elastin and Coronary-Artery-Disease

Four classes of agents capable of producing human illness have been identified: toxicity, heredity, infection and deficiency. The leading paradigm for the etiology and pathophysiology of ischemic heart disease in the 20th century was that of intoxication by too much of the wrong kind of dietary fat. This overemphasis on lipid metabolism persists because important data are neglected and because of inattention to details. For example, heart disease risk does not correlate with fat intake within nations in contrast to between nations. Also development of ischemic heart disease involves inter alia arterial spasm, cardiac rhythm, metabolism of connective tissue, glucose and homocysteine, plus paraoxonase activity and thrombus formation which generally are unaffected by dietary fat. Homocysteine thiolactone accumulates when homocysteine is high. This lactone specifically inhibits lysyl oxidase which depends on copper to catalyze cross linking of collagen and elastin in arteries and bone. The lactone is hydrolyzed by paraoxonase, activity of which can be decreased by copper deficiency. Just as cholesterol was an important focus for heart disease as intoxication, homocysteine can become an excellent focus for a paradigm shift to heart disease as deficiency because supplementation with several nutrients can alter homocysteine metabolism and decrease its plasma concentration. These supplements include betaine, copper, folate, pyridoxine and vitamin B-12. Opportunities for research on ischemic heart disease as deficiency disease are plentiful.

Topics: Animals; Aryldialkylphosphatase; Catalysis; Collagen; Coronary Artery Disease; Cross-Linking Reagents; Dietary Supplements; Elastin; Glucose; Heart Diseases; Homocysteine; Humans; Hydrolysis; Lipid Metabolism; Myocardial Ischemia; Vitamins

Vascular calcification occurs at two distinct sites within the vessel wall: the intima and the media. Intimal calcification occurs in the context of atherosclerosis, associated with lipid, macrophages and vascular smooth muscle cells, whereas medial calcification can exist independently of atherosclerosis and is associated with elastin and vascular smooth muscle cells.. In this review we compare intimal and medial calcification, particularly discussing the mechanisms which may be responsible for each type of calcification. Similar mechanisms probably initiate and regulate both forms of calcification including the generation of matrix vesicles/apoptotic bodies and local expression of mineralization-regulating proteins. However, since different modifying agents such as lipids in the intima and elastin in the media are present at the sites of calcification and are associated with particular diseases, this implies that the etiologies of these processes differ. For example, intimal calcification is associated with atherosclerosis while medial calcification occurs commonly in the diabetic neuropathic leg.. Since both types of calcification correlate with significant morbidity and mortality, we discuss the different types of calcification in terms of their clinical importance.

Topics: Adult; Age Factors; Aged; Animals; Apoptosis; Arteriosclerosis; Calcinosis; Cells, Cultured; Coronary Artery Disease; Diabetic Neuropathies; Elastin; Endothelium, Vascular; Gene Expression; Humans; Lipid Metabolism; Mice; Mice, Knockout; Muscle, Smooth, Vascular; Phenotype; Risk Factors; Tunica Intima

This report is the continuation of two earlier reports that defined human arterial intima and precursors of advanced atherosclerotic lesions in humans. This report describes the characteristic components and pathogenic mechanisms of the various advanced atherosclerotic lesions. These, with the earlier definitions of precursor lesions, led to the histological classification of human atherosclerotic lesions found in the second part of this report. The Committee on Vascular Lesions also attempted to correlate the appearance of lesions noted in clinical imaging studies with histological lesion types and corresponding clinical syndromes. In the histological classification, lesions are designated by Roman numerals, which indicate the usual sequence of lesions progression. The initial (type I) lesion contains enough atherogenic lipoprotein to elicit an increase in macrophages and formation of scattered macrophage foam cells. As in subsequent lesion types, the changes are more marked in locations of arteries with adaptive intimal thickening. (Adaptive thickenings, which are present at constant locations in everyone from birth, do not obstruct the lumen and represent adaptations to local mechanical forces). Type II lesions consist primarily of layers of macrophage foam cells and lipid-laden smooth muscle cells and include lesions grossly designated as fatty streaks. Type III is the intermediate stage between type II and type IV (atheroma, a lesion that is potentially symptom-producing). In addition to the lipid-laden cells of type II, type III lesions contain scattered collections of extracellular lipid droplets and particles that disrupt the coherence of some intimal smooth muscle cells. This extracellular lipid is the immediate precursor of the larger, confluent, and more disruptive core of extracellular lipid that characterizes type IV lesions. Beginning around the fourth decade of life, lesions that usually have a lipid core may also contain thick layers of fibrous connective tissue (type V lesion) and/or fissure, hematoma, and thrombus (type VI lesion). Some type V lesions are largely calcified (type Vb), and some consist mainly of fibrous connective tissue and little or no accumulated lipid or calcium (type Vc).

Topics: Aneurysm; Arteriosclerosis; Blood Vessels; Calcium; Collagen; Coronary Artery Disease; Coronary Vessels; Elastin; Extracellular Matrix; Fibrinogen; Foam Cells; Humans; Lipid Metabolism; Lipoproteins; Lymphocytes; Muscle, Smooth, Vascular; Proteoglycans; Thrombosis; Tunica Intima

Kawasaki disease (KD) is the most common acquired heart disease in children of the developed world, and triggers progressive coronary artery lesions (CAL) in 30% of cases if left untreated. Despite standard anti-inflammatory treatment for KD, CAL (dilation or aneurysm) still occurs in 5-10% of children, increasing their risk for fatal coronary artery complications. CAL is mediated by enhanced matrix metalloproteinase activity and elastin breakdown induced by the inflammatory process in the coronary artery wall. Doxycycline is an effective inhibitor of matrix metalloproteinases, and has been shown to reduce elastin breakdown and CAL in a mouse model of KD, but has not been evaluated in patients.. We aim to evaluate the efficacy of doxycycline in the prevention of CAL in children during the acute phase of KD.. This is a phase II prospective, randomized, double-blinded, clinical trial in two steps. In Step 1, any child older than 1month with the diagnosis of KD will be included. Children with KD will be included in Step 2 if they develop coronary artery dilation (z-score≥2.5) within 20days from the onset of fever. Study subjects in Step 2 will be randomized to receive a 3-week course of doxycycline or placebo.. The efficacy of a 3-week doxycycline course during the acute phase of KD will be evaluated by measuring the decline in coronary artery z-scores from baseline with doxycycline treatment compared to placebo.. This study was registered on clinicaltrials.gov (NCT01917721).

Topics: Adolescent; Child; Child, Preschool; Coronary Artery Disease; Double-Blind Method; Doxycycline; Echocardiography; Elastin; Female; Humans; Infant; Male; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Mucocutaneous Lymph Node Syndrome; Prospective Studies

Damage to elastin fibres in coronary media might lead to coronary artery ectasia (CAE). This study evaluated whether CAE can be distinguished by detecting circulating soluble elastin (s-elastin), which is a degradation product of elastin fibres, and elastase, which is the main enzyme of elastin fibres.. Fifty-eight patients with CAE, 58 with coronary heart disease (CHD) and 61 with relatively normal coronary arteries, were included. Circulating s-elastin and elastase were measured, and receiver operating characteristic curves were used to demonstrate their respective optimal cut-off values for predicting CAE.. The concentrations of s-elastin and elastase were higher in the CAE group than in the CHD and relatively-normal-coronary groups. Their cut-off values for screening of CAE were 13.148 ng/mL and 25.549 ng/mL, respectively; for sensitivity of CAE were 0.690 and 0.773, respectively; and for specificity of CAE were 0.862 and 0.571, respectively. A combination of s-elastin and elastase in series (one of the two higher than its cut-off value) had a better sensitivity for screening for CAE, whereas their combination in parallel (both higher than their cut-off values) had a better specificity.. Circulating s-elastin and elastase are promising biomarkers for assisting in CAE diagnosis.

Topics: Coronary Angiography; Coronary Artery Disease; Dilatation, Pathologic; Elastin; Humans; Pancreatic Elastase

Dysregulation of the metabolism of the extracellular matrix (ECM) may contribute to coronary artery ectasia (CAE). This study evaluated the turnover of main ECM components and related proteolytic enzymes activities. In this study, thirty patients with CAE, 30 patients with coronary artery disease (CAD) and 30 subjects with normal coronary arteries (Control) were selected. The following circulating ECM metabolism markers were measured: soluble elastin (sElastin), collagen type I cross-linked telopeptides (ICTP), procollagen type I carboxy terminal peptide (PICP), protocollagen III N-terminal propeptide (PIIINP), and procollagen a1(III) C-terminal propeptide (PIIICP). Serum total elastase activity and total matrix metalloproteinase (MMP) activity were also determined. The level of sElastin was higher in the CAE group than in the CAD and Control groups (P1 = 0.009, P2 = 0.000). There was no difference in ICTP (P = 0.168) or PIIICP (P = 0.079) among the three groups. PICP was significantly elevated in CAE (P1 = 0.001, P2 = 0.002). PIIINP was also significantly increased in CAE (P1 = 0.002, P2 = 0.007). Total elastase activity was higher in the CAE group than in the other two groups (P1 = 0.006, P2 = 0.022). Total MMP activity was significantly higher in the CAE group than the Control group (P2 = 0.013) but not higher than the CAD group (P1 = 0.477). In conclusion, within CAE patients the main changes in ECM metabolism were increased degradation of elastin fibres and the transition of collagen from type III to type I. Elastase and MMPs appear to be associated with this kind of ECM turnover.

Topics: Aged; Biomarkers; Case-Control Studies; Collagen Type I; Collagen Type III; Coronary Artery Disease; Coronary Vessels; Dilatation, Pathologic; Elastin; Extracellular Matrix; Female; Humans; Male; Matrix Metalloproteinases; Middle Aged; Pancreatic Elastase; Peptide Fragments; Proteolysis

Proteolytic enzymes possibly contribute to coronary artery ectasia (CAE). This study aimed to determine whether neutrophils, neutrophil serine proteases (NSPs), and their endogenous inhibitors participated in the pathological process of CAE.. The study consisted of 30 patients with CAE, 30 patients with coronary artery disease (CAD), and 29 subjects with normal coronary arteries (Control). The following circulating items were measured: the main NSPs, including human neutrophil elastase (HNE), cathepsin G (CG), and proteinase 3 (PR3); soluble elastin (sElastin), which was a degradation product of elastin fibres; NSP inhibitors such as α1-protease inhibitor (α1-PI), α2-macroglobulin (α2-MG), secretory leucoprotease inhibitor (SLPI), and elafin; as well as two neutrophil activation markers (myeloperoxidase and lactoferrin) and three classic neutrophil activators [tumor necrosis factor-α (TNF-α), interleukin-8 (IL-8), and bacterial endotoxin].. The levels of HNE, CG, and sElastin were elevated in the CAE group. The levels of α1-PI and α2-MG were also significantly increased in the CAE group. The levels of myeloperoxidase and lactoferrin were higher in the CAE group. The levels of TNF-α, IL-8, and endotoxin were unchanged in the CAE group compared with those in the CAD group.. Neutrophils may participate in the process of vessel extracellular matrix destruction and coronary ectasia by releasing NSPs in a non-classical manner.

Topics: Case-Control Studies; Cathepsin G; Coronary Artery Disease; Cross-Sectional Studies; Dilatation, Pathologic; Elastin; Female; Fibrinolysis; Humans; Leukocyte Elastase; Male; Middle Aged; Neutrophils; Serine Proteases

Elastin is a major arterial structural protein, and elastin-derived peptides are related to arterial change. We previously reported on a novel assay developed using aortic elastin peptides; however, its clinical implications remain unclear. In this study, we assessed whether anti-elastin antibody titers reflect the risk of coronary artery disease (CAD) or its characteristics.. We included 174 CAD patients and 171 age- and sex-matched controls. Anti-elastin antibody titers were quantified by enzyme-linked immunosorbent assay. Parameters of arterial stiffness, including the augmentation index (AI) and heart-to-femoral pulse wave velocity (hfPWV), were measured non-invasively. The clinical and angiographic characteristics of CAD patients were also evaluated. Associations between anti-elastin levels and vascular characteristics were examined by linear regression analysis.. The median blood level of anti-elastin was significantly lower in the CAD group than in the controls [197 arbitrary unit (a.u.) vs. 63 a.u., p<0.001]. Levels of anti-elastin were significantly lower in men and in subjects with hypertension, diabetes mellitus, hyperlipidemia, or high hfPWV. Nevertheless, anti-elastin levels were not dependent on atherothrombotic events or the angiographic severity of CAD. In a multivariate analysis, male sex (β=-0.38, p<0.001), diabetes mellitus (β=-0.62, p<0.001), hyperlipidemia (β=-0.29, p<0.001), and AI (β=-0.006, p=0.02) were ultimately identified as determinants of anti-elastin levels.. Lower levels of anti-elastin are related to CAD. The association between antibody titers and CAD is linked to arterial stiffness rather than the advancement of atherosclerosis.

Topics: Aged; Angiography; Antibodies; Atherosclerosis; Coronary Artery Disease; Elastin; Enzyme-Linked Immunosorbent Assay; Female; Humans; Hyperlipidemias; Hypertension; Male; Middle Aged; Pulse Wave Analysis; Vascular Stiffness

To investigate the potential of endogenous multispectral fluorescence lifetime imaging microscopy (FLIM) for biochemical characterization of human coronary atherosclerotic plaques.. Endogenous multispectral FLIM imaging was performed on the lumen of 58 segments of postmortem human coronary artery. The fluorescence was separated into three emission bands targeting the three main arterial endogenous fluorophores (390±20 nm for collagen, 452±22.5 nm for elastin, and 550±20 for lipids). The fluorescence normalized intensity and average lifetime from each emission band was used to classify each pixel of an image as either "High-Collagen", "High-Lipids" or "Low-Collagen/Lipids" via multiclass Fisher's linear discriminant analysis.. Classification of plaques as either "High-Collagen", "High-Lipids" or "Low-Collagen/Lipids" based on the endogenous multispectral FLIM was achieved with a sensitivity/specificity of 96/98%, 89/99%, and 99/99%, respectively, where histopathology served as the gold standard.. The endogenous multispectral FLIM approach we have taken, which can readily be adapted for in vivo intravascular catheter based imaging, is capable of reliably identifying plaques with high content of either collagen or lipids.

Topics: Autopsy; Biomarkers; Collagen; Coronary Artery Disease; Coronary Vessels; Discriminant Analysis; Elastin; Feasibility Studies; Humans; Linear Models; Lipids; Microscopy, Fluorescence; Plaque, Atherosclerotic; Predictive Value of Tests; Reproducibility of Results; Sensitivity and Specificity

To investigate the influence of hypertension on large artery elasticity and the microstructure of the ascending aortic media in patients with coronary artery disease (CAD), and the association between arterial compliance and composition of the ascending aorta.. 60 patients with CAD who underwent coronary artery bypass graft surgery were divided into two groups: 30 patients in a hypertension group and 30 patients in a non-hypertension group. Carotid-femoral pulse wave velocity (cfPWV) was measured by an automatic device (Complior, Artech, France). The severity of coronary atherosclerosis was assessed after selective coronary angiography using the Gensini score system. A quantitative study was conducted on ascending aorta specimens by histological and computer image analysis.. cfPWV of the hypertension group was higher than that of the non-hypertension group. The relative content of collagen in the ascending aortic media of the hypertension group was higher than that of the non-hypertension group, while the relative content of elastin in the ascending aortic media of the hypertension group was lower than that of the non-hypertension group. cfPWV showed a positive correlation with relative contents of collagen in the ascending aorta and a negative correlation with relative contents of elastin in the ascending aorta in the two groups.. Hypertension may raise the contents of collagen and decrease the contents of elastin in the ascending aortic media of patients with CAD, which in turn may decrease the patients' large artery compliance. cfPWV may reflect the quantitative changes of collagen and elastin in the ascending aortic media in CAD patients independently of hypertension.

Topics: Aged; Aorta; Blood Flow Velocity; Blood Pressure; Carotid Arteries; Chi-Square Distribution; Collagen; Coronary Artery Disease; Elasticity; Elastin; Female; Femoral Artery; Humans; Hypertension; Male; Middle Aged; Pulse; Tunica Media

Laser-induced fluorescence (LIF) and intrinsic fluorescence spectroscopy (IFS) have been used experimentally for diagnosing coronary atherosclerosis. In this study, we demonstrated the diagnostic superiority of IFS at 342-nm excitation (IFS(342)) versus LIF (LIF(342)) and described a protocol for head-to-head comparison of old (LIF) versus new (IFS) generations of similar diagnostic methods, labeled as "generational comparison model". IFS(342) and LIF(342) were modeled with basis spectra of media, fibrous caps, and superficial foam cells and of their correspondent chemicals (elastin, collagen, and lipoproteins). The average accuracy and receiver operating characteristic area under the curve of IFS(342) in single-, double-, and triple-parameter diagnostic algorithm iterations, geared toward identifying 84 atherosclerotic specimens from a group of 117 coronary segments, was 90% ± 1% and 0.87 ± 0.025, superior to LIF(342) (84% ± 3% and 0.84 ± 0.016; P = 0.0002 and 0.02, respectively) in a generational comparison model.

Topics: Algorithms; Collagen; Coronary Artery Disease; Coronary Vessels; Diagnostic Imaging; Elastin; Foam Cells; Humans; Lasers; Reproducibility of Results; Spectrometry, Fluorescence

Kawasaki disease (KD) is an acute inflammatory illness marked by coronary arteritis. However, the factors increasing susceptibility to coronary artery lesions are unknown. Because transforming growth factor (TGF) β increases elastin synthesis and suppresses proteolysis, we hypothesized that, in contrast to the benefit observed in aneurysms forming in those with Marfan syndrome, inhibition of TGF-β would worsen inflammatory-induced coronary artery lesions. By using a murine model of KD in which injection of Lactobacillus casei wall extract (LCWE) induces coronary arteritis, we show that LCWE increased TGF-β signaling in the coronary smooth muscle cells beginning at 2 days and continuing through 14 days, the point of peak coronary inflammation. By 42 days, LCWE caused fragmentation of the internal and external elastic lamina. Blocking TGF-β by administration of a neutralizing antibody accentuated the LCWE-mediated fragmentation of elastin and induced an overall loss of medial elastin without increasing the inflammatory response. We attributed these increased pathological characteristics to a reduction in the proteolytic inhibitor, plasminogen activator inhibitor-1, and an associated threefold increase in matrix metalloproteinase 9 activity compared with LCWE alone. Therefore, our data demonstrate that in the coronary arteritis associated with KD, TGF-β suppresses elastin degradation by inhibiting plasmin-mediated matrix metalloproteinase 9 activation. Thus, strategies to block TGF-β, used in those with Marfan syndrome, are unlikely to be beneficial and could be detrimental.

Topics: Animals; Cell Wall; Collagen Type I; Complex Mixtures; Coronary Artery Disease; Coronary Vessels; Disease Models, Animal; Elastin; Lacticaseibacillus casei; Matrix Metalloproteinase 9; Mice; Mucocutaneous Lymph Node Syndrome; Plasminogen Activator Inhibitor 1; Protein Processing, Post-Translational; Signal Transduction; Transforming Growth Factor beta; Tropoelastin

Kawasaki disease (KD) is a multisystem vasculitis leading to damage in the coronary circulation and aneurysm formation. Because cardiac tissue from affected children is not available, investigation of the mechanisms responsible for coronary artery damage in KD requires use of a disease model. The present study was undertaken to examine, in an experimental model, the role of matrix metalloproteinase 9 (MMP-9) on coronary artery inflammation and vascular damage.. C57BL/6 mice were injected with Lactobacillus casei cell wall extract to induce coronary arteritis. Hearts were isolated and assayed for MMP-9 protein expression and enzymatic activity by immunoblotting or confocal microscopy and zymography, respectively. MMP-9-deficient mice were used to examine the necessity of MMP-9 for disease development.. Localized inflammation at the coronary artery led to elastin breakdown and aneurysm formation. This occurred in the absence of smooth muscle cell apoptosis. Following disease induction, there was an increase in the amount and enzymatic activity of MMP-9, an elastolytic protease. MMP-9 was up-regulated by tumor necrosis factor alpha (TNFalpha) and produced primarily by vascular smooth muscle cells. In MMP-9-deficient animals, vascular inflammation continued to develop, but the incidence of elastin breakdown was significantly reduced. Elastin breakdown in the coronary artery was virtually eliminated by ablation of MMP-9.. These findings show that TNFalpha up-regulates expression of MMP-9, an important proteinase responsible for extracellular matrix breakdown, leading to coronary artery damage in this model of KD. These results have important implications regarding treatments for improving coronary outcome in affected children.

Topics: Animals; Apoptosis; Bacterial Proteins; Coronary Artery Disease; Coronary Vessels; Disease Models, Animal; Elasticity; Elastin; Gene Expression Regulation, Enzymologic; Lacticaseibacillus casei; Matrix Metalloproteinase 9; Mice; Mice, Inbred C57BL; Mice, Knockout; Mucocutaneous Lymph Node Syndrome; Muscle, Smooth, Vascular; Tumor Necrosis Factor-alpha

Patients with diabetes are at substantially increased risk for atherosclerosis and clinical cardiovascular events. Because arterial extracellular matrix contains several molecules, including biglycan, versican, hyaluronan, and elastin, that may affect plaque lipid retention and stability, we determined whether diabetes affects plaque content of these molecules in a porcine model of hyperlipidemia and diabetes. Coronary artery sections were studied from non-diabetic normolipidemic (n=11, N-NL), diabetic normolipidemic (n=10, DM-NL), non-diabetic hyperlipidemic (n=16, N-HL), and diabetic hyperlipidemic (n=15, DM-HL) animals. Hyaluronan, biglycan, versican, and apolipoprotein B (apoB) were detected with monospecific peptides or antisera, and elastin with Movat's pentachrome stain, and contents of each were quantified by computer-assisted morphometry. In the hyperlipidemic groups, diabetes was associated with a 4-fold increase in intimal area, with strong correlations between intimal area and immunostained areas for hyaluronan (R(2) = 0.83, p<0.0001), biglycan (R(2) = 0.72, p<0.0001), and apoB (R(2) = 0.23, p=0.0069). In contrast, median (interquartile range) intimal elastin content was significantly lower with diabetes [N-HL: 5.2% (2.4-8.2%) vs DM-HL: 1.5% (0.5-4.2%), p=0.01], and there was a strong negative correlation between intimal total and elastin areas (Spearman r = -0.62, p=0.001). In this porcine model, diabetes was associated with multiple extracellular matrix changes that have been associated with increased lesion instability, greater atherogenic lipoprotein retention, and accelerated atherogenesis.

Topics: Animals; Apolipoproteins B; Biglycan; Coronary Artery Disease; Coronary Vessels; Diabetes Mellitus, Experimental; Elastin; Extracellular Matrix; Extracellular Matrix Proteins; Hyaluronic Acid; Hyperlipidemias; Lipoproteins, LDL; Male; Proteoglycans; Swine; Tunica Intima; Versicans

Coronary artery remodeling implies structural changes in the vessel wall in response to various pathophysiologic conditions. However, the classification of remodeling is unclear. We hypothesized that the adaptive, positive-outward remodeling is a reactive and compensatory response to the stress. The maladaptive negative-inward constrictive remodeling is a passive atherosclerotic condition in which the vessel becomes stiffer.. Patients with atherosclerotic lesions underwent intravascular ultrasound (IVUS) scans. The size of the vessels distal to and proximal to plaques were analyzed by IVUS. Diabetes was created in mice by an intraperitoneal injection of alloxan (65 mg/kg). To reduce remodeling, mice received ciglitazone, an agonist of peroxisome proliferators activated receptor-gamma (PPARgamma) in drinking water. After 8 weeks, atherosclerotic vessels were analyzed for collagen and elastin.. IVUS data suggest an adaptive coronary arterial remodeling was a positive compensatory response to various pathologic stimuli; for example, with the deposition of atherosclerotic plaque, coronary arterial segments enlarged to maintain luminal area. This phenomenon was commonly observed during the initial phases of the development of atherosclerosis. However, negative coronary artery remodeling, or a decrease in vessel area with the formation of atherosclerotic plaque, was maladaptive and was associated with smoking, hypertension, hyperhomocysteinemia, diabetes mellitus, and also after percutaneous coronary interventions (restenosis). In diabetic mice, there was increased collagen and decreased elastin contents; however, treatment with ciglitazone ameliorated the decrease in elastin contents.. Global enlargement of the coronary vascular tree occurs during pressure and volume overload associated with ventricular hypertrophic states such as athletic conditioning, hypertensive heart disease, and dilated cardiomyopathy. On the other hand, maladaptive coronary arterial remodeling occurs in patients with severe deconditioning, diabetes mellitus, after coronary artery bypass surgery, and in some instances, postintervention.

Topics: Animals; Collagen; Coronary Artery Disease; Coronary Vessels; Diabetes Complications; Diabetes Mellitus, Experimental; Elastin; Humans; Hyperhomocysteinemia; Male; Mice; PPAR gamma; Thiazolidinediones; Ultrasonography

Heart disease is directly associated with aging as well as progression of atherosclerosis. The vessels begin to stiffen with age. It is speculated that the increase in stiffness can occur as a result of either increase progression of atherosclerosis or possibly due to the deterioration of the elastic components of the arterial wall. Regardless of the mechanism, an increase in vessel stiffness can lead to significant increase in the pathophysiological progression of the disease. The overall objectives of this investigation were to evaluate the coronary artery obtained from cadavers in their 7th, 8th and 9th of life and characterized the level of atherosclerosis and to identify using special elastin staining techniques the involvement of fiber disruption in atherosclerosis. The coronary arteries were obtained from cadaveric donors at the University of Saskatoon (average age 81.7 years, range 77-92 years of age). The arteries were fixed, sectioned and stained for routine analysis as well as with an Elastin staining protocol. The arteries were screened and the level of atherosclerosis was measured as well as thickness changes within the arteries. Digital imaging was used to capture the areas of elastin disruption. The overall results suggest elastin disruption occurs as the atherosclerotic plaque progresses. The imaging system in conjunction with elastin staining allows for a very sensitive method to analyze the tissue for the progression of pathophysiological disease mechanisms.

Topics: Aged; Aged, 80 and over; Aging; Arteries; Cadaver; Coronary Artery Disease; Coronary Vessels; Elastin; Female; Humans; Image Enhancement; Male; Microscopy

The Dahl sodium-sensitive hypertensive rat exhibits atherogenic lesions after the initiation of a high-sodium/high-fat diet. This study was designed to gauge the effect of a preadolescent high-fat diet on the postadolescent rate of atherogenesis after supplementation of the diet with sodium.. Fifty-three Dahl S male rats were assigned to 2 dietary groups for the postweaning to early adolescence period (3 to 12 weeks): 29 to a standard diet (low-fat/low-sodium) and 24 to a high-fat/low-sodium diet. At age 9 weeks (just after puberty), animals from the high-fat group exhibited a relatively diminished density of coronary elastic fibers. There was no evidence of either lipid or monocytic infiltration of the subendothelial space. At age 12 weeks, most or all of the remaining animals in both groups were switched to a high-sodium/high-fat diet and were sampled through the following 8 weeks for the appearance of arterial lipid. After the switch, the high-fat-conditioned animals developed more extensive atherosclerotic pathological lesions more rapidly than their prepubertal standard-diet counterparts. The importance of the animal's stage of maturation in this effect was underscored by the observation that delaying onset of the high-fat diet to early adolescence resulted in no ultimate difference from the pubertal controls in elastic fiber density.. The maturation-dependent high-fat conditioning of these postweanling rats correlated with an accelerated rate of atherogenesis on the initiation of the high-sodium/high-fat diet, possibly as a direct result of an alteration in arterial elasticity.

Topics: Aging; Animals; Coronary Artery Disease; Coronary Vessels; Diet, Atherogenic; Diet, Sodium-Restricted; Dietary Fats; Disease Models, Animal; Disease Progression; Elastic Tissue; Elastin; Lipids; Male; Rats; Rats, Inbred Dahl; Sexual Maturation; Sodium, Dietary

Vulnerable plaque generally contains a thin fibrous cap, lipid pools, and reduced internal plaque collagen. Arterial fluorescence analysis can differentiate atherosclerotic lesions from normal arteries; however, the contribution of the lipid core to atherosclerotic arterial fluorescence remains controversial. This study aimed to identify lipid core fluorophores and to differentiate the lipid core from normal artery and atheroma. The helium-cadmium laser-induced fluorescence spectra of cadaveric arteries and known chemical constituents were recorded. Lipid core fluorescence spectra exhibited marked red shifts and broadening compared with the fluorescence spectra of normal tissue and atheroma. Similar fluorescence spectra were obtained for lipid core and oxidized low density lipoprotein, for atheroma and collagen, and for normal artery and elastin. A classification based on collagen, elastin, and oxidized low density lipoprotein spectral decomposition could discriminate the lipid core (n=29), normal artery (n=74), atheroma (n=73), and preatheroma (n=10) with 86% accuracy. Fibrous cap thickness was correlated with the spectral collagen content index (r=0.65, P<0.0001), especially at a thickness of <200 microm. We conclude that a classification algorithm based on chemical spectral decomposition can accurately classify the fluorescence spectra of normal artery, atheroma, and lipid core and may be useful in identifying vulnerable atheroma in vivo.

Topics: Adult; Algorithms; Arterial Occlusive Diseases; Cadaver; Collagen; Coronary Artery Disease; Elastin; Femoral Artery; Humans; Lasers; Lipids; Lipoproteins, LDL; Microscopy, Fluorescence; Oxidation-Reduction

To obtain more detailed information about the relationship of intimal thickening to defects in the elastin structure of the arterial wall, the internal elastic lamina and subsequent elastin formation in the intima was studied by very oblique sectioning of paraffin sections of the arterial wall, and by scanning electron microscopy of formic acid digested preparations. Comparison was made in the same subject between the internal thoracic artery (a vessel showing only slight intimal thickening) and the anterior descending coronary (which usually develops advanced intimal thickening). There was no evidence of penetration of the normal fenestrations of the internal elastic lamina by medial smooth muscle cells. This took place through major defects of this lamina and resulted in a change from transverse to longitudinal orientation of these cells and the accompanying elastin fibers of the intima. A further condensation of elastin (greater for the internal thoracic) occurred in the intima subjacent to the endothelial cells.

Topics: Adolescent; Adult; Child; Child, Preschool; Coronary Artery Disease; Coronary Vessels; Elastin; Female; Humans; Infant; Infant, Newborn; Male; Microscopy, Electron, Scanning; Middle Aged; Thoracic Arteries; Tunica Intima

Constrictive remodeling plays a prominent role in restenosis after balloon angioplasty, but its regulation remains unclear. Because endothelial dysfunction and changes in extracellular matrix have been reported after angioplasty, this study was designed to simultaneously evaluate endothelial function and collagen and elastin changes after restenosis and arterial remodeling.. Atherosclerosis was induced in femoral arteries of 22 New Zealand White rabbits by air-desiccation and a high-cholesterol diet. One month later, angioplasty was performed. Histomorphometry and in vitro assessment of endothelial function were performed 4 weeks after angioplasty. Restenosis correlated with constrictive remodeling (r=0.60, P=0.01) but not with neointimal growth (r=-0.06, P=0.79). Restenosis correlated with an impaired relaxation to acetylcholine (ACh; r=0.61, P=0.02) but not with the response to the endothelium-independent vasodilator sodium nitroprusside (r=-0.25, P=0.40). Restenosis correlated positively with collagen accumulation (r=0.69, P=0.004) and inversely with elastin density (r=-0.48, P=0.05). Relaxations to ACh were significantly more decreased in arteries with constrictive remodeling than in those with enlargement remodeling (3.7+/-7.9% versus 35.5+/-15.0%, P=0.04). Neointimal collagen density was significantly higher in arteries with constrictive remodeling than in those with enlargement remodeling (34.5+/-4.5% versus 18.2+/-4.7%, P=0.03). Endothelial function and collagen and elastin density were independent predictors of restenosis in the study.. These results demonstrate that the severity of restenosis after angioplasty correlated with both defective endothelium-dependent relaxation and increased collagen density.

Topics: Angioplasty, Balloon; Animals; Collagen; Constriction, Pathologic; Coronary Angiography; Coronary Artery Disease; Coronary Vessels; Elastin; Endothelium, Vascular; Extracellular Matrix; Rabbits; Recurrence; Vasoconstriction

This paper describes a combined ultrasonic and spectroscopic system for remotely obtaining physico-chemical images of normal arterial tissue and atherosclerotic plaque. Despite variations in detector-tissue separation, R, fluorescence powers corresponding to pixels in the image are converted to the same set of calibrated units using distance estimations from A-mode ultrasound reflection times. An empirical model, validated by Monte Carlo simulations of light propagation in tissue, is used to describe changes in fluorescence power as a function of R. Fluorescence spectra of normal and atherosclerotic human aorta obtained with this system are presented as a function of R. To compensate for changes in fluorescence power with R, the empirical model was used in each case to calculate the fluorescence power at a constant reference value of R(Rref = 1.67 mm). Prior to compensation, tissue fluorescence power decreased more than a factor of two as R was increased from 2.5 to 5 mm. Following compensation, the fluorescence power varied less than +/- 10% of the average compensated peak. The chemical composition of each sample was determined by fitting its fluorescence spectrum (in calibrated units) to a model of tissue fluorescence incorporating structural protein and ceroid fluorescence, as well as structural protein and hemoglobin attenuation. Parameters of the fit were used to classify tissue type. Without compensation for distance variation, classification of tissue type was frequently incorrect; however, with compensation, predictive value was high. A 1-D chemical image of a section of human aorta containing both normal and atherosclerotic regions obtained with this system is also presented. After compensation for detector-sample separation, tissue classifications along the cross-section closely resemble those obtained from histology. Regions of elevated ceroid concentration and intimal thickening are clearly observable in the resultant chemical image. The potential value of this type of system in the diagnosis and treatment of coronary artery disease is discussed.

Topics: Aorta; Calibration; Collagen; Coronary Artery Disease; Elastin; Humans; Image Processing, Computer-Assisted; In Vitro Techniques; Models, Cardiovascular; Monte Carlo Method; Predictive Value of Tests; Spectrometry, Fluorescence; Ultrasonography

Since structure-function correlations have not been determined for cryopreserved allograft heart valves, we studied 20 explanted valves in place several hours to nine years, as either orthotopic aortic valves/root replacements or right ventricle to pulmonary artery conduits. They were explanted primarily due to growth-related conduit or valve stenosis, valve regurgitation, or infection. Controls included seven unused cryopreserved allograft valves and 16 aortic valves removed from transplanted allograft hearts obtained at either autopsy (n = 15) or retransplantation (n = 1), two days to four years postoperatively, following myocardial rejection (n = 4), graft coronary arteriosclerosis (n = 4), and other (n = 8). Analysis included gross inspection, radiography, light microscopy, electron microscopy, and immunohistochemical studies (to allow identification/localization of endothelial cells, mononuclear inflammatory cells, and T and B lymphocyte subsets). Cryopreserved allograft valves implanted more than one day had progressively severe loss of normal structure and were devoid of surface endothelium and stainable deep connective tissue cells. Inflammatory cellularity varied from none (most valves) to prominent (primarily T lymphocytes in one valve). Transmission electron microscopy of three long term valvular allografts revealed no viable cells, remarkable preservation of the collagenous valve matrix and focal cell-oriented calcification. In contrast, aortic valves from transplanted hearts showed remarkable structural preservation, including layered architecture, endothelium and deep connective tissue cells; inflammatory infiltrates were generally sparse, even in cases with fatal myocardial rejection. We conclude that cryopreserved allograft valves are morphologically non-viable valves, whose structural basis for function seems primarily related to the largely preserved collagen.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Aortic Valve; Aortic Valve Insufficiency; Aortic Valve Stenosis; B-Lymphocyte Subsets; Calcinosis; Cell Survival; Collagen; Connective Tissue; Coronary Artery Disease; Cryopreservation; Elastin; Endocarditis, Bacterial; Endothelium; Follow-Up Studies; Graft Rejection; Humans; Immunohistochemistry; Leukocytes, Mononuclear; Microscopy, Electron; Pulmonary Valve; Pulmonary Valve Insufficiency; Pulmonary Valve Stenosis; Radiography; T-Lymphocyte Subsets; Tissue Preservation; Transplantation, Homologous

Unstained frozen sections of normal and atherosclerotic human aorta and coronary artery were examined using histochemical and fluorescence microscopic techniques to identify the structures responsible for autofluorescence under 351 to 364 nm laser excitation. These structures included elastin and collagen in normal and atherosclerotic specimens, calcium deposits in calcified plaques, and granular or ring-shaped deposits histochemically identified as ceroid found in both calcified and non-calcified plaques. Qualitatively, both the color and intensity of ceroid autofluorescence differed greatly from that of elastin or collagen. The emission spectra of elastin, collagen, and ceroid were examined by microscopic spectrofluorimetry, and were found to differ significantly as well. When compared with spectra of elastin and collagen, spectra of ceroid were broader, shifted to the red, and were somewhat resistant to bleaching. We conclude that detection of laser-induced ceroid autofluorescence may aid in identifying plaques for laser ablation.

Topics: Angioplasty, Laser; Aorta; Arteriosclerosis; Ceroid; Collagen; Coronary Artery Disease; Coronary Vessels; Elastin; Fluorescence; Humans; In Vitro Techniques; Lasers; Microscopy, Fluorescence; Microscopy, Ultraviolet; Spectrometry, Fluorescence; Ultraviolet Rays

The possibility of elastase contributing to degradation of the arterial wall in atherosclerosis and to the formation of ectasia has prompted us to assay the main protease inhibitors, alpha 1-antitrypsin and alpha 2-macroglobulin, in patients with angiographic coronary disease with and without coronary ectasia. Serum concentrations of these two proteins were measured by immunonephelometry in 203 patients admitted for coronary arteriography. The results obtained were analyzed according to the presence of atheromatous lesions and their severity and to the presence or absence of ectasia. There was no correlation between the values observed and the presence or severity of coronary atherosclerosis, but the concentration of alpha 1-antitrypsin was significantly higher in patients with coronary ectasia (247.2 +/- 40.5 mg/ml) than in patients without ectasia (213.5 +/- 36.6 mg/100 ml; p less than 0.001). This study shows that coronary ectasia is associated with disturbances in the protease-antiprotease system, which may be consecutive to initial changes in elastase activity. Our results support the theory that elastase and protease inhibitors play a specific role in some atheromatous processes.

Topics: Adult; Aged; Coronary Angiography; Coronary Artery Disease; Elastin; Female; Humans; Male; Middle Aged; Protease Inhibitors; Statistics as Topic