Acute type A intramural hematoma: analysis of current management strategy.

Background: Management of acute type A intramural hematoma (IMH) remains controversial, varying from immediate surgery to medical management only. Conversion to typical dissection remains a concern. We analyzed our experience managing acute type A IMH.

Surgical treatment of patients enrolled in the national registry of genetically triggered thoracic aortic conditions.

Background: Genetic disorders are an important cause of thoracic aortic aneurysms (TAAs) in young patients. Despite advances in the treatment of genetically triggered TAAs, the optimal syndrome-specific treatment approach remains undefined. We used data from the National Institutes of Health-funded, multicenter National Registry of Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions (GenTAC) to characterize the contemporary surgical treatment of patients with genetically triggered TAAs.

Analysis of multigenerational families with thoracic aortic aneurysms and dissections due to TGFBR1 or TGFBR2 mutations.

Background: Mutations in the transforming growth factor beta receptor type I and II genes (TGFBR1 and TGFBR2) cause Loeys-Dietz syndrome (LDS), characterised by thoracic aortic aneurysms and dissections (TAAD), aneurysms and dissections of other arteries, craniosynostosis, cleft palate/bifid uvula, hypertelorism, congenital heart defects, arterial tortuosity, and mental retardation. TGFBR2 mutations can also cause TAAD in the absence of features of LDS in large multigenerational families, yet only sporadic LDS cases or parent-child pairs with TGFBR1 mutations have been reported to date.

Methods: The authors identified TGFBR1 missense mutations in multigenerational families with TAAD by DNA sequencing.

Mutations in smooth muscle alpha-actin (ACTA2) cause coronary artery disease, stroke, and Moyamoya disease, along with thoracic aortic disease.

The vascular smooth muscle cell (SMC)-specific isoform of alpha-actin (ACTA2) is a major component of the contractile apparatus in SMCs located throughout the arterial system. Heterozygous ACTA2 mutations cause familial thoracic aortic aneurysms and dissections (TAAD), but only half of mutation carriers have aortic disease. Linkage analysis and association studies of individuals in 20 families with ACTA2 mutations indicate that mutation carriers can have a diversity of vascular diseases, including premature onset of coronary artery disease (CAD) and premature ischemic strokes (including Moyamoya disease [MMD]), as well as previously defined TAAD.

Valve-sparing and valve-replacing techniques for aortic root replacement in patients with Marfan syndrome: Analysis of early outcome.

Objective: A prospective, international registry study was initiated to provide contemporary comparative data on short-term clinical outcomes after aortic valve-sparing and aortic valve-replacing root operations in patients with Marfan syndrome. The purpose of this initial report is to describe the study design and to compare early outcomes in the first 151 enrolled patients.

Methods: We assessed 30-day outcomes in 151 patients who met strict Ghent diagnostic criteria for Marfan syndrome and underwent aortic root replacement with either valve-replacing (n = 46) or valve-sparing techniques (n = 105) at one of 18 participating centers.

Sequencing of TGF-beta pathway genes in familial cases of intracranial aneurysm.

Background And Purpose: Familial aggregation of intracranial aneurysms (IA) strongly suggests a genetic contribution to pathogenesis. However, genetic risk factors have yet to be defined. For families affected by aortic aneurysms, specific gene variants have been identified, many affecting the receptors to transforming growth factor-beta (TGF-beta).

Valve-sparing and valve-replacing techniques for aortic root replacement in patients with Marfan syndrome: analysis of early outcome.

Objective: A prospective, international registry study was initiated to provide contemporary comparative data on short-term clinical outcomes after aortic valve-sparing and aortic valve-replacing root operations in patients with Marfan syndrome. The purpose of this initial report is to describe the study design and to compare early outcomes in the first 151 enrolled patients.

Methods: We assessed 30-day outcomes in 151 patients who met strict Ghent diagnostic criteria for Marfan syndrome and underwent aortic root replacement with either valve-replacing (n = 46) or valve-sparing techniques (n = 105) at one of 18 participating centers.

Characterization of the inflammatory cells in ascending thoracic aortic aneurysms in patients with Marfan syndrome, familial thoracic aortic aneurysms, and sporadic aneurysms.

Objective: This study sought to characterize the inflammatory infiltrate in ascending thoracic aortic aneurysm in patients with Marfan syndrome, familial thoracic aortic aneurysm, or nonfamilial thoracic aortic aneurysm.

Background: Thoracic aortic aneurysms are associated with a pathologic lesion termed "medial degeneration," which is described as a noninflammatory lesion. Thoracic aortic aneurysms are a complication of Marfan syndrome and can be inherited in an autosomal dominant manner of familial thoracic aortic aneurysm.

An FBN1 pseudoexon mutation in a patient with Marfan syndrome: confirmation of cryptic mutations leading to disease.

Marfan syndrome (MFS) results from heterozygous mutations in FBN1. However, genetic analyses of deoxyribonucleic acid (DNA) from approximately 10-30% of MFS patients who meet diagnostic criteria do not reveal an identifiable FBN1 mutation. In a patient who met the diagnostic criteria for MFS, bidirectional DNA sequencing of exons and intron-exon boundaries of FBN1 failed to reveal a mutation.

The FBN2 gene: new mutations, locus-specific database (Universal Mutation Database FBN2), and genotype-phenotype correlations.

Congenital contractural arachnodactyly (CCA) is an extremely rare disease, due to mutations in the FBN2 gene encoding fibrillin-2. Another member of the fibrillin family, the FBN1 gene, is involved in a broad phenotypic continuum of connective-tissue disorders including Marfan syndrome. Identifying not only what is in common but also what differentiates these two proteins should enable us to better comprehend their respective functions and better understand the multitude of diseases in which these two genes are involved.

Genetic basis of thoracic aortic aneurysms and dissections: focus on smooth muscle cell contractile dysfunction.

Thoracic aortic aneurysms leading to type A dissections (TAAD) can be inherited in isolation or in association with genetic syndromes, such as Marfan syndrome and Loeys-Dietz syndrome. When TAAD occurs in the absence of syndromic features, it is inherited in an autosomal dominant manner with decreased penetrance and variable expression, the disease is referred to as familial TAAD. Familial TAAD exhibits significant clinical and genetic heterogeneity.

Mutations in smooth muscle alpha-actin (ACTA2) lead to thoracic aortic aneurysms and dissections.

The major function of vascular smooth muscle cells (SMCs) is contraction to regulate blood pressure and flow. SMC contractile force requires cyclic interactions between SMC alpha-actin (encoded by ACTA2) and the beta-myosin heavy chain (encoded by MYH11). Here we show that missense mutations in ACTA2 are responsible for 14% of inherited ascending thoracic aortic aneurysms and dissections (TAAD).

A Marfan syndrome gene expression phenotype in cultured skin fibroblasts.

Background: Marfan syndrome (MFS) is a heritable connective tissue disorder caused by mutations in the fibrillin-1 gene. This syndrome constitutes a significant identifiable subtype of aortic aneurysmal disease, accounting for over 5% of ascending and thoracic aortic aneurysms.

Results: We used spotted membrane DNA macroarrays to identify genes whose altered expression levels may contribute to the phenotype of the disease.

MYH11 mutations result in a distinct vascular pathology driven by insulin-like growth factor 1 and angiotensin II.

Non-syndromic thoracic aortic aneurysms and dissections (TAADs) are inherited in an autosomal dominant manner in approximately 20% of cases. Familial TAAD is genetically heterogeneous and four loci have been mapped for this disease to date, including a locus at 16p for TAAD associated with patent ductus arteriosus (PDA). The defective gene at the 16p locus has recently been identified as the smooth muscle cell (SMC)-specific myosin heavy chain gene (MYH11).

Severe aortic and arterial aneurysms associated with a TGFBR2 mutation.

Background: A 24-year-old man presented with previously diagnosed Marfan's syndrome. Since the age of 9 years, he had undergone eight cardiovascular procedures to treat rapidly progressive aneurysms, dissection and tortuous vascular disease involving the aortic root and arch, the thoracoabdominal aorta, and brachiocephalic, vertebral, internal thoracic and superior mesenteric arteries. Throughout this extensive series of cardiovascular surgical repairs, he recovered without stroke, paraplegia or renal impairment.

Universal primer applications for pyrosequencing.

Pyrosequencing is a high-throughput technique for single-nucleotide polymorphism (SNP) genotyping, DNA sequencing, and SNP allele frequency and DNA methylation assays. The Pyrosequencing assay involves initially purifying PCR-generated single-strand DNA labeled with biotin as a sequencing template. The disadvantage of the synthesis of a biotinylated sequence-specific primer to assay each DNA variant lies in costs and time consumption.

Pathogenesis of thoracic and abdominal aortic aneurysms.

The major disease processes affecting the aorta are aortic aneurysms and dissections. Aneurysms are usually described in terms of their anatomic location, with thoracic aortic aneurysms (TAAs) involving the ascending and descending aorta in the thoracic cavity and abdominal aortic aneurysms (AAAs) involving the infrarenal abdominal aorta. Both thoracic and abdominal aortas are elastic arteries, and share similarities in their physical structures and cellular components.

Genetic basis of thoracic aortic aneurysms and dissections: potential relevance to abdominal aortic aneurysms.

Ascending thoracic aortic aneurysms leading to type A dissections (TAAD) have long been known to occur in association with a genetic syndrome such as Marfan syndrome (MFS). More recently, TAAD has also been demonstrated to occur as an autosomal dominant disorder in the absence of syndromic features, termed familial TAAD. Familial TAAD demonstrates genetic heterogeneity, and linkage studies have identified TAAD loci at 5q13-14 (TAAD1), 11q23 (FAA1), 3p24-25 (TAAD2), and 16p12.

The role of MMP-2 and MMP-9 polymorphisms in sporadic intracranial aneurysms.

Object: Matrix metalloproteinases (MMPs) are a family of endopeptidases that mediate vascular remodeling by degrading extracellular matrix components, such as collagen and elastin. On the basis of accumulating evidence that implicates increased MMP-2 (gelatinase A) and MMP-9 (gelatinase B) amounts and activity in the pathogenesis of aneurysms, the authors investigated the genetic association between polymorphisms in MMP-2 and MMP-9 and sporadic intracranial aneurysms.

Methods: Eight polymorphisms located in MMP-2 and MMP-9 were genotyped, and the association of these variations with disease was assessed in a Caucasian population consisting of 125 patients with intracranial aneurysms and 234 ethnically matched healthy volunteers.

Aneurysm syndromes caused by mutations in the TGF-beta receptor.

Background: The Loeys-Dietz syndrome is a recently described autosomal dominant aortic-aneurysm syndrome with widespread systemic involvement. The disease is characterized by the triad of arterial tortuosity and aneurysms, hypertelorism, and bifid uvula or cleft palate and is caused by heterozygous mutations in the genes encoding transforming growth factor beta receptors 1 and 2 (TGFBR1 and TGFBR2, respectively).

Methods: We undertook the clinical and molecular characterization of 52 affected families.

Spectrum of aortic operations in 300 patients with confirmed or suspected Marfan syndrome.

Background: Cardiovascular disease is the main cause of morbidity and mortality in patients with Marfan syndrome. Many patients with presumed Marfan syndrome do not meet current diagnostic criteria. This study reviews the surgical aspects of aortic disease in 300 patients referred with the diagnosis of Marfan syndrome.

Familial thoracic aortic aneurysms and dissections: three families with early-onset ascending and descending aortic dissections in women.

Ascending thoracic aortic aneurysms leading to type A dissections can be inherited in an autosomal dominant manner with variable age of onset and decreased penetrance, primarily in women. Three families are described with autosomal dominant inheritance of either ascending aortic aneurysms leading to type A dissections or type B dissections, and a young age of onset of aortic dissections in both men and women. Pedigree analysis suggests that a de novo mutation is responsible for the disease in one family.

The molecular genetics of Marfan syndrome and related disorders.

Marfan syndrome (MFS), a relatively common autosomal dominant hereditary disorder of connective tissue with prominent manifestations in the skeletal, ocular, and cardiovascular systems, is caused by mutations in the gene for fibrillin-1 (FBN1). The leading cause of premature death in untreated individuals with MFS is acute aortic dissection, which often follows a period of progressive dilatation of the ascending aorta. Recent research on the molecular physiology of fibrillin and the pathophysiology of MFS and related disorders has changed our understanding of this disorder by demonstrating changes in growth factor signalling and in matrix-cell interactions.

Long-term survival in a child with severe congenital contractural arachnodactyly, autism and severe intellectual disability.

The severe form of congenital contractural arachnodactyly is usually associated with early mortality due to multisystem complications. Here, we report a 9-year-old male child with severe skeletal manifestations of congenital contractural arachnodactyly. He had none of the cardiovascular or gastrointestinal features that have been described in severe congenital contractural arachnodactyly.