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1.
Eur Heart J Case Rep ; 2019 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-31365055

RESUMO

BACKGROUND : The aetiology of dilated cardiomyopathy (DCM) is highly heterogeneous including genetic and/or acquired (infective, toxic, immune, endocrine, and nutritional) factors. The major part of acquired DCM in developed countries is caused by either viral or autoimmune myocarditis. It is believed that the activation of the T-lymphocyte cell system is the major pathomechanism underlying autoimmune myocarditis and inflammatory DCM (DCMi). However, in the hearts of a subset of patients, a significant number of CD20+ B-lymphocytes can be detected too. Limited information exists on the role of B-cell-dependent mechanisms in the progression of DCMi. Particularly CD20+ B-lymphocytes, which can be targeted by anti-CD20+ B-lymphocytes antibodies or inhibitors, might contribute to the pathogenesis of myocardial damage beyond antibody production. CASE SUMMARY : Here, we present a case series of six patients with subacute and chronic endomyocardial biopsy-proven CD20+ B-lymphocyte-associated DCMi, where symptomatic heart failure therapy, with or without combined immunosuppressive therapy with steroid-based treatment regime, was insufficient to improve cardiac function. Five patients improved clinically several weeks after a standard infusion protocol with rituximab, a chimeric monoclonal antibody against the pan-B-cell surface molecule CD20. DISCUSSION : Our case series shows that CD20+ B-lymphocyte persistence can play a pathophysiologic role in a subset of DCMi patients and highlights the potential of targeting CD20+ B cells in patients with prominent CD20+ B-lymphocyte persistence.

2.
Diabetes Obes Metab ; 21(1): 120-128, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30091218

RESUMO

AIMS: To evaluate the safety, pharmacokinetics and pharmacodynamics of SAR425899, a novel polypeptide, active as an agonist at both the glucagon-like peptide-1 receptor (GLP-1R) and the glucagon receptor (GCR), in healthy volunteers and in overweight/obese patients with type 2 diabetes (T2D). METHODS: Subcutaneous administrations of SAR425899 were tested in two randomized, placebo-controlled, double-blind clinical trials. In the first trial, healthy overweight volunteers (body mass index [BMI] 25-30 kg/m2 ; n = 32) received single-ascending doses (0.01-0.1 mg) of SAR425899 or placebo. In the second, a multiple-ascending-dose trial (NCT02411825), healthy normal- to overweight volunteers (BMI 20-30 kg/m2 ; n = 40) and overweight/obese patients with T2D (BMI 28-42 kg/m2 ; n = 36) received daily doses of SAR425899 or placebo over 21 or 28 days, respectively. RESULTS: The most frequently reported adverse events were gastrointestinal; gastrointestinal side effects were less pronounced in patients with T2D compared with healthy volunteers. SAR425899 significantly reduced levels of fasting plasma glucose (P < 0.05 vs. placebo) and glycated haemoglobin (P < 0.001 versus placebo) in patients with T2D. Additionally, SAR425899 led to reductions in body weight, with a maximal reduction of 5.32 kg in healthy volunteers and 5.46 kg in patients with T2D (P < 0.001 vs. placebo) at end of treatment. CONCLUSIONS: SAR425899 was well tolerated and led to favourable glycaemic effects in patients with T2D and weight reduction in both healthy volunteers and patients. Whether dual GLP-1R/GCR agonism represents a treatment method that is superior to pure GLP-1R agonists for obesity and diabetes treatment remains to be confirmed.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Hipoglicemiantes , Receptores de Glucagon/agonistas , Adolescente , Adulto , Glicemia/análise , Glicemia/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Diabetes Mellitus Tipo 2/complicações , Feminino , Humanos , Hipoglicemiantes/efeitos adversos , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Lipídeos/sangue , Masculino , Pessoa de Meia-Idade , Obesidade/complicações , Placebos , Adulto Jovem
3.
Lancet ; 391(10140): 2607-2618, 2018 06 30.
Artigo em Inglês | MEDLINE | ID: mdl-29945727

RESUMO

BACKGROUND: Weight loss is often key in the management of obese or overweight patients with type 2 diabetes, yet few treatments for diabetes achieve clinically meaningful weight loss. We aimed to assess the efficacy, tolerability, and safety of treatment with MEDI0382, a balanced glucagon-like peptide-1 and glucagon receptor dual agonist developed to provide glycaemic control and weight loss, in patients with type 2 diabetes. METHODS: This randomised, placebo-controlled, double-blind, combined multiple-ascending dose (MAD) and phase 2a study was done at 11 study sites (hospitals and contract research organisations) in Germany. We enrolled patients aged 18-65 years with controlled type 2 diabetes (glycated haemoglobin A1c [HbA1c] levels of 6·5-8·5% at screening) and a body-mass index between 27 kg/m2 and 40 kg/m2. An interactive web-response system was used to randomly assign patients to receive MEDI0382 or placebo. Patients were randomly assigned 2:1 in cohorts A-C and 3:1 in cohorts D and E in the MAD portion of the study, and 1:1 in the phase 2a portion. Randomisation was done by a contracted third-party operator who was not involved in the clinical operations of the study. The pharmacists, participants, and study site personnel involved in treating and assessing participants were masked to treatment allocation. Patients received once-daily subcutaneous injections of the study drug at doses of no more than 300 µg for 22 days or less in the MAD portion of the study, and a dose of no more than 200 µg for 41 days or less in the phase 2a portion. The two primary endpoints of the phase 2a portion were the change from baseline to day 41 in glucose area under the curve at 0-4 h (AUC0-4 h) after a mixed-meal tolerance test (MMTT), assessed in all participants who received at least one dose of study drug and whose measurements were taken at baseline and day 41, and change from baseline in bodyweight, assessed in the intention-to-treat (ITT) population. Safety analyses were done in all participants who received any study drug analysed according to the treatment they received. This study is registered with ClinicalTrials.gov, number NCT02548585. FINDINGS: Patients were recruited between Dec 9, 2015, and Feb 24, 2017. 61 patients were randomly assigned to the MAD part of the study (42 to MEDI0382 and 19 to placebo). 51 patients were randomly assigned to the phase 2a part, of whom 25 were randomly assigned to MEDI0382 and 26 to placebo. In the phase 2a study, three patients in the MEDI0382 group and one in the placebo group discontinued, all as a result of adverse events. 22 (88%) patients in the MEDI0382 group and 25 (96%) in the placebo group received at least one dose and had measurements taken at baseline and day 41. Glucose AUC0-4 h post MMTT decreased significantly with MEDI0382 versus placebo (least squares [LS] mean -32·78% [90% CI -36·98 to -28·57] vs -10·16% [-14·10 to -6·21], and the mean difference was -22·62% [-28·40 to -16·85]; p<0·0001). In the ITT population, reduction in bodyweight was significantly greater with MEDI0382 than with placebo (LS mean -3·84 kg [90% CI -4·55 to -3·12] vs -1·70 kg [-2·40 to -1·01] and mean difference of 2·14 kg [-3·13 to -1·31]; p=0·0008). The proportion of patients who had a treatment-emergent adverse event (TEAE) was similar between treatment groups (22 [88%] of 25 in the MEDI0382 group vs 23 [88%] of 26 in the placebo group); gastrointestinal disorders (18 [72%] vs 13 [40%]) and decreased appetite (five [20%] vs none) occurred more frequently with MEDI0382 than placebo. No participants in the MEDI0382 group had a grade 3 or worse TEAE (vs two [8%] in the placebo group). INTERPRETATION: MEDI0382 has the potential to deliver clinically meaningful reductions in blood glucose and bodyweight in obese or overweight individuals with type 2 diabetes. FUNDING: MedImmune.

4.
Pediatr Cardiol ; 36(2): 295-9, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25135600

RESUMO

The genetic basis of congenital heart disease remains unknown in most of the cases. Recently, a novel mouse model shed new light on the role of CCN1/CYR61, a matricellular regulatory factor, in cardiac morphogenesis. In a candidate gene approach, we analyzed a cohort of 143 patients with atrial septal defects (ASD) by sequencing the coding exons of CCN1. In addition to three frequent polymorphisms, we identified an extremely rare novel heterozygous missense mutation (c.139C > T; p.R47W) in one patient with severe ASD. The mutation leads to an exchange of residues with quite different properties in a highly conserved position of the N-terminal insulin-like growth factor binding protein module. Further bioinformatic analysis, exclusion of known ASD disease genes as well as the exclusion of the mutation in a very high number of ethnically matched controls (more than 1,000 individuals) and in public genetic databases, indicates that the p.R47W variant is a probable disease-associated mutation. The report about ASD in mice in heterozygous Ccn 1 +/- animals strongly supports this notion. Our study is the first to suggest a relationship between a probable CCN1 mutation and ASD. Our purpose here was to draw attention to CCN1, a gene that we believe may be important for genetic analysis in patients with congenital heart disease.


Assuntos
Proteína Rica em Cisteína 61/genética , Comunicação Interatrial/genética , Adulto , Análise Mutacional de DNA , Feminino , Estudos de Associação Genética , Variação Genética , Comunicação Interatrial/diagnóstico por imagem , Humanos , Masculino , Mutação , Polimorfismo de Nucleotídeo Único/genética , Ultrassonografia
5.
Eur J Cardiothorac Surg ; 47(1): e29-33, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25349161

RESUMO

OBJECTIVES: Mechanical circulatory support (MCS) creates improvement of cardiac function in a small portion of patients with idiopathic dilated cardiomyopathy (iDCM). Among other factors, cardiomyocyte hypertrophy seems to represent an important prerequisite for MCS-related cardiac recovery. We have previously shown that connective tissue growth factor (CTGF) leads to adaptive cardiomyocyte hypertrophy associated with a protective cardiac function in transgenic mice. To test whether a functional genetic variant in the CTGF promoter impacts MCS-related cardiac recovery, three groups of iDCM patients with and without cardiac recovery on MCS were genotyped. METHODS: The CTGF promoter variant (c.-945C>G) was analysed in 314 patients with iDCM receiving medical treatment only (Group I). Forty-nine iDCM patients who were either weaned from MCS for more than 6 months (Group II; n=20) or bridged to cardiac transplantation (Group III: n=29) were also genotyped. Patients on MCS were followed up for at least 12 months. Clinical characteristics and outcome on MCS were correlated with the respective genotypes. RESULTS: The c.-945C>G allele frequencies in 314 iDCM patients (Group I) were similar to controls deposited in the HapMap database or those published in a recent study. There were no differences in allele prevalence between patients with mild to moderate iDCM (Group I) compared with patients with severe iDCM requiring MCS (Groups II and III). Intriguingly, 50% of patients who were weaned from MCS (Group II) were homozygous for the G allele compared with only 17.2% of patients included in Group III, which is a significant difference (P=0.03). CONCLUSIONS: Homozygosity of the promoter-activating G allele in the CTGF_c.-945C>G variant is overrepresented in patients with cardiac recovery on MCS when compared with iDCM patients without cardiac recovery. Further studies are needed to evaluate c.-945C>G as a genetic predictor for clinical outcome on MCS.


Assuntos
Cardiomiopatia Dilatada/genética , Fator de Crescimento do Tecido Conjuntivo/genética , Coração Auxiliar , Polimorfismo de Nucleotídeo Único/genética , Regiões Promotoras Genéticas/genética , Adulto , Cardiomiopatia Dilatada/cirurgia , Feminino , Frequência do Gene/genética , Marcadores Genéticos/genética , Genótipo , Homozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento
6.
Eur J Hum Genet ; 21(3): 294-300, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22892539

RESUMO

Recently, missense mutations in titin-associated proteins have been linked to the pathogenesis of dilated cardiomyopathy (DCM). The objective of this study was to search for novel disease-associated mutations in the two human titin-binding proteins myopalladin and its amino-terminal-interacting partner cardiac ankyrin-repeat protein (CARP). In a cohort of 255 cases with familial and sporadic DCM, we analyzed the coding regions and all corresponding intron flanks located in the MYPN and CARP-encoding ANKRD1 gene. Two heterozygous missense mutations were detected in the MYPN gene (p.R955W and p.P961L), but neither of these mutations was found in 300 healthy controls. Both mutations were located in the α-actinin-binding region of myopalladin. Endomyocardial biopsies from the p.R955W carrier showed normal subcellular localization of myopalladin and α-actinin in cardiac myocytes, while their regular sarcomeric staining pattern was significantly disrupted in the p.P961L carrier, indicating that disturbed myofibrillogenesis and altered sarcomere assembly are the cause of the disease. In the ANKRD1 gene, we identified synonymous base exchanges (c.108T>C and c.-79C>T, respectively), but no non-synonymous mutations. In summary, we have identified novel missense mutations in the third immunoglobulin-like domain of myopalladin, which have either no or profound effects on the molecular composition of the sarcomere. According to our epidemiological data, the prevalence of ANKRD1 mutations seems to be lower than that of its binding partner myopalladin, indicating the clinical significance of myopalladin for the functional integrity of the sarcomeric apparatus and the protection against DCM.


Assuntos
Cardiomiopatia Dilatada/genética , Proteínas Musculares/genética , Proteínas Musculares/metabolismo , Mutação , Sarcômeros/metabolismo , Adulto , Cardiomiopatia Dilatada/patologia , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Proteínas Nucleares/genética , Polimorfismo de Nucleotídeo Único , Proteínas Repressoras/genética , Sarcômeros/genética
7.
PLoS One ; 6(12): e28872, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-22194935

RESUMO

Secundum-type atrial septal defects (ASDII) account for approximately 10% of all congenital heart defects (CHD) and are associated with a familial risk. Mutations in transcription factors represent a genetic source for ASDII. Yet, little is known about the role of mutations in sarcomeric genes in ASDII etiology. To assess the role of sarcomeric genes in patients with inherited ASDII, we analyzed 13 sarcomeric genes (MYH7, MYBPC3, TNNT2, TCAP, TNNI3, MYH6, TPM1, MYL2, CSRP3, ACTC1, MYL3, TNNC1, and TTN kinase region) in 31 patients with familial ASDII using array-based resequencing. Genotyping of family relatives and control subjects as well as structural and homology analyses were used to evaluate the pathogenic impact of novel non-synonymous gene variants. Three novel missense mutations were found in the MYH6 gene encoding alpha-myosin heavy chain (R17H, C539R, and K543R). These mutations co-segregated with CHD in the families and were absent in 370 control alleles. Interestingly, all three MYH6 mutations are located in a highly conserved region of the alpha-myosin motor domain, which is involved in myosin-actin interaction. In addition, the cardiomyopathy related MYH6-A1004S and the MYBPC3-A833T mutations were also found in one and two unrelated subjects with ASDII, respectively. No mutations were found in the 11 other sarcomeric genes analyzed. The study indicates that sarcomeric gene mutations may represent a so far underestimated genetic source for familial recurrence of ASDII. In particular, perturbations in the MYH6 head domain seem to play a major role in the genetic origin of familial ASDII.


Assuntos
Miosinas Cardíacas/genética , Doença/genética , Comunicação Interatrial/genética , Cadeias Pesadas de Miosina/genética , Sarcômeros/genética , Sarcômeros/patologia , Adulto , Criança , Pré-Escolar , Família , Feminino , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Mutação/genética , Linhagem , Fenótipo
8.
PLoS One ; 6(6): e20711, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21673957

RESUMO

Patent foramen ovale (PFO) is associated with clinical conditions including cryptogenic stroke, migraine and varicose veins. Data from studies in humans and mouse suggest that PFO and the secundum form of atrial septal defect (ASDII) exist in an anatomical continuum of septal dysmorphogenesis with a common genetic basis. Mutations in multiple members of the evolutionarily conserved cardiac transcription factor network, including GATA4, cause or predispose to ASDII and PFO. Here, we assessed whether the most prevalent variant of the GATA4 gene, S377G, was significantly associated with PFO or ASD. Our analysis of world indigenous populations showed that GATA4 S377G was largely Caucasian-specific, and so subjects were restricted to those of Caucasian descent. To select for patients with larger PFO, we limited our analysis to those with cryptogenic stroke in which PFO was a subsequent finding. In an initial study of Australian subjects, we observed a weak association between GATA4 S377G and PFO/Stroke relative to Caucasian controls in whom ASD and PFO had been excluded (OR = 2.16; p = 0.02). However, in a follow up study of German Caucasians no association was found with either PFO or ASD. Analysis of combined Australian and German data confirmed the lack of a significant association. Thus, the common GATA4 variant S377G is likely to be relatively benign in terms of its participation in CHD and PFO/Stroke.


Assuntos
Forame Oval Patente/complicações , Forame Oval Patente/genética , Fator de Transcrição GATA4/genética , Miocárdio/metabolismo , Polimorfismo Genético , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/genética , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Feminino , Forame Oval Patente/diagnóstico por imagem , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Ultrassonografia , Adulto Jovem
9.
Eur J Med Genet ; 53(4): 201-3, 2010 Jul-Aug.
Artigo em Inglês | MEDLINE | ID: mdl-20363377

RESUMO

Familial recurrence of atrial fibrillation (AF) is reported in up to 15% of patients with lone AF. Recently, it was proposed that congenital defects in the morphogenesis of the pulmonary vein myocardium are involved in genetic pathogenesis of lone AF. GATA4 is a cardiac transcription factor essentially involved in myocardial development. Mutations in GATA4 are associated with congenital cardiac malformations. To investigate whether GATA4 mutations represent a genetic origin for AF the coding region of GATA4 was sequenced in 96 patients with lone AF. We found a GATA4 mutation (M247T) in a patient with familial lone AF and atrial septal aneurysm without interatrial shunts. The mutation affects a deeply conserved domain adjacent to the first zinc finger domain of GATA4 and was not reported before. A second GATA4 mutation (A411V) was found in a female patient with sporadic lone AF. This variant was previously reported in patients with cardiac septal defects. However, no anomalies of the atrial or ventricular septa were noted in the AF patient harboring A411V. We report for the first time that mutations in the cardiac transcription factor GATA4 may represent a genetic origin of lone AF. The study proposes that lone AF may share a common genetic origin with congenital cardiac malformations.


Assuntos
Fibrilação Atrial/genética , Fator de Transcrição GATA4/genética , Defeitos dos Septos Cardíacos/genética , Mutação/genética , Adulto , Idoso , Sequência de Aminoácidos , Fibrilação Atrial/patologia , Feminino , Defeitos dos Septos Cardíacos/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Linhagem , Homologia de Sequência de Aminoácidos
10.
Eur J Hum Genet ; 18(6): 694-9, 2010 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20145677

RESUMO

The cytotoxic T-lymphocyte antigen 4 (CTLA4) is an inhibitory receptor expressed on activated T cells with downregulatory properties. The aim of this study was to analyse whether single-nucleotide polymorphisms (SNPs) within the CTLA4 gene are associated with the diagnosis and disease course of dilated cardiomyopathy (DCM). In two independent cohorts of DCM patients (n=251 and 223) and healthy controls (n=591), the promoter and all four exons of the CTLA4 gene, including their flanking regions, were genotyped, and the resulting allele and genotype distributions of the identified SNPs were compared between the groups. We confirmed two known SNPs in the promoter region (-318C>T) and in exon 1 (+49A>G;Thr17Ala). The allelic frequencies and genotypic distribution of the promoter SNP were similar for DCM patients compared with controls. However, the G/G genotype of the Thr17Ala variant was significantly more frequent in DCM patients compared with controls (37 out of 251 patients (14.7%) versus 44 out of 591 controls (7.4%), P=0.005). The higher frequency of the G/G genotype was confirmed in an additional DCM cohort (29 out of 223 patients (13.0%), P=0.039), indicating that this SNP functions as a risk factor for DCM. At follow-up after 1 year, the ejection fraction and the end-diastolic diameter of the left ventricle did not differ significantly between DCM patients carrying the G/G genotype versus other genotypes (n=199). Our data indicate that the common CTLA4 variant, Thr17Ala, confers susceptibility for DCM, but does not seem to influence the course of the disease 1 year after diagnosis.


Assuntos
Antígenos CD/fisiologia , Cardiomiopatia Dilatada/genética , Predisposição Genética para Doença , Adulto , Alelos , Antígenos CD/genética , Antígeno CTLA-4 , Estudos de Casos e Controles , Estudos de Coortes , Progressão da Doença , Feminino , Frequência do Gene , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/fisiologia
11.
Clin Res Cardiol ; 99(3): 137-47, 2010 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-20012542

RESUMO

Congenital heart defects (CHD) are the most common developmental errors in humans, affecting 8 out of 1,000 newborns. Clinical diagnosis and treatment of CHD has dramatically improved in the last decades. Hence, the majority of CHD patients are now reaching reproductive age. While the risk of familial recurrence has been evaluated in various population studies, little is known about the genetic pathogenesis of CHD. In recent years significant progress has been made in uncovering genetic processes during cardiac development. Data from human genetic studies in CHD patients indicate that the genetic aetiology was presumably underestimated in the past. Inherited mutations in genes encoding cardiac transcription factors and sarcomeric proteins were found as an underlying cause for familial recurrence of non-syndromic CHD in humans, in particular cardiac septal defects. Notably, the cardiac phenotypes most frequently seen in mutation carriers are ostium secundum atrial septal defects (ASDII). This review outlines experimental approaches employed for the detection of CHD-related genes in humans and summarizes recent findings in molecular genetics of congenital cardiac septal defects with an emphasis on ASDII.


Assuntos
Cardiopatias Congênitas/genética , Comunicação Interatrial/genética , Biologia Molecular/métodos , Animais , Humanos , Recém-Nascido , Mutação , Fatores de Risco , Sarcômeros/genética , Sarcômeros/metabolismo , Fatores de Transcrição/genética
12.
Int J Cardiol ; 145(1): 105-6, 2010 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-19540604

RESUMO

A proper interaction between the endocardial-derived ligand Neuregulin-1 and the myocardial "Human Epidermal growth factor Receptor 2" (HER2) is essential for maintaining heart function. The shed extracellular domain (ECD) of HER2 circulates in blood and serves as a surrogate marker for breast cancer. Altered cardiac loading conditions are accompanied by dysregulation of the myocardial HER2 gene expression. We studied 193 controls with preserved ejection fraction (EF>55%) and 572 patients with different degrees of systolic heart failure: 98 had EF 45-55%, 138 patients EF 35-44%, and 336 patients, EF <35%, respectively. The corresponding mean HER2 levels were 6.44 ± 0.46 ng/mL, 6.07 ± 0.76 ng/mL and 6.57 ± 0.87 ng/mL, and 6.17 ± 0.71 ng/mL, respectively. Furthermore, there was no significant association between plasma HER2 levels and left ventricular filling pressures or the left ventricular wall thickness. The HER2 plasma levels do not reflect the cardiac function and are therefore not useful as a biomarker for heart failure.


Assuntos
Insuficiência Cardíaca/sangue , Testes de Função Cardíaca , Hipertrofia Ventricular Esquerda/sangue , Receptor ErbB-2/sangue , Idoso , Biomarcadores/sangue , Feminino , Insuficiência Cardíaca/fisiopatologia , Humanos , Hipertrofia Ventricular Esquerda/fisiopatologia , Masculino , Pessoa de Meia-Idade
13.
Int J Cardiol ; 145(2): 316-317, 2010 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-20022124

RESUMO

Atrial fibrillation (AF) is the most frequently encountered arrhythmia in clinical practice. In a subgroup of patients, AF is regarded as idiopathic when no signs of structural heart disease or other causes of the arrhythmia can be identified during conventional clinical work-up. Recent studies have demonstrated that AF has a substantial genetic basis in a number of cases. The entire coding sequences, including intron-exon boundaries, of the genes PITX2 and NKX2-5 were screened for genetic variants by means of initial polymerase chain reaction followed by DNA sequencing in 96 patients with idiopathic AF. Although we detected a number of variants, our candidate gene approach did not result in identification of mutations associated with AF in the coding regions of PITX2 or NKX2-5 in our well characterized AF cohort.


Assuntos
Fibrilação Atrial/genética , Análise Mutacional de DNA , Proteínas de Homeodomínio/genética , Fatores de Transcrição/genética , Idoso , Fibrilação Atrial/diagnóstico , Estudos de Coortes , Análise Mutacional de DNA/métodos , Feminino , Variação Genética/genética , Proteína Homeobox Nkx-2.5 , Humanos , Masculino , Pessoa de Meia-Idade
14.
J Med Genet ; 47(4): 230-5, 2010 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19762328

RESUMO

BACKGROUND: Ostium secundum atrial septal defects (ASDII) account for approximately 10% of all congenital heart defects (CHD), and mutations in cardiac transcription factors, including TBX20, were identified as an underlying cause for ASDII. However, very little is known about disease penetrance in families and functional consequences of inherited TBX20 mutations. METHODS: The coding region of TBX20 was directly sequenced in 170 ASDII patients. Functional consequences of one novel mutation were investigated by surface plasmon resonance, CD spectropolarymetry, fluorescence spectrophotometry, luciferase assay and chromatin immunoprecipitation. RESULTS: We found a novel mutation in a highly conserved residue in the T-box DNA binding domain (I121M) segregating with CHD in a three generation kindred. Four mutation carriers revealed cardiac phenotypes in terms of cribriform ASDII, large patent foramen ovale or cardiac valve defects. Interestingly, tertiary hydrophobic interactions within the mutant TBX20 T-box were significantly altered leading to a more dynamic structure of the protein. Moreover, Tbx20-I121M resulted in a significantly enhanced transcriptional activity, which was further increased in the presence of co-transcription factors GATA4/5 and NKX2-5. Occupancy of DNA binding sites on target genes was also increased. CONCLUSIONS: We suggest that TBX20-I121M adopts a more fluid tertiary structure leading to enhanced interactions with cofactors and more stable transcriptional complexes on target DNA sequences. Our data, combined with that of others, suggest that human ASDII may be related to loss-of-function as well as gain-of-function TBX20 mutations.


Assuntos
Forame Oval Patente/genética , Comunicação Interatrial/genética , Valvas Cardíacas/anormalidades , Mutação , Proteínas com Domínio T/genética , Adolescente , Animais , Sequência de Bases , Células COS , Estudos de Casos e Controles , Cercopithecus aethiops , Imunoprecipitação da Cromatina , Dicroísmo Circular , DNA/genética , DNA/metabolismo , Feminino , Forame Oval Patente/metabolismo , Comunicação Interatrial/metabolismo , Humanos , Masculino , Modelos Moleculares , Dados de Sequência Molecular , Linhagem , Alinhamento de Sequência , Homologia Estrutural de Proteína , Proteínas com Domínio T/metabolismo , Ativação Transcricional
15.
PLoS One ; 4(8): e6743, 2009 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-19707545

RESUMO

Connective tissue growth factor (CTGF) is a secreted protein that is strongly induced in human and experimental heart failure. CTGF is said to be profibrotic; however, the precise function of CTGF is unclear. We generated transgenic mice and rats with cardiomyocyte-specific CTGF overexpression (CTGF-TG). To investigate CTGF as a fibrosis inducer, we performed morphological and gene expression analyses of CTGF-TG mice and rat hearts under basal conditions and after stimulation with angiotensin II (Ang II) or isoproterenol, respectively. Surprisingly, cardiac tissues of both models did not show increased fibrosis or enhanced gene expression of fibrotic markers. In contrast to controls, Ang II treated CTGF-TG mice displayed preserved cardiac function. However, CTGF-TG mice developed age-dependent cardiac dysfunction at the age of 7 months. CTGF related heart failure was associated with Akt and JNK activation, but not with the induction of natriuretic peptides. Furthermore, cardiomyocytes from CTGF-TG mice showed unaffected cellular contractility and an increased Ca(2+) reuptake from sarcoplasmatic reticulum. In an ischemia/reperfusion model CTGF-TG hearts did not differ from controls.Our data suggest that CTGF itself does not induce cardiac fibrosis. Moreover, it is involved in hypertrophy induction and cellular remodeling depending on the cardiac stress stimulus. Our new transgenic animals are valuable models for reconsideration of CTGF's profibrotic function in the heart.


Assuntos
Cardiomegalia/prevenção & controle , Fator de Crescimento do Tecido Conjuntivo/metabolismo , Miocárdio/citologia , Angiotensina II/administração & dosagem , Animais , Sequência de Bases , Cálcio/metabolismo , Cardiomegalia/genética , Cardiomegalia/fisiopatologia , Fator de Crescimento do Tecido Conjuntivo/genética , Primers do DNA , Ativação Enzimática , Humanos , Isoproterenol/administração & dosagem , MAP Quinase Quinase 4/metabolismo , Camundongos , Camundongos Transgênicos , Isquemia Miocárdica/metabolismo , Reação em Cadeia da Polimerase , Pressão , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos
16.
Heart Rhythm ; 6(4): 480-6, 2009 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19324307

RESUMO

BACKGROUND: Familial dilated cardiomyopathy is a highly heterogeneous genetic disease. Thus, identification of disease-causing mutations is a challenging and time-consuming task. Genotype-phenotype associations may alleviate identification of the underlying mutation. OBJECTIVE: The purpose of this study was to investigate cardiac phenotypes within a family harboring a familial dilated cardiomyopathy-related mutation in the gene encoding phospholamban. METHODS: Complete genetic and clinical analyses were performed in a family with familial dilated cardiomyopathy due to the PLN-R14Del mutation. Family relatives were studied by ECG, Holter ECG, echocardiography, ECG body surface potential mapping, and cardiac magnetic resonance imaging. RESULTS: A candidate gene approach resulted in identification of a heterozygous deletion of arginine 14 in the gene encoding phospholamban (PLN-R14Del) segregating with dilated cardiomyopathy in the family pedigree. Mutation carriers suffered from familial dilated cardiomyopathy associated with cardiac death between the ages of 26 and 50 years. Interestingly, all adult mutation carriers revealed strikingly attenuated R amplitudes on standard ECG, regardless of the absence or presence of echocardiographic abnormalities. Gadolinium-enhanced cardiac magnetic resonance imaging showed late enhancement in PLN-R14Del carriers with preserved ejection fraction. Late enhancement was regionally related to areas of most pronounced R-amplitude attenuation as assessed by body surface potential mapping. CONCLUSION: Attenuated R amplitudes were identified as an early ECG phenotype in a family with familial dilated cardiomyopathy due to the PLN-R14Del mutation. All adults harboring PLN-R14Del had attenuated R waves irrespective of echocardiographic abnormalities. The study findings suggest a mutation-related remodeling process preceding ventricular dysfunction.


Assuntos
Arginina/genética , Proteínas de Ligação ao Cálcio/genética , Cardiomiopatia Dilatada/genética , Adulto , Idade de Início , Mapeamento Potencial de Superfície Corporal , Cardiomiopatia Dilatada/etiologia , Meios de Contraste , Ecocardiografia , Eletrocardiografia , Feminino , Genótipo , Alemanha , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Mutação , Linhagem , Fenótipo , Estudos Prospectivos , Fatores de Risco , Deleção de Sequência , Fatores Sexuais
17.
Basic Res Cardiol ; 104(1): 90-9, 2009 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-18795223

RESUMO

The familial form of dilated cardiomyopathy (DCM) occurs in about 20%-50% of DCM cases. It is a heterogeneous genetic disease: mutations in more than 20 different genes have been shown to cause familial DCM. LMNA, encoding the nuclear membrane protein lamin A/C, is one of the most important disease gene for that disease. Therefore, we analyzed the LMNA gene in a large cohort of 73 patients with familial DCM. Clinical examination (ECG, echocardiography, and catheterization) was followed by genetic characterization of LMNA by direct sequencing. We detected five heterozygous missense mutations (prevalence 7%) in five different families characterized by severe DCM and heart failure with conduction system disease necessitating pacemaker implantation and heart transplantation. Four of these variants clustered in the protein domain coil 1B, which is important for lamin B interaction and lamin A/C dimerization. Although we identified two novel mutations (E203V, K219T) besides three known ones (E161K, R190Q, R644C), it was remarkable that four mutations represent LMNA hot spots. DCM patients with LMNA mutations show a notable homogenous severe phenotype as we could confirm in our study. Testing LMNA in such families seems to be recommended because genotype information in an individual could definitely be useful for the clinician.


Assuntos
Cardiomiopatia Dilatada/genética , Lamina Tipo A/genética , Mutação , Estudos de Coortes , DNA/genética , DNA/isolamento & purificação , Primers do DNA , Éxons , Feminino , Humanos , Linfócitos/fisiologia , Masculino , Linhagem , Reação em Cadeia da Polimerase , Polimorfismo de Nucleotídeo Único
18.
Int J Cardiol ; 136(1): 108-11, 2009 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-18614244

RESUMO

Genetic research on heart failure (HF) requires large cohorts of well-phenotyped patients. The German Competence Network of Heart Failure (CNHF) organized a biobank in 2004 to supply the necessary infrastructure and standard operating procedures (SOPs) for a centralized collection of blood specimen. We centralized data and collected serum, plasma and DNA of well characterized HF subjects all over Germany. Different pseudonyms were created automatically to address data safety and other concerns about privacy. Thus far, we have collected 85,000 sample specimen from 9,500 prospectively evaluated patients with HF. Detailed medical data were prospectively acquired together with corresponding blood samples. In 2008 clinician-scientists can apply for access to the material. Our biobank represents a major facet of the CNHF and has already documented research and clinical utility.


Assuntos
Bancos de Sangue/normas , Bases de Dados Genéticas/normas , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/genética , Bancos de Tecidos/normas , Alemanha , Insuficiência Cardíaca/classificação , Humanos , Estudos Prospectivos , Manejo de Espécimes/métodos , Manejo de Espécimes/normas
19.
Dis Markers ; 25(3): 131-9, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-19096125

RESUMO

Mitochondrial transcription factors mtTFA, mtTFB1 and mtTFB2 are required for the replication of mitochondrial DNA (mtDNA), regulating the number of mtDNA copies. Mice with a mtTFA deletion showed a reduced number of mtDNA copies, a reduction in respiratory chain activity, and a characteristic dilated cardiomyopathy. DNA variants in these genes could be involved in the risk for cardiac hypertrophy (HCM). We determined the variation in the TFAM, TFB1M, and TFB2M genes (using SSCA, DHPLC, and direct sequencing) in a total of 200 HCM-patients from Spain and Germany, and in 250 healthy controls. We found several common polymorphisms that defined haplotype blocks in these genes, with frequencies that did not differ between patients and controls. We also found four novel variants in patients which were absent in the controls: -91 C > A (5'-UTR) and Ala105 > Thr in TFAM, and Thr211 > Ala and Arg256 > Lys in TFB1M. The three missense changes were in highly conserved amino acids, and could be involved in HCM-risk. In conclusion, common variants in the mitochondrial transcription factors were not associated with the risk for HCM. However, rare DNA variants (putative mutations) could be involved in the pathogenesis of HCM in a reduced number of cases.


Assuntos
Cardiomegalia/genética , Proteínas de Ligação a DNA/genética , Metiltransferases/genética , Proteínas Mitocondriais/genética , Fatores de Transcrição/genética , Adulto , Idoso , Animais , Cardiomegalia/etiologia , Estudos de Casos e Controles , DNA Mitocondrial/genética , Feminino , Marcadores Genéticos , Variação Genética , Genótipo , Haplótipos , Humanos , Desequilíbrio de Ligação , Masculino , Camundongos , Pessoa de Meia-Idade , Fatores de Risco , Adulto Jovem
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