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Biomedical subjects

Philippe Giral

Publications and source records attributed to Philippe Giral.

At least 19 recordsLinked to original sources
PubMed2006

Carotid atherosclerosis is not related to past tuberculosis in hypercholesterolemic patients.

BACKGROUND: Tuberculosis is a chronic recurrent infection and inflammation is part of the disease which may remain undiagnosed for months. Furthermore immunization with recombinant heat shock protein-65-rich mycobacterium tuberculosis increased atherogenesis in hypercholesterolemic animal models. OBJECTIVE: To investigate the potential interrelationships between past tuberculosis with carotid and femoral atherosclerosis in hypercholesterolemic patients. DESIGN AND SETTING: Case control study in a university hospital. PATIENTS: Two groups of hypercholesterolemic patient group (n=147) studied in a cardiovascular prevention unit during the same quarter, age (+/-1 year) and sex-matched. The first group presented a history of tuberculosis in the past and the second group never. METHODS: Atherosclerosis was assessed by carotid and femoral external echography. Measurements of maximum plaque diameter were done in longitudinal planes, and the extent of atherosclerosis was graded according to the most severe visible changes on the scanned arteries. RESULTS: The frequency and the distribution of atherosclerosis was similar in the two groups, whatever the arterial site explored, carotid or femoral. None of the clinical and biological studied variables were different between the two groups of patients. CONCLUSION: Past tuberculosis is not associated with increased frequency of atherosclerotic lesions in hypercholesterolemic patients.

Carotid Artery Diseases↗
PubMed2006

[Ezetimibe with statins].

Ezetimibe is the first cholesterol absorption inhibitor, a novel class of lipopenic drugs that inhibit intestinal absorption of biliary and dietary cholesterol. From a pathophysiological point of view, combining complementary drugs that act on different cholesterol metabolism pathways is particularly interesting. This interest has been confirmed in clinical studies combining ezetimibe and statins, which inhibit cholesterol synthesis in the liver. Adding ezetimibe (10 mg/d) to statin therapy decreased LDL cholesterol by as much as an additional 20%. It may thus be especially useful in patients who are unable to reach the LDL cholesterol target with diet and statins alone. Ezetimibe is well tolerated and is indicated alone in statin-intolerant patients.

Azetidines↗
PubMed2006

Use of an indirect effect model to describe the LDL cholesterol-lowering effect by statins in hypercholesterolaemic patients.

Statins are the most commonly prescribed agents for the treatment of hypercholesterolaemia. This is due to their efficacy in reducing low-density lipoprotein cholesterol (LDL) level which is the primary goal of the treatment especially for patients with multiple risk factors or with established coronary heart diseases. The purpose of this study was to develop a pharmacokinetic/pharmacodynamic (PK/PD) model that describes the LDL-lowering process in patients with hypercholesterolaemia treated with atorvastatin, fluvastatin or simvastatin. A total of 100 patients were studied retrospectively. They received atorvastatin (n = 57), fluvastatin (n = 26) or simvastatin (n = 17). As no pharmacokinetic data were available, the absorption rate was fixed to 1/h and atorvastatin, simvastatin and fluvastatin elimination half-lives were fixed to 14, 2 and 2.5 h respectively. A total of 309 LDL levels were measured and the data were analysed by nonmem v. The time course of the LDL-lowering effect of statins was described by an indirect-response model with precursor (LDL synthesis, input rate K(in)) and response (circulating LDL, input and output rates K) compartments. The following parameters were estimated: LDL input rate (K(in)) 0.14 +/- 0.015 g/L/day (mean +/- SD); inhibition fraction of K(in) (INH) 0.21 +/- 0.017; and dose producing 50% increase of LDL removal (D50), 26 +/- 7.8, 1.3 +/- 0.48 and 15 +/- 5.25 mg for atorvastatin, simvastatin and fluvastatin, respectively. Gender, bodyweight, age, calories/day, sugar/day, lipids/day, hyperlipidaemia types and waist/hip circumference, renal and hepatic functions had no effect on the pharmacodynamic parameters. The pharmacodynamic parameters for the three statins were accurately estimated. The PK/PD model developed successfully predicted the time course of the LDL-lowering effect of statins.

Adolescent↗
PubMed2006

One third of the variability in HDL-cholesterol level in a large dyslipidaemic population is predicted by age, sex and triglyceridaemia: The Paris La Pitié Study.

OBJECTIVE: The objective of this study was to identify key determinants of high-density lipoprotein-cholesterol (HDL-C) level, including subclinical inflammation and insulin resistance, and to determine the prevalence of a low HDL-C phenotype in dyslipidaemic patients at high cardiovascular risk. METHODS: In a cross-sectional study, we assessed the prevalence of low HDL-C phenotypes in 14 667 dyslipidaemic patients attending our specialised lipid clinic and evaluated the potential relationships between HDL-C level and 16 clinical and biological parameters. RESULTS: In univariate analysis, women exhibited higher plasma concentrations of HDL-C as compared with men. Levels of triglycerides, fasting blood glucose, uric acid, waist circumference, body mass index, high sensitivity C-reactive protein (hs-CRP), insulin resistance (as HOMA-IR index) and smoking were all negatively correlated with HDL-C, whereas age was positively correlated with HDL-C levels. Moderate drinkers (10-30 g/day) displayed higher HDL-C concentrations as compared with abstinent subjects; in contrast, consumption of more than 30 g alcohol/day was associated with a further non-significant elevation of HDL-C levels as compared to moderate drinkers. Multivariate analysis identified eight independent correlates of HDL-C. Age, sex and TG accounted for 37% of variability in HDL-C; modifiable factors including waist circumference, alcohol consumption and smoking, in addition to HOMA-IR and hs-CRP, accounted for an additional 5% of the variability in HDL-C. Using a cut-off of 40 mg/dL (1.03 mmol/L) for men and 50 mg/dL (1.29 mmol/L) for women, 33% and 28% of men and women displayed low levels of HDL-C. CONCLUSION: Eight independent determinants of HDL-C account for 41% of variability in HDL-C in our dyslipidaemic population. Three of them, i.e. age, sex and degree of triglyceridaemia accounted for more than one third of such variability. The high prevalence of low HDL-C phenotypes in dyslipidaemic patients at elevated cardiovascular risk emphasises the need for both lifestyle and pharmacological strategies of intervention to raise HDL-C.

Adult↗
PubMed2005

Elevated serum levels of proinflammatory cytokines and biomarkers of matrix remodeling in never-treated patients with familial hypercholesterolemia.

BACKGROUND: Familial hypercholesterolemia (FH) is a common inherited disorder of lipoprotein metabolism, whose origin involves mutations in the gene coding for the low-density lipoprotein receptor protein. Although FH is monogenic, wide variation occurs in the onset and severity of atherosclerosis in these patients. METHODS: Since data on levels of inflammatory proteins and/or active factors in FH patients who have never received lipid-lowering treatment are lacking, serum levels of MMP-3, active MMP-9 and TIMP-1 as well as pro-inflammatory cytokines (TNF-alpha, IL-18) were determined in never-treated homozygous FH Moroccan patients (n=4) and compared to those of heterozygous FH subjects (n=7) and of healthy control subjects (n=5). RESULTS: When compared to controls, homozygous FH patients exhibited levels of active MMP-9 and TIMP-1 (p<0.05), and of both high sensitive-CRP and IL-18 which were significantly elevated (p<0.05 and p<0.01, respectively). In heterozygous FH patients, intermediate values between FH homozygotes and healthy controls were observed for these markers, with the exception of MMP-9 activity whose levels were significantly elevated (p<0.05). Multivariate analysis revealed a positive correlation between apolipoprotein B, TIMP-1 and IL-18 levels, and between hs-CRP and IL-18 (p<0.01). CONCLUSIONS: Although the sample size of this FH group was limited, our data suggest that nontreated homozygous FH patients, and to a lesser degree heterozygous FH patients, exhibit not only a markedly proinflammatory vascular state but also pronounced extracellular matrix remodeling, as reflected by elevated circulating levels of inflammatory cytokines and MMPs.

Adolescent↗
PubMed2005

Sampling variability of liver biopsy in nonalcoholic fatty liver disease.

BACKGROUND & AIMS: In nonalcoholic fatty liver disease (NAFLD), the distinction between steatosis and steatohepatitis (NASH) and the assessment of the severity of the disease rely on liver histology alone. The aim of this study was to assess the sampling error of liver biopsy and its impact on the diagnosis and staging of NASH. METHODS: Fifty-one patients with NAFLD underwent percutaneous liver biopsy with 2 samples collected. The agreement between paired biopsy specimens was assessed by the percentage of discordant results and by the kappa reliability test. RESULTS: No features displayed high agreement; substantial agreement was only seen for steatosis grade; moderate agreement for hepatocyte ballooning and perisinusoidal fibrosis; fair agreement for Mallory bodies; acidophilic bodies and lobular inflammation displayed only slight agreement. Overall, the discordance rate for the presence of hepatocyte ballooning was 18%, and ballooning would have been missed in 24% of patients had only 1 biopsy been performed. The negative predictive value of a single biopsy for the diagnosis of NASH was at best 0.74. Discordance of 1 stage or more was 41%. Six of 17 patients with bridging fibrosis (35%) on 1 sample had only mild or no fibrosis on the other and therefore could have been under staged with only 1 biopsy. Intraobserver variability was systematically lower than sampling variability and therefore could not account for most of the sampling error. CONCLUSIONS: Histologic lesions of NASH are unevenly distributed throughout the liver parenchyma; therefore, sampling error of liver biopsy can result in substantial misdiagnosis and staging inaccuracies.

Adult↗
PubMed2004

Fenofibrate increases homocystinemia through a PPARalpha-mediated mechanism.

Plasma homocysteine levels increase in humans treated with fibrates but the molecular mechanisms are unknown. The goal of the present study was to determine the mechanism of this increase using animal models. Firstly, an increase in homocysteine was observed in mice treated with fenofibrate irrespective of the genetic background C57BL/6 or SV129. Secondly, as the effect of fenofibrate on gene expression is mediated through activation of the peroxisome proliferator-activated receptor alpha (PPARalpha), a transcription factor belonging to the nuclear receptor family, it was determined whether the effect of fenofibrate on homocysteine levels were modulated through PPARalpha activation. Using PPARalpha-deficient mice, it was shown that the homocysteine increase after fenofibrate treatment was completely abolished in these animals. It can be concluded that fibrates increase homocystinemia through a PPARalpha-mediated mechanism and that mice constitute an animal model for analyzing the molecular mechanisms behind the homocysteine increase after fibrate therapy in dyslipidemic patients.

Animals↗
PubMed2004

Risk stratification for the prevention of cardiovascular complications of hypertension.

Arterial hypertension is a well established risk factor for both coronary artery disease (CAD) and stroke. The decision to treat hypertension and prevent cardiovascular complications has, for many years, been based on the level of blood pressure. The present review, based on a cross-sectional and careful analysis of major trials, emphasises the need to assess the cardiovascular risk for each patient in order to make appropriate treatment decisions. Evaluation of cardiovascular risk in untreated hypertensive subjects indicates that coronary risk is two to three times higher than cerebrovascular risk. The same results have been observed in outcome trials where hypertensive patients were treated with antihypertensive drugs. Even though the results of outcome trials for antihypertensive drugs can be explained by blood pressure differences between randomised groups, antihypertensive drugs are, for the same reduction in blood pressure, more efficient in preventing cerebrovascular events than in preventing (CAD). Meta-analysis indicates that each reduction of 2 mmHg in systolic blood pressure levels is associated with a 25% reduction in stroke events, but a difference of at least 5 mmHg for systolic pressure between groups is necessary to obtain prevention of coronary events. A number of controlled trials using statins have shown that these drugs were particularly effective in preventing coronary disease. An appropriate therapeutic strategy for cardiovascular risk reduction in hypertensive patients should therefore include both antihypertensive therapy and prescription of a statin. The efficacy of this strategy was recently reported in the ASCOT trial, which estimated that for 100 hypertensive patients with a high cardiovascular risk and followed up for 10 years, the number of coronary events is 13, 10 and 7 for those without antihypertensive treatment, with antihypertensive therapy only and with both antihypertensive therapy and statin therapy, respectively.

Antihypertensive Agents↗
PubMed2004

Metabolic syndrome is associated with elevated oxidative stress and dysfunctional dense high-density lipoprotein particles displaying impaired antioxidative activity.

A metabolic syndrome (MetS) phenotype is characterized by insulin-resistance, atherogenic dyslipidemia, oxidative stress, and elevated cardiovascular risk and frequently involves subnormal levels of high-density lipoprotein (HDL) cholesterol. We evaluated the capacity of physicochemically distinct HDL subfractions from MetS subjects to protect low-density lipoprotein against oxidative stress.MetS subjects presented an insulin-resistant phenotype, with central obesity and elevation in systolic blood pressure and plasma triglyceride, LDL-cholesterol, apolipoprotein B, glucose, and insulin levels. Systemic oxidative stress, assessed as plasma 8-isoprostanes, was significantly higher (3.7-fold) in MetS subjects (n = 10) compared with nonobese normolipidemic controls (n = 11). In MetS, small, dense HDL3a, 3b, and 3c subfractions possessed significantly lower specific antioxidative activity (up to -23%, on a unit particle mass basis) than their counterparts in controls. In addition, HDL2a and 3a subfractions from MetS patients possessed lower total antioxidative activity (up to -41%, at equivalent plasma concentrations). The attenuated antioxidative activity of small, dense HDL subfractions correlated with systemic oxidative stress and insulin resistance and was associated with HDL particles exhibiting altered physicochemical properties (core triglyceride enrichment and cholesteryl ester depletion). We conclude that antioxidative activity of small, dense HDL subfractions of altered chemical composition is impaired in MetS and associated with elevated oxidative stress and insulin resistance. Induction of selective increase in the circulating concentrations of dense HDL subfractions may represent an innovative therapeutic approach for the attenuation of high cardiovascular risk in MetS.

Adult↗
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

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

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

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

Survival, liver failure, and hepatocellular carcinoma in obesity-related cryptogenic cirrhosis.

Despite the rising incidence of obesity and diabetes, there is little emphasis on morbidity and mortality from obesity-related cirrhosis, usually considered a rare and asymptomatic condition. Our aim was to assess survival and the occurrence of hepatocellular carcinoma and complications of hepatic insufficiency in obesity-related cryptogenic cirrhosis compared with cirrhosis of other origins. We analyzed retrospectively 27 overweight patients with cryptogenic cirrhosis (CC-O), 10 lean patients with cryptogenic cirrhosis (CC-L) and 391 patients with hepatitis C virus-related cirrhosis (C-HCV). In CC-O patients, cirrhosis was detected later in life than in C-HCV and CC-L patients. Severe liver disease was as frequent in CC-O as in C-HCV patients as indicated by the proportion of Child B or C or of episodes of hepatic decompensation. Survival of CC-O patients was lower than that of untreated, age- and sex-matched C-HCV controls (P <.02 at 30 months), with a higher mortality of Child B or C patients. Hepatocellular carcinoma was detected in 8 of 27 (27%) CC-O patients versus 21% of matched C-HCV controls with a similar age cumulated incidence, suggesting a comparable carcinogenic potential. In conclusion, obesity-related cirrhosis should now be recognized as a distinct entity that can cause severe liver disease and death. Increased awareness of and better diagnostic strategies for nonalcoholic steatohepatitis in overweight patients are urgently needed.

Adult↗
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↗