Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 20 de 78
Filter
1.
Clin Chim Acta ; 411(21-22): 1625-31, 2010 Nov 11.
Article in English | MEDLINE | ID: mdl-20699090

ABSTRACT

Changes in bile acid (BA) metabolism and gallbladder function are critical factors in the pathogenesis of gallstones. Patients with hypertriglyceridemia (HTG) - often overweight and insulin resistant - are at risk for gallstone disease. The question arises whether HTG itself contributes to gallstone formation or whether gallstone disease only associates with this disorder. Triglycerides are formed in response to fluxes of non-esterified fatty acids and glucose. Hypertriglyceridemia results from either overproduction of triglycerides by the liver, impaired lipolysis or a combination of both. Hyperinsulinemia, as observed in the insulin resistant state, stimulates very low-density lipoprotein (VLDL)-triglyceride synthesis. Peroxisome proliferator-activated receptors (PPARs), liver X receptors (LXRs), farnesoid X receptor (FXR) and hepatocyte nuclear factor 4α (HNF4α) are the nuclear receptors involved in the regulation of lipogenesis. Microsomal triglyceride transfer protein (MTP) is involved in the production of VLDL and its activation is also under control of transcription factors as FXR and Forkhead box-O1 (FoxO1). Triglyceride and BA metabolism are linked. There is an inverse relationship between bile acid fluxes and pool size and VLDL production and SHP (small heterodimer partner) and FXR are the link between BAs and TG metabolism. BAs are also ligands for FXR and G-protein-coupled receptors, such as TGR5. FXR activation by BAs suppresses the expression of MTP, transcription factor sterol regulatory element binding protein (SREBP)-1c and other lipogenic genes. LXRs stimulate lipogenesis whereas FXRs inhibit the metabolic process. Synthesis of BAs from cholesterol occurs either via the classical pathway (7α-hydroxylation of cholesterol; CYP7A1) or via the alternate pathway (CYP39A1 or CYP7B1). BAs induce FXR, which inhibits CYP7A1 transcription by activation of SHP and inhibition of HNF4α transactivation. Bile composition (supersaturation with cholesterol), gallbladder dysmotility, inflammation, hypersecretion of mucin gel in the gallbladder and slow large intestinal motility and increased intestinal cholesterol absorption may contribute to the pathogenesis of cholesterol gallstones. In HTG patients supersaturated bile may be related to the presence of obesity rather than to HTG itself. Contraction and relaxation of the gallbladder are regulated by neuronal, hormonal and paracrine factors. Postprandial gallbladder emptying is regulated by cholecystokinin (CCK). Poor postprandial gallbladder contraction may be due to the magnitude of the CCK response and to the amount of CCK receptors in the gallbladder smooth muscle cells. In the fasting state gallbladder motility is associated with the intestinal migrating motor complex (MMC) activity and with elevated plasma motilin levels. Fibroblast growth factor (FGF19), produced on arrival of bile acids in the ileum, is also important for gallbladder motility. Gallbladder motility is impaired in HTG patients compared to BMI matched controls. There is evidence that the gallbladder in HTG is less sensitive to CCK and that this sensitivity improves after reversal of high serum TG levels by use of TG lowering agents. In hypertriglyceridemia TG lowering therapy (fibrates or fish-oil) is essential to prevent cardiovascular disease and pancreatitis. Fibrates, however, also increase the risk for cholelithiasis by increasing biliary cholesterol saturation and by reduction of bile acid synthesis. On the other hand fish-oil decreases biliary cholesterol saturation. Fish-oil may increase bile acid synthesis by activation of 7alpha-hydroxylase and may inhibit VLDL production and secretion through activation of nuclear factors and increased apoB degradation. In HTG patients, gallbladder motility improves during bezafibrate as well as during fish-oil therapy. The question remains whether improvement of gallbladder motility and increased lithogenicity of bile by bezafibrate therapy counteract each other or still result in gallstone formation in HTG patients.


Subject(s)
Gallstones/metabolism , Triglycerides/metabolism , Gallstones/etiology , Humans , Hypertriglyceridemia/complications , Hypertriglyceridemia/metabolism , Lipid Metabolism
2.
J Psychopharmacol ; 23(7): 831-40, 2009 Sep.
Article in English | MEDLINE | ID: mdl-18583436

ABSTRACT

Omega-3 polyunsaturated fatty acid (n-3 PUFA) supplementation may be beneficial in the treatment of several psychiatric disorders, including depression. A small number of studies have suggested that there may also be cognitive and mood effects in healthy samples. The purpose of the present study was to investigate the effects of n-3 PUFA on depression-relevant cognitive functioning in healthy individuals. Fifty-four healthy university students were randomized to receive either n-3 PUFA supplements or placebo for 4 weeks in a double-blind design. The test battery included measures of cognitive reactivity, attention, response inhibition, facial emotion recognition, memory and risky decision-making. Results showed few effects of n-3 PUFAs on cognition and mood states. The n-3 PUFA group made fewer risk-averse decisions than the placebo group. This difference appeared only in non-normative trials of the decision-making test, and was not accompanied by increased impulsiveness. N-3 PUFAs improved scores on the control/perfectionism scale of the cognitive reactivity measure. No effects were found on the other cognitive tasks and no consistent effects on mood were observed. The present findings indicate that n-3 PUFA supplementation may have a selective effect on risky decision making in healthy volunteers, which is unrelated to impulsiveness.


Subject(s)
Cognition/drug effects , Fatty Acids, Omega-3/pharmacology , Affect/drug effects , Decision Making/drug effects , Depression/diet therapy , Dietary Supplements , Fatty Acids, Omega-3/blood , Fatty Acids, Omega-3/therapeutic use , Female , Humans , Male , Patient Compliance , Psychomotor Performance/drug effects , Young Adult
4.
Neth J Med ; 65(5): 185-7, 2007 May.
Article in English | MEDLINE | ID: mdl-17519514

ABSTRACT

Long-term treatment with minocycline is occasionally associated with the development of black thyroid syndrome in which thyroid cancer is frequently found. Here, we report a patient with cutaneous, pulmonary and thyroid sarcoidosis who developed papillary thyroid carcinoma in the presence of a black thyroid syndrome after being treated with minocycline for 2.5 years.


Subject(s)
Anti-Bacterial Agents/adverse effects , Carcinoma, Papillary/chemically induced , Minocycline/adverse effects , Sarcoidosis/drug therapy , Thyroid Neoplasms/chemically induced , Adult , Carcinoma, Papillary/pathology , Carcinoma, Papillary/surgery , Female , Humans , Pigmentation/drug effects , Thyroid Neoplasms/pathology , Thyroid Neoplasms/surgery , Thyroidectomy
5.
Eur J Hum Genet ; 12(11): 935-41, 2004 Nov.
Article in English | MEDLINE | ID: mdl-15241483

ABSTRACT

The rate-limiting enzyme in the conversion of cholesterol into bile acids is cholesterol 7alpha-hydroxylase (CYP7A1). An A to C substitution 278 bp upstream in the promoter of the CYP7A1 gene was found to be associated with variations in serum lipid levels in normolipidaemic populations. In the present study, we investigated the involvement of this polymorphism in four different lipid disorders: hypertriglyceridaemia (HTG), combined hyperlipidaemia (CH), familial dysbetalipoproteinaemia (FD) and familial hypercholesterolaemia (FH). In a normolipidaemic male population, homozygous for the apoE3 isoform, an association was found between the AA genotype and higher levels of serum triglycerides (AA: +34%, P = 0.036). In HTG patients, the AA genotype was associated with significantly higher concentrations of total cholesterol (+23%, P = 0.005). There was a tendency towards increased levels of serum triglycerides (+39%, P = 0.06), VLDL-triglycerides (+48%, P = 0.053) and VLDL-cholesterol (+35%, P = 0.059). No significant associations were found between serum lipid levels and the CYP7A1 polymorphism in patients with CH, FD and FH. Our results show that the A-278C polymorphism in the CYP7A1 gene has an effect on triglyceride levels in normolipidaemic males and on cholesterol levels in patients with hypertriglyceridaemia..


Subject(s)
Cholesterol 7-alpha-Hydroxylase/genetics , Hypertriglyceridemia/genetics , Polymorphism, Genetic , Promoter Regions, Genetic , Adult , Aged , Female , Gene Frequency , Genotype , Humans , Male , Middle Aged , Triglycerides/blood , Triglycerides/metabolism
6.
Atherosclerosis ; 172(2): 329-35, 2004 Feb.
Article in English | MEDLINE | ID: mdl-15019543

ABSTRACT

Patients with familial hypercholesterolemia (FH) are at an increased risk of premature cardiovascular disease (CVD). The benefits of statin therapy are not well known since no placebo controlled studies have been performed in these patients. The aim of this study was to determine the CVD event and mortality risk in statin-treated patients with FH. A total of 345 FH patients were followed prospectively for 8 years. Mortality from CVD was compared to that of the general population. The absolute risk of CVD in patients without a previous history of CVD was 3% per year for men and 1.6% for women. Mortality from CVD in patients without a previous history was 1.4-fold (95% CI = 0.6-3.3) increased and ischaemic heart disease (IHD) mortality was 2.6-fold (95% CI = 1.1-6.3) higher compared to the general population. This mortality risk was highest in patients aged 40-59 years. Female FH patients had no increased CVD or IHD mortality risk. Over a period of 8 years the event risk of patients with a history of CVD was almost 30% per year under age 40 years and 15% in patients aged 60 years and over. When compared to the general population, mortality from other causes than CVD was lower for patients with FH, the relative risks not reaching statistical significance. The relative risk of mortality from all causes was 1.5 (P < 0.05) for men and 1.0 for women. In conclusion, male patients with FH, treated from middle-age with statins remain at an increased risk of developing CVD.


Subject(s)
Cardiovascular Diseases/epidemiology , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Hyperlipoproteinemia Type I/drug therapy , Adult , Cardiovascular Diseases/mortality , Female , Humans , Male , Middle Aged , Myocardial Ischemia/epidemiology , Myocardial Ischemia/mortality , Prognosis
8.
Semin Vasc Med ; 4(3): 249-57, 2004 Aug.
Article in English | MEDLINE | ID: mdl-15630634

ABSTRACT

In humans, apolipoprotein E (apoE) is a polymorphic protein of which three common isoforms can be distinguished, designated apoE2, apoE3, and apoE4. This genetic variation is associated with different plasma lipoprotein levels, different response to diet and lipid-lowering therapy, and a variable risk for cardiovascular disease and Alzheimer's disease. An example of an apoE-mediated, autosomal recessive, lipid disorder is familial dysbetalipoproteinemia (FD), caused by mutations in the apolipoprotein E gene. Homozygosity for APOE*2 (1 in 170 persons) causes FD or type III hyperlipoproteinemia in less than 20% of the adult APOE*2 homozygotes. Less common, dominant negative mutations may also cause the disorder. The patients may present with typical skin lesions and elevated plasma levels of cholesterol and triglycerides, mainly in very-low-density lipoprotein remnants and intermediate-density lipoproteins. The disorder is associated with peripheral and coronary artery disease. Additional gene and environmental factors are necessary for the expression of this hyperlipoproteinemia. Hyperinsulinemia and defects in genes involved in the hydrolysis of triglycerides are associated with this lipid disorder. Diet and weight reduction are effective but usually not sufficient to normalize the lipid levels. Additional therapy with statins or fibrates is necessary and effective in most patients.


Subject(s)
Apolipoproteins E/genetics , Hyperlipoproteinemia Type III/genetics , Apolipoproteins E/metabolism , Genetic Variation , Homozygote , Humans , Hyperlipoproteinemia Type III/diagnosis , Hyperlipoproteinemia Type III/metabolism , Hyperlipoproteinemia Type III/therapy , Lipoproteins/metabolism , Mutation
9.
Atherosclerosis ; 171(2): 311-9, 2003 Dec.
Article in English | MEDLINE | ID: mdl-14644402

ABSTRACT

A cohort of 13 female and 14 male heterozygotes for ATP binding cassette A1 (ABCA1) gene defects was directly compared with 13 and 14 unaffected female and male family members of almost exact same age. The activities of three proteins that play key roles in HDL metabolism were measured in addition to extensive lipid and (apo) lipoprotein subfraction analysis. Compared to controls, LCAT activity was reduced by 15% in affected subjects (P < 0.001) while PLTP activity was unaffected. Interestingly, CETP activity was elevated by 50% in the heterozygote siblings of one kindred but was unaffected in heterozygotes of the three other families. With respect to lipids, the heterozygotes had normal total cholesterol (TC), and LDL-cholesterol concentrations but presented with a trend towards increased triglyceride levels (13%; P = 0.08). HDL metabolism, by contrast, was severely affected as illustrated by 40% reductions in HDL-cholesterol (P < 0.001) with concomitant reductions in apoAI (25%; P < 0.001) levels and in lipoprotein subfraction LpAI (28%; P < 0.001), LpAI:AII (24%; P=0.014), and LpCIII:nonB (34%; P < 0.001) concentrations. We furthermore observed reduced average HDL particle size (5%; P = 0.004; 16% in female and 3.6% in male) and reduced plasma apoCIII concentration (15%; P = 0.006) while apoAII, apoAIV, apoE and apoB levels were unchanged. In conclusion, heterozygosity for ABCA1 defects was associated with reduced LCAT activity in absence of effects on PLTP activity. Of special interest was our finding that the effects of compromised ABCA1 function on HDL were more pronounced in women than in men.


Subject(s)
ATP-Binding Cassette Transporters/genetics , Apolipoproteins/metabolism , Codon, Nonsense , Hyperlipoproteinemia Type II/genetics , Lipoproteins/metabolism , Mutation, Missense , Phosphatidylcholine-Sterol O-Acyltransferase/metabolism , ATP Binding Cassette Transporter 1 , Analysis of Variance , Apolipoproteins/analysis , Case-Control Studies , Cohort Studies , Female , Follow-Up Studies , Heterozygote , Humans , Hyperlipoproteinemia Type II/epidemiology , Hyperlipoproteinemia Type II/metabolism , Lipoproteins/analysis , Male , Multivariate Analysis , Particle Size , Phosphatidylcholine-Sterol O-Acyltransferase/analysis , Probability , Reference Values , Risk Assessment
10.
Ned Tijdschr Geneeskd ; 147(4): 157-9, 2003 Jan 25.
Article in Dutch | MEDLINE | ID: mdl-12635547

ABSTRACT

Familial dysbetalipoproteinaemia is an autosomal recessive, hereditary disorder of lipid metabolism caused by mutations in the apolipoprotein E gene. Homozygosity for apoE2 (1 in 170 persons) causes type III hyperlipoproteinaemia in less than 20% of the adult E2 homozygotes. The patients may present with typical skin lesions and have elevated plasma levels of cholesterol and triglycerides, mainly in very-low-density lipoprotein remnants and intermediate density lipoproteins. The disorder is associated with peripheral and coronary artery disease. Additional genetic and environmental factors are necessary for the expression of this hyperlipoproteinaemia. Hyperinsulinaemia and defects in genes involved in the hydrolysis of triglycerides are associated with this disorder.


Subject(s)
Apolipoproteins E/genetics , Hyperlipoproteinemia Type III/genetics , Cholesterol/blood , Cholesterol, VLDL/blood , Coronary Artery Disease/etiology , Homozygote , Humans , Hyperinsulinism/etiology , Hyperlipoproteinemia Type III/blood , Hyperlipoproteinemia Type III/complications , Triglycerides/blood
11.
Gut ; 52(1): 109-15, 2003 Jan.
Article in English | MEDLINE | ID: mdl-12477770

ABSTRACT

BACKGROUND AND AIM: The aim of this study was to unravel the mechanisms responsible for the increased risk of gall stone disease in hypertriglyceridaemia (HTG) and to compare the effects of triglyceride lowering therapy by bezafibrate and fish oil on determinants of cholelithiasis (biliary lipid composition and gall bladder motility) in HTG patients. PATIENTS AND METHODS: Gall bladder motility (ultrasonography) was studied postprandially and during infusion of cholecystokinin (CCK). Determinants of cholelithiasis and serum lipids were compared between nine HTG patients and 10 age, sex, and body mass index matched normolipidaemic controls. The effects of bezafibrate and fish oil in HTG patients were studied in a randomised cross over trial. RESULTS: HTG patients showed 14-fold higher serum triglyceride (TG) levels than controls. Biliary lipid composition, fasting gall bladder volumes, and CCK levels did not differ between HTG patients and controls. Gall bladder emptying was reduced in HTG patients compared with controls during CCK infusion (-22%) as well as in response to a meal (-37%; both p<0.001). Postprandial CCK levels were significantly higher in HTG patients. Both bezafibrate and fish oil reduced serum TG levels (-68% and -51% v baseline, respectively; both p<0.01). Fasting CCK levels were not affected whereas CCK induced gall bladder emptying increased during bezafibrate (+29%; p<0.001) and tended to increase on fish oil therapy (+13%; p=0.07). Postprandial gall bladder motility improved on bezafibrate and fish oil (+47 and +25% v baseline, respectively; both p<0.02) at least partly due to increased gall bladder sensitivity to CCK (both p<0.05 v baseline). Bezafibrate but not fish oil increased the molar ratio of cholesterol to bile acids (+40%; p

Subject(s)
Cholelithiasis/etiology , Gallbladder/physiopathology , Hypertriglyceridemia/complications , Analysis of Variance , Bezafibrate/therapeutic use , Bile/chemistry , Case-Control Studies , Cholecystokinin , Cholelithiasis/drug therapy , Cholesterol/analysis , Cross-Over Studies , Fish Oils/therapeutic use , Gallbladder/diagnostic imaging , Gallbladder Emptying/drug effects , Humans , Hypertriglyceridemia/drug therapy , Hypertriglyceridemia/physiopathology , Hypolipidemic Agents/therapeutic use , Lipids/analysis , Male , Risk , Statistics, Nonparametric , Ultrasonography
12.
Heart ; 88(3): 234-8, 2002 Sep.
Article in English | MEDLINE | ID: mdl-12181212

ABSTRACT

BACKGROUND: Fibric acid derivatives and HMG-CoA reductase inhibitors are effective in combination for treating patients with familial dysbetalipoproteinaemia and severe combined dyslipidaemia, but combination therapy affects compliance and increases the risk of side effects. AIM: To evaluate the efficacy and safety of monotherapy with atorvastatin, an HMG-CoA reductase inhibitor with superior efficacy in lowering low density lipoprotein cholesterol and triglyceride concentrations, in patients with dysbetalipoproteinaemia and severe combined dyslipidaemia. METHODS: Atorvastatin was tested as single drug treatment in 36 patients with familial dysbetalipoproteinaemia and 23 patients with severe combined dyslipidaemia. RESULTS: After 40 weeks of 40 mg atorvastatin treatment decreases in total cholesterol, triglycerides, and apolipoprotein B of 40%, 43%, and 41%, respectively, were observed in the combined dyslipidaemia group, and of 46%, 40%, and 43% in the dysbetalipoproteinaemic patients. Target concentrations of total cholesterol (< 5 mmol/l) were reached by 63% of the patients, and target concentrations of triglycerides (< 3.0 mmol/l) by 66%. Treatment with atorvastatin was well tolerated and no serious side effects were reported. CONCLUSIONS: Atorvastatin is very effective as monotherapy in the treatment of familial dysbetalipoproteinaemia and severe combined dyslipidaemia.


Subject(s)
Heptanoic Acids/therapeutic use , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Hyperlipidemias/drug therapy , Hyperlipoproteinemia Type III/drug therapy , Pyrroles/therapeutic use , Adult , Aged , Apolipoproteins B/blood , Apolipoproteins B/genetics , Atorvastatin , Cholesterol/blood , Female , Heptanoic Acids/adverse effects , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/adverse effects , Hyperlipidemias/blood , Hyperlipoproteinemia Type III/blood , Male , Middle Aged , Pyrroles/adverse effects , Treatment Outcome , Triglycerides/blood
13.
J Intern Med ; 251(2): 148-55, 2002 Feb.
Article in English | MEDLINE | ID: mdl-11908467

ABSTRACT

OBJECTIVE: To investigate the short-term effect of treatment with tibolone on plasma lipid and lipoprotein levels in postmenopausal women with type III hyperlipoproteinemia (HLP). DESIGN AND INTERVENTION: Patients were randomized to receive, in a double-blind cross-over fashion, a fixed dose of tibolone, 2.5 mg once daily or placebo for 8 weeks. The two treatment periods were separated by a wash-out period of 6 weeks. At each visit body weight and blood pressure were determined. Before and after each treatment period, fasting venous blood samples were obtained from the patients for biochemical measurements. SETTING: The Leiden University Medical Center. SUBJECTS: Postmenopausal women with type III HLP (aged < or = 65 years) were recruited from the Lipid Clinics of the Leiden University Medical Center, the Amsterdam Medical Center, the Utrecht Medical Center and the University Hospital Rotterdam. Five out of 25 women with type III HLP were eligible to be included in the study. Four of the five included patients completed the study according to the protocol. One patient was excluded from blinded therapy because total cholesterol levels increased above 20 mmol L(-1). MAIN OUTCOME MEASURES: A significant reduction of plasma triglyceride, total cholesterol, VLDL cholesterol and VLDL triglyceride levels. RESULTS: Plasma triglyceride and total cholesterol levels decreased from 6.82 +/- 3.58 to 2.45 +/- 1.36 mmol L(-1) and from 13.53 +/- 3.64 to 6.61 +/- 2.03 mmol L(-1), respectively (both P < 0.05). The body mass index remained unchanged. The glycated haemoglobin percentage decreased significantly from 5.8 to 5.3%. Treatment with tibolone resulted in a profound reduction in plasma apolipoprotein E, VLDL cholesterol and VLDL triglyceride levels (mean reductions of 66, 77 and 70%, respectively, P < 0.05). CONCLUSIONS: Tibolone is a valuable adjuvant to current therapy in postmenopausal women with type III HLP.


Subject(s)
Climacteric/drug effects , Hyperlipoproteinemia Type III/drug therapy , Lipoproteins/blood , Norpregnenes/therapeutic use , Cholesterol/blood , Cholesterol, VLDL/blood , Climacteric/blood , Cross-Over Studies , Double-Blind Method , Female , Humans , Hyperlipoproteinemia Type III/blood , Lipoproteins, VLDL/blood , Middle Aged , Norpregnenes/adverse effects , Triglycerides/blood
14.
Cardiovasc Res ; 53(2): 496-501, 2002 Feb 01.
Article in English | MEDLINE | ID: mdl-11827701

ABSTRACT

OBJECTIVES: To infer the relative impact of elevated triglyceride levels and insulin resistance on endothelial dysfunction in patients with chronic hypertriglyceridemia (HTG). METHODS: Endothelial function was studied in 11 HTG patients and 16 normolipidemic controls. Cumulative-dose infusions of 5-hydroxytryptamine (5HT) and sodium nitroprusside were infused locally into the brachial artery to study endothelium-dependent and endothelium-independent vasodilation, respectively. Data of the HTG patients were dichotomized around the median of insulin resistance, calculated as HOMA-index, forming HTG groups with mild (HTG-MIR) and severe insulin resistance (HTG-SIR). RESULTS: HTG patients had higher triglyceride levels and smaller LDL particle size than controls (both P< or =0.001), whereas these parameters did not differ between both HTG groups. Insulin resistance was higher in both HTG groups than in controls (11.1 (7.0-14.5) and 4.9 (4.0-6.7) vs. 2.4 (4.9-5.2), respectively, both P<0.001). Similarly, free fatty acid levels, another indicator of insulin resistance, were highest in the HTG-SIR group, followed by those in the HTG-MIR and control group (0.7 (0.6-0.8), 0.5 (0.4-0.6) and 0.4 (0.3-0.4) mmol/l, respectively, all P<0.05). Endothelial-dependent vasodilation was similar in HTG-MIR and controls. In contrast, the response to 5HT was attenuated in the HTG-SIR group compared to controls (low and high dose by, respectively, -60 and -44%, both P<0.01), and tended to be lower than in the HTG-MIR group (-43%, P=0.068 and -41%, P=0.100, respectively). Endothelium-independent vasodilation did not differ between the three groups. CONCLUSION: These findings indicate that chronic hypertriglyceridemia per se is not associated with endothelial dysfunction. In contrast, the presence of insulin resistance, characterized by hyperinsulinemia and FFA elevation, contributes to the induction of endothelial dysfunction in chronic HTG.


Subject(s)
Endothelium, Vascular/physiopathology , Hypertriglyceridemia/physiopathology , Insulin Resistance , Nitroprusside , Serotonin , Vasodilator Agents , Adult , Case-Control Studies , Chronic Disease , Dose-Response Relationship, Drug , Fatty Acids, Nonesterified/metabolism , Humans , Hypertriglyceridemia/metabolism , Lipoproteins, LDL , Middle Aged , Particle Size , Statistics, Nonparametric
15.
Blood Coagul Fibrinolysis ; 12(8): 705-12, 2001 Dec.
Article in English | MEDLINE | ID: mdl-11734672

ABSTRACT

Hypertriglyceridemia (HTG) is an independent risk factor for cardiovascular disease (CVD). Hemostatic variables [factor VII antigen (FVIIag), factor VII coagulant activity (FVIIc), activated factor VII (FVIIa), free and endothelial-associated (EC) tissue factor pathway inhibitor (TFPI) antigen, pre- and post-heparin total TFPI activity, EC-TFPI activity, prothrombin fragment 1 + 2 (F1 + 2), fibrinogen and D-dimer] were compared between 18 HTG patients and 20 controls to investigate whether HTG is associated with alterations in the extrinsic pathway and whether such alterations create a procoagulant state, as expressed by F1 + 2 and D-dimer levels. In addition, the effects of bezafibrate therapy (6 weeks, 400 mg/day) on these variables were studied in 18 HTG patients in a double-blind, placebo-controlled, cross-over study. FVIIag, FVIIc, free TFPI and fibrinogen were significantly higher in HTG patients (by 44, 30, 45 and 31%, respectively; all P < 0.02), while FVIIa, EC-TFPIag and activity, total TFPI activities, F1 + 2 and D-dimer levels were similar in patients and controls. Bezafibrate reduced serum TG and fibrinogen levels (by 62 and 20%, respectively; both P < 0.001), whereas the other hemostatic variables were unaffected. In conclusion, the observed alterations in the extrinsic pathway in HTG are not associated with a procoagulant state. In contrast, the presence of elevated fibrinogen levels in HTG might enhance the risk for CVD. Bezafibrate therapy improved the adverse lipid profile and decreased fibrinogen levels in HTG patients.


Subject(s)
Blood Coagulation Factors/metabolism , Hypertriglyceridemia/metabolism , Thrombophilia/etiology , Adult , Antigens/drug effects , Antigens/metabolism , Bezafibrate/pharmacology , Bezafibrate/therapeutic use , Factor VII/drug effects , Factor VII/metabolism , Factor VIIa/drug effects , Factor VIIa/metabolism , Female , Hemostasis/drug effects , Humans , Hypolipidemic Agents/pharmacology , Hypolipidemic Agents/therapeutic use , Lipids/blood , Lipoproteins/blood , Lipoproteins/drug effects , Lipoproteins/metabolism , Male , Middle Aged , Thrombophilia/blood
16.
Atherosclerosis ; 157(2): 491-4, 2001 Aug.
Article in English | MEDLINE | ID: mdl-11472751

ABSTRACT

Patients with familial hypercholesterolemia (FH) are especially at risk for premature cardiovascular disease (CVD). Recent studies revealed C-reactive protein (CRP) as a strong predictor of future first or recurrent CVD events, suggesting that CRP plays an important role in the development of atherosclerosis. The aim of this study was to evaluate the effect of one year of simvastatin treatment on serum levels of CRP and to assess the influence of risk factors for CVD on CRP concentrations in patients with FH. We measured baseline CRP levels in 337 patients with FH. A second blood sample, collected after one year of treatment with simvastatin (20--40 mg once daily) was measured in a subgroup of 129 patients. Patients with CVD present at baseline had significantly higher serum levels of CRP (2.26 mg/l versus 1.55 mg/l, P<0.001). CRP levels were associated with smoking, body mass index, age, levels of triglycerides (TG), and the use of NSAIDs or anticoagulation drugs. Simvastatin therapy significantly improved lipid profiles in the intervention group. There was a small, but non-significant decrease of CRP levels upon treatment. CRP decreased from 1.51 mg/l median (interquartile range (IQR) 0.76--3.41) at baseline to 1.24 mg/l median (IQR 0.72--2.92) after treatment, (P=0.328). In conclusion, CRP levels were associated with the presence of CVD in FH patients. Simvastatin therapy had no significant effect on CRP levels in these patients.


Subject(s)
C-Reactive Protein/analysis , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Hyperlipoproteinemia Type II/blood , Hyperlipoproteinemia Type II/drug therapy , Simvastatin/therapeutic use , Adolescent , Adult , Aged , Aged, 80 and over , Cardiovascular Diseases/etiology , Female , Humans , Lipids/blood , Male , Middle Aged , Osmolar Concentration , Risk Factors
17.
J Hypertens ; 19(4): 749-55, 2001 Apr.
Article in English | MEDLINE | ID: mdl-11330878

ABSTRACT

OBJECTIVE: In hypertriglyceridemic patients, hypertension occurs frequently and may be associated with hyperinsulinemia and elevated plasma levels of free fatty acids (FFA). Besides the lipid-lowering effects, fibrates have been shown to reduce blood pressure in hypertensive patients. The present study was undertaken to investigate the effects of bezafibrate on hemodynamics in relation to insulin, FFA, sympathetic activity, renal sodium absorption, cyclic-GMP (cGMP) and endothelin-1 in hypertriglyceridemic patients. SUBJECTS AND METHODS: Hypertriglyceridemic patients (17) were randomized to receive in a double-blind placebo-controlled study bezafibrate or placebo for 6 weeks. At the end of both treatment periods, blood pressure and heart rate were measured automatically. Plasma insulin, FFA, aldosterone, catecholamines, cGMP, endothelin-1 levels and 24 h urine catecholamines and sodium excretion were assessed. RESULTS: Bezafibrate therapy decreased serum triglycerides (-65%, P < 0.001) and hemodynamic parameters: heart rate decreased from 69 to 66/min (P = 0.009), systolic blood pressure from 137 to 132 mmHg (P = 0.01), diastolic blood pressure from 81 to 79 mmHg (P = 0.07) and mean blood pressure from 102 to 99 mmHg (P = 0.06). Bezafibrate therapy reduced FFA and insulin (-55 and -57% respectively, both P < 0.001), while sympathetic activity and renal sodium absorption were not affected. cGMP increased (+17%, P = 0.008), whereas endothelin-1 levels tended to decrease upon bezafibrate therapy (-10%, P = 0.077) CONCLUSION: Bezafibrate reduces heart rate, blood pressure, insulin and FFA in hypertriglyceridemic patients. The hemodynamic effects cannot be attributed to changes in sympathetic activity or renal sodium absorption. Instead, based on the increase in plasma cGMP levels, the bezafibrate-induced hemodynamic effects are most likely to be caused by bezafibrate-induced improvement of endothelial function.


Subject(s)
Bezafibrate/therapeutic use , Blood Pressure/drug effects , Heart Rate/drug effects , Hypertriglyceridemia/drug therapy , Hypertriglyceridemia/physiopathology , Hypolipidemic Agents/therapeutic use , Absorption , Adult , Cyclic GMP/blood , Double-Blind Method , Fatty Acids, Nonesterified/blood , Female , Hemodynamics/drug effects , Humans , Insulin/blood , Kidney/metabolism , Lipids/blood , Male , Middle Aged , Sodium/metabolism , Sympathetic Nervous System/physiopathology
18.
BMJ ; 322(7293): 1019-23, 2001 Apr 28.
Article in English | MEDLINE | ID: mdl-11325764

ABSTRACT

OBJECTIVE: To estimate all cause mortality from untreated familial hypercholesterolaemia free from selection for coronary artery disease. DESIGN: Family tree mortality study. SETTING: Large pedigree in Netherlands traced back to a single pair of ancestors in the 19th century. SUBJECTS: All members of pedigree aged over 20 years with 0.5 probability of carrying a mutation for familial hypercholesterolaemia. MAIN OUTCOME MEASURE: All cause mortality. RESULTS: A total of 70 deaths took place among 250 people analysed for 6950 person years. Mortality was not increased in carriers of the mutation during the 19th and early 20th century; it rose after 1915, reached its maximum between 1935 and 1964 (standardised mortality ratio 1.78, 95% confidence interval 1.13 to 2.76; P=0.003), and fell thereafter. Mortality differed significantly between two branches of the pedigree (relative risk 3.26, 95% confidence interval 1.74 to 6.11; P=0.001). CONCLUSIONS: Risk of death varies significantly among patients with familial hypercholesterolaemia. This large variability over time and between branches of the pedigree points to a strong interaction with environmental factors. Future research is required to identify patients with familial hypercholesterolaemia who are at extreme risk and need early and vigorous preventive measures.


Subject(s)
Hyperlipoproteinemia Type II/mortality , Adult , Aged , Female , Heterozygote , Humans , Hyperlipoproteinemia Type II/genetics , Male , Middle Aged , Mutation , Netherlands/epidemiology , Pedigree , Regression Analysis , Sex Factors , Survival Rate/trends
19.
Am J Cardiovasc Drugs ; 1(6): 455-66, 2001.
Article in English | MEDLINE | ID: mdl-14728004

ABSTRACT

Accumulating evidence indicates that hypertriglyceridemia (HTG) is a risk factor for cardiovascular disease. This increased risk is probably substantially mediated through the metabolic interrelationships between serum triglyceride (TG) levels and other risk factors, such as the atherogenic lipid profile (low high density lipoprotein-cholesterol levels and elevated small dense low density lipoprotein levels), insulin resistance, a prothrombotic propensity and low grade systemic inflammation. TG-lowering strategy in patients with HTG encompasses dietary modification and pharmacological agents, such as fibric acid derivatives, fish-oil and hydroxymethylglutaryl coenzyme A reductase inhibitors, which have, besides their known effects on the atherogenic lipid profile, beneficial effects on other determinants of cardiovascular disease. However, in spite of data from trials investigating fibric acid derivative-induced reduction in coronary events in patients with distinct types of hyperlipidemia, no specific trials have been performed that investigated this risk reduction in patients with HTG, in whom other cardiovascular risk factors are clustered as well. Small-scale studies on determinants of cardiovascular disease in patients with HTG and post-hoc analyses of the Helsinki Heart, Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial and Bezafibrate Infarction Prevention trials in patients with high serum TG levels suggest a drug-induced reduction in cardiovascular events. However, a specific trial should be conducted to investigate the effects of lipid-lowering therapy on clinical end-points in patients with HTG of defined types.


Subject(s)
Hypertriglyceridemia/therapy , Lipids/blood , Adult , Cardiovascular Diseases/etiology , Cardiovascular Diseases/prevention & control , Clinical Trials as Topic , Clofibric Acid/analogs & derivatives , Clofibric Acid/therapeutic use , Feeding Behavior , Fish Oils/therapeutic use , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Hypertriglyceridemia/complications , Insulin Resistance/physiology , Risk Factors , Triglycerides/blood
20.
Arterioscler Thromb Vasc Biol ; 20(11): 2434-40, 2000 Nov.
Article in English | MEDLINE | ID: mdl-11073849

ABSTRACT

Although there is evidence that hyperlipidemia and predominance of small dense low density lipoproteins (LDLs) are associated with increased oxidative stress, the oxidation status in patients with hypertriglyceridemia (HTG) has not been studied in detail. Therefore, we studied urinary levels of F(2)-isoprostanes (8-isoprostaglandin F(2alpha) and 2,3-dinor-5,6-dihydro-8-isoprostaglandin F(2alpha)) and susceptibility of very low density lipoproteins (VLDLs) and LDLs to oxidation ex vivo in 18 patients with endogenous HTG and 20 matched control subjects. In addition, the effects of 6 weeks of bezafibrate therapy were assessed in a double-blind, placebo-controlled, crossover trial. Urinary levels of F(2)-isoprostanes were similar in the HTG and normolipidemic group. Bezafibrate caused an increase in 8-isoprostaglandin F(2alpha) (762+/-313 versus 552+/-245 ng/24 h for bezafibrate and placebo therapy, respectively; P=0.03), whereas 2,3-dinor-5, 6-dihydro-8-isoprostaglandin F(2alpha) levels tended to be increased (1714+/-761 versus 1475+/-606 ng/24 h for bezafibrate and placebo therapy, respectively; P=0.11). VLDLs and LDLs were more resistant to copper-induced oxidation in patients with HTG than in control subjects. Bezafibrate reversed the oxidation resistance to the normal range. In conclusion, these results indicate the following: (1) HTG is associated with normal in vivo oxidative stress and enhanced ex vivo resistance of lipoproteins to oxidation. (2) Bezafibrate reduces the resistance of lipoproteins to copper-induced oxidation and enhances oxidative stress in HTG patients.


Subject(s)
Bezafibrate/therapeutic use , Dinoprost/analogs & derivatives , Hypertriglyceridemia/drug therapy , Hypertriglyceridemia/metabolism , Lipoproteins/blood , Oxidative Stress/drug effects , Cholesterol, HDL/blood , Cholesterol, HDL/metabolism , Cholesterol, LDL/blood , Cholesterol, LDL/metabolism , Cross-Over Studies , Dinoprost/metabolism , Dinoprost/urine , Double-Blind Method , Female , Humans , Hypertriglyceridemia/blood , In Vitro Techniques , Lipid Metabolism , Lipids/blood , Lipoproteins/metabolism , Lipoproteins, VLDL/blood , Male , Middle Aged , Oxidation-Reduction
SELECTION OF CITATIONS
SEARCH DETAIL
...