PubMed Health⌕ Search

Biomedical subjects

P Cullen

Publications and source records attributed to P Cullen.

At least 37 records · Page 2Linked to original sources
PubMed2001

Implications of the human genome project for the identification of genetic risk of coronary heart disease and its prevention in children.

Most male citizens of Western countries already have some degree of atherosclerosis by the age of 18, indicating that initiation of atherosclerosis in childhood is a virtually ubiquitous process. This process has a strong genetic component. However, identifying the exact nature of that component is not an easy task, because in the overwhelming majority of cases atherosclerosis is due not to disorders in single genes but to the effects of many genes operating together against a variable environmental background. The preliminary results of the sequencing of the human genome indicate fewer genes, but more complexity in the regulation of the expression of these genes, than was previously thought. For these reasons it is likely that prediction and management of atherosclerotic risk in children in the next years will depend not on the results of genetic testing, but on the differentiated analysis of classical risk factors. These issues are discussed in detail in this review.

Arteriosclerosis↗
PubMed2000

Evidence that triglycerides are an independent coronary heart disease risk factor.

In the past, the relation between hypertriglyceridemia and coronary heart disease (CHD) has been uncertain. However, a recent multivariate analysis of 8-year follow-up data from the large-scale Prospective Cardiovascular Münster study found hypertriglyceridemia to be an independent risk factor for major coronary events after controlling for low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol. Hypertriglyceridemia combined with elevated LDL cholesterol and high LDL:HDL cholesterol ratio (>5) increased the CHD event risk by approximately sixfold. Similarly, a large meta-analysis of 17 prospective trials reported hypertriglyceridemia to be an independent risk factor for cardiovascular disease. In this study, an 88 mg/dl (1.0 mmol/L) increase in plasma triglyceride levels significantly increased the relative risk of cardiovascular disease by approximately 30% in men and 75% in women; the corresponding rates were somewhat lower (14% and 37%) but still statistically significant after adjustment for HDL cholesterol level. These data and observations from patients in the Helsinki Heart Study and the Stockholm Ischemic Heart study, that the greatest coronary benefit during lipid-lowering drug therapy occurred among hypertriglyceridemic patients, argue strongly for an independent role for hypertriglyceridemia in CHD risk. In the recent Veterans Affairs Cooperative Studies Program High-Density Lipoprotein Cholesterol Intervention Trial, the use of gemfibrozil to raise HDL cholesterol levels and lower levels of triglycerides without lowering LDL cholesterol levels reduced coronary events in men with established CHD, whereas preliminary results from the Bezafibrate Infarction Prevention Trial indicate a reduction in coronary end points in patients with elevated baseline triglyceride levels. To achieve the greatest possible reduction in CHD risk, antihyperlipidemic treatment strategies should also be aimed at reducing elevated triglycerides.

Adult↗
PubMed2000

Endogenous apolipoprotein E modulates cholesterol efflux and cholesteryl ester hydrolysis mediated by high-density lipoprotein-3 and lipid-free apolipoproteins in mouse peritoneal macrophages.

We investigated the effect of endogenous apolipoprotein (apo) E synthesis in mouse peritoneal macrophages on cholesterol efflux and intracellular cholesteryl ester hydrolysis mediated by high-density lipoprotein-3 (HDL3) and lipid-free apolipoproteins (apo). After loading with acetylated LDL (acLDL) peritoneal macrophages from wild-type (apoE(+/+)) and apoE-deficient (apoE(-/-)) mice were incubated with medium alone or with liposomes, HDL3, lipid-free apoA-I, or lipid-free apoE3. Cholesterol and cholesteryl esters in the cells and culture media were quantified by HPLC. Incubation of apoE(+/+) or apoE(-/-) macrophages for 18 h with medium alone or with liposomes did not cause significant changes in cellular cholesterol. Addition of HDL3, apoA-I, or apoE3 to the medium led to significant cholesterol efflux, which was less efficient in apoE(-/-) macrophages than in apoE(+/+) macrophages. HDL and lipid-free apolipoproteins were more effective in reducing the cellular content of cholesteryl esters of apoE(+/+) macrophages than of apoE(-/-) macrophages, suggesting that endogenous apoE stimulates cholesteryl ester hydrolysis. The difference in the mass of cholesteryl esters was more pronounced for cholesteryl arachidonate and linoleate than for cholesteryl oleate or palmitate. Furthermore, in [(14)C]arachidonate labeling experiments cholesterol arachidonate hydrolysis was higher in apoE(+/+) macrophages than in apoE(-/-) macrophages in the presence of cholesterol efflux mediated by HDL3 or apoA-I. In contrast, in the absence of cholesterol efflux cholesterol arachidonate synthesis was higher in apoE(+/+) macrophages than in apoE-/- macrophages. Taken together, our data suggest that endogenous apoE stimulates cholesterol efflux and intracellular cholesteryl ester hydrolysis mediated by HDL3 and lipid-free apolipoproteins in mouse peritoneal macrophages. This may contribute to the antiatherogenic effect of apoE.

Animals↗
PubMed2000

Prevalence of hepatitis G in patients on chronic hemodialysis.

Hepatitis G virus (HGV) is a newly described RNA virus from the family of flaviviridae. It is closely related to the hepatitis C Virus (HCV) but is more common than HCV among healthy blood donors. The pathogenicity of HGV in immunosuppressed patients such as those undergoing hemodialysis is unclear. We measured the incidence of HGV in 105 patients undergoing hemodialysis in a chronic outpatient hemodialysis facility. HGV-RNA was detected using a RT-PCR method with primers directed against the 5' non-coding region and the NS5a gene of HGV. Nine (8.6%) patients were HGV RNA positive, eleven (10.5%) were anti-HCV positive, three (2.9%) were positive for hepatitis B surface antigen. Four patients were positive for both HGV and HCV; three of them had normal liver enzymes while one showed elevated ALT levels but no other signs of exacerbation of preexisting hepatitis. The prevalence of HGV among dialysis patients is comparable to that of HCV. The transmission route for HCV is nosocomial transmission during dialysis, whereas HGV shows both ways of transmission: blood transfusion mediated by a high prevalence of HGV among healthy blood donors and nosocomial transmission. HGV appears to play a minor role in acute hepatitis, even in immunosuppressed patients.

Adult↗
PubMed2000

Primary prevention of coronary heart disease: from controversy to consensus.

In recent years, interest has tended to focus on prevention of coronary events in high-risk groups, particularly those with established coronary heart disease. While this is understandable, it has led to a lack of emphasis on primary prevention. Yet it is only by means of primary or even pri-mordial prevention that a substantial reduction in coronary mortality on a population level will be achieved. This becomes clear when we consider that half of all persons who suffer a first myocardial infarction will die within the first month thereafter. Nevertheless, major progress has been made in primary prevention. Reliable risk algorithms have been constructed in Europe (PROCAM) and the U.S., and preliminary analyses on both sides of the Atlantic indicate that these algorithms can be useful applied to populations which are geographically and ethnically distinct from those in which they were derived. A notable trend in recent years is the increasing recognition of the metabolic syndrome with its key components of abdominal obesity, hypertriglyceridemia hypertension, low HDL-C, small, dense LDL, insulin resistance and hyperinsulinemia as being perhaps the most common and dangerous metabolic abnormality of all. Newer risk markers are being evaluated. The position of homocysteine remains unclear. Despite a strong association of elevated homocysteine with risk in case-control studies, prospective investigations have been less convincing. Evidence is beginning to accumulate from cross-sectional and prospective studies that markers of inflammation such as C-reactive peptide may improve our ability to predict risk of coronary events. While these data are encouraging, results of further studies must be awaited before the true place of these markers can be determined. The same can be said of many genetic markers of risk. Though a very large number of association studies have indicated links between a variety of genetic markers and coronary risk, these effects have tended to disappear after controlling for epigenetic and confounding factors and with increasing sample sizes. Finally, much attention is being devoted to non-invasive imaging of the coronary arteries. Such methods hold much promise as a screening test to exclude coronary stenosis in low-risk individuals. However, the measurement of calcium content of the arterial wall by EBCT has yet to prove its usefulness as a predictor of coronary events.

Algorithms↗
PubMed1999

Apolipoprotein A-I (R151C)Paris is defective in activation of lecithin: cholesterol acyltransferase but not in initial lipid binding, formation of reconstituted lipoproteins, or promotion of cholesterol efflux.

ApoA-I(R151)Paris is a natural apolipoprotein (apo) A-I variant that is associated with low levels of high-density lipoprotein cholesterol (HDL-cholesterol) and the partial deficiency of lecithin:cholesterol acyl-transferase (LCAT) in the plasma of heterozygous carriers. We compared the abilities of recombinant normal apoA-I and recombinant apoA-I(R151C)Paris to clear an emulsion of dimyristoylphosphatidylcholine (DMPC), to form reconstituted lipoproteins with dipalmitoylphosphatidylcholine (DPPC), to activate LCAT, and to promote efflux of biosynthetic cholesterol from porcine aortic smooth muscle cells (SMCs) or of exogenous cholesterol from lipid-loaded mouse peritoneal macrophages. Recombinant apoA-I(R151C)Paris occurred in monomeric and dimeric forms at a ratio of 60:40. Normal apoA-I and apoA-I(R151C)Paris cleared DMPC emulsions at equal rates. Both isoforms associated completely with DPPC during cholate dialysis. Normal apoA-I formed one single particle with a mean diameter of 9.3 nm, whereas apoA-I(R151)Paris gave rise to three particles with mean diameters of 9.3 nm (containing 74% of apoA-I), 10.6 nm, and 12.1 nm, respectively. Compared to normal apoA-I, apoA-I(R151C)Paris had a reduced LCAT-cofactor activity with a 60% lower Vmax/Km ratio due to a 50% higher affinity constant, Km. During incubations for 10 min and 360 min, normal apoA-I/DPPC complexes and apoA-I(R151C)Paris/DPPC complexes were equally efficient in releasing biosynthetic cholesterol from SMCs. In the lipid-free form, apoA-I(R151C)Paris induced normal hydrolysis of cholesteryl esters and normal cholesterol efflux from lipid-loaded mouse-peritoneal macrophages. In conclusion, in addition to its ability to form homo- and heterodimers, apoA-I(R151C)Paris is characterized by defective LCAT-cofactor activity but by normal lipid binding and cholesterol-efflux-promoting abilities.

1,2-Dipalmitoylphosphatidylcholine↗
PubMed1999

High risk strategies for atherosclerosis.

Calculating a person's chances of developing coronary heart disease (CHD) is not simple, as many risk factors interact in a complex fashion. Thus many markers, though significant in univariate comparisons, are no longer so when multivariate analysis is performed. Those factors contributing independently to risk can be identified only in prospective investigations such as the Münster Heart (PROCAM) or the Framingham studies. In the Münster Heart study, follow-up of middle-aged men for eight years identified the following nine independent risk variables: age, smoking history, personal history of angina pectoris, family history of myocardial infarction, systolic blood pressure, raised plasma low density lipoprotein cholesterol (LDL-C), low plasma high density lipoprotein cholesterol, raised fasting plasma triglyceride and presence of diabetes mellitus. These have been used to generate an algorithm for prediction of first coronary events which is available in interactive fashion on the internet'. Large trials have shown that lowering LDL-C reduces the risk of CHD, and diminishes CHD morbidity and mortality in persons without prior evidence of coronary atherosclerosis (primary prevention). This is even more the case in patients with such evidence (secondary prevention). It appears that lowering of LDL-C also reduces all-cause mortality in secondary prevention.

Algorithms↗
PubMed1999

Obesity, mortality and cardiovascular disease in the Münster Heart Study (PROCAM).

In the Münster Heart Study (PROCAM), 16,288 men aged 40.6 +/- 11.3 years (mean +/- S.D.) and 7328 women aged 36.0 +/- 12.3 years were enrolled between 1979 and 1991. Mean body mass indices (BMIs) were 25.6 +/- 3.3 and 23.8 +/- 4.1 kg/m2 in men and women, respectively. There was a graded and continuous positive interaction in both men and women between BMI, age and serum total cholesterol, low density lipoprotein (LDL) cholesterol, and blood pressure (both systolic and diastolic). High density lipoprotein (HDL) cholesterol tended to increase with age, but decreased in graded fashion with increases in BMI in both sexes. Triglyceride increased with BMI in both sexes and with age in women, but decreased in the older age groups of overweight and obese men. Though fasting blood glucose increased with age and BMI in both sexes, the increase was more marked in women. Among the 10,856 men aged 36-65 years at study entry, 313 deaths occurred within a follow-up period of 7.1 +/- 2.4 years. Among these men, increased mortality was seen at high BMIs in both smokers and non-smokers and was caused by coronary heart disease (CHD). Increased mortality at low BMI was seen in smokers but not in non-smokers and was due to an increase in cancer deaths. The BMI-associated increase in CHD death was completely accounted for by the factors contained in the Münster Heart Study (PROCAM) risk algorithm, indicating that the effect of overweight and obesity on CHD is mediated via other risk factors.

Adult↗