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Mutations in human TBXS, a member of the T-box transcription factor gene family, cause congenital cardiac septation defects and isomerism in autosomal dominant Holt-Oram syndrome. To determine the cellular function of TBX5 in cardiogenesis, we overexpressed wild-type and mutant human TBX5 isoforms in vitro and in vivo. TBX5 inhibited cell proliferation of D17 canine osteosarcoma cells and MEQC quail cardiomyocyte-like cells in vitro. Mutagenesis of the 5' end of the T-box but not the 3' end of the T-box abolished this effect. Overexpression of TBX5 in embryonic chick hearts showed that TBX5 inhibits myocardial growth and trabeculation. TBX5 effects in vivo were abolished by Gly80Arg missense mutation of the 5' end of the T-box. PCNA analysis in transgenic chick hearts revealed that TBX5 overexpression does suppress embryonic cardiomyocyte proliferation in vivo. Inhibitory effects of TBX5 on cardiomyocyte proliferation include a noncell autonomous process in vitro and in vivo. TBX5 inhibited proliferation of both nontransgenic cells cocultured with transgenic cells in vitro and nontransgenic cardiomyocytes in transgenic chick hearts with mosaic expression of TBX5 in vivo. Immunohistochemical studies of human embryonic tissues, including hearts, also demonstrated that TBX5 expression is inversely related to cellular proliferation. We propose that TBX5 can act as a cellular arrest signal during vertebrate cardiogenesis and thereby participate in modulation of cardiac growth and development.

Background: For patients with thoracic aortic aneurysms (TAA), aortic size on imaging is widely used to guide clinical decision making. This study examined the impact of methodological variance on aortic quantification. Methods: We studied enrollees in the National Registry of Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions. Aortic size on computed tomography was quantified by 2 linear methods; cross-sectional dimensions in axial (AX) and double oblique (DO) plane. Calculated area was compared to planimetry. Established cutoffs (area/height >10 cm2/m, diameter ≥ 5cm) for prophylactic TAA repair were used to compare surgical eligibility by each method. Results: Fifty subjects were studied. Aortic size differed between AX and DO at all locations (p ≤ 0.001), with magnitude greatest at the sinotubular junction (4.8 ± 1.1 vs 4.0 ± 1.0 cm, p < 0.001). The difference between AX and DO correlated with aortic angular displacement (r = 0.37, p < 0.01), which was threefold larger at the sinotubular junction (37 ± 12 degrees) than the ascending aorta (12 ± 5 degrees; p < 0.001). At all locations, aortic area calculated using DO yielded smaller differences with planimetry than AX (p < 0.05). DO and planimetry yielded equal prevalence (24%) of subjects eligible for prophylactic TAA repair based on area-height cutoff, whereas AX prevalence was higher (44%; p = 0.006). Using a linear cutoff, AX yielded over a twofold greater prevalence of surgically eligible subjects (56%) than did DO (24%; p < 0.001). Conclusions: Established linear methods for aortic measurement yield different results that impact surgical eligibility. DO yielded improved agreement with planimetry and differed with AX in proportion to aortic geometric obliquity. Findings support DO measurements for imaging evaluation of subjects with TAA. [ABSTRACT FROM AUTHOR]

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. Methods: GenTAC''s aim is to collect longitudinal clinical data and banked biospecimens from 2800 patients with genetically triggered TAAs. We analyzed data from the 606 patients (mean age, 37.5 years) enrolled in GenTAC to date whose clinical data were available. Results: The patients'' primary diagnoses included Marfan syndrome (35.8%), bicuspid aortic valve with aneurysm (29.2%), and familial TAAs and dissections (10.7%). Of these, 56.4% had undergone at least one operation; the most common indications were aneurysm (85.7%), valve dysfunction (65.8%), and dissection (25.4%). Surgical procedures included replacement of the aortic root (50.6%), ascending aorta (64.8%), aortic arch (27.9%), and descending or thoracoabdominal aorta (12.4%). Syndrome-specific differences in age, indications for operation, and procedure type were identified. Conclusions: Patients with genetically transmitted TAAs evaluated in tertiary care centers frequently undergo surgical repair. Aneurysm repairs most commonly involve the aortic root and ascending aorta; distal repairs are less common. Like TAAs themselves, complications of TAAs, including dissection and aortic valve dysfunction, are important indications for intervention. Future studies will focus on syndrome- and gene-specific phenotypes, biomarkers, treatments, and outcomes to improve the treatment of patients with TAAs. [Copyright &y& Elsevier]

Examines the genetic heterogeneity of familial atrial myxoma syndromes. Incidence; Transmission; Signs and symptoms; Isolation of genomic DNA; Importance of gene identification; Cause of familial atrial myxomas.

Background: Genetically triggered thoracic aortic conditions (GenTACs) represent an important problem for patients and their families. Accordingly, the National Heart, Lung, and Blood Institute established the first phase of its national GenTAC Registry in 2006. Enrollment and Diagnoses: Between 2007 and 2010, 6 enrolling centers established the GenTAC I Registry consisting of 2,046 patients (Marfan syndrome 576 [28.2%], bicuspid aortic valve disease 504 [24.6%], aneurysm or dissection age <50 years 369 [18%], and others). Biologic samples for DNA analyses (white blood cells or saliva) are available in 97%, and stored plasma is available in 60% of enrollees. Results: Initial scientific inquiry using the GenTAC Registry has included validation studies of genetic causes for aortic syndromes, potential usefulness of transforming growth factor beta (TGFB) blood levels in Marfan subjects, and current surgical approaches to ascending aortic conditions. Future Opportunity: The second phase of GenTAC will allow biannual follow-up of GenTAC I enrollees for up to 9 years, enrollment of an additional 1,500 subjects, further integration of imaging findings with clinical and genetic data through utilization of an imaging core laboratory, important validation of phenotype-genotype correlations through a phenotyping core laboratory, and integration of a scientific advisory committee to help define the full range and depth of the Registry''s scientific capabilities. The registry resources are available to the external scientific community through an application process accessible at https://gentac.rti.org. [Copyright &y& Elsevier]

Summary: Carney complex is a familial multiple neoplasia disorder with characteristic features such as cardiac and cutaneous myxomas and spotty pigmentation of the skin. Clinical genetic analyses have shown that Carney complex is transmitted in an autosomal dominant way and can present with a wide array of other tumours, such as psammomatous melanotic schwannoma, testicular Sertoli-cell tumours, and pituitary adenomas. Molecular genetic studies show that mutations in the PRKAR1A gene, encoding the R1α regulatory subunit of cyclic-AMP-dependent protein kinase A, are the cause of Carney complex in most patients. Investigation of genetically engineered animal models confirms the role of PRKAR1A as a tumour suppressor and has begun to elaborate mechanisms underlying tumorigenesis in this disorder. Further genetic studies in human beings have highlighted novel variant phenotypes, such as congenital contractures, which are potentially associated with Carney complex, and have identified alternative genetic pathways to cardiac tumorigenesis, including mutation of the MYH8 gene that encodes perinatal myosin. [Copyright &y& Elsevier]

Background: Evidence suggests that interleukin (IL)-1β is important in the pathogenesis of atherosclerosis and its complications and that inhibiting IL-1β may favorably affect vascular disease progression.Objectives: The goal of this study was to evaluate the effects of IL-1β inhibition with canakinumab versus placebo on arterial structure and function, determined by magnetic resonance imaging.Methods: Patients (N = 189) with atherosclerotic disease and either type 2 diabetes mellitus or impaired glucose tolerance were randomized to receive placebo (n = 94) or canakinumab 150 mg monthly (n = 95) for 12 months. They underwent magnetic resonance imaging of the carotid arteries and aorta.Results: There were no statistically significant differences between canakinumab compared with placebo in the primary efficacy and safety endpoints. There was no statistically significant change in mean carotid wall area and no effect on aortic distensibility, measured at 3 separate anatomic sites. The change in mean carotid artery wall area was -3.37 mm2 after 12 months with canakinumab versus placebo. High-sensitivity C-reactive protein was significantly reduced by canakinumab compared with placebo at 3 months (geometric mean ratio [GMR]: 0.568; 95% confidence interval [CI]: 0.436 to 0.740; p < 0.0001) and 12 months (GMR: 0.56; 95% CI: 0.414 to 0.758; p = 0.0002). Lipoprotein(a) levels were reduced by canakinumab compared with placebo (-4.30 mg/dl [range: -8.5 to -0.55 mg/dl]; p = 0.025] at 12 months), but triglyceride levels increased (GMR: 1.20; 95% CI: 1.046 to 1.380; p = 0.01). In these patients with type 2 diabetes mellitus or impaired glucose tolerance, canakinumab had no effect compared with placebo on any of the measures assessed by using a standard oral glucose tolerance test.Conclusions: There were no statistically significant effects of canakinumab on measures of vascular structure or function. Canakinumab reduced markers of inflammation (high-sensitivity C-reactive protein and interleukin-6), and there were modest increases in levels of total cholesterol and triglycerides. (Safety & Effectiveness on Vascular Structure and Function of ACZ885 in Atherosclerosis and Either T2DM or IGT Patients; NCT00995930). [ABSTRACT FROM AUTHOR]

Background: Aortic dissection (AoD) is a serious complication of thoracic aortic aneurysm (TAA). Relative risk for AoD in relation to TAA etiology, incidence, and pattern after prophylactic TAA surgery are poorly understood.Objectives: This study sought to determine the incidence, pattern, and relative risk for AoD among patients with genetically associated TAA.Methods: The population included adult GenTAC participants without AoD at baseline. Standardized core laboratory tests classified TAA etiology and measured aortic size. Follow-up was performed for AoD.Results: Bicuspid aortic valve (BAV) (39%) and Marfan syndrome (MFS) (22%) were the leading diagnoses in the studied GenTAC participants (n = 1,991). AoD occurred in 1.6% over 3.6 ± 2.0 years; 61% of AoD occurred in patients with MFS. Cumulative AoD incidence was 6-fold higher among patients with MFS (4.5%) versus others (0.7%; p < 0.001). MFS event rates were similarly elevated versus those in patients with BAV (0.3%; p < 0.001). AoD originated in the distal arch or descending aorta in 71%; 52% of affected patients, including 68% with MFS, had previously undergone aortic grafting. In patients with proximal aortic surgery, distal aortic size (descending thoracic, abdominal aorta) was larger among patients with AoD versus those without AoD (both p < 0.05), whereas the ascending aorta size was similar. Conversely, in patients without previous surgery, aortic root size was greater in patients with subsequent AoD (p < 0.05), whereas distal aortic segments were of similar size. MFS (odds ratio: 7.42; 95% confidence interval: 3.43 to 16.82; p < 0.001) and maximal aortic size (1.86 per cm; 95% confidence interval: 1.26 to 2.67; p = 0.001) were independently associated with AoD. Only 4 of 31 (13%) patients with AoD had pre-dissection images that fulfilled size criteria for prophylactic TAA surgery at a subsequent AoD site.Conclusions: Among patients with genetically associated TAA, MFS augments risk for AoD even after TAA grafting. Although increased aortic size is a risk factor for subsequent AoD, events typically occur below established thresholds for prophylactic TAA repair. [ABSTRACT FROM AUTHOR]

New observations reveal that GATA-4 mutations are one underlying cause of human cardiac septal defects. Recent data has shed light on a potential multiprotein complex formed by GATA-4, TBX5 and NKX2.5, which might act synergistically to transcriptionally regulate other cardiac specific genes. The addition of GATA-4 to the list of genes involved in human congenital heart malformation prompts consideration of how modern molecular genetic advances should be applied to clinical care. [Copyright &y& Elsevier]