Notch Signaling in Descending Thoracic Aortic Aneurysm and Dissection

Background

Descending thoracic aortic aneurysm and dissection (DTAAD) is characterized by progressive medial degeneration, which may result from excessive tissue destruction and insufficient repair. Resistance to tissue destruction and aortic self-repair are critical in preventing medial degeneration. The signaling pathways that control these processes in DTAAD are poorly understood. Because Notch signaling is a critical pathway for cell survival, proliferation, and tissue repair, we examined its activation in DTAAD.

Methods

We studied descending thoracic aortic tissue from patients with sporadic thoracic aortic aneurysm (TAA; n = 14) or chronic thoracic aortic dissection (TAD; n = 16) and from age-matched organ donors (n = 12). Using western blot, real-time RT-PCR, and immunofluorescence staining, we examined aortic tissue samples for the Notch ligands Delta-like 1, Delta-like 4 (DLL1/4), and Jagged1; the Notch receptor 1 (Notch1); the Notch1 intracellular domain (NICD); and Hes1, a downstream target of Notch signaling.

Results

Western blots and RT-PCR showed higher levels of the Notch1 protein and mRNA and the NICD and Hes1 proteins in both TAA and TAD tissues than in control tissue. However, immunofluorescence staining showed a complex pattern of Notch signaling in the diseased tissue. The ligand DLL1/4 and Notch1 were significantly decreased and NICD and Hes1 were rarely detected in medial vascular smooth muscle cells (VSMCs) in both TAA and TAD tissues, indicating downregulation of Notch signaling in aortic VSMCs. Interestingly Jagged1, NICD, and Hes1 were highly present in CD34+ stem cells and Stro-1+ stem cells in aortas from TAA and TAD patients. NICD and Hes1 were also detected in most fibroblasts and macrophages that accumulated in the aortic wall of DTAAD patients.

Conclusions

Notch signaling exhibits a complex pattern in DTAAD. The Notch pathway is impaired in medial VSMCs but activated in stem cells, fibroblasts, and macrophages.     

Short-Term Curative Effect of Endovascular Stent-Graft Treatment for Aortic Diseases in China: A Systematic Review

Introduction

We analyzed the short-term efficacy of endovascular treatment for aortic diseases by summarizing all available published data on endovascular stent-graft treatment for abdominal aortic aneurysm (AAA), thoracic aortic aneurysm (TAA), type A aortic dissection (type A AD) and type B aortic dissection (type B AD) in China.

Methods

We performed a systematic analysis of 935 published series on retrograde endovascular treatment for aortic diseases in China from January 1996 to November 2010. Based on the inclusion criteria, 159 studies, involving a total of 5531 patients, were included.

Results

There were no significant differences in procedural success among the studies (P>0.05). The rates of overall neurologic complications and stroke were significantly different in all two-group comparisons (P<0.01). The type A AD patients had the highest rates of neurologic complications (both 6.67±0.00%), and the AAA patients had the lowest rates (0.31±0.04% and 0.11±0.02%). Significant differences were noted in the rates of cardiac, renal, pulmonary and visceral complications, which were all higher in the type A AD patients than in the other three groups (P<0.01). The endoleak rate was highest in the TAA patients (19.27±5.74%) and was similar in the type A AD patients (P>0.05). A significant difference was noted between the 30-day mortality rate of the type A AD patients and the AAA or type B AD patients (P<0.05).

Conclusion

Endovascular stent-graft is a feasible and safe treatment for aortic diseases, with high procedural success and low incidences of post-procedural complications and short-term mortality. Endovascular treatment for AAA and type B AD is more efficient than for type A AD and TAA.     

Computed Tomography of Aortic Wall Calcifications in Aortic Dissection Patients

Objectives

To investigate the frequency of aortic calcifications at the outer edge of the false lumen and the frequency of fully circular aortic calcifications in a consecutive series of patients with aortic dissection who underwent contrast-enhanced CT.

Methods

The study population compromised of 69 consecutive subjects aged 60 years and older with a contrast-enhanced CT scan demonstrating an aortic dissection. All CT scans were evaluated for the frequency of aortic calcifications at the outer edge of the false lumen and the frequency of fully circular aortic calcifications by two experienced observers. Between observer reliability was evaluated by using Cohen’s Kappa. Differences between groups were tested using unpaired T test and Chi-square test.

Results

Presumed media calcifications were observed in 22 (32%) patients of 60 years and older and were found more frequently in chronic aortic dissection (N = 12/23, 52%) than in acute aortic dissection (N = 10/46, 22%).

Conclusion

As the intima has been torn away by the aortic dissection it is highly likely that CT scans can visualize the calcifications in the tunica media of the aorta.     

Genetic Variants in FBN-1 and Risk for Thoracic Aortic Aneurysm and Dissection

Objectives

A recent genome wide association study (GWAS) by LeMaire et al. found that two single nucleotide polymorphisms (SNPs), rs2118181 and rs10519177 in the FBN-1 gene (encoding Fibrillin-1), were associated with thoracic aortic dissection (TAD), non-dissecting thoracic aortic aneurysm (TAA), and thoracic aortic aneurysm or dissection (TAAD); the largest effect was observed for the association of rs2118181 with TAD. We investigated whether rs2118181 and rs10519177 were associated with TAD, TAA, and TAAD in the Yale study.

Methods

The genotypes of rs2118181 and rs10519177 were determined for participants in the Yale study: 637 TAAD cases (140 TAD, 497 TAA) and 275 controls from the United States, Hungary, and Greece. The association of the genotypes with TAD, TAA and TAAD were assessed using logistic regression models adjusted for sex, age, study center and hypertension.

Results and Conclusions

In the Yale study, rs2118181 was associated with TAD: compared with non-carriers, carriers of the risk allele had an unadjusted odds ratio for TAD of 1.80 (95% CI 1.15–2.80) and they had odds ratio for TAD of 1.87 (95% CI 1.09–3.20) after adjusting for sex, age, study center and hypertension. We did not find significant differences in aortic size, a potential confounder for TAD, between rs2118181 risk variant carriers and non-carriers: mean aortic size was 5.56 (95% CI: 5.37–5.73) for risk variant carriers (CC+CT) and was 5.48 (95% CI: 5.36–5.61) for noncarriers (TT) (p = 0.56). rs2118181 was not associated with TAA or TAAD. rs10519177 was not associated with TAD, TAA, or TAAD in the Yale study. Thus, the Yale study provided further support for the association of the FBN-1 rs2118181SNP with TAD.     

Astrocyte-specific expression patterns associated with the PDGF-induced glioma microenvironment

Background

The tumor microenvironment contains normal, non-neoplastic cells that may contribute to tumor growth and maintenance. Within PDGF-driven murine gliomas, tumor-associated astrocytes (TAAs) are a large component of the tumor microenvironment. The function of non-neoplastic astrocytes in the glioma microenvironment has not been fully elucidated; moreover, the differences between these astrocytes and normal astrocytes are unknown. We therefore sought to identify genes and pathways that are increased in TAAs relative to normal astrocytes and also to determine whether expression of these genes correlates with glioma behavior.

Methodology/Principal Findings

We compared the gene expression profiles of TAAs to normal astrocytes and found the Antigen Presentation Pathway to be significantly increased in TAAs. We then identified a gene signature for glioblastoma (GBM) TAAs and validated the expression of some of those genes within the tumor. We also show that TAAs are derived from the non-tumor, stromal environment, in contrast to the Olig2+ tumor cells that constitute the neoplastic elements in our model. Finally, we validate this GBM TAA signature in patients and show that a TAA-derived gene signature predicts survival specifically in the human proneural subtype of glioma.

Conclusions/Significance

Our data identifies unique gene expression patterns between populations of TAAs and suggests potential roles for stromal astrocytes within the glioma microenvironment. We show that certain stromal astrocytes in the tumor microenvironment express a GBM-specific gene signature and that the majority of these stromal astrocyte genes can predict survival in the human disease.     

Structure of a Burkholderia pseudomallei Trimeric Autotransporter Adhesin Head

Background

Pathogenic bacteria adhere to the host cell surface using a family of outer membrane proteins called Trimeric Autotransporter Adhesins (TAAs). Although TAAs are highly divergent in sequence and domain structure, they are all conceptually comprised of a C-terminal membrane anchoring domain and an N-terminal passenger domain. Passenger domains consist of a secretion sequence, a head region that facilitates binding to the host cell surface, and a stalk region.

Methodology/Principal Findings

Pathogenic species of Burkholderia contain an overabundance of TAAs, some of which have been shown to elicit an immune response in the host. To understand the structural basis for host cell adhesion, we solved a 1.35 Å resolution crystal structure of a BpaA TAA head domain from Burkholderia pseudomallei, the pathogen that causes melioidosis. The structure reveals a novel fold of an intricately intertwined trimer. The BpaA head is composed of structural elements that have been observed in other TAA head structures as well as several elements of previously unknown structure predicted from low sequence homology between TAAs. These elements are typically up to 40 amino acids long and are not domains, but rather modular structural elements that may be duplicated or omitted through evolution, creating molecular diversity among TAAs.

Conclusions/Significance

The modular nature of BpaA, as demonstrated by its head domain crystal structure, and of TAAs in general provides insights into evolution of pathogen-host adhesion and may provide an avenue for diagnostics.     

Coupling between MRI-assessed regional aortic pulse wave velocity and diameters in patients with thoracic aortic aneurysm: a feasibility study

Aims

Thoracic aortic aneurysm (TAA) is potentially life-threatening and requires close follow-up to prevent aortic dissection. Aortic stiffness and size are considered to be coupled. Regional aortic stiffness in patients with TAA is unknown. We aimed to evaluate coupling between regional pulse wave velocity (PWV), a marker of vascular stiffness, and aortic diameter in TAA patients.

Methods

In 40 TAA patients (59 ± 13 years, 28 male), regional aortic diameters and regional PWV were assessed by 1.5 T MRI. The incidence of increased diameter and PWV were determined for five aortic segments (S1, ascending aorta; S2, aortic arch; S3, thoracic descending aorta; S4, suprarenal and S5, infrarenal abdominal aorta). In addition, coupling between regional PWV testing and aortic dilatation was evaluated and specificity and sensitivity were assessed.

Results

Aortic diameter was 44 ± 5 mm for the aortic root and 39 ± 5 mm for the ascending aorta. PWV was increased in 36 (19 %) aortic segments. Aortic diameter was increased in 28 (14 %) segments. Specificity of regional PWV testing for the prediction of increased regional diameter was ≥ 84 % in the descending thoracic to abdominal aorta and ≥ 68 % in the ascending aorta and aortic arch.

Conclusion

Normal regional PWV is related to absence of increased diameter, with high specificity in the descending thoracic to abdominal aorta and moderate results in the ascending aorta and aortic arch.     

Emergent Endovascular vs. Open Surgery Repair for Ruptured Abdominal Aortic Aneurysms: A Meta-Analysis

Objectives

To systematically review studies comparing peri-operative mortality and length of hospital stay in patients with ruptured abdominal aortic aneurysms (rAAAs) who underwent endovascular aneurysm repair (EVAR) to patients who underwent open surgical repair (OSR).

Methods

The Medline, Cochrane, EMBASE, and Google Scholar databases were searched until Apr 30, 2013 using keywords such as abdominal aortic aneurysm, emergent, emergency, rupture, leaking, acute, endovascular, stent, graft, and endoscopic. The primary outcome was peri-operative mortality and the secondary outcome was length of hospital stay.

Results

A total of 18 studies (2 randomized controlled trials, 5 prospective studies, and 11 retrospective studies) with a total of 135,734 rAAA patients were included. rAAA patients who underwent EVAR had significantly lower peri-operative mortality compared to those who underwent OSR (overall OR = 0.62, 95% CI = 0.58 to 0.67, P<0.001). rAAA patients with EVAR also had a significantly shorter mean length of hospital stay compared to those with OSR (difference in mean length of stay ranged from −2.00 to −19.10 days, with the overall estimate being −5.25 days (95% CI = −9.23 to −1.26, P = 0.010). There was no publication bias and sensitivity analysis showed good reliability.

Conclusions

EVAR confers significant benefits in terms of peri-operative mortality and length of hospital stay. There is a need for more randomized controlled trials to compare outcomes of EVAR and OSR for rAAA.     

Adiponectin Protein Exists in Aortic Endothelial Cells

Aims

Inflammation is closely associated with the development of atherosclerosis and metabolic syndrome. Adiponectin, an adipose-derived secretory protein, possesses an anti-atherosclerotic property. The present study was undertaken to elucidate the presence and significance of adiponectin in vasculature.

Methods and Results

Immunofluorescence staining was performed in aorta of wild-type (WT) mice and demonstrated that adiponectin was co-stained with CD31. Thoracic aorta was cut through and then aortic intima was carefully shaved from aorta. Western blotting showed the existence of adiponectin protein in aortic intima, while there was no adiponectin mRNA expression. Adiponectin knockout (Adipo-KO) and WT mice were administered with a low-dose and short-term lipopolysaccharide (LPS) (1 mg/kg of LPS for 4 hours). The endothelium vascular adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) were highly increased in Adipo-KO mice compared to WT mice after LPS administration.

Conclusions

Adiponectin protein exists in aortic endothelium under steady state and may protect vasculature from the initiation of atherosclerosis.     

The extent of the raphe in bicuspid aortic valves is associated with aortic regurgitation and aortic root dilatation

Background

The clinical course of bicuspid aortic valves (BAVs) is variable. Data on predictors of aortopathy and valvular dysfunction mainly focus on valve morphology.

Aim

To determine whether the presence and extent of the raphe (fusion site of valve leaflets) is associated with the degree of aortopathy and valvular dysfunction in patients with isolated BAV and associated aortic coarctation (CoA).

Methods

Valve morphology and aortic dimensions of 255 BAV patients were evaluated retrospectively by echocardiography.

Results

BAVs with a complete raphe had a significantly higher prevalence of valve dysfunction (especially aortic regurgitation) than BAVs with incomplete raphes (82.9 vs. 66.7 %, p = 0.01). Type 1A BAVs (fusion of right and left coronary leaflets) and complete raphe had larger aortic sinus diameters compared with the rest of the population (37.74 vs. 36.01, p = 0.031). Patients with CoA and type 1A BAV had significantly less valve regurgitation (13.6 vs. 55.8 %, p < 0.001) and smaller diameters of the ascending aorta (33.7 vs. 37.8 mm, p < 0.001) and aortic arch (25.8 vs. 30.2 mm, p < 0.001) than patients with isolated BAV.

Conclusions

Type 1A BAV with complete raphe is associated with more aortic regurgitation and root dilatation. The majority of CoA patients have incomplete raphes, associated with smaller aortic root diameters and less valve regurgitation.     

Clinical course of patients diagnosed with severe aortic stenosis in the Rotterdam area: insights from the AVARIJN study

Objective

To prospectively evaluate the clinical course of patients with severe aortic stenosis (AS) and identify factors associated with treatment selection and patient outcome.

Methods

Patients diagnosed with severe AS in the Rotterdam area were included between June 2006 and May 2009. Patient characteristics, echocardiogram, brain natriuretic peptide (NT-proBNP), and treatment strategy were assessed at baseline, and after 6, 12, and 24 months. Endpoints were aortic valve replacement (AVR) / transcatheter aortic valve implantation (TAVI) and death.

Results

The study population comprised 191 patients, 132 were symptomatic and 59 asymptomatic at study entry. Two-year cumulative survival of symptomatic patients was 89.8 % (95 % CI 79.8–95.0 %) after AVR/TAVI and 72.6 % (95 % CI 59.7–82.0 %) with conservative treatment. Two-year cumulative survival of asymptomatic patients was 91.5 % (95 % CI 80.8–96.4 %). Two-year cumulative incidence of AVR/TAVI was 55.9 % (95 % CI 47.5–63.5 %) in symptomatic patients. Sixty-eight percent of asymptomatic patients developed symptoms, median time to symptoms was 13 months; AVR/TAVI cumulative incidence was 38.3 % (95 % CI 23.1–53.3 %). Elderly symptomatic patients with multiple comorbidities were more likely to receive conservative treatment.

Conclusions

In contemporary Dutch practice many symptomatic patients do not receive invasive treatment of severe AS. Two-thirds of asymptomatic patients develop symptoms within 2 years, illustrating the progressive nature of severe AS. Treatment optimisation may be achieved through careful individualised assessment in a multidisciplinary setting.     

Serum Autoantibody Measurement for the Detection of Hepatocellular Carcinoma

Background

Individuals with liver disease, and especially those with Hepatitis B or C, are at an increased risk of developing hepatocellular carcinoma (HCC) which is the third most common cause of cancer-related death worldwide. Inadequate screening tests largely account for presentation of advanced tumours and high mortality rates. Early detection of HCC amongst high-risk groups is paramount in improving prognosis. This research aimed to further characterise the previously described humoral immune response raised to tumour-associated antigens (TAAs) in the serum of patients with HCC.

Methods

Serum from 96 patients with confirmed HCC, 96 healthy controls matched for age and sex, 78 patients with confirmed liver cirrhosis and 91 patients with confirmed chronic liver disease were analysed for the presence of IgG autoantibodies raised to 41 recombinant TAAs/antigen fragments by ELISA.

Results

Varying autoantibody specificities (97–100%) and sensitivities (0–10%) were observed to individual TAAs. A 21-antigen panel achieved a specificity of 92% and sensitivity of 45% for the detection of HCC. This same panel identified 21% of 169 high-risk controls as having elevated autoantibody levels. A reproducible panel of 10 antigens achieved a specificity of 91% and sensitivity of 41% in HCC. 15% of 152 high-risk controls gave positive results with this panel.

Conclusions

This minimally invasive blood test has the potential to offer advantages over currently available tools for the identification of HCC amongst pre-disposed patients. Results are comparable to current gold standards in HCC (Ultrasonography) and to similar tests in other cancers (EarlyCDT-Lung).     

Homocysteine Level and Risk of Abdominal Aortic Aneurysm: A Meta-Analysis

Objectives

Previous studies have reported inconsistent findings regarding the association between elevated plasma homocysteine (Hcy) levels and abdominal aortic aneurysm (AAA). We investigated this association between Hcy levels in patients with AAA and unaffected controls by conducting a meta-analysis and systematic review.

Methods

We conducted a systematic literature search (up to August 2013) of the PubMed database and Embase. We selected observational studies that evaluated Hcy levels in subjects with AAA compared to unaffected controls. Criteria for inclusion were the assessment of baseline Hcy and risk of AAA as an outcome. The results were presented as odd ratio (OR) and corresponding 95% confidence intervals (CI) comparing AAA patients to the control subjects.

Results

7 studies with 6,445 participants were identified and analyzed. Overall, elevated plasma Hcy was associated with an increased risk of AAA (3.29; 95% CI 1.66–6.51). The pooled adjusted OR from a random effect model of only men participants in the AAA compared with the control group was 2.36 (95% CI 0.63–8.82).

Conclusion

This meta-analysis and systematic review suggested that Hcy significantly increased the risk of AAA.     

Breast Cancer “Tailored Follow-up” in Italian Oncology Units: A Web-Based Survey

Purpose

Breast cancer follow-up procedures after primary treatment are still a controversial issue. Aim of this study was to investigate, through a web-based survey, surveillance methodologies selected by Italian oncologists in everyday clinical practice.

Methods

Referents of Italian medical oncology units were invited to participate to the study via e-mail through the SurveyMonkey website. Participants were asked how, in their institution, exams of disease staging and follow-up are planned in asymptomatic women and if surveillance continues beyond the 5^th year.

Results

Between February and May 2013, 125 out of 233 (53.6%) invited referents of Italian medical oncology units agreed to participate in the survey. Ninety-seven (77.6%) referents state that modalities of breast cancer follow-up are planned according to the risk of disease progression at diagnosis and only 12 (9.6%) oncology units apply the minimal follow-up procedures according to international guidelines. Minimal follow-up is never applied in high risk asymptomatic women. Ninety-eight (78.4%) oncology units continue follow-up in all patients beyond 5 years.

Conclusions

Our survey shows that 90.4% of participating Italian oncology units declare they do not apply the minimal breast cancer follow-up procedures after primary treatment in asymptomatic women, as suggested by national and international guidelines. Interestingly, about 80.0% of interviewed referents performs the so called “tailored follow-up”, high intensity for high risk, low intensity for low risk patients. There is an urgent need of randomized clinical trials able to determine the effectiveness of risk-based follow-up modalities, their ideal frequency and persistence in time.     

Leukotriene B4 Levels in Human Atherosclerotic Plaques and Abdominal Aortic Aneurysms

Background

Leukotriene B4 (LTB4) has been associated with the initiation and progression of atherosclerosis and abdominal aortic aneurysm (AAA) formation. However, associations of LTB4 levels with tissue characteristics and adverse clinical outcome of advanced atherosclerosis and AAA are scarcely studied. We hypothesized that LTB4 levels are associated with a vulnerable plaque phenotype and adverse clinical outcome. Furthermore, that LTB4 levels are associated with inflammatory AAA and adverse clinical outcome.

Methods

Atherosclerotic plaques and AAA specimens were selected from two independent databases for LTB4 measurements. Plaques were isolated during carotid endarterectomy from asymptomatic (n = 58) or symptomatic (n = 317) patients, classified prior to surgery. LTB4 levels were measured without prior lipid extraction and levels were corrected for protein content. LTB4 levels were related to plaque phenotype, baseline patient characteristics and clinical outcome within three years following surgery. Seven non-diseased mammary artery specimens served as controls. AAA specimens were isolated during open repair, classified as elective (n = 189), symptomatic (n = 29) or ruptured (n = 23). LTB4 levels were measured similar to the plaque measurements and were related to tissue characteristics, baseline patient characteristics and clinical outcome. Twenty-six non-diseased aortic specimens served as controls.

Results

LTB4 levels corrected for protein content were not significantly associated with histological characteristics specific for vulnerable plaques or inflammatory AAA as well as clinical presentation. Moreover, it could not predict secondary manifestations independently investigated in both databases. However, LTB4 levels were significantly lower in controls compared to plaque (p = 0.025) or AAA (p = 0.017).

Conclusions

LTB4 levels were not associated with a vulnerable plaque phenotype or inflammatory AAA or clinical presentation. This study does not provide supportive evidence for a role of LTB4 in atherosclerotic plaque destabilization or AAA expansion. However, these data should be interpreted with care, since LTB4 measurements were performed without prior lipid extractions.     

Long-Term Results after Proximal Thoracic Aortic Redo Surgery

Objective

To evaluate early and mid-term results in patients undergoing proximal thoracic aortic redo surgery.

Methods

We analyzed 60 patients (median age 60 years, median logistic EuroSCORE 40) who underwent proximal thoracic aortic redo surgery between January 2005 and April 2012. Outcome and risk factors were analyzed.

Results

In hospital mortality was 13%, perioperative neurologic injury was 7%. Fifty percent of patients underwent redo surgery in an urgent or emergency setting. In 65%, partial or total arch replacement with or without conventional or frozen elephant trunk extension was performed. The preoperative logistic EuroSCORE I confirmed to be a reliable predictor of adverse outcome- (ROC 0.786, 95%CI 0.64–0.93) as did the new EuroSCORE II model: ROC 0.882 95%CI 0.78–0.98. Extensive individual logistic EuroSCORE I levels more than 67 showed an OR of 7.01, 95%CI 1.43–34.27. A EuroSCORE II larger than 28 showed an OR of 4.44 (95%CI 1.4–14.06). Multivariate logistic regression analysis identified a critical preoperative state (OR 7.96, 95%CI 1.51–38.79) but not advanced age (OR 2.46, 95%CI 0.48–12.66) as the strongest independent predictor of in-hospital mortality. Median follow-up was 23 months (1–52 months). One year and five year actuarial survival rates were 83% and 69% respectively. Freedom from reoperation during follow-up was 100%.

Conclusions

Despite a substantial early attrition rate in patients presenting with a critical preoperative state, proximal thoracic aortic redo surgery provides excellent early and mid-term results. Higher EuroSCORE I and II levels and a critical preoperative state but not advanced age are independent predictors of in-hospital mortality. As a consequence, age alone should no longer be regarded as a contraindication for surgical treatment in this particular group of patients.     

Ang II Enhances Noradrenaline Release from Sympathetic Nerve Endings Thus Contributing to the Up-Regulation of Metalloprotease-2 in Aortic Dissection Patients' Aorta Wall

Object

To test the hypothesis that angiotensin II (Ang II) could enhance noradrenaline (NA) release from sympathetic nerve endings of the aorta thus contributing to the up-regulation of matrix metalloproteinase 2 (MMP-2) during the formation of aortic dissection (AD).

Methods

Ang II, NA, MMP-2, MMP-9 of the aorta sample obtained during operation from aortic dissection patients were detected by High Performance Liquid Chromatography and ELISA and compared with controls. Isotope labelling method was used to test the impact of exogenous Ang II and noradrenaline on the NA release and MMP-2, MMP-9 expression on Sprague Dawley (SD) rat aorta rings in vitro. Two kidneys, one clip, models were replicated for further check of that impact in SD rats in vivo.

Results

The concentration of Ang II, MMP-2, 9 was increased and NA concentration was decreased in aorta samples from AD patients. Exogenous Ang II enhanced while exogenous NA restrained NA release from aortic sympathetic endings. The Ang II stimulated NA release and the following MMP-2 up-regulation could be weakened by Losartan and chemical sympathectomy. Beta blocker did not influence NA release but down-regulated MMP-2. Long term in vivo experiments confirmed that Ang II could enhance NA release and up-regulate MMP-2.

Conclusions

AD is initiated by MMP-2 overexpression as a result of increased NA release from sympathetic nervous endings in response to Ang II. This indicates an interaction of RAS and SAS during the formation of AD.     

Aortic Unfolding Determined Using Non-Contrast Cardiac Computed Tomography: Correlations with Age and Coronary Artery Calcium Score

Objective

Aortic unfolding occurs with aging and reflects proximal aortic dilation, aortic arch widening, and decreased curvature. This study 1) evaluated the relationship between aortic unfolding measured using non-contrast cardiac-gated computed tomography (CT) and age, 2) assessed factors influencing aortic unfolding, and 3) determined the association of this measurement with coronary artery calcium (CAC) score.

Methods

We reviewed the charts of 219 subjects (142 men, 77 women; mean age 54.2±9.3 years) who underwent coronary artery calcium scanning during routine health screening from December 2010 to May 2011. Multivariate regression analysis according to cardiovascular risk factors was performed. We also analyzed the relationship between aortic unfolding measurements and CAC score using stepwise multiple linear regression.

Results

Mean aortic unfolding was 103.7±13.9 mm (men, 106.5±13.5 mm; women, 98.4±12.9 mm). Age, body surface area, and hypertension were exclusively associated with aortic unfolding. The association between aortic unfolding and CAC score was significant after adjustment for age and gender (β = 1.89, p = 0.017) and for Framingham risk score (β = 2.83, p<0.001).

Conclusions

Aortic unfolding defined by measuring aortic width was a reproducible and practical method with non-contrast cardiac CT and associated with age, body surface area, and hypertension. CAC score, a well-established surrogate marker of cardiovascular disease, is positively associated with aortic unfolding. Further study to evaluate aortic unfolding as a potential predictor of cardiovascular risk is warranted.     

The Role of Biological Agents in the Management of Large Vessel Vasculitis (LVV): A Systematic Review and Meta-Analysis

Background

Giant cell arteritis (GCA) and Takayasu''s arteritis (TAA) are large vessel vasculitides (LVV) for which corticosteroids (CS) are the mainstay for treatment. In patients with LVV unable to tolerate CS, biological agents have been used with variable effectiveness.

Objective

To systematically review the effectiveness and safety of biological agents in patients with LVV.

Methods

We searched 5 electronic databases (inception to October 2012) and conference abstracts with no language restrictions. Two reviewers independently selected studies, extracted data and assessed methodological quality. Our protocol was registered in PROSPERO.

Results

We included 25 studies (3 RCTs and 22 case series with ≥2 cases). 95 GCA and 98 TAA patients received biological agents. The RCTs using anti-TNF agents (infliximab, etanercept and adalimumab) did not suggest a benefit in GCA. GCA patients receiving tocilizumab, in case series, achieved remission (19 patients) and reduction of corticosteroid dose (mean difference, –16.55 mg/day (95% CI: –26.24, –6.86)). In case series, 75 patients with refractory TAA treated with infliximab discontinued CS 32% of the time. Remission was variably defined and the studies were clinically heterogeneous which precluded further analysis.

Conclusion

This systematic review demonstrated a weak evidence base on which to assess the effectiveness of biological treatment in LVV. Evidence from RCTs suggests that anti-TNF agents are not effective for remission or reduction of CS use. Tocilizumab and infliximab may be effective in the management of LVV and refractory TAA, respectively, although the evidence comes from case series. Future analytical studies are needed to confirm these findings.