Fibulin-4 is essential for maintaining arterial wall integrity in conduit but not muscular arteries

Homozygous or compound heterozygous mutations in fibulin-4 (FBLN4) lead to autosomal recessive cutis laxa type 1B (ARCL1B), a multisystem disorder characterized by significant cardiovascular abnormalities, including abnormal elastin assembly, arterial tortuosity, and aortic aneurysms. We sought to determine the consequences of a human disease-causing mutation in FBLN4 (E57K) on the cardiovascular system and vascular elastic fibers in a mouse model of ARCL1B. Fbln4E57K/E57K mice were hypertensive and developed arterial elongation, tortuosity, and ascending aortic aneurysms. Smooth muscle cell organization within the arterial wall of large conducting vessels was abnormal, and elastic fibers were fragmented and had a moth-eaten appearance. In contrast, vessel wall structure and elastic fiber integrity were normal in resistance/muscular arteries (renal, mesenteric, and saphenous). Elastin cross-linking and total elastin content were unchanged in large or small arteries, whereas elastic fiber architecture was abnormal in large vessels. While the E57K mutation did not affect Fbln4 mRNA levels, FBLN4 protein was lower in the ascending aorta of mutant animals compared to wild-type arteries but equivalent in mesenteric arteries. We found a differential role of FBLN4 in elastic fiber assembly, where it functions mainly in large conduit arteries. These results suggest that elastin assembly has different requirements depending on vessel type. Normal levels of elastin cross-links in mutant tissue call into question FBLN4\u27s suggested role in mediating lysyl oxidase-elastin interactions. Future studies investigating tissuespecific elastic fiber assembly may lead to novel therapeutic interventions for ARCL1B and other disorders of elastic fiber assembly. 2017 © The Authors, some rights reserved

Modeling the Structural and Mechanical Properties of Pulmonary Arteries in an Animal Model of Pulmonary Arterial Hypertension

Pulmonary arterial hypertension (PAH) is a progressive disease characterized by elevated mean pulmonary arterial pressure. Although the cause of the disease onset is unclear, manifestations such as remodeling and occlusion of the distal pulmonary arteries lead to pressure overload of the right ventricle, eventually leading to heart failure. While much research has focused on the remodeling of smooth muscle and endothelial cells in the pulmonary arteries, collagen extracellular matrix changes in structure and function are not well defined. In this thesis, mechanical and microstructural properties of pulmonary arteries were investigated during the progression of PAH. Results indicated that the axial and circumferential directions to not respond the same to mechanical loading, collagen fibers become less tortuous and realign to a preferred direction, and left and right pulmonary arteries do not remodel identically. Five models of the pulmonary arterial mechanics were developed to determine the role of structural features in the vascular mechanical response found with biaxial tubular testing of vessels in a rat model of PAH. Models included families of fibers, viscoelasticity, and elasticity theory. While the viscoelasticity-based model was able to identify the changes in the vessel stiffness, it did not account for the structural changes undergone by the vessel. On the other hand, the fiber-family models were able to incorporate collagen fiber preferred directions but were either over-parameterized and or did not account for tortuosity and collagen diameter changes. The elasticity-based model was found to fit measured data, and identify differences in the modulus of elasticity found in circumferential and axial directional data. Future iterations of the model should include measurements such as individual fiber diameter, data from fibers throughout the vessel, or contributions from other vessel constituents such as elastin fibers

A clinical case of idiopathic pulmonary arterial hypertension in patient with comorbid ischemic heart disease: the key stages of diagnosis

Despite the progress achieved in the development of new directions in the diagnosis and treatment of idiopathic pulmonary arterial hypertension, it remains one of the most severe and prognostically unfavorable diseases. The article presents a clinical case and an algorithm for diagnosis of this rare disease, in respect to the decisionmaking in clinical practice. The present case underscores the need to consider a broad differential diagnosis for marked dyspnea in mature patients, especially when the intensity of dyspnea is out of proportion to the severity of underlying heart or lung diseases, or when symptoms fail to subside as expected in response to conventional therapy. Early diagnosis of idiopathic pulmonary arterial hypertension is vitally important for initiating modern therapy in order to improve the quality and duration of life in such patientsyesBelgorod State Universit

Clinical history and management recommendations of the smooth muscle dysfunction syndrome due to ACTA2 arginine 179 alterations

Smooth muscle dysfunction syndrome (SMDS) due to heterozygous ACTA2 arginine 179 alterations is characterized by patent ductus arteriosus, vasculopathy (aneurysm and occlusive lesions), pulmonary arterial hypertension, and other complications in smooth muscle-dependent organs. We sought to define the clinical history of SMDS to develop recommendations for evaluation and management. Medical records of 33 patients with SMDS (median age 12 years) were abstracted and analyzed. All patients had congenital mydriasis and related pupillary abnormalities at birth and presented in infancy with a patent ductus arteriosus or aortopulmonary window. Patients had cerebrovascular disease characterized by small vessel disease (hyperintense periventricular white matter lesions; 95%), intracranial artery stenosis (77%), ischemic strokes (27%), and seizures (18%). Twelve (36%) patients had thoracic aortic aneurysm repair or dissection at median age of 14 years and aortic disease was fully penetrant by the age of 25 years. Three (9%) patients had axillary artery aneurysms complicated by thromboembolic episodes. Nine patients died between the ages of 0.5 and 32 years due to aortic, pulmonary, or stroke complications, or unknown causes. Based on these data, recommendations are provided for the surveillance and management of SMDS to help prevent early-onset life-threatening complications

Blood flow dynamics in surviving patients with repaired Tetralogy of Fallot

Tetralogy of Fallot (TOF) is a congenital heart disease that causes structural abnormalities in the pulmonary arteries, which in turn disrupt the blood flow. Surgical repair is necessary early in childhood, but chronic complications are common in the adult surviving patients. Pulmonary valve replacement is an operation performed in the repaired TOF (rTOF) patients to overcome the right ventricular overload, but the optimal timing remains a challenge. The main research question is whether the haemodynamic environment of the pulmonary junction can clarify the interplay between the upstream and downstream pulmonary vasculature. Therefore, an extensive analysis of the effect of morphological and flow characteristics in healthy and rTOF models was performed, under various boundary conditions (BCs). The effects of branch angle and origin, branch stenosis, flow splits and pulmonary resistance were investigated in idealised two-dimensional geometries, representative of healthy and rTOF cases, explaining the elevated pressure in the LPA, and clearly showing that downstream pressure and peripheral resistance alter the flow development and the flow split between the two daughter branches. Various modelling parameters were also tested, demonstrating the importance of the valve, and how it disturbs the flow patterns along the MPA. The elasticity of arterial wall had a minimal effect on the flow development while the WSS deviated based on the rheological model assumed. Finally, anatomically realistic three-dimensional models of rTOF patients and healthy volunteers were reconstructed and morphological and flow features were analysed. Higher curvature and tortuosity were correlated with more complex secondary flow patterns, and higher Reynolds and Dean numbers, with increased regions of time-averaged wall shear stress. More importantly, the importance of patient-specificity in the rTOF models, and the variability of the geometric and flow characteristics within the population was highlighted, contrary to the observations in the healthy models. The results of this work could help clinicians evaluate the haemodynamic environment in the rTOF population and potentially predict patients at higher risk, prior to the appearance of severe complications.Tetralogy of Fallot (TOF) is a congenital heart disease that causes structural abnormalities in the pulmonary arteries, which in turn disrupt the blood flow. Surgical repair is necessary early in childhood, but chronic complications are common in the adult surviving patients. Pulmonary valve replacement is an operation performed in the repaired TOF (rTOF) patients to overcome the right ventricular overload, but the optimal timing remains a challenge. The main research question is whether the haemodynamic environment of the pulmonary junction can clarify the interplay between the upstream and downstream pulmonary vasculature. Therefore, an extensive analysis of the effect of morphological and flow characteristics in healthy and rTOF models was performed, under various boundary conditions (BCs). The effects of branch angle and origin, branch stenosis, flow splits and pulmonary resistance were investigated in idealised two-dimensional geometries, representative of healthy and rTOF cases, explaining the elevated pressure in the LPA, and clearly showing that downstream pressure and peripheral resistance alter the flow development and the flow split between the two daughter branches. Various modelling parameters were also tested, demonstrating the importance of the valve, and how it disturbs the flow patterns along the MPA. The elasticity of arterial wall had a minimal effect on the flow development while the WSS deviated based on the rheological model assumed. Finally, anatomically realistic three-dimensional models of rTOF patients and healthy volunteers were reconstructed and morphological and flow features were analysed. Higher curvature and tortuosity were correlated with more complex secondary flow patterns, and higher Reynolds and Dean numbers, with increased regions of time-averaged wall shear stress. More importantly, the importance of patient-specificity in the rTOF models, and the variability of the geometric and flow characteristics within the population was highlighted, contrary to the observations in the healthy models. The results of this work could help clinicians evaluate the haemodynamic environment in the rTOF population and potentially predict patients at higher risk, prior to the appearance of severe complications

Features of Marfan syndrome not listed in the Ghent nosology : the dark side of the disease

Introduction: The revised Ghent nosology presents the classical features of Marfan syndrome. However, behind its familiar face, Marfan syndrome hides less well-known features. Areas covered: The German Marfan Organization listed unusual symptoms and clinical experts reviewed the literature on clinical features of Marfan syndrome not listed in the Ghent nosology. Thereby we identified the following features: (1) bicuspid aortic valve, mitral valve prolapse, pulmonary valve prolapse, tricuspid valve prolapse, (2) heart failure and cardiomyopathy, (3) supraventricular arrhythmia, ventricular arrhythmia, and abnormal repolarization, (4) spontaneous coronary artery dissection, anomalous coronary arteries, and atherosclerotic coronary artery disease, tortuosity-, aneurysm-, and dissection of large and medium-sized arteries, (5) restrictive lung disease, parenchymal lung disease, and airway disorders, (6) obstructive- and central sleep apnea, (7) liver and kidney cysts, biliary tract disease, diaphragmatic hernia, and adiposity, (8) premature labor, and urinary incontinence, (9) myopathy, reduced bone mineral density, and craniofacial manifestations, (10) atrophic scars, (11) caries, and craniomandibular dysfunction, (12) headache from migraine and spontaneous cerebrospinal fluid leakage, (13) cognitive dysfunction, schizophrenia, depression, fatigue, and pain, (14) and activated fibrinolysis, thrombin, platelets, acquired von Willebrand disease, and platelet dysfunction. Expert commentary: Future research, nosologies, and guidelines may consider less well-known features of Marfan syndrome

Takayasu arteritis: a comprehensive review of literature

Takayasu arteritis is an inflammatory pulseless disease of large arteries with unknown etiology which advances in three stages i.e. early systemic, vascular, and burnout stage. It is more prevalent in Asian women of childbearing age. Hypertension, fever, weight loss, arthralgia, limb claudication, light-headedness, and arterial pain are common manifestations. Angiography is a gold standard test to evaluate TA. There is no reliable serological marker has been identified. Control on the inflammatory process and hypertension are two imperative angles to treat the disease. Steroids are most used. Reconstructive surgeries are limited to severe and stenotic lesions. This review aims to report comprehensive evidence about Takayasu arteritis. We conducted an integrative review of theoretical and empirical publications reporting epidemiology, etiopathogenesis, classification, diagnostic evaluation, and management of TA. The authors searched PubMed, Embase, and Scopus until March 2020.  A total of 1104 records found, we included 37 papers for review after reading the articles. Remaining was excluded because of no innovative content, insufficient details, and no clear endpoints. This review of the literature presents comprehensive evidence in all fields of TA. Still, large areas need to be studied for better management of patients with TA

Safety and efficacy of endovascular treatment for carotid artery stenoses using proximal protection systems: 30-day follow-up

Introduction. Although surgical endarterectomy remains the treatment of choice for carotid artery stenosis, carotid artery stenting (CAS) with use of proximal protection systems (PPS) plays an important role as alternative treatment modality, especially in high risk patients. This study was aimed at the assessment of safety of CAS with use of the PPS and also at identification of risk factors associated with this procedure. Material and methods. This was a post hoc analysis, with 30-day follow-up. We analysed results of treatment of 94 patients who underwent 97 CAS with PPS, 47 such procedures in asymptomatic, and 50 in symptomatic individuals. Results. There were 0 strokes during 30-day follow-up. Transient ischaemic attacks occurred in 2 patients (2%) in symptomatic group. Risk factors of these adverse events comprised: tortuosity of the managed artery, chronic obstructive pulmonary disease, long lesion of the internal carotid artery and history of myocardial infarction. Conclusions. CAS with the use of PPS seems to be a relatively very safe procedure in high risk patients.Introduction. Although surgical endarterectomy remains the treatment of choice for carotid artery stenosis, carotid artery stenting (CAS) with use of proximal protection systems (PPS) plays an important role as alternative treatment modality, especially in high risk patients. This study was aimed at the assessment of safety of CAS with use of the PPS and also at identification of risk factors associated with this procedure. Material and methods. This was a post hoc analysis, with 30-day follow-up. We analysed results of treatment of 94 patients who underwent 97 CAS with PPS, 47 such procedures in asymptomatic, and 50 in symptomatic individuals. Results. There were 0 strokes during 30-day follow-up. Transient ischaemic attacks occurred in 2 patients (2%) in symptomatic group. Risk factors of these adverse events comprised: tortuosity of the managed artery, chronic obstructive pulmonary disease, long lesion of the internal carotid artery and history of myocardial infarction. Conclusions. CAS with the use of PPS seems to be a relatively very safe procedure in high risk patients

Characterization of Flow Dynamics in the Pulmonary Bifurcation of Patients With Repaired Tetralogy of Fallot: A Computational Approach

The hemodynamic environment of the pulmonary bifurcation is of great importance for adult patients with repaired tetralogy of Fallot (rTOF) due to possible complications in the pulmonary valve and narrowing of the left pulmonary artery (LPA). The aim of this study was to computationally investigate the effect of geometrical variability and flow split on blood flow characteristics in the pulmonary trunk of patient-specific models. Data from a cohort of seven patients was used retrospectively and the pulmonary hemodynamics was investigated using averaged and MRI-derived patient-specific boundary conditions on the individualized models, as well as a statistical mean geometry. Geometrical analysis showed that curvature and tortuosity are higher in the LPA branch, compared to the right pulmonary artery (RPA), resulting in complex flow patterns in the LPA. The computational analysis also demonstrated high time-averaged wall shear stress (TAWSS) at the outer wall of the LPA and the wall of the RPA proximal to the junction. Similar TAWSS patterns were observed for averaged boundary conditions, except for a significantly modified flow split assigned at the outlets. Overall, this study enhances our understanding about the flow development in the pulmonary bifurcation of rTOF patients and associates some morphological characteristics with hemodynamic parameters, highlighting the importance of patient-specificity in the models. To confirm these findings, further studies are required with a bigger cohort of patients