Patients with heritable connective tissue disorders (HCTDs), represented by Marfan syndrome, can develop fatal aortic and/or arterial complications before age 50. Therefore, accurate diagnosis, appropriate medical treatment, and early prophylactic surgical treatment of aortic and arterial lesions are essential to improve prognosis. Patients with HCTDs generally present with specific physical features due to connective tissue abnormalities, while some patients with heritable thoracic aortic diseases (HTADs) have few distinctive physical characteristics. The development of genetic testing has made it possible to provide accurate diagnoses for patients with HCTDs/HTADs. This review provides an overview of the diagnosis and treatment of HCTDs/HTADs, including current evidence on cardiovascular interventions for this population.

Background Differences in the clinical course of heritable thoracic aortic disease based on the disease-causing gene have not been fully evaluated. To clarify the clinical relevance of causative genes in heritable thoracic aortic disease, we assessed the clinical course of patients categorized based on genetic diagnosis. Methods and Results We investigated cardiovascular events and mortality in 518 genetically diagnosed patients in 4 groups: Group 1, FBN1 (n=344); Group 2, TGFBR1, TGFBR2, SMAD3, or TGFB2 (n=74); Group 3, COL3A1 (n=60); and Group 4, ACTA2 or MYH11 (n=40). The median age at the first cardiovascular event ranged from 30.0 to 35.5 years (P=0.36). Patients with gene variants related to transforming growth factor-β signaling had a significantly higher rate of subsequent events than those with FBN1 variants (adjusted hazard ratio, 2.33 [95% CI, 1.60-3.38]; P<0.001). Regarding the incidence of aortic dissection, there were no significant differences among the 4 groups in male patients (36.3%, 34.3%, 21.4%, and 54.2%, respectively; P=0.06). Female patients with COL3A1 variants had a significantly lower incidence than female patients in the other 3 groups (34.2%, 59.0%, 3.1%, and 43.8%, respectively; P<0.001). Conclusions Gene variants related to transforming growth factor-β signaling are associated with a higher incidence of subsequent cardiovascular events than FBN1 variants. COL3A1 variants might be related to a lower incidence of aortic dissection than other gene variants in women only. Identifying the genetic background of patients with heritable thoracic aortic disease is important for determining appropriate treatment.

OBJECTIVE: Actin, alpha-2, smooth muscle, aorta (ACTA2) mutations are one of the major causes of familial thoracic aortic aneurysms and dissections. The aim of this study was to review our clinical results of young adult patients with aortic disease caused by ACTA2 mutations.
METHODS: We reviewed the medical records of 251 patients (<50 years old) who underwent surgery for thoracic aortic diseases between 2004 and 2014. Among them, nine patients (3.5%) had ACTA2 mutations. Their average age was 35 years (range 22-47) and two patients (22.2%) were males. No patients fulfilled the diagnostic criteria for Marfan syndrome. Preoperative diagnoses included annulo-aortic ectasia (n = 2), localized dissection of the sinus of Valsalva (n = 2), acute type B aortic dissection (n = 1), and chronic type B (n = 4). Eight patients (88.9%) had hypertension.
RESULTS: A thoracoabdominal aortic replacement was required in three patients who had descending replacement for residual chronic type B aortic dissection. A patient who had thoracic endovascular aortic repair for complicated acute type B aortic dissection showed no aortic dilatation for 7 years after TEVAR. Histological results revealed cystic medial necrosis (CMN) in most cases (7/8; 87.5%).
CONCLUSIONS: Surgical outcomes for patients with ACTA2 mutations were satisfactory. CMN was a major histological finding and family history of aortic event was detected in only half of the patients with ACTA2 mutations. Despite no characteristic physical findings besides hypertension, connective tissue disease including ACTA2 mutations should be considered for aortic dissection in young adult patients.

Genetic studies in patients reveal that mutations to genes that encode contractile proteins in medial smooth muscle cells can cause thoracic aortic aneurysms and dissections. Mouse models of such mutations, including Acta2(-/-) and Myh11(R247C/R247C), surprisingly do not present with any severe vascular phenotype under normal conditions. This observation raises the question whether these mutations nevertheless render the thoracic aorta increasingly vulnerable to aneurysms or dissections in the presence of additional, epigenetic, factors such as hypertension, a known risk factor for thoracic aortic disease. Accordingly, we compared the structure and biaxial mechanical properties of the ascending and descending thoracic aorta from male wild-type and Myh11(R247C/R247C) mice under normotension and induced hypertension. On average, the mutant aortas exhibited near normal biomechanics under normotensive hemodynamics and near normal adaptations to hypertensive hemodynamics, yet the latter led to intramural delaminations or premature deaths in over 20% of these mice. Moreover, the delaminated vessels exhibited localized pools of mucoid material, similar to the common histopathologic characteristic observed in aortas from humans affected by thoracic aortic aneurysms and dissections. The present findings suggest, therefore, that mutations to smooth muscle cell contractile proteins may place the thoracic aorta at increased risk to epigenetic factors and that there is a need to focus on focal, not global, changes in aortic structure and properties, including the pooling of glycosaminoglycans/proteoglycans that may lead to thoracic aortic dissection.