Normalization of Cardiac Function After Bariatric Surgery Is Related to Autonomic Function and Vitamin D.

PURPOSE: Subclinical cardiac dysfunction is common in patients with obesity. Bariatric surgery is associated with normalization of subclinical cardiac function in 50% of the patients with obesity. The aim of this study was to identify predictors for a lack of improvement of subclinical cardiac dysfunction 1-year post-bariatric surgery. METHODS: Patients who were referred for bariatric surgery were enrolled in a longitudinal study. Inclusion criteria were age 35-65 years and BMI ≥ 35 kg/m2. Patients with a suspicion of or known cardiovascular disease were excluded. Conventional and advanced echocardiography, Holter monitoring, and blood tests were performed pre- and 1-year post-bariatric surgery. Subclinical cardiac dysfunction was defined as either a reduced left ventricular ejection fraction, decreased global longitudinal strain (GLS), diastolic dysfunction, arrhythmia, or an increased BNP or hs Troponin I. RESULTS: A total of 99 patients were included of whom 59 patients had cardiac dysfunction at baseline. Seventy-two patients completed the 1-year follow-up after bariatric surgery. There was a significant reduction in weight and cardiovascular risk factors. Parameters of cardiac function, such as GLS, improved. However, in 20 patients cardiac dysfunction persisted. Multivariate analysis identified a decreased heart rate variability (which is a measure of autonomic function), and a decreased vitamin D pre-surgery as predictors for subclinical cardiac dysfunction after bariatric surgery. CONCLUSION: Although there was an overall improvement of cardiac function 1-year post-bariatric surgery, autonomic dysfunction and a decreased vitamin D pre-bariatric surgery were predictors for a lack of improvement of subclinical cardiac dysfunction.

A placebo-controlled proof-of-concept study of alirocumab on postprandial lipids and vascular elasticity in insulin-treated patients with type 2 diabetes mellitus.

AIM: Type 2 diabetes mellitus (T2DM) is associated with an increased risk of cardiovascular disease (CVD) linked to atherogenic dyslipidaemia and postprandial hyperlipidaemia. Alirocumab, a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, improves CVD risk by reducing the concentration of low-density lipoprotein-cholesterol (LDL-C). However, effects of PCK9 inhibitors on other aspects of diabetic dyslipidaemia, particularly in the postprandial situation, are less clear. MATERIAL AND METHODS: Twelve male patients with T2DM on an intensive insulin regimen completed a 6-week randomized, double-blind, placebo-controlled, proof-of-concept study. Participants received three biweekly dosages of subcutaneous alirocumab (150 mg) or placebo. Before and after the intervention, fasting and postprandial triglyceride (TG) plasma levels, apolipoprotein (apo) B48, lipoprotein composition isolated by ultracentrifugation, vascular function and markers of inflammation were evaluated. RESULTS: Alirocumab treatment reduced fasting plasma TG levels (between group median change -24.7%; P = 0.018) and fasting apoB48 serum levels (-35.9%; P = 0.039) compared with placebo. Alirocumab reduced the plasma TG area under the curve (AUC) (-26.4%; P = 0.006) and apoB48 AUC (-55.7%; P = 0.046), as well as plasma TG incremental AUC (-21.4%; P = 0.04) and apoB48 incremental AUC (-26.8%; P = 0.02). In addition, alirocumab reduced fasting and postprandial TG levels in very low-density lipoprotein (VLDL) and LDL. Alirocumab improved fasting pulse wave velocity, but no changes in postprandial markers of inflammation were observed. CONCLUSIONS: In addition to the well-known LDL-C-reducing effects, 6 weeks of alirocumab treatment lowered both fasting and postprandial plasma TG levels by reducing the TG levels in VLDL and LDL and the concentration of intestinal remnants.

Development of grading scales of pedal sensory loss using Mokken scale analysis on the Rotterdam Diabetic Foot Study Test Battery data.

INTRODUCTION: Loss of sensation due to diabetes-related neuropathy often leads to diabetic foot ulceration. Several test instruments are used to assess sensation, such as static and moving 2-point discrimination (S2PD, M2PD), monofilaments, and tuning forks. METHODS: Mokken scale analysis was applied to the Rotterdam Diabetic Foot Study data to select hierarchies of tests to construct measurement scales. RESULTS: We developed 39-item and 31-item scales to measure loss of sensation for research purposes and a 13-item scale for clinical practice. All instruments were strongly scalable and reliable. The 39 items can be classified into 5 hierarchically ordered core clusters: S2PD, M2PD, vibration sense, monofilaments, and prior ulcer or amputation. DISCUSSION: Guided by the presented scales, clinicians may better classify the grade of sensory loss in diabetic patients' feet. Thus, a more personalized approach concerning individual recommendations, intervention strategies, and patient information may be applied.

Effect of Vitamin D3 on the Postprandial Lipid Profile in Obese Patients: A Non-Targeted Lipidomics Study.

Abstract: Postprandial lipemia can lead to an accumulation of atherogenic lipoproteins in the circulation associated with systemic low-grade inflammation and an increased risk of cardiovascular disease. Lifestyle and pharmacological treatments are usually prescribed for prevention. Vitamin D3 (cholecalciferol), as an anti-atherogenic agent, is being taken into consideration due to its potential beneficial effects in lipid metabolism and its anti-inflammatory potency. To assess the effects of vitamin D3 in the postprandial lipid profile in obese, vitamin D-deficient women, a non-targeted lipidomics approach using liquid chromatography coupled to a quadrupole time-of flight mass spectrometer was used to identify and quantitate a wide-range of circulating lipid species, including diglycerides, lysophosphatidylcholines, phosphatidylcholines, phosphatidylethanolamines, sphingomyelins and triglycerides. The most important changes were found in plasmatic sphingomyelin levels, which experience a decrease after vitamin D3 intake. Our results suggest a turnover of sphingomyelins, probably due to an increased activity of neutral sphingomyelinases, and, therefore, with implications in the clearance of chylomicrons, LDL and VLDL, decreasing postprandial inflammation and macrophage adherence to endothelia, potentially improving cardiovascular disease risk.

Grading the loss of sensation in diabetic patients: A psychometric evaluation of the rotterdam diabetic foot study test battery.

INTRODUCTION: Static- and moving 2-point discrimination (S2PD, M2PD), 10-g monofilaments- and tuning fork are validated outcome measures of clinical manifestations of diabetes-related neuropathy. No modern statistical techniques have been used to investigate how well these instruments combine to measure sensory loss. METHODS: To grade sensory loss at the feet, we fitted parametric forms of Item Response Theory models to the data of these instruments. RESULTS: The fit statistics indicate that the loss of sensation is gradable, with readily available instruments. S2PD and M2PD are lost first, followed by vibration sense, the 10-g monofilament and the ability to feel a cold stimulus. CONCLUSIONS: This test battery appears to provide sound measurement properties in a group of diabetic patients with diverse amounts of sensory loss. This approach may be used in clinical practice to grade sensory loss reliably and quickly, with instruments that are easy to use. Muscle Nerve 58: 559-565, 2018.

Do traditional cardiovascular risk factors solely explain intima-media thickening in youth with type 1 diabetes?

AIMS: The aim of this study was to assess age-specific carotid intima-media thickness (cIMT) in children and adolescents with type 1 diabetes and to investigate associations between cIMT, age, classical cardiovascular disease (CVD) and other risk factors. METHODS: This study included a cross-sectional analysis of cIMT in 178 patients with type 1 diabetes and 208 healthy controls across age categories. In patients, the impact of gender, socio-economic status, ethnicity, current and historical body mass index, blood pressure, hemoglobin A1c, high-density lipoprotein, and low-density lipoprotein cholesterol on cIMT was studied in a retrospective follow-up cohort study. RESULTS: Median cIMT was equally greater in patients versus controls across all age categories (P≤0.03). Regression models in patients confirmed a lack of association between cIMT and classical CVD risk factors. CONCLUSIONS: Children and adolescents with type 1 diabetes showed greater cIMT than controls in all age categories. Increased cIMT did not seem to be consistently associated with classical adult CVD risk factors, adding to the current debate in pediatrics about the impact on classical CVD risk factors to the development of subclinical atherosclerosis in type 1 diabetes. Future studies are warranted to determine if cIMT could assist in predicting macrovascular complications of type 1 diabetes.

Coronary leukocyte activation in relation to progression of coronary artery disease.

Leukocyte activation has been linked to atherogenesis, but there is little in vivo evidence for its role in the progression of atherosclerosis. We evaluated the predictive value for progression of coronary artery disease (CAD) of leukocyte activation markers in the coronary circulation. Monocyte and neutrophil CD11b, neutrophil CD66b expression and intracellular neutrophil myeloperoxidase (MPO) in the coronary arteries were determined by flow cytometry in patients undergoing coronary angiography. The primary outcome included fatal and nonfatal myocardial infarction or arterial vascular intervention due to unstable angina pectoris. In total 99 subjects who were included, 70 had CAD at inclusion (26 patients had single-vessel disease, 18 patients had twovessel disease and 26 patients had three-vessel disease). The median follow-up duration was 2242 days (interquartile range: 2142-2358). During follow-up, 13 patients (13%) developed progression of CAD. Monocyte CD11b, neutrophil CD11b and CD66b expression and intracellular MPO measured in blood obtained from the coronary arteries were not associated with the progression of CAD. These data indicate that coronary monocyte CD11b, neutrophil CD11b and CD66b expression and intracellular MPO do not predict the risk of progression of CAD.

Glucose-dependent leukocyte activation in patients with type 2 diabetes mellitus, familial combined hyperlipidemia and healthy controls.

BACKGROUND: Leukocyte activation has been associated with vascular complications in type 2 diabetes mellitus (T2DM). Hyperglycemia may be involved in this leukocyte activation. Our aim was to investigate the role of elevated glucose concentrations on leukocyte activation in patients with a wide range of insulin sensitivity. METHODS: Leukocyte activation was determined after ingestion of 75 gram glucose in subjects with T2DM, familial combined hyperlipidemia (FCH) and healthy controls. Leukocyte activation markers were measured by flow cytometry. Postprandial changes were calculated as the area under the curve (AUC), and the incremental area under the curve corrected for baseline values (dAUC). RESULTS: 51 Subjects (20 T2DM, 17 FCH and 14 controls) were included. Fasting neutrophil CD66b expression and CD66b-AUC were respectively 36% and 39% higher in T2DM patients than in controls (p=0.004 and p=0.003). Fasting neutrophil CD66b expression correlated positively with glucose-AUC (Spearman's rho 0.481, p<0.001) and HbA1c (rho 0.433, p=0.002). Although fasting monocyte CD11b expression was not significantly different between subjects, monocyte CD11b-AUC was 26% higher in T2DM than in controls (p=0.006). Similar trends were observed for FCH patients. Monocyte CD11b-dAUC correlated positively with glucose-AUC (rho 0.322, p=0.022) and HbA1c (rho 0.319, p=0.023). CONCLUSIONS: These data suggest that both acute and chronic hyperglycemia, associated with insulin resistance as seen in T2DM and FCH, are involved in the increased fasting and postprandial leukocyte activation observed in these conditions.

Differential complement activation pathways promote C3b deposition on native and acetylated LDL thereby inducing lipoprotein binding to the complement receptor 1.

Lipoproteins can induce complement activation resulting in opsonization and binding of these complexes to complement receptors. We investigated the binding of opsonized native LDL and acetylated LDL (acLDL) to the complement receptor 1 (CR1). Binding of complement factors C3b, IgM, C1q, mannose-binding lectin (MBL), and properdin to LDL and acLDL were investigated by ELISA. Subsequent binding of opsonized LDL and acLDL to CR1 on CR1-transfected Chinese Hamster Ovarian cells (CHO-CR1) was tested by flow cytometry. Both native LDL and acLDL induced complement activation with subsequent C3b opsonization upon incubation with normal human serum. Opsonized LDL and acLDL bound to CR1. Binding to CHO-CR1 was reduced by EDTA, whereas MgEGTA only reduced the binding of opsonized LDL, but not of acLDL suggesting involvement of the alternative pathway in the binding of acLDL to CR1. In vitro incubations showed that LDL bound C1q, whereas acLDL bound to C1q, IgM, and properdin. MBL did neither bind to LDL nor to acLDL. The relevance of these findings was demonstrated by the fact that ex vivo up-regulation of CR1 on leukocytes was accompanied by a concomitant increased binding of apolipoprotein B-containing lipoproteins to leukocytes without changes in LDL-receptor expression. In conclusion, CR1 is able to bind opsonized native LDL and acLDL. Binding of LDL to CR1 is mediated via the classical pathway, whereas binding of acLDL is mediated via both the classical and alternative pathways. Binding of lipoproteins to CR1 may be of clinical relevance due to the ubiquitous cellular distribution of CR1.

MTP gene polymorphisms and postprandial lipemia in familial combined hyperlipidemia: effects of treatment with atorvastatin.

BACKGROUND: The microsomal triglyceride transfer protein (MTP) is involved in hepatic and intestinal apoB secretion. We studied the effect of the functional MTP-493G/T polymorphism on fasting and postprandial lipoproteins in patients with familial combined hyperlipidemia (FCH) before and after treatment with atorvastatin. METHODS: Eight FCH heterozygote carriers of the rare -493T allele were compared to 9 matched FCH homozygotes for the wild-type allele in a pilot study. Oral fat loading tests were carried out to measure triglycerides (TG) and apo B48 and B100 in the different fractions of triglyceride-rich lipoproteins (TRLs) before and after treatment with atorvastatin. RESULTS: Before treatment, TG were similar between the -493T allele carriers and non-carriers. In the T-allele carriers, a trend was observed for increased postprandial apo B48 and B100 concentrations in Sf >400 and Sf 60-400 compared to non-carriers. After treatment, fasting and postprandial TG were significantly lowered in carriers of the T allele, but atorvastatin had no effect on postprandial TG in non-carriers. Atorvastatin resulted in similar reductions of apo B48 and B100 in TRLs in both groups. CONCLUSION: The MTP-493G/T polymorphism modulates postprandial apo B48 and apo B100 of TRLs in FCH. Atorvastatin decreases postprandial TG in T-allele carriers with FCH.

Diurnal triglyceridemia in relation to alcohol intake in men.

Fasting and postprandial triglyceride concentrations largely depend on dietary and lifestyle factors. Alcohol intake is associated with triglycerides, but the effect of alcohol on diurnal triglyceridemia in a free living situation is unknown. During three days, 139 men (range: 18-80 years) measured their own capillary triglyceride (cTG) concentrations daily on six fixed time-points before and after meals, and the total daily alcohol intake was recorded. The impact of daily alcohol intake (none; low, <10 g/day; moderate, 10-30 g/day; high, >30 g/day) on diurnal triglyceridemia was analyzed by the incremental area under the cTG curve (∆cTG-AUC) reflecting the mean of the six different time-points. Fasting cTG were similar between the alcohol groups, but a trend of increased cTG was observed in men with moderate and high alcohol intake after dinner and at bedtime (p for trend <0.001) which persisted after adjustment for age, smoking and body mass index. The ∆cTG-AUC was significantly lower in males with low alcohol intake (3.0 ± 1.9 mmol·h/L) (n = 27) compared to males with no (7.0 ± 1.8 mmol·h/L) (n = 34), moderate (6.5 ± 1.8 mmol·h/L) (n = 54) or high alcohol intake (7.2 ± 2.2 mmol·h/L) (n = 24), when adjusted for age, smoking and body mass index (adjusted p value < 0.05). In males, low alcohol intake was associated with decreased diurnal triglyceridemia, whereas moderate and high alcohol intake was associated with increased triglycerides after dinner and at bed time.

Erythrocyte-bound apolipoprotein B in relation to atherosclerosis, serum lipids and ABO blood group.

INTRODUCTION: Erythrocytes carry apolipoprotein B on their membrane, but the determining factors of erythrocyte-bound apolipoprotein B (ery-apoB) are unknown. We aimed to explore the determinants of ery-apoB to gain more insight into potential mechanisms. METHODS: Subjects with and without CVD were included (N = 398). Ery-apoB was measured on fresh whole blood samples using flow cytometry. Subjects with ery-apoB levels ≤ 0.20 a.u. were considered deficient. Carotid intima media thickness (CIMT) was determined as a measure of (subclinical) atherosclerosis. RESULTS: Mean ery-apoB value was 23.2% lower in subjects with increased CIMT (0.80 ± 0.09 mm, N = 140) compared to subjects with a normal CIMT (0.57 ± 0.08 mm, N = 258) (P = 0.007, adjusted P<0.001). CIMT and ery-apoB were inversely correlated (Spearman's r: -0.116, P = 0.021). A total of 55 subjects (13.6%) were considered ery-apoB deficient, which was associated with a medical history of CVD (OR: 1.86, 95% CI 1.04-3.33; adjusted OR: 1.55; 95% CI 0.85-2.82). Discontinuation of statins in 54 subjects did not influence ery-apoB values despite a 58.4% increase in serum apolipoprotein B. Subjects with blood group O had significantly higher ery-apoB values (1.56 ± 0.94 a.u.) when compared to subjects with blood group A (0.89 ± 1.15 a.u), blood group B (0.73 ± 0.1.12 a.u.) or blood group AB (0.69 ± 0.69 a.u.) (P-ANOVA = 0.002). CONCLUSION: Absence or very low values of ery-apoB are associated with clinical and subclinical atherosclerosis. While serum apolipoprotein B is not associated with ery-apoB, the ABO blood group seems to be a significant determinant.

Dyslipidemia in obesity: mechanisms and potential targets.

Obesity has become a major worldwide health problem. In every single country in the world, the incidence of obesity is rising continuously and therefore, the associated morbidity, mortality and both medical and economical costs are expected to increase as well. The majority of these complications are related to co-morbid conditions that include coronary artery disease, hypertension, type 2 diabetes mellitus, respiratory disorders and dyslipidemia. Obesity increases cardiovascular risk through risk factors such as increased fasting plasma triglycerides, high LDL cholesterol, low HDL cholesterol, elevated blood glucose and insulin levels and high blood pressure. Novel lipid dependent, metabolic risk factors associated to obesity are the presence of the small dense LDL phenotype, postprandial hyperlipidemia with accumulation of atherogenic remnants and hepatic overproduction of apoB containing lipoproteins. All these lipid abnormalities are typical features of the metabolic syndrome and may be associated to a pro-inflammatory gradient which in part may originate in the adipose tissue itself and directly affect the endothelium. An important link between obesity, the metabolic syndrome and dyslipidemia, seems to be the development of insulin resistance in peripheral tissues leading to an enhanced hepatic flux of fatty acids from dietary sources, intravascular lipolysis and from adipose tissue resistant to the antilipolytic effects of insulin. The current review will focus on these aspects of lipid metabolism in obesity and potential interventions to treat the obesity related dyslipidemia.

Alcohol and plasma triglycerides.

PURPOSE OF REVIEW: This study reviews recent developments concerning the effects of alcohol on plasma triglycerides. The focus will be on population, intervention and metabolic studies with respect to alcohol and plasma triglycerides. RECENT FINDINGS: Alcohol consumption and fat ingestion are closely associated and stimulated by each other via hypothalamic signals and by an elevated cephalic response. A J-shaped relationship between alcohol intake and plasma triglycerides has been described. A normal body weight, polyphenols in red wine and specific polymorphisms of the apolipoprotein A-V and apolipoprotein C-III genes may protect against alcohol-associated hypertriglyceridemia. In contrast, obesity exaggerates alcohol-associated hypertriglyceridemia and therefore the risk of pancreatitis. SUMMARY: High alcohol intake remains harmful since it is associated with elevated plasma triglycerides, but also with cardiovascular disease, alcoholic fatty liver disease and the development of pancreatitis. Alcohol-induced hypertriglyceridemia is due to increased very-low-density lipoprotein secretion, impaired lipolysis and increased free fatty acid fluxes from adipose tissue to the liver. However, light to moderate alcohol consumption may be associated with decreased plasma triglycerides, probably determined by the type of alcoholic beverage consumed, genetic polymorphisms and lifestyle factors. Nevertheless, patients should be advised to reduce or stop alcohol consumption in case of hypertriglyceridemia.

Systemic inflammation and lung function impairment in morbidly obese subjects with the metabolic syndrome.

BACKGROUND: Obesity and asthma are associated. There is a relationship between lung function impairment and the metabolic syndrome. Whether this relationship also exists in the morbidly obese patients is still unknown. Hypothesis. Low-grade systemic inflammation associated with the metabolic syndrome causes inflammation in the lungs and, hence, lung function impairment. METHODS: This is cross-sectional study of morbidly obese patients undergoing preoperative screening for bariatric surgery. Metabolic syndrome was assessed according to the revised NCEP-ATP III criteria. RESULTS: A total of 452 patients were included. Patients with the metabolic syndrome (n = 293) had significantly higher blood monocyte (mean 5.3 versus 4.9, P = 0.044) and eosinophil percentages (median 1.0 versus 0.8, P = 0.002), while the total leukocyte count did not differ between the groups. The FEV1/FVC ratio was significantly lower in patients with the metabolic syndrome (76.7% versus 78.2%, P = 0.032). Blood eosinophils were associated with FEV1/FVC ratio (adj. B -0.113, P = 0.018). CONCLUSION: Although the difference in FEV1/FVC ratio between the groups is relatively small, in this cross-sectional study, and its clinical relevance may be limited, these data indicate that the presence of the metabolic syndrome may influence lung function impairment, through the induction of relative eosinophilia.

Exploring the value of apoB48 as a marker for atherosclerosis in clinical practice.

BACKGROUND: Postprandial accumulation of atherogenic remnants has been described in patients with type 2 diabetes mellitus (T2DM), familial combined hyperlipidaemia (FCH), familial hypercholesterolaemia (FH) and coronary artery disease (CAD). Scarce data are available on fasting plasma apolipoprotein (apo) B48 levels in relation to these conditions and atherosclerosis. DESIGN: Treated patients with FCH (18), FH (20), T2DM (26), CAD (65), T2DM with CAD (T2DM/CAD) (28) and 33 healthy controls were included. Intima-media thickness (IMT) measurements were carried out to investigate subclinical atherosclerosis. RESULTS: LDL-C and total apoB were lowest in patients with T2DM/CAD owing to the more frequent use of lipid-lowering medication. Fasting plasma apoB48 was elevated in patients with FCH (11·38 ± 1·50 mg/L) and T2DM/CAD (9·65 ± 1·14 mg/L) compared with the other groups (anova, P < 0·01). CAD patients (8·09 ± 0·57 mg/L) had higher apoB48 levels than controls (5·74 ± 0·55 mg/L) and FH patients (5·40 ± 0·51 mg/L) (P = 0·02). IMT was highest in subjects with T2DM/CAD (0·77 ± 0·03 mm) (P < 0·01). The lowest IMT was measured in controls (0·56 ± 0·02 mm) and FCH patients (0·60 ± 0·03 mm). In the total group, the best association for apoB48 was found with fasting triglyceride (Pearson's r = 0·72, P < 0·001). In the subjects not using statins (n = 74), the best correlation was found with IMT (r = 0·52; P < 0·001), whereas total apoB was not associated with IMT (r = 0·20, P = 0·12). CONCLUSIONS: ApoB48 concentrations are highest in patients with FCH and in atherosclerotic subjects with T2DM. In patients not using statins, the surrogate atherosclerosis marker IMT correlates best with apoB48, suggesting that fasting apoB48 may help to detect subjects at risk.

Hypertriglyceridemia, Metabolic Syndrome, and Cardiovascular Disease in HIV-Infected Patients: Effects of Antiretroviral Therapy and Adipose Tissue Distribution.

The use of combination antiretroviral therapy (CART) in HIV-infected patients has resulted in a dramatic decline in AIDS-related mortality. However, mortality due to non-AIDS conditions, particularly cardiovascular disease (CVD) seems to increase in this population. CART has been associated with several metabolic risk factors, including insulin resistance, low HDL-cholesterol, hypertriglyceridemia and postprandial hyperlipidemia. In addition, HIV itself, as well as specific antiretroviral agents, may further increase cardiovascular risk by interfering with endothelial function. As the HIV population is aging, CVD may become an increasingly growing health problem in the future. Therefore, early diagnosis and treatment of cardiovascular risk factors is warranted in this population. This paper reviews the contribution of both, HIV infection and CART, to insulin resistance, postprandial hyperlipidemia and cardiovascular risk in HIV-infected patients. Strategies to reduce cardiovascular risk are also discussed.

[Cholesterol homeostasis and enterohepatic connection: new insights in cholesterol absorption]. / Cholesterolhomeostase en enterohepatische connectie: nieuwe inzichten in cholesterolabsorptie.

The intestines have been proposed as the 'new player' in the field of atherosclerosis as a result of recent discoveries on intestinal cholesterol absorption and excretion. 'Niemann-Pick C1-like 1' is one of the most important transport proteins in the process of intestinal and biliary cholesterol absorption. Cholesterol is not only excreted via the hepato-biliary route but is also excreted directly into the intestinal lumen; this transintestinal cholesterol excretion is particularly important in mice. Other cholesterol transporters have also been identified, including the ABC transporters, which have been linked to rare disorders such as sitosterolemia. Inhibition of intestinal cholesterol absorption increases the hepatic synthesis of cholesterol and vis versa; several different genes and hormones play an important role in this process. When the effect of statins is insufficient or they cause too many side-effects, additional inhibition of intestinal cholesterol absorption is indicated.

Mannose binding lectin 2 haplotypes do not affect the progression of coronary atherosclerosis in men with proven coronary artery disease treated with pravastatin.

OBJECTIVE: Mannose binding lectin (MBL) is one of the three initiators of complement activation. Polymorphisms of the MBL2 gene and its promoter, and especially haplotypes, determine MBL plasma levels. MBL deficiency has been associated with the development of atherosclerosis. We evaluated whether the rate of angiographic progression of coronary atherosclerosis during pravastatin treatment was associated with MBL2 haplotypes in REGRESS, a placebo-controlled 2 years intervention study. METHODS: Three polymorphic sites in exon 1 (rs1800450, rs1800451 and rs5030737) of the MBL2 gene and 2 sites (rs7096206 and rs11003125) in the promoter region were genotyped in 398 subjects. Genotyping was performed using Applied Biosystems® TaqMan® Genotyping Assays. We divided the group in high, intermediate and low MBL2 secretor haplotypes. Quantitative coronary angiography was performed. Endpoints were mean segment diameter (MSD) and minimum obstruction diameter (MOD) established by quantitative coronary angiography. RESULTS: At inclusion, 50.1, 31.7 and 17.6% of the patients in the REGRESS cohort carried the high, intermediate and low MBL2 secretor haplotypes, respectively. In 0.6% of the patients, the haplotype was not informative. There were no baseline differences between the MBL2 haplotypes for age, BMI, lipid levels, leukocyte counts, CRP, MSD and MOD. The intermediate MBL2 placebo group showed the greatest increase in MSD compared to the low MBL2 group (P=0.03). No difference was found for the change in MOD. No significant interaction between MBL2 haplotype groups and pravastatin therapy was observed. CONCLUSION: In men with proven coronary artery disease, MBL2 secretor haplotypes are not associated to the rate of progression of coronary sclerosis nor does pravastatin treatment influence progression based on MBL2 haplotypes.