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Query: UMLS:C0020473 (hyperlipidemia)
 15,891 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In this unifying hypothesis directed to the etiology and pathogenesis of atherosclerosis, the importance of focal arterial lesion-prone sites has been emphasized. Key initial participants in these sites include the focal intimal influx and accumulation of low-density lipoprotein (LDL) and a preferential recruitment of blood monocytes. Both are further enhanced in the presence of hyperlipidemia, when the quantity of intimal LDL and the oxidative potential of the intima exceed the capacity of macrophages to remove, via the non-down-regulating scavenger receptor, cytotoxic anionic (Ox-LDL) macromolecules. Foam cells, pathognomonic of the fatty streak, form during the receptor-mediated uptake of Ox-LDL by the macrophages. Interstitial free radicals and the excess of Ox-LDL particles injure and kill cells, including the foam cells, with the formation of the necrotic extracellular lipid core, a key transitional step in lesion progression. Monocyte-macrophage recruitment to the intima is likely to be regulated not only by a multiplicity of endothelial adhesive cytokines, integrins, and selectins, but also by the monocyte-specific chemoattractant, MCP-1, constitutively synthesized and secreted by intimal smooth muscle and endothelial cells. Its synthesis and secretion is augmented by mildly oxidized LDL. Free radicals, pivotal in the oxidation of LDL, and derived from activated macrophages, and also endothelial and smooth muscle cells. Smooth muscle cells migrate from the media through the intimal endothelial layer (IEL) and proliferate under the regulation of a number of mitogens, including platelet-derived growth factor (PDGF). Collagen synthesis by smooth muscle cells is substantial. Lymphocytes, as a source of interferons, invade the plaque and are present in the adventitia in substantial numbers, likely representing an autoimmune response in the later stages of plaque development. Platelets and mural thrombosis directly contribute to subsequent plaque growth, particularly after plaque rupture or fissure and disruption of the thromboresistant endothelial cells (EC). Plaque regression in all likelihood involves the conversion of the inert pool of extracellular lipid to a metabolically active intracellular pool and subsequent clearance by the high-density lipoprotein mediated reverse cholesterol transport system. The atherogenic cascades so described conceptually represent arterial inflammatory and healing processes occurring in a hyperlipidemic environment. Many components of pathogenesis are the targets for modulation by genetic, hemodynamic and selected risk factors. The prevention and treatment of the disease should logically target reduction in plasma LDL levels, the inhibition of the oxidative modification of lipoproteins, including LDL, by free radical scavengers, and augmentation of the reverse cholesterol transport system.
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PMID:The pathogenesis of atherosclerosis: an overview. 204 53

Based on the findings presented in this study, we propose the hypothesis that calcium could be a mediator for the development of atherosclerosis. Figure 8 shows a schematic illustration of the hypothesis. The presence of risk factors such as hypertension, hyperlipidemia, and smoking may increase the influx of calcium into vascular ECs. We have shown that reactive oxygen species, which are considered to be a risk factor for the development of atherosclerosis, actually increase [Ca++]i in vascular ECs. Increased intracellular calcium may damage the function of ECs, resulting in platelet aggregation at the damaged site. Increased intracellular calcium may also increase uptake of macromolecules in plasma such as fibrinogen and LDL, eventually forming atherosclerotic plaque. We have also shown that the influx of calcium into vascular ECs is associated with LDL transport across vascular ECs. The pretreatment by nifedipine inhibited both the increase in [Ca++]i and the increase in LDL transport, suggesting that intracellular calcium modulates LDL transport across ECs. Growth factors released from platelets may provoke migration and proliferation of medial SMCs in the aterial intima. It has been reported that migration of SMCs from arterial media to intima is enhanced by the presence of calcium, and can be inhibited by the pretreatment of calcium antagonist. As demonstrated in this study, calcium also plays an important role in the proliferation of SMCs provoked by some kinds of growth factors such as EGF. On the other hand, we found that an increased amount of dietary Mg suppressed the development of atherosclerotic lesions in the aorta of cholesterol-fed rabbits without affecting plasma total cholesterol and HDL-cholesterol concentrations. The mechanism of action might also be related to the calcium entry blocking action. The clinical and nutritional implications of these phenomena should be investigated further. The evidences presented in this study, however, would not be sufficient to fully explain the etiological role of calcium in atherogenesis. Further studies are required to elucidate the mechanism of the contribution of calcium to atherogenesis. The efficacy of calcium antagonist for the prevention of atherosclerosis in humans should also be investigated further.
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PMID:The role of calcium and magnesium in the development of atherosclerosis. Experimental and clinical evidence. 224 57

New Zealand strain white male rabbits were divided into four groups to study the effects of 8501, extracted from a Chinese herb, on hyperlipidemia and the TXA2/PGI2 ratio in atherosclerotic rabbits. The results indicate that serum cholesterol and the levels of cholesterol and cholesteryl ester in aortic tissue were significantly increased in cholesterol-fed rabbits. The percentage of alpha-lipoprotein was significantly decreased and the aortic atherosclerotic plaque area was significantly increased. The data also demonstrate that the level of plasma TXB2 was markedly increased, while that of 6-keto-PGF1 alpha was significantly decreased. The TXB2/6-keto-PGF1 alpha ratio (T/6) was significantly increased. The decrease of 6-keto-PGF1 alpha occurred prior to the increase of TXB2. Compound 8501 not only lowered serum total cholesterol and aortic total cholesterol and cholesteryl ester but also antagonized the decrease of alpha-lipoprotein and atherosclerotic plaque formation. In addition, 8501 prevented the decrease of plasma 6-keto-PGF1 alpha and the increase of TXB2, and so the T/6 ratio was significantly decreased.
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PMID:Effects of purified compound (8501) on hyperlipidemia and the balance between thromboxane A2 and prostacyclin in rabbits. 229 35

Coronary arteriography was performed in 1,029 consecutive patients with ischemic heart disease and the relationship between the arteriographic features of coronary atherosclerosis and coronary risk factors was analyzed by case control studies. Patients were divided into four groups according to coronary arteriographic findings. Patients with normal or near normal coronary arteriograms (Group I) showed a high prevalence of smoking habit and a higher value of serum uric acid compared with the control group, so smoking and hyperuricemia were considered to be the risk factors for coronary atherosclerosis in patients of group. Four selected variables: smoking, hyperuricemia, hypertension and hyperlipidemia, were identified to be risk factors for the patients with minor plaques in the coronary arteries (Group II). As in Group I, smoking and hyperuricemia had a close relationship to solitary tight plaque in a branch of the coronary artery (Group III). Multiple tight stenoses in the coronary arteries (Group IV) correlated closely with smoking, hyperuricemia, hypertension, hyperlipidemia and diabetes mellitus. Thus, there were many strong risk factors for patients with diffuse, extended coronary atherosclerosis (Group II and Group IV), while only two factors, smoking and hyperuricemia, were considered to be risk factors for the patients with near normal coronary arteries ies or a solitary plaque in a branch of the coronary artery. These findings suggest that the role of the coronary risk factors on the pathogenesis of coronary atherosclerosis is not uniform but variable depending on the morphologic variability of the coronary atherosclerosis and on the pathophysiology of the ischemic heart disease.
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PMID:Relationship between coronary risk factor and arteriographic feature of coronary atherosclerosis. 239 25

Arteries respond to long-term changes in flow rate by alterations in caliber that tend to restore wall shear stress to normal baseline levels. Changes in radius, pressure, or geometric configuration elicit changes in structure and composition of the media in keeping with the altered level and distribution of tensile stresses. Similar stabilizing adaptations occur in the presence of conditions that induce the formation of atherosclerotic plaques, but the ultimate effectiveness of these reactions is variable. Several recent experiments provide information on the possible effects of hyperlipidemia on the smooth muscle cell (SMC) response to normal or increased levels of mechanical stress: (a) Normolipemic serum increases collagen synthesis by SMCs grown on purified elastin membranes compared to synthesis in serum-free medium, but synthesis is not further enhanced by cyclic stretching of the cells. Collagen production increase is less marked in hyperlipemic serum, but cyclic stretching raises synthesis to a degree comparable to that noted for serum-free medium. (b) The increase in artery diameter in response to increased flow rate and the elaboration of media components in relation to the increase in diameter are not hampered by hyperlipidemia. (c) The compensatory enlargement of arteries in response to plaque formation is not prevented by hyperlipidemia even in the presence of hypertension. (d) The healing of a transmural necrotizing injury of the media is, however, retarded and incomplete in the presence of hyperlipidemia. These findings indicate that hyperlipidemia per se does not necessarily interfere with the SMC response to mechanical stimuli. The usual adaptive reactions remain intact.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Limited effects of hyperlipidemia on the arterial smooth muscle response to mechanical stress. 247 33

High correlation of plasma lipid levels, especially low density lipoprotein (LDL) cholesterol levels, with the risk of coronary heart disease has been clearly indicated by epidemiologic studies. This study was undertaken to use an animal model of nondiet-induced hyperlipidemia in the homozygous Watanabe heritable hyperlipidemic rabbit (WHHL) to evaluate the effect of plasma cholesterol lowering on the progression of atherosclerosis, and to correlate plasma cholesterol levels with the amount of atherosclerotic plaque. Studies were carried out on ten homozygous WHHL rabbits divided into two groups: lipid lowering (treated) and control (nontreated). Lipid lowering was accomplished by thermofiltration (on-line plasma membrane filtration at 39 degrees C for removal of VLDL and LDL). The treated group had a significantly lower mean plasma level of total cholesterol over the course of the study than the nontreated group (293 vs. 655 mg/dl, p = 0.004). The amount of aortic atherosclerotic plaque in the treated group was also significantly lower than that in the control group (16.9 vs. 44.2%, p = 0.003). Microscopically, thickness measurements of the atherosclerotic lesions revealed that the control group had a thicker intima than the treated group. This study convincingly demonstrated the slowing or interdiction of progression of atherosclerotic lesions with lowering of the plasma total cholesterol level by thermofiltration.
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PMID:The effect of extracorporeal cholesterol removal on the progression of atherosclerosis. 259 78

Accumulating mainly experimental evidence from research of the last 3 decades shows that many types of arterial wall injury can accelerate and intensify the development of atherosclerosis in arteries exposed to chronic hyperlipemia by increasing the permeability of their endothelium for plasma lipoproteins, proteins and several types of smooth muscle mitogens (including soluble platelet-derived growth factor). Of the numerous artery-injuring agents studied experimentally today only those that can be proven to operate in humans at concentrations and durations of action that injure animal arteries can be accepted as capable of playing a role in human atherogenesis. Seven such groups of agents can be recognized at present: blood turbulence, hypertension, certain viruses, metabolic disturbances (including hyperlipemia), certain immune insults, exogenous chemicals, and obstruction of adventitial lymphatics. Most of the above agents cause various degenerative changes in individual endothelial cells or open interendothelial junctions, and they seem to promote the penetration of plasma macromolecules into the wall in 3 different ways: directly through the altered endothelial cytoplasm, through opened interendothelial junctions or through transport in the cytoplasm of immigrating monocytes. None of the commonly occurring injury agents produce complete endothelial denudation of wide areas of the arterial cylinders. New findings from the transmission electron microscopic study of step-serial sections of human arteries obtained under conditions minimizing artificial endothelial loss indicate that endothelial denudation accompanied by platelet adherence and aggregation does not occur over early myoproliferative lesions but occasionally develops over small areas of advanced plaques with mostly necrotic or damaged caps and is, therefore, not an initiating event but a late complication of atherosclerosis. Light microscopic serial section studies of human thrombosed vessels in several centers reveal that thrombogenesis in most human atherosclerotic arteries is initiated by a severe structural injury of the cap of advanced plaques that leads to a microscopic break of the plaque surface through which some blood can enter the plaque interior before it is sealed by a thrombus.
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PMID:The role of arterial wall injury in atherogenesis and arterial thrombogenesis. 268 99

Three main atherogenic processes are recognised today: hyperlipemia, arterial wall injury and parietal thrombosis. The role of hyperlipemia is supported, among other things, by the following: 1. Experimentally, protracted hyperlipemia can reproduce faithfully the lesions and all complications of advanced human atherosclerosis. 2. Immunohistochemically, plaque lipoproteins are identical with certain blood lipoproteins. 3. The incidence of atherosclerosis in different populations roughly parallels the average blood lipid levels of these populations. 4. Dietary and pharmacological reductions of blood lipid levels in certain populations have reduced the clinical manifestations of atherosclerosis in these populations. Prolonged hyperlipemia generates arterial plaques by causing penetration of blood lipids into the myocytes of the inner arterial wall, immigration of lipid-laden monocytes into the subendothelial space, and increased endothelial permeability for blood lipoproteins and mitogens. All types of arterial wall injury diminish the endothelial barrier and increase endothelial permeability for blood lipoproteins and mitogenic factors. Seven groups of naturally occurring arterial insults are recognised today: hemodynamic turbulence, hypertension, metabolic insults (including hyperlipemia), immune insults, viruses, exogenous chemicals, and obstruction of adventitial lymphatics. These insults usually cause a functional increase of endothelial permeability (when mild) or a loosening of interendothelial junctions (when intense). Parietal thrombosis develops practically only in atherosclerotic-almost never in normal-arteries. It is most frequently initiated by tiny breaks of plaque surfaces, breaks which expose blood to the highly thrombogenic collagen and lipid masses that abound in the atherosclerotic--but are absent from the normal arterial wall. parietal thrombi are overgrown by endothelium, turned into fibrous tissue and incorporated into the underlying plaques, whose thickness they can thus greatly increase.
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PMID:[New aspects on the etiology and pathogenesis of arteriosclerosis from the pathologic viewpoint]. 304 56

Atherosclerosis can be defined in terms of the processes involved rather than in morphological terms, and there is evidence for possible roles of the macrophage in atherogenesis. The relevance of hyperlipidaemia to the morphogenesis of the atherosclerotic plaque is important, and this has been described in animal models including a strain of rabbit with a genetically determined hyperlipidaemia resembling familial combined hyperlipidaemia. Treatment of these animals with the HMG CoA reductase inhibitor lovastatin from the time of weaning results in a significant degree of inhibition of lesion formation.
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PMID:Interaction of lipoproteins with the artery wall. 307 20

Current concepts of the pathogenesis of atherosclerosis have been reviewed, emphasizing some of the similarities of the mechanisms and events involved to those in inflammation. Figure 2 is a schematic summary of these events. Hyperlipidemia, or some component of hyperlipidemic serum, as well as other risk factors, are thought to cause endothelial injury, resulting in adhesion of platelets and/or monocytes and release of PDGF (and other growth factors), which leads to smooth muscle migration and proliferation. It is clear that endothelial injury need not be denuding, and in fact may consist of altered endothelial function (dysfunction); adhesion of monocytes, increased permeability of endothelium, and disturbances in growth control can occur without morphologically obvious endothelial injury. Hyperlipidemia, hypertension, smoking, immune injury, and other risk factors may contribute to this endothelial dysfunction in different ways and sometimes in combination. Smooth muscle cells produce large amounts of collagen, elastin, and proteoglycans and these form part of the atheromatous plaque. Hyperlipidemia contributes in a number of ways (as discussed earlier), and indeed, in the severely hypercholesterolemic patient, such as one with familial hypercholesterolemia, is alone sufficient to cause atherosclerosis in the absence of other risk factors. Foam cells of atheromatous plaques are derived both from macrophages and from smooth muscle cells; from macrophages via the beta-VLDL receptor and also possibly by way of LDL modification, recognized by the acetyl-LDL receptor (such as oxidized LDL); and from smooth muscle cells by less certain mechanisms. Extracellular lipid is derived from insudation from the lumen, particularly in the presence of hypercholesterolemia, and also from degenerating foam cells. Cholesterol accumulation in the plaque should be viewed as reflecting imbalance between influx and efflux, and it is possible that high-density lipoprotein is the molecule which helps clear the cholesterol from these accumulations (134). The diagram (right) also depicts the possibility that smooth muscle proliferation may occur without endothelial injury at all. There are several postulated mechanisms for such an occurrence: loss of growth control, direct smooth muscle injury (such as by LDL), and autonomous proliferation by the mechanisms suggested by Benditt. The theoretical scheme presented is based largely on in vitro work, only partly substantiated by experimental and human studies, and does not explain the precise mechanisms by which all risk factors increase the susceptibility to atherosclerosis.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:The pathogenesis of atherosclerosis: atherogenesis and inflammation. 327 59


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