Dietary intake of marine n-3 PUFA has been negatively associated with the risk of CHD among subjects with known CHD, whereas an effect in healthy subjects is less documented. We assessed the hypothesis that dietary intake of marine n-3 PUFA is negatively associated with the risk of acute coronary syndrome (ACS) in healthy subjects. In the Danish Diet, Cancer and Health cohort study, 57 053 participants were enrolled. Dietary intake of total n-3 PUFA, including EPA, docosapentaenoic acid (DPA) and DHA, was assessed. During a mean follow-up period of 7.6 years, we identified all cases (n 1150) from this cohort with an incident ACS diagnosis in the Danish National Patient Registry or the Cause of Death Registry. Diagnoses were verified through medical record review. In Cox proportional hazard models, we adjusted for established risk factors for CHD. Men in the four highest quintiles of n-3 PUFA intake (>0.39 g n-3 PUFA per d) had a lower incidence of ACS compared with men in the lowest quintile. The hazard ratio was 0.83 (95 % CI 0.67, 1.03) when we compared men in the second lowest and lowest quintile of n-3 PUFA intake. Higher intake of n-3 PUFA did not strengthen this association. Associations for EPA, DPA and DHA were all negative, but less consistent. No convincing associations were found among women. In conclusion, we found borderline significant negative associations between the intake of marine n-3 PUFA and ACS among healthy men.

Aims To study the effect of fish consumption on the risk of acute coronary syndrome (ACS) in healthy subjects. Methods and results This Danish follow-up study included 57 053 men and women between 50 and 64 years. Intake of lean and fatty fish was estimated from a detailed and validated food frequency questionnaire. Potential cases of ACS were identified through nationwide medical databases. A total of 1122 cases of ACS were verified during a mean follow-up period of 7.6 years. Among men, intake of fatty fish was associated with a lower risk of ACS. For men in the highest quintile of fish intake compared with the lowest quintile, the hazard ratio was 0.67 (95% confidence interval: 0.53-0.85). The inverse association was observed for intakes >6 g of fatty fish per day with no obvious additional benefit observed for higher intakes. Intake of lean fish was not associated with ACS. There were few cases of ACS and results were not consistent in women. Conclusion In conclusion, a modest intake of fatty fish was associated with a lower risk of ACS in middle-aged men, whereas no consistent associations were observed among women.

BACKGROUND: The use of specific COX-2 inhibitors in cancer prevention has been associated with higher risk of acute coronary syndrome (ACS) and myocardial infarction. The aim of this study was to investigate if the polymorphisms COX2 T8473C (rs5275), and COX2 A-1195G (rs689466), which modify the enzyme levels of COX-2, were associated with risk of ACS and if alcohol intake, smoking, and use of NSAID would modify the associations. We also wanted to investigate associations with blood lipid levels. METHODS: A case-cohort study including 1031 ACS cases and a sub-cohort of 1703 persons was nested within the population-based prospective study Diet, Cancer and Health of 57,053 individuals aged 55-64 at recruitment 1993-1997. RESULTS: Male variant allele carriers of COX-2 T8473C were at lower risk of ACS (IRR=0.75, CI=0.61-0.93, p=0.008) than homozygous wildtype carriers. There were no statistically significant interactions between genotypes and alcohol intake, smoking and NSAID use in relation to risk of ACS. Among males, there was interaction between COX-2 T8473C and alcohol in relation to total cholesterol, non-HDL cholesterol and LDL levels (p for interaction: 0.003, 0.007 and 0.01, respectively), such that variant allele carriers with low alcohol intake had the lowest lipid levels. No statistically significant associations were observed in females. CONCLUSION: This study suggests that genetically determined COX-2 levels are associated with risk of ACS and blood lipid levels among males. No consistent associations were found for females.

The objective was primarily to describe short term intra-individual variation in serum levels of soluble adhesion molecules (sCAMs: E-selectin, P-selectin, intercellular adhesion molecule-1(sICAM-1) and vascular cellular adhesion molecule-1(sVCAM-1)) in healthy subjects. Secondly, sCAMs were correlated to brachial artery flow mediated vasodilation (FMD).Forty healthy subjects aged 24-66 years had sCAMs measured twice with 4 week intervals and short-term intra-individual variation was estimated as variation in the paired measurements after correcting for the analytical precision of the used method. At baseline, brachial FMD was measured.No difference was observed in mean sCAMs in the whole study group. Estimated intra-subject variations in sCAMs were 7.6-11.3%. In a regression analysis, significant negative association was found between sE-selectin and FMD after controlling for possible confounders (p < 0.04) while no significant correlation could be demonstrated between the other sCAMs and FMD.In conclusion, short term intra-individual variations in sCAMs were 7.6-11.3% in healthy subjects. We also found a significant negative association between sE-selectin and FMD, indicating an possible association between inflammation and dysfunction of the vascular endothelium; however further studies are required to confirm this preliminary finding.

Sudden strenuous exercise increases the risk of ischemic cardiac events in patients with coronary artery disease. The exact mechanism behind this observation is unknown, but platelet activation induced by exercise may be of importance. We hypothesized that brief strenuous exercise would activate platelets in healthy men, assessed by the Platelet Function Analyzer 100 and light transmittance aggregometry. Nearly all participants exhibited increased platelet reactivity after exercise measured by the Platelet Function Analyzer 100, whereas only minor changes were detected by light transmittance aggregometry. A significant increase in plasma von Willebrand Factor was also found in response to exercise. In conclusion, platelet activation occurs during exercise in healthy individuals. This activation is not prevented by use of aspirin or clopidogrel, and may partly be explained by an increase in plasma von Willebrand Factor.

Aims Endothelial lipase (LIPG) is implicated in the metabolism of high-density lipoprotein cholesterol (HDL-C). Small studies in selected populations have reported higher HDL-C levels among carriers of the common T111I variant in LIPG, but whether this variant is associated with plasma lipids and risk of coronary heart disease (CHD) in the general population is unclear. The objective of this study was to address the associations of the T111I variant with plasma lipids and risk of CHD in three independent prospective studies of generally healthy men and women. Methods and results The T111I variant was genotyped in case-control studies of CHD nested within the Diet, Cancer, and Health study with 998 cases, Nurses' Health Study with 241 cases, and Health Professionals Follow-up Study with 262 cases. The minor allele frequency in the combined pool of controls was 0.29. The T111I variant was not associated with HDL-C or any other lipid and lipoprotein measures. Compared with wildtype homozygotes, the pooled estimate for risk of CHD was 0.95 (0.85-1.06) per T111I allele. Conclusion Our analysis among healthy Caucasian men and women from three independent studies does not support an association between the T111I variant and HDL-C, other plasma lipids, or risk of CHD.

BACKGROUND: Lipoprotein lipase (LPL) has a prominent role in the metabolism of triglycerides (TGs) and high-density lipoprotein cholesterol (HDL-C) and is a potential interesting target for the development of antiatherogenic treatment. To provide deeper insight into the role of natural variation in this gene, we investigated the association between the LPL S447X variant with lipids and risk of coronary heart disease (CHD) in 3 independent, prospective studies. METHODS: The S447X variant was genotyped in case-control studies of incident CHD nested within the Nurses' Health Study (NHS), the Health Professionals Follow-up Study (HPFS), and the Danish Diet, Cancer and Health (DCH) study, totaling 245, 258, and 962 cases, respectively. RESULTS: S447X carriers tended to have lower TG and higher HDL-C concentrations than noncarriers. The S447X variant was associated with a lower risk of CHD in the NHS; the association was weaker in the HPFS and not statistically significant in the DCH women and men. The pooled relative risk per minor allele was 0.74 (0.56-1.00). There was a suggestion that the associations of the S447X variant with plasma lipids and CHD risk were more pronounced in obese individuals in the NHS study, but this finding was not consistent across the studies. CONCLUSIONS: The LPL S447X variant tended to be associated with lower TG and higher HDL-C levels, and lower risk of CHD in all 3 cohorts. Lipoprotein lipase is an attractive target for clinical intervention, but studies are needed to clarify whether greater benefit from this variant may be conferred in some subgroups.

Objective . Endothelial dysfunction is a critical, prerequisite step in atherosclerosis, and may be evaluated by flow-mediated vasodilatation (FMD). The objective of this study was to examine interrelationships between FMD and plasma lipids and lipoproteins, and to determine the between-operator and within-subject variability associated with this technique. Material and methods. FMD, plasma lipids and lipoproteins, including small dense LDL (sdLDL), were measured twice in 40 healthy volunteers, 4 weeks apart. Interrelationships between mean FMD responses and plasma lipids and lipoproteins were examined by correlation analysis. FMD measurements were taken by two independent operators, allowing determination of between-operator variability. Within-subject variability was determined by obtaining two measurements, 4 weeks apart, in every subject, and carried out by the same operator. Results. FMD was inversely related to plasma triglycerides (r =-0.47, p = 0.002), total cholesterol/HDL cholesterol (r =-0.35, p = 0.03) and apolipoprotein B (r =-0.36, p = 0.02), but not to other plasma lipids and lipoproteins. When measuring variation in FMD, the following results were found: Between operators (SD = 4.0 FMD%) and within subjects (SD = 2.9 FMD%). Conclusions. The associations between FMD, plasma triglycerides and apoB provide evidence supporting a role for triglyceride-rich lipoproteins in endothelial dysfunction.

There are no generally accepted definitions for low-response (frequently called resistance) to the platelet inhibitors, aspirin and clopidogrel. Low-response may increase the risk of cardiovascular events in atherosclerotic patients. We aimed to define the normal drug responses in healthy men. Platelet function was measured in 20 healthy men during 11 days of aspirin or clopidogrel intake, using light transmission aggregometry (LTA) and the Platelet Function Analyzer 100 (PFA-100). The lower limits for LTA at baseline were 64% and 61%, using arachidonic acid and ADP as agonists, respectively. During aspirin intake the LTA results were stable from day to day, and an upper limit of 9% arachidonic acid stimulated aggregation was found. Clopidogrel intake was best shown by ADP induced aggregation. However, two out of 20 individuals exhibited low-response to clopidogrel. In the remaining 18 volunteers an upper limit of 48% aggregation was found. We found an upper limit for collagen-epinephrine stimulated PFA-100 results of 166 s at baseline. During aspirin intake, these results varied considerably from day to day in nine out of 20 men, resulting in an overlap between the reference ranges at baseline and during therapy. In conclusion, platelet inhibition by aspirin and clopidogrel assessed by aggregometry was stable during 11 days of treatment and reference ranges were established. The PFA-100 results varied greatly and low-response was not precisely defined by this method.

Marine n-3 polyunsaturated fatty acids (n-3 PUFAs) in particular eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) may reduce the risk of coronary heart disease (CHD) and have anti-inflammatory effects. We examined whether levels of serum adiponectin were related to the occurrence and extent of CHD, and whether intake of n-3 PUFAs was associated to high levels of adiponectin. Serum adiponectin and the content of n-3 PUFAs in subcutaneous adipose tissue, platelets and granulocytes were measured in 291 patients referred to elective coronary angiography. Significantly lower levels of serum adiponectin were observed in patients with coronary stenoses compared to patients without stenoses (7336+/-3598 ng/ml vs 10,203+/-8396 ng/ml; p=0.003), but no significant correlation was seen between serum adiponectin and the extent of CHD. In men, serum adiponectin correlated to levels of the content of EPA in platelets (r=0.26; p<0.01) and in granulocytes (r=0.23; p<0.01) and to the content of DHA in subcutaneous adipose tissue (r=0.15; p<0.05) and granulocytes (r=0.17; p<0.05). After regression analysis EPA in platelets (p=0.017) and granulocytes (p=0.030) remained an independent correlate of adiponectin levels, while DHA was no longer an independent correlate. In conclusion, serum levels of adiponectin were lower in patients with angiographically documented coronary artery disease. Also, intake of EPA may increase serum adiponectin and through this exert a protective effect on CHD.