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Eric Bruckert

Publications and source records attributed to Eric Bruckert.

At least 37 records · Page 2Linked to original sources
PubMed2004

Matrix metalloproteinases, inflammation and atherosclerosis: therapeutic perspectives.

Matrix metalloproteinases (MMPs), also called matrixins, are proteinases that participate in extracellular matrix remodelling and degradation. Under normal physiological conditions, the activities of MMPs are precisely regulated at the level of transcription, of activation of the pro-MMP precursor zymogens and of inhibition by endogenous inhibitors (tissue inhibitors of metalloproteinases; TIMPs). Alteration in the regulation of MMP activity is implicated in diseases such as cancer, fibrosis, arthritis and atherosclerosis. The pathological effects of MMPs and TIMPs in cardiovascular diseases involve vascular remodelling, atherosclerotic plaque instability and left ventricular remodelling after myocardial infarction. Since excessive tissue remodelling and increased matrix metalloproteinase activity have been demonstrated during atherosclerotic lesion progression (including plaque disruption), MMPs represent a potential target for therapeutic intervention aimed at modification of vascular pathology by restoring the physiological balance between MMPs and TIMPs. This review describes the members of the MMP and TIMP families and discusses the structure, function and regulation of MMP activity; finally, pharmacological approaches to MMP inhibition are highlighted.

Animals↗
PubMed2003

Magnitude of HDL cholesterol variation after high-dose atorvastatin is genetically determined at the LDL receptor locus in patients with homozygous familial hypercholesterolemia.

OBJECTIVE: The combination of LDL apheresis with high doses of a potent hepatic hydroxymethylglutaryl coenzyme A reductase inhibitor, such as atorvastatin, has been the best therapy available for the prevention of cardiovascular disease in patients with homozygous familial hypercholesterolemia (HFH). However, some concerns have been made about the effect of atorvastatin on HDL cholesterol levels in these patients. METHODS AND RESULTS: HDL cholesterol levels were determined bimonthly over the course of 2 years of treatment with high-dose atorvastatin in genotypically defined HFH patients either receptor-defective (n=6) or receptor-negative (n=6) under long-term treatment with LDL apheresis. We additionally stratified the atorvastatin effect on HDL cholesterol according to the genotype as an indicator of residual in vivo LDL receptor activity. Our findings indicate that (1) an early and transitory reduction of plasma HDL cholesterol levels occurs during the first 4 weeks of atorvastatin treatment; (2) the degree of the transient HDL reduction is higher in receptor-negative than in receptor-defective patients (-21+/-11 versus -10+/-4%; P=0.01); and (3) after long-term treatment, HDL cholesterol concentration remains higher in receptor-defective than receptor-negative patients (P=0.026). CONCLUSIONS: The present study reveals that HDL cholesterol reduction after high-dose atorvastatin is an early and transient event in HFH patients which magnitude depends on the presence of a residual LDL-R activity.

Adolescent↗
PubMed2003

Serum plasma pregnancy-associated protein A: a potential marker of echogenic carotid atherosclerotic plaques in asymptomatic hyperlipidemic subjects at high cardiovascular risk.

OBJECTIVE: The proteolytic activity of metalloproteinases, proinflammatory enzymes that degrade extracellular matrix, is elevated in lipid-rich atherosclerotic plaques, thereby contributing to plaque fragility and rupture. Pregnancy-associated plasma protein (PAPP-A) is a metalloproteinase, expressed in unstable atherosclerotic plaques, whose circulating levels are elevated in acute coronary syndromes. We evaluated serum PAPP-A levels as a marker of the premature development of atherosclerosis in hyperlipidemic subjects at elevated cardiovascular risk. METHODS AND RESULTS: Serum PAPP-A levels were determined in asymptomatic hyperlipidemic male subjects (n=64; mean+/-SD age, 51+/-7 years) in whom intima-media thickness (IMT) and lesion status in the carotid artery were evaluated by noninvasive ultrasonography and compared with those of a normolipidemic control group (n=25). No difference was observed in circulating PAPP-A levels between hyperlipidemic subjects and controls (8.99+/-2.93 and 8.03+/-2.75 mIU/L, respectively; mean+/-SD) nor between hyperlipidemic subjects who presented with a luminal obstruction of the carotid artery (9.26+/-2.53 mIU/L) and those who did not (8.85+/-3.29 mIU/L). By contrast, in patients with atheromatous carotid plaques, a positive association between serum levels of PAPP-A and C-reactive protein was observed (P<0.05); moreover, subjects exhibiting hyperechoic or isoechoic, echogenic lesions had significantly higher PAPP-A levels compared with those with hypoechoic lesions (10.32+/-2.72 vs 8.27+/-2.18 mIU/L, P<0.05) and with normolipidemic controls (P<0.05). CONCLUSIONS: Elevated serum PAPP-A levels represent a potential marker of the degree of echogenicity of carotid atherosclerotic plaques in asymptomatic hyperlipidemic patients at high cardiovascular risk and equally of an enhanced local inflammatory state involving remodeling of subendothelial extracellular matrix.

Arteriosclerosis↗
PubMed2003

Serum matrix metalloproteinase-3 and tissue inhibitor of metalloproteinases-1 as potential markers of carotid atherosclerosis in infraclinical hyperlipidemia.

The proteolytic activity of proinflammatory matrix metalloproteinases (MMPs) is elevated in lipid-rich atherosclerotic plaques, thereby contributing to plaque fragility and rupture. We hypothesized that changes in circulating levels of MMPs and their specific inhibitors (TIMPs) could reflect the atherosclerotic process occurring within the arterial wall. We determined serum levels of MMP-3, MMP-9, TIMP-1 and TIMP-2 in dyslipidemic subjects and compared them to those of age- and sex-matched normolipidemic healthy controls. Serum levels of MMP-3, MMP-9 and TIMP-1 were significantly increased in hyperlipidemic subjects versus controls (+54, +29 and +15%, respectively; P<0.001). We also noted a trend to elevated serum MMP-3 levels in patients with atherosclerotic lesions when compared to patients free of atherosclerosis (P=0.07). Circulating levels of MMPs and TIMPs were associated neither with those of C-reactive protein, nor with those of alpha2-macroglobulin (a nonspecific MMP inhibitor), nor with intima-media thickness values. Nonetheless, when divided into tertiles, MMP-3 and TIMP-1 levels in the highest tertile were positively associated with the presence of carotid artery lesions (odds ratios=3.4 and 2.0, confidence intervals 1.7-13.9 and 1.3-7.9, respectively). Thus, serum levels of MMP-3, -9 and TIMP-1 are significantly elevated in asymptomatic hyperlipidemic subjects at high cardiovascular risk; however, MMP-3 and TIMP-1 levels are strongly positively associated with the presence of carotid lesions. Such elevations might reflect enhanced vascular matrix remodeling, a key feature of the progression of atherosclerotic disease.

Biomarkers↗
PubMed2003

Mutations in PCSK9 cause autosomal dominant hypercholesterolemia.

Autosomal dominant hypercholesterolemia (ADH; OMIM144400), a risk factor for coronary heart disease, is characterized by an increase in low-density lipoprotein cholesterol levels that is associated with mutations in the genes LDLR (encoding low-density lipoprotein receptor) or APOB (encoding apolipoprotein B). We mapped a third locus associated with ADH, HCHOLA3 at 1p32, and now report two mutations in the gene PCSK9 (encoding proprotein convertase subtilisin/kexin type 9) that cause ADH. PCSK9 encodes NARC-1 (neural apoptosis regulated convertase), a newly identified human subtilase that is highly expressed in the liver and contributes to cholesterol homeostasis.

Amino Acid Substitution↗
PubMed2003

Lipoprotein lipase activity and common gene variants in severely hypertriglyceridemic patients with and without diabetes.

OBJECTIVES: In severe type IV hypertriglyceridemia (triglyceride levels >10 g/l), it is yet unknown whether lipoprotein lipase (LPL) differs according to the presence or not of diabetes. METHODS: We compared LPL activity and the presence of four common variants in the LPL gene (Asp 9 Asn (exon 2), Gly 188 Glu (exon 5), Asn 291 Ser (exon 6) and Ser 447 Ter (exon 9)) in a group of 34 patients of whom 17 presented diabetes mellitus. RESULTS: Maximum triglyceride, cholesterol levels and distribution of apolipoprotein E phenotypes did not differ between the two subgroups. Mean post-heparin LPL activity was lower in non-diabetic compared to diabetic patients (9.74 vs. 12.98 micromol FFA/ml/h, p=0.033). Four patients were carrying a mutation in exon 9 (1 non-diabetic), 6 patients in exon 2 (4 non-diabetic) and 1 patient in the non-diabetic subgroup in exon 5. All mutations were at the heterozygous state. CONCLUSION: We found that LPL activity was lower in type IV hyperlipidemia in the absence of diabetes. Genetic defects in the LPL gene that could lead to this lower LPL tended to be more frequently observed in patients without diabetes. These data suggest that the pathomechanisms which contribute to severe type IV hyperlipidemia are different according to the presence or not of diabetes.

Adult↗
PubMed2003

Action of ciprofibrate in type IIb hyperlipoproteinemia: modulation of the atherogenic lipoprotein phenotype and stimulation of high-density lipoprotein-mediated cellular cholesterol efflux.

The effects of ciprofibrate (100 mg/d) on apolipoprotein (apo)B- and apoAI-containing lipoprotein subclasses, cholesteryl ester (CE) transfer protein activity, and plasma high-density lipoprotein (HDL)-mediated cellular cholesterol efflux were evaluated in 10 patients displaying type IIB hyperlipidemia. Plasma concentrations of large very low-density lipoprotein (VLDL)-1 (Sf 60-400) and of small VLDL-2 (Sf 20-60) were markedly diminished after fibrate treatment (-40%, P = 0.001; and -25%, P = 0.003, respectively). We observed a reduction (-17%; P = 0.005) in plasma low-density lipoprotein (LDL) levels resulting from significant reductions in concentrations of dense LDL particles (-46%; P < 0.0001). Ciprofibrate induced elevation in plasma total HDL (+13%; P = 0.005) levels; such elevation occurred preferentially in HDL-3 (+22%; P = 0.009). Marked reduction in numbers of atherogenic apoB100-containing particle acceptors was associated with a 25% decrease (P < 0.02) in CE transfer protein-mediated CE transfer from HDL. Finally, a significant fibrate-mediated elevation (+13%; P = 0.01 compared with baseline) in the capacity of plasma from type IIB subjects to mediate free cholesterol efflux from scavenger receptor class B, type I-expressing Fu5AH hepatoma cells was observed. In conclusion, the action of ciprofibrate in type IIB dyslipidemia leads to preferential reduction in particle numbers of atherogenic VLDL-1, VLDL-2, and dense LDL and, concomitantly, to elevation in HDL-3 levels that are associated with stimulation of HDL-mediated cellular free cholesterol efflux through the scavenger receptor class B, type I receptor pathway.

Adult↗
PubMed2003

New lipid-modifying therapies.

Lipid abnormalities are central among the risk factors for the development of cardiovascular disease and their correction remains a major target for the medical community. Inhibitors of 3-hydroxy-3-methyl glutaryl coenzyme A reductase (statins) are the most widely prescribed and best tolerated of the currently available lipid-modifying therapies. Newer agents in this class (e.g., rosuvastatin) have proven to be more effective at lowering levels of low-density lipoprotein cholesterol. New formulations of drugs such as nicotinic acid, which improve treatment regimens and reduce unpleasant side effects, may result in improved patient compliance with this therapy. The development of novel drugs such as cholesterol absorption inhibitors (e.g., ezetimibe) and acyl-coenzyme A cholesterol acyltransferase inhibitors (e.g., avasimibe) will provide clinicians with therapeutic options that exploit different pathways to those currently being utilised. By combining these agents with statins, greater improvements in the lipid profile than those seen to date could be produced. In addition, advances in our understanding of the pathophysiology of dyslipidaemia have enabled other novel therapeutic targets to be identified and studies with experimental drugs underscore the potential of these approaches.

Antioxidants↗
PubMed2003

Patients' and physicians' perceptions and experience of hypercholesterolaemia: a qualitative study.

BACKGROUND: A better understanding of patients' and physicians' perceptions and experience of hypercholesterolaemia will help to improve cardiovascular disease prevention and aid the development of appropriate educational strategies. AIM: To identify perceptions, experience, educational needs, and barriers to learning in hypercholesterolaemic patients at high risk of cardiovascular disease. DESIGN OF STUDY: A qualitative study involving interviews with 27 hypercholesterolaemic outpatients and 21 physicians. SETTING: 21 centres in Paris, Bordeaux and Lille. METHODS: Semi-structured interviews were conducted by a sociologist with the aid of two interview guides focusing on hypercholesterolaemia. Interviews were recorded and subsequently transcribed, and qualitative analysis was performed to identify emerging themes. RESULTS: Six main themes emerged: understanding hypercholesterolaemia--a 'virtual' disease; understanding cardiovascular risk--a vague concept; lifestyle measures; long-term effects of medication; medical language difficulties; and patients' expectations and needs. Patients and physicians disagreed over the terms used to describe hypercholesterolaemia and cardiovascular risk, and the complexities of medical language. In contrast, patients and physicians agreed on the difficulties associated with implementing lifestyle changes and adhering to long-term treatment. CONCLUSIONS: The differences in perception and experience between physicians and patients indicate that physician-patient communication is sub-optimal and highlights the need to improve educational material for cardiovascular disease prevention. This analysis helps to identify appropriate educational objectives and methods for patients at risk of cardiovascular disease, and develop a structured educational programme.

Adult↗
PubMed2002

[Factors associated with the opinion of hypercholesterolemic patients on the duration of their treatment. Results of the FRACTION study].

INTRODUCTION: The treatment of hypercholesterolemia is regularly limited by non compliance over the long-term. Studies conducted on the subject underline the interest of considering compliance as a behaviour composed of multiple determinants that require better knowledge. The patients' opinion concerning the severity and evolution of their health problem, as well as the use and duration of their treatment, are, in this context, essential. OBJECTIVES: Based on the hypothesis that hypercholesterolemic patients who believe that their problem only requires short-term treatment are "candidates" for poor compliance, we attempted to identify the factors that determine their opinion on the duration of treatment. METHODS: 1595 files of hypercholesterolemic patients, who had participated in a survey describing how they represented cholesterol and its impact on their health (the FRACTION study), were analyzed. Two groups of opposing opinion on the duration of treatment for hypercholesterolemia (limited or prolonged) were formed. Their socio-demographic and clinical characteristics and the way they represented their health were compared. The factors predicting their opinion on the duration of treatment were identified. RESULTS: The opinion that only short-term treatment was required was associated with younger age, lower education, the fact of not (or not yet) being treated pharmacologically, personal experience of the disease (presence of hypertension, cardiovascular family history or perception of diminished health), little correct knowledge on cholesterol and hypercholesterolemia and greater erroneous beliefs or prejudice with regard to treatment. After adjustment to the socio-demographic and clinical factors, many representations of health continue to predict the opinion in favor of short-term treatment. CONCLUSION: This study demonstrates, for the first time, the importance of knowledge on health, beliefs and personal judgement that are among the determinating factors of patients' opinion on the duration of their treatment. It shows the justification of their individual approach to compliance, behaviour highly influenced by the representation each patient has of his health. It emphasizes the interest of personalizing educative messages addressed to hypercholesterolemic patients, by taking into better account the potential factors of resistance to compliance.

Adult↗
PubMed2002

Efficacy and safety of ezetimibe coadministered with atorvastatin or simvastatin in patients with homozygous familial hypercholesterolemia.

BACKGROUND: Patients with homozygous familial hypercholesterolemia (HoFH) have a high incidence of cardiovascular morbidity and mortality from premature atherosclerosis, and the efficacy of pharmacological therapy has been limited. We evaluated the efficacy, safety, and tolerability of ezetimibe, a novel cholesterol absorption inhibitor, in a multicenter, double-blind, randomized trial of HoFH patients receiving atorvastatin or simvastatin. Methods and Results- Fifty patients with a diagnosis of HoFH on the National Cholesterol Education Program Step 1 or stricter diet and taking open-label atorvastatin 40 mg/d or simvastatin 40 mg/d (statin-40) with (n=25) or without (n=25) concomitant LDL apheresis were randomized to 1 of 3 double-blind treatments: atorvastatin or simvastatin 80 mg/d (statin-80, n=17); ezetimibe 10 mg/d plus atorvastatin or simvastatin 40 mg/d (n=16); or ezetimibe 10 mg/d plus atorvastatin or simvastatin 80 mg/d (n=17) for 12 weeks. The primary end point was mean percentage change in LDL cholesterol (LDL-C) from statin-40 baseline to the end point for patients receiving statins alone (statin-80) versus patients receiving ezetimibe plus atorvastatin or simvastatin at either dose (ezetimibe plus statin-40/80). Ezetimibe plus statin-40/80 significantly reduced LDL-C levels compared with statin-80 (-20.7% versus -6.7%, P=0.007). In the high-dose statin cohorts, ezetimibe plus statin-80 reduced LDL-C by an additional 20.5% (P=0.0001) versus statin-80. Similar significant reductions in LDL-C concentrations were observed for patients with genotype-confirmed HoFH (n=35). Ezetimibe was safe and well tolerated. CONCLUSIONS: Ezetimibe coadministered with atorvastatin or simvastatin in patients with HoFH produced clinically important LDL-C reductions compared with best current therapy. Ezetimibe provides a new, complementary pharmacological approach for this high-risk population.

Adolescent↗
PubMed2002

New advances in lipid-modifying therapies for reducing cardiovascular risk.

Over the last 30 years, several epidemiological and prospective studies have identified a number of risk factors for the development of cardiovascular disease. Lipid abnormalities are central among these risk factors, and their correction has been a major target for the medical community. The 3-hydroxy-3-methyl glutaryl coenzyme A reductase (HMG-CoA reductase) inhibitors (statins) are the most widely prescribed and best tolerated of the currently available lipid-modifying therapies. Newer agents in this class (e.g. rosuvastatin) have been developed that have proven to be more effective at lowering levels of low-density lipoprotein cholesterol (LDL-C). New formulations of drugs such as nicotinic acid can improve treatment regimens and reduce unpleasant side-effects, thereby improving patient compliance with this therapy. In terms of developing novel drugs, the introduction of cholesterol absorption inhibitors (e.g. ezetimibe) and ACAT inhibitors (e.g. avasimibe) will provide clinicians with therapies that exploit different therapeutic pathways to those currently being utilised. Combining these agents with statins could produce greater improvements in lipid profile than those seen to date. In addition, advances in our understanding of the pathophysiology of dyslipidaemia have led to the identification of other novel therapeutic targets, including cholesteryl ester transfer protein. Studies with experimental drugs have already demonstrated the potential of these approaches.

Acetamides↗
PubMed2002

Adipose tissue IL-6 content correlates with resistance to insulin activation of glucose uptake both in vivo and in vitro.

Obesity and type 2 diabetes are associated with insulin resistance, the mechanisms of which remain poorly understood. A significant correlation between circulating IL-6 level and insulin sensitivity has recently been found in humans. Because adipose tissue could be a significant source of IL-6, we analyzed the relationship between the levels of adipose tissue IL-6 and insulin action in vivo, during a hyperinsulinemic normoglycemic clamp, and in vitro by measuring glucose transport in adipocytes from 12 obese subjects with (n = 7) or without (n = 5) diabetes. We observed an inverse correlation between adipose tissue IL-6 content and maximal insulin-responsiveness measured in vivo (P < 0.02) and in vitro (P < 0.02). Conversely, there was no significant correlation between these two later parameters and adipose tissue leptin or tumor necrosis factor-alpha protein contents. Furthermore, we showed, for the first time, the presence of immunoreactive IL-6 receptors in the plasma membrane of human abdominal sc adipocytes. This suggests that locally secreted IL-6 could act on adipocytes by an autocrine/paracrine mechanism. In conclusion, increased IL-6 production by sc adipose cells might participate to the insulin-resistant state observed in human obesity.

Adipose Tissue↗
PubMed2002

LDL particle subclasses in hypercholesterolemia. Molecular determinants of reduced lipid hydroperoxide stability.

Hypercholesterolemia is characterized by elevated plasma levels of LDL in which the cholesteryl ester (CE)-rich LDL subclasses of light and intermediate density (LDL1+2 and LDL3, respectively) typically predominate. The molecular mechanisms implicated in oxidation of LDL particle subclasses in hypercholesterolemia are indeterminate. Lipid hydroperoxides (LOOH), primary oxidation products in LDL, are implicated in atherogenesis. LOOH formation was evaluated in light (LDL1+2), intermediate (LDL3), and dense (LDL4+5) LDL subclasses from hypercholesterolemic (HC) subjects (n = 7) during copper-mediated oxidative stress, and compared with that in corresponding subclasses from normolipidemic subjects (n = 7). HC LDL subclasses were distinguished by lower polyunsaturated phospholipid-alpha-tocopherol ratios (P < 0.02), lower contents of phosphatidyl choline (PC)16:0-18:0/18:2 and PC16:0-18:0/20:4+22:6 (P < 0.002), and higher surface phospholipid-free cholesterol ratios (P < 0.04). The LDL3, LDL4, and LDL5 subclasses in HC subjects displayed low-core polyunsaturated CE-alpha-tocopherol ratios (P < 0.05), despite similar PUFA CE content. These physicochemical differences did not modify the oxidative susceptibility of HC LDL but underlie the marked instability of cholesterol linoleate hydroperoxides in HC LDL1+2, LDL3, and LDL4 subclasses. Elevated concentrations of large, CE-rich, light, and intermediate LDL subclasses (LDL1+2, LDL3) in hypercholesterolemia may therefore act as an abundant proatherogenic source of highly unstable LOOH in the arterial wall.

Apolipoprotein B-100↗
PubMedDate not supplied

A comprehensive description of muscle symptoms associated with lipid-lowering drugs.

UNLABELLED: A spectrum of disease from myalgia to rhabdomyolysis exists as classic side-effect of lipid-lowering treatment (LLT). While myopathy has generated considerable interest, mild musculo-skeletal symptoms are poorly assessed. OBJECTIVE: To report on the muscular side-effects of LLT with a particular focus on the overlooked milder ones. METHODS: Hyperlipidemic patients under LLT and complaining of muscle symptoms were asked to complete a self administered questionnaire. Among the 815 adult hyperlipidemic patients under LLT and referred to the cardiovascular prevention unit of La Pitie Hospital, 165 patients answered that they experienced, or had experienced, muscle symptoms which they attributed to the LLT. One hundred and thirty three of these completed and returned a self-administered questionnaire. RESULTS: A clear chronological link between symptoms and the LLT was revealed, either because they appeared soon after drug initiation or because of an improvement after drug withdrawal. While cramps and stiffness were the most frequent symptoms, tendonitis-associated pain was surprisingly common, reported in almost half the cases. Pain was often diffuse with a focus on a given location, mainly lower limbs. 39% of patients had used analgesics for pain relief. Unpredictably, a majority of patients reported pain during rest and the lying position. In a number of cases, a family history of pain under LLT was revealed. CONCLUSION: The impact of these mild symptoms on daily activities might not be negligible in a subset of patients. The role and importance of a genetic background predisposing to low-grade myopathy deserves further investigation.

Clofibric Acid↗