elastin and Cardiovascular-Diseases

Aortic stiffness increases with advancing age, more than doubling during the human life span, and is a robust predictor of cardiovascular disease (CVD) clinical events independent of traditional risk factors. The aorta increases in diameter and length to accommodate growing body size and cardiac output in youth, but in middle and older age the aorta continues to remodel to a larger diameter, thinning the pool of permanent elastin fibers, increasing intramural wall stress and resulting in the transfer of load bearing onto stiffer collagen fibers. Whereas aortic stiffening in early middle age may be a compensatory mechanism to normalize intramural wall stress and therefore theoretically "good" early in the life span, the negative clinical consequences of accelerated aortic stiffening beyond middle age far outweigh any earlier physiological benefit. Indeed, aortic stiffness and the loss of the "windkessel effect" with advancing age result in elevated pulsatile pressure and flow in downstream microvasculature that is associated with subclinical damage to high-flow, low-resistance organs such as brain, kidney, retina, and heart. The mechanisms of aortic stiffness include alterations in extracellular matrix proteins (collagen deposition, elastin fragmentation), increased arterial tone (oxidative stress and inflammation-related reduced vasodilators and augmented vasoconstrictors; enhanced sympathetic activity), arterial calcification, vascular smooth muscle cell stiffness, and extracellular matrix glycosaminoglycans. Given the rapidly aging population of the United States, aortic stiffening will likely contribute to substantial CVD burden over the next 2-3 decades unless new therapeutic targets and interventions are identified to prevent the potential avalanche of clinical sequelae related to age-related aortic stiffness.

Topics: Adolescent; Aged; Aging; Aorta; Blood Pressure; Cardiovascular Diseases; Collagen; Elastin; Humans; Middle Aged; Vascular Stiffness

Elastin is an important protein of the extracellular matrix of higher vertebrates, which confers elasticity and resilience to various tissues and organs including lungs, skin, large blood vessels and ligaments. Owing to its unique structure, extensive cross-linking and durability, it does not undergo significant turnover in healthy tissues and has a half-life of more than 70 years. Elastin is not only a structural protein, influencing the architecture and biomechanical properties of the extracellular matrix, but also plays a vital role in various physiological processes. Bioactive elastin peptides termed elastokines - in particular those of the GXXPG motif - occur as a result of proteolytic degradation of elastin and its non-cross-linked precursor tropoelastin and display several biological activities. For instance, they promote angiogenesis or stimulate cell adhesion, chemotaxis, proliferation, protease activation and apoptosis. Elastin-degrading enzymes such as matrix metalloproteinases, serine proteases and cysteine proteases slowly damage elastin over the lifetime of an organism. The destruction of elastin and the biological processes triggered by elastokines favor the development and progression of various pathological conditions including emphysema, chronic obstructive pulmonary disease, atherosclerosis, metabolic syndrome and cancer. This review gives an overview on types of human elastases and their action on human elastin, including the formation, structure and biological activities of elastokines and their role in common biological processes and severe pathological conditions.

Topics: Aging; Animals; Cardiovascular Diseases; Cysteine Proteases; Elastin; Humans; Matrix Metalloproteinases; Neoplasms; Pancreatic Elastase; Pepsin A; Proteolysis; Pulmonary Disease, Chronic Obstructive; Receptors, Cell Surface; Serine Proteases; Tropoelastin

The Cardiovascular Continuum describes a sequence of events from cardiovascular risk factors to end-stage heart disease. It includes conventional pathologies affecting cardiovascular functions such as hypertension, atherosclerosis or thrombosis and was traditionally considered from the metabolic point of view. This Cardiovascular Continuum, originally described by Dzau and Braunwald, was extended by O'Rourke to consider also the crucial role played by degradation of elastic fibers, occurring during aging, in the appearance of vascular stiffness, another deleterious risk factor of the continuum. However, the involvement of the elastin degradation products, named elastin-derived peptides, to the Cardiovascular Continuum progression has not been considered before. Data from our laboratory and others clearly showed that these bioactive peptides are central regulators of this continuum, thereby amplifying appearance and evolution of cardiovascular risk factors such as diabetes or hypertension, of vascular alterations such as atherothrombosis and calcification, but also nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. The Elastin Receptor Complex has been shown to be a crucial actor in these processes. We propose here the participation of these elastin-derived peptides and of the Elastin Receptor Complex in these events, and introduce a revisited Cardiovascular Continuum based on their involvement, for which elastin-based pharmacological strategies could have a strong impact in the future.

Topics: Animals; Cardiovascular Diseases; Elastin; Humans; Metabolic Syndrome; Peptides; Receptors, Cell Surface

Large, elastic arteries are composed of cells and a specialized extracellular matrix that provides reversible elasticity and strength. Elastin is the matrix protein responsible for this reversible elasticity that reduces the workload on the heart and dampens pulsatile flow in distal arteries. Here, we summarize the elastin protein biochemistry, self-association behavior, cross-linking process, and multistep elastic fiber assembly that provide large arteries with their unique mechanical properties. We present measures of passive arterial mechanics that depend on elastic fiber amounts and integrity such as the Windkessel effect, structural and material stiffness, and energy storage. We discuss supravalvular aortic stenosis and autosomal dominant cutis laxa-1, which are genetic disorders caused by mutations in the elastin gene. We present mouse models of supravalvular aortic stenosis, autosomal dominant cutis laxa-1, and graded elastin amounts that have been invaluable for understanding the role of elastin in arterial mechanics and cardiovascular disease. We summarize acquired diseases associated with elastic fiber defects, including hypertension and arterial stiffness, diabetes, obesity, atherosclerosis, calcification, and aneurysms and dissections. We mention animal models that have helped delineate the role of elastic fiber defects in these acquired diseases. We briefly summarize challenges and recent advances in generating functional elastic fibers in tissue-engineered arteries. We conclude with suggestions for future research and opportunities for therapeutic intervention in genetic and acquired elastinopathies.

Topics: Animals; Biomechanical Phenomena; Cardiovascular Diseases; Coronary Vessels; Elastin; Humans

Elastin-like polypeptides (ELPs) constitute a genetically engineered class of 'protein polymers' derived from human tropoelastin. They exhibit a reversible phase separation whereby samples remain soluble below a transition temperature (T

Topics: Administration, Ophthalmic; Animals; Antineoplastic Agents; Cardiovascular Diseases; Drug Delivery Systems; Elastin; Humans; Nanomedicine; Peptides

Elastin peptides, also known as elastin-derived peptides or elastokines, are soluble polypeptides in blood and tissue. The blood levels of elastin peptides are usually low but can increase during cardiovascular diseases, such as atherosclerosis, aortic aneurysm and diabetes with vascular complications. Generally, elastin peptides are derived from the degradation of insoluble elastic polymers. The biological activities of elastin peptides are bidirectional, e.g., a pro-inflammatory effect on monocyte migration induction vs. a protective effect on vasodilation promotion. However, recent in vivo studies have demonstrated that elastin peptides promote the formation of atherosclerotic plaques in hypercholesterolemic mice and induce hyperglycemia and elevations in plasma lipid levels in fasted mice. More important, the detrimental effects induced by elastin peptides can be largely inhibited by genetic or pharmacological blockade of the elastin receptor complex or by neutralization of an antibody against elastin peptides. These studies indicate new therapeutic strategies for the treatment of cardiovascular diseases by targeting elastin peptide metabolism. Therefore, the goal of this review is to summarize current knowledge about elastin peptides relevant to cardiovascular pathologies to further delineate their potential application in cardiovascular disease.

Topics: Animals; Cardiovascular Diseases; Cardiovascular System; Elastin; Homeostasis; Humans; Lipid Metabolism; Myocytes, Smooth Muscle; Peptide Fragments

Vascular calcification is an independent risk factor for the development of cardiovascular disease and is classified into two types based on the site of calcification : intimal atherosclerotic calcification and Mönckeberg's medial calcification. Matrix vesicles released from macrophages and vascular smooth muscle cells (VSMC) during apoptosis play a pivotal role in formation of fine granular calcification, while osteogenic differentiation of VSMC contributes to progression of advanced calcification. Recent noninvasive imaging studies of atherosclerotic calcification provide robust evidence that inflammation precedes active calcification, leading to establish the inflammation-dependent calcification paradigm. On the other hand, elastin degradation by increased elastolytic activities and disturbance of regulatory systems of extracellular pyrophosphate metabolism play an important role in development of Mönckeberg's medial calcification.

Topics: Animals; Apoptosis; Calcinosis; Cardiovascular Diseases; Cellular Senescence; Diphosphates; Elastin; Extracellular Matrix; Humans; Macrophages; Mice; Muscle, Smooth, Vascular; Osteogenesis; Risk Factors; Vascular Calcification

Arterial stiffness is an independent risk factor for premature cardiovascular morbidity and mortality that can be evaluated by noninvasive methods and can be reduced by good clinical management. The present chapter examines the association between arterial stiffness and cardiovascular risk factors including hypertension, metabolic syndrome, diabetes, advanced renal failure, hypercholesterolemia and obesity. The mechanisms responsible for the structural and functional modifications of the arterial wall are also described. We deal with parameters related to arterial compliance, focusing on two of them, pulse wave velocity and the augmentation index, useful in rapid assessment of arterial compliance by the bedside. Data that highlight the role of aortic pulse wave velocity and the augmentation index as independent factors in predicting fatal and nonfatal cardiovascular events in different populations are briefly presented. A number of lifestyle changes and traditional antihypertensive agents that improve arterial compliance are finally discussed. Novel therapies, such as statins, thiazolidindinediones, phosphodiesterase inhibitors and inhibitors or breakers of advanced glycation end product cross-links between colagen and elastin hold substantial promise.

Topics: Arteries; Blood Pressure; Cardiovascular Diseases; Diabetic Angiopathies; Elasticity; Elastin; Fibronectins; Humans; Hypertension; Matrix Metalloproteinases; Metabolic Syndrome; Obesity; Proteoglycans; Pulse

Williams-Beuren syndrome (WBS) is a microdeletion disorder caused by heterozygous loss of approximately 1.5-Mb pairs of DNA from chromosome 7. Patients with WBS have a characteristic constellation of medical and cognitive findings, with a hallmark feature of generalized arteriopathy presenting as stenoses of elastic arteries and hypertension. Human and mouse studies establish that defects in the elastin gene, leading to elastin haploinsufficiency, underlie the arteriopathy. In this review we describe potential links between elastin expression and arteriopathy, possible explanations for disease variability, and current treatment options and their limitations, and we propose several new directions for the development of nonsurgical preventative therapies based on insights from elastin biology.

Topics: Animals; Aorta; Blood Vessels; Cardiovascular Diseases; Elastin; Humans; Williams Syndrome

The growing prevalence and associated risk of arterial stiffness provide a major challenge to better understand the underlying causes and the resultant physiological impact of this condition. Structural components within the arterial wall, mainly collagen and elastin, are considered to be major determinants of arterial stiffness. Thus, quantitative and qualitative alterations of collagen and elastin fibers are involved in arterial stiffening that is associated with the aging process and disease states such as hypertension, diabetes, atherosclerosis, and chronic renal failure. Elucidation of mechanisms leading to the above alterations will aid in more specifically targeted therapeutic interventions because currently available cardiovascular medications fall short at reducing the stiffness of the large arteries. Reduction of arterial stiffness will likely have a significant impact on morbidity and mortality of older adults, as well as subjects suffering from cardiovascular and renal diseases.

Topics: Animals; Arteries; Cardiovascular Diseases; Collagen; Elastin; Extracellular Matrix; Humans; Integrins; Vascular Resistance

1. Arterial stiffness, which has independent predictive value for cardiovascular events, seems to have a genetic component, largely independent of the influence of blood pressure and other cardiovascular risk factors. 2. In animal models of essential hypertension (stroke-prone spontaneously hypertensive rats and spontaneously hypertensive rats), structural modifications of the arterial wall include an increase in the number of elastin-smooth muscle cell connections and smaller fenestrations of the internal elastic lamina, possibility leading to redistribution of the mechanical load towards elastic materials. These modifications may give rise to mechanisms explaining why changes in arterial wall material accompanying wall hypertrophy in these animals are not associated with an increase in arterial stiffness. 3. In monogenic connective tissue diseases (Marfan, Williams and Ehlers-Danlos syndromes) and the corresponding animal models, precise characterization of the arterial phenotype makes it possible to determine the influence of abnormal, genetically determined, wall components on arterial stiffness. 4. Such studies have highlighted the role of extracellular matrix signalling in the vascular wall and have shown that elastin and collagen not only display elasticity or rigidity, but are also involved in the control of smooth muscle cell function. 5. These data provide strong evidence that arterial stiffness is affected by the amount and density of stiff wall material and the spatial organization of that material.

Topics: Animals; Arteries; Cardiovascular Diseases; Collagen; Compliance; Disease Models, Animal; Ehlers-Danlos Syndrome; Elastin; Extracellular Matrix; Gene Expression Profiling; Genetic Predisposition to Disease; Humans; Hypertension; Marfan Syndrome; Oligonucleotide Array Sequence Analysis; Polymorphism, Genetic; Risk Factors; Tunica Intima; Tunica Media; Williams Syndrome

Cardiovascular disease is largely a consequence of coronary artery blockage through excessive proliferation of smooth muscle cells. It in turn leads to myocardial infarction and permanent and functionally devastating tissue damage to the heart wall. Our studies have revealed that elastin is a primary player in maintaining vascular smooth muscle cells in their dormant state and thus may be a useful therapeutic in vascular disease. By studying zebrafish, which unlike humans, can repair damage to heart muscle, we have begun to uncover some of the genes that seem necessary to undertake the de-differentiation steps that currently fail and prevent the formation of new proliferating cardiomyocytes at the site of damage in a mammalian heart.

Topics: Animals; Cardiovascular Diseases; Cell Differentiation; Coronary Vessels; Disease Models, Animal; Elastin; Heart; Humans; Muscle, Smooth; Regeneration; Zebrafish

Elastic fibres are an important component of connective tissue. They are composed of two elements: protein-elastin and microfibrils. Tissue rich in elastin include: aorta and major vessels, lungs, ligaments, tendons and skin. Elastases are a group of enzymes, which are able to degrade elastin. They are liberated from different cells including granulocytes, monocytes, lymphocytes, skin fibroblasts, cancer cells and others. The product of elastin degradation is known as elastin-derived peptides (EDP) and is a marker of elastolysis. Elastin-derived peptides are thought to act on elastin-laminin receptor (ELR), which is located on membrane of fibroblasts, granulocytes, lymphocytes, monocytes and' cancer cells. An increased elastin turnover can occur in several disorders, including malignancies, but its role is not well known. There are a group of inherited diseases affecting elastic fibres e.g. Marfan syndrome. It seems, that elastin degradation plays an important role in pathogenesis of some cardiovascular and pulmonary diseases. An enhanced elastolytic activity in malignancies is also observed. The data are rather sparse and above all concern lung and breast cancer. A trial estimating the role of elastin turnover in patients with hematologic malignancies, who underwent bone marrow transplantation, is now conducting in our department and preliminary results are promising.

Topics: Autoimmune Diseases; Cardiovascular Diseases; Elastic Tissue; Elastin; Humans; Lung Diseases; Neoplasms; Peptide Fragments; Receptors, Laminin; Risk Factors

Topics: Adult; Cardiovascular Diseases; Child; Child, Preschool; Chromosome Deletion; Chromosomes, Human, Pair 7; Cytogenetic Analysis; Elastin; Female; Humans; Male; Prognosis; Williams Syndrome

Extracellular matrix (ECM) in the heart and vascular wall includes fibrous proteins and proteoglycans. Fibrous proteins are classified within two categories: structural (collagen and elastin) and adhesive molecules (laminin and fibronectin). These ECM components are important in maintenance of both structure and function of the heart and vascular tissues. Myocardial infarction, hypertrophy, hypertension and heart failure are well known to be associated with progressive cardiac fibrosis. Vascular hypertrophy and thickening has been associated with the pathological series of events that attends both hypertension and restenosis. The accumulation of ECM in the cardiovascular system plays an important role in the development of heart failure after myocardial infarction and hypertension, as well as in vascular hypertrophy and restenosis. Angiotensin II (angiotensin) and transforming growth factor beta 1 are known to play a role in signalling the abnormal accumulation of ECM in these cardiovascular diseases. Administration of angiotensin-converting enzyme inhibitor or angiotensin receptor type 1 antagonist is associated with regression of cardiac hypertrophy and fibrosis as well as vascular hypertrophy.

Topics: Angiotensin I; Angiotensin-Converting Enzyme Inhibitors; Cardiomegaly; Cardiovascular Diseases; Collagen; Elastin; Extracellular Matrix; Fibronectins; Heart Failure; Humans; Myocardial Infarction; Proteoglycans

Copper, as a component of numerous cuproenzymes, plays a vital role in many physiologic functions in man and animals. From the stand-point of human health there are at least three functional areas of prime importance. Copper is involved in the development and maintenance of cardiovascular and skeletal integrity, central nervous system structure and function, and erythropoietic function including iron metabolism. Although there is no evidence for widespread copper deficiency in the human population, it does occur, owing to genetic defects and other precipitating factors. A clear understanding of the functions of copper and its mechanisms of action could prove highly beneficial in the solution of present and unforeseen problems in medicine.

Topics: Anemia; Animals; Bone Diseases; Brain Diseases; Cardiovascular Diseases; Central Nervous System Diseases; Collagen; Copper; Deficiency Diseases; Elastin; Enzymes; Female; Growth Disorders; Hair; Humans; Infant; Infant, Newborn; Metalloproteins; Pigmentation Disorders; Pregnancy; Pregnancy Complications; Protein-Lysine 6-Oxidase

Topics: Adolescent; Animals; Aorta; Arteries; Arteriosclerosis; Calcium; Cardiovascular Diseases; Child; Collagen; Connective Tissue; Elastin; Endothelium; Female; Glycopeptides; Glycosaminoglycans; Heparin; Hexosamines; Humans; Lipids; Lipoproteins; Macromolecular Substances; Male; Vascular Diseases

Topics: Animals; Bone Diseases; Cardiovascular Diseases; Catalysis; Collagen; Connective Tissue; Copper; Deficiency Diseases; Elastic Tissue; Elastin; Female; Fibroblasts; Glycosaminoglycans; Growth; Humans; Nutritional Physiological Phenomena; Osteogenesis; Pregnancy

Arterial stiffness is a hallmark of vascular ageing that precedes and strongly predicts the development of cardiovascular diseases. Age-dependent stiffening of large elastic arteries is primarily attributed to increased levels of matrix metalloproteinase-2 (MMP-2). However, the mechanistic link between age-dependent arterial stiffness and MMP-2 remains unclear. Thus, we aimed to investigate the efficacy of MMP-2 knockdown using small-interfering RNA (siRNA) on age-dependent arterial stiffness.. Pulse wave velocity (PWV) was assessed in right carotid artery of wild-type (WT) mice from different age groups. MMP-2 levels in the carotid artery and plasma of young (3 months) and old (20-25 months) WT mice were determined. Carotid PWV as well as vascular and circulating MMP-2 were elevated with increasing age in mice. Old WT mice (18- to 21-month old) were treated for 4 weeks with either MMP-2 or scrambled (Scr) siRNA via tail vein injection. Carotid PWV was assessed at baseline, 2 and 4 weeks after start of the treatment. MMP-2 knockdown reduced vascular MMP-2 levels and attenuated age-dependent carotid stiffness. siMMP-2-treated mice showed increased elastin-to-collagen ratio, lower plasma desmosine (DES), enhanced phosphorylation of endothelial nitric oxide synthase (eNOS), and higher levels of vascular cyclic guanosine monophosphate (cGMP). An age-dependent increase in direct protein-protein interaction between MMP-2 and eNOS was also observed. Lastly, DES, an elastin breakdown product, was measured in a patient cohort (n = 64, 23-86 years old), where carotid-femoral PWV was also assessed; here, plasma levels of DES directly correlated with age and arterial stiffness.. MMP-2 knockdown attenuates age-dependent carotid stiffness by blunting elastin degradation and augmenting eNOS bioavailability. Given the increasing clinical use of siRNA technology, MMP2 knockdown should be investigated further as a possible strategy to mitigate age-dependent arterial stiffness and related CV diseases.

Topics: Animals; Cardiovascular Diseases; Carotid Arteries; Elastin; Humans; Matrix Metalloproteinase 2; Mice; Nitric Oxide Synthase Type III; Pulse Wave Analysis; RNA, Small Interfering; Vascular Stiffness

Extracellular matrix (ECM) remodeling is one of the key components in the formation of vulnerable atherosclerotic plaques and cardiovascular events. We recently showed that the full-length ECM-proteoglycan osteoglycin was associated with plaque vulnerability and future cardiovascular events. In the present study, we aimed to investigate the association of cleaved osteoglycin with plaque phenotype.. Two-hundred human carotid plaques were analyzed by immunohistochemistry. Cleaved osteoglycin and active caspase-3 were assessed by ELISA. ECM components (collagen, elastin and glycosaminoglycans) were assessed by colorimetric assays in plaque tissue homogenates. Matrix metalloproteinases (MMPs) were assessed using Milliplex. MMP-cleavage of osteoglycin and its effect on apoptosis were studied in vitro. Cardiovascular events were recorded during follow-up using national registries.. Plaque levels of cleaved osteoglycin were significantly higher in asymptomatic plaques and correlated to α-actin plaque area, collagen, elastin and inversely to lipids, active. caspase-3 and a histological vulnerability index. Cleaved osteoglycin correlated to several MMPs, especially MMP-12, which was also shown to cleave osteoglycin in vitro. In vitro cleavage of osteoglycin was also associated with less smooth muscle cell apoptosis. Patients with high plaque levels of cleaved osteoglycin had a significantly lower risk to suffer from future cardiovascular events.. The current study shows that cleaved osteoglycin is associated with a stable plaque phenotype and lower risk for future cardiovascular events. Potentially due to reduced cell apoptosis and ability to retain LDL. These results indicate that targeting the cleavage of osteoglycin may be a potential therapeutic strategy to stabilize plaques.

Topics: Cardiovascular Diseases; Caspase 3; Collagen; Elastin; Humans; Matrix Metalloproteinases; Peptide Hydrolases; Phenotype; Plaque, Atherosclerotic

Aging leads to central artery stiffening and associated hemodynamic sequelae. Because healthy arteries exhibit differential geometry, composition, and mechanical behaviors along the central vasculature, we sought to determine whether wall structure and mechanical function differ across five vascular regions-the ascending and descending thoracic aorta, suprarenal and infrarenal abdominal aorta, and common carotid artery-in 20 versus 100-week-old male wild-type mice. Notwithstanding generally consistent changes across these regions, including a marked thickening of the arterial wall, diminished in vivo axial stretch, and loss of elastic energy storage capacity, the degree of changes tended to be slightly greater in abdominal than in thoracic or carotid vessels. Likely due to the long half-life of vascular elastin, most mechanical changes in the arterial wall resulted largely from a distributed increase in collagen, including thicker fibers in the media, and localized increases in glycosaminoglycans. Changes within the central arteries associated with significant increases in central pulse pressure and adverse changes in the left ventricle, including increased cardiac mass and decreased diastolic function. Given the similar half-life of vascular elastin in mice and humans but very different life-spans, there are important differences in the aging of central vessels across these species. Nevertheless, the common finding of aberrant matrix remodeling contributing to a compromised mechanical homeostasis suggests that studies of central artery aging in the mouse can provide insight into mechanisms and treatment strategies for the many adverse effects of vascular aging in humans.

Topics: Aging; Animals; Aorta, Abdominal; Aorta, Thoracic; Biomechanical Phenomena; Cardiovascular Diseases; Cardiovascular System; Carotid Arteries; Carotid Artery, Common; Diastole; Disease Models, Animal; Elastin; Extracellular Matrix Proteins; Hemodynamics; Homeostasis; Humans; Male; Mice; Models, Cardiovascular; Pressure; Recombinant Proteins; Stress, Mechanical; Time Factors; Vascular Stiffness

Topics: Aged; Aorta; Blood Pressure; Blood Pressure Determination; Cardiovascular Diseases; Carotid Arteries; Correlation of Data; Elastin; Female; Glucose; Humans; Hypertension; Male; Middle Aged; Pulse Wave Analysis; Risk Factors; Ultrasonography; Vascular Remodeling; Vascular Stiffness

Diabetes mellitus type 2 (T2DM) is a significant risk factor for the development of cardiovascular diseases (CVDs). In a previous microarray study of internal mammary arteries from patients with and without T2DM, we observed several elastin-related genes with altered mRNA-expression in diabetic patients, namely matrix metalloproteinase 2 (MMP-2), lysyl oxidase (LOX) and elastin itself. In this study we investigate whether the serum concentrations of elastin-related proteins correlate to signs of CVD in patients with T2DM.. Blood samples from 302 type 2 diabetic patients were analysed for MMP-2, LOX, and the elastin degradation products ELM and ELM2. The results were investigated for correlations to signs of CVD in different vascular territories, as determined by myocardial perfusion scintigraphy, carotid artery thickness and ankle-brachial blood pressure index.. T2DM patients with peripheral arterial disease (low ankle-brachial index) (PAD) display higher levels of MMP-2 and ELM compared to patients without PAD. However, none of the proteins or degradation products correlated with myocardial ischemia or a combined measure of CVD-signs, including myocardial ischemia, increased carotid thickness and decreased ankle-brachial blood pressure.. Our results suggest that the diabetic environment affects the circulating amounts of MMP-2 and ELM in patients with PAD. However, the same connection could not be seen in diabetic patients with CVD broadly identified in three vascular territories. LOX and ELM-2 did not correlate to any type of CVD. Overall, serum levels of elastin-related molecules are only remotely related to CVD in type 2 diabetes.

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Elastin; Female; Humans; Male; Matrix Metalloproteinase 2; Middle Aged; Protein-Lysine 6-Oxidase; Proteolysis; Regression Analysis

Elastin degradation is a key feature of emphysema and may have a role in the pathogenesis of atherosclerosis associated with chronic obstructive pulmonary disease (COPD). Circulating desmosine is a specific biomarker of elastin degradation. We investigated the association between plasma desmosine (pDES) and emphysema severity/progression, coronary artery calcium score (CACS) and mortality.pDES was measured in 1177 COPD patients and 110 healthy control subjects from two independent cohorts. Emphysema was assessed on chest computed tomography scans. Aortic arterial stiffness was measured as the aortic-femoral pulse wave velocity.pDES was elevated in patients with cardiovascular disease (p<0.005) and correlated with age (rho=0.39, p<0.0005), CACS (rho=0.19, p<0.0005) modified Medical Research Council dyspnoea score (rho=0.15, p<0.0005), 6-min walking distance (rho=-0.17, p<0.0005) and body mass index, airflow obstruction, dyspnoea, exercise capacity index (rho=0.10, p<0.01), but not with emphysema, emphysema progression or forced expiratory volume in 1 s decline. pDES predicted all-cause mortality independently of several confounding factors (p<0.005). In an independent cohort of 186 patients with COPD and 110 control subjects, pDES levels were higher in COPD patients with cardiovascular disease and correlated with arterial stiffness (p<0.05).In COPD, excess elastin degradation relates to cardiovascular comorbidities, atherosclerosis, arterial stiffness, systemic inflammation and mortality, but not to emphysema or emphysema progression. pDES is a good biomarker of cardiovascular risk and mortality in COPD.

Topics: Adult; Aged; Biomarkers; Body Composition; Bronchodilator Agents; Calcinosis; Cardiovascular Diseases; Case-Control Studies; Coronary Vessels; Desmosine; Disease Progression; Elastin; Emphysema; Female; Forced Expiratory Volume; Humans; Inflammation; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Pulmonary Emphysema; Pulse Wave Analysis; Respiratory Function Tests; Risk Factors; Smoking; Vascular Stiffness

We explored the use of recently developed gels obtained by the catalyst free click reaction of elastin-like recombinamers (ELRs) to fabricate a new class of covered stents. The approach consists in embedding bare metal stents in the ELR gels by injection molding, followed by endothelialization under dynamic pressure and flow conditions in a bioreactor. The mechanical properties of the gels could be easily tuned by choosing the adequate concentration of the ELR components and their biofunctionality could be tailored by inserting specific sequences (RGD and REDV). The ELR-covered stents exhibited mechanical stability under high flow conditions and could undergo crimping and deployment without damage. The presence of RGD in the ELR used to cover the stent supported full endothelialization in less than 2weeks in vitro. Minimal platelet adhesion and fibrin adsorption were detected after exposure to blood, as shown by immunostaining and scanning electron microscopy. These results prove the potential of this approach towards a new and more effective generation of covered stents which exclude the atherosclerotic plaque from the blood stream and have high biocompatibility, physiological hemocompatibility and reduced response of the immune system.

Topics: Cardiovascular Diseases; Coated Materials, Biocompatible; Elastin; Human Umbilical Vein Endothelial Cells; Humans; Microscopy, Electron, Scanning; Stents; Thrombosis

Peripheral vascular resistance is increased in essential hypertension. This involves structural changes of resistance arteries and stiffening of the arterial wall, including remodeling of the extracellular matrix. We hypothesized that biopsies of the human parietal pericardium, obtained during coronary artery bypass grafting or cardiac valve replacement surgeries, can serve as a source of resistance arteries for structural research in cardiovascular disease patients. We applied two-photon excitation fluorescence microscopy to study the parietal pericardium and isolated pericardial resistance arteries with a focus on the collagen and elastin components of the extracellular matrix. Initial findings in pig tissue were confirmed in patient biopsies. The microarchitecture of the internal elastic lamina in both the pig and patient pericardial resistance arteries (studied at a transmural pressure of 100 mm Hg) is fiber like, and no prominent external elastic lamina could be observed. This microarchitecture is very different from that in rat mesenteric arteries frequently used for resistance artery research. In conclusion, we add three-dimensional information on the structure of the extracellular matrix in resistance arteries from cardiovascular disease patients and propose further use of patient pericardial resistance arteries for studies of the human microvasculature.

Topics: Aged; Animals; Cardiovascular Diseases; Coronary Vessels; Elastic Tissue; Elastin; Extracellular Matrix; Female; Humans; Male; Mesenteric Arteries; Microscopy, Fluorescence, Multiphoton; Middle Aged; Pericardium; Rats; Species Specificity; Sus scrofa; Swine; Vascular Resistance

A high incidence of cardiovascular (CV) risk factors has been reported in adults with Williams-Beuren syndrome (WS). However, the prevalence of these factors in children and adolescents with WS is unknown. Therefore, the purpose of this study was to evaluate the prevalence of CV risk factors in these patients.. Thirty-two WS patients aged <18 years were enrolled in the study. Oxidized low-density lipoprotein levels (n = 32), oral glucose tolerance test results (n = 20), plasma renin and aldosterone levels (n = 31), 24-h ambulatory blood pressure (ABP; n = 24), carotid artery intima-media thickness (IMT; n = 15), and brachial artery flow-mediated dilatation (FMD; n = 15) were measured and analyzed.. The lipid profile revealed hypercholesterolemia in 22% and elevated oxidized low-density lipoprotein levels in 94% of the patients. Glucose metabolism abnormalities were found in 70% of the patients. Insulin resistance was observed in 40% of the patients. High plasma renin and aldosterone levels were detected in 45 and 39% of the patients, respectively. A mean systolic blood pressure above the 90th percentile was noted in 29% of patients. High IMT (>0.65 mm) and low FMD (<9%) were detected in 80 and 73% of patients, respectively.. In patients with WS, CV risk factors are frequently present from childhood. In children with WS, screening tests for the early detection of CV risk factors and long-term follow-up are required to determine whether long-term exposure to these factors increases the risk for CV events in adulthood.

Topics: Adolescent; Aldosterone; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Cardiovascular Diseases; Carotid Intima-Media Thickness; Child; Child, Preschool; Elastin; Female; Humans; Infant; Japan; Lipoproteins, LDL; Male; Prevalence; Risk Factors; Williams Syndrome

The level of circulating soluble elastin (CSE) is reported to increase proportionally with the degree of clinical atherosclerosis; however, its diagnostic use is limited because CSE also increases with age. We aimed to investigate whether alterations in CSE concentrations are implicated in potential cardiovascular dysfunctions (indicated by standard physiological parameters) in medical check-up individuals, taking age into consideration.. In a total of 531 individuals (age 20-89 years), CSE levels were correlated most significantly with age. The groups of male and female individuals were each further divided into two subgroups: those with higher and those with lower CSE levels than the reference values determined by polynomial regression.. Male participants with lower CSE levels (n = 128) than the age-adjusted reference baseline levels showed higher serum glucose (P < 0.008), uric acid (P < 0.008) and triglyceride (P < 0.02) levels than those with higher CSE levels (n = 126). However, most of the parameters tested in female participants with lower CSE levels (n = 140) were statistically comparable to those with higher CSE levels (n = 137). The ratio of CSE level to the age-adjusted reference level was calculated in each of the male participants, and declines in the ratio were significantly correlated with increases of serum glucose, uric acid and triglyceride levels (P < 0.005, P < 0.02 and P < 0.006, respectively).. The decrease in age-adjusted CSE levels is a potential indicator of eventual cardiovascular dysfunction in medical check-up individuals, as predicted by the risk factors dyslipidemia, hyperuricemia or diabetes.

Topics: Adult; Age Factors; Aged; Aged, 80 and over; Aging; Biomarkers; Cardiovascular Diseases; Diabetes Complications; Down-Regulation; Dyslipidemias; Elastin; Female; Humans; Hyperuricemia; Male; Middle Aged; Risk Factors; Young Adult

Although cardiovascular disease (CVD) and type 2 diabetes mellitus (T2D) share many common risk factors, potential molecular mechanisms that may also be shared for these 2 disorders remain unknown.. Using an integrative pathway and network analysis, we performed genome-wide association studies in 8155 blacks, 3494 Hispanic American, and 3697 Caucasian American women who participated in the national Women's Health Initiative single-nucleotide polymorphism (SNP) Health Association Resource and the Genomics and Randomized Trials Network. Eight top pathways and gene networks related to cardiomyopathy, calcium signaling, axon guidance, cell adhesion, and extracellular matrix seemed to be commonly shared between CVD and T2D across all 3 ethnic groups. We also identified ethnicity-specific pathways, such as cell cycle (specific for Hispanic American and Caucasian American) and tight junction (CVD and combined CVD and T2D in Hispanic American). In network analysis of gene-gene or protein-protein interactions, we identified key drivers that included COL1A1, COL3A1, and ELN in the shared pathways for both CVD and T2D. These key driver genes were cross-validated in multiple mouse models of diabetes mellitus and atherosclerosis.. Our integrative analysis of American women of 3 ethnicities identified multiple shared biological pathways and key regulatory genes for the development of CVD and T2D. These prospective findings also support the notion that ethnicity-specific susceptibility genes and process are involved in the pathogenesis of CVD and T2D.

Topics: Aged; Black People; Cardiovascular Diseases; Collagen Type I; Collagen Type I, alpha 1 Chain; Collagen Type III; Diabetes Mellitus, Type 2; Elastin; Female; Gene Regulatory Networks; Genetic Loci; Genome-Wide Association Study; Hispanic or Latino; Humans; Middle Aged; Polymorphism, Single Nucleotide; Protein Interaction Maps; Risk Factors; White People

We assessed the effects of D-penicillamine (D-PA) on cross-linkages in elastin and vaso-regulatory function in rats. After administration of D-PA at a dose of 100 mg/kg/day for 7 weeks to adult and young rats, the thoracic aortas were isolated. The elastic lamellae in the aorta were disrupted histopathologically in all the treated groups. The content of cross-linkages in elastin, i.e. desmosine and isodesmosine, which gives elasticity to the aortic wall, was significantly reduced in the D-PA treated groups versus the control groups. On the other hand, the content of pyridinoline as a marker of insoluble collagen was significantly reduced in the D-PA treated groups, even though the total collagen content was not changed. In addition, after 7 weeks of treatment with D-PA, the change between systolic blood pressure before and after sympathetic stimulation (Δ-SBP) by L-epinephrine was about 2.5-fold larger than that in the control group. Similar results were obtained using angiotensin II or ouabain instead of L-epinephrine. These findings demonstrated that D-PA disrupted elastic lamellae of the rat aorta by reduction of the cross-linkages in elastin and collagen, which caused dysfunction of vaso-regulation. Also, they suggested the possibility that long-term treatment with D-PA in patients could cause a decrease in vaso-regulatory function and could increase the risk of cardiovascular events.

Topics: Administration, Oral; Age Factors; Amino Acids; Animals; Aorta; Arterial Pressure; Cardiovascular Diseases; Chelating Agents; Desmosine; Elastic Tissue; Elasticity; Elastin; Humans; Injections, Subcutaneous; Isodesmosine; Male; Penicillamine; Rats; Rats, Sprague-Dawley

We assessed the effects of rofecoxib on cross-linkage formation in elastin and vaso-regulatory function in rats. After administration of rofecoxib at a dose of 10 mg/kg for 7 weeks to young rats and for 7 and 10 weeks to adult rats, thoracic aortas were isolated. The elastic lamellae in the aortas were disrupted histopathologically in all the treated groups. However, the content of cross-linkages in elastin, i.e. desmosine and isodesmosine, which give elasticity to the aortic wall, was not significantly different between the rofecoxib treated and control groups. On the other hand, although the baseline blood pressure was not changed during the treatment period in both young and adult rats, after several weeks of treatment with rofecoxib the change between systolic blood pressure before and after sympathetic stimulation by L-epinephrine was 2 to 3-fold larger than that in the control group. Similar results were obtained using angiotensin II instead of L-epinephrine. The exposure to rofecoxib (area under the plasma concentration-time curve) of rats after single administration was a few times higher than that of humans in clinical use. These findings indicate that rofecoxib did not directly inhibit formation of cross-linkages in elastin of the aorta in rats. However, the treatment with rofecoxib for several weeks disrupted elastic lamellae and caused depression of vaso-regulatory function in rats, which could bring on an increased risk of cardiovascular events in human.

Topics: Administration, Oral; Age Factors; Amino Acids; Animals; Aorta; Arterial Pressure; Cardiovascular Diseases; Cyclooxygenase 2 Inhibitors; Desmosine; Elastic Tissue; Elasticity; Elastin; Humans; Injections, Subcutaneous; Isodesmosine; Lactones; Male; Rats; Rats, Sprague-Dawley; Sulfones

Preterm birth affects 8-12% of live births and is associated with the development of elevated arterial blood pressure and aortic narrowing in later life; this suggests that preterm birth may alter the development of arteries. Our objective was to determine the effects of preterm birth, accompanied by antenatal corticosteroid administration, on the structure of the aorta and pulmonary artery, which experience different alterations in pressure flow at birth.. At 11 wk, preterm lambs had significantly thicker aortic walls and a smaller lumen, whereas the morphometry of the pulmonary artery was unaffected. Elastin deposition was markedly increased in the aorta and pulmonary artery and smooth muscle content was reduced in the aorta only. In preterm lambs we found injury in the aorta only; controls were unaffected.. We conclude that moderate preterm birth after antenatal betamethasone can cause injury and persistent alterations in the structure and composition of the aorta, with lesser effects in the pulmonary artery. Our findings suggest that preterm birth may increase the risk of atherosclerosis and aortic aneurysms in later life.. Using an established ovine model of preterm birth, lambs were born at 0.9 of gestation and underwent necropsy at 11 wk after birth; controls were born at term.

Topics: Adrenal Cortex Hormones; Androstenols; Animals; Aorta; Betamethasone; Cardiovascular Diseases; Collagen; Disease Models, Animal; Drug Administration Schedule; Elastin; Female; Gestational Age; Pregnancy; Premature Birth; Pulmonary Artery; Sheep

Vascular calcification is the most important cause of cardiovascular disease in patients with chronic kidney disease (CKD). Medial layer vascular calcification, which is recognized to be an active process (i.e. the transformation of vascular smooth muscle cells into osteoblast-like cells), is common in CKD patients. We have recently reported the possibility of an interaction between elastin degradation and medial layer vascular calcification. Matrix metalloproteinase-2 (MMP-2), which induces the degradation of elastin, has been implicated in the elastic calcification in arteries of dialysis patients; however, the precise mechanisms by which elastin degradation interacts with the development of vascular calcification remain to be studied. To clarify the mechanisms by which elastin degradation is involved in the development of medial layer vascular calcification in the uremic milieu, we induced aortic medial layer calcification in 5/6 nephrectomized uremic rats (male Sprague-Dawley rats) fed a diet containing high phosphate (1.2%) and lactate (20%). After 10 weeks, the rats were euthanized for the measurement of serum chemistry profiles and histological analyses. The uremic rats showed significant increases in blood pressure, serum creatinine, phosphate, and parathyroid hormone levels compared with normal rats. Von Kossa staining showed medial layer aortic calcification in the uremic rats. In calcified lesions, thin elastic lamellae were observed by elastin staining, indicating that elastin degradation could occur in the area. Furthermore, MMP-2 expression determined by immunohistochemistry was also observed in the same area. Elastin degradation accompanied by MMP-2 expression might be involved in the development of medial layer vascular calcification in uremic rats.

Topics: Animals; Aorta; Blood Pressure; Calcinosis; Cardiovascular Diseases; Chronic Disease; Creatinine; Elastin; Kidney Diseases; Male; Matrix Metalloproteinase 2; Parathyroid Hormone; Phosphates; Rats; Rats, Sprague-Dawley; Uremia

The development of atherosclerotic lesions and abdominal aortic aneurysms involves degradation and loss of extracellular matrix components, such as collagen and elastin. Releases of the elastin cross-links desmosine (DES) and isodesmosine (IDE) may reflect elastin degradation in cardiovascular diseases. This study investigated the production of soluble elastin cross-linking structures by proteinases implicated in arterial diseases. Recombinant MMP-12 and neutrophil elastase liberated DES and IDE as amino acids from insoluble elastin. DES and IDE were also released from insoluble elastin exposed to monocyte/macrophage cell lines or human primary macrophages derived from peripheral blood monocytes. Elastin oxidized by reactive oxygen species (ROS) liberated more unconjugated DES and IDE than did non-oxidized elastin when incubated with MMP-12 or neutrophil elastase. These results support the exploration of free DES and IDE as biomarkers of elastin degradation.

Topics: Animals; Biomarkers; Cardiovascular Diseases; Cell Line; Desmosine; Elastin; Humans; Isodesmosine; Leukocyte Elastase; Matrix Metalloproteinase 12; Mice; Reactive Oxygen Species; Recombinant Proteins

Intrauterine growth restriction caused by uteroplacental insufficiency increases the risk of cardiovascular disease in adulthood. Vascular mechanisms in female offspring are poorly understood. The aim of this study was to investigate the effects of uteroplacental insufficiency on blood pressure, vascular reactivity and arterial stiffness in four vascular beds in female offspring born growth restricted. Uteroplacental insufficiency was induced on day 18 of gestation in Wistar Kyoto rats by bilateral uterine vessel ligation (Restricted) or sham surgery (Controls). Wire and pressure myography were used to test endothelial and smooth muscle function, and passive mechanical wall properties, respectively, in uterine, mesenteric, renal and femoral arteries of 18-month-old female offspring. Collagen and elastin fibres were quantified using circular crossed-polarized light microscopy and quantitative real time polymerase chain reaction. Restricted female offspring were born 10-15% smaller. Restricted females were normotensive, had plasma triglycerides 2-fold elevated and had uterine endothelial dysfunction, attributed to a 23% reduction in the maximal relaxation produced by endothelium-derived hyperpolarizing factor. Uterine artery stiffness was increased, with an augmented proportion of thick and decreased proportion of thin collagen fibres. Vascular reactivity and mechanical wall properties were preserved in mesenteric, renal and femoral arteries in growth restricted females. Female offspring born growth restricted have selective uterine artery endothelial dysfunction and increased wall stiffness. The preserved vascular function in other arteries may explain the lack of hypertension in these females. The uterine artery specific dysfunction has potential implications for impaired pregnancy adaptations and a compromised intrauterine environment of the next generation.

Topics: Animals; Arteries; Blood Pressure; Body Weight; Cardiovascular Diseases; Collagen; Elastin; Endothelium, Vascular; Female; Lipids; Litter Size; Muscle Relaxation; Muscle, Smooth, Vascular; Placental Insufficiency; Pregnancy; Rats; Rats, Inbred WKY; Risk; RNA; Uterus; Vascular Diseases

Cardiovascular disease (CVD) is the leading cause of death in the United States, with 70% of CVD mortalities the result of sequelae of atherosclerosis. An urgent need for enhanced delineation of vulnerable plaques has catalyzed the development of novel atherosclerosis imaging strategies that use X-ray computed tomography, magnetic resonance and ultrasound modalities. As suggested by the pathophysiology of plaque development and progression to vulnerability, insight to the focal material, i.e., mechanical, properties of arterial walls and plaques may enhance atherosclerosis characterization. We present acoustic radiation force impulse (ARFI) ultrasound in application to mechanically characterizing a raised focal atherosclerotic plaque in an iliac artery extracted from a relevant pig model. ARFI results are correlated to matched immunohistochemistry, indicating elastin and collagen composition. In regions of degraded elastin, slower recovery rates from peak ARFI-induced displacements were observed. In regions of collagen deposition, lower ARFI-induced displacements were achieved. This work demonstrates ARFI for characterizing the material nature of an atherosclerotic plaque.

Topics: Animals; Atherosclerosis; Cardiovascular Diseases; Collagen; Disease Models, Animal; Elasticity; Elastin; Hyperlipoproteinemia Type II; Iliac Artery; Swine; Ultrasonography

Topics: Animals; Aorta; Cardiovascular Diseases; Collagen; Elastin; Female; Fetal Growth Retardation; Male; Maternal Nutritional Physiological Phenomena; Models, Animal; Neovascularization, Physiologic; Pregnancy; Rats

The long-term performance of tissue-derived, glutaraldehyde (Glut)-treated cardiovascular implants such as prosthetic heart valves and vascular grafts is limited by the bio-degeneration of tissue components. While collagen is satisfactorily preserved by Glut, elastin is not stabilized and is highly vulnerable to degradation. The aim of our studies was to develop methods for efficient stabilization of elastin and subsequently reduce its vulnerability towards enzymatic degradation. More specifically, we investigated the use of tannic acid (TA)1 as a novel agent that specifically targets elastin stabilization. Basic investigations on in vitro interactions between Glut, TA and pure aortic elastin provided clear evidence that Glut treatment does not protect elastin from enzymatic degradation. TA bound to elastin in a time-dependent pattern and this binding increased the resistance of elastin to enzymatic degradation. In addition, when TA was used in mixture with Glut, the kinetic of TA binding to elastin was enhanced and this was translated into improved elastin stabilization. Our results clearly documented the superiority of TA as an elastin-stabilizing agent by comparison with the commonly utilized Glut-based tissue crosslinking techniques.

Topics: Animals; Aorta; Biodegradation, Environmental; Cardiovascular Diseases; Drug Resistance; Elastin; Glutaral; Hydrolyzable Tannins; Kinetics; Pancreatic Elastase; Prostheses and Implants; Swine; Tissue Fixation

The prevalence and types of various cardiovascular diseases in different age groups as well as the outcomes of cardiac surgery and other interventions were assessed in a population of 75 Williams syndrome (WS) patients aged 4 months to 76 years (median 22.7 years).. The diagnosis of WS was in each case confirmed by the clinical phenotype and by a FISH test showing elastin hemizygosity. Clinical and operative data were collected from all hospitals where the patients had been treated.. Cardiovascular symptoms were evident in 35 of 75 (47%) WS children at birth. During follow up, 44 of 75 (53%) WS patients were found to have cardiovascular defects. Among them, the definitive diagnosis was made before 1 year of age in 23 (52%) infants, between 1 year and 15 years of age in 14 (32%) children, and older than 15 years of age in 7 (16%) adults. Multiple obstructive cardiovascular diseases were found in six infants. Supravalvular aortic stenosis (SVAS) was diagnosed in 32/44 (73%), pulmonary arterial stenosis (PAS) in 18/44 (41%), aortic or mitral valve defect in 5/44 (11 %) of cases, and tetralogy of Fallot in one (2%) case. Altogether, 17/44 (39 %) underwent surgery or intervention. Surgery was most frequently performed in the infant group (6% v 21% v 0%, p=0.004). After 1 year of age, seven patients underwent SVAS relief and two cases PAS relief. Postoperatively there was no mortality (median follow up time 6.9 years). Arterial hypertension was found in 55% of adults. In three adults, arterial vasculopathy was not diagnosed until necropsy.. Our data indicate the following in WS. Cardiac symptoms are common in neonates. Heart disease diagnosed in infancy frequently requires operation. After 1 year of age, PAS tends to improve and SVAS to progress. Life long cardiac follow up is necessary because of the risks of developing vasculopathy or arterial hypertension.

Topics: Adolescent; Adult; Aged; Cardiac Surgical Procedures; Cardiovascular Diseases; Cardiovascular Surgical Procedures; Child; Child, Preschool; Coronary Vessels; Elastin; Female; Humans; In Situ Hybridization, Fluorescence; Infant; Male; Middle Aged; Phenotype; Treatment Outcome; Williams Syndrome

To analyze the incidence and severity of cardiovascular disease in patients with Williams syndrome (WS) and to identify factors contributing to its variable expression.. Clinical data on patients with WS were collected from several WS centers. Elastin gene deletions were confirmed in all patients. Age at diagnosis, growth data, and cardiovascular diagnoses were recorded retrospectively. Cardiac diagnoses were made on the basis of echocardiographic data. The severity of supravalvular aortic stenosis was recorded by using a 4-step scale (none, mild, moderate, severe).. Statistical analysis of the data revealed that the severity of both supravalvular aortic stenosis and total cardiovascular disease was significantly greater in male patients than female patients (P <.002 and P <.002, respectively; Kruskal-Wallis rank-sum test). This difference was not accounted for by differences in height, weight, body mass index, or head circumference. The clinical diagnosis of WS was made at a significantly younger age in male patients (P <.01, Student t test). Earlier diagnosis was partly because of increased incidence and severity of cardiovascular disease. Another determinant of early diagnosis was low body mass index.. Penetrance and severity of the elastin arteriopathy in patients with WS is affected by sex. We hypothesize that differences by sex in arterial stenoses may be related to prenatal hormonal effects. Future epidemiologic and in vitro studies may provide additional insight into the pathogenetic mechanisms of these observed differences.

Topics: Adolescent; Adult; Cardiovascular Diseases; Child; Child, Preschool; Elastin; Female; Gene Deletion; Gene Expression; Humans; Infant; Infant, Newborn; Male; Middle Aged; Retrospective Studies; Severity of Illness Index; Sex Factors; Time Factors; Ultrasonography; Williams Syndrome

The relations of biological markers of extracellular matrix (plasma elastin peptides and elastase inhibitors) to the clinical history of cardiovascular diseases and risk factors for atherosclerosis were examined in a large population study (the EVA Study) on vascular and cognitive aging performed in 1389 men and women aged 59-71 years. A moderate decrease in elastin peptides was observed in women with a self-reported history of coronary heart disease (P < 0.091) and stroke (P < 0.03) as well as with diabetes (P < 0.043). Similar but non-significant trends were found in men. Furthermore, elastin peptides were significantly and positively correlated to HDL-cholesterol and apolipoprotein A1 in both sexes. On the other hand, elastase inhibitor titers were significantly higher in women than in men. A moderate increase was also found in men (P < 0.097) and women (P < 0.068) with a history of coronary heart disease that reached significance level after pooling both sexes (P < 0.014). Furthermore, elastase inhibitor titers were significantly and positively related to fibrinogen and C reactive protein in either sex. No consistent associations were observed between both biological markers of extracellular matrix and age, blood pressure, body mass index and tobacco or alcohol consumption. These results suggest that a decrease in elastin peptides and an increase in elastase inhibitors might be associated with risk factors of atherogenesis as well as with atherosclerosis-related diseases.

Topics: Aged; Aging; Apolipoprotein A-I; Apolipoproteins B; Blood Vessels; Cardiovascular Diseases; Cholesterol, HDL; Elastin; Enzyme Inhibitors; Female; Humans; Longitudinal Studies; Male; Middle Aged; Pancreatic Elastase; Risk Factors; Sex Characteristics; Triglycerides

Topics: Adolescent; Brain; Cardiovascular Diseases; Cerebellum; Cerebral Cortex; Chromosomes, Human, Pair 7; Cognition; Down Syndrome; Elastin; Gene Deletion; Humans; Intellectual Disability; Intelligence; Language; Magnetic Resonance Imaging; Music; Williams Syndrome

Topics: Aorta, Thoracic; Biomechanical Phenomena; Blood Flow Velocity; Cardiovascular Diseases; Elastin; Humans; Pulse

Topics: Aneurysm; Animals; Aorta, Thoracic; Arteries; Arteriosclerosis; Cardiovascular Diseases; Collagen; Copper; Deficiency Diseases; Elastin; Pedigree; Rupture; Swine; Vascular Diseases