elastin and Myocardial-Infarction

Topics: Aging; Arteriosclerosis; Blood Pressure; Calcinosis; Cholesterol; Collagen; Diastole; Elastin; Endothelium, Vascular; Humans; Myocardial Infarction

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

We aimed to establish an enzyme-linked immunosorbent assay for measuring soluble elastin fragments (sELAF) in serum and to reveal its usefulness in diagnosing acute aortic dissection (AAD).. An enzyme-linked immunosorbent assay to measure sELAF in serum was developed by using the newly created double monoclonal antibodies, which recognize the different epitopes of human aortic elastin. Twenty-five AAD patients, 50 patients with acute myocardial infarction (AMI), and 474 healthy individuals were enrolled in the study. The sELAF levels from healthy subjects gradually increased with aging. When the cutoff point for positivity was set at the mean+3 SD (ie, 3 SD above the mean in healthy subjects at each age), 16 AAD patients (64.0%) were found be positive, whereas only 1 AMI patient was found to be positive (2.0%). AAD patients with either an open or a partially open pseudolumen were found be 88.9% positive for sELAF, whereas those with its early closure were 0% positive. The difference in the sELAF levels between AAD patients with and without a thrombotic closure of false lumen was significant (60.3+/-15.6 versus 135.4+/-53.2 ng/mL, respectively; P<0.005).. The sELAF level in serum may be a useful marker for helping in the diagnosis and screening of AAD and may also help to distinguish AAD from AMI.

Topics: Acute Disease; Adult; Aged; Aortic Aneurysm; Aortic Dissection; Biomarkers; Case-Control Studies; Diagnosis, Differential; Elastin; Enzyme-Linked Immunosorbent Assay; Female; Humans; Male; Middle Aged; Myocardial Infarction; Reference Values; Risk Factors

Myocardial infarction (MI) is among the leading causes of death worldwide. Following MI, necrotic cardiomyocytes are replaced by a stiff collagen-rich scar. Compared to collagen, the extracellular matrix protein elastin has high elasticity and may have more favorable properties within the cardiac scar. We sought to improve post-MI healing by introducing tropoelastin, the soluble subunit of elastin, to alter scar mechanics early after MI.. We developed an ultrasound-guided direct intramyocardial injection method to administer tropoelastin directly into the left ventricular anterior wall of rats subjected to induced MI. Experimental groups included shams and infarcted rats injected with either PBS vehicle control or tropoelastin. Compared to vehicle treated controls, echocardiography assessments showed tropoelastin significantly improved left ventricular ejection fraction (64.7±4.4% versus 46.0±3.1% control) and reduced left ventricular dyssynchrony (11.4±3.5 ms versus 31.1±5.8 ms control) 28 days post-MI. Additionally, tropoelastin reduced post-MI scar size (8.9±1.5% versus 20.9±2.7% control) and increased scar elastin (22±5.8% versus 6.2±1.5% control) as determined by histological assessments. RNA sequencing (RNAseq) analyses of rat infarcts showed that tropoelastin injection increased genes associated with elastic fiber formation 7 days post-MI and reduced genes associated with immune response 11 days post-MI. To show translational relevance, we performed immunohistochemical analyses on human ischemic heart disease cardiac samples and showed an increase in tropoelastin within fibrotic areas. Using RNA-seq we also demonstrated the tropoelastin gene. We demonstrate for the first time that purified human tropoelastin can significantly repair the infarcted heart in a rodent model of MI and that human cardiac fibroblast synthesize elastin. Since human cardiac fibroblasts are primarily responsible for post-MI scar synthesis, our findings suggest exciting future clinical translation options designed to therapeutically manipulate this synthesis.

Topics: Animals; Cicatrix; Collagen; Elastin; Humans; Myocardial Infarction; Myocardium; Myocytes, Cardiac; Rats; Stroke Volume; Tropoelastin; Ventricular Function, Left; Ventricular Remodeling

A previous study has found an association between chronic inflammatory disorders e.g. psoriasis, rheumatoid arthritis, and inflammatory bowel disease and increased vascular stiffness(1). Psoriasis and hidradenitis suppurativa (HS) are believed to have shared comorbidities and pathophysiology despite their morphologically different manifestations in the skin. In order to evaluate a putative association between the chronic inflammatory skin disease HS and arterial stiffness, an observational cross-sectional retrospective study was carried out as part of the Danish General Suburban Population Study (GESUS) (1), in which 430 patients with HS from the general population (representing mild HS; Table 1), 32 patients with HS from a hospital-based out-patient clinic (representing severe HS, Table 1), and 20,780 controls underwent measurements of arterial vascular tone and stiffness using photoplethysmography (Pulse Trace PCA2®; Micro Medical Ltd, Kent, UK). The method of Pulse Trace has been validated by correlation with intra-arterial sensing techniques, and is a simple cost-effective screening method[2]. All analyses were performed using SAS 9.3. This study was accepted by the ethics committee of Region Zealand (project number SJ-191, SJ-113, SJ-114) in Denmark (2,3). RESULTS Reflection index (RI) is an expression of arterial vascular tone and stiffness of small arteries. The raw data showed a significantly lower RI for both HS groups groups, compared to controls. The results remained significant when adjusting for confounders (age, sex, smoking and metabolic syndrome) in the out-patient clinic HS group (-11.26 (-17.75- -4.76), P=0.0002*), but not in the population HS group (Table 2). Stiffness index (SI) expresses arterial stiffness in large arteries. Both HS groups showed no significant difference in either SI or vascular age in multivariate analysis, when compared with controls (Table 2). DISCUSSION This study suggests that decreased vascular tone and stiffness of small arteries may be associated with severe HS, and at the same time found no difference in arterial stiffness in large arteries. The significance for the out-patient clinic HS group, but not the population HS group may reflect a dose-response relationship. Vascular tone in vascular smooth muscle cells of small arteries depends on competing vasodilators and vasoconstrictors. We speculate that the inflammation of HS may induce a dysfunctional balance e.g. through increased TNF-alpha with subsequent

Topics: Arteries; Cicatrix; Cross-Sectional Studies; Elastin; Hidradenitis Suppurativa; Histamine; Humans; Hydrocortisone; Inflammation; Myocardial Infarction; Nitric Oxide; Psoriasis; Retrospective Studies; Stroke; Tumor Necrosis Factor-alpha; Vasoconstrictor Agents; Vasodilator Agents

Ischemic heart disease is a leading cause of mortality due to irreversible damage to cardiac muscle. Inspired by the post-ischemic microenvironment, we devised an extracellular matrix (ECM)-mimicking hydrogel using catalyst-free click chemistry covalent bonding between two elastin-like recombinamers (ELRs). The resulting customized hydrogel included functional domains for cell adhesion and protease cleavage sites, sensitive to cleavage by matrix metalloproteases overexpressed after myocardial infarction (MI). The scaffold permitted stromal cell invasion and endothelial cell sprouting in vitro. The incidence of non-transmural infarcts has increased clinically over the past decade, and there is currently no treatment preventing further functional deterioration in the infarcted areas. Here, we have developed a clinically relevant ovine model of non-transmural infarcts induced by multiple suture ligations. Intramyocardial injections of the degradable ELRs-hydrogel led to complete functional recovery of ejection fraction 21 days after the intervention. We observed less fibrosis and more angiogenesis in the ELRs-hydrogel-treated ischemic core region compared to the untreated animals, as validated by the expression, proteomic, glycomic, and histological analyses. These findings were accompanied by enhanced preservation of GATA4

Topics: Animals; Elastin; Hydrogels; Myocardial Infarction; Myocardium; Proteomics; Sheep; Ventricular Remodeling

Fibrosis is characterized by the excessive deposition of extracellular matrix and crosslinked proteins, in particular collagen and elastin, leading to tissue stiffening and disrupted organ function. Lysyl oxidases are key players during this process, as they initiate collagen crosslinking through the oxidation of the ε-amino group of lysine or hydroxylysine on collagen side-chains, which subsequently dimerize to form immature, or trimerize to form mature, collagen crosslinks. The role of LOXL2 in fibrosis and cancer is well documented, however the specific enzymatic function of LOXL2 and LOXL3 during disease is less clear. Herein, we describe the development of PXS-5153A, a novel mechanism based, fast-acting, dual LOXL2/LOXL3 inhibitor, which was used to interrogate the role of these enzymes in models of collagen crosslinking and fibrosis. PXS-5153A dose-dependently reduced LOXL2-mediated collagen oxidation and collagen crosslinking in vitro. In two liver fibrosis models, carbon tetrachloride or streptozotocin/high fat diet-induced, PXS-5153A reduced disease severity and improved liver function by diminishing collagen content and collagen crosslinks. In myocardial infarction, PXS-5153A improved cardiac output. Taken together these results demonstrate that, due to their crucial role in collagen crosslinking, inhibition of the enzymatic activities of LOXL2/LOXL3 represents an innovative therapeutic approach for the treatment of fibrosis.

Topics: Amino Acid Oxidoreductases; Animals; Carbon Tetrachloride; Collagen; Cross-Linking Reagents; Elastin; Enzyme Inhibitors; Extracellular Matrix; Fibrosis; Male; Mice; Mice, Inbred C57BL; Myocardial Infarction; Non-alcoholic Fatty Liver Disease; Rats; Rats, Wistar

There is a need for animal models of plaque rupture. We previously reported that elastin fragmentation, due to a mutation (C1039G(+/-)) in the fibrillin-1 (Fbn1) gene, promotes atherogenesis and a highly unstable plaque phenotype in apolipoprotein E deficient (ApoE(-/-)) mice on a Western-type diet (WD). Here, we investigated whether plaque rupture occurred in ApoE(-/-)Fbn1(C1039G+/-) mice and was associated with myocardial infarction, stroke, and sudden death.. Female ApoE(-/-)Fbn1(C1039G+/-) and ApoE(-/-) mice were fed a WD for up to 35 weeks. Compared to ApoE(-/-) mice, plaques of ApoE(-/-)Fbn1(C1039G+/-) mice showed a threefold increase in necrotic core size, augmented T-cell infiltration, a decreased collagen I content (70 ± 10%), extensive neovascularization, intraplaque haemorrhage, and a significant increase in matrix metalloproteinase-2, -9, -12, and -13 expression or activity. Plaque rupture was observed in 70% of ascending aortas and in 50% of brachiocephalic arteries of ApoE(-/-)Fbn1(C1039G+/-) mice. In ApoE(-/-) mice, plaque rupture was not seen in ascending aortas and only in 10% of brachiocephalic arteries. Seventy percent of ApoE(-/-)Fbn1(C1039G+/-) mice died suddenly, whereas all ApoE(-/-) mice survived. ApoE(-/-)Fbn1(C1039G+/-) mice showed coronary plaques and myocardial infarction (75% of mice). Furthermore, they displayed head tilt, disorientation, and motor disturbances (66% of cases), disturbed cerebral blood flow (73% of cases; MR angiograms) and brain hypoxia (64% of cases), indicative of stroke.. Elastin fragmentation plays a key role in plaque destabilization and rupture. ApoE(-/-)Fbn1(C1039G+/-) mice represent a unique model of acute plaque rupture with human-like complications.

Topics: Animals; Aorta; Apolipoproteins E; Biomarkers; Brachiocephalic Trunk; Cardiomegaly; Carotid Artery, Common; Cerebrovascular Circulation; Death, Sudden; Diet, Western; Disease Models, Animal; Elastin; Female; Fibrillin-1; Fibrillins; Hemorrhage; Hypoxia, Brain; Mice; Microfilament Proteins; Microvessels; Myocardial Infarction; Neovascularization, Pathologic; Nervous System Diseases; Plaque, Atherosclerotic; Rupture, Spontaneous; Stroke; Ventricular Dysfunction, Left

Well-defined inflammation, proliferation, and maturation phases orchestrate the remodeling of the injured myocardium after myocardial infarction (MI) by controlling the formation of new extracellular matrix. The extracellular matrix consists mainly of collagen but also fractions of elastin. It is thought that elastin is responsible for maintaining elastic properties of the myocardium, thus reducing the risk of premature rupture. An elastin/tropoelastin-specific contrast agent (Gd-ESMA) was used to image tropoelastin and mature elastin fibers for in vivo assessment of extracellular matrix remodeling post-MI.. Gd-ESMA enhancement was studied in a mouse model of myocardial infarction using a 7 T MRI scanner and results were compared to those achieved after injection of a nonspecific control contrast agent, gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA). In the infarcted tissue, Gd-ESMA uptake (measured as R1 relaxation rate) steadily increased from day 3 to day 21 as a result of the synthesis of elastin/tropoelastin. R1 values were in good agreement with histological findings. A similar R1 behavior was observed in the remote myocardium. No mature cross-linked elastin was found at any time point. In contrast, Gd-DTPA uptake was only observed in the infarct with no changes in R1 values between 3 and 21 days post-MI.. We demonstrate the feasibility of in vivo imaging of extracellular matrix remodeling post-MI using a tropoelastin/elastin binding MR contrast agent, Gd-ESMA. We found that tropoelastin is the main contributor to the increased MRI signal at late stages of MI where its augmentation in areas of infarction was in good agreement with the R1 increase.

Topics: Animals; Biomarkers; Contrast Media; Disease Models, Animal; Elastin; Feasibility Studies; Female; Gadolinium DTPA; Injections, Intravenous; Magnetic Resonance Imaging, Cine; Mice, Inbred C57BL; Myocardial Infarction; Myocardium; Predictive Value of Tests; Protein Binding; Tropoelastin; Ventricular Remodeling

To prospectively evaluate an elastin-specific MR contrast agent (ESMA) for in vivo targeting of elastic fibers in myocardial infarction (MI) and postinfarction scar remodeling.. MI was induced in C57BL/6J mice (n=40) by permanent ligation of the left anterior descending coronary artery. MRI was performed at 7 and 21 days after MI. The merits of gadolinium-based ESMA (Gd-ESMA) were compared with gadopentetic acid (Gd-DTPA) for infarct size determination, contrast-to-noise ratio (CNR), and enhancement kinetics. Specific binding in vivo was evaluated by blocking the molecular target using nonparamagnetic lanthanum-ESMA. In vivo imaging results were confirmed by postmortem triphenyltetrazolium chloride staining, elastica van Gieson staining, and Western blotting. Delayed enhancement MRI revealed prolonged enhancement of Gd-ESMA in the postischemic scar compared with Gd-DTPA. Infarct size measurements showed good agreement between Gd-ESMA and Gd-DTPA and were confirmed by ex vivo triphenyltetrazolium chloride staining. Preinjection of the blocking lanthanum-ESMA resulted in significantly lower CNR of Gd-ESMA at the infarct site (P=0.0019). Although no significant differences in CNR were observed between delayed enhancement imaging and Gd-DTPA between days 7 and 21 (1.8± versus 3.8; P=ns), Gd-ESMA showed markedly higher CNR on day 21 after MI (14.1 versus 4.9; P=0.0032), which correlated with increased synthesis of tropoelastin detected by Western blot analysis and histology. Higher CNR values for Gd-ESMA further correlated with improved ejection fraction of the mice on day 21 after MI.. Gd-ESMA enables targeting of elastin within the infarct scar in a mouse model of MI. The imaging properties of Gd-ESMA allow quantification of intrascar elastin content in vivo and thereby provide potential for noninvasive characterization of postinfarction scar remodeling.

Topics: Animals; Cicatrix; Contrast Media; Coronary Vessels; Disease Models, Animal; Elastic Tissue; Elastin; Female; Follow-Up Studies; Gadolinium DTPA; Magnetic Resonance Imaging, Cine; Mice; Mice, Inbred C57BL; Myocardial Infarction; Myocardium; Predictive Value of Tests; Prospective Studies; Time Factors

It has been previously reported that oral or intra-peritoneal administration of tanshinone IIA can alleviate the ventricular hypertrophy and fibrosis that develops in rats after experimental cardiac infarction. Our present studies, performed on cultures of human cardiac fibroblasts, investigated the mechanism by which tanshinone IIA produces these beneficial effects. We found that treatment of cardiac fibroblasts with 0.1-10µM tanshinone IIA significantly inhibited their deposition of collagen I, while enhancing production of new elastic fibers. Moreover, both anti-collagenogenic and pro-elastogenic effects of tanshinone IIA occurred only after selective activation of the G protein-coupled estrogen receptor (GPER). This subsequently leads to initiation of the PKA/CREB phosphorylation pathway that inversely modulated transcription of collagen I and elastin genes. Interestingly, treatment of human cardiac fibroblasts with tanshinone IIA additionally up-regulated the production of the 67-kDa elastin binding protein, which facilitates tropoelastin secretion, and increased synthesis of lysyl oxidase, catalyzing cross-linkings of tropoelastin. Moreover, tanshinone IIA also caused up-regulation in the synthesis of collagenolytic MMP-1, but down-regulated levels of elastolytic MMP-2 and MMP-9. In summary, our data validate a novel mechanism in which tanshinone IIA, interacting with a non-classic estrogen receptor, maintains the proper balance between the net deposition of collagen and elastin, allowing for optimal durability and resiliency of the newly deposited matrix.

Topics: Abietanes; Anti-Inflammatory Agents, Non-Steroidal; Cell Line; Collagen Type I; Cyclic AMP Response Element-Binding Protein; Cyclic AMP-Dependent Protein Kinases; Down-Regulation; Elastic Tissue; Elastin; Enzyme Activation; Extracellular Matrix; Humans; Matrix Metalloproteinase 1; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Myocardial Infarction; Myocardium; Myocytes, Cardiac; Phosphorylation; Phytoestrogens; Protein Binding; Protein-Lysine 6-Oxidase; Receptors, Estrogen; Receptors, G-Protein-Coupled; Tropoelastin; Up-Regulation

Many cardiac diseases have been associated with increased fibrosis and changes in the organization of fibrillar collagen. The degree of fibrosis is routinely analyzed with invasive histological and immunohistochemical methods, giving a limited and qualitative understanding of the tissue's morphological adaptation to disease. Our aim is to quantitatively evaluate the increase in fibrosis by three-dimensional imaging of the collagen network in the myocardium using the non-linear optical microscopy techniques Two-Photon Excitation microscopy (TPE) and Second Harmonic signal Generation (SHG). No sample staining is needed because numerous endogenous fluorophores are excited by a two-photon mechanism and highly non-centrosymmetric structures such as collagen generate strong second harmonic signals. We propose for the first time a 3D quantitative analysis to carefully evaluate the increased fibrosis in tissue from a rat model of heart failure post myocardial infarction. We show how to measure changes in fibrosis from the backward SHG (B(SHG)) alone, as only backward-propagating SHG is accessible for true in vivo applications. A 5-fold increase in collagen I fibrosis is detected in the remote surviving myocardium measured 20 weeks after infarction. The spatial distribution is also shown to change markedly, providing insight into the morphology of disease progression.

Topics: Animals; Collagen; Disease Progression; Elastin; Fibrosis; Heart Failure; Imaging, Three-Dimensional; Male; Microscopy, Fluorescence, Multiphoton; Myocardial Infarction; Myocytes, Cardiac; Nonlinear Dynamics; Optical Phenomena; Rats; Rats, Sprague-Dawley

Elastin is a signature protein of the arteries and lungs, thus it was hypothesized that elastin is subject to enzymatic degradation during cardiovascular and pulmonary diseases. The aim was to investigate if different fragments of the same protein entail different information associated to two different diseases and if these fragments have the potential of being diagnostic biomarkers.. Monoclonal antibodies were raised against an identified fragment (the ELM-2 neoepitope) generated at the amino acid position '552 in elastin by matrix metalloproteinase (MMP) -9/-12. A newly identified ELM neoepitope was generated by the same proteases but at amino acid position '441. The distribution of ELM-2 and ELM, in human arterial plaques and fibrotic lung tissues were investigated by immunohistochemistry. A competitive ELISA for ELM-2 was developed. The clinical relevance of the ELM and ELM-2 ELISAs was evaluated in patients with acute myocardial infarction (AMI), no AMI, high coronary calcium, or low coronary calcium. The serological release of ELM-2 in patients with chronic obstructive pulmonary disease (COPD) or idiopathic pulmonary fibrosis (IPF) was compared to controls.. ELM and ELM-2 neoepitopes were both localized in diseased carotid arteries and fibrotic lungs. In the cardiovascular cohort, ELM-2 levels were 66% higher in serum from AMI patients compared to patients with no AMI (p<0.01). Levels of ELM were not significantly increased in these patients and no correlation was observed between ELM-2 and ELM. ELM-2 was not elevated in the COPD and IPF patients and was not correlated to ELM. ELM was shown to be correlated with smoking habits (p<0.01).. The ELM-2 neoepitope was related to AMI whereas the ELM neoepitope was related to pulmonary diseases. These results indicate that elastin neoepitopes generated by the same proteases but at different amino acid sites provide different tissue-related information depending on the disease in question.

Topics: Antibodies, Monoclonal, Murine-Derived; Elastin; Enzyme-Linked Immunosorbent Assay; Epitopes; Female; Humans; Idiopathic Pulmonary Fibrosis; Male; Myocardial Infarction; Plaque, Atherosclerotic; Proteolysis; Pulmonary Disease, Chronic Obstructive

Biodegradable polyurethane patches have been applied as temporary mechanical supports to positively alter the remodeling and functional loss following myocardial infarction. How long such materials need to remain in place is unclear. Our objective was to compare the efficacy of porous onlay support patches made from one of three types of biodegradable polyurethane with relatively fast (poly(ester urethane)urea; PEUU), moderate (poly(ester carbonate urethane)urea; PECUU), and slow (poly(carbonate urethane)urea; PCUU) degradation rates in a rat model of ischemic cardiomyopathy. Microporous PEUU, PECUU or PCUU (n = 10 each) patches were implanted over left ventricular lesions 2 wk following myocardial infarction in rat hearts. Infarcted rats without patching and age-matched healthy rats (n = 10 each) were controls. Echocardiography was performed every 4 wk up to 16 wk, at which time hemodynamic and histological assessments were performed. The end-diastolic area for the PEUU group at 12 and 16 wk was significantly larger than for the PECUU or PCUU groups. Histological analysis demonstrated greater vascular density in the infarct region for the PECUU or PCUU versus PEUU group at 16 wk. Improved left ventricular contractility and diastolic performance in the PECUU group was observed at 16 wk compared to infarction controls. The results indicate that the degradation rate of an applied elastic patch influences the functional benefits associated patch placement, with a moderately slow degrading PECUU patch providing improved outcomes.

Topics: Animals; Biocompatible Materials; Cardiomyopathies; Catheterization; Collagen; Elasticity; Elastin; Female; Heart Ventricles; Hemodynamics; Macrophages; Magnetic Resonance Imaging; Materials Testing; Microscopy, Electron, Scanning; Myocardial Infarction; Myocardial Ischemia; Polyurethanes; Prosthesis Implantation; Rats; Rats, Inbred Lew; Time Factors; Tissue Scaffolds; Ultrasonography

Extracellular matrix (ECM) remodelling of the vessel wall is hypothesized to be an important step in atherosclerosis. Changes of the ECM are associated with the gradual progression of an atherosclerotic lesion from a lipid streak to complicated unstable plaque, leading to a complete vessel occlusion and eventually myocardial infarction (MI). Understanding of this process is critical in the treatment and prevention of ischaemic heart disease (IHD).. We investigated the histopathological characteristics of aortic wall ECM in IHD patients. Collagen I, collagen III and elastin were assessed immunohistochemically in patients with acute MI and those with stable angina, using aortic punch tissues obtained from coronary artery bypass graft surgery. Fluorescence tissue images were analysed using the tissue microarray technique.. The results showed that collagen III expression was found to be significantly lower in the acute MI group (P < 0.001). As a result of this change, the patients with MI also revealed a significant reduction in the collagen III/collagen I ratio. The elastin/collagen III ratio was significantly higher in the MI group (P < 0.001).. Our study provided evidence of a decrease in collagen III content in patients with MI, which could possibly explain the mechanism of plaque vulnerability and weakening of the plaque cap. A reduction in collagen III content, particularly away from the atherosclerotic lesions, might be explained by the systemic vascular changes in patients with MI, and inflammation and immune responses could be potential causes of these systemic transformations. The biochemical mechanisms and factors regulating collagen III production might be potential markers to predict possible cardiovascular events.

Topics: Aged; Angina, Stable; Aorta; Biomarkers; Biopsy; Case-Control Studies; Collagen Type I; Collagen Type III; Coronary Artery Bypass; Elastin; Female; Humans; Immunohistochemistry; Male; Microscopy, Fluorescence; Middle Aged; Myocardial Infarction; Tissue Array Analysis

After a myocardial infarction, thinning and expansion of the fibrotic scar contribute to progressive heart failure. The loss of elastin is a major contributor to adverse extracellular matrix remodelling of the infarcted heart, and restoration of the elastic properties of the infarct region can prevent ventricular dysfunction. We implanted cells genetically modified to overexpress elastin to re-establish the elastic properties of the infarcted myocardium and prevent cardiac failure. A full-length human elastin cDNA was cloned, subcloned into an adenoviral vector and then transduced into rat bone marrow stromal cells (BMSCs). In vitro studies showed that BMSCs expressed the elastin protein, which was deposited into the extracellular matrix. Transduced BMSCs were injected into the infarcted myocardium of adult rats. Control groups received either BMSCs transduced with the green fluorescent protein gene or medium alone. Elastin deposition in the infarcted myocardium was associated with preservation of myocardial tissue structural integrity (by birefringence of polarized light; P < 0.05 versus controls). As a result, infarct scar thickness and diastolic compliance were maintained and infarct expansion was prevented (P < 0.05 versus controls). Over a 9-week period, rats implanted with BMSCs demonstrated better cardiac function than medium controls; however, rats receiving BMSCs overexpressing elastin showed the greatest functional improvement (P < 0.01). Overexpression of elastin in the infarcted heart preserved the elastic structure of the extracellular matrix, which, in turn, preserved diastolic function, prevented ventricular dilation and preserved cardiac function. This cell-based gene therapy provides a new approach to cardiac regeneration.

Topics: Adenoviridae; Animals; Cardiomegaly; Cicatrix; Cloning, Molecular; Diastole; Elastin; Extracellular Matrix; Female; Genetic Therapy; Genetic Vectors; Heart; Heart Failure; Mesenchymal Stem Cells; Myocardial Infarction; Organisms, Genetically Modified; Rats; Rats, Inbred Lew

Myoblast sheet transplantation for cardiac failure is a promising therapy to enhance cardiac function via paracrine mechanism. However, their efficacies of treatment showed a gradual decline. The gene modification of the implanted myoblast is important in improving the long-term results of the treatment. Elastin fiber enhances the extensibility of the infarcted wall and can prevent left ventricular dilation. We therefore hypothesized that the elastin gene modification of the implanted myoblast could strengthen and maintain the long-term improvement effects of cardiac function. In this study, we evaluated long-term follow-up benefits of functional myoblast sheets that secrete elastin in an infarcted model. The animal models were divided into three groups: a group transplanted with nontransfected, wild-type, skeletal myoblast-type sheets (WT-rSkM); group transplanted with myoblast sheets that secreted elastin fragments (ELN-rSkM); and a control group (ligation only). Cardiac function was examined by echocardiography, and cardiac remodeling after infarction was evaluated by histological examination. The cardiac function was significantly improved and the left ventricle end-diastolic dimensions were significantly reduced in the ELN-rSkM group. Histological analysis showed that left ventricular remodeling was attenuated in the ELN-rSkM group and that elastic fiber was formed in the epicardial area of ELN-rSkM group. The functionalization of myoblast sheet by elastin gene transfer showed the long-term improvement of cardiac function. Expressed recombinant elastin fiber prevented the dilation of the left ventricular chamber after myocardial infarction. The functional myoblast sheet transplantation maintained the treatment effect by the paracrine effect of myoblast and the formed recombinant elastin.

Topics: Animals; Echocardiography; Elastin; Female; Myoblasts, Skeletal; Myocardial Infarction; Myocardium; Rats; Rats, Inbred Lew; Recombinant Proteins; Recovery of Function; Transplantation, Homologous

Cell-based therapy has emerged as a treatment modality for myocardial repair. Especially cardiac resident stem cells are considered a potential cell source since they are able to differentiate into cardiomyocytes and have improved heart function after injury in a preclinical model for myocardial infarction. To avoid or repair myocardial damage it is important not only to replace the lost cardiomyocytes, but also to remodel and replace the scar tissue by "healthy" extracellular matrix (ECM). Interestingly, the role of cardiac stem cells in this facet of cardiac repair is largely unknown. Therefore, we investigated the expression and production of ECM proteins, matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) in human cardiomyocyte progenitor cells (CMPCs) undergoing differentiation towards the cardiomyogenic lineage. Our data suggest that CMPCs have the capacity to synthesize and modulate their own matrix environment, especially during differentiation towards the cardiomyogenic lineage. While undifferentiated CMPCs expressed collagen I, III, IV and fibronectin, but no elastin, during the process of differentiation the expression of collagen I, III, IV and fibronectin increased and interestingly also elastin expression was induced. Furthermore, undifferentiated CMPCs express MMP-1 -2 and -9 and upon differentiation the expression of MMP-1 decreased, while the expression of MMP-2 and MMP-9, although the latter only in the early stage of differentiation, increased. Additionally, the expression of TIMP-1, -2 and -4 was induced during differentiation. This study provides new insights into the matrix production and remodeling capacity of human CMPCs, with potential beneficial effects for the treatment of cardiac injury.

Topics: Cell Differentiation; Cells, Cultured; Collagen; Elastin; Extracellular Matrix; Extracellular Matrix Proteins; Fibronectins; Humans; Matrix Metalloproteinase 1; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Myocardial Infarction; Myocytes, Cardiac; Stem Cells; Tissue Inhibitor of Metalloproteinases

Cathepsin-L (CTSL) is a member of the lysozomal cysteine protease family, which participates in remodelling of various tissues. Herein, we sought to examine the potential regulation of CTSL in cardiac remodelling post-infarction.. Experimental myocardial infarction (MI) was created in CTSL-deficient (Ctsl(-/-)) mice (B6 × FSB/GnEi a/a Ctsl(fs)/J) and wild-type littermates (Ctsl(+/+)) by left coronary artery ligation. At days 3, 7, 14, and 28 post-MI, we monitored survival rate and evaluated cardiac function, morphology, and molecular endpoints of repair and remodelling. Survival was 56% in Ctsl(-/-) mice in contrast to 80% (P < 0.05) in Ctsl(+/+) mice post-MI by day 28. The Ctsl(-/-) mice exhibited greater scar dilatation, wall thinning, and worse cardiac dysfunction when compared with Ctsl(+/+) mice. Cardiac matrix metallopeptidase-9 (MMP-9) activity was also diminished, and c-kit-positive cells, natural killer cells, fibrocytes, and monocytes mobilized to peripheral blood and deposited to the infarcted myocardium were significantly decreased in Ctsl(-/-) mice. Furthermore, the local inflammatory response, and granulocyte-colony stimulating factor, stem cell factor (SCF), and stromal cell-derived factor-1 (SDF-1α) expression, as well as cell proliferation, revascularization, and myofibroblast deposition were significantly decreased in Ctsl(-/-) mice compared with Ctsl(+/+) mice.. Our data indicate that CTSL regulates cardiac repair and remodelling post-MI through a mechanism with multiple pathways.

Topics: Animals; Bone Marrow; Cathepsin L; Cell Proliferation; Collagen; Cytokines; Disease Models, Animal; Elastin; Endothelial Cells; Enzyme Activation; Male; Matrix Metalloproteinase 9; Mice; Mice, Knockout; Myocardial Infarction; Myocardium; Myofibroblasts; Neovascularization, Physiologic; Proto-Oncogene Proteins c-kit; Time Factors; Ventricular Function, Left; Ventricular Remodeling

Congestive heart failure developing after acute myocardial infarction (AMI) is a major cause of morbidity and mortality. Clinical trials of cell-based therapy after AMI evidenced only a moderate benefit. We could show previously that suspensions of apoptotic peripheral blood mononuclear cells (PBMC) are able to reduce myocardial damage in a rat model of AMI. Here we experimentally examined the biochemical mechanisms involved in preventing ventricular remodelling and preserving cardiac function after AMI. Cell suspensions of apoptotic cells were injected intravenously or intramyocardially after experimental AMI induced by coronary artery ligation in rats. Administration of cell culture medium or viable PBMC served as controls. Immunohistological analysis was performed to analyse the cellular infiltrate in the ischaemic myocardium. Cardiac function was quantified by echocardiography. Planimetry of the infarcted hearts showed a significant reduction of infarction size and an improvement of post AMI remodelling in rats treated with suspensions of apoptotic PBMC (injected either intravenously or intramoycardially). Moreover, these hearts evidenced enhanced homing of macrophages and cells staining positive for c-kit, FLK-1, IGF-I and FGF-2 as compared to controls. A major finding in this study further was that the ratio of elastic and collagenous fibres within the scar tissue was altered in a favourable fashion in rats injected with apoptotic cells. Intravenous or intramyocardial injection of apoptotic cell suspensions results in attenuation of myocardial remodelling after experimental AMI, preserves left ventricular function, increases homing of regenerative cells and alters the composition of cardiac scar tissue. The higher expression of elastic fibres provides passive energy to the cardiac scar tissue and results in prevention of ventricular remodelling.

Topics: Animals; Apoptosis; Cells, Cultured; Cicatrix; Collagen; Echocardiography; Elastin; Humans; Leukocytes, Mononuclear; Male; Myocardial Infarction; Myocardium; Rats; Rats, Sprague-Dawley; Suspensions; Ventricular Remodeling

Ventricular dilation after myocardial infarction can cause heart failure. Increasing strength and elasticity in the infarct region might prevent ventricular dilation. Because elastin provides strength, extensibility, and resilience to tissues and maintains tissue architecture, we studied the effect of elastin expression in the infarct on scar expansion and heart function. COS-7 cells transfected with a plasmid with an elastin gene fragment or a vector were seeded into a Gelfoam mesh and cultured. Mechanical stretch test (n = 5/group) showed that the elastin mesh was more elastic (P < 0.05) and tensile (P < 0.05) than the vector mesh. In an in vivo study in rats, 6 days after left anterior descending coronary artery ligation, COS-7 cells (Cell group, n = 7) or COS-7 cells with elastin gene (Elastin group, n = 9) or vector (Vector group, n = 9) were transplanted into the infarct; infarcted rats served as controls (n = 7). Over 8 wk the Cell group did not demonstrate effects on scar expansion and deterioration of heart function vs. controls. In contrast, infarct expansion was smaller and heart function was better maintained in the Elastin group vs. the Vector group (P < 0.05). At 8 wk after cell transplantation Langendorff data showed that the Elastin group had greater (P < 0.01) developed pressure and a smaller left ventricular volume than the Vector group. Western blot and histology showed accumulated elastin in the Elastin group infarct. Changing the extracellular matrix composition of a myocardial infarct by increasing elastin fragment content attenuated scar expansion, ventricular dilation, and onset of heart dysfunction.

Topics: Animals; Aorta; Base Sequence; Chlorocebus aethiops; Cicatrix; COS Cells; DNA Primers; Elastin; Extracellular Matrix; Genetic Vectors; Heart; Myocardial Infarction; Peptide Fragments; Rats; Recombinant Proteins; Reverse Transcriptase Polymerase Chain Reaction; Transfection

After a myocardial infarction, the injured region becomes fibrotic and the myocardial scar may expand if the ventricular wall lacks elasticity. Cardiac dilatation may precipitate the vicious cycle of progressive heart failure. The present study evaluated the functional benefits of increasing elastin within a myocardial scar using cell based gene therapy.. A myocardial infarction was generated by ligation of the left anterior descending artery in rats. Six days later, 2 x 10(6) syngeneic rat endothelial cells transfected with the rat elastin gene (elastin group, n=14) or an empty plasmid (control group, n=14) were transplanted into the infarct scar. Cardiac function, left ventricular (LV) volume, and infarct size were monitored over 3 months by echocardiography, Langendorff measurements, and planimetry. Elastin deposition was evaluated in the cells and in the infarct region by Western blot assay and by histological examination. Recombinant elastin was found in the scar in the elastin group but not the control group during the 3 months after cell transplantation. Histological assessment demonstrated organized elastic fibers within the infarct region. LV volume and infarct size were significantly smaller (P<0.05) in the elastin group than in the control group. Cardiac function evaluated by echocardiography and during Langendorff perfusion was significantly better (P<0.05) in the elastin group than in the control group.. Expressing recombinant elastin within the myocardial scar reduced scar expansion and prevented LV enlargement after a myocardial infarction. Altering matrix remodeling after an infarct preserved the LV function for at least 3 months.

Topics: Animals; Cells, Cultured; Cicatrix; Drug Evaluation, Preclinical; Elastin; Endothelial Cells; Extracellular Matrix; Genetic Therapy; Heart Failure; Hypertrophy, Left Ventricular; Male; Myocardial Infarction; Myocardium; Random Allocation; Rats; Rats, Inbred Lew; Recombinant Fusion Proteins; Single-Blind Method; Transfection; Ultrasonography; Ventricular Function, Left; Ventricular Remodeling

Autologous cell transplantation may restore viable muscle after a myocardial infarction. We compared the effect of three cell types or an angiotensin-converting enzyme (ACE) inhibitor on preservation of ventricular function after cardiac injury.. A uniform transmural myocardial scar was created in adult rats by cryoinjury. Three weeks later the rats were randomly assigned to one of four blinded treatments: transplantation with 5 x 10(6) aortic smooth muscle cells (SMC, n = 12), ventricular heart cells (VHC, n = 13), skeletal muscle cells (SKC, n = 13) or culture medium alone (control, n = 11). The ACE inhibitor group (n = 8) received enalapril (1.0 mg/kg per day), also beginning 3 weeks after cryoinjury. Five and 12 weeks after transplantation, left ventricle (LV) function was assessed in a Langendorff apparatus, and histologic and immunohistological evaluation of the LV scars was performed.. At 5 weeks, greater scar elastin content and better LV function was noted with cell transplantation or ACE inhibitor therapy compared with control rats (p < 0.05). Twelve weeks after transplantation, cell-transplanted rats still had greater elastin content and better LV function than control rats, although elastin content and LV function had declined in ACE inhibitor-treated animals to levels below those observed in control rats (p < 0.05).. Transplantation of SMC, VHC, and SKC preserved ventricular function equivalent to the effects of an ACE inhibitor. Muscle cell transplantation, but not ACE inhibitor therapy, continues to be effective later after cryoinjury. No differences were detected between the muscle cells.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Aorta; Cardiac Output, Low; Cell Transplantation; Cells, Cultured; Cicatrix; Cryopreservation; Elastin; Enalapril; Heart Injuries; Heart Ventricles; Immunohistochemistry; Muscle, Skeletal; Muscle, Smooth, Vascular; Myocardial Infarction; Myocardium; Rats; Rats, Inbred Lew; Ventricular Function, Left

Topics: Adult; Aortic Stenosis, Supravalvular; Cytosine; Elastin; Exons; Female; Frameshift Mutation; Humans; Male; Mutation; Myocardial Infarction; Nuclear Family; Point Mutation; Sequence Deletion

Central venous catheters (CVC) in the internal jugular vein have become an important adjunct to the overall management of intensive care patients, but their use is associated with frequent neck complications. In a review of the literature anatomical variation in size, form and function of the valve system of the internal vein was found.. This study macroscopically and microscopically investigates the anatomical variety of the vein valves of the inferior internal jugular vein.. 100 cadavers from legal autopsies were investigated. We selected 45 patients with an acute myocardial infarction death and a control group (55 patients) formed by different causes of death. The veins were prepared for light microscopic study, the specimens were serially sectioned (ca. 30 sections) and stained with hematoxylin and eosin.. Anatomical variety was observed predominantly unilateral on the right side of the internal jugular vein. The valves were often bicuspid at the right side (92%) and tricuspid on the left side (64%) and mostly located ca. 2 cm above the subclavia-jugularis bifurcation. In the histological study, a variability of the net of collagen and elastin fibres in the tunica intima and media was observed. The structure of the adventitia was constant. 18 patients with a jugular valve vein incompetence (age over 60) appeared to have thickening of the tuberculum in the sinus of the valve. The cups of the valves were found rudimentary in these patients with advanced stages of tricuspid incompetence.. The present study demonstrates the variety of the valves of the jugular vein. They play an important role to impede the retrograde flow during cardiopulmonary resuscitation as well as in jugular vein cannulation.

Topics: Adolescent; Adult; Aged; Autopsy; Cadaver; Cause of Death; Child; Child, Preschool; Collagen; Coloring Agents; Elastin; Female; Humans; Infant; Infant, Newborn; Jugular Veins; Male; Middle Aged; Myocardial Infarction; Resuscitation; Tunica Intima; Tunica Media

We report a 3-year-old child with Williams syndrome in whom the first vascular feature of the syndrome was a myocardial infarction related to the occlusion of the left main coronary artery trunk. This coronary artery occlusion was not associated with supravalvular aortic stenosis.. This report emphazises that acute vascular events related to systemic artery anomalies may reveal Williams syndrome.

Topics: Child, Preschool; Chromosomes, Human, Pair 7; Coronary Angiography; Coronary Artery Bypass; Elastin; Humans; Long QT Syndrome; Male; Myocardial Infarction; Risk Factors; Williams Syndrome

Early reperfusion after a coronary occlusion may reduce myocardial infarct size, but late reperfusion into necrotic myocardium may alter post-infarction healing. In rabbits, we compared 1- or 3-week-old scars resulting from permanent coronary occlusion to those resulting from a 1- or 3-hour occlusion followed by reperfusion. Reperfusion at 1 hour post-occlusion did not affect scar mechanical properties assessed at 1 week post-infarction, but at 3 weeks post-infarction, these scars had a tensile strength significantly lower than those not reperfused (78 +/- 11 vs. 158 +/- 15 g/mm2, P less than 0.001). They also were composed of a mixture of fibrous tissue (58 +/- 8%) and myocytes (43 +/- 8%) with a hydroxyproline content of 23 +/- 2.5 mg/g dry weight. The nonreperfused scars had a higher proportion of fibrous tissue (73 +/- 3%) by histological evaluation and a 35% higher hydroxyproline content (31 +/- 2 mg/g dry weight, P less than 0.001) than the scars reperfused after 1 hour. In contrast, 3-week-old scars resulting from "late" reperfusion at 3 hours post-occlusion were similar to nonreperfused scars in fibrous tissue composition and hydroxyproline content. Nonetheless, the tensile strength of these scars reperfused 3 hours post-occlusion was significantly less than that of the nonreperfused scars (72 +/- 5 vs. 158 +/- 15 g/mm2, P less than 0.001). The lower tensile strength was associated with a lower collagen cross-link density in this reperfused group of scars. At physiological stress levels (approximately 3 g/mm2), all groups of reperfused and nonreperfused scars had similar mechanical properties in terms of natural strain, stiffness, creep, and stress relaxation. Thus, although the reperfused scars ruptured more easily at high stresses, when assessed at physiological stresses their mechanical properties were not significantly different from those of nonreperfused scars.

Topics: Animals; Arteries; Cicatrix; Collagen; Coronary Vessels; Desmosine; Elastin; Hydroxyproline; Ligation; Male; Myocardial Infarction; Norleucine; Perfusion; Rabbits; Stress, Mechanical; Tensile Strength