scholarly journals Case Report: Occurrence of Severe Thoracic Aortic Aneurysms (Involving the Ascending, Arch, and Descending Segments) as a Result of Fibulin-4 Deficiency: A Rare Pathology With Successful Management

2021 ◽  
Vol 8 ◽  
Author(s):  
Paul Thomas ◽  
Aparna Venugopalan ◽  
Siddharth Narayanan ◽  
Thomas Mathew ◽  
Lakshmi Parvathi Deepti Cherukuwada ◽  
...  
Keyword(s):  
Matrix Protein ◽  
Genetic Disorder ◽  
Female Child ◽  
Aortic Aneurysms ◽  
Cutis Laxa ◽  
Extracellular Matrix Protein ◽  
Successful Outcome ◽  
High Morbidity ◽  
Aortic Diseases ◽  
Thoracic Aortic Aneurysms

Aortic diseases requiring surgery in childhood are distinctive and rare. Very few reports in the literature account for the occurrence of multiple thoracic aortic aneurysms in the same pediatric patient because of a genetic cause. We report a rare occurrence of severe thoracic aortic aneurysms (involving the ascending, arch and descending aortic segments) with severe aortic insufficiency in a 7-year-old female child secondary to the extremely rare and often lethal genetic disorder, cutis laxa. She was eventually identified as a carrier of a homozygous EFEMP2 (alias FBLN4) mutation. This gene encodes the extracellular matrix protein fibulin-4, and its mutation is associated with autosomal recessive cutis laxa type 1B that leads to severe aortopathy with aneurysm formation and vascular tortuosity. Parents of the child were not known to be consanguineous. Significant symptomatic improvement in the patient could be discerned after timely intervention with the valve-sparing aortic root replacement (David V procedure) and a concomitant aortic arch replacement. This is a unique report with a successful outcome that highlights the occurrence of a rare hereditary aortopathy associated with a high morbidity and mortality, and the importance of an early diagnosis and timely management. It also offers insight to physicians in having a very broad differential and multimodal approach in handling rare pediatric cardio-pathologies with a genetic predisposition.

scholarly journals Differences in genetic signaling, and not mechanical properties of the wall, are linked to ascending aortic aneurysms in fibulin-4 knockout mice

2015 ◽  
Vol 309 (1) ◽  
pp. H103-H113 ◽  
Author(s):  
Jungsil Kim ◽  
Jesse D. Procknow ◽  
Hiromi Yanagisawa ◽  
Jessica E. Wagenseil
Keyword(s):  
Gene Expression ◽  
Matrix Protein ◽  
Mechanical Response ◽  
Aortic Aneurysms ◽  
Extracellular Matrix Protein ◽  
Elastic Fibers ◽  
Newborn Mice ◽  
Thoracic Aortic Aneurysms ◽  
Neutrophil Collagenase

Fibulin-4 is an extracellular matrix protein that is essential for proper assembly of arterial elastic fibers. Mutations in fibulin-4 cause cutis laxa with thoracic aortic aneurysms (TAAs). Sixty percent of TAAs occur in the ascending aorta (AA). Newborn mice lacking fibulin-4 ( Fbln4−/−) have aneurysms in the AA, but narrowing in the descending aorta (DA), and are a unique model to investigate locational differences in aneurysm susceptibility. We measured mechanical behavior and gene expression of AA and DA segments in newborn Fbln4−/− and Fbln4+/+ mice. Fbln4−/− AA has increased diameters compared with Fbln4+/+ AA and Fbln4−/− DA at most applied pressures, confirming genotypic and locational specificity of the aneurysm phenotype. When diameter compliance and tangent modulus were calculated from the mechanical data, we found few significant differences between genotypes, suggesting that the mechanical response to incremental diameter changes is similar, despite the fragmented elastic fibers in Fbln4−/− aortas. Fbln4−/− aortas showed a trend toward increased circumferential stretch, which may be transmitted to smooth muscle cells (SMCs) in the wall. Gene expression data suggest activation of pathways for SMC proliferation and inflammation in Fbln4−/− aortas compared with Fbln4+/+. Additional genes in both pathways, as well as matrix metalloprotease-8 ( Mmp8), are upregulated specifically in Fbln4−/− AA compared with Fbln4+/+ AA and Fbln4−/− DA. Mmp8 is a neutrophil collagenase that targets type 1 collagen, and upregulation may be necessary to allow diameter expansion in Fbln4−/− AA. Our results provide molecular and mechanical targets for further investigation in aneurysm pathogenesis.

Thrombospondin-4 knockout in hypertension protects small-artery endothelial function but induces aortic aneurysms

2016 ◽  
Vol 310 (11) ◽  
pp. H1486-H1493 ◽  
Author(s):  
Teresa Palao ◽  
Catarina Rippe ◽  
Henk van Veen ◽  
Ed VanBavel ◽  
Karl Swärd ◽  
...  
Keyword(s):  
Calcium Binding ◽  
Matrix Protein ◽  
Pressure Overload ◽  
Aortic Aneurysms ◽  
Endoplasmic Reticulum Stress Response ◽  
Extracellular Matrix Protein ◽  
Ang Ii ◽  
Wild Type ◽  
Resistance Arteries ◽  
Thrombospondin 4

Thrombospondin-4 (TSP-4) is a multidomain calcium-binding protein that has both intracellular and extracellular functions. As an extracellular matrix protein, it is involved in remodeling processes. Previous work showed that, in the cardiovascular system, TSP-4 expression is induced in the heart in response to experimental pressure overload and infarction injury. Intracellularly, it mediates the endoplasmic reticulum stress response in the heart. In this study, we explored the role of TSP-4 in hypertension. For this purpose, wild-type and TSP-4 knockout ( Thbs4 −/−) mice were treated with angiotensin II (ANG II). Hearts from ANG II-treated Thbs4 −/− mice showed an exaggerated hypertrophic response. Interestingly, aortas from Thbs4 −/− mice treated with ANG II showed a high incidence of aneurysms. In resistance arteries, ANG II-treated wild-type mice showed impaired endothelial-dependent relaxation. This was not observed in ANG II-treated Thbs4 −/− mice or in untreated controls. No differences were found in the passive pressure-diameter curves or stress-strain relationships, although ANG II-treated Thbs4 −/− mice showed a tendency to be less stiff, associated with thicker diameters of the collagen fibers as revealed by electron microscopy. We conclude that TSP-4 plays a role in hypertension, affecting cardiac hypertrophy, aortic aneurysm formation, as well as endothelial-dependent relaxation in resistance arteries.

scholarly journals Giant Aortic Aneurysm in Child with Cutis Laxa Syndrome: Unusual Presentation, New Surgical Technique

2021 ◽  
Vol 24 (6) ◽  
pp. E1054-E1056
Author(s):  
Mazen Shamsaldeen Faden ◽  
Nada Ahmed Noaman ◽  
Osman Osama Osman Osama ◽  
Ahmed Abdelrahman Elassal ◽  
Arwa Mohammed Al-ghamdi ◽  
...  
Keyword(s):  
Final Diagnosis ◽  
Ascending Aorta ◽  
Accurate Diagnosis ◽  
Aortic Aneurysms ◽  
Cutis Laxa ◽  
Descending Aorta ◽  
Aorta Aneurysm ◽  
Thoracic Aortic Aneurysms ◽  
Valvular Insufficiency ◽  
New Surgical Technique

Ascending thoracic aortic aneurysms are rare in childhood and typically are seen in the setting of connective tissue defect syndromes. These aneurysms may lead to rupture, dissection, or valvular insufficiency, so root replacement is recommended. Here, we present a 17-month-old girl who presented with fever, cough, and pericardial effusion. Initially, we suspected this could be a COVID-19 case, so a nasopharyngeal swap was performed. An ascending aorta aneurysm involving the aortic arch was confirmed by echo, and urgent ascending aorta and arch replacement were done by utilizing the descending aorta as a new arch. The final diagnosis came with cutis laxa syndrome. In similar cases, good outcomes can be achieved with accurate diagnosis and appropriate surgical management.

Abstract 15539: Single-cell Analysis of Aortic Tissues From Patients With Marfan Syndrome Reveals Changes in Smooth Muscle Cell Differentiation

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Ashley Dawson ◽  
Yanming Li ◽  
Pingping Ren ◽  
Hernan Vasquez ◽  
Chen Zhang ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Single Cell ◽  
Marfan Syndrome ◽  
Immune Cells ◽  
Matrix Protein ◽  
Immune Cell ◽  
Aortic Aneurysms ◽  
Extracellular Matrix Protein ◽  
Cardiac Transplant ◽  
Control Tissue

Background: Thoracic aortic aneurysms associated with Marfan syndrome (MFS) carry a high risk of mortality; however, the molecular and cellular processes leading to aortopathy in this population remain poorly understood. We aimed to use single-cell RNA (scRNA) sequencing to define the non-immune cell populations present within the aortic wall in MFS, hypothesizing that these would differ from those of non-aneurysmal control tissue. Methods: We performed scRNA sequencing of ascending aortic aneurysm tissues from MFS patients (n=3) undergoing aneurysm repair and of age-matched, non-aneurysmal control tissue from cardiac transplant donors and recipients (n=4). The Seurat package in R was used for analysis. Differentially expressed genes were identified using edgeR. Results: Eighteen non-immune cell clusters were identified, with conserved gene expression of the largest of the clusters consistent with smooth muscle cells (SMCs; n=6), fibroblasts (n=3), and endothelial cells (n=3). The SMCs and fibroblasts exhibited graded changes in their expression of contractile and extracellular matrix protein genes, supportive of a phenotypic continuum. Additionally, we identified differences in the proportions of non-immune cells in MFS tissues compared to controls. In control tissues, the most common non-immune cells expressed markers of contractile SMC maturity including CNN1 , MYH11 , and SMTN . In contrast, the largest clusters in MFS tissue were most closely related to SMCs on correlation analysis, but displayed increased expression of cyclin genes as well as immune, endothelial, and fibroblast genes indicative of de-differentiated, proliferative SMCs. Additionally, expression of genes associated with SMC phenotypic maturity, including MYH11 and MYOCD , were significantly downregulated in several of the MFS SMC clusters. Conclusion: Our data demonstrate a phenotypic continuum between fibroblasts and SMCs, with aortas from patients with MFS exhibiting an increased proportion of de-differentiated, proliferative SMCs compared to controls. Additionally, markers of SMC maturity were downregulated in SMCs in MFS compared to controls. This may be due to disruption of signaling pathways that promote differentiation.

Aortic Aneurysm

2018 ◽  
Author(s):  
Christine E Lee ◽  
Leily Naraghi ◽  
Beatrice Hoffmann
Keyword(s):  
Aortic Aneurysm ◽  
Aortic Dissection ◽  
Intramural Hematoma ◽  
Aortic Disease ◽  
Magnetic Resonance Images ◽  
Aortic Aneurysms ◽  
High Morbidity ◽  
Aortic Diseases ◽  
Decision Algorithm ◽  
Type B Dissection

Aortic diseases are relatively rare but are associated with high morbidity and mortality. Emergency physicians (EPs) should consider aortic disease in all patients with pain in the torso, particularly those with other diverse or seemingly unconnected complaints. This review summarizes the pathophysiology, stabilization and assessment, diagnosis and treatment, and disposition and outcomes for patients with abdominal aortic aneurysms (AAAs), thoracic aortic aneurysms (TAAs), and aortic dissection. Figures show a transverse image of an AAAs with a transmural hematoma, a three-dimensional computed tomographic angiogram (CTA) rendering of a thoracic aneurysm associated with a bicuspid aortic valve in the typical ascending aortic location, a chest x-ray film demonstrating prominent and blurred aortic knob due to TAA, acute aortic dissection subtypes, an electrocardiogram and transesophageal echocardiography of a patient with acute ascending aortic dissection, magnetic resonance images of a patient with dissection of the proximal descending aorta, CT representations of a type A dissection involving a dilated ascending aorta and a type B dissection involving the descending thoracic aorta, and a decision algorithm for evaluation and treatment of a suspected aortic dissection. Tables list normal aortic dimensions by CTA and echocardiography, average annual rate of expansion and rupture of AAA based on current diameter, and the etiology of TAA. Key words: AAA, aorta, aortic dissection, ascending aortic dissection, descending aortic dissection, intimal tear, intramural hematoma, thoracic aortic aneurysm

Valve-Sparing Root and Total Arch Replacement for Cutis Laxa Aortopathy

2017 ◽  
Vol 10 (3) ◽  
pp. 376-379
Author(s):  
Anji T. Yetman ◽  
James Hammel ◽  
Jennifer N. Sanmann ◽  
Lois J. Starr
Keyword(s):  
Genetic Disorder ◽  
Snp Array ◽  
Aortic Aneurysms ◽  
Cutis Laxa ◽  
Cannulation Technique ◽  
Aorta Replacement ◽  
Valve Sparing ◽  
Regions Of Homozygosity ◽  
Ascending Aorta Replacement

Aortic aneurysms requiring surgery in early childhood are rare. Herein we describe the case of a three-year-old with massive aneurysmal aortic dilation secondary to the rare and often lethal genetic disorder, cutis laxa. Initial thoracic aortic aneurysm gene panel was negative. Parents of the child were not known to be consanguineous, but high-density SNP array revealed several regions of homozygosity. This prompted targeted sequence analysis that identified a novel homozygous missense mutation in the gene for cutis laxa, EFEMP2. The patient underwent aortic valve–sparing aortic root and ascending aorta replacement and total aortic arch replacement, with continuous, moderately hypothermic cardiopulmonary bypass, using a dual cannulation technique. He was discharged well on the third postoperative day and remains free of aneurysmal disease at two-year follow-up.

scholarly journals Tryptophan Catabolism and Inflammation: A Novel Therapeutic Target For Aortic Diseases

2021 ◽  
Vol 12 ◽  
Author(s):  
Tharmarajan Ramprasath ◽  
Young-Min Han ◽  
Donghong Zhang ◽  
Chang-Jiang Yu ◽  
Ming-Hui Zou
Keyword(s):  
Mammalian Cells ◽  
Inflammatory Process ◽  
Cell Types ◽  
Aortic Disease ◽  
Kynurenine Pathway ◽  
Aortic Aneurysms ◽  
Health Concern ◽  
High Morbidity ◽  
Aortic Diseases ◽  
And Migration

Aortic diseases are the primary public health concern. As asymptomatic diseases, abdominal aortic aneurysm (AAA) and atherosclerosis are associated with high morbidity and mortality. The inflammatory process constitutes an essential part of a pathogenic cascade of aortic diseases, including atherosclerosis and aortic aneurysms. Inflammation on various vascular beds, including endothelium, smooth muscle cell proliferation and migration, and inflammatory cell infiltration (monocytes, macrophages, neutrophils, etc.), play critical roles in the initiation and progression of aortic diseases. The tryptophan (Trp) metabolism or kynurenine pathway (KP) is the primary way of degrading Trp in most mammalian cells, disturbed by cytokines under various stress. KP generates several bioactive catabolites, such as kynurenine (Kyn), kynurenic acid (KA), 3-hydroxykynurenine (3-HK), etc. Depends on the cell types, these metabolites can elicit both hyper- and anti-inflammatory effects. Accumulating evidence obtained from various animal disease models indicates that KP contributes to the inflammatory process during the development of vascular disease, notably atherosclerosis and aneurysm development. This review outlines current insights into how perturbed Trp metabolism instigates aortic inflammation and aortic disease phenotypes. We also briefly highlight how targeting Trp metabolic pathways should be considered for treating aortic diseases.

Aortic Aneurysm

2018 ◽  
Author(s):  
Christine E Lee ◽  
Leily Naraghi ◽  
Beatrice Hoffmann
Keyword(s):  
Aortic Aneurysm ◽  
Aortic Dissection ◽  
Intramural Hematoma ◽  
Aortic Disease ◽  
Magnetic Resonance Images ◽  
Aortic Aneurysms ◽  
High Morbidity ◽  
Aortic Diseases ◽  
Decision Algorithm ◽  
Type B Dissection

Aortic diseases are relatively rare but are associated with high morbidity and mortality. Emergency physicians (EPs) should consider aortic disease in all patients with pain in the torso, particularly those with other diverse or seemingly unconnected complaints. This review summarizes the pathophysiology, stabilization and assessment, diagnosis and treatment, and disposition and outcomes for patients with abdominal aortic aneurysms (AAAs), thoracic aortic aneurysms (TAAs), and aortic dissection. Figures show a transverse image of an AAAs with a transmural hematoma, a three-dimensional computed tomographic angiogram (CTA) rendering of a thoracic aneurysm associated with a bicuspid aortic valve in the typical ascending aortic location, a chest x-ray film demonstrating prominent and blurred aortic knob due to TAA, acute aortic dissection subtypes, an electrocardiogram and transesophageal echocardiography of a patient with acute ascending aortic dissection, magnetic resonance images of a patient with dissection of the proximal descending aorta, CT representations of a type A dissection involving a dilated ascending aorta and a type B dissection involving the descending thoracic aorta, and a decision algorithm for evaluation and treatment of a suspected aortic dissection. Tables list normal aortic dimensions by CTA and echocardiography, average annual rate of expansion and rupture of AAA based on current diameter, and the etiology of TAA. This review contains 3 figures, 3 tables, 4 videos and 66 references. Key words: AAA, aorta, aortic dissection, ascending aortic dissection, descending aortic dissection, intimal tear, intramural hematoma, thoracic aortic aneurysm

Abstract 382: Reduced Mitochondrial Function and Metabolic Dysregulation in Aneurysmal Fibulin-4 Mice.

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Ingrid van der Pluijm ◽  
P.M. van Heijningen ◽  
A. IJpma ◽  
N. van Vliet ◽  
W Sluiter ◽  
...  
Keyword(s):  
Mitochondrial Function ◽  
Matrix Protein ◽  
Molecular Mechanisms ◽  
Early Death ◽  
Predictive Biomarker ◽  
Underlying Mechanism ◽  
Aortic Aneurysms ◽  
Extracellular Matrix Protein ◽  
Aneurysm Formation ◽  
Metabolic Dysregulation

Thoracic aortic aneurysms are a life-threatening condition often diagnosed too late. The underlying mechanism is largely unknown. An accurate and early predictive biomarker for aneurysm formation has not yet been identified, although some molecular processes, such as disturbed TGF-β signalling, have been implicated. To discover novel robust biomarkers, we aimed to better understand the molecular mechanisms involved in aneurysm initiation and progression. In Fibulin-4 R/R mice, the extracellular matrix protein Fibulin-4 is 4-fold reduced, resulting in progressive ascending aneurysm formation and early death around 3 months of age. We performed LC-MS/MS proteomics and transcriptomics analyses on the aortas of Fibulin-4 R/R and Fibulin-4 +/+ mice. Protein and gene data sets were separately analysed for genotype specific differences with Ingenuity Pathway analysis tools. Intriguingly, we observed alterations in mitochondrial composition in aortas from Fibulin-4 R/R mice. Consistently, functional studies in Fibulin-4 R/R vascular smooth muscle cells (VSMCs) revealed lower oxygen consumption rates, but increased acidification rates compared to Fibulin-4 +/+ . The mitochondria in VSMCs of Fibulin-4 R/R mice were reduced in size and had increased complex I-IV levels. Furthermore, aortas of aneurysmal Fibulin-4 R/R mice displayed increased levels of ROS. Consistent with these findings, gene expression analyses revealed the dysregulation of metabolic pathways. In accordance, ketone levels in the blood of Fibulin-4 R/R mice were reduced and liver fatty acids were decreased, while liver glycogen was increased. As predicted by these findings, activity of PGC1α, a key regulator between mitochondrial function and organismal metabolism, was downregulated in Fibulin-4 R/R VSMCs. In conclusion, our data indicate altered mitochondrial function and metabolic dysregulation, leading to increased ROS levels and altered energy production, as a novel mechanism, which may contribute to thoracic aortic aneurysm formation. This discovery will not only provide new biomarkers that can be validated in human aortas, but they will also provide the rational for new interventions such as alterations in diet to prevent aneurysm formation.

scholarly journals The genetics and biomechanics of thoracic aortic diseases

2019 ◽  
Vol 1 (1) ◽  
pp. R13-R25
Author(s):  
Amer Harky ◽  
Ka Siu Fan ◽  
Ka Hay Fan
Keyword(s):  
Structural Instability ◽  
Aortic Aneurysms ◽  
Telomere Dysfunction ◽  
Aortic Diseases ◽  
Thoracic Aortic Aneurysms ◽  
Treatment And Prevention ◽  
Inflammatory State ◽  
Biomechanical Changes ◽  
Thoracic Aneurysms ◽  
Aortic Dissections

Thoracic aortic aneurysms and aortic dissections (TAAD) are highly fatal emergencies within cardiothoracic surgery. With increasing age, thoracic aneurysms become more prevalent and pose an even greater threat when they develop into aortic dissections. Both diseases are multifactorial and are influenced by a multitude of physiological and biomechanical processes. Structural stability of aorta can be disrupted by genes, such as those for extracellular matrix and contractile protein, as well as telomere dysfunction, which leads to senescence of smooth muscle and endothelial cells. Biomechanical changes such as increased luminal pressure imposed by hypertension are also very prevalent and lead to structural instability. Furthermore, ageing is associated with a pro-inflammatory state that exacerbates degeneration of vessel wall, facilitating the development of both aortic aneurysms and aortic dissection. This literature review provides an overview of the aetiology and pathophysiology of both thoracic aneurysms and aortic dissections. With an improved understanding, new therapeutic targets may eventually be identified to facilitate treatment and prevention of these diseases.

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