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Biomedical subjects

M C Alessi

Publications and source records attributed to M C Alessi.

At least 19 recordsLinked to original sources
PubMed2007

Prognostic value of plasma tissue factor and tissue factor pathway inhibitor for cardiovascular death in patients with coronary artery disease: the AtheroGene study.

BACKGROUND: Tissue factor (TF) and its specific inhibitor, tissue factor pathway inhibitor (TFPI), are important contributors to the initiation of the coagulation process. OBJECTIVES: To compare plasma levels of soluble TF (sTF) and free-TFPI (f-TFPI) between patients with stable angina pectoris (SAP) and acute coronary syndrome (ACS) and to assess the impact of the two variables on long-term prognosis. PATIENTS/METHODS: Patients with SAPs (n = 1146) and acute coronary syndrome (n = 523) from the AtheroGene study were included and followed for 2.3 years. Because of the strong impact of unfractionated heparin (UFH) on f-TFPI levels, but not on sTF levels, patients having received UFH before blood drawing were excluded from the analyses on f-TFPI (n = 226). RESULTS: On admission, no significant differences in sTF levels were observed between SAP and ACS patients. By comparison to patients with stable angina, f-TFPI levels significantly increased in patients with acute unstable angina and further increased in patients presenting with non-ST-elevation myocardial infarction and ST-elevation myocardial infarction (P < 10(-4)). Among the 1669 individuals with a coronary artery disease, 56 died from a cardiovascular cause. In prospective analyses, high sTF levels were independently associated with an increased risk of cardiovascular death in individuals with ACS (fully adjusted hazard ratio associated with one quartile increase = 2.06; 95% confidence interval 1.24-3.45; P = 0.006) but not in those with SAP (hazard ratio = 1.07; 95% confidence interval 0.78-1.46; P = 0.67). In SAP and ACS patients, high f-TFPI levels were not independently associated with an increased risk of cardiovascular death. CONCLUSIONS: Plasma sTF levels were predictive of cardiovascular mortality in individuals with ACS, whereas f-TFPI levels were associated with the severity of myocardial damage on admission but were not independently related to outcome.

Aged↗
PubMed2006

[Beneficial effect of a loading dose of 600 mg of clopidogrel on platelet parameters in patients admitted for acute coronary syndrome].

INTRODUCTION: Despite the beneficial effect of an aspirin-clopidogrel combination in acute coronary syndrome, the incidence of ischaemic recurrences remains significant and very probably implicates a variability in the response to anti-platelet agents. OBJECTIVE: We sought to demonstrate the evidence for a beneficial effect, in terms of anti-platelet effect, of a higher loading dose of 600 mg of clopidogrel compared to the usual 300 mg in patients admitted to our centre with acute coronary syndrome. MATERIALS AND METHODS: Platelet reactivity was evaluated with the ADP 10_mol test and the degree of platelet activation by the expression of P-selectin. 178 consecutive patients admitted for acute coronary syndrome received 250 mg of intravenous aspirin together with either a loading dose of 300 mg of clopidogrel (n = 104) or 600 mg (n = 74) administered 12 to 24 hours prior to coronary angiography. RESULTS: The patients who received 600 mg of clopidogrel had an average aggregation intensity to ADP and a rate of platelet high reactivity post treatment that was significantly lower [48+20 vs 58+18, p = 0.0011 and 11 patients (15%) vs 26 patients (25%), p = 0.0003 respectively]. The degree of platelet activation evaluated with P-selectin was significantly lower in patients receiving 600mg [0.33 + 0.17 vs 0.50+0.29, p < 0.001]. CONCLUSION: Our study provides evidence for a beneficial effect of a loading dose of 600mg of clopidogrel compared to the usual 300 mg in terms of platelet reactivity and platelet activation post treatment.

Acute Disease↗
PubMed2006

[Platelet function after a high dose bolus of tirofiban immediately after coronary angioplasty].

In the TARGET trial, the lower incidence of cardiac events at one month with abciximab compared with tirofiban was attributed to a lack of efficacy in the first hour because of suboptimal dosage. The object of this study was to confirm that high dose tirofibal is associated with over 90% platelet inhibition during the first hour and to analyse the effect of this new dosage on platelet activation. Thirty-three patients treated with clopidogrel and aspirin for an acute coronary syndrome without ST elevation were given before angioplasty a bolus of 25 microg/Kg of tirofiban injected in 3 minutes, followed by an infusion of 0.15 microg/kg/min. Blood samples were taken before the treatment (TO) and at the 45th minute (T1) to measure platelet aggregation induced by ADP, the expression of P-selection, the quantification of circulating monocyte-platelet aggregates and the phospholyration of VASP protein. The results showed that all patients had over 90% (100%) inhibition of platelet aggregation at T1. The expression of P-selection was significantly reduced (T0: 0.195 +/- 0.057 MFI; T1: 0.186 +/- 0.055 MFI, p = 0.03). There was no significant difference in the number of monocyte-platelet aggregates or in the phosphorylation of VASP. In conclusion, a bolus of 25 microg/Kg/3 min of tirofiban provides over 90% inhibition of platelet aggregation in the first hour. The initial platelet proactivator effect at this dosage was shown to have disappeared with an inhibition of platelet activation.

Acute Disease↗
PubMed2005

Biological and genetic factors influencing plasma factor VIII levels in a healthy family population: results from the Stanislas cohort.

The mechanisms underlying the variability of factor VIII (FVIII) levels are still poorly understood. The only receptor of FVIII identified so far is the lipoprotein receptor-related protein (LRP), which is thought to be involved in FVIII degradation. We aimed to characterize biological and genetic factors related to FVIII variability, focusing on coding polymorphisms of the LRP gene and polymorphisms potentially detected by molecular screening of the LRP-binding domains of the FVIII gene. Plasma FVIII coagulant activity (FVIII:C) and von Willebrand factor (VWF:Ag) antigen levels were measured in a sample of 100 healthy nuclear families (200 parents and 224 offspring). The ABO blood group and the three coding polymorphisms of the LRP gene (A217V, D2080N and C766T) were genotyped. Lipids and anthropometric factors poorly contributed to the variability of FVIII:C (<5%). A strong effect of ABO blood groups on FVIII:C levels was observed that remained significant after adjustment for VWF:Ag levels (P = 0.02). These two factors explained more than 50% of FVIII:C variability. After adjustment for VWF:Ag and ABO blood groups, a residual resemblance for FVIII:C persisted between biological relatives (rho = 0.13 +/- 0.06 between parents and offspring, rho = 0.24 +/- 0.09 between siblings) compatible with an additional genetic influence. The N allele of the LRP/D2080N polymorphism was associated with decreased levels of FVIII:C (90.4 +/- 8.7 vs. 102.2 +/- 3.5 IU/dl, P = 0.03) and VWF:Ag levels (109.1 +/- 11.2 vs. 125.4 +/- 4.4 IU/dl, P = 0.02). No polymorphism was detected in the LRP-binding domains of the FVIII gene. This study reinforces the hypothesis of a genetic influence of FVIII levels beyond the influence of VWF:Ag and ABO blood groups. The D2080N polymorphism of the LRP gene weakly contributed to the variability of FVIII:C levels in this healthy population.

ABO Blood-Group System↗
PubMed2004

Interaction between the C-260T polymorphism of the CD14 gene and the plasma IL-6 concentration on the risk of myocardial infarction: the HIFMECH study.

Experimental and clinical observations suggest that innate immunity plays a major role in the pathogenesis and progression of atherosclerosis. A common C-260T polymorphism in the promoter of the CD14 gene, the trans-membrane receptor of lipopolysaccharides, has been inconsistently associated with coronary heart disease. Our objective was to evaluate the contribution of the CD14 polymorphism to the inflammatory response and to the risk of myocardial infarction (MI). We used an European case-control study, the HIFMECH study, comparing 533 men with MI and 575 sex- and age-matched controls. Associations between genotype and disease outcome, according to interleukin-6 (IL-6) and C-reactive protein (CRP) levels, were assessed using conditional logistic regression. The CD14/C-260T polymorphism was associated with plasma IL-6 levels, T/T subjects having higher plasma levels than C/C in cases but not in controls (mean+/-S.D.: 2.04+/-1.37 versus 1.70+/-1.15, p=0.01; 1.20+/-0.75 versus 1.35+/-0.88, p=0.31, respectively). Overall, the CD14/C-260T polymorphism was not associated with the risk of MI. However, in individuals with IL-6 plasma levels in the highest tertile, T allele carriers had a higher risk of MI than C/C (OR: 1.85; CI 95 1.05-3.25). IL-6 increased the risk of MI in carriers of the T allele (OR for first versus third IL-6 tertile: 4.02; CI 95 2.24-7.21), but not in C/C (OR: 0.75; CI 95 0.32-1.74, p=0.004 for interaction). The data indicate a role for CD14/C-260T in MI. The risk mediated by the polymorphism is highly dependent on IL-6 plasma levels.

Arteriosclerosis↗
PubMed2004

Endothelial cell markers and the risk of coronary heart disease: the Prospective Epidemiological Study of Myocardial Infarction (PRIME) study.

BACKGROUND: Tissue factor pathway inhibitor (TFPI), von Willebrand factor (vWF), and thrombomodulin (TM) are 3 major hemostatic regulatory molecules synthesized by endothelium. Data from epidemiological studies aiming to evaluate the relation between plasma levels of these molecules and the development of coronary heart disease (CHD) are sparse or contradictory. METHODS AND RESULTS: We examined the association between these endothelial-cell markers and the incidence of fatal or nonfatal myocardial infarction (hard CHD) and stable or unstable angina (angina pectoris) in a prospective cohort (the PRIME Study) of nearly 10 000 healthy men recruited in France and Northern Ireland. We measured baseline plasma concentration of the free form of TFPI (f-TFPI), vWF, and the soluble form of TM (sTM) among 296 participants who subsequently developed CHD over the 5-year follow-up (158 with hard CHD and 142 with angina pectoris) and in 563 control subjects by use of a nested case-control design. Individuals with plasma vWF levels in the highest quartile showed a 3.04-fold increase in the risk of hard CHD compared with those in the lowest quartile (95% CI, 1.59 to 5.80). Individuals with f-TFPI levels below the 10th percentile had a 2.13-fold increased risk of hard CHD compared with those with levels above it (95% CI, 1.08 to 4.18). The risk for both molecules persisted after control for inflammatory parameters. Individuals with vWF levels in the highest quartile and f-TFPI levels below the 10th percentile presented a 6.9-fold increased risk of hard CHD compared with those with vWF levels in the lowest quartile and f-TFPI levels above the 10th percentile (95% CI, 1.3 to 37.8). CONCLUSIONS: vWF and f-TFPI plasma levels were independent risk factors for hard CHD events.

Angina Pectoris↗
PubMed2004

Contribution of PAI-1 in cardiovascular pathology.

Plasminogen activator inhibitor-1 (PAI-1), is a serpin whose major function is to negate plasminogen activation and impair fibrinolysis. It occurs in plasma and tissues. Studies in genetically modified mice indicate that PAI-1 might be involved in thrombosis, vascular healing and atherosclerosis although contradictory findings have been obtained in the latter two processes. Differences between results depend on the types and the lengths of the models and underline the fact that besides its role in regulating fibrinolysis, PAI-1 plays a role in several cellular processes independent of plasminogen activation. In patients, high plasma PAI-1 levels worsen the prognosis of myocardial infarction in the acute phase and have been considered as a risk factor for coronary heart disease. The predictive capacity of PAI-1 is mainly related to several metabolic covariates which constitute the metabolic syndrome (MS). This syndrome is associated with increased cardiovascular morbidity and mortality and is becoming one of the major health problems as its prevalence is growing rapidly. Accelerated atherothrombotic process in the MS is attributed not only to metabolic abnormalities but also to a specific inflammatory state which leads to increased plasma PAI-1 levels. Modifying PAI-1 expression by PAI-1 inhibitors may open a new field of research and may reveal the true role of PAI-1 in atherosclerotic and insulin resistance processes.

Fibrinolysis↗
PubMed2003

Weak and non-independent association between plasma TAFI antigen levels and the insulin resistance syndrome.

Increased plasma thrombin-activatable fibrinolysis inhibitor (TAFI) levels were recently shown to be a part of the insulin resistance syndrome. We investigated the relationship between plasma TAFI antigen levels and insulin resistance markers and compared these results with those obtained for PAI-1 and fibrinogen which are known to be closely related to insulin resistance syndrome and fat mass, respectively. Eighty-nine obese females had 1.3-, 1.2-, and 3-fold higher circulating TAFI, fibrinogen and PAI-1, respectively, compared with 64 lean females. Univariate analysis showed that the significance level for association between TAFI or fibrinogen concentrations and insulin resistance markers was lower than the significance level for association between PAI-1 and insulin resistance markers. Nevertheless, TAFI, fibrinogen, and PAI-1 plasma levels were significantly associated to each other. In linear stepwise ascendant analysis, insulin resistance markers accounted for 50% of the interindividual variability of plasma PAI-1 and only for 10% of plasma TAFI and 13% of fibrinogen variability. The contribution of insulin resistance markers to plasma TAFI antigen levels variability disappeared when PAI-1 or fibrinogen was entered in the statistical model. TAFI mRNA was detected in the liver but not in adipose tissue and endothelial cells. No TAFI mRNA was detected in normal or atherosclerotic vessels either. These results suggest that elevated TAFI antigen levels found in obese subjects are not independently associated with the metabolic markers of the insulin resistance syndrome. Increased plasma TAFI antigen levels in obesity might reflect a specific pathway of regulation at the liver level.

Adipose Tissue↗
PubMed2003

The plasminogen activator inhibitor-1 -675 4G/5G genotype influences the risk of myocardial infarction associated with elevated plasma proinsulin and insulin concentrations in men from Europe: the HIFMECH study.

UNLABELLED: Although the potential role of plasminogen activator inhibitor-1 (PAI-1) in the development of coronary artery disease is strongly supported by its biological characteristics, results of clinical studies remain controversial. OBJECTIVES: To investigate whether plasma PAI-1 concentrations and the -675 4G/5G polymorphism located in the PAI-1 gene could constitute risk markers for myocardial infarction (MI). PATIENTS AND METHODS: We used a European case-control study, the HIFMECH study, comparing 598 men with MI and 653 age-matched controls. RESULTS: Insulin resistance explained a major part of the variation in PAI-1 (24%) whereas inflammation had only a minor contribution (0.01%). For both cases and controls plasma PAI-1 concentrations were significantly higher in the North than the South, and in both regions were higher in individuals with MI compared with control subjects [overall odds ratio (OR) for a 1 SD increase=1.54, 95% confidence interval (CI) 1.34, 1.77]. This difference was observed in all the centers studied. Overall, the difference between cases and control subjects remained significant after controlling for inflammation variables (OR=1.30, 95% CI 1.08, 1.57), but lost significance after controlling for insulin resistance variables (OR=1.17, 95% CI 0.98, 1.40). The 4G allele was associated with significantly higher PAI-1 levels in cases but not controls and, taken independently, did not modify the risk of MI (P=0.9). However, a significant interaction was observed with both insulin or proinsulin and the risk of MI (P=0.05 and 0.02, respectively), but not with triglycerides or body mass index (BMI). The insulin or proinsulin effect on risk was observed only in the carriers of the 4G/4G genotype. This interaction appeared not to be mediated by plasma PAI-1 antigen concentrations (P=0.01 and 0.02 after adjustment for PAI-1 plasma levels). The interaction with proinsulin but not insulin remained statistically significant after further adjustment for other factors associated with insulin resistance (triglycerides and BMI) and C-reactive protein (P=0.01). CONCLUSION: This study suggests that PAI-1 has a role in risk of MI in the presence of underlying insulin resistance. A significant interaction between insulin or proinsulin and the -675 4G/5G polymorphism was observed in risk for MI. The mechanisms for these interactions remain to be determined.

Case-Control Studies↗
PubMed2003

Statins: maid-of-all-work in cardiovascular diseases!

Inhibitors of HMG-CoA reductase (statins) lower the level of circulating LDL-C by blocking the activity of HMG-CoA reductase. Their efficiency to prevent cardiovascular events was demonstrated in several clinical trials for primary and secondary prevention. However, subgroups analysis of trials together with experimental studies have increasingly documented that the beneficial effects of statins extend beyond the sole reduction in LDL-C. These effects include improvements of vasoreactivity, haemostasis and plaque stability, reduction of pro-inflammatory events such as a decrease in monocyte adhesion and infiltration, oxidation level and pericellular proteolysis. Possible repair of ischemic tissues through enhancement of mobilization of endothelial progenitor cells are also described, although more investigation are needed to clearly identify the role and safety of statins in angiogenesis. These pleiotropic effects are generally explained by the fact that statins inhibit the intracellular production of metabolites located downstream of mevalonate in the cholesterol pathway, such as isoprenoids (farnesyl pyrophosphate and geranylgeranylpyrophosphate). These hydrophobic metabolites allow the membrane anchorage of small G proteins (Ras and Rho) as well as the Gy subunit of heterotrimeric G proteins, a post-translational step that is critical in the regulation of G protein signaling activity. These drugs are therefore a valuable tool not only for the clinician but also for the biologist, allowing to investigate the regulation of gene expression that is controlled by the intracellular activity of membrane-anchored prenylated signaling proteins.

C-Reactive Protein↗
PubMed2002

Plasma thrombin-activatable fibrinolysis inhibitor antigen concentration and genotype in relation to myocardial infarction in the north and south of Europe.

The thrombin-activatable fibrinolysis inhibitor (TAFI) is a recently described inhibitor of fibrinolysis that decreases plasminogen binding to the fibrin surface. The plasma TAFI concentration is almost entirely genetically determined. We investigated whether plasma TAFI levels and polymorphisms located in the TAFI gene could constitute risk markers of myocardial infarction (MI). Plasma TAFI antigen (Ag) levels were assayed by ELISA and 2 TAFI gene polymorphisms (Ala147Thr and C+1542G in the 3' untranslated region) were determined in a large European case-control study. This study compared 598 men recruited 3 to 6 months after MI with 653 age-matched controls from North Europe (Stockholm, Sweden, and London, England) and South Europe (Marseilles, France, and San Giovanni Rotondo, Italy). A TAFI Ag value above the 90th percentile was associated with a significantly lower risk of MI (odds ratio 0.55, P<0.02), indicating that elevated TAFI may be protective against MI. As previously shown, the 2 TAFI gene polymorphisms were in strong linkage disequilibrium and were associated with the TAFI Ag concentration, with carriers of the Thr147 and 1542C alleles having higher levels (P<0.0005). These effects were similar in controls and cases and in each center. There was a difference in allele frequency between cases and controls for the Ala147Thr polymorphism, with Thr147 allele carriers being more frequent in controls than in cases in 2 centers, Stockholm (P=0.03) and San Giovanni Rotondo (P=0.03); the odds ratio for the entire cohort was 0.78 (P<0.05). In conclusion, patients with a recent MI presented lower values of TAFI Ag and higher frequencies of the "TAFI-decreasing" alleles. The geographical differences observed do not contribute to explaining the North-South gradient in MI risk in Europe.

Alleles↗
PubMed2001

Identification of polymorphisms in the promoter and the 3' region of the TAFI gene: evidence that plasma TAFI antigen levels are strongly genetically controlled.

Thrombin-activable fibrinolysis inhibitor (TAFI) is a recently described carboxypeptidase that is potentially involved in the regulation of fibrinolysis by decreasing plasminogen binding to the fibrin surface. This role makes the TAFI gene a good candidate in atherothrombotic diseases. The great interindividual variability of plasma TAFI antigen levels is poorly explained by lifestyle characteristics, thus suggesting its genetic determination. To test this hypothesis, the promoter and the 3'-untranslated region of the TAFI gene were screened for polymorphisms, and their contribution to the variability of plasma TAFI antigen levels was evaluated. Seven new polymorphisms are described, 5 in the promoter (C-2599G, -2345 2G/1G, A-1690G, G-1102T, and G-438A) and 2 in the 3'UTR (C+1542G and T+1583A). All these polymorphisms were in strong linkage disequilibrium with each other and with the previously described Ala147Thr polymorphism. They generated 4 main haplotypes, accounting for 80% of all observed haplotypes. In univariate analyses, all polymorphisms were associated with plasma TAFI Ag levels and, individually, contributed to a large fraction of plasma TAFI Ag levels, ranging from 20% to 52%. In a stepwise regression analysis including all polymorphisms, several combinations remained significantly and independently associated with plasma TAFI Ag levels: C+1542G associated with Ala147Thr, T+1583A, or -2345 2G/1G explaining 61.6%, 60.2%, and 58.1% of the variance, respectively. These findings clearly demonstrate that circulating levels of TAFI are strongly determined by polymorphic variations in the promoter and the 3'UTR of the TAFI gene. (Blood. 2001;97:2053-2058)

3' Untranslated Regions↗
PubMed2001

Subcutaneous abdominal, but not femoral fat expression of plasminogen activator inhibitor-1 (PAI-1) is related to plasma PAI-1 levels and insulin resistance and decreases after weight loss.

AIMS/HYPOTHESIS: Abdominal fat produces plasminogen activator inhibitor-1 (PAI-1) and could contribute to increased plasma PAI-1 values in human obesity associated with insulin resistance. Femoral fat, which is not associated with insulin resistance, is thought to be metabolically different from the abdominal fat. This study aimed to assess PAI-1 expression in these two fat territories in obese and lean subjects and to determine if concomitant changes of plasma and adipose tissue PAI-1 values occur after weight reduction. METHODS: In 24 obese and 16 lean subjects, PAI-1 expression in abdominal and femoral subcutaneous fat, plasma PAI-1, insulin, triglyceride concentrations and insulin resistance were determined at the start of the study and in obese subjects after a 3-month weight reduction programme as well. RESULTS: PAI-1 mRNA content in the abdominal subcutaneous fat was higher in obese than in lean subjects and positively correlated with plasma PAI-1 values (p < 0.01) and markers of insulin resistance (p < 0.05). In 18 obese subjects, re-examined after successful dieting, PAI-1 mRNA content decreased in the abdominal subcutaneous fat along with plasma PAI-1. However, the absolute changes of these two variables were not associated. In contrast, PAI-1 mRNA content in the femoral subcutaneous fat did not differ between lean and obese subjects, was not associated with plasma PAI-1 values or with markers of insulin resistance, and did not change after weight loss. CONCLUSION/INTERPRETATION: Only the abdominal, but not the femoral subcutaneous fat PAI-1 expression is a potential contributor to increases in plasma PAI-1 in obesity. Both plasma and abdominal subcutaneous fat PAI-1 values decreased significantly after weight reduction, although their absolute changes were not associated.

Abdomen↗
PubMed2001

[Acquired factor V inhibitor: etiology, bleeding risk and therapeutic management with regard to three cases].

INTRODUCTION: Acquired factor V inhibitor is rare and clinical symptoms are quite variable. Bleeding is the leading symptom but some patients are asymptomatic. Several diseases or conditions are associated with factor V inhibitors. Various treatments have been attempted but randomized or prospective trials are not available. EXEGESIS: Here we report three cases of acquired factor V inhibitor. These reports highlight the clinical variability of this disorder. Pathogenesis and therapy with reference to the literature are discussed. CONCLUSION: Factor V inhibitors are rare and associated to several diseases or conditions. Pathogenesis is still unclear except in patients exposed to bovine thrombin. The majority of the cases developed after surgery. In a few cases there is an association to a malignant or autoimmune disease. Plasmapheresis and platelet transfusions might be the best treatment in case of severe bleeding. High-dose intravenous immunoglobulin infusions have been used successfully in some cases and we report here their efficacy in two cases.

Aged↗