Dilatation Of Thoracic Aorta Research Articles

Medical Therapies for Marfan Syndrome and Other Thoracic Aortic Dilatation in Adults: A Contemporary Review.

Thoracic aortic dilatation often has an asymptomatic course but may present with lethal complications such as aortic rupture or dissection, particularly when the thoracic aorta is aneurysmally enlarged; therefore, appropriate diagnosis, surveillance, and management are vital. Recommendations regarding imaging and surgical management are outlined in contemporary clinical practice guidelines. Dedicated guidelines regarding medical therapies for the management of thoracic aortic dilatation are lacking. Most of the medical treatment strategies, especially recommendations regarding pharmacological medical therapies related to β-blockade and angiotensin receptor blockers, are derived from data on patients with Marfan syndrome. The main aims of medical therapies for the management of thoracic aortic dilatation are (1) to control the progression of the disease, and (2) to prevent complications related to the disease (such as aortic dissection and mortality). This paper reviews the contemporary evidence and highlights the gaps in evidence to be investigated in further studies.

Aortic enlargement in chronic obstructive pulmonary disease (COPD) and emphysema: The Multi-Ethnic Study of Atherosclerosis (MESA) COPD study

BackgroundThe prevalence of abdominal aortic aneurysm is high in chronic obstructive pulmonary disease (COPD) population. Emphysema involves proteolytic destruction of elastic fibers. Therefore, emphysema may also contribute to thoracic aorta dilatation. This study assessed aorta dilation in smokers stratified by presence of COPD, emphysema and airway thickening. MethodsAorta diameters were measured on 3D magnetic resonance angiography in smokers recruited from the Multi-Ethnic Study of Atherosclerosis (MESA), the Emphysema and Cancer Action Project (EMCAP), and the local community. COPD was defined by standard spirometric criteria; emphysema was measured quantitatively on computed tomography and bronchitis was determined from medical history. ResultsParticipants (n = 315, age 58–79) included 150 with COPD and 165 without COPD, of whom 56% and 19%, respectively, had emphysema. Subjects in the most severe quartile of emphysematous change showed the largest diameter at all four aorta locations compared to those in the least severe quartiles (all p < 0.001). Comparing subjects with and without COPD, aorta diameters were larger in participants with severe COPD in ascending and arch (both p < 0.001), and abdominal aorta (p = 0.001). Chronic bronchitis and bronchial wall thickness did not correlate with aorta diameter. In subjects with emphysema, subjects with coexistence of COPD showed larger aorta than those without COPD in ascending (p = 0.003), arch (p = 0.002), and abdominal aorta (p = 0.04). ConclusionsThis study showed larger aorta diameter in subjects with COPD and severe emphysema compared to COPD related to chronic bronchitis or bronchial wall thickening.

Measurement accuracy of prototype non-contrast, compressed sensing-based, respiratory motion-resolved whole heart cardiovascular magnetic resonance angiography for the assessment of thoracic aortic dilatation: comparison with computed tomography angiography

BackgroundPatients with thoracic aortic dilatation who undergo annual computed tomography angiography (CTA) are subject to repeated radiation and contrast exposure. The purpose of this study was to evaluate the feasibility of a non-contrast, respiratory motion-resolved whole-heart cardiovascular magnetic resonance angiography (CMRA) technique against reference standard CTA, for the quantitative assessment of cardiovascular anatomy and monitoring of disease progression in patients with thoracic aortic dilatation. MethodsTwenty-four patients (68.6 ± 9.8 years) with thoracic aortic dilatation prospectively underwent clinical CTA and research 1.5T CMRA between July 2017 and November 2018. Scans were repeated in 15 patients 1 year later. A prototype free-breathing 3D radial balanced steady-state free-precession whole-heart CMRA sequence was used in combination with compressed sensing-based reconstruction. Area, circumference, and diameter measurements were obtained at seven aortic levels by two experienced and two inexperienced readers. In addition, area and diameter measurements of the cardiac chambers, pulmonary arteries and pulmonary veins were also obtained. Agreement between the two modalities was assessed with intraclass correlation coefficient (ICC) analysis, Bland–Altman plots and scatter plots.ResultsArea, circumference and diameter measurements on a per-level analysis showed good or excellent agreement between CTA and CMRA (ICCs > 0.84). Means of differences on Bland–Altman plots were: area 0.0 cm2 [− 1.7; 1.6]; circumference 1.0 mm [− 10.0; 12.0], and diameter 0.6 mm [− 2.6; 3.6]. Area and diameter measurements of the left cardiac chambers showed good agreement (ICCs > 0.80), while moderate to good agreement was observed for the right chambers (all ICCs > 0.56). Similar good to excellent inter-modality agreement was shown for the pulmonary arteries and veins (ICC range 0.79–0.93), with the exception of the left lower pulmonary vein (ICC < 0.51). Inter-reader assessment demonstrated mostly good or excellent agreement for both CTA and CMRA measurements on a per-level analysis (ICCs > 0.64). Difference in maximum aortic diameter measurements at baseline vs follow up showed excellent agreement between CMRA and CTA (ICC = 0.91).ConclusionsThe radial whole-heart CMRA technique combined with respiratory motion-resolved reconstruction provides comparable anatomical measurements of the thoracic aorta and cardiac structures as the reference standard CTA. It could potentially be used to diagnose and monitor patients with thoracic aortic dilatation without exposing them to radiation or contrast media.

Self-navigated 3D whole-heart MRA for non-enhanced surveillance of thoracic aortic dilation: a comparison to CTA

Abstract Funding Acknowledgements Type of funding sources: None. Background The natural history of thoracic aortic aneurysm (TAA) is one of progressive expansion. Asymptomatic patients who do not meet criteria for repair require conservative management including ongoing aneurysm surveillance, mostly carried out by contrast-enhanced computed tomography angiography (CTA). Purpose To prospectively compare image quality and reliability of a prototype non-contrast, self-navigated 3D whole-heart magnetic resonance angiography (MRA) with contrast-enhanced computed tomography angiography (CTA) for sizing of thoracic aortic aneurysm (TAA). Methods Self-navigated 3D whole-heart 1.5 T MRA was performed in 20 patients (aged 67 ± 8.6 years, 75% male) for sizing of TAA; a subgroup of 18 (90%) patients underwent additional contrast-enhanced CTA on the same day. Subjective image quality was scored according to a 4-point Likert scale and ratings between observers were compared by Cohen’s Kappa statistics. Continuous MRA and CTA measurements were analyzed with regression and Bland-Altman analysis. Results Overall subjective image quality as rated by two observers was 1 [interquartile range (IQR) 1-2] for self-navigated MRA and 1.5 [IQR 1-2] for CTA (p = 0.717). For MRA a perfect inter-observer agreement was found for presence of artefacts and subjective image sharpness (κ=1). Subjective signal inhomogeneity correlated highly with objectively quantified inhomogeneity of the blood pool signal (r = 0.78-0.824, all p &amp;lt;0.0001). Maximum diameters of TAA as measured by self-navigated MRA and CTA showed excellent correlation (r = 0.997, p &amp;lt; 0.0001) without significant inter-method bias (bias -0.0278, lower and upper limit of agreement -0.74 and 0.68, p = 0.749). Inter- and intraobserver correlation of aortic aneurysm as measured by MRA was excellent (r = 0.963 and 0.967, respectively) without significant bias (all p ≤ 0.05). Conclusion Self-navigated 3D whole-heart MRA enables reliable contrast- and radiation free aortic dilation surveillance without significant difference to standardized CTA while providing predictable acquisition time and by offering excellent image quality. Abstract Figure.

Two-Dimensional Aortic Size Normalcy: A Novelty Detection Approach.

Background: To develop a tool for assessing normalcy of the thoracic aorta (TA) by echocardiography, based on either a linear regression model (Z-score), or a machine learning technique, namely one-class support vector machine (OC-SVM) (Q-score). Methods: TA diameters were measured in 1112 prospectively enrolled healthy subjects, aging 5 to 89 years. Considering sex, age and body surface area we developed two calculators based on the traditional Z-score and the novel Q-score. The calculators were compared in 198 adults with TA > 40 mm, and in 466 patients affected by either Marfan syndrome or bicuspid aortic valve (BAV). Results: Q-score attained a better Area Under the Curve (0.989; 95% CI 0.984–0.993, sensitivity = 97.5%, specificity = 95.4%) than Z-score (0.955; 95% CI 0.942–0.967, sensitivity = 81.3%, specificity = 93.3%; p < 0.0001) in patients with TA > 40 mm. The prevalence of TA dilatation in Marfan and BAV patients was higher as Z-score > 2 than as Q-score < 4% (73.4% vs. 50.09%, p < 0.00001). Conclusions: Q-score is a novel tool for assessing TA normalcy based on a model requiring less assumptions about the distribution of the relevant variables. Notably, diameters do not need to depend linearly on anthropometric measurements. Additionally, Q-score can capture the joint distribution of these variables with all four diameters simultaneously, thus accounting for the overall aortic shape. This approach results in a lower rate of predicted TA abnormalcy in patients at risk of TA aneurysm. Further prognostic studies will be necessary for assessing the relative effectiveness of Q-score versus Z-score.

Self-navigated 3D whole-heart MRA for non-enhanced surveillance of thoracic aortic dilation: A comparison to CTA

PurposeTo prospectively compare image quality and reliability of a non-contrast, self-navigated 3D whole-heart magnetic resonance angiography (MRA) sequence with contrast-enhanced computed tomography angiography (CTA) for sizing of thoracic aortic aneurysm (TAA). MethodsSelf-navigated 3D whole-heart 1.5 T MRA was performed in 20 patients (aged 67 ± 9 years, 75% male) for sizing of TAA; a subgroup of 18 (90%) patients underwent additional contrast-enhanced CTA on the same day. Subjective image quality was scored according to a 4-point Likert scale and ratings between observers were compared by Cohen's Kappa statistics. For MRA, subjective motion blurring and signal inhomogeneity was rated according to a 3-point scale, respectively. Objective signal inhomogeneity of MRA was quantified as standard deviation of the voxel intensities in a circular region of interest (ROI) placed in the ascending aorta divided by their mean value. Continuous MRA and CTA measurements were analyzed with regression and Bland-Altman analysis. ResultsOverall subjective image quality as rated by two observers was 1 [interquartile range (IQR) 1–2] for self-navigated MRA and 1.5 [IQR 1–2] for CTA (p = 0.717). For MRA, perfect inter-observer agreement was found regarding presence of artefacts and subjective image sharpness (κ = 1). Subjective signal inhomogeneity agreed moderately between the observers (κ = 0.58, p = 0.007), however, it correlated strongly with objectively quantified inhomogeneity of the blood pool signal (r = 0.78, p < 0.0001). Maximum diameters of TAA as measured by self-navigated MRA and CTA showed very strong correlation (r = 0.99, p < 0.0001) without significant inter-method bias (bias −0.03 mm, lower and upper limit of agreement −0.74 and 0.68 mm, p = 0.749). Inter-observer correlation of aortic aneurysm as measured by MRA was very strong (r = 0.96) without significant bias (p = 0.695). ConclusionSelf-navigated 3D whole-heart MRA enables reliable contrast- and radiation free aortic dilation surveillance without significant difference to standardized CTA while providing predictable acquisition time and offering excellent image quality.

Incidental Thoracic Aortic Dilation on Chest Computed Tomography in Patients With Atrial Fibrillation

Patients with atrial fibrillation (AF) have risk factors that predispose to thoracic aneurysmal disease (TAD) and atherosclerosis. In this study in patients with AF, we assessed the occurrence of incidental TAD and assessed if a validated predictive score used to predict AF, the CHARGE-AF score, was associated with greater aortic dimensions. We also assessed the prevalence of coronary calcification. We conducted a cross-sectional study of 1,000 consecutive patients with AF undergoing chest multidetector CT during evaluation for pulmonary vein isolation. A dilated aortic root or ascending aorta (AA, dimension/ body surface area >2.05 cm/m2) were found in 195 (20%). A total of 12 (1%) had significant aortic aneurysmal enlargement of > 5.0 cm. Advancing age, a bicuspid aortic valve, hypertension, and male gender were associated with increased aortic dimensions. Aortic root dimensions increased linearly (p < 0.001) and ascending aortic dimensions increased nonlinearly across CHARGE-AF deciles (p < 0.001). Nearly two-thirds (63%) had coronary calcification, 38% of whom were not on lipid-lowering therapy. In conclusion, in patients with AF undergoing gated chest CT, 1 in 5 had previously undetected TAD, with a small proportion having significantly aneurysmal dimensions approaching surgical thresholds. Risk factors previously established to increase the propensity to develop AF are also associated with increased TAD. These findings raise the need to consider a surveillance strategy for TAD in patients with AF, particularly in those with other risk factors for aortic disease. A high prevalence of coronary calcium was also detected, representing an opportunity to optimize statin therapy in patients with AF.

Thoracic Aortic Dilation after Endovascular Repair of Blunt Traumatic Aortic Injury

Thoracic endovascular aneurysm repair (TEVAR) has become the current standard of care for emergent treatment of traumatic blunt thoracic aortic injuries (BTAI). Although aortic dilation (AD) of the infrarenal neck after EVAR for aortic aneurysms has been studied, changes in aortic diameter after TEVAR for BTAI is not well understood. This study aims to characterize changes in thoracic aortic diameter after stent-graft placement in the setting of nonaneurysmal traumatic aortic injury. A single-center, retrospective review was performed involving patients presenting with BTAI treated with TEVAR. Only patients with at least 12months follow-up were included. Aortic diameter, defined as the outer-to-outer diameter on 3D center-line imaging, was measured at six locations along the proximal and mid thoracic aorta. The first postoperative CT (≤1month) served as a baseline from which interval measurements were compared. Twenty patients with BTAI treated from 2011 to 2017 had adequate imaging available for review and were included in this study cohort. Median follow-up time was 46.8 (12-80, range) months. At the latest follow-up, AD occurred at all measured locations within the endograft, starting from the proximal graft edge (0.62±0.69mm, P=0.027) to the distal graft edge (1.21±1.28mm, P=0.003). AD was most pronounced in the distal graft segment 2cm proximal to the distal graft edge, with a mean AD of 1.32±1.59mm (+5.3%, P<0.001). At this location, AD was found to increase in a linear manner with an estimated rate of 0.67±0.20mm/year (P=0.006). The native aorta proximal and distal to the endograft was not found to significantly dilate during follow-up (P=0.280-0.897). Seventy percent of the patients were found to have AD >5%. The amount of AD was not found to be associated with either graft oversizing (P=0.151) or age (P=0.340). There were no cases of graft migration, erosion, or endoleak. AD is a common benign finding after TEVAR for BTAI. AD is most pronounced at the near the distal end of the stent graft. In late-term follow-up, there are no known associated complications related to AD.

Education Level Predicts Appropriate Follow-Up of Incidental Findings From Lung Cancer Screening.

The aim of this study was to identify predictors of appropriate follow-up for clinically significant incidental findings (IFs) detected with low-dose CT during lung cancer screening. Charts of 1,458 prospectively enrolled lung screening patients from January 1, 2015, to October 31, 2018, were reviewed. IFs, other than coronary artery calcification and emphysema, were identified. ACR practice guidelines defined appropriate patient follow-up. Patient demographic and social characteristics were obtained from the initial shared decision-making visit and the electronic medical record. Factors of interest included age, gender, race, education level, and insurance status. Education level was reported as high school graduate or less or education past high school. A multivariate logistic regression was estimated to assess patient factors associated with appropriate follow-up. One hundred thirty-eight participants (9%) with 141 actionable IFs were identified. The overall appropriate follow-up rate was 82%. The most common IFs were renal lesions (16%), dilated thoracic aorta (10%), and pulmonary fibrosis (10%). Univariate analysis of appropriate patient follow-up revealed a significant difference for education level (P= .02). A greater than high school education remained strongly associated with appropriate follow-up after controlling for other demographic factors. Appropriate patient follow-up of clinically significant IFs from lung cancer screening is a well-recognized avenue to improve population health. Education level is a significant independent predictor of appropriate follow-up of IFs, whether as a surrogate for low socioeconomic status or as an indication of health literacy. To address these realities, lung screening shared decision making should adapt to consider health care access and health literacy.

Doxorubicin Induces Endotheliotoxicity and Mitochondrial Dysfunction via ROS/eNOS/NO Pathway.

Background: Doxorubicin (Dox) can induce endotheliotoxicity and damage the vascular endothelium (VE). The most principle mechanism might be excess reactive oxygen species (ROS) generation. Nevertheless, the characteristics of ROS generation, downstream mechanisms, and target organelles in Dox-induced endotheliotoxicity have yet to be elucidated. Methods and Results: In order to explore the related problems, the VE injury models were established in mice and human umbilical vein endothelial cells (HUVECs) by Dox-induced endotheliotoxicity. Results showed that the activities of lactate dehydrogenase (LDH) and creatine kinase of mice’s serum increased after injected Dox. The thoracic aortic strips’ endothelium-dependent dilation was significantly impaired, seen noticeable inflammatory changes, and brown TUNEL-positive staining in microscopy. After Dox-treated, HUVECs viability lowered, LDH and caspase-3 activities, and apoptotic cells increased. Both intracellular/mitochondrial ROS generation significantly increased, and intracellular ROS generation lagged behind mitochondria. HUVECs treated with Dox plus ciclosporin A (CsA) could basically terminate ROS burst, but plus edaravone (Eda) could only delay or inhibit, but could not completely cancel ROS burst. Meanwhile, the expression of endothelial nitric oxide synthase (eNOS) decreased, especially phosphorylation of eNOS significantly. Then nitric oxide content decreased, the mitochondrial function was impaired, mitochondrial membrane potential (MMP) impeded, mitochondrial swelled, mitochondrial permeability transition pore (mPTP) was opened, and cytochrome C was released from mitochondria into the cytosol. Conclusion: Dox produces excess ROS in the mitochondria, thereby weakens the MMP, opens mPTP, activates the ROS-induced ROS release mechanism, induces ROS burst, and leads to mitochondrial dysfunction, which in turn damages VE. Therefore, interrupting any step of the cycles, as mentioned above can end the related vicious cycle and prevent the occurrence and development of injury.

Comparison of Risk Factor Profiles of Ascending and Descending Aortic dilatations. A Substudy from the Population-Based Randomized Dancavas Trial

Introduction - Aneurysms of the ascending aorta (AAo) develop due to cystic media degeneration of the arterial wall, whereas aneurysms of the descending aorta (DAo) often are associated with arteriosclerosis. (1) This could indicate different etiology and risk factors. In spite of this discrepancy, guidelines recommend screening of the whole aorta if one dilatation is discovered. (2) The objectives of this study were to compare risk factor profiles of ascending and descending aortic dilatations and to estimate the proportions of aortic dilatations elsewhere in case of detection of a thoracic aortic dilatation.

6124Aorta and sports. the silent threat

Abstract Background Thoracic aorta is the less known component of the athlete's heart and current publications shown that may be larger in athletes. It is known that high static training and body collision sports could increase the risk of sudden death, especially in patients with aortic disease (AD). Large scale traditional screening detects underlying cardiovascular diseases which may cause sudden cardiac death (SCD), however AD might be subdiagnosed. OBJECTIVE To describe AD burden on preparticipation screening and to assess diagnostic precision of traditional screening for AD detection in trained athletes. Methods Different sports athletes were recruited to follow current European guidelines (clinical history and cardiac examination, including resting 12-lead ECG) for preparticipation screening program (PSP). Bidimensional transthoracic echocardiography (TTE) was performed in all patients to detect AD: bicuspid aortic valve (BAV), thoracic aorta dilatation by Z score (TAD) and BAV plus TAD (BAD). Athletes were excluded from competition following international criteria. Sensitivity (Sn) and specificity (Sp) were calculated with 95% Clopper-Pearson confidence intervals and results are expressed as percentajes. McNemar paired chi-square test for one sample of individuals was used to compare diagnostic precision (Sn, Sp) of PSP vs gold standard: complete assessment (for sport exclusion, SpE) or TTE (for AD or BAD detection). Significance was set at p&lt;0.05 Results Included population (n=1123) was 22.3±6.2 y-o and 222 (19.8%) female. Five athletes (0.44% of total) were excluded from competition due to different causes. AD was found on 11 athletes (0.98%) and 4 of them had BAD (0.36%), a high risk condition with poor prognosis. Three patients with BAD were competitive cyclists and close follow up was indicated. The remaining patient with BAD was a rugby player and was excluded from competition (one out of 5 excluded patients, 20%). Diagnostic precision of PSP was better for SpE than for AD or BAD diagnosis. PSP tended to have less Sn for AD [36.4 (10.9–69.2)] and BAD [25 (0.6–80.6)] detection, than for SpE [80 (28.4–99.5); p=NS]. PSP had significant less Sp for AD [91.1 (89.3–92.7)] and BAD [90.9 (89–92.5)] diagnosis, than for SpE [97.2 (96.1–98.1); p&lt;0.05]. Conclusions AD is subdiagnosed by current PSP and its burden may be overlooked. Despite BAD is less frequent, its finding is determinant in a significant proportion of cases to decide exclusion from competitive (high static or body collision) sports. Although PSP has good sensitivity to detect potential pathologies of SCD, AD cannot be ruled out only by normal ECG and clinical examination. Diagnostic precision of PSP for AD and BAD detection could be enhanced by TTE screening, new studies with a larger number of athletes may answer the question.

P2788First argentine national registry of echocardiograpphic aortic dimensions: body surface area, age and ethnicity are determinants of aortic dimensions

Abstract Background Transthoracic echocardiography (TTE) remains the screening tool of choice for thoracic aorta (TA) dilatation. Differences in TA diameters (TAD) according to gender (G), age (A) and body surface area (BSA) have been previously reported. However, these reports are limited by a small sample size, different measurement sites or heterogeneous cohorts. There is scarce data on the influence of ethnicitiy on TAD. Moreover, surgery indication for TA aneurysms is still based mainly on absolute TAD with no reference to G, A or BSA. Purpose We designed a prospective nationwide multicenter registry to determine the normal range of TAD at all TA segments in healthy adults of both G and their correlations with A, ethnicity and BSA. Methods Healthy adult individuals without cardiovascular risk factors, TA aneurysm, aortic valve disease, cardiac surgery or genetic aortopathies were recruited from 53 centers in Argentina. TTEs were acquired and measured following standard protocols based on EACVI/ASE Guidelines. TAD were measured at six levels: annulus, sinuses of Valsalva, sinotubular junction, tubular ascending aorta, aortic arch and proximal descending aorta. Annulus was measured at mid-systole (inner to inner edge method) and all other at end-diastole (leading to leading edge). Multiple linear regression models were conducted to obtain coefficients of determination (R2) and 95% prediction intervals. We defined upper normal limits (95th percentile) for 4 age categories, both G and analyzed differences according to ethnicity. Results The MATEAR registry included 905 healthy adult patients (mean age: 38.3±13 years, 508 women, BSA: 1.8±0.2 m2). 529 (58.4%) were caucasian and 332 (36.6%) native-american, representative of the ethnic composition of Argentine population. Pooled data showed a positive correlation between all TAD and A or BSA (p&lt;0.001), similar in both G. Women had smaller absolute TAD due to their lower BSA. Nomograms were obtained for 4 age categories to predict TAD from BSA with no need of G distinction. Native americans showed significatly lower absolute and indexed TAD than caucasian (p&lt;0.01) from annulus to isthmus. TAD differences according to ethnicity Conclusions While age and BSA were significant determinants of aortic dimensions at six levels, we have also detected differences in TAD according to ethnicity, suggesting normative values should also be defined for each ethnic group. We propose nomograms of indexed TAD for different age and ethnic groups without G distinction.

Scavenger receptor A1 attenuates aortic dissection via promoting efferocytosis in macrophages

Macrophage class A1 scavenger receptor (SR-A1) is a pattern recognition receptor with an anti-inflammatory feature in cardiovascular diseases. However, its role in acute aortic dissection (AD) is not known yet. Using an aortic dissection model in SR-A1-deficient mice and their wild type littermates, we found that SR-A1 deficiency aggravated beta-aminopropionitrile monofumarate induced thoracic aortic dilation, false lumen formation, extracellular matrix degradation, vascular inflammation and accumulation of apoptotic cells. These pathological changes were associated with an impaired macrophage efferocytosis mediated by tyrosine-protein kinase receptor Tyro3 in vitro and in vivo. SR-A1 could directly interact with Tyro3 and was required for Tyro3 phosphorylation to activate its downstream PI3K/Akt signaling pathway. Importantly, co-culture of SR-A1−/− macrophages with apoptotic Jurkat cells resulted in less devoured apoptotic cells accompanied by swelling mitochondria and damaged ATP generation, following poor IL-10 and robust TNF-α production. Deficiency of SR-A1 did not influence phagolysosome formation during the efferocytosis. Lentiviral overexpression of Tyro3 in SR-A1−/− macrophages induced restorative phagocytosis in vitro. Administration of Tyro3 agonist protein S could restore SR-A1−/− macrophages phagocytosis in vitro and in vivo. These findings suggest that SR-A1-Tyro3 axis in macrophages mitigate AD damage by promoting efferocytosis and inhibiting inflammation.

Clinical Significance of Electrocardiograph Abnormalities: Analysis on Electrocardiographs of 75 Marfan Cases Complicated with Aortic Disease

Purpose: Marfan syndrome (MFS) is one of the most common hereditary connective tissue disorders, with various adverse manifestations ranging from typical ocular, cardiovascular, and musculoskeletal abnormalities to manifestations involving the lungs, skin, and central nervous system. In patients with MFS, the most lethal manifestations are aortic lesion presenting as aortic insufficiency, thoracic and abdominal aortic dilatation, aneurysm, and dissection. Clinically, these patients often present with various types of arrhythmias and abnormal electrocardiographs (EKGs); however, there have been few studies of MFS-associated arrhythmias either in China or abroad. This investigation aims to elucidate the association between Marfan-associated aortic lesions and accompanying arrhythmia characteristics. Methods: From September 2016 to January 2018, 75 consecutive patients diagnosed with MFS and aortic disease manifestation were enrolled in the study (MFS group). During the same time period, 76 consecutive nonMFS patients with aortic disease were enrolled as positive controls (dissection group) and 100 consecutive healthy patients were enrolled during routine health checkups as negative controls (checkup group). EKG characteristics between the three groups were analyzed. Results: Compared to the checkup group, both the MFS group and dissection group showed more EKG abnormalities (P 0.05), the MFS group showed a significantly higher occurrence of sinus bradycardia and first-degree atrioventricular block (P

Prevalence of Incidentally Identified Thoracic Aortic Dilations: Insights for Screening Criteria

BackgroundSystematic screening for ascending thoracic aortic aneurysms and dilations does not exist currently with unknown prevalence and diagnostic yields. We evaluated the prevalence of ascending thoracic aortic dilation. MethodsComputed tomography scans including the chest in adult patients carried out during 2016 were reviewed at our institution. Aortic dilation was defined as the ascending thoracic aorta diameter ≥ 4.0 cm, with sensitivity analyses using height-indexed values and thresholds of 3.5, 4.25, and 4.5 cm. The prevalence of aortic dilation was evaluated by age and sex. Potential diagnostic yield along the continuum of age threshold was calculated by sex. ResultsOf the 5662 scans from unique patients, the prevalence of aortic dilation was 2.1% overall, 3.2% for males and 0.9% for females. Patients with aneurysms were significantly older (70.2 ± 9.9 vs 58.3 ± 16.4 years, P < 0.001) and more likely to be male (81.0% vs 54.2%, P < 0.001). The highest diagnostic yield of aneurysm ≥ 4.5 cm in females occurred at the age threshold of ≥ 73 years, with the yield of 0.5%. The highest diagnostic yield of aneurysm ≥ 4.5 cm in males occurred at age ≥ 84 years, with the yield of 5.7%. In males, the diagnostic yields at age thresholds of ≥ 50, ≥ 60, and ≥ 70 years were 1.3%, 1.6%, and 2.2%, respectively. ConclusionsAortic dilation was identified in 2.8% of individuals with age ≥ 50 years. In females, aneurysm was uncommon. In males, there was an incremental increase in the diagnostic yield with age. Male patients with age ≥ 50 years may be the demographic group with a high prevalence of dilation.

Is there a role for autophagy in ascending aortopathy associated with tricuspid or bicuspid aortic valve?

Autophagy is a conserved process by which cytoplasmatic elements are sequestered in vesicles and degraded after their fusion with lysosomes, thus recycling the precursor molecules. The autophagy-mediated removal of redundant/harmful/damaged organelles and biomolecules plays not only a replenishing function, but protects against stressful conditions through an adaptive mechanism. Autophagy, known to play a role in several pathological conditions, is now gaining increasing attention also in the perspective of the identification of the pathogenetic mechanisms at the basis of ascending thoracic aortic aneurysm (TAA), a localized or diffused dilatation of the aorta with an abnormal widening greater than 50 percent of the vessel's normal diameter. TAA is less frequent than abdominal aortic aneurysm (AAA), but is encountered with a higher percentage in patients with congenital heart disease or known genetic syndromes. Several biological aspects of TAA pathophysiology remain to be elucitated and therapeutic needs are still widely unmet. One of the most controversial and epidemiologically important forms of TAA is that associated with the congenital bicuspid malformation of the aortic valve (BAV). Dysregulated autophagy in response, for example, to wall shear stress alterations, has been demonstrated to affect the phenotype of vascular cells relevant to aortopathy, with potential consequences on signaling, remodeling, and angiogenesis. The most recent findings and hypotheses concerning the multiple aspects of autophagy and of its dysregulation are summarized, both in general and in the context of the different vascular cell types and of TAA progression, with particular reference to BAV-related aortopathy.

3204 Renin-Angiotensin System Inhibitors Do Not Improve Survival in Fibrillin-1 Hypomorphic Mice with Established Aortic Aneurysm

OBJECTIVES/SPECIFIC AIMS: Drugs to attenuate aortic growth are usually not initiated in patients with Marfan syndrome until aortic dilation is already present. Therefore, we measured the impact of drugs (the renin-angiotensin system inhibitors losartan and enalapril) on survival and thoracic aortic growth in a mouse model of Marfan syndrome when extensive aortic dilation was already present. METHODS/STUDY POPULATION: Male and female fibrillin-1 hypomorphic (FBN1 mgR/mgR) mice (n=10-12/group) were stratified into treatment groups by aortic diameter at 6 weeks of age to ensure an equivalent average aortic diameter in each group at the start of the study. Osmotic mini pumps filled with PBS (vehicle), enalapril (2 mg/kg/d), or losartan (20 mg/kg/d) were implanted subcutaneously into mice after stratification. Mini pumps infusing drug or vehicle were replaced every 4 weeks for a total duration of 12 weeks. Wild type littermates (n=10) were infused with PBS as a negative control to the Marfan mouse model. Ascending aortic diameters from male and female FBN1 mgR/mgR mice and their wild type littermates were assessed by ultrasound every 4 weeks from 6 to 18 weeks of age. Aortic diameters were measured luminal edge to luminal edge during diastole. RESULTS/ANTICIPATED RESULTS: 6 week old FBN1 mgR/mgR mice exhibited significantly dilated ascending thoracic aortas at study initiation compared to their wild type sex-matched littermates (in males: FBN1 mgR/mgR = 1.87 +/− 0.07mm, wild type = 1.23 +/− 0.07mm; p &lt;0.001) (in females: FBN1 mgR/mgR = 1.56 +/− 0.07mm, wild type = 1.18 +/− 0.07mm; p &lt;0.001). Baseline mortality of FBN1 mgR/mgR mice infused with PBS was 36% in male and 22% in female mice at the time of study termination. Within sex-matched mgR littermates, there was no significant difference in survival between groups treated with PBS, enalapril, or losartan after 12 weeks (p=0.224 for males, p=0.094 in females). In the same groups, no significant difference in maximum ascending aortic diameter was detected after treatment for 12 weeks (in males: PBS=2.69 +/− 0.19 mm, enalapril=2.04 +/− 0.27 mm, losartan=2.42 +/− 0.28 mm; p=0.24) (in females: PBS = 1.92 +/− 0.13, enalapril=1.89 +/− 0.31, losartan=1.98 +/− 0.17; p=0.86). Furthermore, aortic diameters in the FBN1 mgR/mgR mice were found to demonstrate sexual dimorphism. DISCUSSION/SIGNIFICANCE OF IMPACT: This research shows that losartan is not effective when administered after significant thoracic aortic dilation has already occurred in FBN1 mgR/mgR mice. This has important translational implications because losartan is usually not started in patients with Marfan syndrome until significant aortic dilation is already present. Therefore, more research needs to be done to determine the critical time period within which this medicine will be effective if given to patients. In addition, this research demonstrates that male FBN1mgR/mgR mice have a significantly larger aortic diameter than female FBN1mgR/mgR mice. This sexual dimorphism has recently been observed in patients with Marfan syndrome as well. Additional studies for understanding the mechanism underlying this sexual dimorphism have the potential to elucidate new therapeutic approaches for aortic disease.

Correction: 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 MO 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 MO recruitment and infiltration in HASMCs and aortic tissues of TAAD patients. We found that MO 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 MO recruitment, M1 type inflammatory response via activated TGF-β signaling, and further promoted vascular remodeling and pathological progress of TAAD.

Relationships Between Phenotype and Function of Blood CD4+ T-Cells and Ascending Thoracic Aortic Aneurysm: an Experimental Study.

IntroductionNon-familial ascending thoracic aorta dilation and aneurysms (TAAs) are silent diseases in elderly patients. Histopathology revealed that functionally polarized infiltrating CD4+ T-cells play a key role in aortic wall weakening.ObjectiveTo evaluate the possible associations between phenotype and cytokine production of circulating CD4+ T-lymphocytes and the presence of TAA in patients with aortic valve disease (AVD).MethodsWe studied blood samples from 10 patients with TAA and 10 patients with AVD. Flow cytometry was used to quantify: a) CD4+ T-lymphocytes surface expression of CD25, CD28, and chemokine receptors (CCR5, CXCR3, CX3CR1); b) fractions of in vitro stimulated CD4+ T-cells producing cytokines (interferon gamma [IFN-γ], interleukin [IL]-17A, IL-21, IL-10); c) CD4+CD25highFoxP3+ regulatory T-cells (Treg) fraction. Enzyme-linked immunosorbent assays (ELISA) were performed for cytokines (IFN-γ, IL-6, IL-10, IL-17A, IL-23, transforming growth factor beta [TGF-β]) and chemokines (RANTES, CX3CL1).ResultsThe total CD4+CD28±CD4+/CX3CR1+ T-cells fraction was higher (P=0.0323) in AVD (20.452±4.673) than in TAA patients (8.633±2.030). The frequency ratio of CD4+ T-lymphocytes producing IFN-γ vs. IL-17A+IL-21 cytokine-producing CD4+ T-cells was higher (P=0.0239) in AVD (2.102±0.272) than in TAA (1.365±0.123) patients. The sum of CD4+CD28±CD4+/CX3CR1+ T-cells correlated positively with values of the previous cytokine ratio (P=0.0002, R=0.732). The ratio of CD4+CD28±CD4+/CX3CR1+ T-cells vs. Treg was higher (P=0.0008) in AVD (20.859±3.393) than in TAA (6.367±1.277) patients.ConclusionOur results show that the presence of TAA in subjects with AVD is associated with imbalance between phenotypic and cytokine-producing subsets of circulating CD4+ T-lymphocytes, prevalently oriented towards a pro-fibrotic and IFN-γ counteracting effect to functional polarization.