacional de DNA , Eletrocardiografia , Éxons , Humanos , Masculino , Miocárdio/patologia
5.
Europace ; 16(12): 1838-46, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24938629

RESUMO

AIMS: Risk stratification for sudden death in arrhythmogenic right ventricular cardiomyopathy (ARVC) is challenging in clinical practice. We lack recommendations for the risk stratification of exclusive left-sided phenotypes. The aim of this study was to investigate genotype-phenotype correlations in patients carrying a novel DSP c.1339C>T, and to review the literature on the clinical expression and the outcomes in patients with DSP truncating mutations. METHODS AND RESULTS: Genetic screening of the DSP gene was performed in 47 consecutive patients with a phenotype of either an ARVC (n = 24) or an idiopathic dilated cardiomyopathy (DCM), who presented with ventricular arrhythmias or a family history of sudden death (n = 23) (aged 40 ± 19 years, 62% males). Three unrelated probands with DCM were found to be carriers of a novel mutation (c.1339C>T). Cascade family screening led to the identification of 15 relatives who are carriers. Penetrance in c.1339C>T carriers was 83%. Sustained ventricular tachycardia was the first clinical manifestation in six patients and nine patients were diagnosed with left ventricular impairment (two had overt severe disease and seven had a mild dysfunction). Cardiac magnetic resonance revealed left ventricular involvement in nine cases and biventricular disease in three patients. Extensive fibrotic patterns in six and non-compaction phenotype in five patients were the hallmark in imaging. CONCLUSION: DSP c.1339C>T is associated with an aggressive clinical phenotype of left-dominant arrhythmogenic cardiomyopathy and left ventricular non-compaction. Truncating mutations in desmoplakin are consistently associated with aggressive phenotypes and must be considered as a risk factor of sudden death. Since ventricular tachycardia occurs even in the absence of severe systolic dysfunction, an implantable cardioverter-defibrillator should be indicated promptly.


Assuntos
Displasia Arritmogênica Ventricular Direita/epidemiologia , Displasia Arritmogênica Ventricular Direita/genética , Desmoplaquinas/genética , Predisposição Genética para Doença/epidemiologia , Predisposição Genética para Doença/genética , Disfunção Ventricular Esquerda/epidemiologia , Disfunção Ventricular Esquerda/genética , Adulto , Feminino , Testes Genéticos , Heterozigoto , Humanos , Incidência , Masculino , Mutação/genética , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco , Espanha/epidemiologia
6.
Fam Cancer ; 13(3): 431-5, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24633894

RESUMO

Mutations in breast cancer susceptibility (BRCA) genes lead to defects in DNA repair processes resulting in elevated genome instability and predisposing to breast and ovarian cancer. We report a novel mutation (c.1918C>T) in the exon 11 of the BRCA1 gene that consists of a nonsense mutation that causes a stop codon downstream in the 640 position of the protein. The mutation was present in two Spanish unrelated families and was associated with four breast cancer cases, including two bilateral breast cancer (one of them synchronous). The median age/mean age (range) was 48.5/44.25 years (27-53). This finding led us to perform haplotype analysis in all family carriers. Four highly polymorphic microsatellite markers were used (17-3858, 17-3930, D17S855, D17S1326) to establish whether or not all these families had a common ancestor. This analysis showed that all mutation carriers of these families had a common haplotype. None of the noncarriers of the mutation or of the 24 healthy controls showed this haplotype. Therefore, the c.1918C>T mutation carriers from these two families allows us to assert that all analyzed mutation carriers share a common ancestry.


Assuntos
Neoplasias da Mama/genética , Genes BRCA1 , Predisposição Genética para Doença/genética , Neoplasias Ovarianas/genética , Adulto , Códon sem Sentido , Análise Mutacional de DNA , Feminino , Haplótipos , Humanos , Pessoa de Meia-Idade , Linhagem , Reação em Cadeia da Polimerase
9.
Rev. lab. clín ; 5(1): 49-53, ene.-mar. 2012.
Artigo em Espanhol | IBECS | ID: ibc-99803

RESUMO

El objetivo de esta nota técnica es la descripción y comentarios de un caso clínico reciente de intoxicación por sobredosificación por vitamina D, y la correcta interpretación clínica y de los parámetros de laboratorio. Caso clínico. Lactante de 6 meses en tratamiento con Biominol® (suplemento vitamínico), ingresó debido a un estado de decaimiento e irritabilidad. Las analíticas iniciales muestran concentraciones de calcio iónico en sangre de 2,11mmol/L (intervalo de referencia (IR): 1,15-1,29mmol/L), y concentración de calcio total plasmático de 5,5mmol/L (IR: 2,25-2,75mmol/L). En nuestro laboratorio, las vitaminas D2 y D3 fueron determinadas por cromatografía líquida de alta resolución (HPLC), y por un método electroquimioluminiscente, que mide la vitamina D total. Los valores de vitamina D2 fueron 419ng/mL y vitamina D total 482ng/mL (IR: 30-100ng/mL). La intoxicación de vitamina D tuvo origen exógeno, debido al incremento de vitamina D2. El diagnóstico definitivo fue hipercalcemia severa secundaria a intoxicación por vitamina D y nefrocalcinosis secundaria a esta con función renal normal con hipercalciuria. Como conclusión, cabe destacar la importancia de la correcta dosificación de los pacientes y la determinación de las diferentes formas de vitamina D para averiguar su origen, realizando una correcta interpretación (AU)


The objective of this technical note describes and comments on a recent clinical case of poisoning by overdose of vitamin D, and the correct interpretation of clinical and laboratory parameters. Vitamin D is a fat-soluble vitamin involved in the absorption of calcium and phosphorus in the intestine. Administration of high doses for prolonged periods can cause hypercalcemia, leading to kidney failure and renal calcifications. Clinical case. The definitive diagnosis of this patient was severe hypercalcemia secondary to exogenous vitamin D poisoning, and nephrocalcinosis secondary to this with normal renal function with hypercalciuria. In conclusion, the correct dosing of patients and determination of different forms of vitamin D to trace its origin and making a correct interpretation is important. Male, 6 months old in treatment with Biominol® (vitamin D supplement), was admitted to the emergency department because of a state of decline and irritability. The initial analytical results showed an ionized calcium concentration in blood of 2.11mmol/L (reference interval (RI): 1.15 - 1.29mmol/L), and plasma total calcium concentration of 5.5mmol/L (RI: 2.25–2.75mmol/L). In our laboratory, Vitamin D2 and D3 were determined by liquid chromatography high resolution (HPLC), and an electrochemiluminescence method. The results showed a vitamin D2 419ng/mL and total vitamin D 482ng/mL (RI: 30–100ng/mL). It was found that the vitamin D overdose was of exogenous origin, due to increased vitamin D2 (AU)


Assuntos
Humanos , Masculino , Lactente , Overdose de Drogas/complicações , Overdose de Drogas/terapia , Vitamina D/administração & dosagem , Vitamina D/efeitos adversos , Diurese/fisiologia , Cromatografia , Cromatografia Líquida de Alta Pressão/instrumentação , Cromatografia Líquida de Alta Pressão , Peso-Estatura/fisiologia , Eletrocardiografia , Diurese , Ergocalciferóis/toxicidade , Colecalciferol/toxicidade
11.
Heart ; 96(24): 1980-4, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21088121

RESUMO

BACKGROUND: Mutations in the cardiac myosin-binding protein C (MYBPC3) gene are frequently found as a cause of hypertrophic cardiomyopathy (HCM). However, only a few studies have analysed genotype-phenotype correlations in small series of patients. The present study sought to determine the clinical characteristics, penetrance and prognosis of HCM with an identical mutation in MYBPC3. METHODS: 154 non-related patients with HCM (aged 55±16 years, 100 (64.9%) males) were studied. 18 (11.7%) were found to have an identical mutation in the MYBPC3 gene (IVS23+1G→A). Pedigree analysis, including both clinical evaluation and genotyping, was performed. RESULTS: 152 individuals (mean age 37±18 years, 53.3% males) from 18 families were evaluated. 65 carriers of the IVS23+1G→A mutation were identified, 61.5% of whom met HCM diagnostic criteria. Penetrance of the disease increased with age, with 50% affected at 46 years of age. Males tended to develop the disease earlier than females. 7 (15.6%) had systolic dysfunction. Compared with the rest of the HCM cohort, probands with the mutation had more hypertrophy and were younger at diagnosis. There was a trend towards a reduced survival free from sudden death (SD) (HR 1.71; 95% CI 0.98 to 2.98, p=0.059). There were 17 SD cases in 12 families with the mutation. CONCLUSIONS: The MYBPC3 IVS23+1G→A mutation is associated with middle-age onset disease and poor outcome, with a significant proportion of patients developing systolic impairment and a high SD risk profile.


Assuntos
Cardiomiopatia Hipertrófica Familiar/genética , Proteínas de Transporte/genética , Mutação/genética , Adulto , Idoso , Eletrocardiografia , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Penetrância , Fenótipo , Espanha
14.
Rev. lab. clín ; 3(3): 97-103, jul.-sept. 2010. tab
Artigo em Espanhol | IBECS | ID: ibc-85217

RESUMO

Introducción. El test combinado del primer trimestre permite seleccionar a las gestantes con un riesgo elevado de portar un feto con cromosomopatía con una sensibilidad y especificidad elevadas. Estas gestantes tras consejo genético pueden decidir someterse a una técnica invasiva para confirmar el diagnóstico. El objetivo de este trabajo es calcular la sensibilidad, el valor predictivo negativo y la tasa de falsos positivos del test combinado del primer trimestre en nuestro laboratorio. Material y métodos. Se estudiaron 4.494 gestantes (incluidas tanto las de embarazo único como gemelar) a las que se realizó el test combinado del primer trimestre: PAPP-A, b-HCG libre y translucencia nucal. Se comprobó el resultado del cariotipo en las gestantes cuyo cribado fue de riesgo elevado para Síndrome de Down (SD), de Edwards (SE) o ambos. En aquellas gestantes que decidieron no someterse a técnicas diagnósticas invasivas, se utilizó el cariotipo de los recién nacidos. El riesgo se calculó con el programa Prisca v.4.0.15.9® de DPC Dipesa® considerándose elevado un riesgo >1/270. Resultados. De todas las gestantes estudiadas, 260 mostraron un riesgo elevado: 201 para SD, 39 para SE y 20 para ambos. Se obtuvieron para SD y SE, respectivamente: verdaderos positivos (VP): 5 y 5; falsos positivos (FP): 216 y 54; verdaderos negativos (VN): 4273 y 4435; falsos negativos (FN): 0 y 0; Sensibilidad (S): 100% para ambos; Especificidad (E): 95% y 99%. Valor predictivo positivo (VPP): 2% y 8%; valor predictivo negativo(VPN): 100% para ambos. La tasa de falsos positivos fue del 4,83% para SD y de 1,20% para SE. Conclusiones. El cribado del primer trimestre es una herramienta eficaz que permite seleccionar a las gestantes con un riesgo >1/270 de portar un feto con cromosomopatía con una sensibilidad, especificidad y valor predictivo negativo elevados. Además su realización conlleva una disminución del número de técnicas diagnósticas invasivas (AU)


Introducción. El test combinado del primer trimestre permite seleccionar a las gestantes con un riesgo elevado de portar un feto con cromosomopatía con una sensibilidad y especificidad elevadas. Estas gestantes tras consejo genético pueden decidir someterse a una técnica invasiva para confirmar el diagnóstico. El objetivo de este trabajo es calcular la sensibilidad, el valor predictivo negativo y la tasa de falsos positivos del test combinado del primer trimestre en nuestro laboratorio. Material y métodos. Se estudiaron 4.494 gestantes (incluidas tanto las de embarazo único como gemelar) a las que se realizó el test combinado del primer trimestre: PAPP-A, b-HCG libre y translucencia nucal. Se comprobó el resultado del cariotipo en las gestantes cuyo cribado fue de riesgo elevado para Síndrome de Down (SD), de Edwards (SE) o ambos. En aquellas gestantes que decidieron no someterse a técnicas diagnósticas invasivas, se utilizó el cariotipo de los recién nacidos. El riesgo se calculó con el programa Prisca v.4.0.15.9(R) de DPC Dipesa(R) considerándose elevado un riesgo >1/270. Resultados. De todas las gestantes estudiadas, 260 mostraron un riesgo elevado: 201 para SD, 39 para SE y 20 para ambos. Se obtuvieron para SD y SE, respectivamente: verdaderos positivos (VP): 5 y 5; falsos positivos (FP): 216 y 54; verdaderos negativos (VN): 4273 y 4435; falsos negativos (FN): 0 y 0; Sensibilidad (S): 100% para ambos; Especificidad (E): 95% y 99%. Valor predictivo positivo (VPP): 2% y 8%; valor predictivo negativo (VPN): 100% para ambos. La tasa de falsos positivos fue del 4,83% para SD y de 1,20% para SE. Conclusiones. El cribado del primer trimestre es una herramienta eficaz que permite seleccionar a las gestantes con un riesgo >1/270 de portar un feto con cromosomopatía con una sensibilidad, especificidad y valor predictivo negativo elevados. Además su realización conlleva una disminución del número de técnicas diagnósticas invasivas (AU)


Assuntos
Humanos , Feminino , Gravidez , Adulto , Programas de Rastreamento/métodos , Síndrome de Down/diagnóstico , Síndrome de Down/genética , Síndrome de Down/prevenção & controle , Primeiro Trimestre da Gravidez/fisiologia , Valor Preditivo dos Testes , Sensibilidade e Especificidade , Biomarcadores/análise , Biomarcadores/sangue , Cariótipo/métodos , Citogenética/métodos , Estudos Retrospectivos , Coleta de Dados/tendências , Coleta de Dados
15.
Thromb Res ; 126(1): e46-50, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20156645

RESUMO

UNLABELLED: Hypertrophic cardiomyopathy (HCM) is characterised by inappropriate hypertrophy, small-vessel coronary artery disease, myocyte disarray and increased interstitial fibrosis. Microvascular dysfunction is a common finding in HCM and its extent has been proposed as an important prognostic marker. Plasma von Willebrand factor (vWf) is an established marker of endothelial damage or dysfunction; however it has scarcely been studied in HCM. We hypothesised that vWf could be raised in patients with HCM and be related to different variables associated with severity of HCM. METHODS: We included 124 HCM patients, 93 males, aged 48+/-15 years, 59 healthy control subjects with similar age and sex and 20 patients with ischemic heart disease but clinical stability for the last 6 months. A complete history and clinical examination was performed, including 12-lead electrocardiogram, echocardiography, 24 hours ECG-Holter monitoring, and symptom limited treadmill exercise test. Risk factors for sudden death were evaluated. A blinded cardiac MRI was performed with late enhanced study with Gadolinium. Plasma vWf levels were assayed by commercial ELISA. RESULTS: Patients showed higher levels of vWf (140.0+/-65.0 UI/ml vs 105.0+/-51.0 UI/ml, p<0.001) even after adjusting for ABO blood group. vWf levels were found raised in patients with severe functional class (168.4+/-65.9 UI/mL vs 132.4+/-60.7 UI/mL, p=0.020), atrial fibrillation (175.8+/-69.4 UI/mL vs 133.0+/-59.0 UI/mL, p=0.005), hypertension (161.4+/-60.8 vs 128.9+/-60.5, p=0.010) obstruction (153.9+/-67.9 vs 128.2+/-57.4 UI/mL, p=0.046) and non sustained ventricular tachycardia (159.3+/-59.1 vs 133.0+/-63.0, p=0.049). vWf correlated with age (r:0.26; p=0.006) and obstruction (r:0.22; p=0.021). CONCLUSIONS: We show, for the first time, patients with HCM present significantly raised levels of vWf. These are associated with different conditions related to the severity of the disease.


Assuntos
Cardiomiopatia Hipertrófica/diagnóstico , Cardiomiopatia Hipertrófica/fisiopatologia , Fator de von Willebrand/análise , Adulto , Biomarcadores/sangue , Cardiomiopatia Hipertrófica/complicações , Ecocardiografia/efeitos adversos , Eletrocardiografia/efeitos adversos , Eletrocardiografia Ambulatorial , Teste de Esforço/efeitos adversos , Gadolínio , Humanos , Hipertensão/complicações , Imagem por Ressonância Magnética/efeitos adversos , Masculino , Pessoa de Meia-Idade , Isquemia Miocárdica/complicações , Fatores de Risco
16.
Rev Esp Cardiol ; 61(8): 853-60, 2008 Aug.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-18684368

RESUMO

INTRODUCTION AND OBJECTIVES: Using gadolinium-enhanced cardiovascular magnetic resonance, it is possible to evaluate the presence of myocardial fibrosis in hypertrophic cardiomyopathy. Classical disease markers are weak predictors of functional disability in affected patients. Our objective was to study the relationship between the degree of myocardial fibrosis observed by cardiac magnetic resonance and exercise capacity. METHODS: We performed cardiac magnetic resonance, echocardiography, exercise testing and Holter monitoring, along with the usual clinical assessments, in 98 patients (age, 46.3+/-15.4 years, 71.4% male) referred from two specialist hypertrophic cardiomyopathy clinics. Cardiac magnetic resonance assessment included quantifying the degree of fibrosis (i.e., the percentage of the myocardium showing enhancement) 10 min after gadolinium infusion. Symptom-limited exercise testing was used to determine exercise capacity (in metabolic equivalent [MET] units). In 71 patients, the basal N-terminal probrain natriuretic peptide (NT-proBNP) level was also measured. RESULTS: Late enhancement was observed on cardiac magnetic resonance in 67 (68.4%) patients. These patients had a lower exercise capacity (8.04+/-3.56 MET vs. 10.41+/-3.57 MET; P=.003). There was an inverse correlation between the percentage of fibrosis and exercise capacity (r=-0.21; P=.044). The best predictor of exercise capacity was the logarithm of the NT-proBNP level (r=-0.5; P< .0001). Multivariate analysis confirmed that age, a history of atrial fibrillation, the basal NT-proBNP level and the presence of fibrosis were independent predictors of exercise capacity (r2 for the model=0.47). CONCLUSIONS: The observation of areas of late gadolinium enhancement on cardiac magnetic resonance was independently associated with poor exercise capacity in patients with hypertrophic cardiomyopathy.


Assuntos
Cardiomiopatia Hipertrófica/diagnóstico , Meios de Contraste , Teste de Esforço , Gadolínio , Imagem por Ressonância Magnética , Feminino , Humanos , Imagem por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade
17.
Am Heart J ; 156(1): 85-91, 2008 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-18585501

RESUMO

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is defined by the presence of unexplained left ventricular hypertrophy, myocyte disarray, and interstitial fibrosis. An increase in extracellular matrix produces interstitial fibrosis, by raised amounts of collagen type I/III. Regions of myocardial late gadolinium enhancement by cardiac magnetic resonance (CMR) represented increased myocardial collagen. Regarding the role of matrix metalloproteinases (MMPs) in myocardial remodeling and subsequent fibrosis, the aim of our study was to explore the relation between MMP system and myocardial late gadolinium enhancement by CMR (as expression of image-documented fibrosis) and N-terminal pro-brain natriuretic peptide (NT-proBNP) (as a marker of cardiac overload) in HCM. METHODS: We included 67 HCM patients (44 men aged 49 +/- 14 years) and were compared to 58 controls with similar age and sex. Risk factors for sudden death were recorded. A blinded CMR was performed with gadolinium. Matrix metalloproteinase 1, MMP-2, and MMP-9 plasma levels were assayed by enzyme-linked immunosorbent assay. Serum samples were used for measurement of NT-proBNP. RESULTS: In patients, >50% of MMP-1 values were below the lowest limit of detection of the technique. Raised levels of MMP-2, MMP-9, and NT-proBNP were observed in HCM patients (all P < .01). Matrix metalloproteinase 2 was associated with dyspnea (P = .049) and correlated with MMP-9 (r = 0.28, P = .025) and NT-proBNP (r = 0.39, P = .001). Matrix metalloproteinase 9 was associated with the presence of gadolinium enhancement in CMR (P = .001) and correlated with NT-proBNP (r = 0.52, P < .001). NT-proBNP was also associated with gadolinium enhancement (P = .006). Both MMP-2 and MMP-9 correlated negatively with exercise capacity (metabolic equivalent units), (r = -0.36 and r = -0.42 respectively, both P < .01). On multivariate analysis (adjusted by sudden death risk factors and echocardiographic markers), only MMP-9 was associated with fibrosis (P = .011). CONCLUSIONS: Matrix metalloproteinase 9 is independently associated with gadolinium enhancement on CMR in patients with hypertrophic cardiomyopathy, suggesting that the MMP system has an important role in cardiac remodeling and fibrosis in this condition.


Assuntos
Cardiomiopatia Hipertrófica/diagnóstico , Aumento da Imagem , Metaloproteinases da Matriz/sangue , Remodelação Ventricular/fisiologia , Adulto , Biomarcadores/sangue , Cardiomiopatia Hipertrófica/sangue , Cardiomiopatia Hipertrófica/mortalidade , Estudos de Casos e Controles , Estudos de Coortes , Ensaio de Imunoadsorção Enzimática , Feminino , Gadolínio DTPA , Humanos , Imagem por Ressonância Magnética , Masculino , Metaloproteinase 1 da Matriz/sangue , Metaloproteinase 2 da Matriz/sangue , Metaloproteinase 9 da Matriz/sangue , Pessoa de Meia-Idade , Probabilidade , Prognóstico , Valores de Referência , Sensibilidade e Especificidade , Índice de Gravidade de Doença , Análise de Sobrevida , Inibidor Tecidual de Metaloproteinase-1/sangue
18.
Rev. esp. cardiol. (Ed. impr.) ; 61(8): 853-860, ago. 2008. ilus, tab
Artigo em Espanhol | IBECS | ID: ibc-66614

RESUMO

Introducción y objetivos. La cardiorresonancia magnéticacon gadolinio permite estudiar la fibrosis miocárdicaen la miocardiopatía hipertrófica. Los marcadores clásicos de la enfermedad predicen débilmente la limitación funcional de estos pacientes. Nuestro objetivo es estudiar la relación entre la fibrosis en la cardiorresonancia magnética y la capacidad de ejercicio.Métodos. Se realizó cardiorresonancia magnética, ecocardiografía, ergometría y Holter, junto con la valoración clínica habitual, a 98 pacientes procedentes de dos consultas especializadas de miocardiopatía hipertrófica (edad, 46,3 ± 15,4 años; el 71,4% varones). El estudio de cardiorresonancia magnética incluyó cuantificación de fibrosis (porcentaje de miocardio realzado) 10 min tras la inyección de gadolinio. Mediante ergometría limitada por síntomas, se determinó la capacidad de esfuerzo (MET). En 71 pacientes se obtuvieron además concentraciones plasmáticas basales de NT-proBNP.Resultados. Presentaron áreas de realce tardío en lacardiorresonancia magnética 67 (68,4%) pacientes. Estospacientes tenían peor capacidad de esfuerzo (8,04 ± 3,56frente a 10,41 ± 3,57 MET; p = 0,003). Se observó correlación negativa entre el porcentaje de fibrosis y los MET alcanzados (r = –0,21; p = 0,044). El mejor predictor de capacidad de esfuerzo fue el logNT-proBNP (r = –0,5; p <0,0001). El análisis multivariado confirmó que la edad, los antecedentes de fibrilación auricular, las concentraciones basales de NT-proBNP y la fibrosis son predictores independientes de la capacidad de esfuerzo (r2 del modelo = 0,47).Conclusiones. La presencia de áreas de realce tardíocon gadolinio en la cardiorresonancia magnética se asociade forma independiente con una peor capacidad deesfuerzo en pacientes con miocardiopatía hipertrófica


Introduction and objectives. Using gadoliniumenhancedcardiovascular magnetic resonance, it ispossible to evaluate the presence of myocardial fibrosis in hypertrophic cardiomyopathy. Classical disease markersare weak predictors of functional disability in affectedpatients. Our objective was to study the relationshipbetween the degree of myocardial fibrosis observed bycardiac magnetic resonance and exercise capacity.Methods. We performed cardiac magnetic resonance,echocardiography, exercise testing and Holter monitoring,along with the usual clinical assessments, in 98 patients(age, 46.3±15.4 years, 71.4% male) referred from twospecialist hypertrophic cardiomyopathy clinics. Cardiacmagnetic resonance assessment included quantifying thedegree of fibrosis (i.e., the percentage of the myocardium showing enhancement) 10 min after gadolinium infusion. Symptom-limited exercise testing was used to determine exercise capacity (in metabolic equivalent [MET] units). In 71 patients, the basal N-terminal probrain natriuretic peptide (NT-proBNP) level was also measured.Results. Late enhancement was observed on cardiacmagnetic resonance in 67 (68.4%) patients. Thesepatients had a lower exercise capacity (8.04±3.56 METvs. 10.41±3.57 MET; P=.003). There was an inversecorrelation between the percentage of fibrosis andexercise capacity (r=–0.21; P=.044). The best predictor of exercise capacity was the logarithm of the NT-proBNPlevel (r=–0.5; P<.0001). Multivariate analysis confirmedthat age, a history of atrial fibrillation, the basalNT-proBNP level and the presence of fibrosis wereindependent predictors of exercise capacity (r2 for themodel=0.47).Conclusions. The observation of areas of lategadolinium enhancement on cardiac magnetic resonancewas independently associated with poor exercise capacityin patients with hypertrophic cardiomyopathy


Assuntos
Humanos , Cardiomiopatia Hipertrófica/fisiopatologia , Espectroscopia de Ressonância Magnética/métodos , Gadolínio , Teste de Esforço , Morte Súbita Cardíaca/prevenção & controle , Ergometria/métodos
19.
J Card Fail ; 14(5): 414-9, 2008 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-18514934

RESUMO

BACKGROUND: Hypertrophic cardiomyopathy (HCM) shows increased myocardial collagen and disarray. Late gadolinium enhancement in cardiovascular magnetic resonance (CMR) is observed in regions of increased myocardial collagen. The extent of late gadolinium enhancement has been associated with higher prevalence of risk factors of sudden death. The aim of the present study was to describe the clinical characteristics and the presence of risk factors for sudden death in a series of patients from 2 referral centers for HCM in relation to late gadolinium enhancement in CMR. METHODS AND RESULTS: A total of 120 patients (47 +/- 16 years) were included. All patients fulfilled conventional criteria for HCM. A complete history and clinical examination were performed. Risk factors for sudden death were evaluated. A blinded CMR was performed with late gadolinium enhancement in the left ventricular short-axis orientation. NT pro B-type natriuretic protein (BNP) and C-reactive protein were determined in serum samples. A total of 83 patients (69%) showed late gadolinium enhancement. These patients had higher maximal left ventricular wall thickness (22 +/- 5 versus 17 +/- 3 mm, P < .001), showed more frequently obstruction (42% versus 16%, P = .006), nonsustained ventricular tachycardia (38% versus 8%, P = .001), worse exercise capacity (8 +/- 4 versus 10 +/- 4 METs, P = .003) and increased levels of NT BNP (656 [300-1948] versus 290 [122-948] pg/mL, P = .020). On multivariate analysis, maximal left ventricular wall thickness (P < .001) and nonsustained ventricular tachycardia (P = .011) remained associated with gadolinium-enhanced imaging. Number of risk factors for sudden death was associated with late gadolinium enhancement (OR 2.18, 95%CI 1.45-3.20, P < .001). CONCLUSIONS: Late gadolinium enhancement in CMR is a common finding in HCM. Increased maximal left ventricular wall thickness and nonsustained ventricular tachycardia are associated with late gadolinium enhancement. Associations with risk factors for sudden death and functional status are observed.


Assuntos
Cardiomiopatia Hipertrófica/diagnóstico , Cardiomiopatia Hipertrófica/fisiopatologia , Morte Súbita Cardíaca/etiologia , Gadolínio , Imagem Cinética por Ressonância Magnética , Proteína C-Reativa/metabolismo , Cardiomiopatia Hipertrófica/complicações , Meios de Contraste , Morte Súbita Cardíaca/prevenção & controle , Teste de Esforço , Tolerância ao Exercício , Feminino , Fibrose/diagnóstico , Humanos , Imagem Cinética por Ressonância Magnética/instrumentação , Imagem Cinética por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Peptídeo Natriurético Encefálico/sangue , Fragmentos de Peptídeos/sangue , Estudos Prospectivos , Fatores de Risco
20.
Brain Res ; 1170: 119-28, 2007 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-17719017

RESUMO

Numerous studies have tested for associations between an intronic polymorphism (rs165932) of presenilin-1 (PS-1) gene and the risk of Alzheimer's disease (AD), but results have been conflicting. To throw light on this issue, we investigate the possible involvement of PS-1 genotype in a case-control study based on a relatively stable population in Spain and a meta-analysis of published studies. An examination was conducted of 85 patients with probable or possible AD, along with controls from the same community, by using an chi(2) test for homogeneity and a binary logistic regression model. For comparison purposes, a meta-analysis of data from all available published studies was assessed. In our patients, homozygosity of the allele 2 in the PS-1 gene increased for late-onset AD (OR 2.38, 95% CI 1.07-5.29, P<0.05). The presence of at least one allele of apoE was also associated with AD (OR 4.01, 95% CI 1.93-8.34, p<0.05). The regression model showed that, overall, the presence of the apoE epsilon 4 allele and the PS-1 2/2 genotype were independent factors for the development of AD in our sample. In our genotype-based meta-analysis, the PS-1 2/2 genotype was probably related with AD for the European sub-group (fixed effects model, OR 1.19, 95% CI 1.02-1.37, p<0.05), but there are many confusing factors between different studies. Presenilin-1 2/2 genotype is a risk factor for late onset Alzheimer disease in the Spanish population, and probably, for Europeans.


Assuntos
Doença de Alzheimer/epidemiologia , Doença de Alzheimer/genética , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla/estatística & dados numéricos , Polimorfismo Genético/genética , Presenilina-1/genética , Apolipoproteína E4/genética , Estudos de Casos e Controles , Análise Mutacional de DNA , Frequência do Gene/genética , Testes Genéticos , Genótipo , Humanos , Íntrons/genética , Risco , Espanha/epidemiologia
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