M Walker

Inhibition of lipoprotein-associated phospholipase A2 reduces complex coronary atherosclerotic plaque development

Increased lipoprotein-associated phospholipase A2 (Lp-PLA2) activity is associated with increased risk of cardiac events, but it is not known whether Lp-PLA2 is a causative agent. Here we show that selective inhibition of Lp-PLA2 with darapladib reduced development of advanced coronary atherosclerosis in diabetic and hypercholesterolemic swine. Darapladib markedly inhibited plasma and lesion Lp-PLA2 activity and reduced lesion lysophosphatidylcholine content. Analysis of coronary gene expression showed that darapladib exerted a general anti-inflammatory action, substantially reducing the expression of 24 genes associated with macrophage and T lymphocyte functioning. Darapladib treatment resulted in a considerable decrease in plaque area and, notably, a markedly reduced necrotic core area and reduced medial destruction, resulting in fewer lesions with an unstable phenotype. These data show that selective inhibition of Lp-PLA2 inhibits progression to advanced coronary atherosclerotic lesions and confirms a crucial role of vascular inflammation independent from hypercholesterolemia in the development of lesions implicated in the pathogenesis of myocardial infarction and stroke.

Body weight: implications for the prevention of coronary heart disease, stroke, and diabetes mellitus in a cohort study of middle aged men

Abstract Objective:To determine the body mass index associated with the lowest morbidity and mortality. Design:Prospective study of a male cohort. Setting:One general practice in each of 24 British towns. Subjects:7735 men aged 40-59 years at screening. Main outcome measures:All cause death rate, heart attacks, and stroke (fatal and non-fatal) and development of diabetes, or any of these outcomes (combined end point) over an average follow up of 14.8 years. Results:There were 1271 deaths from all causes, 974 heart attacks, 290 strokes, and 245 new cases of diabetes mellitus. All cause mortality was increased only in men with a body mass index (kg/m2) <20 and in men with an index ≥30. However, risk of cardiovascular death, heart attack, and diabetes increased progressively from an index of <20 even after age, smoking, social class, alcohol consumption, and physical activity were adjusted for. For the combined end point the lowest risks were seen for an index of 20.0-23.9. In never smokers and former smokers, deaths from any cause rose progressively from an index of 20.0-21.9 and for the combined end point, from 20.0-23.9. Age adjusted levels of a wide range of cardiovascular risk factors rose or fell progressively from an index <20. Conclusion:A healthy body mass index in these middle aged British men seems to be about 22. Key messages The body mass index associated with the lowest mortality and the lowest incidence of coronary heart disease, stroke, and diabetes mellitus is not known In this study of middle aged men the risk of cardiovascular mortality, heart attack, and diabetes increased progressively from a body mass index <20 For a combined end point (heart attack, stroke, diabetes, or death from any cause) the lowest risk was in the range 20-24 Levels of a wide range of cardiovascular risk factors increased progressively from an index of <20 A healthy body mass index in middle aged men seems to be around 22

Rehabilitation therapy services for stroke patients living at home: systematic review of randomised trials.

BACKGROUNDnStroke-unit care can be valuable for stroke patients in hospital, but effectiveness of outpatient care is less certain. We aimed to assess the effects of therapy-based rehabilitation services targeted at stroke patients resident in the community within 1 year of stroke onset or discharge from hospital.nnnMETHODSnWe did a systematic review of randomised trials of outpatient services, including physiotherapy, occupational therapy, and multidisciplinary teams. We used Cochrane collaboration methodology.nnnFINDINGSnWe identified a heterogeneous group of 14 trials (1617 patients). Therapy-based rehabilitation services for stroke patients living at home reduced the odds of deteriorating in personal activities of daily living (odds ratio 0.72 [95% CI 0.57-0.92], p=0.009) and increased ability of patients to do personal activities of daily living (standardised mean difference 0.14 [95% CI 0.02-0.25], p=0.02). For every 100 stroke patients resident in the community receiving therapy-based rehabilitation services, seven (95% CI 2-11) would not deteriorate.nnnINTERPRETATIONnTherapy-based rehabilitation services targeted at selected patients resident in the community after stroke improve ability to undertake personal activities of daily living and reduce risk of deterioration in ability. These findings should be considered in future service planning.

Physical activity and risk of cancer in middle-aged men

A prospective study was carried out to examine the relationship between physical activity and incidence of cancers in 7588 men aged 40–59 years with full data on physical activity and without cancer at screening. Physical activity at screening was classified as none/occasional, light, moderate, moderately-vigorous or vigorous. Cancer incidence data were obtained from death certificates, the national Cancer Registration Scheme and self-reporting on follow-up questionnaires of doctor-diagnosed cancer. Cancer (excluding skin cancers) developed in 969 men during mean follow-up of 18.8 years. After adjustment for age, smoking, body mass index, alcohol intake and social class, the risk of total cancers was significantly reduced only in men reporting moderately-vigorous or vigorous activity; no benefit seen at lesser levels. Sporting activity was essential to achieve significant benefit and was associated with a significant dose-response reduction in risk of prostate cancer and upper digestive and stomach cancer. Sporting (vigorous) activity was associated with a significant increase in bladder cancer. No association was seen with colo-rectal cancer. Non-sporting recreational activity showed no association with cancer. Physical activity in middle-aged men is associated with reduced risk of total cancers, prostate cancer, upper digestive and stomach cancer. Moderately-vigorous or vigorous levels involving sporting activities are required to achieve such benefit.

Adiposity-related heterogeneity in patterns of type 2 diabetes susceptibility observed in genome wide association data.

OBJECTIVE—This study examined how differences in the BMI distribution of type 2 diabetic case subjects affected genome-wide patterns of type 2 diabetes association and considered the implications for the etiological heterogeneity of type 2 diabetes. RESEARCH DESIGN AND METHODS—We reanalyzed data from the Wellcome Trust Case Control Consortium genome-wide association scan (1,924 case subjects, 2,938 control subjects: 393,453 single-nucleotide polymorphisms [SNPs]) after stratifying case subjects (into “obese” and “nonobese”) according to median BMI (30.2 kg/m2). Replication of signals in which alternative case-ascertainment strategies generated marked effect size heterogeneity in type 2 diabetes association signal was sought in additional samples. RESULTS—In the “obese-type 2 diabetes” scan, FTO variants had the strongest type 2 diabetes effect (rs8050136: relative risk [RR] 1.49 [95% CI 1.34–1.66], P = 1.3 × 10−13), with only weak evidence for TCF7L2 (rs7901695 RR 1.21 [1.09–1.35], P = 0.001). This situation was reversed in the “nonobese” scan, with FTO association undetectable (RR 1.07 [0.97–1.19], P = 0.19) and TCF7L2 predominant (RR 1.53 [1.37–1.71], P = 1.3 × 10−14). These patterns, confirmed by replication, generated strong combined evidence for between-stratum effect size heterogeneity (FTO: PDIFF = 1.4 × 10−7; TCF7L2: PDIFF = 4.0 × 10−6). Other signals displaying evidence of effect size heterogeneity in the genome-wide analyses (on chromosomes 3, 12, 15, and 18) did not replicate. Analysis of the current list of type 2 diabetes susceptibility variants revealed nominal evidence for effect size heterogeneity for the SLC30A8 locus alone (RRobese 1.08 [1.01–1.15]; RRnonobese 1.18 [1.10–1.27]: PDIFF = 0.04). CONCLUSIONS—This study demonstrates the impact of differences in case ascertainment on the power to detect and replicate genetic associations in genome-wide association studies. These data reinforce the notion that there is substantial etiological heterogeneity within type 2 diabetes.

Geographic variation in incidence of coronary heart disease in Britain : the contribution of established risk factors

OBJECTIVE To determine the extent to which geographic variation in the incidence of major coronary heart disease (CHD) in Great Britain may be explained by established risk factors. DESIGN Prospective study. SETTING 24 British towns with widely differing CHD mortality. SUBJECTS 7735 men followed up from screening in 1978–80 for 15 years. MAIN OUTCOME MEASURES Percentage of variance between the towns in major CHD incidence that can be explained by individual characteristics of men in the towns. RESULTS Age standardised incidence rates over a 15 year period varied from 0.52% per annum in Maidstone to 1.07% per annum in Dewsbury and tended to follow the known pattern of higher rates in Scottish and northern English towns and lower rates in southern English towns (“north-south gradient”). Higher town incidence rates were related to prevalence of current cigarette smoking, low physical activity, and low alcohol consumption, and to mean body mass index, mean systolic blood pressure, low mean height, and prevalence of manual social class, but not to mean serum total cholesterol. The 95% range for true age adjusted CHD incidence (over 15 years) was estimated as 0.58–1.03% per annum among British towns. After adjustment for baseline smoking status, physical activity, body mass index, alcohol consumption, systolic blood pressure, serum total cholesterol, occupational social class, and height, this variation was reduced by 50%. A model based on these eight variables accounted for the major part of the north-south gradient. CONCLUSIONS Much of the variation in CHD incidence among British towns was accounted for by established risk variables. The remaining unexplained variation may be related to measurement error in the established risk variables, to environmental factors such as climate, or to the combined effect of a wide range of minor risk factors.

Low prevalence of lipid lowering drug use in older men with established coronary heart disease

Objective: To determine the prevalence and correlates of lipid lowering drug use among older British men with established coronary heart disease (CHD). Design: Cross sectional survey within a cohort study (British regional heart study) carried out at 20 years of follow up in 1998–2000. Setting: General practices in 24 British towns. Participants: 3689 men aged 60–75 years (response rate 76%). Main outcome measures: Diagnoses of myocardial infarction and angina based on detailed review of general practice records. Lipid lowering drug use and blood cholesterol concentrations ascertained at 20 year follow up examination. Results: Among 286 men with definite myocardial infarction, 102 (36%) were taking a lipid lowering drug (93 (33%) a statin); among 360 men with definite angina without myocardial infarction, 84 (23%) were taking a lipid lowering drug (78 (21%) a statin). Most men with documented CHD who were not receiving a lipid lowering drug had a total cholesterol concentration of 5.0 mmol/l or more (87% of those with myocardial infarction, 82% with angina). Fewer than half of men with CHD receiving a statin had a total cholesterol concentration below 5.0 mmol/l (45% of those with myocardial infarction and 47% of those with angina). Only one third of the men taking a statin were receiving trial validated dosages. Among men with CHD, a history of revascularisation, more recent diagnosis, and younger age at diagnosis were associated with a higher probability of receiving lipid lowering drug treatment. Conclusion: Among patients with established CHD, the prevalence of lipid lowering drug use remains low and statin regimens suboptimal. Major improvements in secondary prevention are essential if the benefits of statins are to be realised.

Both the Peroxisome Proliferator‐Activated Receptor δ Agonist, GW0742, and Ezetimibe Promote Reverse Cholesterol Transport in Mice by Reducing Intestinal Reabsorption of HDL‐Derived Cholesterol

Peroxisome proliferator‐activated receptor δ (PPARδ) agonism increases HDL cholesterol and has therefore the potential to stimulate macrophage‐to‐feces reverse cholesterol transport (RCT). To test whether PPAR™ activation promotes RCT in mice, in vivo macrophage RCT was assessed using cholesterol‐loaded/3H‐cholesterol‐labeled macrophages injected intraperitoneally. PPAR™ agonist GW0742 (10 mg/kg per day) did not change 3H‐tracer plasma appearance, but increased fecal 3H‐free sterols excretion by 103% (p < 0.005) over 48 hours. Total free cholesterol efflux from macrophages to serum (collected from both control and GW0742 groups) was not different, although ABCA1‐mediated efflux was significantly higher with GW0742. The metabolic fate of HDL labeled with 3H‐cholesteryl ether or 3H‐cholesteryl oleate was also measured. While 3H‐cholesteryl ether tissue uptake was unchanged, the 3H‐tracer recovered in fecal free sterol fraction after 3H‐cholesteryl oleate injection increased by 88% with GW0742 (p < 0.0005). This was associated with a lower Niemann‐Pick C1 like 1 (NPC1L1) mRNA expression in the small intestine (p < 0.05). The same experiments in mice treated with ezetimibe, which blocks NPC1L1, showed a similar 2‐fold increase in fecal free sterol excretion after labeled macrophages or HDL injection. In conclusion, PPAR™ activation enhances excretion of macrophage or HDL‐derived cholesterol in feces through reduced NPC1L1 expression in mice, comparable to the effect of ezetimibe.

SCAP ligands are potent new lipid-lowering drugs

Upregulation of low-density lipoprotein receptor (LDLr) is a key mechanism to control elevated plasma LDL-cholesterol levels. Here we identify a new class of compounds that directly binds to the sterol regulatory element-binding protein (SREBP) cleavage-activating protein (SCAP). We show that a 14C-labeled, photo-activatable analog specifically labeled both SCAP and a truncated form of SCAP containing the sterol-sensing domain. When administered to hyperlipidemic hamsters, SCAP ligands reduced both LDL cholesterol and triglycerides levels by up to 80% with a three-fold increase in LDLr mRNA in the livers. Using human hepatoma cells, we show that these compounds act through the sterol-responsive element of the LDLr promoter and activate the SCAP/SREBP pathway, leading to increased LDLr expression and activity, even in presence of excess of sterols. These findings have led to the identification of a class of compounds that represent a promising new class of hypolipidemic drugs.

Role of risk factors for major coronary heart disease events with increasing length of follow up

BACKGROUND It has been suggested that the predictive value of certain risk factors for coronary heart disease (CHD) measured at one point in time diminishes with increasing length of follow up. DESIGNS AND METHODS The relation was examined between a wide range of risk factors and the risk of major CHD events over 15 years’ total (cumulative) follow up and for three separate five year periods (0–5.0, 5.1–10.0, and 10.1–15.0 years) in men with and without diagnosed CHD in a large prospective study of 7735 men aged 40–59 years. SETTING General practices in 24 towns in the UK. RESULTS The cumulative CHD event rate for all men was 9.4/1000 person-years for the 15 years of follow up. In men with no recall of a diagnosis of CHD, the established risk factors—serum total cholesterol, high density lipoprotein cholesterol, systolic and diastolic blood pressure, physical activity, body mass index (BMI), alcohol intake, diabetes mellitus, parental history, and evidence of CHD on chest pain questionnaire or on ECG—were predictive of CHD events occurring in the three specific periods after baseline measurement. Blood pressure (systolic and diastolic) was still predictive of events occurring 10.1–15.0 years later with some attenuation in the relative risk associated with systolic blood pressure. The risks associated with blood glucose and serum insulin concentration, factors measured with greater imprecision, attenuated with longer follow up and were not predictive of events occurring 10.1–15.0 years later. In men with recall of diagnosed CHD, the absolute risk was very high (38.8/1000 person-years); only cigarette smoking, BMI, total cholesterol, and serum insulin were predictive of CHD events occurring 10.1–15.0 years later. CONCLUSION In men without recall of diagnosed CHD most major risk factors measured in middle age predict risk of CHD events occurring in up to 15 years of follow up, both cumulatively and in the three separate five year periods. Risk factors measured at one point in time in middle age may be regarded as reliable indicators for long term prognosis of major CHD events on a group basis, despite the changes that may take place in these risk factors in some individuals during prolonged follow up.