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1.
Chest ; 2019 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-31794700

RESUMO

BACKGROUND: High-resolution chest CT (HRCT) scan is recommended after pulmonary arteriovenous malformation (PAVM) embolotherapy to assess for PAVM persistence and untreated PAVM growth. Graded transthoracic contrast echocardiography (TTCE) predicts the need for embolotherapy in PAVM screening. This study sought to determine whether postembolotherapy graded TTCE can similarly predict the need for repeat embolotherapy. METHODS: Thirty-two patients (8 men and 24 women; mean age, 51.1 ± 12.6 years) with prior PAVM embolotherapy and follow-up HRCT scan were prospectively enrolled. Patients underwent graded TTCE using a validated three-point quantitative grading scale. TTCE grade and HRCT findings were compared. RESULTS: Median time between most recent HRCT scan and TTCE was 7 days (interquartile range, 0-272 days). Thirty patients (94%) had no PAVMs requiring repeat embolotherapy on HRCT scan. Two patients (6%) had PAVMs requiring repeat embolotherapy (feeding artery [FA] ≥ 3 mm), one with untreated PAVM growth and one with treated PAVM persistence. TTCE was positive in 88% of patients (n = 28). All patients (n = 4, 12%) with negative TTCE had no visible PAVMs on HRCT scan. Nine patients (32%) had grade 1 shunt, 10 (35%) had grade 2 shunt, and nine (32%) had grade 3 shunt. No patients with grade 1 shunt had PAVMs amenable to repeat embolotherapy on HRCT scan. All patients (n = 2) with PAVMs requiring repeat embolotherapy (FA ≥ 3 mm) had grade 3 shunt. TTCE grade was significantly associated with PAVM FA diameter (P < .001). CONCLUSIONS: Postembolotherapy graded TTCE can predict the need for repeat embolotherapy on HRCT scan. Patients with negative TTCE and grade 1 shunt may not require HRCT follow-up and can potentially be followed with serial graded TTCE. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT02936349; URL: www.clinicaltrials.gov.

2.
Ann Thorac Surg ; 2019 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-31568749

RESUMO

BACKGROUND: Although patients with various types of heritable aortopathy often require distal aortic repair, data are limited regarding the most extensive operations-open thoracoabdominal aortic aneurysm (TAAA) repairs. The objective of this multicenter registry study was to characterize TAAA repairs in a large cohort of patients with different heritable aortic diseases. METHODS: From the 3,699 patients enrolled at 8 participating centers in the Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions (GenTAC) Registry, we identified 155 open TAAA repairs in 142 unique patients. We examined data related to clinical characteristics, surgical techniques, and outcomes. RESULTS: The primary diagnoses included Marfan syndrome (n=76; 54%), familial thoracic aortic aneurysm and dissections (FTAAD) (n=31; 22%), and Loeys-Dietz syndrome (n=10; 7%). Most repairs were performed for aneurysms associated with aortic dissection (n=110; 71%). The most common repairs involved the entire descending thoracic aorta with distal extension (21% Crawford extent I and 36% extent II). Adjuncts used during repair varied substantially. The operative mortality rate was 1.3%. Other complications included paraplegia (4%), acute renal failure (5%), and vocal cord paralysis (21%). Reoperation after TAAA repair was required in a subset of cases for early bleeding (n=15; 10%) and late repair failure (n=7; 5%). CONCLUSIONS: Open TAAA repairs are necessary in a variety of heritable aortic diseases. These patients often require extensive surgical repair, and a variety of adjunctive techniques are employed. The risk of repair failure and the need for reoperation in a subset of patients supports the need for vigilant long-term surveillance after repair.

6.
J Pediatr ; 204: 250-255.e1, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30270167

RESUMO

OBJECTIVE: To assess health-related quality of life (HRQOL) in a large multicenter cohort of children and young adults with Marfan syndrome participating in the Pediatric Heart Network Marfan Trial. STUDY DESIGN: The Pediatric Quality of Life Inventory (PedsQL) 4.0 Generic Core Scales were administered to 321 subjects with Marfan syndrome (5-25 years). PedsQL scores were compared with healthy population norms. The impact of treatment arm (atenolol vs losartan), severity of clinical features, and number of patient-reported symptoms on HRQOL was assessed by general linear models. RESULTS: Mean PedsQL scores in children (5-18 years) with Marfan syndrome were lower than healthy population norms for physical (P ≤ .003) and psychosocial (P < .001) domains; mean psychosocial scores for adults (19-25 years) were greater than healthy norms (P < .001). HRQOL across multiple domains correlated inversely with frequency of patient-reported symptoms (r = 0.30-0.38, P < .0001). Those <18 years of age with neurodevelopmental disorders (mainly learning disability, attention-deficit/hyperactivity disorder) had lower mean PedsQL scores (5.5-7.4 lower, P < .04). A multivariable model found age, sex, patient-reported symptoms, and neurodevelopmental disorder to be independent predictors of HRQOL. There were no differences in HRQOL scores by treatment arm, aortic root z score, number of skeletal features, or presence of ectopia lentis. CONCLUSIONS: Children and adolescents with Marfan syndrome were at high risk for impaired HRQOL. Patient-reported symptoms and neurodevelopmental disorder, but not treatment arm or severity of Marfan syndrome-related physical findings, were associated with lower HRQOL.


Assuntos
Anti-Hipertensivos/uso terapêutico , Atenolol/uso terapêutico , Losartan/uso terapêutico , Síndrome de Marfan/psicologia , Qualidade de Vida , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Indicadores Básicos de Saúde , Humanos , Masculino , Síndrome de Marfan/complicações , Síndrome de Marfan/tratamento farmacológico , Medidas de Resultados Relatados pelo Paciente , Índice de Gravidade de Doença , Adulto Jovem
8.
Genet Med ; 21(8): 1683-1690, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30573797

RESUMO

Life expectancy for a person with Marfan syndrome has essentially doubled over the past four decades. During this period, the clinical histories of the organs managed routinely have improved, and will continue to be. Prominent examples are the eyes, the heart and aorta, and some features of the skeletal system. Meanwhile, the natural histories of organ systems that have not been subjected to treatment need to be described. This is particularly important as due to the improved life span many symptoms and organ systems are only recently being recognized as being intrinsic to Marfan syndrome. Examples are the distal aorta and peripheral arteries, ventricular function, the central nervous system, sleep apnea, and adiposity. As a result, each person with Marfan syndrome will need to be evaluated and followed by more specialists than previously. Moreover, the coordinator of diagnostic testing and clinical referral must be aware of the expanded phenotype as people with Marfan syndrome age and the importance of life-long management of classical and novel features. The benefits of increased longevity and its consequences need to be addressed by investigators, health-care providers, and patients alike.


Assuntos
Expectativa de Vida , Longevidade/fisiologia , Síndrome de Marfan/fisiopatologia , Esqueleto/fisiopatologia , Aorta/fisiopatologia , Sistema Nervoso Central/fisiopatologia , Olho/fisiopatologia , Coração/fisiopatologia , Humanos , Síndrome de Marfan/epidemiologia
9.
J Med Genet ; 55(12): 824-830, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30244195

RESUMO

INTRODUCTION: Hereditary haemorrhagic telangiectasia (HHT) is a genetically heterogeneous disorder caused by mutations in the genes ENG, ACVRL1, and SMAD4. Yet the genetic cause remains unknown for some families even after exhaustive exome analysis. We hypothesised that non-coding regions of the known HHT genes may harbour variants that disrupt splicing in these cases. METHODS: DNA from 35 individuals with clinical findings of HHT and 2 healthy controls from 13 families underwent whole genome sequencing. Additionally, 87 unrelated cases suspected to have HHT were evaluated using a custom designed next-generation sequencing panel to capture the coding and non-coding regions of ENG, ACVRL1 and SMAD4. Individuals from both groups had tested negative previously for a mutation in the coding region of known HHT genes. Samples were sequenced on a HiSeq2500 instrument and data were analysed to identify novel and rare variants. RESULTS: Eight cases had a novel non-coding ACVRL1 variant that disrupted splicing. One family had an ACVRL1intron 9:chromosome 3 translocation, the first reported case of a translocation causing HHT. The other seven cases had a variant located within a ~300 bp CT-rich 'hotspot' region of ACVRL1intron 9 that disrupted splicing. CONCLUSIONS: Despite the difficulty of interpreting deep intronic variants, our study highlights the importance of non-coding regions in the disease mechanism of HHT, particularly the CT-rich hotspot region of ACVRL1intron 9. The addition of this region to HHT molecular diagnostic testing algorithms will improve clinical sensitivity.


Assuntos
Receptores de Activinas Tipo II/genética , Genômica , Íntrons , Mutação , Processamento de RNA , Telangiectasia Hemorrágica Hereditária/diagnóstico , Telangiectasia Hemorrágica Hereditária/genética , Sequência de Bases , Estudos de Casos e Controles , Mapeamento Cromossômico , Biologia Computacional/métodos , Feminino , Estudos de Associação Genética/métodos , Predisposição Genética para Doença , Genômica/métodos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Família Multigênica , Linhagem , RNA não Traduzido , Análise de Sequência de DNA , Translocação Genética
10.
Am J Cardiol ; 122(4): 689-695, 2018 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-29970240

RESUMO

The DeBakey classification divides type A acute aortic dissection (AAD) into type I and type II; the latter limited to the ascending aorta. We endeavored to examine differences in DeBakey groups in a contemporary registry. We divided 1,872 patients with noniatrogenic AAD from the International Registry of Acute Aortic Dissection into type I (n = 1691, 90.3%) and type II (n = 181, 9.7%). Patients with type II AAD were older. On presentation, patients with type I AAD reported more back and abdominal pain and were more likely to have pulse deficit. Intramural hematoma was more frequent in type II AAD. Most patients with both types were treated surgically. Lower rates of renal failure, coma, mesenteric and limb ischemia were noted in those with type II AAD. In-hospital death was less frequent (16.6% vs 22.5%) after type II AAD, a trend that did not reach significance. There was no difference in the incidence of new dissection, rapid aortic growth, late aortic intervention or survival at 5 years. In conclusion, AAD limited to the ascending aorta (DeBakey type II) appears to be associated with improved clinical outcomes compared with dissection that extend to the aortic arch or beyond. Although fewer dissection-related complications were noted in patients presenting with type II AAD, as was a trend toward reduced in-hospital mortality, 5-year survival and descending aortic sequelae are not reduced in this contemporary report from International Registry of Acute Aortic Dissection.


Assuntos
Aneurisma Dissecante/classificação , Aneurisma da Aorta Torácica/classificação , Implante de Prótese Vascular/métodos , Sistema de Registros , Stents , Doença Aguda , Idoso , Aneurisma Dissecante/mortalidade , Aneurisma Dissecante/cirurgia , Aneurisma da Aorta Torácica/mortalidade , Aneurisma da Aorta Torácica/cirurgia , Canadá/epidemiologia , Europa (Continente)/epidemiologia , Feminino , Seguimentos , Mortalidade Hospitalar/tendências , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Taxa de Sobrevida/tendências , Fatores de Tempo , Resultado do Tratamento , Estados Unidos/epidemiologia
11.
J Vasc Interv Radiol ; 29(7): 981-985, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29935788

RESUMO

Seven patients with pulmonary arteriovenous malformations (PAVMs) not well suited to coil and/or plug treatment were treated with expanded polytetrafluoroethylene-covered stents. Mean diameter of treated arteries was 6 mm. Complete technical success was achieved in 7 of 8 PAVMs, 6 using only covered stents and 1 using both a covered and a bare stent owing to endoleak. In 1 patient, the parent vessel was sacrificed after identification of additional feeding vessels following stent graft placement. In 6 patients with median imaging follow-up of 8 months (range, 1-121 months), all stent grafts were patent, and all treated PAVMs were completely excluded without persistence.


Assuntos
Malformações Arteriovenosas/cirurgia , Implante de Prótese Vascular/instrumentação , Prótese Vascular , Procedimentos Endovasculares/instrumentação , Artéria Pulmonar/cirurgia , Veias Pulmonares/cirurgia , Stents , Adolescente , Adulto , Angiografia Digital , Malformações Arteriovenosas/diagnóstico por imagem , Malformações Arteriovenosas/fisiopatologia , Implante de Prótese Vascular/efeitos adversos , Angiografia por Tomografia Computadorizada , Procedimentos Endovasculares/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Politetrafluoretileno , Desenho de Prótese , Artéria Pulmonar/anormalidades , Artéria Pulmonar/diagnóstico por imagem , Artéria Pulmonar/fisiopatologia , Circulação Pulmonar , Veias Pulmonares/anormalidades , Veias Pulmonares/diagnóstico por imagem , Veias Pulmonares/fisiopatologia , Fatores de Tempo , Resultado do Tratamento , Grau de Desobstrução Vascular
12.
Pediatr Cardiol ; 39(7): 1453-1461, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29948025

RESUMO

Few data exist regarding predictors of rapid aortic root dilation and referral for aortic surgery in Marfan syndrome (MFS). To identify independent predictors of the rate of aortic root (AoR) dilation and referral for aortic surgery, we investigated the data from the Pediatric Heart Network randomized trial of atenolol versus losartan in young patients with MFS. Data were analyzed from the echocardiograms at 0, 12, 24, and 36 months read in the core laboratory of 608 trial subjects, aged 6 months to 25 years, who met original Ghent criteria and had an AoR z-score (AoRz) > 3. Repeated measures linear and logistic regressions were used to determine multivariable predictors of AoR dilation. Receiver operator characteristic curves were used to determine cut-points in AoR dilation predicting referral for aortic surgery. Multivariable analysis showed rapid AoR dilation as defined by change in AoRz/year > 90th percentile was associated with older age, higher sinotubular junction z-score, and atenolol use (R2 = 0.01) or by change in AoR diameter (AoRd)/year > 90th percentile with higher sinotubular junction z-score and non-white race (R2 = 0.02). Referral for aortic root surgery was associated with higher AoRd, higher ascending aorta z-score, and higher sinotubular junction diameter:ascending aorta diameter ratio (R2 = 0.17). Change in AoRz of 0.72 SD units/year had 42% sensitivity and 92% specificity and change in AoRd of 0.34 cm/year had 38% sensitivity and 95% specificity for predicting referral for aortic surgery. In this cohort of young patients with MFS, no new robust predictors of rapid AoR dilation or referral for aortic root surgery were identified. Further investigation may determine whether generalized proximal aortic dilation and effacement of the sinotubular junction will allow for better risk stratification. Rate of AoR dilation cut-points had high specificity, but low sensitivity for predicting referral for aortic surgery, limiting their clinical use. Clinical Trial Number ClinicalTrials.gov number, NCT00429364.


Assuntos
Aorta/patologia , Doenças da Aorta/etiologia , Síndrome de Marfan/complicações , Procedimentos Cirúrgicos Vasculares/estatística & dados numéricos , Adolescente , Adulto , Bloqueadores do Receptor Tipo 1 de Angiotensina II , Anti-Hipertensivos/uso terapêutico , Aorta/cirurgia , Doenças da Aorta/epidemiologia , Doenças da Aorta/cirurgia , Atenolol/uso terapêutico , Criança , Pré-Escolar , Dilatação , Ecocardiografia/métodos , Feminino , Humanos , Lactente , Losartan/uso terapêutico , Masculino , Síndrome de Marfan/tratamento farmacológico , Síndrome de Marfan/cirurgia , Curva ROC , Encaminhamento e Consulta/estatística & dados numéricos , Medição de Risco/métodos , Fatores de Risco , Adulto Jovem
13.
Am J Cardiol ; 121(9): 1094-1101, 2018 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-29631804

RESUMO

The Pediatric Heart Network randomized trial of atenolol versus losartan in the Marfan syndrome showed no treatment differences in the rates of aortic-root growth or clinical outcomes. In this report we present treatment effects on aortic stiffness and determine whether baseline aortic stiffness predicts aortic-root growth and clinical outcomes. Echocardiograms at 0, 6, 12, 24, and 36 months from 608 subjects (6 months to 25 years) who met original Ghent criteria and had a maximum aortic-root z-score (ARz) >3 were centrally reviewed. Stiffness index (SI) and elastic modulus (EM) were calculated for aortic root and ascending aorta. Data were analyzed using multivariable mixed effects modeling and Cox regression. Heart rate-corrected aortic-root SI over 3 years decreased with atenolol but did not change with losartan (-0.298 ± 0.139 vs 0.141 ± 0.139/year, p = 0.01). In the entire cohort, above-median aortic-root SI (>9.1) and EM (>618 mm Hg) predicted a smaller annual decrease in ARz (p ≤0.001). Upper-quartile aortic-root EM (>914 mm Hg) predicted the composite outcome of aortic-root surgery, dissection, or death (hazard ratio 2.17, 95% confidence interval 1.02 to 4.63, p = 0.04). Crude 3-year event rates were 10.4% versus 3.2% for higher versus lower EM groups. In conclusion, atenolol was associated with a decrease in aortic-root SI, whereas losartan was not. Higher baseline aortic-root SI and EM were associated with a smaller decrease in ARz and increased risk for clinical outcomes. These data suggest that noninvasive aortic stiffness measures may identify patients at higher risk of progressive aortic enlargement and adverse clinical outcomes, potentially allowing for closer monitoring and more aggressive therapy.


Assuntos
Doenças da Aorta/tratamento farmacológico , Atenolol/administração & dosagem , Losartan/administração & dosagem , Síndrome de Marfan/diagnóstico por imagem , Síndrome de Marfan/tratamento farmacológico , Rigidez Vascular/efeitos dos fármacos , Adolescente , Aorta/diagnóstico por imagem , Aorta/efeitos dos fármacos , Doenças da Aorta/diagnóstico por imagem , Doenças da Aorta/etiologia , Técnicas de Imagem Cardíaca/métodos , Criança , Pré-Escolar , Relação Dose-Resposta a Droga , Esquema de Medicação , Humanos , Estimativa de Kaplan-Meier , Modelos Lineares , Síndrome de Marfan/complicações , Prognóstico , Modelos de Riscos Proporcionais , Medição de Risco , Índice de Gravidade de Doença , Taxa de Sobrevida , Resultado do Tratamento
14.
Ann Cardiothorac Surg ; 6(6): 595-598, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29270371

RESUMO

Much has changed regarding Marfan syndrome (MFS) over the past few decades. Once described solely as a heritable disorder of connective tissue, MFS is now one of a number of conditions recognized to be a disorder of abnormal signalling in the TGF-ß pathway. The cardinal features of MFS, once encompassed by the ocular, skeletal and cardiovascular systems, are now known to encompass many more organ systems, especially as people with MFS grow older. They are growing older by several decades compared to the 1970's because of profound improvements in diagnosis and management of the cardiovascular features, especially dilatation of the aortic root. This dilatation can be detected first in infancy and followed up by echocardiography. Progressive enlargement increases the risk of type A dissection and aortic regurgitation, the major causes of early mortality, in untreated patients today. Medical therapy with ß-adrenergic blockade, first shown to be effective in the 1980's, can retard this dilatation. In the past decade, angiotensin receptor blockade, which reduces aberrant signalling through one of the TGF-ß pathways, also can be effective. However, when dilatation of the root becomes such that the risk of dissection increases to an unacceptable degree, surgical therapy becomes necessary. In the mid-1970's, the composite graft, introduced by Hugh Bentall, markedly reduced mortality. In the past decade, a valve-spring aortic root replacement, advanced by Tirone David, has become widely adopted. Mid-term results are quite encouraging. Other cardiovascular involvement, such as mitral valve prolapse, type B dissection, and dilatation and dissection of aortic branches, also require close monitoring. Currently, life-expectancy in people with MFS who are diagnosed early and treated prophylactically is approaching that of the general population.

15.
Heart Fail Clin ; 13(4): 697-701, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28865779

RESUMO

Acute aortic syndromes are highly morbid conditions that require prompt diagnosis and management. Aortic dissections have rhythmic patterns, with notable peaks at certain points in every 24 hours as well as weekly and seasonal variations. Several retrospective studies have assessed the chronobiology of acute aortic dissections and there seems to be a winter seasonal peak and morning daily peak in incidence. Although the pathophysiology of this chronobiology is unclear, there are several environmental and physiologic possibilities. This article reviews the major studies examining the chronobiology of acute aortic dissection, and summarizes some theories on the pathophysiology of this phenomenon.


Assuntos
Doenças da Aorta/fisiopatologia , Estações do Ano , Doença Aguda , Doenças da Aorta/epidemiologia , Saúde Global , Humanos , Morbidade/tendências , Síndrome
16.
Am J Cardiol ; 120(7): 1171-1175, 2017 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-28802510

RESUMO

This study analyzed the impact of sex, hemodynamic profile, and valve fusion pattern on aortopathy associated with bicuspid aortic valve (BAV). The National Heart Lung and Blood Institute-sponsored National Registry of Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions (GenTAC) provided comprehensive information on a large population of well-characterized patients with BAV. Of 969 enrolled patients with BAV, 551 (57%, 77% male) had already undergone valvular and/or aortic surgery. Echocardiographic imaging data were available on 339 unoperated or preoperative participants who formed the basis of this study. BAV function was normal in 45 (14%), with a predominant aortic regurgitation (AR) in 127 (41%) and a predominant aortic stenosis (AS) in 76 (22%). Moderate-severe AR was associated with larger sinus of Valsalva (SOV) diameters compared with normal function and AS (all p <0.01). Moderate-severe AS was associated with a larger ascending aortic (AscAo) diameter compared with normal function (p = 0.003) but not with AR. The SOV diameter was larger in men than in women (3.7 ± 0.7 vs 3.3 ± 0.6 cm, p <0.0001), whereas AscAo diameters were comparable (3.9 ± 0.9 vs 3.7 ± 0.9 cm, p = 0.08). Right-left commissural fusion was associated with a larger SOV diameter (3.7 ± 0.7 vs 3.3 ± 0.6 cm, p <0.0001) compared with a right-noncoronary fusion pattern. Predominant AR was more common in men (45% vs 27%, p = 0.004), whereas AS was more common in women (29% vs 18%, p = 0.04). In conclusion, in the GenTAC Registry, AR was associated with diffuse (annular, SOV, and AscAo) enlargement, whereas moderate-severe AS was only associated with AscAo enlargement. Male sex and right-left cusp pattern of cusp fusion were associated with larger SOV diameters and a greater likelihood of AR, whereas women had a higher prevalence of AS.


Assuntos
Aorta Torácica/diagnóstico por imagem , Aneurisma da Aorta Torácica/etiologia , Valva Aórtica/anormalidades , Doenças das Valvas Cardíacas/complicações , Hemodinâmica/fisiologia , Sistema de Registros , Adolescente , Adulto , Idoso , Aorta Torácica/fisiopatologia , Aneurisma da Aorta Torácica/epidemiologia , Aneurisma da Aorta Torácica/fisiopatologia , Valva Aórtica/fisiopatologia , Criança , Pré-Escolar , Ecocardiografia , Feminino , Seguimentos , Doenças das Valvas Cardíacas/epidemiologia , Doenças das Valvas Cardíacas/fisiopatologia , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Prevalência , Estudos Retrospectivos , Fatores de Risco , Fatores Sexuais , Estados Unidos/epidemiologia , Adulto Jovem
17.
Congenit Heart Dis ; 12(6): 740-745, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28805011

RESUMO

BACKGROUND: Unicuspid aortic valve (UAV) is a rare disorder, often difficult to distinguish from bicuspid aortic valve (BAV). BAV and UAV share valve pathology such as the presence of a raphe, leaflet fusion, aortic stenosis, aortic regurgitation, and/or ascending aortic dilatation, but a comprehensive echocardiographic comparison of patients with UAV and BAV has not been previously performed. METHODS: We investigated UAV and BAV patients at an early stage of disease included in GenTAC, a national registry of genetically related aortic aneurysms and associated cardiac conditions. Clinical and echocardiographic data from the GenTAC Registry were compared between 17 patients with UAV and 17 matched-controls with BAV. RESULTS: Baseline characteristics including demographics, clinical findings including family history of BAV and aortic aneurysm/coarctation, and echocardiographic variables were similar between BAV and UAV patients; aortic stenosis was more common and more severe in patients with UAV. This was evidenced by higher mean and peak gradient, smaller aortic valve area, and more advanced valvular degeneration (all P < .05). There were no significant differences in aortic dimensions, with a similar pattern of enlargement of the ascending aorta. CONCLUSIONS: The similar baseline characteristics with more accelerated aortic valve degeneration and stenosis suggest that UAV represents an extreme in the spectrum of BAV syndromes. Therefore, it is reasonable to consider application of recommendations for the management of patients with BAV to those with the rarer UAV.


Assuntos
Valva Aórtica/anormalidades , Doenças das Valvas Cardíacas/genética , Sistema de Registros , Adolescente , Adulto , Aorta/diagnóstico por imagem , Valva Aórtica/diagnóstico por imagem , Criança , Pré-Escolar , Diagnóstico Diferencial , Ecocardiografia , Feminino , Doenças das Valvas Cardíacas/congênito , Doenças das Valvas Cardíacas/diagnóstico , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Fenótipo , Estudos Retrospectivos , Adulto Jovem
18.
Circulation ; 136(11): 1037-1048, 2017 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-28687708

RESUMO

BACKGROUND: Most arteriovenous malformations (AVMs) are localized and occur sporadically. However, they also can be multifocal in autosomal-dominant disorders, such as hereditary hemorrhagic telangiectasia and capillary malformation (CM)-AVM. Previously, we identified RASA1 mutations in 50% of patients with CM-AVM. Herein we studied non-RASA1 patients to further elucidate the pathogenicity of CMs and AVMs. METHODS: We conducted a genome-wide linkage study on a CM-AVM family. Whole-exome sequencing was also performed on 9 unrelated CM-AVM families. We identified a candidate gene and screened it in a large series of patients. The influence of several missense variants on protein function was also studied in vitro. RESULTS: We found evidence for linkage in 2 loci. Whole-exome sequencing data unraveled 4 distinct damaging variants in EPHB4 in 5 families that cosegregated with CM-AVM. Overall, screening of EPHB4 detected 47 distinct mutations in 54 index patients: 27 led to a premature stop codon or splice-site alteration, suggesting loss of function. The other 20 are nonsynonymous variants that result in amino acid substitutions. In vitro expression of several mutations confirmed loss of function of EPHB4. The clinical features included multifocal CMs, telangiectasias, and AVMs. CONCLUSIONS: We found EPHB4 mutations in patients with multifocal CMs associated with AVMs. The phenotype, CM-AVM2, mimics RASA1-related CM-AVM1 and also hereditary hemorrhagic telangiectasia. RASA1-encoded p120RASGAP is a direct effector of EPHB4. Our data highlight the pathogenetic importance of this interaction and indicts EPHB4-RAS-ERK signaling pathway as a major cause for AVMs.


Assuntos
Malformações Arteriovenosas/diagnóstico , Malformações Arteriovenosas/genética , Capilares/anormalidades , Mutação em Linhagem Germinativa/genética , Sistema de Sinalização das MAP Quinases/fisiologia , Mancha Vinho do Porto/diagnóstico , Mancha Vinho do Porto/genética , Receptor EphB4/genética , Proteína p120 Ativadora de GTPase/genética , Bases de Dados Genéticas , Feminino , Estudo de Associação Genômica Ampla/métodos , Humanos , Masculino , Linhagem
19.
Circ Cardiovasc Genet ; 10(3)2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28600386

RESUMO

BACKGROUND: The associations of age and sex with phenotypic features of Marfan syndrome have not been systematically examined in a large cohort of both children and adults. METHODS AND RESULTS: We evaluated 789 Marfan patients enrolled in the National Heart, Lung, and Blood Institute GenTAC (Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions) Registry (53% male; mean age 31 [range: 1-86 years]). Females aged ≥15 and males aged ≥16 years were considered adults based on average age of skeletal maturity. Adults (n=606) were more likely than children (n=183) likely to have spontaneous pneumothorax, scoliosis, and striae but were comparable in revised Ghent systemic score, ectopia lentis, and most phenotypic features, including prevalence of aortic root dilatation. Prophylactic aortic root replacement and mitral valve surgery were rare during childhood versus adulthood (2% versus 35% and 1% versus 9%, respectively, both P<0.0001). Adult males were more likely than females to have aortic root dilatation (92% versus 84%), aortic regurgitation (55% versus 36%), and to have undergone prophylactic aortic root replacement (47% versus 24%), all P<0.001. Prevalence of previous aortic dissection tended to be higher in males than females (25% versus 18%, P=0.06); 44% of dissections were type B. Type B dissection was strongly associated with previous prophylactic aortic root replacement. CONCLUSIONS: Pulmonary, skeletal, and aortic complications, but not other phenotypic features, are more prevalent in adults than children in Marfan syndrome. Aortic aneurysms and prophylactic aortic surgery are more common in men. Aortic dissection, commonly type B, occurs in an appreciable proportion of Marfan patients, especially in men and after previous prophylactic aortic root replacement.


Assuntos
Síndrome de Marfan/diagnóstico , Sistema de Registros , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Aneurisma Aórtico/etiologia , Doenças da Aorta/epidemiologia , Doenças da Aorta/cirurgia , Valva Aórtica/cirurgia , Doenças Cardiovasculares/complicações , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Cardiopatias Congênitas/cirurgia , Doenças das Valvas Cardíacas/cirurgia , Humanos , Lactente , Masculino , Síndrome de Marfan/complicações , Pessoa de Meia-Idade , National Heart, Lung, and Blood Institute (U.S.) , Fenótipo , Fatores Sexuais , Estados Unidos , Adulto Jovem
20.
Cardiovasc Intervent Radiol ; 40(7): 1003-1009, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28188364

RESUMO

PURPOSE: To determine current practice regarding screening, management, and follow-up of pulmonary arteriovenous malformations (PAVMs), particularly those with feeding arteries <3 mm in diameter, in those patients with hereditary hemorrhagic telangiectasia (HHT) at HHT Centers of Excellence. MATERIALS AND METHODS: A 32-question survey focusing on PAVM screening, management, and follow-up was sent to 147 participants at HHT Centers worldwide. RESULTS: Thirty-three responses were received (22%); 60% from interventional radiologists and 20% from pulmonologists; 67% from the USA, 21% European, and 6% Asian. In HHT patients with initial negative screening echocardiogram, 60% recommended repeat screening contrast echocardiogram in 5 years, while 15% felt that no additional screening was necessary in these patients. Fifty-nine percentage reported never having seen a patient with initial negative contrast echocardiogram become positive. In patients with grade 1 echocardiograms, 41% recommended contrast-enhanced CT as the next step in management, 22% recommended non-contrast CT, and 22 and 3% recommended repeat echocardiogram in 5 and 10 years, respectively. In patients with grade 1 echocardiograms but no visible PAVMs, opinions regarding the use of bubble filters were evenly divided, while 79% recommended prophylactic antibiotics prior to invasive procedures. Eighty percentages of respondents treat PAVMs with feeding artery less than 3 mm, and 52% treat feeders less than 2 mm. Regarding follow-up, 71% reported seeing PAVM recurrence at the site of a previously completely treated PAVM. CONCLUSION: There is inconsistency in practice regarding PAVM screening, management, and follow-up, suggesting a need for further research and guideline development.


Assuntos
Fístula Arteriovenosa/diagnóstico , Fístula Arteriovenosa/terapia , Programas de Rastreamento , Artéria Pulmonar/anormalidades , Veias Pulmonares/anormalidades , Telangiectasia Hemorrágica Hereditária/diagnóstico , Telangiectasia Hemorrágica Hereditária/terapia , Adulto , Fístula Arteriovenosa/epidemiologia , Meios de Contraste , Estudos Transversais , Ecocardiografia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Inquéritos e Questionários , Telangiectasia Hemorrágica Hereditária/epidemiologia
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