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1.
Exp Mol Pathol ; 114: 104402, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32061942

RESUMO

The aim of this study was to investigate the roles of CD4+ T cells and transforming growth factor beta (TGFß1) in the pathological process of valvular hyperblastosis and fibrosis of patients with rheumatic heart disease (RHD). A total of 151 patients were enrolled, among whom, 78 patients were with RHD, and 73 were age and gender matched RHD negative patients. Blood samples and valve specimens were collected for analysis. Pathological changes and collagen fibers contents of valves were analyzed using HE and Masson staining. Percentage of peripheral blood CD4+ T cells was tested through flow cytometry. TGFß1 level in serum were identified by ELISA. CD4+ T cells infiltration and expression of TGFß1, p-p38, p-JNK, p-ERK in valves were detected by immunohistochemistry. The mRNA and protein levels of p38, JNK, ERK, TGFß1, I-collagen and α-SMA were detected by qRT-PCR and western blotting, respectively. The heart valve tissues of RHD patients showed higher degrees of fibrosis, calcification and lymphocytes infiltration, which were mainly CD4+ T cells. In addition, compared with control group, RHD patients had more total CD4+ T cells in peripheral blood and valve tissues. Expression of TGFß1, phosphorylation of JNK and p38, and synthesis of I-collagen in valve tissues of RHD patients were also significantly increased. Furthermore, we found a strong positive correlation between TGFß1 expression and phosphorylation of JNK and p38. CD4+ T cells, and fibrogenic cytokine TGFß1, which activate the intracellular MAPK signaling pathway may participate in the fibrosis of heart valve in RHD patients.


Assuntos
Doenças das Valvas Cardíacas/genética , Estenose da Valva Mitral/genética , Cardiopatia Reumática/genética , Fator de Crescimento Transformador beta1/genética , Adulto , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD4-Positivos/fisiologia , MAP Quinases Reguladas por Sinal Extracelular/sangue , MAP Quinases Reguladas por Sinal Extracelular/genética , Feminino , Fibrose/sangue , Fibrose/genética , Fibrose/patologia , Regulação da Expressão Gênica/genética , Doenças das Valvas Cardíacas/sangue , Doenças das Valvas Cardíacas/patologia , Humanos , MAP Quinase Quinase 4/sangue , MAP Quinase Quinase 4/genética , Sistema de Sinalização das MAP Quinases/genética , Masculino , Pessoa de Meia-Idade , Estenose da Valva Mitral/sangue , Estenose da Valva Mitral/patologia , Cardiopatia Reumática/sangue , Cardiopatia Reumática/patologia , Fator de Crescimento Transformador beta1/sangue , Proteínas Quinases p38 Ativadas por Mitógeno/sangue , Proteínas Quinases p38 Ativadas por Mitógeno/genética
2.
Cardiology ; 142(4): 253-258, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31163449

RESUMO

OBJECTIVE: It is increasingly recognized that cardiac amyloidosis can occur in patients with severe aortic stenosis undergoing both surgical and transcatheter valve replacements. We aimed to investigate whether unrecognized cardiac amyloidosis may also occur in patients with severe mitral valve disease undergoing surgery. METHODS: The pathology department database at our center was retrospectively analyzed over a 10-year period for cases in which the mitral valve or another type of cardiac tissue removed at the time of mitral surgery demonstrated incidental amyloidosis. Clinical and echocardiographic variables were collected from the electronic medical record and the echocardiographic database. RESULTS: Between 2007 and 2016, a total of 7,733 mitral valve surgical specimens were received. Of these, there were 15 cases in which the mitral valve, or another type of cardiac tissue removed at surgery, demonstrated incidentally detected amyloidosis. The most frequent comorbidities were hypertension (87%) and atrial fibrillation (80%); 13 patients (87%) underwent bioprosthetic mitral valve replacement, and 2 patients (13%) underwent mitral valve repair. Sites of amyloid deposition were the mitral valve (80%), left atrial appendage (33%), and subaortic tissue (7%); 14 patients (93%) had wild-type transthyretin amyloid. The mean duration of follow-up was 1,023 days (range: 29-2,811 days). There were no surgical complications in the follow-up period. CONCLUSIONS: Over a 10-year period, incidentally detected cardiac amyloidosis occurred in 0.2% of the mitral valve surgical cases. The outcomes for these patients undergoing mitral valve surgery were excellent, with no complications or deaths attributable to surgery at a mean follow-up of 1,023 days.


Assuntos
Amiloidose/epidemiologia , Amiloidose/patologia , Estenose da Valva Mitral/genética , Idoso , Idoso de 80 Anos ou mais , Comorbidade , Feminino , Humanos , Masculino , Valva Mitral/patologia , Valva Mitral/cirurgia , Estenose da Valva Mitral/epidemiologia , Estenose da Valva Mitral/patologia , Estenose da Valva Mitral/cirurgia , Estudos Retrospectivos
3.
Front Immunol ; 9: 3009, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30619357

RESUMO

Rheumatic fever (RF) and its subsequent progression to rheumatic heart disease (RHD) are chronic inflammatory disorders prevalent in children and adolescents in underdeveloped countries, and a contributing factor for high morbidity and mortality rates worldwide. Their primary cause is oropharynx infection by Streptococcus pyogenes, whose acetylated residues are recognized by ficolin-1. This is the only membrane-bound, as well as soluble activator molecule of the complement lectin pathway (LP). Although LP genetic polymorphisms are associated with RF, FCN1 gene's role remains unknown. To understand this role, we haplotyped five FCN1 promoter polymorphisms by sequence-specific amplification in 193 patients (138 with RHD and 55, RF only) and 193 controls, measuring ficolin-1 serum concentrations in 78 patients and 86 controls, using enzyme-linked immunosorbent assay (ELISA). Patients presented lower ficolin-1 serum levels (p < 0.0001), but did not differ according to cardiac commitment. Control's genotype distribution was in the Hardy-Weinberg equilibrium. Four alleles (rs2989727: c.-1981A, rs10120023: c.-542A, rs10117466: c.-144A, and rs10858293: c.33T), all associated with increased FCN1 gene expression in whole blood or adipose subcutaneous tissue (p = 0.000001), were also associated with increased protection against the disease. They occur within the *3C2 haplotype, associated with an increased protection against RF (OR = 0.41, p < 0.0001) and with higher ficolin-1 levels in patient serum (p = 0.03). In addition, major alleles of these same polymorphisms comprehend the most primitive *1 haplotype, associated with increased susceptibility to RF (OR = 1.76, p < 0.0001). Nevertheless, instead of having a clear-cut protective role, the minor c.-1981A and c.-144A alleles were also associated with additive susceptibility to valvar stenosis and mitral insufficiency (OR = 3.75, p = 0.009 and OR = 3.37, p = 0.027, respectively). All associations were independent of age, sex or ethnicity. Thus, minor FCN1 promoter variants may play a protective role against RF, by encouraging bacteria elimination as well as increasing gene expression and protein levels. On the other hand, they may also predispose the patients to RHD symptoms, by probably contributing to chronic inflammation and tissue injury, thus emphasizing the dual importance of ficolin-1 in both conditions.


Assuntos
Lectinas/genética , Estenose da Valva Mitral/genética , Cardiopatia Reumática/genética , Streptococcus pyogenes/imunologia , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Progressão da Doença , Feminino , Predisposição Genética para Doença , Haplótipos/genética , Haplótipos/imunologia , Humanos , Lectinas/sangue , Lectinas/imunologia , Lectinas/metabolismo , Masculino , Pessoa de Meia-Idade , Estenose da Valva Mitral/sangue , Estenose da Valva Mitral/imunologia , Estenose da Valva Mitral/microbiologia , Polimorfismo de Nucleotídeo Único , Regiões Promotoras Genéticas/genética , Cardiopatia Reumática/sangue , Cardiopatia Reumática/imunologia , Cardiopatia Reumática/microbiologia , Adulto Jovem , Ficolinas
4.
Indian J Med Res ; 144(5): 718-724, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28361825

RESUMO

BACKGROUND & OBJECTIVES: Right ventricular (RV) dysfunction is one of the causes of morbidity and mortality in valvular heart disease. The phenomenon of apoptosis, though rare in cardiac muscle may contribute to loss of its function. Role of apoptosis in RV in patients with rheumatic valvular heart disease is investigated in this study. METHODS: Patients with rheumatic mitral valve stenosis formed two groups based on RV systolic pressure (RVSP) as RVSP <40 mmHg (group I, n=9) and RVSP ≥40 mmHg (group II, n=30). Patients having atrial septal defect (ASD) with RVSP <40 mmHg served as control (group III, n=15). Myocardial performance index was assessed for RV function. Real-time polymerase chain reaction was performed on muscle biopsy procured from RV to assess expression of pro-apoptotic genes (Bax, cytochrome c, caspase 3 and Fas) and anti-apoptotic genes (Bcl-2). Apoptosis was confirmed by histopathology and terminal deoxynucleotide-transferase-mediated dUTP nick end labelling. RESULTS: Group II had significant RV dysfunction compared to group I (P=0.05) while caspase 3 (P=0.01) and cytochrome c (P=0.03) were expressed excessively in group I. When group I was compared to group III (control), though there was no difference in RV function, a highly significant expression of pro-apoptotic genes was observed in group I (Bax, P=0.02, cytochrome c=0.001 and caspase 3=0.01). There was a positive correlation between pro-apoptotic genes. Nuclear degeneration was present conforming to apoptosis in valve disease patients (groups I and II) while it was absent in patients with ASD. INTERPRETATION & CONCLUSION: Our findings showed evidence of apoptosis in RV of patients with valvular heart disease. Apoptosis was set early in the course of rheumatic valve disease even with lower RVSP, followed by RV dysfunction; however, expression of pro-apoptotic genes regressed.


Assuntos
Apoptose/genética , Estenose da Valva Mitral/fisiopatologia , Cardiopatia Reumática/fisiopatologia , Disfunção Ventricular Direita/genética , Adolescente , Adulto , Idoso , Biópsia , Ecocardiografia , Feminino , Valvas Cardíacas/patologia , Valvas Cardíacas/cirurgia , Ventrículos do Coração/patologia , Ventrículos do Coração/cirurgia , Humanos , Masculino , Pessoa de Meia-Idade , Estenose da Valva Mitral/genética , Estenose da Valva Mitral/cirurgia , Cardiopatia Reumática/genética , Cardiopatia Reumática/cirurgia , Disfunção Ventricular Direita/fisiopatologia , Disfunção Ventricular Direita/cirurgia , Adulto Jovem
5.
PLoS One ; 10(6): e0128965, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26039365

RESUMO

OBJECTIVE: Valvular calcification occurs via ongoing endothelial injury associated with inflammation. IL-10 is an anti-inflammatory cytokine and 75% of the variation in IL-10 production is genetically determined. However, the relationship between genetic polymorphisms of IL-10 and valvular calcification has not been studied. The objective of this study was to investigate the association between valvular calcification and IL-10 genetic polymorphisms in the Han, Uygur and Kazak populations in China. PATIENTS AND METHODS: All of the participants were selected from subjects participating in the Cardiovascular Risk Survey (CRS) study. The single nucleotide polymorphisms (SNPs) rs1800871 and rs1800872 of the IL-10 gene were genotyped using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Three independent case-control studies involving the Han population, the Uygur population and the Kazak population were used in the analysis. RESULTS: For the Han and Kazak populations, rs1800871 was found to be associated with valvular calcification in the recessive model, and the difference remained statistically significant following multivariate adjustment (p<0.001, p=0.031, respectively). For the Han, Uygur and Kazak populations, rs1800872 was found to be associated with valvular calcification in the dominant model, and the difference remained statistically significant following multivariate adjustment (p<0.001, p=0.009, and p=0.023,respectively). CONCLUSION: Both rs1800871 and rs1800872 of the IL-10 gene are associated with valvular calcification in the Han and Kazak populations in China. Rs1800872 is also associated with valvular calcification in the Uygur population.


Assuntos
Estenose da Valva Aórtica/genética , Valva Aórtica/patologia , Calcinose/genética , Interleucina-10/genética , Estenose da Valva Mitral/genética , Polimorfismo de Nucleotídeo Único , Idoso , Estenose da Valva Aórtica/diagnóstico , Estenose da Valva Aórtica/etnologia , Estenose da Valva Aórtica/patologia , Calcinose/diagnóstico , Calcinose/etnologia , Calcinose/patologia , Estudos de Casos e Controles , China , Etnicidade , Feminino , Expressão Gênica , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Estenose da Valva Mitral/diagnóstico , Estenose da Valva Mitral/etnologia , Estenose da Valva Mitral/patologia , Fatores de Risco
6.
J Thorac Cardiovasc Surg ; 148(5): 1970-6, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24412254

RESUMO

OBJECTIVE: This study demonstrated left atrial endocardial dysfunction and platelet activation in patients with atrial fibrillation and mitral stenosis. METHODS: Study included 80 patients with mitral stenosis and atrial fibrillation (40 each with and without left atrial thrombosis), 15 healthy volunteers, and 10 left atrial appendage (LAA) specimens from donor hearts. Blood samples were collected through peripheral vein and left atrium, with peripheral blood samples of volunteers as controls. LAA specimens were collected during operations. LAA expressions of von Willebrand factor (vWF) and P-selectin were determined immunohistochemically; plasma concentrations were measured by enzyme-linked immunosorbent assay. LAA expressions of vWF and P-selectin genes in were quantitated with real-time fluorescent quantitative polymerase chain reaction. RESULTS: The difference in vWF and P-selectin plasma levels between left atrial and peripheral venous blood was not significant; however, peripheral plasma levels of vWF and P-selectin were significantly higher in those with thrombosis than without thrombosis, which in turn were higher than in healthy subjects. Both vWF and P-selectin proteins were stained in both left atrial endocardium and cardiomyocytes. The normalized vWF gene expression relative to control was 3.04 in patients with thrombosis and 2.16 in those without thrombosis (P<.01). The difference in P-selectin gene expressions among the groups was not significant. CONCLUSIONS: No differences were observed in plasma levels of vWF and P-selectin between left atrial and peripheral venous blood. Over expression of vWF gene in LAA may contribute to increased plasma vWF levels. P-selectin and vWF together may play a role in thrombosis.


Assuntos
Fibrilação Atrial/complicações , Função do Átrio Esquerdo , Endocárdio/fisiopatologia , Estenose da Valva Mitral/complicações , Ativação Plaquetária , Trombose/etiologia , Adulto , Apêndice Atrial/química , Fibrilação Atrial/sangue , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/genética , Fibrilação Atrial/fisiopatologia , Biomarcadores/sangue , Estudos de Casos e Controles , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Estenose da Valva Mitral/sangue , Estenose da Valva Mitral/diagnóstico , Estenose da Valva Mitral/genética , Estenose da Valva Mitral/fisiopatologia , Selectina-P/sangue , Selectina-P/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Trombose/sangue , Trombose/diagnóstico , Trombose/genética , Trombose/fisiopatologia , Fator de von Willebrand/análise , Fator de von Willebrand/genética
7.
BMC Cardiovasc Disord ; 14: 10, 2014 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-24461008

RESUMO

BACKGROUND: Structural changes of the left and right atria associated with atrial fibrillation (AF) in mitral stenosis (MS) patients are well known, and alterations in microRNA (miRNA) expression profiles of the right atria have also been investigated. However, miRNA changes in the left atria still require delineation. This study evaluated alterations in miRNA expression profiles of left atrial tissues from MS patients with AF relative to those with normal sinus rhythm (NSR). METHODS: Sample tissues from left atrial appendages were obtained from 12 MS patients (6 with AF) during mitral valve replacement surgery. From these tissues, miRNA expression profiles were created and analyzed using a human miRNA microarray. Results were validated via reverse-transcription and quantitative PCR for 5 selected miRNAs. Potential miRNA targets were predicted and their functions and potential pathways analyzed via the miRFocus database. RESULTS: The expression levels of 22 miRNAs differed between the AF and NSR groups. Relative to NSR patients, in those with AF the expression levels of 45% (10/22) of these miRNAs were significantly higher, while those of the balance (55%, 12/22) were significantly lower. Potential miRNA targets and molecular pathways were identified. CONCLUSIONS: AF alters the miRNA expression profiles of the left atria of MS patients. These findings may be useful for the biological understanding of AF in MS patients.


Assuntos
Apêndice Atrial/química , Fibrilação Atrial/genética , Perfilação da Expressão Gênica , MicroRNAs/análise , Estenose da Valva Mitral/genética , Adulto , Fibrilação Atrial/diagnóstico , Estudos de Casos e Controles , Feminino , Perfilação da Expressão Gênica/métodos , Regulação da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Masculino , Pessoa de Meia-Idade , Estenose da Valva Mitral/diagnóstico , Análise de Sequência com Séries de Oligonucleotídeos , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa
9.
Rev. bras. cir. cardiovasc ; 27(4): 512-519, out.-dez. 2012. ilus, tab
Artigo em Inglês | LILACS | ID: lil-668112

RESUMO

OBJECTIVES: Rheumatic fever is a highly prevalent disease in Brazil, and it poses a major public health problem. It is the leading cause of acquired heart disease in childhood and adolescence. The aim of this study was to evaluate the gene expression of ET-3 and its receptors, in replaced rheumatic mitral valves. METHODS: We studied the gene expression of endothelin-3 (ET-3) and its receptors, endothelin receptor A and endothelin receptor B (ETr-A and ETr-B), in the rheumatic mitral valves of 17 patients who underwent valve replacement surgery. The samples also underwent a histological analysis. RESULTS: Our data showed that almost all patients, regardless of individual characteristics such as gender or age, expressed the endothelin receptor genes, but did not express the genes for ET-3. In quantitative analysis, the ETr-A/GAPDH mean ratio was 33.04 ± 18.09%; while the ETr-B/GAPDH mean ratio was 114.58 ± 42.30%. Regarding histopathological individual features, the frequency of fibrosis is 100%, 88.23% of mononuclear infiltrate, 52.94% of neovascularization, 58.82% of calcification and absence of ossification. CONCLUSION: The presence of receptors ETr-A and ETr-B in rheumatic mitral valves suggests its interaction with the system of circulating endothelins, particularly ETr-B (known for acting in the removal of excess endothelin) detected in a greater proportion, which could explain the lack of expression of endothelin in rheumatic mitral valve, process to be elucidated.


OBJETIVOS: A febre reumática é uma doença altamente prevalente no Brasil, e representa um importante problema de saúde pública. É a principal causa de cardiopatia adquirida na infância e adolescência. O objetivo deste estudo foi avaliar a expressão gênica de ET-3 e seus receptores, em valvas mitrais reumáticas substituídas. Métodos: Estudamos a expressão gênica de endotelina-3 (ET-3) e de seus receptores, receptor da endotelina A e receptor da endotelina B (ETr-A e ETr-B), nas valvas mitrais reumáticas de 17 pacientes que se submeteram à cirurgia de troca valvar. As amostras também foram submetidas à análise histológica. RESULTADOS: Nossos dados mostraram que praticamente todos os pacientes, independentemente de características individuais, como sexo ou idade, expressaram os genes de receptores de endotelina, porém não expressaram os genes para ET-3. Na análise quantitativa, a média da proporção ETr-A/GAPDH foi de 33,04 ± 18,09%; enquanto que a média da proporção ETr-B/GAPDH foi de 114,58 ± 42,30%. Em relação às características histopatológicas individuais, a frequência de fibrose foi de 100%, infiltrado mononuclear de 88,23%, neovascularização de 52,94%, calcificação de 58,82% e houve ausência de ossificação. CONCLUSÃO: A presença de receptores ETr-A e ETr-B em valvas mitrais reumáticas sugere sua interação com o sistema de endotelinas circulantes, particularmente ETr-B (reconhecido por atuar na remoção do excesso de endotelina), detectado em maior proporção, o que poderia explicar a ausência da expressão de endotelina em valva mitral reumática, processo a ser elucidado.


Assuntos
Adulto , Feminino , Humanos , Masculino , /genética , Expressão Gênica/genética , Estenose da Valva Mitral/genética , Receptor de Endotelina A/genética , Receptor de Endotelina B/genética , Cardiopatia Reumática/genética , /metabolismo , Implante de Prótese de Valva Cardíaca , Estenose da Valva Mitral/cirurgia , Receptor de Endotelina A/metabolismo , Receptor de Endotelina B/metabolismo , Cardiopatia Reumática/metabolismo , Cardiopatia Reumática/cirurgia
10.
Rev Bras Cir Cardiovasc ; 27(4): 512-9, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23515723

RESUMO

OBJECTIVES: Rheumatic fever is a highly prevalent disease in Brazil, and it poses a major public health problem. It is the leading cause of acquired heart disease in childhood and adolescence. The aim of this study was to evaluate the gene expression of ET-3 and its receptors, in replaced rheumatic mitral valves. METHODS: We studied the gene expression of endothelin-3 (ET-3) and its receptors, endothelin receptor A and endothelin receptor B (ETr-A and ETr-B), in the rheumatic mitral valves of 17 patients who underwent valve replacement surgery. The samples also underwent a histological analysis. RESULTS: Our data showed that almost all patients, regardless of individual characteristics such as gender or age, expressed the endothelin receptor genes, but did not express the genes for ET-3. In quantitative analysis, the ETr-A/GAPDH mean ratio was 33.04 ± 18.09%; while the ETr-B/GAPDH mean ratio was 114.58 ± 42.30%. Regarding histopathological individual features, the frequency of fibrosis is 100%, 88.23% of mononuclear infiltrate, 52.94% of neovascularization, 58.82% of calcification and absence of ossification. CONCLUSION: The presence of receptors ETr-A and ETr-B in rheumatic mitral valves suggests its interaction with the system of circulating endothelins, particularly ETr-B (known for acting in the removal of excess endothelin) detected in a greater proportion, which could explain the lack of expression of endothelin in rheumatic mitral valve, process to be elucidated.


Assuntos
Endotelina-3/genética , Expressão Gênica/genética , Estenose da Valva Mitral/genética , Receptor de Endotelina A/genética , Receptor de Endotelina B/genética , Cardiopatia Reumática/genética , Adulto , Endotelina-3/metabolismo , Feminino , Implante de Prótese de Valva Cardíaca , Humanos , Masculino , Estenose da Valva Mitral/cirurgia , Receptor de Endotelina A/metabolismo , Receptor de Endotelina B/metabolismo , Cardiopatia Reumática/metabolismo , Cardiopatia Reumática/cirurgia
12.
Physiol Genomics ; 43(11): 655-64, 2011 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-21325063

RESUMO

The aim of this study was to investigate the microRNA (miRNA) signature in atrial fibrillation (AF) with mitral stenosis (MS). miRNA arrays were used to evaluate the expression signature of the right atrial appendages of healthy individuals (n=9), patients with MS and AF (n=9) and patients with MS without AF (n=4). The results were validated with qRT-PCR analysis. GOmir was used to predict the potential miRNA targets and to analyze their functions. DIANA-mirPath was used to incorporate the miRNAs into pathways. miRNA arrays revealed that 136 and 96 miRNAs were expressed at different levels in MS patients with AF and in MS patients without AF, respectively, compared with healthy controls. More importantly, 28 miRNAs were expressed differently in the MS patients with AF compared with the MS patients without AF; of these miRNAs, miR-1202 was the most dysregulated. The unsupervised hierarchical clustering analysis based on the 28 differently expressed miRNAs showed that the heat map of miRNA expression categorized two well-defined clusters that corresponded to MS with AF and MS without AF. The qRT-PCR results correlated well with the microarray data. Bioinformatic analysis indicated the potential miRNA targets and molecular pathways. This study shows that there is a distinct miRNA expression signature in AF with MS. The findings may be useful for the development of therapeutic interventions that are based on rational target selection in these patients.


Assuntos
Fibrilação Atrial/genética , MicroRNAs/genética , Estenose da Valva Mitral/genética , Adulto , Idoso , Fibrilação Atrial/complicações , Fibrilação Atrial/metabolismo , Análise por Conglomerados , Feminino , Perfilação da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Estenose da Valva Mitral/etiologia , Estenose da Valva Mitral/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos
13.
Hemodial Int ; 13(2): 176-80, 2009 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19432691

RESUMO

Cardiac valvular calcification (VC) is a frequent finding in chronic hemodialysis patients. In addition to demographic and metabolic factors, genetic susceptibility may also influence the occurrence and severity of these abnormalities and account for interindividual variability among patients. In this report, we studied the relation of calcium-sensing receptor (CaSR) gene polymorphisms to the development of VC in chronic hemodialysis patients. A total of 41 chronic hemodialysis patients (26 male, mean age 47.23 +/- 11.36 years vs. 15 females, mean age 48.13 +/- 14.66 years) undergoing treatment for more than 1 year were evaluated with transthoracic echocardiography. In patients with and without VC, CaSR gene polymorphisms (A990G, C1011G) were investigated by PCR, using allele-specific primers. In randomly chosen subjects, PCR analysis was verified by DNA sequencing. Cardiac valve calcification was detected in 21 patients (51.2%). Five of these patients (12.2%) had mitral valve calcification, 4 (9.75%) had aortic valve calcification, and 12 (29.27%) had both. In patients with VC, the frequency of the A/G genotype was slightly higher than those with no VC with a borderline P value (42.9% vs. 15%, chi(2)=3.840, P=0.050). The frequency of the C/C genotype was similar in patients with and without VC (90.5% vs. 85%, P>0.05). The results of this study are not enough to prove the role of CaSR gene polymorphisms in the development of VC. There is a need for large-scale studies on this topic.


Assuntos
Estenose da Valva Aórtica/genética , Calcinose/genética , Estenose da Valva Mitral/genética , Receptores de Detecção de Cálcio/genética , Insuficiência Renal Crônica/genética , Adulto , Estenose da Valva Aórtica/complicações , Calcinose/complicações , Feminino , Frequência do Gene , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Estenose da Valva Mitral/complicações , Projetos Piloto , Polimorfismo Genético , Diálise Renal , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/terapia
14.
Clin Dysmorphol ; 18(2): 98-102, 2009 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19077675

RESUMO

The phenotypes associated with subtle deletions of the subtelomeric regions of many chromosomes have been reported. This is a detailed description of the clinical characteristics of two children with subtelomeric deletions of the long arm of chromosome 11 that were not apparent on the initial karyotype. We compare and contrast these with the clinical characteristics of a patient with a cytogenetically visible terminal 11q deletion, who shares similar craniofacial characteristics. All three suffered from moderate learning disability. Subtelomeric 11q deletions can be associated with mild-to-moderate learning difficulties and specific facial features, namely hypertelorism, down-slanting palpebral fissures and ptosis.


Assuntos
Anormalidades Múltiplas/genética , Bandeamento Cromossômico , Deleção Cromossômica , Cromossomos Humanos Par 11 , Cariotipagem , Anormalidades Múltiplas/patologia , Adolescente , Estenose da Valva Aórtica/genética , Estenose da Valva Aórtica/patologia , Blefaroptose/genética , Blefaroptose/patologia , Criança , Pré-Escolar , Feminino , Humanos , Hipertelorismo/genética , Hipertelorismo/patologia , Deficiências da Aprendizagem/genética , Deficiências da Aprendizagem/patologia , Masculino , Estenose da Valva Mitral/genética , Estenose da Valva Mitral/patologia , Telômero/genética
15.
Heart Lung Circ ; 15(4): 242-7, 2006 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-16860607

RESUMO

BACKGROUND: Spontaneous echo contrast (SEC) is common in patients with mitral stenosis (MS) and presence of SEC in left atrium (LA) is associated with a higher risk of thromboembolism. Recently, an increase in activation of platelets was demonstrated in patients with SEC raising the hypothesis that platelets are involved in the pathogenesis of SEC. In this study, we evaluated effects of autonomic nervous system activity on SEC formation in patients with rheumatic MS and sinus rhythm by heart rate variability analysis. METHODS AND RESULTS: Twenty-six patients with LASEC were compared with 28 patients without LASEC. Mean heart rate, low frequency (LF) and low frequency/high frequency (LF/HF) ratio were significantly higher, standard deviation of all NN (SDNN), root mean square of successive differences (RMSSD), number of NN intervals that differed by more than 50 ms from adjacent interval divided by the total number of all NN intervals (PNN50) and high frequency (HF) values were lower in the patients with LASEC. A standard deviation of all NN intervals <90ms separated the patients with LASEC from control subjects with a sensitivity of 77% and specificity of 90%; a low frequency >79.5 with a sensitivity of 92% and specificity of 90; a low frequency/high frequency ratio >3.7 with a sensitivity of 96% and specificity of 90%. A left atrial diameter >4.3 cm increased the LASEC formation by 3.0 folds, HR >78 beats/min by 6.4 folds, standard deviation of all NN intervals <90 ms by 9.2 folds, a low frequency/high frequency ratio >3.7 by 6.4 folds, sP-selectin>142 by 5.8 folds. Variables affecting sP-selectin levels were LA diameter, mitral valve area, transmitral mean gradient, left ventricular ejection fraction, the presence of mitral regurgitation, HR, standard deviation of all NN intervals, low frequency, high frequency and low frequency/high frequency ratio. CONCLUSION: Sympathetic overactivity and reduced heart rate variability are important determinants for LASEC formation and increased s-P selectin levels. Therefore, platelet activation via increased sympathetic activity may play an important role in pathogenesis of LASEC.


Assuntos
Ecocardiografia , Átrios do Coração/fisiopatologia , Estenose da Valva Mitral/fisiopatologia , Nó Sinoatrial/fisiopatologia , Sistema Nervoso Simpático/fisiopatologia , Adulto , Sistema Nervoso Autônomo/fisiopatologia , Estudos de Casos e Controles , Feminino , Regulação da Expressão Gênica , Frequência Cardíaca/fisiologia , Humanos , Masculino , Estenose da Valva Mitral/etiologia , Estenose da Valva Mitral/genética , Estenose da Valva Mitral/metabolismo , Selectina-P/genética , Selectina-P/metabolismo , Periodicidade , Ativação Plaquetária/genética , Ativação Plaquetária/fisiologia , Fatores de Risco , Sensibilidade e Especificidade
16.
Am J Cardiol ; 96(3): 464-6, 2005 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-16054484

RESUMO

Three brothers with arthrogryposis multiplex congenita survived into adulthood. In their fourth decade, the clinical course for each brother became complicated by severe stenoses of their aortic and mitral valves. One brother died suddenly, and the remaining 2 developed heart failure. requiring valvular replacement.


Assuntos
Estenose da Valva Aórtica/genética , Artrogripose/genética , Estenose da Valva Mitral/genética , Adulto , Estenose da Valva Aórtica/cirurgia , Evolução Fatal , Implante de Prótese de Valva Cardíaca , Humanos , Masculino , Estenose da Valva Mitral/cirurgia
17.
Eur J Clin Invest ; 34(11): 723-30, 2004 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-15530144

RESUMO

BACKGROUND: Abnormal intracellular Ca2+ homeostasis is an important modulator of chronic atrial fibrillation. Sarcolipin, a homologue of phospholamban, is specifically expressed in the atria, and may play an important role in modulating intracellular Ca2+ homeostasis in the atria. The aim of this study was to investigate the expression of sarcolipin mRNA in the atrial myocardium of patients with chronic atrial fibrillation. METHODS: We analyzed the expression of sarcolipin, phospholamban, cardiac calsequestrin and sodium calcium exchanger mRNAs in the right atrial myocardium from nine patients with mitral valvular disease with atrial fibrillation (MVD/AF), nine patients with MVD who had normal sinus rhythm (MVD/NSR), and 10 control patients with normal sinus rhythm who received open heart surgery (controls). The expression of mRNA was measured using the ABI PRISM 7700 Sequence Detection System (Applied Biosystems, Foster City, CA). RESULTS: Relative expression levels of sarcolipin mRNA were significantly lower in MVD/AF (0.60 +/- 0.11) than in either MVD/NSR (1.28 +/- 0.17, P < 0.01) or controls (1.10 +/- 0.10, P < 0.05). The expression levels of sarcolipin mRNA were significantly lower in the group with high values for right atrial pressure. The expression levels of phospholamban, cardiac calsequestrin and sodium calcium exchanger mRNAs were comparable among all three groups. CONCLUSIONS: Chronic electrical and mechanical overload decreased the expression of sarcolipin mRNA in the right atrial myocardium in patients with chronic atrial fibrillation. Down-regulation of sarcolipin mRNA may be part of atrial fibrillation-induced atrial remodelling.


Assuntos
Fibrilação Atrial/genética , Proteínas Musculares/genética , Proteolipídeos/genética , RNA Mensageiro/análise , Adulto , Idoso , Fibrilação Atrial/etiologia , Proteínas de Ligação ao Cálcio/genética , Calsequestrina/genética , Doença Crônica , Regulação para Baixo/genética , Feminino , Expressão Gênica/genética , Átrios do Coração/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Insuficiência da Valva Mitral/complicações , Insuficiência da Valva Mitral/genética , Estenose da Valva Mitral/complicações , Estenose da Valva Mitral/genética , Miocárdio/metabolismo , Trocador de Sódio e Cálcio/genética
18.
Am Heart J ; 148(1): 181-6, 2004 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-15215809

RESUMO

BACKGROUND: Scarring and collagen deposition in the valves and destruction of myocytes may result from the combined effects of a smoldering rheumatic process and a constant trauma to the mitral valve or aortic valve by the turbulent flow in rheumatic heart disease (RHD). Transforming growth factor-beta1 (TGF-beta1) may be responsible for the increased valvular fibrosis and calcification in the pathogenesis of RHD. However, the role of TGF-beta1 genetic variant in RHD has not been studied. This case-controlled study was carried out to investigate the possible relationship between the TGF-beta1 gene C-509T and T869C polymorphisms and RHD among the Chinese population in Taiwan. METHODS: A group of 115 patients with RHD documented by using echocardiography and 100 age- and sex-matched healthy control patients were studied. TGF-beta1 gene C-509T and T869C polymorphisms were identified with polymerase chain reaction-based restriction analysis. RESULTS: A significant difference was seen in the distribution of genotypes between patients with RHD and control patients for either TGF-beta1 C-509T polymorphism (P <.0001) or T869C polymorphism (P <.0001). The frequency of TGF-beta1 C-509T CC genotype was lower in the RHD group than in the control group (chi2 = 19.05, P <.0001), which suggests that this genotype may confer protective effects against RHD. A significant difference was seen in the distribution of allelic frequency between patients with RHD and control patients for TGF-beta1 T869C polymorphism (P =.04). The odds ratio (OR) for risk of RHD associated with TGF-beta1 T869C T allele was 1.49 (95% CI, 1.02-2.19). Further categorization of patients with RHD into mitral valve disease and combined valve disease subgroups revealed no statistical difference in these gene polymorphisms when compared with the 2 subgroups. CONCLUSIONS: Patients with RHD have a lower frequency of TGF-beta1 C-509T CC genotype and a higher frequency of T869C T allele, which supports a role for the TGF-beta1 gene C-509T and T869C polymorphisms in determining the risk/protection of RHD in Taiwan Chinese patients.


Assuntos
Doenças das Valvas Cardíacas/genética , Estenose da Valva Mitral/genética , Cardiopatia Reumática/genética , Fator de Crescimento Transformador beta/genética , Adulto , Idoso , Estudos de Casos e Controles , China/etnologia , Feminino , Genética Populacional , Genótipo , Doenças das Valvas Cardíacas/etnologia , Humanos , Masculino , Pessoa de Meia-Idade , Insuficiência da Valva Mitral/etnologia , Insuficiência da Valva Mitral/genética , Estenose da Valva Mitral/diagnóstico por imagem , Estenose da Valva Mitral/etnologia , Polimorfismo Genético , Cardiopatia Reumática/classificação , Cardiopatia Reumática/etnologia , Índice de Gravidade de Doença , Taiwan , Fator de Crescimento Transformador beta1 , Ultrassonografia
19.
Circulation ; 108(15): 1804-8, 2003 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-14530190

RESUMO

BACKGROUND: Studies on apolipoprotein E (apoE) alleles have reported an increased risk of coronary heart disease in patients with the apoE4 allele. Given the risk factor and histological similarities between coronary and calcific valvular heart disease (aortic stenosis [AS] and mitral annular calcification [MAC]), we postulated that apoE alleles might be associated with the development of these valvular lesions. METHODS AND RESULTS: We evaluated the association between apoE alleles and calcific valvular lesions in 802 patients undergoing transthoracic echocardiography using logistic regression analyses. No difference was noted in genotype distribution (P=0.59) or prevalence of apoE4 between those with or without MAC (30% versus 27%, respectively; P=0.57). Compared with patients without AS, the genotype distribution of patients with AS differed significantly (P=0.03), with increasing prevalences of the apoE 4 allele (27% in those without versus 40% in those with AS; P=0.01). In multivariate analyses adjusting for age, gender, low-density lipoprotein cholesterol levels, and coronary artery disease, increasing age and the apoE4 allele were significant independent predictors of AS (odds ratio, 1.94; 95% confidence interval, 1.01 to 3.71; P=0.046), whereas the apoE4 allele was not predictive of MAC. CONCLUSIONS: These findings support extension of the importance of the apoE4 allele beyond atherosclerosis and Alzheimer's disease to calcific AS.


Assuntos
Estenose da Valva Aórtica/genética , Apolipoproteínas E/genética , Calcinose/genética , Idoso , Alelos , Estenose da Valva Aórtica/epidemiologia , Apolipoproteína E4 , Calcinose/epidemiologia , Estudos de Coortes , Comorbidade , Diabetes Mellitus/epidemiologia , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Hiperlipidemias/epidemiologia , Hipertensão/epidemiologia , Masculino , Pessoa de Meia-Idade , Estenose da Valva Mitral/epidemiologia , Estenose da Valva Mitral/genética , Prevalência , Fatores de Risco , Fumar/epidemiologia
20.
Circ Res ; 87(10): 888-95, 2000 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-11073884

RESUMO

Heterozygous mutations in the cardiac homeobox gene, NKX2-5, underlie familial cases of atrial septal defect (ASD) with severe atrioventricular conduction block. In this study, mice heterozygous for Nkx2-5-null alleles were assessed for analogous defects. Although ASD occurred only rarely, atrial septal dysmorphogenesis was evident as increased frequencies of patent foramen ovale and septal aneurysm, and decreased length of the septum primum flap valve. These parameters were compounded by genetic background effects, and in the 129/Sv strain, septal dysmorphogenesis bordered on ASD in 17% of Nkx2-5 heterozygotes. In a proportion of neonatal heterozygotes, as well as in adults with ASD, we found that the size of the foramen ovale was significantly enlarged and altered in shape, potentially exposing the normally thin septum primum to excessive hemodynamic forces. Therefore, defective morphogenesis of the septum secundum may be one contributing factor in the generation of patent foramen ovale, septal aneurysm, and certain ASDs. Mild prolongation of P-R interval in females and an increased frequency of stenotic bicuspid aortic valves were also features of the Nkx2-5 heterozygous phenotype. Our data demonstrate that the complex effects of Nkx2-5 haploinsufficiency in mice are weaker but convergent with those in humans. As in the mouse, the phenotype of human NKX2-5 mutations may be modulated by interacting alleles.


Assuntos
Defeitos dos Septos Cardíacos/genética , Valvas Cardíacas/anormalidades , Heterozigoto , Proteínas de Homeodomínio/genética , Mutação/genética , Fatores de Transcrição , Proteínas de Xenopus , Alelos , Animais , Animais Recém-Nascidos , Velocidade do Fluxo Sanguíneo , Ecocardiografia , Eletrocardiografia , Genes Homeobox , Defeitos dos Septos Cardíacos/diagnóstico por imagem , Defeitos dos Septos Cardíacos/patologia , Comunicação Interatrial/diagnóstico por imagem , Comunicação Interatrial/genética , Comunicação Interatrial/patologia , Valvas Cardíacas/diagnóstico por imagem , Valvas Cardíacas/patologia , Proteína Homeobox Nkx-2.5 , Camundongos , Camundongos Endogâmicos , Camundongos Transgênicos , Valva Mitral/anormalidades , Valva Mitral/diagnóstico por imagem , Valva Mitral/patologia , Estenose da Valva Mitral/diagnóstico por imagem , Estenose da Valva Mitral/genética , Estenose da Valva Mitral/patologia
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