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1.
J Pathol ; 243(3): 294-306, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28727149

RESUMO

Marfan syndrome (MFS) is a connective tissue disorder in which aortic rupture is the major cause of death. MFS patients with an aortic diameter below the advised limit for prophylactic surgery (<5 cm) may unexpectedly experience an aortic dissection or rupture, despite yearly monitoring. Hence, there is a clear need for improved prognostic markers to predict such aortic events. We hypothesize that elastin fragments play a causal role in aortic calcification in MFS, and that microcalcification serves as a marker for aortic disease severity. To address this hypothesis, we analysed MFS patient and mouse aortas. MFS patient aortic tissue showed enhanced microcalcification in areas with extensive elastic lamina fragmentation in the media. A causal relationship between medial injury and microcalcification was revealed by studies in vascular smooth muscle cells (SMCs); elastin peptides were shown to increase the activity of the calcification marker alkaline phosphatase (ALP) and reduce the expression of the calcification inhibitor matrix GLA protein in human SMCs. In murine Fbn1C1039G/+ MFS aortic SMCs, Alpl mRNA and activity were upregulated as compared with wild-type SMCs. The elastin peptide-induced ALP activity was prevented by incubation with lactose or a neuraminidase inhibitor, which inhibit the elastin receptor complex, and a mitogen-activated protein kinase kinase-1/2 inhibitor, indicating downstream involvement of extracellular signal-regulated kinase-1/2 (ERK1/2) phosphorylation. Histological analyses in MFS mice revealed macrocalcification in the aortic root, whereas the ascending aorta contained microcalcification, as identified with the near-infrared fluorescent bisphosphonate probe OsteoSense-800. Significantly, microcalcification correlated strongly with aortic diameter, distensibility, elastin breaks, and phosphorylated ERK1/2. In conclusion, microcalcification co-localizes with aortic elastin degradation in MFS aortas of humans and mice, where elastin-derived peptides induce a calcification process in SMCs via the elastin receptor complex and ERK1/2 activation. We propose microcalcification as a novel imaging marker to monitor local elastin degradation and thus predict aortic events in MFS patients. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.


Assuntos
Elastina/metabolismo , Síndrome de Marfan/metabolismo , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Animais , Aorta/metabolismo , Aneurisma Aórtico/metabolismo , Aneurisma Aórtico/patologia , Calcinose/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Humanos , Síndrome de Marfan/patologia , Camundongos , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/patologia
2.
Cardiovasc Pathol ; 38: 1-6, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30359839

RESUMO

Marfan syndrome (MFS) is a connective tissue disorder caused by mutations in the fibrillin-1 gene (FBN1), resulting in aortic aneurysm formation and dissections. Interestingly, variable aortopathy is observed even within MFS families with the same mutation. Thus, additional risk factors determine disease severity. Here, we describe a case of a 2-month-old Fbn1C1039G/+ MFS mouse with extreme aortic dilatation and increased vascular inflammation, when compared to MFS siblings, which coincided with unilateral renal cystic disease. In addition, this mouse presented with increased serum levels of creatinine, angiotensin-converting enzyme, corticosterone, macrophage chemoattractant protein-1, and interleukin-6, which may have contributed to the vascular pathology. Possibly, cystic kidney disease is associated with aneurysm progression in MFS patients. Therefore, we propose that close monitoring of the presence of renal cysts in MFS patients, during regular vascular imaging of the whole aorta trajectory, may provide insight in the frequency of cystic kidney disease and its potential as a novel indicator of aneurysm progression in MFS patients.


Assuntos
Aorta/patologia , Aneurisma Aórtico/etiologia , Fibrilina-1/genética , Doenças Renais Císticas/etiologia , Síndrome de Marfan/genética , Animais , Aorta/metabolismo , Aneurisma Aórtico/sangue , Aneurisma Aórtico/genética , Aneurisma Aórtico/patologia , Aortite/sangue , Aortite/etiologia , Aortite/genética , Aortite/patologia , Biomarcadores/sangue , Dilatação Patológica , Modelos Animais de Doenças , Fibrilina-1/metabolismo , Predisposição Genética para Doença , Doenças Renais Císticas/sangue , Doenças Renais Císticas/genética , Doenças Renais Císticas/patologia , Masculino , Síndrome de Marfan/sangue , Síndrome de Marfan/complicações , Síndrome de Marfan/diagnóstico , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Fenótipo
3.
Open Heart ; 6(1): e000985, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31245011

RESUMO

Background: In Fontan patients with atrial arrhythmias (AA), non-vitamin K antagonist oral anticoagulants(NOACs) have a class III recommendation according to the Pediatric & Congenital Electrophysiology Society (PACES)/Heart Rhythm Society (HRS) guideline in 2014, due to lack of data on outcomes as opposed to evidence of harm. To address this gap in data, we investigated the safety and efficacy of NOACs in adults with a Fontan circulation in a worldwide study. Methods: This is an international multicentre prospective cohort study, using data from the NOTE (non-vitamin K antagonist oral anticoagulants for thromboembolic prevention in patients with congenital heart disease) registry. The study population comprised consecutive adults with a Fontan circulation using NOACs. Follow-up took place at 6 months and yearly thereafter. The primary endpoints were thromboembolism and major bleeding. Secondary endpoint was minor bleeding. Results: From April 2014 onward, 74 patients (mean age 32±10 years (range 18-68), 54% male) with a Fontan circulation using NOACs were included. During a median follow-up of 1.2 (IQR 0.8-2.0) years, three thromboembolic events (2.9 per 100 patient-years (95% CI 0.7 to 7.6)) and three major bleedings (2.9 per 100 patient-years (95% CI 0.7 to 7.6)) occurred in five atriopulmonary Fontan and one total cavopulmonary connection Fontan patients with AA. Fifteen patients experienced minor bleeding episodes (15.8 per 100 patient-years (95% CI 9.1 to 25.2)). In patients (n=37) using vitamin K antagonists (VKAs) prior to the initiation of NOAC, annual incidence of historical thromboembolic events and major bleeding were 2.4% (95% CI 0.4% to 7.4%) (n = 2) and 1.2% (95% CI 0.7% to 5.1%) (n = 1), respectively. Conclusions: In this review of the largest Fontan cohort using NOACs with prospective follow-up, NOACs appear to be well tolerated and their efficacy and safety during short-term follow-up seem comparable to VKAs. Longer term data are required to confirm these promising short-term results.

4.
J Cardiovasc Magn Reson ; 10: 40, 2008 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-18713464

RESUMO

BACKGROUND: The method used to delineate the boundary of the right ventricle (RV), relative to the trabeculations and papillary muscles in cardiovascular magnetic resonance (CMR) ventricular volume analysis, may matter more when these structures are hypertrophied than in individuals with normal cardiovascular anatomy. This study aimed to compare two methods of cavity delineation in patients with systemic RV. METHODS: Twenty-nine patients (mean age 34.7 +/- 12.4 years) with a systemic RV (12 with congenitally corrected transposition of the great arteries (ccTGA) and 17 with atrially switched (TGA) underwent CMR. We compared measurements of systemic RV volumes and function using two analysis protocols. The RV trabeculations and papillary muscles were either included in the calculated blood volume, the boundary drawn immediately within the apparently compacted myocardial layer, or they were manually outlined and excluded. RV stroke volume (SV) calculated using each method was compared with corresponding left ventricular (LV) SV. Additionally, we compared the differences in analysis time, and in intra- and inter-observer variability between the two methods. Paired samples t-test was used to test for differences in volumes, function and analysis time between the two methods. Differences in intra- and inter-observer reproducibility were tested using an extension of the Bland-Altman method. RESULTS: The inclusion of trabeculations and papillary muscles in the ventricular volume resulted in higher values for systemic RV end diastolic volume (mean difference 28.7 +/- 10.6 ml, p < 0.001) and for end systolic volume (mean difference 31.0 +/- 11.5 ml, p < 0.001). Values for ejection fraction were significantly lower (mean difference -7.4 +/- 3.9%, p < 0.001) if structures were included. LV SV did not differ significantly from RV SV for both analysis methods (p = NS). Including structures resulted in shorter analysis time (p < 0.001), and showed better inter-observer reproducibility for ejection fraction (p < 0.01). CONCLUSION: The choice of method for systemic RV cavity delineation significantly affected volume measurements, given the CMR acquisition and analysis systems used. We recommend delineation outside the trabeculations for routine clinical measurements of systemic RV volumes as this approach took less time and gave more reproducible measurements.


Assuntos
Cardiopatias Congênitas/diagnóstico , Imageamento por Ressonância Magnética/métodos , Miocárdio/patologia , Disfunção Ventricular Direita/diagnóstico , Adulto , Feminino , Cardiopatias Congênitas/complicações , Ventrículos do Coração , Humanos , Masculino , Variações Dependentes do Observador , Músculos Papilares/patologia , Reprodutibilidade dos Testes , Volume Sistólico , Disfunção Ventricular Direita/complicações
5.
Anatol J Cardiol ; 19(6): 401-403, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29537971

RESUMO

Sudden cardiac death (SCD), mainly caused by ventricular arrhythmias, is one of the leading causes of mortality in adult congenital heart disease (ACHD) patients. An implantable cardioverter defibrillator (ICD) may prevent SCD, but risk stratification remains challenging. In this review, we will address the current guideline recommendations for ICD implantation in ACHD patients, as well as review a recent study in which the discriminative ability for SCD of these guidelines is evaluated. In this study, the guideline recommendations were applied to patients who died of SCD and living controls. Among SCD cases, 35%-41% of patients were recommended ICD, whereas 16%-17% of controls were recommended ICD. The discriminative ability for SCD of the guidelines was poor, with an area under the receiver operating characteristic curve of 0.61-0.63. Risk stratification for SCD in ACHD patients, therefore, remains to be a work-in-progress.


Assuntos
Morte Súbita Cardíaca/prevenção & controle , Cardiopatias Congênitas , Adulto , Desfibriladores Implantáveis , Cardiopatias Congênitas/complicações , Humanos , Guias de Prática Clínica como Assunto , Medição de Risco
6.
Heart ; 104(9): 738-744, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29092913

RESUMO

OBJECTIVE: To determine the association of pulmonary valve replacement (PVR) with death and sustained ventricular tachycardia (VT) in patients with repaired tetralogy of Fallot (rTOF). METHODS: Subjects with rTOF and cardiac magnetic resonance from an international registry were included. A PVR propensity score was created to adjust for baseline differences. PVR consensus criteria were predefined as pulmonary regurgitation >25% and ≥2 of the following criteria: right ventricular (RV) end-diastolic volume >160 mL/m2, RV end-systolic volume >80 mL/m2, RV ejection fraction (EF) <47%, left ventricular EF <55% and QRS duration >160 ms. The primary outcome included (aborted) death and sustained VT. The secondary outcome included heart failure, non-sustained VT and sustained supraventricular tachycardia. RESULTS: In 977 rTOF subjects (age 26±15 years, 45% PVR, follow-up 5.3±3.1 years), the primary and secondary outcomes occurred in 41 and 88 subjects, respectively. The HR for subjects with versus without PVR (time-varying covariate) was 0.65 (95% CI 0.31 to 1.36; P=0.25) for the primary outcome and 1.43 (95% CI 0.83 to 2.46; P=0.19) for the secondary outcome after adjusting for propensity and other factors. In subjects (n=426) not meeting consensus criteria, the HR for subjects with (n=132) versus without (n=294) PVR was 2.53 (95% CI 0.79 to 8.06; P=0.12) for the primary outcome and 2.31 (95% CI 1.07 to 4.97; P=0.03) for the secondary outcome. CONCLUSION: In this large multicentre rTOF cohort, PVR was not associated with a reduced rate of death and sustained VT at an average follow-up of 5.3 years. Additionally, there were more events after PVR compared with no PVR in subjects not meeting consensus criteria.


Assuntos
Implante de Prótese de Valva Cardíaca , Insuficiência da Valva Pulmonar/cirurgia , Valva Pulmonar/cirurgia , Taquicardia Ventricular/etiologia , Tetralogia de Fallot/cirurgia , Adulto , Feminino , Próteses Valvulares Cardíacas , Humanos , Masculino , Complicações Pós-Operatórias/mortalidade , Complicações Pós-Operatórias/cirurgia , Pontuação de Propensão , Insuficiência da Valva Pulmonar/mortalidade , Taquicardia Ventricular/mortalidade , Tetralogia de Fallot/mortalidade , Fatores de Tempo , Resultado do Tratamento
7.
Heart ; 103(22): 1795-1799, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28468757

RESUMO

BACKGROUND: The effect of FBN1 mutation type on the severity of cardiovascular manifestations in patients with Marfan syndrome (MFS) has been reported with disparity results. OBJECTIVES: This study aims to determine the impact of the FBN1 mutation type on aortic diameters, aortic dilation rates and on cardiovascular events (ie, aortic dissection and cardiovascular mortality). METHODS: MFS patients with a pathogenic FBN1 mutation followed at two specialised units were included. FBN1 mutations were classified as being dominant negative (DN; incorporation of non-mutated and mutated fibrillin-1 in the extracellular matrix) or having haploinsufficiency (HI; only incorporation of non-mutated fibrillin-1, thus a decreased amount of fibrillin-1 protein). Aortic diameters and the aortic dilation rate at the level of the aortic root, ascending aorta, arch, descending thoracic aorta and abdominal aorta by echocardiography and clinical endpoints comprising dissection and death were compared between HI and DN patients. RESULTS: Two hundred and ninety patients with MFS were included: 113 (39%) with an HI-FBN1 mutation and 177 (61%) with a DN-FBN1. At baseline, patients with HI-FBN1 had a larger aortic root diameter than patients with DN-FBN1 (HI: 39.3±7.2 mm vs DN: 37.3±6.8 mm, p=0.022), with no differences in age or body surface area. After a mean follow-up of 4.9±2.0 years, aortic root and ascending dilation rates were increased in patients with HI-FBN1 (HI: 0.57±0.8 vs DN: 0.28±0.5 mm/year, p=0.004 and HI: 0.59±0.9 vs DN: 0.30±0.7 mm/year, p=0.032, respectively). Furthermore, patients with HI-FBN1 tended to be at increased risk for the combined endpoint of dissection and death compared with patients with DN-FBN1 (HR: 3.3, 95% CI 1.0 to 11.4, p=0.060). CONCLUSIONS: Patients with an HI mutation had a more severely affected aortic phenotype, with larger aortic root diameters and a more rapid dilation rate, and tended to have an increased risk of death and dissections compared with patients with a DN mutation.


Assuntos
Aorta/patologia , Aneurisma Aórtico/genética , Dissecção Aórtica/genética , Fibrilina-1/genética , Síndrome de Marfan/genética , Mutação , Adolescente , Adulto , Dissecção Aórtica/diagnóstico por imagem , Dissecção Aórtica/metabolismo , Aorta/diagnóstico por imagem , Aneurisma Aórtico/diagnóstico por imagem , Aneurisma Aórtico/mortalidade , Análise Mutacional de DNA , Dilatação Patológica , Progressão da Doença , Ecocardiografia , Feminino , Predisposição Genética para Doença , Haploinsuficiência , Humanos , Masculino , Síndrome de Marfan/complicações , Síndrome de Marfan/diagnóstico , Síndrome de Marfan/mortalidade , Pessoa de Meia-Idade , Fenótipo , Valor Preditivo dos Testes , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Índice de Gravidade de Doença , Espanha , Fatores de Tempo , Adulto Jovem
8.
Eur J Prev Cardiol ; 24(12): 1319-1327, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28541122

RESUMO

Background Young patients with congenital heart disease reaching adulthood face mandatory transition to adult cardiology. Their new cardiologist needs to assess the chances of major future events such as surgery. Using a large national registry, we assessed if patient characteristics at the age of 18 years could predict the chance of congenital heart surgery in adulthood. Design and methods Of 10,300 patients from the CONCOR national registry, we used general patient characteristics at age 18 years, underlying congenital heart defect, history of complications, and interventions in childhood as potential predictors of congenital heart surgery occurring from age 18 years up to age 40 and 60 years. Cox regression was used to calculate hazard ratios with 95% confidence intervals. Analyses were performed separately for all congenital heart surgery and for valvular surgery alone. Results Altogether 2427 patients underwent congenital heart surgery after age 18 years, 1389 of whom underwent valvular surgery. Underlying heart defect, male sex, multiple defects, childhood endocarditis, supraventricular arrhythmia, aortic complications and paediatric cardiovascular surgery, independently predicted adult congenital heart surgery. The mean chance of congenital heart surgery was 22% up to age 40 and 43% up to age 60 years; individual chances spanned from 9-68% up to age 40 and from 19-93% up to age 60 years. Conclusion At the time of transition from paediatric to adult cardiology, an easily obtainable set of characteristics of patients with congenital heart disease can meaningfully inform cardiologists about the patient's individual chance of surgery in adulthood. Our findings warrant validation in other cohorts.


Assuntos
Procedimentos Cirúrgicos Cardíacos/normas , Previsões , Transição Epidemiológica , Cardiopatias Congênitas/cirurgia , Sistema de Registros , Medição de Risco , Adolescente , Adulto , Distribuição por Idade , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Progressão da Doença , Feminino , Seguimentos , Cardiopatias Congênitas/epidemiologia , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Países Baixos/epidemiologia , Fatores de Risco , Adulto Jovem
10.
Eur J Cardiovasc Nurs ; 11(3): 349-55, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22414583

RESUMO

BACKGROUND: Type D personality, characterized by high levels of negative affectivity and social inhibition, is related to mortality, morbidity, poor health status, quality of life (QoL) and less healthcare utilization in various cardiovascular patient groups. To date, studies in patients with congenital heart disease (CHD) are lacking. AIMS: (1) To examine the prevalence of type D personality in CHD patients; (2) to compare type D to non-type D patients with regard to disease severity, functional status, health status and QoL; and (3) to examine the extent to which type D personality is independently related to healthcare utilization. METHODS: A total of 1109 adult CHD patients were included in a questionnaire survey. Due to missing data, 302 patients were excluded. RESULTS: The prevalence of Type D personality was 20.4%. Type D patients reported a poorer functional status, health status and QoL than non-type D patients (p<0.05). Type D patients reported less healthcare use than non-type D patients (primary and cardiac outpatient healthcare: adjusted OR=0.56, 95% CI=0.35-0.90; inpatient healthcare: adjusted OR=0.38, 95% CI=0.17-0.83). Results of a post-hoc analysis showed a high prevalence of type D personality in patients with a poor functional status who did not consult their cardiologist. CONCLUSION: type D patients report a poorer functional status, health status and QoL, but less healthcare utilization. In clinical practice, patients should be screened for type D personality, since social inhibition may prevent them from contacting a healthcare provider in the event of symptom aggravation.


Assuntos
Atenção à Saúde/estatística & dados numéricos , Nível de Saúde , Cardiopatias Congênitas/psicologia , Personalidade , Qualidade de Vida/psicologia , Adulto , Feminino , Inquéritos Epidemiológicos , Humanos , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença
11.
Eur J Hum Genet ; 19(4): 389-93, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21248739

RESUMO

Down's syndrome (DS), resulting from an additional copy of chromosome 21 (trisomy 21), is frequently associated with congenital heart defects (CHDs). Although the increased dosage of chromosome 21 sequences is likely to be part of the etiology of cardiac defects, only a proportion of DS patients exhibit a congenital heart defect (birth prevalence 40-60%). Through a large-candidate gene-sequencing screen in patients with atrioventricular septal defects, substitutions were identified in bone morphogenetic protein (BMP) type I receptor ALK2 and two other genes in a patient with DS and a primum-type atrial septal defect. Structural modeling of the cytoplasmic domain of the ALK2 receptor suggests that H286 is in close proximity to the nucleotide-binding site of the kinase domain. We investigated whether this p.His286Asp substitution altered ALK2 function by using both in vitro as well as in vivo assays. The p.His286Asp variant demonstrated impaired functional activity as measured by BMP-specific transcriptional response assays. Furthermore, mild dominant-interfering activity was observed in vivo compared with wild-type ALK2 as determined by RNA injection into zebrafish embryos. These data indicate that in the context of a DS background, ALK2-mediated reduction of BMP signaling may contribute to CHDs.


Assuntos
Receptores de Ativinas Tipo I/genética , Síndrome de Down/genética , Cardiopatias Congênitas/etiologia , Cardiopatias Congênitas/genética , Mutação/genética , Receptores de Ativinas Tipo I/química , Receptores de Ativinas Tipo I/metabolismo , Animais , Proteína Morfogenética Óssea 1/metabolismo , Bovinos , Síndrome de Down/complicações , Feminino , Cardiopatias Congênitas/diagnóstico , Comunicação Interatrial/genética , Comunicação Interatrial/patologia , Humanos , Masculino , Conformação Proteica , Peixe-Zebra/genética
12.
Ther Clin Risk Manag ; 6: 359-66, 2010 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-20856682

RESUMO

Pulmonary arterial hypertension (PAH) is a progressive disease with poor survival outcome. PAH is classified by the 2009 updated clinical classification of pulmonary hypertension and a major subgroup is PAH due to congenital heart disease (CHD) with systemic-to-pulmonary shunt. CHD-PAH is a result of systemic-to-pulmonary shunting and chronic increased flow that ultimately results in adaptations of pulmonary vasculature and endothelial dysfunction. The advanced stage is called Eisenmenger syndrome which forms a small percentage (1%) of all CHD patients. Therapies targeted on PAH symptoms are called primary therapy for PAH, but most CHD-PAH patients progress to advanced therapy which is directed at the PAH itself. In CHD-PAH, advanced therapies are extensively investigated for all three major pathways: endothelin-1 receptor antagonists such as bosentan, prostanoids such as epoprostenol and phosphodiesterase 5 inhibitors such as sildenafil. Endpoints in most trials were catheterization hemodynamics, World Health Organization functional class, six-minute walking distance and patient-focused outcomes, based on quality of life questionnaires and Borg dyspnea index. The BREATHE-5 and EARLY study were two important randomized controlled trials showing efficacy of bosentan at short follow-up. Moreover in patients with Eisenmenger syndrome, one recent survival retrospective study with majority of patients on bosentan showed strong survival benefit over conservative therapy. A diversity of prospective cohort and retrospective studies were performed but all with limited data, due to small numbers and heterogeneity of underlying CHD diagnoses. Further larger studies are needed to determine optimal treatment for adults with CHD-PAH. This review focuses on bosentan in CHD-PAH. In particular, we discuss outcome of various clinical trials and compare efficacy and safety of bosentan to other advanced therapies.

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