Objectives Based on the data of the Prospective Cardiovascular Munster (PROCAM) study, a prospective study of men and women at work in the north-west of Germany, we aimed (i) to develop a refined scoring scheme for calculating the risk of acute coronary events among adult and elderly men and women; and (ii) to generate a new scoring scheme for calculating the risk of ischaemic stroke or transient ischaemic attack (TIA).Methods The coronary risk score was derived from a Weibull function using data from 18 460 men and 8515 women who were recruited before 1996 and had a mean follow-up period of 12 +/- 6 years. The stroke score was derived using a Cox proportional hazards model using data of 5905 men and 2225 women aged 35-65 years with at least 10 years of unbroken follow-up.Results The coronary risk score was based on 511 major coronary events, 462 (168 fatal, 294 non-fatal) in men and 49 (18 fatal, 31 non-fatal) in women and included the risk factors LDL cholesterol, HDL cholesterol, systolic blood pressure, smoking status, triglycerides and diabetes mellitus status. It was accurate in both sexes over an age range from 20 to 75 years with an area under the receiver-operating characteristics (ROC) curve of 0.82. The stroke score was based on 85 cerebral ischaemic events (21 TIAs, 64 ischaemic strokes) and included the risk factors age, sex, diabetes mellitus status, smoking status and systolic blood pressure. It had an area under the ROC curve of 0.78 and identified a high-risk group comprising only 4% of the study population that contained 31% of all cerebral ischaemic events.Conclusion Both new PROCAM risk scores provide simple and effective ways to assess the risk of acute coronary events and ischaemic stroke in the general population and will improve the ability of physicians to target measures in an effort to prevent these potentially devastating conditions.

Aims: To investigate the achievement of treatment goals for low density lipoprotein (LDL) cholesterol in men and women with diabetes mellitus receiving statins in a primary-care setting in Germany.Methods: 6,827 men and 5,989 women with diabetes mellitus were recruited from among the 28,200 men and 24,200 women participating in the 4E registry of patients being treated with statins for primary hypercholesterolemia unresponsive to diet and lifestyle. Participants were assessed after 6 weeks and 9 months of statin therapy. Attainment of treatment targets was assessed (i) using individual LDL goals based on each participant's individual level of risk and (ii) based on the 2.6 mmol/L target recommended by current European and U.S. guidelines for persons with diabetes.Results: At baseline, patients with and without diabetes mellitus had similar LDL cholesterol levels patients (men: 4.5 +/- 1 vs. 4.7 +/- 1 mmol/L, women: 4.7 +/- 1 vs. 4.9 +/- 1 mmol/L respectively). The mean drop in LDL cholesterol on statin therapy was similar in men and women with and without diabetes, ranging from 26-27 percent all subgroups. After 9 months of statins, individual LDL goals were achieved by 25 % of men and 24 % of women with diabetes, while only 16% of diabetic men and 12% of diabetic women achieved the 2.6 mmol/L LDL target. These success rates were similar to those of non-diabetics, including those at high risk, in 4E.Conclusions: Patients with diabetes mellitus in 4E responded just as well to statins as patients without diabetes. However, achievement of treatment goals in patients with diabetes was just as poor as in other high-risk groups in the 4E cohort.

The Liver X Receptors (LXRs) are critical transcriptional regulators of cellular metabolism that promote cholesterol efflux and lipogenesis in response to excess intracellular cholesterol. In contrast, the Sterol Response Element Binding Protein-2 (SREBP2) promotes the synthesis and uptake of cholesterol. Oxysterols are products of cholesterol oxidation that accumulate in conditions associated with increased cellular levels of reactive oxygen species, such as hypoxia and oxidative stress, activating LXR and inhibiting SREBP2. While hypoxia and oxidative stress are commonly implicated in placental injury, the impact of the transcriptional regulation of cholesterol homeostasis on placental function is not well characterized.We measured the effects of the synthetic LXR ligand T0901317 and the endogenous oxysterol 25-hydroxycholesterol (25OHC) on differentiation, cytotoxicity, progesterone synthesis, lipid droplet formation, and gene expression in primary human trophoblasts.Exposure to T0901317 promoted lipid droplet formation and inhibited differentiation, while 25OHC induced trophoblast toxicity, promoted hCG and progesterone release at lower concentrations with inhibition at higher concentrations, and had no effect on lipid droplet formation. The discrepant effect of these ligands was associated with distinct changes in expression of LXR and SREBP2 target genes, with upregulation of ABCA1 following 25OHC and T090317 exposure, exclusive activation of the lipogenic LXR targets SREBP1c, ACC1 and FAS by T0901317, and exclusive inhibition of the SREBP2 targets LDLR and HMGCR by 25OHC.These findings implicate cholesterol oxidation as a determinant of trophoblast function and activity, and suggest that placental gene targets and functional pathways are selectively regulated by specific LXR ligands.

BACKGROUND:Dietary fatty acid intake has been proposed to contribute to asthma development with n-6 polyunsaturated fatty acids (PUFA) having a detrimental and n-3 PUFA a protective effect. OBJECTIVE:The aim of our analysis was to explore the relationship between fatty acid composition of serum cholesteryl esters as marker of dietary intake and prevalence of asthma, impaired lung function and bronchial hyper-responsiveness in children. METHODS:The study population consisted of 242 girls and 284 boys aged 8-11 years, living in Munich, Germany. Data were collected by parental questionnaire, lung function measurement and skin prick test according to the International Study of Asthma and Allergies in Childhood phase II protocol. Confounder-adjusted odds ratios (OR) with 95% confidence intervals (CI) were calculated for the association between quartiles of fatty acid concentration and health outcomes with the first quartile as reference. RESULTS:n-3 PUFA: levels of eicosapentaenoic acid were not related to asthma and impaired lung function. Linolenic acid levels were positively associated with current asthma (OR for fourth quartile 3.35, 95% CI 1.29-8.66). Forced expiratory volume in 1 s (FEV(1)) values decreased with increasing levels of linolenic acid (p for trend=0.057). n-6 PUFA: there was a strong positive association between arachidonic acid levels and current asthma (OR(4th quartile) 4.54, 1.77-11.62) and a negative association with FEV(1) (P=0.036). In contrast, linoleic acid was negatively related to current asthma (OR(4th quartile) 0.34, 0.14-0.87) and FEV(1) values increased with increasing levels of linoleic acid (P=0.022). The ratio of measured n-6 to n-3 PUFA as well as levels of palmitic and oleic acid were not consistently related to asthma or lung function. CONCLUSION:Our data do not support the hypothesis of a protective role of n-3 PUFA. Elevated arachidonic acid levels in children with asthma may be because of a disturbed balance in the metabolism of n-6 PUFA or may be secondary to inflammation in these patients.

Der “Deutschland-SCORE” hat eine geringe Aussagekraft und überschätzt bei weitem das tatsächliche kardiovaskuläre Risiko. Seine konsequente Anwendung würde zu einer massiven Überbehandlung führen. Wir können ihn daher nicht empfehlen.

Worldwide, more people die of the complications of atherosclerosis than of any other cause. It is not surprising, therefore, that enormous resources have been devoted to studying the pathogenesis of this condition. This article attempts to summarize present knowledge on the events that take place within the arterial wall during atherogenesis. Classical risk factors are not dealt with as they are the subjects of other parts of this book. First, we deal with the role of endothelial dysfunction and infection in initiating the atherosclerotic lesion. Then we describe the development of the lesion itself, with particular emphasis on the cell types involved and the interactions between them. The next section of the chapter deals with the events leading to thrombotic occlusion of the atherosclerotic vessel, the cause of heart attack and stroke. Finally, we describe the advantages--and limitations--of current animal models as they contribute to our understanding of atherosclerosis and its complications.

The "Deutschland SCORE" has low predicitive power and greatly overestimates the true risk of coronary heart disease in Germany. Widespread use of this score would lead to massive overtreatment. For this reason, we cannot recommend this score for general use.

Drug Prescribing for Patients with Chronic Kidney Disease in General Practice: a Cross-Sectional Study

aInstitute of Arteriosclerosis Research, Domagkstraße 3, bInstitute of Biochemistry, Wilhelm-Klemm-Straße 2 and cOgham GmbH, Mendelstraße 11, 48149 Münster, Germany Correspondence to Dr Stefan Lorkowski, Institut für Arterioskleroseforschung, Domagkstraße 3, 48149 Münster, Germany Tel: +49 (2 51) 83 5 20 72; fax: +49 (2 51) 83 5 20 62; e-mail: [email protected] Abbreviations ABC: ATP-binding cassette apoA-I: apolipoprotein A-I HDL: high-density lipoprotein

The link between raised levels of LDL (low-density lipoprotein) cholesterol in the blood and atherosclerosis is incontrovertible. The situation with regard to TRLs (triacylglycerol-rich lipoproteins) is not as clear. Nevertheless, there is substantial evidence that TRLs may in some cases be just as atherogenic as triacylglycerol-poor LDL. This review focuses on three aspects of the link between TRLs and atherosclerosis: (i) the epidemiological evidence for an association between raised levels of TRLs and atherosclerosis, with particular reference to the results of the PROCAM study; (ii) the possible pathophysiological contribution of TRL to atherogenesis at the level of the arterial wall; and (iii) the case for specific lowering of triacylglycerol levels to prevent atherosclerosis.

By its very nature, rupture of the atherosclerotic plaque is difficult to study directly in humans. A good animal model would help us not only to understand how rupture occurs but also to design and test treatments to prevent it from happening. However, several difficulties surround existing models of plaque rupture, including the need for radical interventions to produce the rupture, lack of direct evidence of rupture per se, and absence of convincing evidence of platelet- and fibrin-rich thrombus at the rupture site. At the present time, attention should therefore focus on the processes of plaque breakdown and thrombus formation in humans, whereas the use of animal models should probably be reserved for studying the function of particular genes and for investigating isolated features of plaques, such as the relationship between cap thickness and plaque stability.

Objective: To determine the incidence of critically ill patients displaying endogenous digitalis-like-immunoreactive substances (DLIS) and to examine the relationship of these hormones to routine laboratory variables, the underlying disease, myocardial function, hemodynamic status, severity of illness, systemic inflammation, and mortality rate.Design: Sera of 401 consecutive critically ill patients, not treated with cardiac glycosides, were analyzed for DLIS (digitoxin and digoxin, TDx; Abbott Diagnostics, North Chicago, IL) and endogenous ouabain. Normal values of endogenous ouabain were determined in 62 healthy volunteers. We measured pro- and anti-inflammatory mediators (L-selectin, tumor necrosis factor-alpha, interleukin-1beta, interleukin-2, interleukin-6, interleukin-10), C-reactive protein, and serum amyloid A protein as well as patients' Acute Physiology and Chronic Health Evaluation II and Goris scores. In a subgroup of patients with a pulmonary artery catheter (n = 95), we determined cardiac output, pulmonary artery occlusion pressure, systemic and pulmonary vascular resistance, left ventricular stroke volume, and right and left stroke work.Setting; Two surgical intensive care units of an university hospital.Subjects: Sera of 401 consecutive critically ill patients.Interventions: Blood sampling.Measurements and Main Results: Of the 401 patients tested, 343 had nonmeasurable DLIS concentrations (DLIS-negative), and 58 (14.5%) had positive digoxin (n = 18) or digitoxin (n = 34) concentrations (DLIS-positive) or were positive in both tests (n = 6). Mean endogenous ouabain concentrations were nine-fold increased in DLIS-positive (3.59 +/- 1.43 nmol/L) and three-fold increased in DLIS-negative (1.34 +/- .81 nmol/L) patients compared with controls (0.38 +/- 0.31 nmol/L). DLIS and ouabain concentrations closely correlated with the Acute Physiology and Chronic Health Evaluation II and Goris score and were associated with increased concentrations of transaminases, bilirubin, aldosterone, cortisol, serum creatinine, fractional sodium excretion, proinflammatory mediators, C-reactive protein, and serum amyloid A (pless than or equal to.009). The hospital mortality rates of DLIS-positive and DLIS-negative patients were 12% and 3.2%, respectively, and for patients with ouabain concentrations above and below 2 nmol/L 38.6% and 0.6%, respectively. In DLIS-positive patients with pulmonary artery catheter (n = 23), cardiac output, stroke volume, and left ventricular stroke work were decreased, and pulmonary artery occlusion pressure and central venous pressure were increased (p <.009).Conclusions; Different types of endogenous glycosides including endogenous ouabain are elevated in a significant proportion of critically ill patients. The occurrence of these substances is associated with increased morbidity and hospital mortality rates, possibly due to systemic inflammatory processes. DLIS but not endogenous ouabain concentrations were found to be related to left ventricular function. (Grit Care Med 2003; 31:1331-1337).

Objective: The objective of this study was to compare the effects of dietary monounsaturated fatty acids (MUFA), n-6 and n-3 polyunsaturated fatty acids (PUFA) on LDL composition and oxidizability. Design, setting and subjects: Sixty-nine healthy young volunteers, students at a nearby college, were included. Six subjects withdrew because of intercurrent illness and five withdrew because they were unable to comply with the dietary regimen. Interventions: The participants received a 2-week wash-in diet rich in saturated fatty acids (SFA) followed by diets rich in refined olive oil, rapeseed oil or sunflower oil for 4 weeks. Intakes of vitamin E and other antioxidants did not differ significantly between the diets. Results: At the end of the study, LDL oxidizability was lowest in the olive oil group (lag time: 72.6 min), intermediate in the rapeseed oil group (68.2 min) and highest in the sunflower oil group (60.4 min, P<0.05 for comparison of all three groups). Despite wide variations in SFA intake, the SFA content of LDL was not statistically different between the four diets (25.8–28.5% of LDL fatty acids). By contrast, the PUFA (43.5%–60.5% of LDL fatty acids) and MUFA content of LDL (13.7–29.1% of LDL fatty acids) showed a wider variability dependent on diet. Conclusions: Enrichment of LDL with MUFA reduces LDL susceptibility to oxidation. As seen on the rapeseed oil diet this effect is independent of a displacement of higher unsaturated fatty acids from LDL. Evidence from this diet also suggests that highly unsaturated n-3 fatty acids in moderate amounts do not increase LDL oxidizability when provided in the context of a diet rich in MUFA. Sponsorship: This work was supported by the Central Marketing Agency of the German Agricultural Industry (CMA), the German Union for the Promotion of Oil- and Protein Plants (UFOP), the Austrian Science Foundation, project F00709 (to P.M.A.) and the Brökelmann Ölmühle Company, Hamm, Germany.

ATP-binding cassette (ABC) proteins form one of the largest known protein families and have been found in all known organisms. Most members of the human ABC protein family are membrane-spanning transporters that use energy derived from the hydrolysis of ATP to transport specific substrates across cell membranes. Mutations in certain human ABC transporters of the subfamilies A, B, C, and D have been shown to cause a wide variety of inherited diseases such as the lung condition cystic fibrosis, the nervous degenerative condition adrenoleukodystrophy (of Lorenzo's Oil fame), hereditary macular degeneration of the eye (Stargardt's disease), and inherited deficiency of circulating high-density lipoproteins (Tangier disease or familial hypoalphalipoproteinemia). Very recent studies showed that mutations in two members of the subfamily G of human ABC transporters (ABCG5 and ABCG8) cause a condition called sitosterolemia in which plant sterols accumulate in the body and may be responsible for influencing total body sterol homeostasis. In addition, other members of the subfamily G, namely ABCG1 and ABCG4, have also been shown to be involved in cellular lipid trafficking and are thought to play important roles during foam cell formation of human macrophages. By contrast, ABCG2 is a multidrug resistance transporter. In this review, we focus on the current knowledge and physiological background of the members of the subfamily G. We also present new insights on the evolutionary relationship of human and nonhuman ABCG proteins.

Some degree of atherosclerosis is an almost invariable accompaniment of aging in developed countries, but by no means all individuals with atherosclerosis suffer its devastating thrombotic complications of myocardial infarction and stroke. Over the last few years, it has become clear that thrombotic occlusion does not generally occur in the region of full-blown fibrotic and calcified atherosclerotic plaques, but rather in the vicinity of smaller and often cell-rich regions in which a thin fibrous cap overlies a central core of extracellular lipids. These regions have been called “culprit lesions” (1, 2). Infra-red thermography has shown that such vulnerable plaques are metabolically active, and histological examinations has revealed them to be particularly rich in macrophages (3). The reasons for the rupture of culprit lesions are not entirely clear, but it is known that the prefinal event of plaque fissuring is the outcome of a complex metabolic drama in which inflammation, apoptosis and lipid metabolism are intimately intertwined (Fig 1). Excessive degradation of the various components of the extracellular matrix of the fibrous cap is considered to be an important causative factor of plaque weakening (4). It is likely that collagenases and other matrix metalloproteinases (MMPs) secreted by various cell types within the atherosclerotic plaque, especially macrophages (5, 6), play a central role in this degradation. As the oxidized low-density lipoproteins (LDL) (7) and pro-inflammatory cytokines found in atherosclerotic lesions, such as tumour necrosis factor α (TNF-α) and interleukin 1-β (IL-1β) (8), induce MMP secretion by macrophages in vitro, one possible avenue to plaque stabilisation is to inhibit MMP secretion and extracellular activation. The effects of a number of compounds on MMP activity have been tested, including naturally occurring substances Nutr Metab Cardiovasc Dis (2002) 12: 3–11