Regulation and splicing of scavenger receptor class B type I in human macrophages and atherosclerotic plaques

BACKGROUND: The protective role of high-density lipoprotein (HDL) in the cardiovascular system is related to its role in the reverse transport of cholesterol from the arterial wall to the liver for subsequent excretion via the bile. Scavenger receptor class B type I (SR-BI) binds HDL and mediates selective uptake of cholesterol ester and cellular efflux of cholesterol to HDL. The role of SR-BI in atherosclerosis has been well established in murine models but it remains unclear whether SR-BI plays an equally important role in atherosclerosis in humans. The aim of this study was to investigate the expression of SR-BI and its isoforms in human macrophages and atherosclerotic plaques. METHODS: The effect of hypoxia and minimally modified low-density lipoprotein (mmLDL), two proatherogenic stimuli, on SR-BI expression was studied in human monocyte-derived macrophages from healthy subjects using real-time PCR. In addition, SR-BI expression was determined in macrophages obtained from subjects with atherosclerosis (n = 15) and healthy controls (n = 15). Expression of SR-BI isoforms was characterized in human atherosclerotic plaques and macrophages using RT-PCR and DNA sequencing. RESULTS: SR-BI expression was decreased in macrophages after hypoxia (p < 0.005). In contrast, SR-BI expression was increased by exposure to mmLDL (p < 0.05). There was no difference in SR-BI expression in macrophages from patients with atherosclerosis compared to controls. In both groups, SR-BI expression was increased by exposure to mmLDL (p < 0.05). Transcripts corresponding to SR-BI and SR-BII were detected in macrophages. In addition, a third isoform, referred to as SR-BIII, was discovered. All three isoforms were also expressed in human atherosclerotic plaque. Compared to the other isoforms, the novel SR-BIII isoform was predicted to have a unique intracellular C-terminal domain containing 53 amino acids. CONCLUSION: We conclude that SR-BI is regulated by proatherogenic stimuli in humans. However, we found no differences between subjects with atherosclerosis and healthy controls. This indicates that altered SR-BI expression is not a common cause of atherosclerosis. In addition, we identified SR-BIII as a novel isoform expressed in human macrophages and in human atherosclerotic plaques

Predictive value for cardiovascular events of common carotid intima media thickness and its rate of change in individuals at high cardiovascular risk - Results from the PROG-IMT collaboration.

AIMS: Carotid intima media thickness (CIMT) predicts cardiovascular (CVD) events, but the predictive value of CIMT change is debated. We assessed the relation between CIMT change and events in individuals at high cardiovascular risk. METHODS AND RESULTS: From 31 cohorts with two CIMT scans (total n = 89070) on average 3.6 years apart and clinical follow-up, subcohorts were drawn: (A) individuals with at least 3 cardiovascular risk factors without previous CVD events, (B) individuals with carotid plaques without previous CVD events, and (C) individuals with previous CVD events. Cox regression models were fit to estimate the hazard ratio (HR) of the combined endpoint (myocardial infarction, stroke or vascular death) per standard deviation (SD) of CIMT change, adjusted for CVD risk factors. These HRs were pooled across studies. In groups A, B and C we observed 3483, 2845 and 1165 endpoint events, respectively. Average common CIMT was 0.79mm (SD 0.16mm), and annual common CIMT change was 0.01mm (SD 0.07mm), both in group A. The pooled HR per SD of annual common CIMT change (0.02 to 0.43mm) was 0.99 (95% confidence interval: 0.95-1.02) in group A, 0.98 (0.93-1.04) in group B, and 0.95 (0.89-1.04) in group C. The HR per SD of common CIMT (average of the first and the second CIMT scan, 0.09 to 0.75mm) was 1.15 (1.07-1.23) in group A, 1.13 (1.05-1.22) in group B, and 1.12 (1.05-1.20) in group C. CONCLUSIONS: We confirm that common CIMT is associated with future CVD events in individuals at high risk. CIMT change does not relate to future event risk in high-risk individuals

Automatic identification of variables in epidemiological datasets using logic regression

textabstractBackground: For an individual participant data (IPD) meta-analysis, multiple datasets must be transformed in a consistent format, e.g. using uniform variable names. When large numbers of datasets have to be processed, this can be a time-consuming and error-prone task. Automated or semi-automated identification of variables can help to reduce the workload and improve the data quality. For semi-automation high sensitivity in the recognition of matching variables is particularly important, because it allows creating software which for a target variable presents a choice of source variables, from which a user can choose the matching one, with only low risk of having missed a correct source variable. Methods: For each variable in a set of target variables, a number of simple rules were manually created. With logic regression, an optimal Boolean combination of these rules was searched for every target variable, using a random subset of a large database of epidemiological and clinical cohort data (construction subset). In a second subset of this database (validation subset), this optimal combination rules were validated. Results: In the construction sample, 41 target variables were allocated on average with a positive predictive value (PPV) of 34%, and a negative predictive value (NPV) of 95%. In the validation sample, PPV was 33%, whereas NPV remained at 94%. In the construction sample, PPV was 50% or less in 63% of all variables, in the validation sample in 71% of all variables. Conclusions: We demonstrated that the application of logic regression in a complex data management task in large epidemiological IPD meta-analyses is feasible. However, the performance of the algorithm is poor, which may require backup strategies

Atherosclerosis and insulin resistance AIR. A cross-sectional study of 58-year old men

The main aim of the study was to test the hypothesis that insulin resistance is associated with atherosclerotic disease in the carotid and femoral arteries as measured using the ultrasound technique in clinically healthy 58-year old men with varying degrees of obesity and insulin resistance. The subjects were recruited from the general population and were free from clinical cardiovascular disease, diabetes mellitus and treatment with antihypertensive, lipid-lowering and anti-diabetic drugs (n=818). The study group (n=391) was based on a stratified sampling of all subjects in the lowest and highest quintiles of an estimate of insulin sensitivity and a random selection (1/5) of those in quintiles 2-4 (n=391). Insulin sensitivity was measured in a randomly selected subgroup (n=104) by the euglycemic hyperinsulinemic clamp technique which is considered to be the "gold standard" method. A reproducibility study which was performed in 32 men showed that glucose infusion rate (GIR) for the final 60 minutes adjusted for fat free mass (DEXA) was the most accurate way to measure insulin sensitivity. There was a negative univariate correlation between insulin sensitivity (GIR) and common carotid IMT, but no association with the carotid bulb or common femoral artery IMT. Plasma concentrations of C-peptide, proinsulin, split proinsulin and insulin measured with cross-reacting RIA, but not intact insulin, were univariately associated with common carotid IMT. Intact insulin and C-peptide were associated with common femoral artery IMT. None of the insulin peptides were associated to carotid bulb IMT. There were numerically similar univariate correlations between risk factors which constitute the metabolic syndrome (waist-hip-ratio, triglycerides, HDL cholesterol), and other risk factors such as serum cholesterol, apoB and smoking with common carotid artery, carotid bulb and femoral artery IMT. Plasma insulin measured with cross-reacting RIA and proinsulin were independently related to insulin sensitivity (GIR). There were also an independent association between plasma insulin (RIA) and common carotid IMT. No independent association between common carotid artery IMT and insulin sensitivity or proinsulin was found in this study.In the studied population, the clustering of risk factors which constitute the metabolic syndrome showed a relation to small LDL particles, common carotid, carotid bulb and common femoral IMT. Small LDL particles were also related to common carotid, carotid bulb and common femoral IMT and plaques in the carotid and femoral artery.The conclusion is that in contrast to well-established cardiovascular risk factors such as blood pressure or smoking, insulin sensitivity and hyperinsulinemia were only weakly and inconsistently associated with IMT in the examined arterial beds. The study did not show any independent relationship between proinsulin and IMT. However, there was a consistent association between the metabolic syndrome and common carotid, carotid bulb and femoral artery IMT. Further, small LDL particles were related to the factors in the metabolic syndrome and IMT and plaque in the carotid and femoral arteries

Heart dysfunction in patients with acute ischemic stroke or TIA does not predict all-cause mortality at long-term follow-up

BACKGROUND: Despite heart failure being a substantial risk factor for stroke, few studies have evaluated the predictive value of heart dysfunction for all-cause mortality in patients with acute ischemic stroke, in particular in the elderly. The aim of this study was to investigate whether impaired heart function in elderly patients can predict all-cause mortality after acute ischemic stroke or transient ischemic attack (TIA). METHODS: A prospective long-term follow-up analysis was performed on a hospital cohort consisting of n = 132 patients with mean age 73 ± 9 years, presenting with acute ischemic stroke or transient ischemic attack, without atrial fibrillation. All patients were examined by echocardiography during the hospital stay. Data about all-cause mortality were collected at the end of the follow-up period. The mean follow-up period was 56 ± 22 months. RESULTS: In this cohort, 58% of patients with acute ischemic stroke or TIA had heart dysfunction. Survival analysis showed that heart dysfunction did not predict all-cause mortality in this cohort. Furthermore, in multivariate regression analysis age (HR 5.401, Cl 1.97-14.78, p < 0.01), smoking (HR 3.181, Cl 1.36-7.47, p < 0.01), myocardial infarction (HR 2.826, Cl 1.17-6.83, p < 0.05) were independent predictors of all-cause mortality. CONCLUSION: In this population with acute ischemic stroke or TIA and without non-valvular atrial fibrillation, impaired heart function does not seem to be a significant predictor of all-cause mortality at long-term follow-up

Neuronal and Glia-Related Biomarkers in Cerebrospinal Fluid of Patients with Acute Ischemic Stroke

Background Cerebral ischemia promotes morphological reactions of the neurons, astrocytes, oligodendrocytes, and microglia in experimental studies. Our aim was to examine the profile of CSF (cerebrospinal fluid) biomarkers and their relation to stroke severity and degree of white matter lesions (WML). Methods A total of 20 patients (mean age 76 years) were included within 5–10 days after acute ischemic stroke (AIS) onset. Stroke severity was assessed using NIHSS (National Institute of Health stroke scale). The age-related white matter changes (ARWMC) scale was used to evaluate the extent of WML on CT-scans. The concentrations of specific CSF biomarkers were analyzed. Results Patients with AIS had significantly higher levels of NFL (neurofilament, light), T-tau, myelin basic protein (MBP), YKL-40, and glial fibrillary acidic protein (GFAP) compared with controls; T-Tau, MBP, GFAP, and YKL-40 correlated with clinical stroke severity, whereas NFL correlated with severity of WML (tested by Mann–Whitney test). Conclusions Several CSF biomarkers increase in AIS, and they correlate to clinical stroke severity. However, only NFL was found to be a marker of degree of WML