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Aortic disease, including dissection, aneurysm, and rupture, carries significant morbidity and mortality and is a notable cause of sudden cardiac death. Much of our knowledge regarding the genetic basis of aortic disease has relied on the study of individuals with Mendelian aortopathies and, until recently, the genetic determinants of population-level variance in aortic phenotypes remained unclear. However, the application of machine learning methodologies to large imaging datasets has enabled researchers to rapidly define aortic traits and mine dozens of novel genetic associations for phenotypes such as aortic diameter and distensibility. In this review, we highlight the emerging potential of genomics for identifying causal genes and candidate drug targets for aortic disease. We describe how deep learning technologies have accelerated the pace of genetic discovery in this field. We then provide a blueprint for translating genetic associations to biological insights, reviewing techniques for locus and cell type prioritization, high-throughput functional screening, and disease modeling using cellular and animal models of aortic disease.
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Aneurisma da Aorta Torácica , Doenças da Aorta , Dissecção Aórtica , Animais , Humanos , Genômica/métodos , Doenças da Aorta/genética , Dissecção Aórtica/genética , Fenótipo , Aneurisma da Aorta Torácica/genéticaRESUMO
BACKGROUND AND AIMS: This study assessed whether a model incorporating clinical features and a polygenic score for ascending aortic diameter would improve diameter estimation and prediction of adverse thoracic aortic events over clinical features alone. METHODS: Aortic diameter estimation models were built with a 1.1 million-variant polygenic score (AORTA Gene) and without it. Models were validated internally in 4394 UK Biobank participants and externally in 5469 individuals from Mass General Brigham (MGB) Biobank, 1298 from the Framingham Heart Study (FHS), and 610 from All of Us. Model fit for adverse thoracic aortic events was compared in 401 453 UK Biobank and 164 789 All of Us participants. RESULTS: AORTA Gene explained more of the variance in thoracic aortic diameter compared to clinical factors alone: 39.5% (95% confidence interval 37.3%-41.8%) vs. 29.3% (27.0%-31.5%) in UK Biobank, 36.5% (34.4%-38.5%) vs. 32.5% (30.4%-34.5%) in MGB, 41.8% (37.7%-45.9%) vs. 33.0% (28.9%-37.2%) in FHS, and 34.9% (28.8%-41.0%) vs. 28.9% (22.9%-35.0%) in All of Us. AORTA Gene had a greater area under the receiver operating characteristic curve for identifying diameter ≥ 4 cm: 0.836 vs. 0.776 (P < .0001) in UK Biobank, 0.808 vs. 0.767 in MGB (P < .0001), 0.856 vs. 0.818 in FHS (P < .0001), and 0.827 vs. 0.791 (P = .0078) in All of Us. AORTA Gene was more informative for adverse thoracic aortic events in UK Biobank (P = .0042) and All of Us (P = .049). CONCLUSIONS: A comprehensive model incorporating polygenic information and clinical risk factors explained 34.9%-41.8% of the variation in ascending aortic diameter, improving the identification of ascending aortic dilation and adverse thoracic aortic events compared to clinical risk factors.
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Myhre syndrome is an increasingly diagnosed ultrarare condition caused by recurrent germline autosomal dominant de novo variants in SMAD4. Detailed multispecialty evaluations performed at the Massachusetts General Hospital (MGH) Myhre Syndrome Clinic (2016-2023) and by collaborating specialists have facilitated deep phenotyping, genotyping and natural history analysis. Of 47 patients (four previously reported), most (81%) patients returned to MGH at least once. For patients followed for at least 5 years, symptom progression was observed in all. 55% were female and 9% were older than 18 years at diagnosis. Pathogenic variants in SMAD4 involved protein residues p.Ile500Val (49%), p.Ile500Thr (11%), p.Ile500Leu (2%), and p.Arg496Cys (38%). Individuals with the SMAD4 variant p.Arg496Cys were less likely to have hearing loss, growth restriction, and aortic hypoplasia than the other variant groups. Those with the p.Ile500Thr variant had moderate/severe aortic hypoplasia in three patients (60%), however, the small number (n = 5) prevented statistical comparison with the other variants. Two deaths reported in this cohort involved complex cardiovascular disease and airway stenosis, respectively. We provide a foundation for ongoing natural history studies and emphasize the need for evidence-based guidelines in anticipation of disease-specific therapies.
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BACKGROUND: Mural cells in ascending aortic aneurysms undergo phenotypic changes that promote extracellular matrix destruction and structural weakening. To explore this biology, we analyzed the transcriptional features of thoracic aortic tissue. METHODS: Single-nuclear RNA sequencing was performed on 13 samples from human donors, 6 with thoracic aortic aneurysm, and 7 without aneurysm. Individual transcriptomes were then clustered based on transcriptional profiles. Clusters were used for between-disease differential gene expression analyses, subcluster analysis, and analyzed for intersection with genetic aortic trait data. RESULTS: We sequenced 71 689 nuclei from human thoracic aortas and identified 14 clusters, aligning with 11 cell types, predominantly vascular smooth muscle cells (VSMCs) consistent with aortic histology. With unbiased methodology, we found 7 vascular smooth muscle cell and 6 fibroblast subclusters. Differentially expressed genes analysis revealed a vascular smooth muscle cell group accounting for the majority of differential gene expression. Fibroblast populations in aneurysm exhibit distinct behavior with almost complete disappearance of quiescent fibroblasts. Differentially expressed genes were used to prioritize genes at aortic diameter and distensibility genome-wide association study loci highlighting the genes JUN, LTBP4 (latent transforming growth factor beta-binding protein 1), and IL34 (interleukin 34) in fibroblasts, ENTPD1, PDLIM5 (PDZ and LIM domain 5), ACTN4 (alpha-actinin-4), and GLRX in vascular smooth muscle cells, as well as LRP1 in macrophage populations. CONCLUSIONS: Using nuclear RNA sequencing, we describe the cellular diversity of healthy and aneurysmal human ascending aorta. Sporadic aortic aneurysm is characterized by differential gene expression within known cellular classes rather than by the appearance of novel cellular forms. Single-nuclear RNA sequencing of aortic tissue can be used to prioritize genes at aortic trait loci.
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Aneurisma da Aorta Torácica , Aneurisma Aórtico , Humanos , Estudo de Associação Genômica Ampla , Músculo Liso Vascular/metabolismo , Actinina/genética , RNA Nuclear/metabolismo , Aorta/patologia , Miócitos de Músculo Liso/metabolismo , Aneurisma da Aorta Torácica/patologia , Aneurisma Aórtico/metabolismo , Análise de Sequência de RNA , Fator de Crescimento Transformador beta/metabolismoRESUMO
OBJECTIVE: Arterial stiffness is a risk factor for cardiovascular disease, including heart failure with preserved ejection fraction (HFpEF). MGP (matrix Gla protein) is implicated in vascular calcification in animal models, and circulating levels of the uncarboxylated, inactive form of MGP (ucMGP) are associated with cardiovascular disease-related and all-cause mortality in human studies. However, the role of MGP in arterial stiffness is uncertain. Approach and Results: We examined the association of ucMGP levels with vascular calcification, arterial stiffness including carotid-femoral pulse wave velocity (PWV), and incident heart failure in community-dwelling adults from the Framingham Heart Study. To further investigate the link between MGP and arterial stiffness, we compared aortic PWV in age- and sex-matched young (4-month-old) and aged (10-month-old) wild-type and Mgp+/- mice. Among 7066 adults, we observed significant associations between higher levels of ucMGP and measures of arterial stiffness, including higher PWV and pulse pressure. Longitudinal analyses demonstrated an association between higher ucMGP levels and future increases in systolic blood pressure and incident HFpEF. Aortic PWV was increased in older, but not young, female Mgp+/- mice compared with wild-type mice, and this augmentation in PWV was associated with increased aortic elastin fiber fragmentation and collagen accumulation. CONCLUSIONS: This translational study demonstrates an association between ucMGP levels and arterial stiffness and future HFpEF in a large observational study, findings that are substantiated by experimental studies showing that mice with Mgp heterozygosity develop arterial stiffness. Taken together, these complementary study designs suggest a potential role of therapeutically targeting MGP in HFpEF.
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Proteínas de Ligação ao Cálcio/sangue , Proteínas da Matriz Extracelular/sangue , Insuficiência Cardíaca/sangue , Rigidez Vascular , Animais , Pressão Sanguínea , Proteínas de Ligação ao Cálcio/genética , Proteínas da Matriz Extracelular/genética , Feminino , Deleção de Genes , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/fisiopatologia , Humanos , Estudos Longitudinais , Masculino , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Estudos Prospectivos , Volume Sistólico , Proteína de Matriz GlaRESUMO
Loss-of-function pathogenic variants in somatic and germline cells in SMAD4 may cause cancer and juvenile polyposis-Hereditary Hemorrhagic Telangiectasia (SMAD4-JP-HHT), respectively. In a similar manner, gain-of-function somatic and germline pathogenic variants in SMAD4 can cause various forms of cancer as well as Myhre syndrome. The different SMAD4 molecular mechanisms result in contrasting clinical phenotypes demonstrated by SMAD4-JP-HHT and Myhre syndrome. We report an additional patient with SMAD4-JP-HHT and aortopathy, and expand the phenotype to include severe valvulopathy, cutaneous, ophthalmologic, and musculoskeletal features consistent with an inherited disorder of connective tissue. We compared this 70-year-old man with SMAD4-JP-HHT to 18 additional literature cases, and also compared patients with SMAD4-JP-HHT to those with Myhre syndrome. In contrast to aorta dilation, hypermobility, and loose skin in SMAD4-JP-HHT, Myhre syndrome has aorta hypoplasia, stiff joints, and firm skin representing an intriguing phenotypic contrast, which can be attributed to different molecular mechanisms involving SMAD4. We remind clinicians about the possibility of significant cardiac valvulopathy and aortopathy, as well as connective tissue disease in SMAD4-JP-HHT. Additional patients and longer follow-up will help determine if more intensive surveillance improves care amongst these patients.
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Telangiectasia Hemorrágica Hereditária , Tecido Conjuntivo , Criptorquidismo , Fácies , Mutação com Ganho de Função , Transtornos do Crescimento , Deformidades Congênitas da Mão , Humanos , Deficiência Intelectual , Polipose Intestinal/congênito , Mutação , Síndromes Neoplásicas Hereditárias , Fenótipo , Proteína Smad4/genética , Telangiectasia Hemorrágica Hereditária/complicações , Telangiectasia Hemorrágica Hereditária/diagnóstico , Telangiectasia Hemorrágica Hereditária/genéticaRESUMO
Tetralogy of Fallot (ToF) can be associated with a wide range of extracardiac anomalies, with an underlying etiology identified in approximately 10% of cases. Individuals affected with Myhre syndrome due to recurrent SMAD4 mutations frequently have cardiovascular anomalies, including congenital heart defects. In addition to two patients in the literature with ToF, we describe five additional individuals with Myhre syndrome and classic ToF, ToF with pulmonary atresia and multiple aorto-pulmonary collaterals, and ToF with absent pulmonary valve. Aorta hypoplasia was documented in one patient and suspected in another two. In half of these individuals, postoperative cardiac dysfunction was thought to be more severe than classic postoperative ToF repair. There may be an increase in right ventricular pressure, and right ventricular dysfunction due to free pulmonic regurgitation. Noncardiac developmental abnormalities in our series and the literature, including corectopia, heterochromia iridis, and congenital miosis suggest an underlying defect of neural crest cell migration in Myhre syndrome. We advise clinicians that Myhre syndrome should be considered in the genetic evaluation of a child with ToF, short stature, unusual facial features, and developmental delay, as these children may be at risk for increased postoperative morbidity. Additional research is needed to investigate the hypothesis that postoperative hemodynamics in these patients may be consistent with restrictive myocardial physiology.
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Cardiopatias Congênitas , Tetralogia de Fallot , Criptorquidismo , Fácies , Transtornos do Crescimento , Deformidades Congênitas da Mão , Cardiopatias Congênitas/complicações , Humanos , Deficiência Intelectual , Masculino , Crista Neural , Fenótipo , Proteína Smad4/genética , Tetralogia de Fallot/complicações , Tetralogia de Fallot/genética , Tetralogia de Fallot/cirurgiaRESUMO
Background: Myhre syndrome, caused by pathogenic variants in SMAD4, is characterized by compact body habitus with short stature, distinctive craniofacial appearance, stiff skin, cardiovascular abnormalities (valve stenosis, coarctation, hypoplasia, or stenosis of aorta), effusions of potential spaces (pericardium, pleura, peritoneum), restricted movement of the joints (including thorax), and hearing loss. Lung and airway disease has been reported, but not always well-defined, to include interstitial lung disease, large airway obstruction, and pulmonary arterial hypertension. Excessive fibroproliferation of tissues especially following trauma or surgical instrumentation has been recognized, although these may also present spontaneously. Method: We report the pathologic features of 1 new patient with progressive choanal stenosis, and 22 literature cases, including the expanded history of 5 patients (3 who died). Results: Examination of patient tissues documents cellular fibroproliferation and deposition of excessive extracellular matrix explaining some of the observed clinical features of Myhre syndrome. Conclusion: Excessive fibrosis is noted in multiple tissues, especially heart, lung, and upper and lower airways. Our research provides the first systematic review to provide a knowledge base of gross and pathologic findings in Myhre syndrome.
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Mutação com Ganho de Função , Deformidades Congênitas da Mão , Masculino , Humanos , Constrição Patológica , Deformidades Congênitas da Mão/diagnóstico , Deformidades Congênitas da Mão/patologia , Fácies , Proteína Smad4/genéticaRESUMO
Importance: Ascending thoracic aortic disease is an important cause of sudden death in the US, yet most aortic aneurysms are identified incidentally. Objective: To develop and validate a clinical score to estimate ascending aortic diameter. Design, Setting, and Participants: Using an ongoing magnetic resonance imaging substudy of the UK Biobank cohort study, which had enrolled participants from 2006 through 2010, score derivation was performed in 30â¯018 participants and internal validation in an additional 6681. External validation was performed in 1367 participants from the Framingham Heart Study (FHS) offspring cohort who had undergone computed tomography from 2002 through 2005, and in 50â¯768 individuals who had undergone transthoracic echocardiography in the Community Care Cohort Project, a retrospective hospital-based cohort of longitudinal primary care patients in the Mass General Brigham (MGB) network between 2001-2018. Exposures: Demographic and clinical variables (11 covariates that would not independently prompt thoracic imaging). Main Outcomes and Measures: Ascending aortic diameter was modeled with hierarchical group least absolute shrinkage and selection operator (LASSO) regression. Correlation between estimated and measured diameter and performance for identifying diameter 4.0 cm or greater were assessed. Results: The 30â¯018-participant training cohort (52% women), were a median age of 65.1 years (IQR, 58.6-70.6 years). The mean (SD) ascending aortic diameter was 3.04 (0.31) cm for women and 3.32 (0.34) cm for men. A score to estimate ascending aortic diameter explained 28.2% of the variance in aortic diameter in the UK Biobank validation cohort (95% CI, 26.4%-30.0%), 30.8% in the FHS cohort (95% CI, 26.8%-34.9%), and 32.6% in the MGB cohort (95% CI, 31.9%-33.2%). For detecting individuals with an ascending aortic diameter of 4 cm or greater, the score had an area under the receiver operator characteristic curve of 0.770 (95% CI, 0.737-0.803) in the UK Biobank, 0.813 (95% CI, 0.772-0.854) in the FHS, and 0.766 (95% CI, 0.757-0.774) in the MGB cohorts, although the model significantly overestimated or underestimated aortic diameter in external validation. Using a fixed-score threshold of 3.537, 9.7 people in UK Biobank, 1.8 in the FHS, and 4.6 in the MGB cohorts would need imaging to confirm 1 individual with an ascending aortic diameter of 4 cm or greater. The sensitivity at that threshold was 8.9% in the UK Biobank, 11.3% in the FHS, and 18.8% in the MGB cohorts, with specificities of 98.1%, 99.2%, and 96.2%, respectively. Conclusions and Relevance: A prediction model based on common clinically available data was derived and validated to predict ascending aortic diameter. Further research is needed to optimize the prediction model and to determine whether its use is associated with improved outcomes.
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Aorta , Aneurisma Aórtico , Modelos Cardiovasculares , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Aorta/diagnóstico por imagem , Aneurisma Aórtico/diagnóstico por imagem , Ecocardiografia , Estudos Retrospectivos , Valor Preditivo dos Testes , Aneurisma da Aorta Torácica/diagnóstico por imagem , Imageamento por Ressonância Magnética , Pesos e Medidas Corporais , Tomografia Computadorizada por Raios X , Estudos LongitudinaisRESUMO
PURPOSE OF REVIEW: Thoracic aortic aneurysms (TAA) have a strong heritable basis, and identification of a genetic etiology has important implications for patients with TAA and their relatives. This review provides an overview of Mendelian causes of TAA, discusses important considerations for genetic testing, and summarizes the impact a genetic diagnosis may have on a patient's medical care. RECENT FINDINGS: Thoracic aortic disease may be non-syndromic or seen as part of a genetic syndrome, such as Marfan syndrome, Loeys-Dietz syndrome, or vascular Ehlers-Danlos syndrome. Expanded access to genetic testing has revealed the wide and overlapping phenotypic spectrum of these conditions, highlighting the need for genetic testing to establish an accurate diagnosis. Important aspects of genetic evaluation include thorough phenotyping through family history and physical examination, selection of an appropriate genetic test driven by the patient's phenotype, and careful interpretation of genetic test results. Improved understanding of the natural history of these conditions has led to tailored management recommendations, including gene-based recommendations for prophylactic surgical repair. Identification of a genetic etiology allows for careful monitoring of disease progression, informs the timing of prophylactic surgical repair, and facilitates the identification of other at-risk relatives through cascade genetic testing.
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Aneurisma da Aorta Torácica , Síndrome de Ehlers-Danlos , Síndrome de Loeys-Dietz , Síndrome de Marfan , Aneurisma da Aorta Torácica/diagnóstico , Aneurisma da Aorta Torácica/genética , Síndrome de Ehlers-Danlos/diagnóstico , Síndrome de Ehlers-Danlos/genética , Testes Genéticos , Humanos , Síndrome de Loeys-Dietz/diagnóstico , Síndrome de Loeys-Dietz/genética , Síndrome de Marfan/diagnóstico , Síndrome de Marfan/genéticaRESUMO
Emerging evidence suggests that males are more susceptible to severe infection by the SARS-CoV-2 virus than females. A variety of mechanisms may underlie the observed gender-related disparities including differences in sex hormones. However, the precise mechanisms by which female sex hormones may provide protection against SARS-CoV-2 infectivity remains unknown. Here we report new insights into the molecular basis of the interactions between the SARS-CoV-2 spike (S) protein and the human ACE2 receptor. We further report that glycosylation of the ACE2 receptor enhances SARS-CoV-2 infectivity. Importantly, estrogens can disrupt glycan-glycan interactions and glycan-protein interactions between the human ACE2 and the SARS-CoV-2 thereby blocking its entry into cells. In a mouse model of COVID-19, estrogens reduced ACE2 glycosylation and thereby alveolar uptake of the SARS-CoV-2 spike protein. These results shed light on a putative mechanism whereby female sex hormones may provide protection from developing severe infection and could inform the development of future therapies against COVID-19.
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Estrogênios/química , Estrogênios/metabolismo , SARS-CoV-2/química , SARS-CoV-2/fisiologia , Internalização do Vírus/efeitos dos fármacos , Enzima de Conversão de Angiotensina 2/química , Enzima de Conversão de Angiotensina 2/metabolismo , Animais , Transporte Biológico , COVID-19/metabolismo , Modelos Animais de Doenças , Estrogênios/farmacologia , Glicosilação/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana , Humanos , Masculino , Camundongos Endogâmicos C57BL , Modelos Moleculares , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Polissacarídeos/química , Polissacarídeos/metabolismo , SARS-CoV-2/efeitos dos fármacos , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/metabolismo , Tunicamicina/farmacologia , Tratamento Farmacológico da COVID-19RESUMO
BACKGROUND: Heart failure (HF) is a morbid and heritable disorder for which the biological mechanisms are incompletely understood. We therefore examined genetic associations with HF in a large national biobank, and assessed whether refined phenotypic classification would facilitate genetic discovery. METHODS: We defined all-cause HF among 488 010 participants from the UK Biobank and performed a genome-wide association analysis. We refined the HF phenotype by classifying individuals with left ventricular dysfunction and without coronary artery disease as having nonischemic cardiomyopathy (NICM), and repeated a genetic association analysis. We then pursued replication of lead HF and NICM variants in independent cohorts, and performed adjusted association analyses to assess whether identified genetic associations were mediated through clinical HF risk factors. In addition, we tested rare, loss-of-function mutations in 24 known dilated cardiomyopathy genes for association with HF and NICM. Finally, we examined associations between lead variants and left ventricular structure and function among individuals without HF using cardiac magnetic resonance imaging (n=4158) and echocardiographic data (n=30 201). RESULTS: We identified 7382 participants with all-cause HF in the UK Biobank. Genome-wide association analysis of all-cause HF identified several suggestive loci (P<1×10-6), the majority linked to upstream HF risk factors, ie, coronary artery disease (CDKN2B-AS1 and MAP3K7CL) and atrial fibrillation (PITX2). Refining the HF phenotype yielded a subset of 2038 NICM cases. In contrast to all-cause HF, genetic analysis of NICM revealed suggestive loci that have been implicated in dilated cardiomyopathy (BAG3, CLCNKA-ZBTB17). Dilated cardiomyopathy signals arising from our NICM analysis replicated in independent cohorts, persisted after HF risk factor adjustment, and were associated with indices of left ventricular dysfunction in individuals without clinical HF. In addition, analyses of loss-of-function variants implicated BAG3 as a disease susceptibility gene for NICM (loss-of-function variant carrier frequency=0.01%; odds ratio,12.03; P=3.62×10-5). CONCLUSIONS: We found several distinct genetic mechanisms of all-cause HF in a national biobank that reflect well-known HF risk factors. Phenotypic refinement to a NICM subtype appeared to facilitate the discovery of genetic signals that act independently of clinical HF risk factors and that are associated with subclinical left ventricular dysfunction.
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Aortopathies encompass a variety of inherited and acquired pathologies that increase risk of life-threatening dissection or rupture. Identifying individuals with hereditary thoracic aortic aneurysm and dissection (HTAAD) for longitudinal monitoring, medical therapy, or elective and preventative repair is paramount to reduce risk of cardiovascular-related mortality and complications from dissection and rupture. Over the past couple of decades, pathogenic variants in numerous genes have been identified in relation to HTAAD. The genetic diagnosis can help stratify patient risk and provide guidance on medical treatment, timing of prophylactic surgical repair, as well as longitudinal surveillance and imaging. Implicated genes and their associated proteins have been found to act on a diverse variety of pathways, cells and structural components linked to transforming growth factor beta (TGF-ß) signaling pathways, disruption of the vascular smooth muscle cell contractile apparatus, and primary disruption of extracellular matrix homeostasis. This review describes relevant genetic variants that may help identify and guide the management of hereditary thoracic aortic aneurysms and dissections.
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Aorta/patologia , Aneurisma da Aorta Torácica/genética , Matriz Extracelular/genética , Predisposição Genética para Doença , Aneurisma da Aorta Torácica/patologia , Dissecação , Matriz Extracelular/patologia , HumanosRESUMO
Myhre syndrome is an increasingly diagnosed rare syndrome that is caused by one of two specific heterozygous gain-of-function pathogenic variants in SMAD4. The phenotype includes short stature, characteristic facial appearance, hearing loss, laryngotracheal stenosis, arthritis, skeletal abnormalities, learning and social challenges, distinctive cardiovascular defects, and a striking fibroproliferative response in the ear canals, airways, and serosal cavities (peritoneum, pleura, pericardium). Confirmation of the clinical diagnosis is usually prompted by the characteristic appearance with developmental delay and autistic-like behavior using targeted gene sequencing or by whole exome sequencing. We describe six patients (two not previously reported) with molecularly confirmed Myhre syndrome and neoplasia. Loss-of-function pathogenic variants in SMAD4 cause juvenile polyposis syndrome and we hypothesize that the gain-of-function pathogenic variants observed in Myhre syndrome may contribute to neoplasia in the patients reported herein. The frequency of neoplasia (9.8%, 6/61) in this series (two new, four reported patients) and endometrial cancer (8.8%, 3/34, mean age 40 years) in patients with Myhre syndrome, raises the possibility of cancer susceptibility in these patients. We alert clinicians to the possibility of detecting this syndrome when cancer screening panels are used. We propose that patients with Myhre syndrome are more susceptible to neoplasia, encourage increased awareness, and suggest enhanced clinical monitoring.
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Criptorquidismo/genética , Neoplasias do Endométrio/genética , Transtornos do Crescimento/genética , Deformidades Congênitas da Mão/genética , Deficiência Intelectual/genética , Neoplasias/genética , Proteína Smad4/genética , Adulto , Criptorquidismo/complicações , Criptorquidismo/patologia , Neoplasias do Endométrio/complicações , Neoplasias do Endométrio/patologia , Fácies , Feminino , Mutação com Ganho de Função/genética , Transtornos do Crescimento/complicações , Transtornos do Crescimento/patologia , Deformidades Congênitas da Mão/complicações , Deformidades Congênitas da Mão/patologia , Heterozigoto , Humanos , Deficiência Intelectual/complicações , Deficiência Intelectual/patologia , Masculino , Pessoa de Meia-Idade , Mutação/genética , Neoplasias/complicações , Neoplasias/patologia , Fenótipo , Fator de Crescimento Transformador beta/genética , Sequenciamento do ExomaRESUMO
Spontaneous coronary artery dissection (SCAD) has emerged as an important cause of acute coronary syndrome, myocardial infarction, and sudden death, particularly among young women and individuals with few conventional atherosclerotic risk factors. Patient-initiated research has spurred increased awareness of SCAD, and improved diagnostic capabilities and findings from large case series have led to changes in approaches to initial and long-term management and increasing evidence that SCAD not only is more common than previously believed but also must be evaluated and treated differently from atherosclerotic myocardial infarction. High rates of recurrent SCAD; its association with female sex, pregnancy, and physical and emotional stress triggers; and concurrent systemic arteriopathies, particularly fibromuscular dysplasia, highlight the differences in clinical characteristics of SCAD compared with atherosclerotic disease. Recent insights into the causes of, clinical course of, treatment options for, outcomes of, and associated conditions of SCAD and the many persistent knowledge gaps are presented.
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American Heart Association , Anomalias dos Vasos Coronários , Doenças Vasculares/congênito , Técnicas de Imagem Cardíaca/normas , Fármacos Cardiovasculares/uso terapêutico , Consenso , Tratamento Conservador/normas , Ponte de Artéria Coronária/normas , Anomalias dos Vasos Coronários/diagnóstico por imagem , Anomalias dos Vasos Coronários/mortalidade , Anomalias dos Vasos Coronários/terapia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Intervenção Coronária Percutânea/normas , Valor Preditivo dos Testes , Gravidez , Prevalência , Medição de Risco , Fatores de Risco , Resultado do Tratamento , Estados Unidos , Doenças Vasculares/diagnóstico por imagem , Doenças Vasculares/mortalidade , Doenças Vasculares/terapiaAssuntos
Síndrome de Ehlers-Danlos/diagnóstico , Dissecção Aórtica/etiologia , Anti-Hipertensivos/uso terapêutico , Infarto Cerebral/etiologia , Colágeno Tipo III/genética , Angiografia por Tomografia Computadorizada , Diagnóstico Diferencial , Síndrome de Ehlers-Danlos/complicações , Síndrome de Ehlers-Danlos/genética , Síndrome de Ehlers-Danlos/terapia , Cefaleia/etiologia , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Mutação , Cervicalgia/etiologiaRESUMO
Thoracic aortic aneurysm (TAA) can lead to fatal complications such as aortic dissection. Since aneurysm dimension poorly predicts dissection risk, microRNAs (miRNAs) may be useful to diagnose or risk stratify TAA patients. We aim to identify miRNAs associated with TAA pathogenesis and that are possibly able to improve TAA diagnosis. MiRNA microarray experiments of aortic media tissue samples from 19 TAA patients and 19 controls allowed identifying 232 differentially expressed miRNAs. Using interaction networks between these miRNAs and 690 genes associated with TAA, we identified miR-574-5p as a potential contributor of TAA pathogenesis. Interestingly, miR-574-5p was significantly down-regulated in the TAA tissue compared to the controls, but was up-regulated in serum samples from a separate group of 28 TAA patients compared to 20 controls (p < 0.001). MiR-574-5p serum levels discriminated TAA patients from controls with an area under the receiver operating characteristic curve of 0.87. In the Fbn1C1041G/+ mouse model, miR-574-5p was down-regulated in aortic tissue compared to wild-type (p < 0.05), and up-regulated in plasma extracellular vesicles from Fbn1C1041G/+ mice compared to wild-type mice (p < 0.05). Furthermore, in vascular smooth muscle cells, angiotensin II appears to induce miR-574-5p secretion in extracellular vesicles. In conclusion, miR-574-5p is associated with TAA pathogenesis and may help in diagnosing this disease.
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Aneurisma da Aorta Torácica/sangue , MicroRNAs/sangue , Animais , Aneurisma da Aorta Torácica/genética , Área Sob a Curva , Biomarcadores/sangue , Células Cultivadas , Estudos de Coortes , Feminino , Redes Reguladoras de Genes , Humanos , Masculino , Camundongos , MicroRNAs/genética , Curva ROC , TranscriptomaRESUMO
PURPOSE OF REVIEW: Marfan syndrome (MFS) is the most common cause of aortic aneurysm in children and is associated with premature mortality. Whereas surgical therapy remains the primary treatment to prevent aortic complications, medical therapy may slow or prevent aortic growth. Pediatricians and pediatric cardiologists should become familiar with the diagnosis and management of MFS. This review focuses on the medical management for the most important life-threatening manifestation of MFS, thoracic aortic disease. RECENT FINDINGS: Several large-scale clinical trials and one meta-analysis have been reported comparing angiotensin receptors blockers with the standard therapy, beta blockers. SUMMARY: From the assembled evidence described in this review, beta blockers and angiotensin receptors blockers show clinical equivalence and either class of agent may be an appropriate choice for the medical management of aortic growth in children with MFS.
Assuntos
Antagonistas Adrenérgicos beta/uso terapêutico , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Aneurisma Aórtico/fisiopatologia , Síndrome de Marfan/fisiopatologia , Aneurisma Aórtico/tratamento farmacológico , Aneurisma Aórtico/etiologia , Ecocardiografia , Humanos , Síndrome de Marfan/complicações , Síndrome de Marfan/tratamento farmacológico , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do TratamentoRESUMO
Thoracic aortic aneurysm is a potentially life-threatening condition in that it places patients at risk for aortic dissection or rupture. However, our modern understanding of the pathogenesis of thoracic aortic aneurysm is quite limited. A genetic predisposition to thoracic aortic aneurysm has been established, and gene discovery in affected families has identified several major categories of gene alterations. The first involves mutations in genes encoding various components of the transforming growth factor beta (TGF-ß) signaling cascade (FBN1, TGFBR1, TGFBR2, TGFB2, TGFB3, SMAD2, SMAD3 and SKI), and these conditions are known collectively as the TGF-ß vasculopathies. The second set of genes encode components of the smooth muscle contractile apparatus (ACTA2, MYH11, MYLK, and PRKG1), a group called the smooth muscle contraction vasculopathies. Mechanistic hypotheses based on these discoveries have shaped rational therapies, some of which are under clinical evaluation. This review discusses published data on genes involved in thoracic aortic aneurysm and attempts to explain divergent hypotheses of aneurysm origin.
Assuntos
Aneurisma da Aorta Torácica/genética , Dissecção Aórtica/genética , Dissecção Aórtica/etiologia , Aneurisma da Aorta Torácica/patologia , Predisposição Genética para Doença , Humanos , Fatores de RiscoRESUMO
BACKGROUND: Improved medical care after initial aortic dissection (AD) has led to increased survivorship and a population of individuals at risk for further cardiovascular events, including recurrent AD. Reports describing recurrent ADs have been restricted to small numbers of patients from single institutions. We used the IRAD (International Registry of Acute Aortic Dissection) database to examine the clinical profiles and outcomes of patients with recurrent AD. METHODS: We identified 204 patients enrolled in IRAD with recurrent AD. For the primary analysis, patient characteristics, interventions, and outcomes were analyzed and compared with 3624 patients with initial AD. Iterative logistic modeling was performed to investigate variables associated with recurrent AD. Cox regression analyses were used to determine variables associated with 5-year survival. A subset of recurrent AD patients was analyzed for anatomic and demographic details of initial and recurrent ADs. RESULTS: Patients with recurrent AD were more likely to have Marfan syndrome (21.5% versus 3.1%; P<0.001) but not bicuspid aortic valve (3.6% versus 3.2%; P=0.77). Descending aortic dimensions were greater in patients with recurrent AD than in patients with initial AD independently of sentinel dissection type (type A: 4.3 cm [3.5-5.6 cm] versus 3.3 cm [2.9-3.7 cm], P<0.001; type B: 5.0 cm [3.9-6.0 cm] versus 4.0 cm [3.5-4.8 cm], P<0.001), and this observation was accentuated among patients with Marfan syndrome. In multivariate analysis, the diagnosis of Marfan syndrome independently predicted recurrent AD (hazard ratio, 8.6; 95% confidence interval, 5.8-12.8; P<0.001). Patients with recurrent AD who presented with proximal followed by distal AD were younger than patients who experienced distal followed by proximal dissection AD (42.1±16.1 versus 54.3±14.8 years; P=0.004). CONCLUSIONS: Among those suffering acute aortic dissection, 5% have a history of a prior aortic dissection. Recurrent AD is strongly associated with Marfan syndrome.