Mannose binding lectin deficiency and triglyceride-rich lipoprotein metabolism in normolipidemic subjects.

Mannose binding lectin (MBL) is one of the three initiators of complement activation and is therefore closely linked to inflammation. MBL deficiency has been associated with the generation of atherosclerosis. Since atherosclerosis, the complement system and postprandial lipemia are linked to inflammation, we studied postprandial lipoprotein metabolism in MBL deficiency. An observational study was carried out in 107 volunteers (21% MBL deficient). Classical cardiovascular risk factors were not different between subjects with and without MBL deficiency. Oral fat loading tests in 8 MBL deficient and 14 MBL sufficient subjects showed similar postprandial triglyceride, free fatty acid, hydroxybutyric acid and complement component 3 concentrations. MBL deficient subjects had 2.4 times lower postprandial Sf>400 (chylomicron)-apoB48 concentrations, but in contrast a 2-3.5 times increased Sf 60-400 (VLDL1-TG) and Sf 60-400-apoB100 response. MBL activity was inversely related to the postprandial Sf 60-400-TG increase. Despite lower postprandial Sf>400-apoB48 concentrations, MBL deficient subjects show an accumulation of Sf 60-400 lipoproteins.

Comparison of different methods to investigate postprandial lipaemia.

Postprandial hyperlipidaemia has been associated with coronary artery disease (CAD). We investigated which of the generally used methods to test postprandial lipaemia differentiated best between patients with premature CAD (50+/-4 years, n=20) and healthy controls. Furthermore, the effects of rosuvastatin 40 mg/day on postprandial parameters were assessed. Standardised oral fat-loading tests (OFLT) and ambulant self-measurements of daylong capillary triglycerides (TGc) were performed. Total responses of individual lipoproteins, plasma TG (TGp) and remnant-like particle cholesterol (RLP-C) were estimated as area under the curve (AUC). Most AUCs were highest in untreated patients and reached control levels after rosuvastatin. From all AUCs, RLP-C-AUC was best associated to TGp-AUC in untreated patients and controls (adjusted R2=0.84, beta=0.92, p.

Effects of rosuvastatin on postprandial leukocytes in mildly hyperlipidemic patients with premature coronary sclerosis.

We investigated whether pro-inflammatory aspects of the postprandial phase can be modulated by rosuvastatin in premature coronary artery disease (CAD) patients. Herefore standardized 8 h oral fat loading tests were performed off-treatment and after rosuvastatin 40 mg/d in 20 male CAD patients (50 +/- 4 years). The expression of leukocyte activation markers CD11a, CD11b, CD62L and CD66b was studied using flowcytometry. Migration of isolated neutrophils towards chemoattractants was determined in a fluorescence-based assay. Rosuvastatin did not affect baseline leukocyte counts nor the postprandial neutrophil increment (maximum mean increase +10% pre- and +14% post-treatment, P < 0.01 for each). Rosuvastatin reduced baseline platelets (from 266 +/- 78 to 225 +/- 74 x 10(9) cells/L, P < 0.001) and blunted the postprandial platelet count change (maximum mean increase +6%, P = 0.01, and 0%, respectively). The baseline expression of CD11a, CD11b and CD62L increased on most types of leukocytes by rosuvastatin, whereas the postprandial responses were unaffected. Pretreatment, postprandial neutrophil migration increased dose-dependently, but there were no postprandial changes after rosuvastatin. The latter effect was unrelated to changes in lipoprotein concentrations. In conclusion, in CAD patients postprandial pro-inflammatory and pro-coagulant changes can be modified by rosuvastatin. These apparently lipid-lowering independent effects may render protection against atherosclerosis.

Activation of leukocytes by postprandial lipemia in healthy volunteers.

Activation of leukocytes is obligatory for inflammation and atherogenesis by adhering to the endothelium via specific ligands. Although in vitro studies have shown that triglycerides (TG) can activate leukocytes, it is unknown whether this occurs in vivo. Using flowcytometry, we studied the expression of leukocyte activation markers CD11A, CD11B, CD62L (all involved in endothelium adhesion) and CD66B (a neutrophil degranulation marker) during a 6 h fat challenge (50 g/m2) and a water test in 10 healthy males (52 +/- 3 years). After fat, neutrophil counts were increased between t=1 and t =6 h, with a maximum at t=3 h (+32% versus t=0, P <0.05), while they remained unchanged after water. Both tests showed gradual lymphocyte count increments. The expression of activation markers on lymphocytes was low and showed comparable responses after both tests. After fat, a significant increase up to a maximum at t=6 h was seen for CD11B on monocytes and on neutrophils for CD11B, CD62L and CD66B. Postprandial activation of monocytes and neutrophils was higher after fat than after water. The maximal postprandial TG increment was significantly related to the increase of CD11B on monocytes (Pearson's R=0.64, P <0.05). In conclusion, postprandially there is a TG-specific increase of neutrophil counts and increased activation of monocytes and neutrophils. These results are suggestive of a pro-inflammatory situation that may correspond with increased adhesive capacity of these cells contributing to the inflammatory component of atherosclerosis.

Postprandial leukocyte increase in healthy subjects.

Atherosclerosis is an inflammatory disorder involving leukocytes and lipids. To study the relationship between leukocytes and lipids in vivo, leukocyte changes were determined in 14 healthy males (age, 23 +/- 3 years; body mass index [BMI], 21.9 +/- 1.5 kg/m(2)) after an 8-hour oral fat load (50 g/m(2)) and after water. The postprandial triglyceride (TG) increment after fat was paralleled by a leukocyte increment, due to an increase in neutrophils in the first 2 hours (142% +/- 69% higher than baseline, P =.04). Neutrophil counts did not return to baseline at the end of the test. Water ingestion did not induce significant neutrophil changes. Blood lymphocytes increased gradually in both tests (142% +/- 30% higher than baseline, P <.001 after fat, and 128% +/- 36%, P =.02 after water). The total leukocyte increment after fat ingestion was related to the postprandial TG increase (Spearman's r = 0.73, P =.003). An early postprandial, lipid-specific, neutrophil increment is a new characteristic of the postprandial phase. Future studies will elucidate the role of postprandial leukocyte changes in the pathogenesis of atherosclerosis.

Postprandial recruitment of neutrophils may contribute to endothelial dysfunction.

Atherosclerosis is a low-grade inflammatory disease involving leukocytes, lipids, and glucose leading to endothelial dysfunction. Since activation of neutrophils by triglycerides and glucose has been described in vitro, we hypothesized that the postprandial phase is an inflammatory state affecting leukocytes, possibly contributing to endothelial dysfunction. We measured postprandial blood leukocyte counts, cytokines, hydroperoxides (HPOs), and flow-mediated vasodilation (FMD) in eight healthy males (age 23 +/- 2 years) after a FAT (50 g/m2) and GLUCOSE challenge (37.5 g/m2), a combination of both (MIXED test), and after WATER. All tests, except WATER, resulted in significantly impaired FMD (10% reduction) between t = 1 h and t = 3 h, accompanied by a significant increase of neutrophils (59% after FAT and 28% after GLUCOSE and MIXED), total plasma HPOs (15 to 31% increase), and plasma interleukin-8 (IL-8) (50-130% increase). WATER did not affect FMD, neutrophils, HPOs, or IL-8. Lymphocytes increased gradually in all tests (40-70% increase at t = 10 h compared with t = 0; P < 0.005), paralleling a gradual 3- to 5-fold interleukin-6 increase. Monocyte and erythrocyte counts did not change in any test. In conclusion, the neutrophil increment during postprandial lipemia and glycemia with concomitant IL-8 and HPO increases may contribute to endothelial dysfunction. Lymphocyte increment is a nonspecific diurnal process. Postprandial intravascular inflammatory changes may be relevant for the pathogenesis of atherosclerosis.

Insulin resistance and vessel endothelial function.

IRS is a complex disease consisting of a clustering of metabolic disorders, of which hyperglycaemia, hyper-insulinaemia and dyslipidaemia are the most important. Endothelial dysfunction plays an important role in the pathogenesis of atherosclerosis. The effects of hyperinsulinaemia seem to depend on lipidaemia and glycaemia. Hyperglycaemia and hyperlipidaemia have detrimental effects on endothelial function in the fasting as well as the postprandial states. In both situations, the generation of ROS and vasoactive molecules plays a major role in interfering with the atheroprotective endothelium-dependent NO system. Treatment of IRS in regard to endothelial function should be focused initially on lifestyle improvement, such as stopping smoking and eating a balanced diet containing antioxidant vitamins, folic-acid, L-arginine and long-chain omega-3 unsaturated FA. Strict glucose control has shown to improve endothelial function and decrease microvascular complications. However, macrovascular complications, in line with endothelial functional improvement, have so far been reduced only when treatment was focused on other characteristics of the IRS syndrome, in particular dyslipidaemia. Other relevant treatments include ACE inhibitors and thiazolidinediones, and probably tetrahydrobiopterin and folic acid supplementation. Future studies should address the effects of therapeutic neovascularization on endothelial dysfunction.