Dilatation Of Thoracic Aorta Research Articles

Elevated Wall Tension Leads to Reduced miR-133a in the Thoracic Aorta by Exosome Release.

BackgroundReduced miR‐133a was previously found to be associated with thoracic aortic (TA) dilation, as seen in aneurysm disease. Because wall tension increases with vessel diameter (Law of Laplace), this study tested the hypothesis that elevated tension led to the reduction of miR‐133a in the TA.Methods and ResultsElevated tension (1.5 g; 150 mm Hg) applied to murine TA ex vivo reduced miR‐133a tissue abundance compared with TA held at normotension (0.7 g; 70 mm Hg). Cellular miR‐133a levels were reduced with biaxial stretch of isolated murine TA fibroblasts, whereas smooth muscle cells were not affected. Mechanisms contributing to the loss of miR‐133a abundance were further investigated in TA fibroblasts. Biaxial stretch did not reduce primary miR‐133a transcription and had no effect on the expression/abundance of 3 microRNA‐specific exoribonucleases. Remarkably, biaxial stretch increased exosome secretion, and exosomes isolated from TA fibroblasts contained more miR‐133a. Inhibition of exosome secretion prevented the biaxial stretch‐induced reduction of miR‐133a. Subsequently, 2 in vivo models of hypertension were used to determine the effect of elevated wall tension on miR‐133a abundance in the TA: wild‐type mice with osmotic pump–mediated angiotensin II infusion and angiotensin II–independent spontaneously hypertensive mice. Interestingly, the abundance of miR‐133a was decreased in TA tissue and increased in the plasma in both models of hypertension compared with a normotensive control group. Furthermore, miR‐133a was elevated in the plasma of hypertensive human subjects, compared with normotensive patients.ConclusionsTaken together, these results identified exosome secretion as a tension‐sensitive mechanism by which miR‐133a abundance was reduced in TA fibroblasts.

A novel software tool for semi-automatic quantification of thoracic aorta dilatation on baseline and follow-up computed tomography angiography

A dedicated software package that could semi-automatically assess differences in aortic maximal cross-sectional diameters from consecutive CT scans would most likely reduce the post-processing time and effort by the physicians. The aim of this study was to present and assess the quality of a new tool for the semi-automatic quantification of thoracic aorta dilation dimensions. Twenty-nine patients with two CTA scans of the thoracic aorta for which the official clinical report indicated an increase in aortic diameters were included in the study. Aortic maximal cross-sectional diameters of baseline and follow-up studies generated semi-automatically by the software were compared with corresponding manual measurements. The semi-automatic measurements were performed at seven landmarks defined on the baseline scan by two operators. Bias, Bland–Altman plots and intraclass correlation coefficients were calculated between the two methods and, for the semi-automatic software, also between two observers. The average time difference between the two scans of a single patient was 1188 ± 622 days. For the semi-automatic software, in 2 out of 29 patients, manual interaction was necessary; in the remaining 27 patients (93.1%), semi-automatic results were generated, demonstrating excellent intraclass correlation coefficients (all values ≥ 0.91) and small differences, especially for the proximal aortic arch (baseline: 0.19 ± 1.30 mm; follow-up: 0.44 ± 2.21 mm), the mid descending aorta (0.37 ± 1.64 mm; 0.37 ± 2.06 mm), and the diaphragm (0.30 ± 1.14 mm; 0.37 ± 1.80 mm). The inter-observer variability was low with all errors in diameters ≤ 1 mm, and intraclass correlation coefficients all ≥ 0.95. The semi-automatic tool decreased the processing time by 40% (13 vs. 22 min). In this work, a semi-automatic software package that allows the assessment of thoracic aorta diameters from baseline and follow-up CTs (and their differences), was presented, and demonstrated high accuracy and low inter-observer variability.

A functional variant of SMAD4 enhances macrophage recruitment and inflammatory response via TGF-β signal activation in Thoracic aortic aneurysm and dissection.

Thoracic aortic aneurysm and dissection (TAAD) is the most fatal macro vascular disease. The mortality of 48h after diagnosis of dissection is up to approximately 50-68%. However, the genetic factors and potential mechanism underlying sporadic TAAD remain largely unknown. Our previous study suggested rs12455792 variant of SMAD4 gene significantly contributed to the increased risk and might participated the pathological progression of TAAD. This investigation aims to test (1) the associations between rs12455792 and MØ recruitment, inflammatory response in aggressiveness of TAAD, and (2) the molecular mechanism accounting for their effects. In TGF-β signaling molecular detection, rs12455792 C>T variant activated the canonical and non-canonical TGF-β mediators. It also increased the secretion of chemotactic factors of HASMCs. To confirm the impact of this change, we detected MØ recruitment and infiltration in HASMCs and aortic tissues of TAAD patients. We found that MØ recruitment in cells and tissues with rs12455792 variant genotypes was increased than that in wild type groups. Moreover, rs12455792 variant increased M1 type inflammatory response, which might contribute much to TAAD progression. To mimic the SMAD4 suppression effect of rs12455792 in vivo, we constructed the SMAD4 KD mouse. After induction with Ang II for 4w, the thoracic aorta dilatation and vascular remodeling were more serious than that of wild type group. In conclusion, rs12455792 increased MØ recruitment, M1 type inflammatory response via activated TGF-β signaling, and further promoted vascular remodeling and pathological progress of TAAD.

Aortic stiffness in families with inherited non-syndromic thoracic aortic disease

Background. In families with an inherited form of non-syndromic thoracic aortic disease (TAAD), aortic diameter alone is not a reliable marker for disease occurrence or progression. To identify other parameters of aortic function, we studied aortic stiffness in families with TAAD. We also compared diameter measurements obtained by transthoracic echocardiography (TTE) and magnetic resonance imaging (MRI). Methods. Seven families, including 116 individuals, with non-syndromic TAAD, were studied. The aortic diameter was measured by TTE and MRI. Aortic stiffness was assessed as local distensibility in the ascending aorta and as regional and global pulse wave velocity (PWV). Individuals with a dilated thoracic aorta (n = 21) were compared with those without aortic dilatation (n = 95). Results. Ascending aortic diameter measured by TTE strongly correlated with the diameter measured by MRI (r2 = 0.93). The individuals with dilated aortas were older than those without dilatation (49 vs 37 years old). Ascending aortic diameter increased and distensibility decreased with increasing age; while, PWV increased with age and diameter. Some young subjects without aortic dilatation showed increased aortic stiffness. Individuals with a dilated thoracic aorta had significantly higher PWV and lower distensibility, measured by MRI than individuals without dilatation. Conclusions. Diameters measured with TTE agree with those measured by MRI. Aortic stiffness might be a complementary marker for aortic disease and progression when used with aortic diameter, especially in young individuals.

RF88 TRANSFEMORAL BARE-METAL STENT FOR TREATMENT OF RESIDUAL AORTIC ARCH DISSECTION AFTER SURGICAL REPAIR OF ACUTE TYPE A AORTIC DISSECTION.

Background and aim: Here we evaluate the usefulness of transfemoral uncovered stent implantation to avoid secondary conventional surgery for residual type A aortic dissection of aortic arch after ascending aorta replacement. Methods: From June 2009 to April 2015, 11 patients were treated with transfemoral implantation of uncovered stents in the aortic arch after surgical replacement of ascending aorta performed on average 4.7 ± 2.3 years earlier.. An enlarged dissected aortic arch or a dangerous median growth of more than 5 mm/yr or impending rupture presenting as chest pain were indications for treatment. The dissected aortic tracts diameter must not exceed 45 mm. 5 patients (45.5%) were treated with Djumbodies Dissection System, 6 patients (54.5%) with Jotec E-XL aortic stent. Results: There were no perioperative deaths or permanent neurologic complications. Primary procedural success was obtained in all patients and the residual type A aortic dissection in aortic arch was obliterated, with disappearance of the false lumen. Median ICU stay was 24 hours, post-operative hospital stay was 5.2 ± 1.4 days. One death, not aortic related, occurred during follow-up period (mean 5.2 ± 1.9 years). Descending thoracic aorta diameter significantly increased in 3 patients (27.3%): one patient (9.0%) needed a secondary conventional surgery, the other 2 (18.2%) of a distal extension with PETTICOAT approach. Conclusions: Endovascular approach with uncovered metal bare stent is surely an evolving strategy to perform a purely endovascular treatment, indicated only for treatment of aortic arch with a diameter of less than 40 or 45 mm, to avoid progressive thoracic aortic dilatation and/or rupture.

Treatment with transfemoral bare-metal stent of residual aortic arch dissection after surgical repair of acute type an aortic dissection.

Here we evaluate the usefulness of transfemoral uncovered stent implantation to avoid secondary conventional surgery for residual type A aortic dissection (TAAD) of the aortic arch after ascending aorta replacement. From June 2009 to April 2015, 11 patients were treated with transfemoral implantation of uncovered stents in the aortic arch after surgical replacement of ascending aorta performed on average 4.7±2.3 years earlier. An enlarged dissected aortic arch or a dangerous median growth of more than 5 mm/yr or impending rupture presenting as chest pain were indications for treatment. The dissected aortic tracts diameter must not exceed 45 mm. Five patients (45.5%) were treated with Djumbodies Dissection System, 6 patients (54.5%) with Jotec E-XL aortic stent. There were no perioperative deaths or permanent neurologic complications. Primary procedural success was obtained in all patients and the residual TAAD in aortic arch was obliterated, with disappearance of the false lumen. Median intensive care unit (ICU) stay was 24 hours; post-operative hospital stay was 5.2±1.4 days. One death, not aortic related, occurred during follow-up period (mean 5.2±1.9 years). Descending thoracic aorta diameter significantly increased in 3 patients (27.3%): one patient (9.0%) needed a secondary conventional surgery, the other 2 (18.2%) of a distal extension with PETTICOAT approach. Endovascular approach with uncovered metal bare stent is surely an evolving strategy to perform a purely endovascular treatment, indicated only for treatment of an aortic arch with a diameter of less than 40 or 45 mm, to avoid progressive thoracic aortic dilatation and/or rupture.

The effect of beta-blockers therapy on progression of thoracic aortic dilatation in the young Marfan syndrome patients: Difference between subtypes of FBN1 gene mutation

Mutation in the FBN1 gene was common in the Marfan syndrome (MFS), and caused aortic dilatation that could be delayed by beta-blocker therapy. This study evaluated the effect of beta-blockers therapy on aortic dilatation in the MFS patients with subtypes of FBN1 gene mutation. A single center observational prospective study included 53 MFS patients less than 20-years-old with predicting-happlo insufficiency (PTC) or dominant-negative (DN) mutation of FBN1 gene. Among 41 patients used beta-blockers therapy, aortic diameter and aortic dilatation rate were evaluated by echocardiography. At the baseline, dimension of aortic sinus of Valsalva of PTC-MFS patients and DN-MFS patients were in the upper bound of normal range (Z-score: 1.76 ± 1.25 vs. 1.69 ± 0.87, P = 0.621, respectively). While, dimension of ascending aorta was in the normal range. After a mean follow-up 1.5 ± 0.71 years with beta-blockers therapy, the dilatation rate at aortic sinus of Valsalva decreased [PTC-MFS: −0.28 ± 0.85 mm/m 2 .year (95% CI: −0.82; 0.26) vs. DN-MFS: −0.32 ± 1.34 mm/m 2 .year (95% CI: −0.91; 1.34), P = 0.069]. The dilatation rate at ascending aorta decreased in PTC-MFS patients [−0.18 ± 1.19 mm/m 2 .year (95% CI: −0.96; 0.61)] and increased in DN-MFS patients [0.4 ± 1.82 mm/m 2 .year (95% CI: −0.43; 1.23)], P = 0.554. Among the FBN1-MFS patients, beta-blockers therapy was effective to reduce the aortic dilatation rate, of which difference between PTC-MFS patients and DN-MFS patients was not significant.

P6042Association of intracranial arterial aneurysms and thoracic aortic aneurysms and dilatation

P6042Association of intracranial arterial aneurysms and thoracic aortic aneurysms and dilatation

2464 Sexual dimorphism in a mouse model of syndromic thoracic aortic aneurysm

OBJECTIVES/SPECIFIC AIMS: Pre-clinical and clinical observations have noted that increased aortic dilation is associated with male sex. Using an experimental model of severe, syndromic thoracic aortic aneurysms, we quantify aortic dilation and elastin stability in male Versus female mice. METHODS/STUDY POPULATION: Ascending aortas from male and female FBN1mgR/mgR mice and their wild type littermates were assessed every 4 weeks from 6 to 18 weeks of age by ultrasound. Measurements were taken luminal edge to luminal edge in diastole. At termination, aortas were harvested for RT-PCR analysis of extracellular matrix genes. Aortas were serially sectioned and elastin fragmentation was imaged by auto-fluorescence. RESULTS/ANTICIPATED RESULTS: At 12 weeks of age, differences of aortic diameters between male and female FBN1mgR/mgR mice were significantly different (2.24±0.43 vs. 1.57±0.22 mm; p=0.002), while there were no significant differences between sexes of wild type littermates (1.29±0.13 vs. 1.23±0.08 mm; p=0.71). Male sex was associated with increased elastin but not fibrillin-1 mRNA expression. Ascending aortas from male and female FBN1mgR/mgR mice significantly differed in the degree of elastin fragmentation (2.76 vs. 1.85 breaks/ 100 µm aorta; p=0.03). DISCUSSION/SIGNIFICANCE OF IMPACT: Sexual dimorphism of thoracic aortic dilation observed in human TAA patients was recapitulated in the fibirllin-1 hypomorphic mouse model of syndromic thoracic aortic aneurysms. Differences in this mouse model could be explained by the differential expression of extracellular matrix genes.

Three-generation family with novel contiguous gene deletion on chromosome 2p22 associated with thoracic aortic aneurysm syndrome.

Latent transforming growth factor binding proteins (LTBP) are a family of extracellular matrix glycoproteins that play an important role in the regulation of transforming growth factor beta (TGF-ß) activation. Dysregulation of the TGF-ß pathway has been implicated in the pathogenesis of inherited disorders predisposing to thoracic aortic aneurysms syndromes (TAAS) including Marfan syndrome (MFS; FBN1) and Loeys-Dietz syndrome (LDS; TGFBR1, TGFBR2, TGFB2, TGFB3, SMAD2, SMAD3). While these syndromes have distinct clinical criteria, they share clinical features including aortic root dilation and musculoskeletal findings. LTBP1 is a component of the TGF-ß pathway that binds to fibrillin-1 in the extracellular matrix rendering TGF-ß inactive. We describe a three-generation family case series with a heterozygous ∼5.1 Mb novel contiguous gene deletion of chromosome 2p22.3-p22.2 involving 11 genes, including LTBP1. The deletion has been identified in the proband, father and grandfather, who all have a phenotype consistent with a TAAS. Findings include thoracic aortic dilation, ptosis, malar hypoplasia, high arched palate, retrognathia, pes planus, hindfoot deformity, obstructive sleep apnea, and low truncal tone during childhood with joint laxity that progressed to reduced joint mobility over time. While the three affected individuals did not meet criteria for either MFS or LDS, they shared features of both. Although the deletion includes 11 genes, given the relationship between LTBP1, TGF-ß, and fibrillin-1, LTBP1 stands out as one of the possible candidate genes for the clinical syndrome observed in this family. More studies are necessary to evaluate the potential role of LTBP1 in the pathophysiology of TAAS.

Thoracic aortic aneurysm in patients with loss of function Filamin A mutations: Clinical characterization, genetics, and recommendations.

The frequency and gender distribution of thoracic aortic aneurysm as a cardiovascular manifestation of loss-of-function (LOF) X-linked FilaminA (FLNA) mutations are not known. Furthermore, there is very limited cardiovascular morbidity or mortality data in children and adults. We analyzed cardiac data on the largest series of 114 patients with LOF FLNA mutations, both children and adults, with periventricular nodular heterotopia (PVNH), including 48 study patients and 66 literature patients, median age of 22.0 years (88 F, 26 M, range: 0-71 years), with 75 FLNA mutations observed in 80 families. Most (64.9%) subjects had a cardiac anomaly or vascular abnormality (80.8% of males and 60.2% of females). Thoracic aortic aneurysms or dilatation (TAA) were found in 18.4% (n = 21), and were associated with other structural cardiac malformations in 57.1% of patients, most commonly patent ductus arteriosus (PDA) and valvular abnormalities. TAA most frequently involved the aortic root and ascending aorta, and sinus of Valsalva aneurysms were present in one third of TAA patients. Six TAA patients (28.5%) required surgery (median age 37 yrs, range 13-41 yrs). TAA with its associated complications was also the only recorded cause of premature, non-accidental mortality in adults (2 M, 2 F). Two adult patients (1 F, 1 M, median 38.5 yrs), died of spontaneous aortic rupture at aortic dimensions smaller than current recommendations for surgery for other aortopathies. Data from this largest series of LOF FLNA mutation patients underscore the importance of serial follow-up to identify and manage these potentially devastating cardiovascular complications.

Genetic Bases of Bicuspid Aortic Valve: The Contribution of Traditional and High-Throughput Sequencing Approaches on Research and Diagnosis.

Bicuspid aortic valve (BAV) is a common (0.5–2.0% of general population) congenital heart defect with increased prevalence of aortic dilatation and dissection. BAV has an autosomal dominant inheritance with reduced penetrance and variable expressivity. BAV has been described as an isolated trait or associated with syndromic conditions [e.g., Marfan Marfan syndrome or Loeys-Dietz syndrome (MFS, LDS)]. Identification of a syndromic condition in a BAV patient is clinically relevant to personalize aortic surgery indication. A 4-fold increase in BAV prevalence in a large cohort of unrelated MFS patients with respect to general population was reported, as well as in LDS patients (8-fold). It is also known that BAV is more frequent in patients with thoracic aortic aneurysm (TAA) related to mutations in ACTA2, FBN1, and TGFBR2 genes. Moreover, in 8 patients with BAV and thoracic aortic dilation, not fulfilling the clinical criteria for MFS, FBN1 mutations in 2/8 patients were identified suggesting that FBN1 or other genes involved in syndromic conditions correlated to aortopathy could be involved in BAV. Beyond loci associated to syndromic disorders, studies in humans and animal models evidenced/suggested the role of further genes in non-syndromic BAV. The transcriptional regulator NOTCH1 has been associated with the development and acceleration of calcium deposition. Genome wide marker-based linkage analysis demonstrated a linkage of BAV to loci on chromosomes 18, 5, and 13q. Recently, a role for GATA4/5 in aortic valve morphogenesis and endocardial cell differentiation has been reported. BAV has also been associated with a reduced UFD1L gene expression or involvement of a locus containing AXIN1/PDIA2. Much remains to be understood about the genetics of BAV. In the last years, high-throughput sequencing technologies, allowing the analysis of large number of genes or entire exomes or genomes, progressively became available. The latter issue together with the development of “BigData” analysis methods improving their interpretation and integration with clinical data represents a promising opportunity to increase the disease knowledge and diagnosis in monogenic and multifactorial complex traits. This review summarized the main knowledge on the BAV genetic bases, the role of genetic diagnosis in BAV patient managements and the crucial challenges for the comprehension of genetics of BAV in research and diagnosis.

Moderately Elevated Homocysteine Does Not Contribute to Thoracic Aortic Aneurysm in Mice

Background: Moderate hyperhomocysteinemia is an attractive target for intervention because it is present in 5-7% of the population and can be reversed by diet. This approach presupposes that hyperhomocysteinemia is directly involved in the disease process. Epidemiologic studies have indicated that moderately elevated homocysteine may contribute to thoracic aortic aneurysm (TAA) dilatation and dissection in humans. In vitro, elevated homocysteine disrupts the structure and function of extracellular matrix components, suggesting that moderate hyperhomocysteinemia may contribute to the development and/or progression of TAA.Objective: We investigated moderately elevated homocysteine in the development and progression of TAA in a mouse model of Marfan syndrome (MFS) and in isogenic wild-type mice. The MFS mouse is a well-described model of a systemic connective tissue disorder characterized by thoracic aortic dilatation, dissection, and rupture. We used this model as a sensitized indicator system to examine the impact of homocysteine on the progression of TAA.Methods: Murine fibrillin 1 gene (Fbn1)C1039G/+ MFS and C57BL/6J wild-type mice were fed a cobalamin-restricted diet to induce moderate hyperhomocysteinemia from weaning until the age of 32 wk. Homocysteine and methylmalonic acid were measured and aortic root diameter assessed with the use of echocardiography in mice aged 3, 7, 15, and 32 wk.Results: Cobalamin-restricted mice exhibited significantly higher homocysteine (P < 0.0001) and methylmalonic acid (P < 0.0001) in the blood. For both strains, no significant difference in thoracic aortic diameter was observed in mice on the cobalamin-restricted diet compared with those on the control diet.Conclusions:Fbn1C1039G/+ mice are a well-characterized model of progressive aortic root dilation. Hyperhomocysteinemia in the physiologic range did not induce abnormal aortic growth in wild-type mice and did not accelerate or otherwise influence aortic root growth and pathologic progression in mice with an underlying predisposition for aortic dilatation.

Aortopathies in adult congenital heart disease and genetic aortopathy syndromes: management strategies and indications for surgery

### Learning objectives 1. Review the epidemiology, histology, pathophysiology and genetics of congenital heart disease-associated aortopathies and genetic aortopathy syndromes. 2. Review and describe 1. appropriate imaging strategies for diagnosis...

Bicuspid aortic valve outcomes.

Bicuspid aortic valve is the most common CHD. Its association with early valvular dysfunction, endocarditis, thoracic aorta dilatation, and aortic dissection is well established. The aim of this study was to assess the incidence and predictors of cardiac events in adults with bicuspid aortic valve. We carried out a retrospective analysis of cardiac outcomes in ambulatory adults with bicuspid aortic valve followed-up in a tertiary hospital centre. Outcomes were defined as follows: interventional - intervention on the aortic valve or thoracic aorta; medical - death, aortic dissection, aortic valve endocarditis, congestive heart failure, arrhythmias, or ischaemic heart disease requiring hospital admission; and a composite end point of both. Kaplan-Meier curves were generated to determine event rates, and predictors of cardiac events were determined by multivariate analysis. A total of 227 patients were followed-up over 13±9 years; 29% of patients developed severe aortic valve dysfunction and 12.3% reached ascending thoracic aorta dimensions above 45 mm. At least one cardiac outcome occurred in 38.8% of patients, with an incidence rate at 20 years of follow-up of 47±4%; 33% of patients were submitted to an aortic valve or thoracic aorta intervention. Survival 20 years after diagnosis was 94±2%. Independent predictors of the composite end point were baseline moderate-severe aortic valve dysfunction (hazard ratio, 3.19; 95% confidence interval, 1.35-7.54; p<0.01) and aortic valve leaflets calcification (hazard ratio, 4.72; 95% confidence interval, 1.91-11.64; p<0.005). In this study of bicuspid aortic valve, the long-term survival was excellent but with occurrence of frequent cardiovascular events. Baseline aortic valve calcification and dysfunction were the only independent predictors of events.

Prognostic implications of descending thoracic aorta dilation after surgery for aortic dissection

BackgroundThe present study assessed whether descending thoracic aorta growth can be measured reliably by volumetric analysis using multi-detector row computed tomography (MDCT) and whether growth influences the need for future aortic interventions in survivors of acute type A aortic dissection. MethodsA total of 51 patients (58 ± 11 years, 61% male) who underwent surgery for type A aortic dissection with ≥2 postoperative MDCT scans ≥5 months apart were included. Volumetric analysis of the descending thoracic aorta was performed with acceptable intraobserver variability. Growth of the complete, false and true lumen was estimated in ml/year and defined as slow growth (≤average growth) or fast growth (>average growth). ResultsThe complete lumen volume increased from 133 ± 8 ml to 163 ± 9 ml after 3.5 years follow-up (p < 0.001), with an average growth rate of 6.1 ml/year. The false lumen volume increased from 81 ± 7 ml to 106 ± 12 ml (p = 0.018) with an average growth rate of 2.8 ml/year. The true lumen changed only slightly from 59 ± 4 ml to 65 ± 8 ml (p = 0.205). Five-year freedom from descending thoracic aorta intervention was significantly lower in patients with above-average growth of the complete lumen (80 ± 9%) compared to slow growth (100%; p = 0.003). Similar observations were made for the false lumen (fast: 74 ± 12% vs. slow: 100%; p = 0.042). ConclusionsIncreased growth of the false lumen of the descending thoracic aorta after type A aortic dissection was associated with a higher risk of secondary interventions.

Nitrative Stress Participates in Endothelial Progenitor Cell Injury in Hyperhomocysteinemia.

In order to investigate the role of nitrative stress in vascular endothelial injury in hyperhomocysteinemia (HHcy), thirty healthy adult female Wistar rats were randomly divided into three groups: control, hyperhomocysteinemia model, and hyperhomocysteinemia with FeTMPyP (peroxynitrite scavenger) treatment. The endothelium-dependent dilatation of thoracic aorta in vitro was determined by response to acetylcholine (ACh). The histological changes in endothelium were assessed by HE staining and scanning electron microscopy (SEM). The expression of 3-nitrotyrosine (NT) in thoracic aorta was demonstrated by immunohistochemistry and immunofluorescence, and the number of circulating endothelial progenitor cells (EPCs) was quantified by flow cytometry. Hyperhomocysteinemia caused significant endothelial injury and dysfunction including vasodilative and histologic changes, associated with higher expression of NT in thoracic aorta. FeTMPyP treatment reversed these injuries significantly. Further, the effect of nitrative stress on cultured EPCs in vitro was investigated by administering peroxynitrite donor (3-morpholino-sydnonimine, SIN-1) and peroxynitrite scavenger (FeTMPyP). The roles of nitrative stress on cell viability, necrosis and apoptosis were evaluated with 3-(4,5-dimethylthiazol)-2,5-diphenyl tetrazolium (MTT) assay, lactate dehydrogenase (LDH) release assay and terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay, respectively. Also, the phospho-eNOS expression and tube formation in Matrigel of cultured EPCs was detected. Our data showed that the survival of EPCs was much lower in SIN-1 group than in vehicle group, both the apoptosis and necrosis of EPCs were much more severe, and the p-eNOS expression and tube formation in Matrigel were obviously declined. Subsequent pretreatment with FeTMPyP reversed these changes. Further, pretreatment with FeTMPyP reversed homocysteine-induced EPC injury. In conclusion, this study indicates that nitrative stress plays a role in vascular endothelial injury in hyperhomocysteinemia, as well as induces endothelial progenitor cell injury directly.

Molecular and Genetic Insights into Thoracic Aortic Dilation in Conotruncal Heart Defects.

Thoracic aortic dilation (AD) has commonly been described in conotruncal defects (CTDs), such as tetralogy of Fallot, double outlet right ventricle and transposition of the great arteries, and truncus arteriosus. Several theories for this have been devised, but fairly recent data indicate that there is likely an underlying histologic abnormality, similar to that seen in Marfan and other connective tissue disease. The majority of aortic dissection in the general population occurs after the age of 45 years, and there have been very few case reports of aortic dissection in CTD. Given advances in cardiac surgery and increasing survival over the past several decades, there has been rising concern that, as patients who have survived surgical correction of these defects age, there may be increased morbidity and mortality due to aortic dissection and aortic regurgitation. This review discusses the most recent developments in research into AD in CTD, including associated genetic mutations.

Effects of aortic root motion on wall stress in the Marfan aorta before and after personalised aortic root support (PEARS) surgery

Aortic root motion was previously identified as a risk factor for aortic dissection due to increased longitudinal stresses in the ascending aorta. The aim of this study was to investigate the effects of aortic root motion on wall stress and strain in the ascending aorta and evaluate changes before and after implantation of personalised external aortic root support (PEARS).Finite element (FE) models of the aortic root and thoracic aorta were developed using patient-specific geometries reconstructed from pre- and post-PEARS cardiovascular magnetic resonance (CMR) images in three Marfan patients. The wall and PEARS materials were assumed to be isotropic, incompressible and linearly elastic. A static load on the inner wall corresponding to the patients’ pulse pressure was applied. Cardiovascular MR cine images were used to quantify aortic root motion, which was imposed at the aortic root boundary of the FE model, with zero-displacement constraints at the distal ends of the aortic branches and descending aorta.Measurements of the systolic downward motion of the aortic root revealed a significant reduction in the axial displacement in all three patients post-PEARS compared with its pre-PEARS counterparts. Higher longitudinal stresses were observed in the ascending aorta when compared with models without the root motion. Implantation of PEARS reduced the longitudinal stresses in the ascending aorta by up to 52%. In contrast, the circumferential stresses at the interface between the supported and unsupported aorta were increase by up to 82%. However, all peak stresses were less than half the known yield stress for the dilated thoracic aorta.

Association of rat thoracic aorta dilatation by astragaloside IV with the generation of endothelium-derived hyperpolarizing factors and nitric oxide, and the blockade of Ca2+ channels.

The aim of the present study was to elucidate the roles of endothelium-derived hyperpolarizing factors (EDHFs) and nitric oxide (NO) in mediating the vasodilatation response to astragaloside IV and the effects of astragaloside IV on voltage-dependent Ca2+ channels and receptor-operated Ca2+ channels in rat thoracic aortic rings precontracted with potassium chloride (KCl; 60 mM) or phenylephrine (PHE; 1 µM). The results showed that astragaloside IV (1×10−4-3×10−1 g/l) concentration-dependently relaxed the contraction induced by KCl (10–90 mM) or PHE (1×10−9-3×10−5 µM) and inhibited concentration-contraction curves for the two vasoconstrictors in the aortic rings. Preincubation with Nω-nitro-L-arginine methyl ester (L-NAME, 100 µM) significantly attenuated astragaloside IV-induced relaxation in the endothelium-intact and -denuded arterial rings precontracted with PHE. Astragaloside IV, following preincubation with L-NAME (100 µM) plus indomethacin (10 µM), exerted vasodilatation, which was depressed by tetraethtylamine (1 mM) and propargylglycine (100 µM), but not by carbenoxolone (10 µM), catalase (500 U/ml) or proadifen hydrochloride (10 µM). The action mode of astragaloside IV was evident in comparison to nifedipine. Inhibition of PHE-induced contraction by astragaloside IV (100 mg/l) was more potent compared to inhibition of KCl-induced contraction, while inhibition of KCl-induced contraction by nifedipine (100 mg/l) was more potent compared to inhibition of PHE-induced contraction by nifedipine (100 mg/l). In addition, the combination of astragaloside IV and nifedipine exhibited synergistic and additive inhibitory effects on contraction evoked by KCl, which was similar to PHE. In conclusion, astragaloside IV, as a Ca2+ antagonist, relaxes the vessels through the blockade of superior receptor-operated Ca2+ and inferior voltage-dependent Ca2+ channels, which modulate NO from vascular endothelial cells and vascular smooth muscle cells, and EDHFs including K+ and hydrogen sulfide.