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The Pathobiological Determinants of Atherosclerosis in Youth (PDAY) study was organized to document the natural history of athersclerosis and to determine the relation of cardiovascular risk factors to atherosclerosis in young subjects. Pathology laboratories in 15 centers collected coronary arteries, aortas, and other tissues from over 3,000 subjects age 15 to 34 who died of external causes between 1987 and 1994. The extent, prevalence, and topography of arterial lesions were evaluated and risk factors were analyzed in a central laboratory. Postmortem risk factors included serum lipoproteins, serum thiocyanate (smoking), glycohemoglobin (diabetes), thickness of panniculus adiposus and body mass index (obesity), changes in small renal arteries (hypertension), and apoprotein isoforms. The PDAY study confirmed the origin of atherosclerosis in childhood, showed that progression toward clinically significant lesions may occur in young adulthood and demonstrated that the progression of atherosclerosis is strongly influenced by coronary heart disease (CHD) risk factors. Recent PDAY studies have shown that a significant number of advanced coronary artery lesions have microscopic qualities associated with susceptibility to rupture and that CHD risk factors are associated with the development of these characteristic microscopic qualities. The PDAY archive continues to provide an important resource for new investigators throughout the world that contribute to the understanding of atherosclerosis, the underlying cause of most cardiovascular disease and the leading cause of debilitating illness and death in this country. The PDAY findings emphasize the need to modify risk factors in young people to retard the development of atherosclerotic lesions, particularly clinically significant lesions. Thus, true primary prevention of atherosclerosis must being in childhood or early adolescence.
Pediatr Pathol Mol Med
PMID:Natural history and risk factors of atherosclerosis in children and youth: the PDAY study. 1194 37

Cardiovascular disease is the leading cause of death in most industrialized countries. However, the diagnosis and management of coronary heart disease is far from optimal. Lipoprotein-associated phospholipase A2 (Lp-PLA2), also known as platelet-activating factor acetylhydrolase, is an enzyme that hydrolyses oxidized phospholipids and is primarily associated with low-density lipoprotein. Discussed in this review is the accumulating evidence supporting the view that Lp-PLA2 is a potential biomarker of coronary heart disease and plays and an important proinflammatory role in the progression of atherosclerosis. A new ELISA method for the quantitative measurement of Lp-PLA2 mass in human plasma developed by diaDexus, Inc. is presented. Furthermore, potential clinical applications of Lp-PLA2 mass measurements are proposed.
Expert Rev Mol Diagn 2002 Jan
PMID:Lp-PLA2: an emerging biomarker of coronary heart disease. 1196 98

Epidemiological and interventional studies indicate that dietary n-3 PUFA reduces mortality due to coronary heart disease (CHD). They act at a low dose, since one or two meals with fatty fish per week is sufficient to provide protection when compared with no fish intake. These fatty acids are effective in providing primary prevention in low- and high-risk subjects and secondary prevention. At high doses, dietary n-3 PUFAs have several beneficial properties. First, they act favourably on blood characteristics: they are hypocholesterolemic and hypotriglyceridemic; they reduce platelet aggregation; they exhibit antithrombotic and fibrinolytic activities; they reduce blood viscosity and they exhibit antiinflammatory action. Second, they reduce ischemia/reperfusion-induced cellular damage. This effect is apparently due to the incorporation of eicosapentaenoic acid in membrane phospholipids. Third, they reduce ischemia and reperfusion arrhythmias. All the effects exerted by n-3 PUFAs at high doses are incompatible with the beneficial action on CHD mortality in humans observed at low doses, where their main properties are related to circulation in the form of free fatty acids. Numerous experimental studies have indicated that low concentrations of exogenous n-3 PUFAs reduce the severity of cardiac arrhythmias. This effect is probably responsible for the protective action of n-3 PUFA on CHD mortality. Further studies are necessary to confirm this assumption in animals. Such studies should take account of the fact that only a low dose of n-3 PUFA (20 mg/kg/day) is necessary to afford protection. Furthermore, since the beneficial effect of n-3 PUFAs on CHD mortality is observed in fish eaters versus no-fish eaters, and since populations in industrialised countries consume excess n-6 PUFAs, control animals in long-term dietary experiments should be fed a diet with only n-6 fatty acids as a source of PUFAs.
Cell Mol Life Sci 2002 Mar
PMID:Dietary n-3 polyunsaturated fatty acids and coronary heart disease-related mortality: a possible mechanism of action. 1196 25

Apolipoprotein E (apo E), a genetic determinant of plasma lipid levels and coronary heart disease (CHD) needs to be investigated in Asian Indians since they have a propensity to develop dyslipidemia and accelerated atherosclerosis. We studied apo E phenotypes and plasma lipid levels in 52 Northern Indian male patients (aged 38-71 years) with angiographically proven CHD, and compared them to 50 healthy blood donors taken as the control group. High levels of Lp(a), (p < 0.05), and a definite trend towards lower levels of HDL-C (p < 0.05), was observed in the CHD patients as compared to the control subjects. The frequency of apo E allele epsilon3 was 0.86 and 0.862, and epsilon4 allele was 0.12 and 0.08 in the patients and controls, respectively. However, a lower frequency of the E2 allele was observed in the patient group (E2 = 0.02) as compared to the controls (epsilon2 = 0.06) (p = ns). In individuals with apo E3/E3 phenotype, significantly lower HDL-C levels was observed in the CHD patients as compared to the control subjects (p < 0.05). A positive correlation was observed between apo E phenotypes and Lp(a) levels in the CHD subjects as compared to the controls (p < 0.05), the level being significantly high in CHD subjects with at least one E4 allele. To conclude, in this sample of Northern Indian subjects with CHD, there is a significant correlation between apo E3/E3 phenotype and low levels of HDL-C as compared to the control subjects. Further, apo E phenotype is positively correlated with high Lp(a) levels in the CHD subjects having at least one E4 allele. However, these relationships need to be explored in a larger sample of subjects.
Mol Cell Biochem 2002 Mar
PMID:Apolipoprotein E polymorphism in Northern Indian patients with coronary heart disease: phenotype distribution and relation to serum lipids and lipoproteins. 1203 Mar 85

Adalimumab (D2E7), a human monoclonal antibody that binds to and neutralizes TNFa, is being developed by Abbott (formerly Knoll), under license from Cambridge Antibody Technology (CAT), for the potential treatment of inflammatory disorders such as rheumatoid arthritis (RA) and Crohn's disease. It is also being investigated for the potential treatment of coronary heart disease. Phase II studies for Crohn's disease and phase III for RA were ongoing throughout 2001. Limited data are only available for RA. In January 2002, it was reported that phase III trials of adalimumab for RA had been completed, but details have not been published in the primary literature so far. At this time CAT and Abbott expected to file for US approval in the second quarter of 2002 with a launch date anticipated for 2003. Phase III data are expected to be presented at the European League Against Rheumatism meeting in June 2002. In November 2000, Lehman Brothers predicted a US launch in June 2002 with peak US sales of $600 million in 2007 and a launch in non-US markets in 2003 with peak sales in these markets of $300 million in 2008. In December 2000, Merrill Lynch predicted regulatory clearance in the second half of 2003. The probability of adalimumab reaching the market is estimated to be 70%. In December 2000, Merrill Lynch predicted a 2003 launch, with estimated sales of pounds sterling 3.65 million in that year rising to pounds sterling 30.14 million in 2010. In March 2001, ABN AMRO predicted sales of $73 million in 2003 rising to $392 million in 2007.
Curr Opin Mol Ther 2002 Apr
PMID:Technology evaluation: adalimumab, Abbott laboratories. 1204 41

Elevated plasma homocysteine is associated with a variety of diseases in humans including coronary heart disease, stroke, peripheral vascular disease, and birth defects. However, the mechanism by which plasma homocysteine affects cells is unknown. We have examined the growth of isogenic wild-type and cystathionine beta-synthase (CBS) deficient yeast in response to homocysteine and its immediate metabolic precursor, S-adenosylhomocysteine (SAH). CBS deficient yeast export significantly more homocysteine into the media than wild-type yeast and have elevated internal pools of homocysteine and SAH. We found that 5 mM homocysteine added to the media had very little effect on the growth of wild-type or CBS deficient yeast, although intracellular homocysteine concentrations increased five- to tenfold. In contrast, as little as 25 microM S-adenosylhomocysteine inhibited the growth of CBS deficient yeast, but had no effect on wild-type yeast. Measurements of the intracellular S-adenosylmethionine (SAM) and SAH indicate that CBS deficient yeast contain reduced SAM/SAH ratios relative to wild-type, and this ratio is further reduced by adding SAH to the media. Growth inhibition by SAH in CBS deficient yeast can be totally reversed by addition of SAM to the media, indicating that the ratio and not absolute level is critical for cell growth. These results suggest that CBS plays a key role in the regulation of the SAM/SAH ratio inside cells and that excessive perturbations of this ratio can inhibit growth. We hypothesize that elevated extracellular homocysteine present in humans may reflect an altered intracellular SAM/SAH ratio and that this may be related to disease pathogenesis.
Mol Genet Metab 2002 Apr
PMID:S-adenosylhomocysteine, but not homocysteine, is toxic to yeast lacking cystathionine beta-synthase. 1205 65

This article, prepared in honor of Daria Haust, reviews some features of research into atherosclerosis and coronary heart disease over the past 150 years, and beyond. Attention is drawn to problems arising when people of strong personality dominate a particular field of research to the exclusion of pertinent observations that do not fit neatly into their particular paradigm. As the world becomes more complex and, in theory at least, communications between scientists become easier, these dangers are not necessarily diminished. Clinical medicine in its broadest sense must continue to relate in the traditional way to the specialties grouped within pathology. Undergraduates must receive instruction concerning the importance of the historical record and an understanding of the nature of science, its strengths, limitations, and boundaries.
Pediatr Pathol Mol Med
PMID:Clinically integrated studies in pathology: their contribution to atherosclerosis research. 1205 1

Our review addresses the development of the cholesterol concept of atherogenesis from the classical investigations of Anitchkov and Chalatov (1913), who induced experimental cholesterol atherosclerosis in rabbits, to the present time. We conclude that based on data obtained to date relating to the presence of different classes of lipoproteins in blood, on the role of peroxidatively modified low density lipoproteins in atherogenesis, and on the involvement of various arterial and blood cells and other factors, the cholesterol concept of atherogenesis has not lost its significance. Moreover, cholesterol-lowering therapy has a leading role in the primary and secondary prevention of coronary heart disease events and other clinical manifestations of atherosclerosis.
Pediatr Pathol Mol Med
PMID:Evolution of cholesterol concept of atherogenesis from Anitchkov to our days. 1205 5

Lipid peroxides were identified among the factors that contribute to the atherosclerotic plaque formation in the arterial wall. We hypothesised that a correlation may exist between the content of antioxidant constituents in the serum and the gravity of atherosclerosis. To this purpose, we have determined the serum total peroxyl radical- trapping potential (TRAP), which is the combined capacity of all antioxidants to neutralize free radicals in serum and followed its variation in hyperlipemic animals in correlation with the stage of atherosclerosis. In addition, we compared TRAP values in the sera of coronary heart disease (CHD) patients, with or without type II diabetes mellitus. Results showed that after 18 weeks of hyperlipemic diet, the mean TRAP values measured in sera isolated from hyperlipemic hamsters exhibited an about 44% decrease, in good agreement with the increase of serum cholesterol and triglycerides. In the 3 groups of CHD patients, TRAP values decreased with about 10% in sera of stable angina patients, 20% in unstable patients, as compared with normal subjects. The lowest TRAP values were detected in the sera of patients with acute myocardial infarction. The results obtained for different experimental animals and for CHD patients sera indicate that the TRAP method, as adapted in our laboratory, is a reliable and reproducible assay, fit to be used in clinical studies as an ex vivo measurable parameter that correlates with the stage of the atherosclerosis.
J Cell Mol Med
PMID:The total peroxyl radical trapping potential in serum - an assay to define the stage of atherosclerosis. 1206 87

Familial hypercholesterolemia (FH) is an inherited disease in humans, which we have used as a model to develop a new strategy of gene therapy. This disease, which is due to mutation in the low density lipoprotein (LDL) receptor gene and results in deficiency of the LDL receptor, is associated with hypercholesterolemia and premature development of coronary heart disease. This disease has been identified as one of the target diseases for gene therapy, because a 50% reduction of cholesterol level would be beneficial in such patients. In this study, we examined the feasibility of gene therapy by the delivery of the human LDL receptor plasmid into the liver via the portal vein. For gene transfer we utilized HVJ-liposome method with which many successful gene transfers have been reported. Administration of the human LDL receptor plasmid by the HVJ-liposome method into the liver resulted in a decrease of total cholesterol level. Moreover, second administration of this gene two weeks after the first administration resulted in sustained lowering of total cholesterol level. Although single administration of plasmid by the HVJ-liposome method induced antibodies against HVJ, this antibody production did not affect gene expression following second administration. These results suggest the possibility of a novel repetitive gene therapy for FH, using human LDL receptor plasmid transfer directly into the liver by the HVJ-liposome method.
Int J Mol Med 2002 Aug
PMID:Therapeutic approach to familial hypercholesterolemia by HVJ-liposomes in LDL receptor knockout mouse. 1211 48


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