Abstract 480: Aortic Microcalcification Associates With Aortic Elastin Fragmentation in Marfan Syndrome

Marfan syndrome (MFS) is a genetic connective tissue disorder, in which aortic rupture is the major cause of death. MFS patients with an aortic diameter below the advised limit for prophylactic surgery (<5cm) may unexpectedly experience an aortic dissection or rupture, despite yearly monitoring. Hence, there is a clear need for improved prognostic markers to predict such aortic events. We hypothesize that elastin fragments play a causal role in aortic calcification in MFS and that microcalcification serves as a novel marker for aortic disease severity. To address this hypothesis, we analyzed MFS patient and mouse aortas. MFS patient aortic tissue showed enhanced microcalcification in areas with extensive elastic lamina fragmentation in the media. A causal relationship between medial injury and microcalcification was revealed by studies in vascular smooth muscle cells (SMCs); elastin peptides were shown to increase the activity of the calcification marker alkaline phosphatase (ALP) and reduce the expression of the calcification inhibitor matrix gla protein (MGP) in human SMCs. In murine Fbn1 C1039G/+ MFS aortic SMCs, ALP mRNA and activity was upregulated when compared to wildtype SMCs. The elastin peptide-induced ALP activity was prevented by incubation with lactose as inhibitor of the elastin receptor complex, and a MEK1/2 kinase inhibitor, indicating downstream involvement of ERK1/2 phosphorylation. Histological analyses in MFS mice revealed macrocalcification in the aortic root, while the ascending aorta contained microcalcification, as identified with the near-infrared fluorescent bisphosphonate probe OsteoSense-800. Significantly, microcalcification correlated strongly with aortic diameter, aortic distensibility, elastin breaks and phosphorylated ERK1/2. In conclusion, microcalcification co-localizes with aortic elastin degradation in MFS aorta of man and mice, where elastin-derived peptides induce a calcification process in SMCs via the elastin receptor complex and ERK1/2 activation. We propose microcalcification as a novel imaging marker to monitor local elastin degradation and thus predict aortic events in MFS patients.

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Cardiovascular Lesions in Bovine Marfan Syndrome

Veterinary Pathology ◽

10.1177/030098589403100501 ◽

1994 ◽

Vol 31 (5) ◽

pp. 501-509 ◽

Cited By ~ 29

Author(s):

K. A. Potter ◽

T. E. Besser

Keyword(s):

Pulmonary Artery ◽

Cardiac Tamponade ◽

Marfan Syndrome ◽

Aortic Rupture ◽

Elastic Fibers ◽

Aortic Tissue ◽

Aortic Dilatation ◽

Cystic Medial Necrosis ◽

Aortic Media ◽

Elastic Laminae

Bovine Marfan syndrome is a genetic disease with many of the clinical and pathologic manifestations of human Marfan syndrome. Major manifestations include ectopia lentis and aortic dilatation, aneurysm, and rupture. Affected cattle have a defect in fibrillin metabolism similar to that in human patients. Ten cattle were followed and their disease progression and lesions documented. Ages ranged from a term fetus (No. 9) to a 4-year-old cow (No. 4); three animals were male (Nos. 1–3) and seven were female (Nos. 4–10). Of eight animals (80%) that died or were euthanatized (Nos. 1–3, 5–9), six (75%) had severe cardiovascular lesions identified at necropsy. Gross cardiovascular lesions of bovine Marfan syndrome included cardiac tamponade secondary to aortic rupture (animal Nos. 3, 6, 8), dissecting aneurysms of the aorta and pulmonary artery (animal No. 5), and intrauterine cardiac tamponade secondary to rupture of the pulmonary artery (animal No. 9). Microscopically, Verhoeff Van Gieson-stained sections of aorta contained severe fragmentation of the elastic laminae in the aortic media, but the cystic medial necrosis seen in human Marfan aortae was not identified, even in the chronic aortic dissection. Ultrastructurally, affected aortic tissue was characterized by thin, dark elastic fibers with abundant, tangled microfibrils on the periphery, Swirls of collagen fibers and bundles of hypertrophic smooth muscle cells replaced damaged elastic laminae. Gross and microscopic cardiovascular lesions in bovine Marfan syndrome are similar to those in human Marfan syndrome. Bovine Marfan syndrome is a valuable model for investigation of molecular pathogenesis and treatment of human Marfan syndrome.

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Abstract 103: Circulating sRAGE is Elevated in Patients with Marfan Syndrome and Decreases After Surgical Replacement of Diseased Aortic Segments

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.36.suppl_1.103 ◽

2016 ◽

Vol 36 (suppl_1) ◽

Author(s):

Eric K Lai ◽

Daniel J Wytowich ◽

Giovanni Ferrari ◽

Joseph E Bavaria ◽

Reed E Pyeritz ◽

...

Keyword(s):

Aortic Valve ◽

Marfan Syndrome ◽

Aortic Surgery ◽

Clinical Information ◽

Aortic Disease ◽

Aortic Diameter ◽

Aortic Tissue ◽

Post Surgery ◽

Fibrillin 1 ◽

One Year

Backgound: The Receptor for Advanced Glycation End products (RAGE) and its ligands are associated with vascular remodeling and trigger the release of a soluble receptor (sRAGE). We previously demonstrated that sRAGE levels are elevated in patients with bicuspid aortic valve and ascending aortic aneurysm. Circulating sRAGE in these patients correlates with the presence of a dysfunctional aortic structure but do not linearly correlate with an increase in the aortic diameter. Severe aortic disease occurs in more than 80% of Marfan Syndrome (MFS) patients. Aortic root and ascending aorta (AA) enlargement in MFS are associated with deficiency/destabilization of fibrillin-1, which leads to a generalized structural impairment of the aortic wall. We hypothesized that sRAGE may be elevated in the plasma of MFS patients and may decrease after surgical replacement of diseased aortic tissue. Methods: Plasma samples and clinical information (MFS=120, Control=37) were obtained from the GenTAC bioregistry and the Tissue Biobank at UPENN. Samples were collected either a few days prior to aortic surgery or at least one year post-surgery. sRAGE was tested using ELISA. Univariate and multivariate analysis were performed. Results: sRAGE levels are significantly higher in MFS patients compared to control (1404±64.35 vs 592±34.86 pg/ml, p<0.001) and are associated with the presence of MFS, independent of age, gender and comorbidities (p<0.001). sRAGE levels are significantly higher in MFS patients undergoing aortic surgery when compared to MFS patients monitored for aortic disease (1485±116.8 vs 1209±82.63 pg/ml, p=0.05). Circulating sRAGE is significantly lower in patients who have received aortic surgery (1185±63.31 pg/ml, p=0.02) and even lower in patients who received more extensive replacement (aortic valve/root and AA) versus those who underwent only aortic valve and root replacement (1313±81.83 vs 963.5±92.54 pg/ml, p=0.008). sRAGE levels do not linearly correlate with root and/or AA diameter. Conclusion: Plasma sRAGE levels are associated with the presence of ascending aortopathies independent of aortic diameter. Longitudinal studies evaluating sRAGE in MFS patients may unveil new markers for the diagnosis and risk stratification of this population.

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Expression levels of cathepsin L and cystatin C in a hyperglycemic environment were associated with aortic aneurysm development in a mouse model

Journal of International Medical Research ◽

10.1177/0300060519847880 ◽

2019 ◽

Vol 47 (6) ◽

pp. 2499-2506

Author(s):

Yang Liu ◽

Yang Jiao ◽

Yuxiang He ◽

Xiangjiu Ding ◽

Qingbo Su ◽

...

Keyword(s):

Mouse Model ◽

Cystatin C ◽

Cathepsin L ◽

Aortic Aneurysms ◽

Aortic Diameter ◽

Aortic Tissue ◽

Mrna Levels ◽

Expression Levels ◽

Elastin Degradation ◽

Elastic Stain

Objectives Diabetes mellitus (DM) attenuates the development of aortic aneurysms (AA). This study investigated the expression of cathepsin L and cystatin C in a hyperglycemic environment, and the influence of these proteins on AA development. Methods Mice were divided into AA and DM+AA groups ( n=30 per group). DM was induced by injection of streptozotocin; AA was induced by injection of angiotensin II. Doppler examination was used to measure aortic diameter, and Weigert’s elastic stain was used to detect elastin degradation. Cathepsin L and cystatin C in aortic tissue were examined by western blotting, immunohistochemistry, and polymerase chain reaction. Results Aortic diameter in the DM+AA group was less than that in the AA group, and elastin fragmentation grade of the aortic wall was reduced in the DM+AA group. More cathepsin L-positive cells were observed in the AA group than in the DM+AA group; conversely, more cystatin C-positive cells were observed in the DM+AA group than in the AA group. Both protein and mRNA levels of cathepsin L and cystatin C showed similar trends to those observed in immunohistochemistry. Conclusions Expression levels of cathepsin L and cystatin C in a hyperglycemic environment were associated with AA development in a mouse model.

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Aortic diameter predicts acute type A aortic dissection in patients with Marfan syndrome but not in patients without Marfan syndrome

Journal of Thoracic and Cardiovascular Surgery ◽

10.1016/j.jtcvs.2013.05.025 ◽

2014 ◽

Vol 147 (5) ◽

pp. 1505-1510 ◽

Cited By ~ 22

Author(s):

Eun Kyoung Kim ◽

Seung Hyuk Choi ◽

Kiick Sung ◽

Wook Sung Kim ◽

Yeon Hyeon Choe ◽

...

Keyword(s):

Aortic Dissection ◽

Marfan Syndrome ◽

Type A ◽

Aortic Diameter ◽

Acute Type ◽

Type A Aortic Dissection

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Serological level of transforming growth factor-β as a predictive biomarker of aortic enlargement in patients with Marfan syndrome

Pediatrician (St Petersburg) ◽

10.17816/ped8161-66 ◽

2017 ◽

Vol 8 (1) ◽

pp. 61-66

Author(s):

Andrey S Rudoy ◽

Alexey M Uryvaev

Keyword(s):

Risk Factors ◽

Growth Factor ◽

Marfan Syndrome ◽

Aortic Root ◽

Transforming Growth Factor ◽

Aortic Rupture ◽

Imaging Techniques ◽

Elevated Serum ◽

Transforming Growth Factor Β ◽

Absolute Size

Marfan syndrome - an inherited, autosomal dominant disease with an expected rate of 3-5/10 000 or fraction of 20-25% of new mutations, accompanied by violation of the connective tissue that occurs as a result of gene mutations FBN1, coding for the synthesis of fibrillin-1, performing the most important role in the modulation physiological bioavailability TGF-β (transforming growth factor-β). Prediction of aortic rupture is based on the identification of risk factors: family history, the absolute size of the aortic root, the rate of expansion of the aorta, which are based on the results of the history and techniques of imaging ultrasound, CT, MRI. At the same time there is a chance of developing aortic rupture under normal aortic root size and the absence of any risk factors, as well as after the prophylactic prosthetic aortic root. This makes it necessary to search for alternative prognostic markers, threatening bundle and rupture of the aorta. Article verified the predictive role of TGF-β as a serological biomarker for assessing the extension of the aortic root in patients with Marfan syndrome (n = 23, F : M / 7 : 16; 33 ± 9.3 years). The article describes the patterns between TGF-β and the size and the reconstruction of the aneurysm of the thoracic aorta. It was found that elevated levels of serum TGF-β1 (49.1 ng/ml Vs 29.15 ng/ml in the control, p < 0.05) in patients with MS diagnosed with an extension of the aortic root (Z > 1.96) can serve as a serological marker to poor prognosis, accompanied by an increase in the size of the aortic root. In patients with normal-sized aorta, and after aortic reconstruction serum TGFβ1 not elevated. Serum TGFβ may be a promising target for therapeutic, diagnostic and prognostic tactics which are not based on imaging techniques.

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Aortic rotational flow patterns and stiffness by 4D flow CMR in patients with Loeys-Dietz syndrome compared to healthy volunteers and patients with Marfan syndrome

European Heart Journal - Cardiovascular Imaging ◽

10.1093/ehjci/jeab090.078 ◽

2021 ◽

Vol 22 (Supplement_2) ◽

Author(s):

A Ruiz Munoz ◽

A Guala ◽

JF Rodriguez-Palomares ◽

L Dux-Santoy ◽

L Servato ◽

...

Keyword(s):

Healthy Volunteers ◽

Marfan Syndrome ◽

Aortic Stiffness ◽

Aortic Flow ◽

Aortic Diameter ◽

Rotational Flow ◽

4D Flow ◽

National Budget ◽

4D Flow Cmr ◽

Public Grant

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): La Marató de TV3, Instituto de Salud Carlos III through the project and Spanish Ministry of Science, Innovation and Universities. BACKGROUND Loeys-Dietz (LDS) and Marfan (MFS) syndromes are rare genetic connective tissue disorders associated with progressive aortic dilation, however, aortic dissections have been observed at lower aortic root diameters in LDS than in MFS. Recent CMR studies in MFS patients reported increased aortic stiffness (1–3) and altered rotational flow (4), but research on aortic flow dynamics and biomechanics in LDS is lacking. PURPOSE The aim of this study was to assess rotational aortic flow and aortic stiffness in LDS compared to healthy volunteers (HV) and MFS patients, using 4Dflow CMR. METHODS Twenty-one LDS and 44 MFS patients, without previous aortic dissection or surgery, and 43 HV underwent a non-contrast-enhanced 4D flow CMR. Aortic stiffness was quantified at the AAo and DAo using pulse wave velocity (PWV). In-plane rotational flow (IRF), systolic flow reversal ratio (SFRR) (5) and local aortic diameters were obtained at 20 equidistant planes from the ascending (AAo) to the proximal descending aorta (DAo). RESULTS LDS patients had lower IRF at the distal AAo and proximal DAo compared to HV (p = 0.053 and 0.004, respectively), once adjusted for age, stroke volume and local aortic diameter; but no differences were found with respect to MFS (Figure). Although SFRR at the proximal DAo was increased in LDS patients compared to both HV (p = 0.037) and MFS populations (p = 0.015), once adjusted for age and aortic diameter, the difference in magnitude was small (Figure). On the other hand, AAo and DAo PWV revealed stiffer aortas in LDS patients compared to HV but no differences versus MFS patients (Table). CONCLUSIONS Patients with Loeys-Dietz syndrome showed decreased in-plane rotational flow and abnormally-high regional aortic stiffness compared to healthy controls, and similar hemodynamics and aortic stiffness with respect to patients with Marfan syndrome.

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Abstract 15530: Single-cell Analysis in Aortic Aneurysmal Tissue From Patients With Marfan Syndrome Reveals Increased Tgf-beta Production but Downregulation of Downstream Canonical Tgf-beta Signaling Pathways

Circulation ◽

10.1161/circ.142.suppl_3.15530 ◽

2020 ◽

Vol 142 (Suppl_3) ◽

Author(s):

Ashley Dawson ◽

Yanming Li ◽

Pingping Ren ◽

Hernan Vasquez ◽

Chen Zhang ◽

...

Keyword(s):

Aortic Aneurysm ◽

Single Cell ◽

Marfan Syndrome ◽

Immune Cells ◽

Single Cell Analysis ◽

Aortic Aneurysms ◽

Differentially Expressed ◽

Aortic Tissue ◽

Cardiac Transplant ◽

Tgf Beta

Background: Marfan syndrome (MFS) is caused by mutations in the gene for fibrillin-1 ( FBN1 ); however, the mechanisms by which these mutations cause aortic aneurysms are poorly understood. Although it was hypothesized previously that dysregulation of the complex TGF-β signaling pathway leads to aortic aneurysm formation, FBN1 mutations appear to have a paradoxical effect on TGF-β signaling in MFS. In this study, we evaluated cell-specific TGF-β expression in non-immune cells in MFS aortic tissue. Methods: We performed single-cell RNA sequencing of ascending aortic aneurysm tissues from MFS patients (n=3) undergoing aneurysm repair and age-matched, non-aneurysmal control tissue from cardiac transplant donors and recipients (n=4). Non-immune cells were separated out from the data and analyzed using the Seurat package in R. Differentially expressed genes were identified using edgeR. Results: Conserved gene expression was used to identify populations of smooth muscle cells (SMCs; n=6), fibroblasts (n=3), and endothelial cells (ECs; n=3). We found that TGFB1 was significantly upregulated in quiescent fibroblasts (identified by increased expression of DCN , LUM , and complement factors) with log2FC of 1.30 and FDR 8.25x10 -8 , as well as in activated fibroblasts (identified by increased expression of genes involved in blood vessel repair and healing including ACTA2 , NOTCH3 , THBS2 , and PDGFRB ) with log2FC of 1.25 and FDR 6.15x10 -22 . Despite this increase in TGFB1 , expression of TGF-β receptor genes (predominately TGFBR2 ) as well as downstream SMAD genes was downregulated significantly in the SMC, fibroblast, and endothelial cell clusters. Finally, genes involved in the non-canonical TGF-β pathway, including ERK , JNK, and p38, were not differentially expressed in non-immune cells in MFS compared with control tissues. Conclusion: Increased expression of TGFB1 in non-immune cells in MFS was driven by two clusters of fibroblasts. Despite this, our data do not support associated upregulation of other genes in the canonical or non-canonical TGF-β pathways and in fact support downregulation of canonical TGF-β signaling in non-immune cells of aneurysmal tissues from MFS patients with advanced aortic disease.

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Abstract 12701: Combined Allometric Normalization of Ascending Aortic Diameter and Assessment of Complication Risk May Support an Earlier Prophylactic Replacement Preventive of Type a Dissection

Circulation ◽

10.1161/circ.142.suppl_3.12701 ◽

2020 ◽

Vol 142 (Suppl_3) ◽

Author(s):

Francisco Nistal ◽

Carlos Juarez ◽

Juan Miguel Redondo ◽

arturo evangelista ◽

Keyword(s):

Type A ◽

Ascending Aorta ◽

Aortic Diameter ◽

Prophylactic Surgery ◽

Risk Indicator ◽

Z Score ◽

Aortic Dilation ◽

Complication Risk ◽

Aortic Replacement ◽

Increased Risk

Introduction: Guideline recommendations of prophylactic surgery in ascending aortic dilation by maximum aortic diameter (MAD) fail to predict > 50% of type-A dissections (AD). Assessment of post-dissection diameters as reference and lack of somatometric normalization may preclude an appropriate risk estimation. Hypothesis: The combined assessment of Z-score and Svensson-index (cross-area/height) based on pre-dissection aortic diameters may be advantageous to indicate prophylactic ascending aortic replacement. Such an approach would include information on normalized vascular dilatation together with a clinical aortic risk indicator. Methods: During two years (2018-2019), data from 515 AD-patients were prospectively recorded at 32 tertiary Spanish hospitals (Registro Español Síndrome Aórtico-III). Pre-dissection aortic diameters were estimated based on the in vitro observations made by Williams et al. on the perimeter change of normal human aortas after the creation of a dissection (PMID: 9122399). Svensson indexes were correlated with ascending aorta Z-scores using quadratic regression. Results (Figure): Setting thresholds of increased risk at Svensson-index >10 cm 2 /m and aortic dilation at Z-score >3, 59% of patients had low Svensson and low Z-score category, 19% low Svensson but high Z-score and 22% high Svensson and high Z-score. No patient with Svensson-index <10 cm 2 /m and Z-score either < or > 3 had an indication for surgery according to guidelines. Among patients with Svensson-index >10 cm 2 /m and aortic dilation at Z-score >3, approximately 1/3 (32%) would have a surgical indication whereas 2/3 (68%) would not. Conclusions: According to current guidelines, only one third of high Svensson and high Z group (7% of the total cohort) would deserve elective surgery. More proactive guidelines, suggesting replacement of ascending aorta in patients with Svensson-index >10 and Z-score>3, would spare from dissection 22% of current cases.

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