Does the metabolic syndrome predict subclinical atherosclerotic damage in an asymptomatic population at intermediate cardiovascular risk?

BACKGROUND AND AIMS: It is not clear whether the metabolic syndrome (MetS) is a distinct entity or a combination of risk factors. Several studies showed the association between MetS and cardiovascular disease (CVD). Subclinical target organ damage (TOD) is a recognized marker of atherosclerosis and predictor of cardiovascular events. Increased burden of subclinical atherosclerosis was detected in individuals with MetS. We thus aimed to examine the association between MetS and cumulative or specific TOD and to assess whether MetS predicts TOD better than the risk factors included in current definitions. METHODS AND RESULTS: We recorded TOD in 979 patients at intermediate cardiovascular risk with and without MetS according to IDF and NCEP criteria. We measured common carotid intima-media thickness, left ventricular mass index (LVMI), urine albumin to creatinine ratio (UACR), and ankle-brachial index. We found no correlation between having at least one TOD and being positive for MetS. A high UACR was associated with MetS using both IDF and NCEP criteria, while only NCEP identified individuals with increased LVMI. Using a multivariate logistic regression model including MetS, age, sex, waist circumference, triglycerides, HDL cholesterol, blood pressure and blood glucose levels we found no correlations between the presence of MetS and at least one TOD. The associations with high UACR and LVMI disappeared when age, blood pressure and glycemia were counted in. CONCLUSION: Although MetS showed some relation with subclinical renal and cardiac damage, it does not predict TOD any better than the risk factors specified in the definitions.

Markers of inflammation, thrombosis and endothelial activation correlate with carotid IMT regression in stable coronary disease after atorvastatin treatment.

BACKGROUND AND AIMS: MIAMI is a prospective multicenter clinical study designed to investigate the relationship between changes in carotid intima-media thickness (C-IMT) and changes in circulating markers of inflammation, thrombosis and endothelial activation in stable coronary patients treated for 20+/-3.7 months with 20mg/day atorvastatin. METHODS AND RESULTS: Eighty-five subjects had their C-IMT, blood lipids and soluble markers measured at baseline, at the 12th month and at the end of the study. Almost all soluble markers decreased upon treatment except for high-sensitivity C-reactive protein (hs-CRP), interleukin-18 (IL-18), tissue factor pathway inhibitor-free (TFPI-free) and soluble vascular cell adhesion molecules-1 (sVCAM-1) which did not change significantly, and interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha) and soluble CD40 ligand (sCD40L) which increased. sCD40L, fibrinogen, tissue factor pathway inhibitor-total (TFPI-total), soluble intercellular adhesion molecules-1 (sICAM-1), sE-selectin, interleukin-8 (IL-8) and von Willebrand factor (vWF) changed significantly even after application of the Bonferroni correction for multiple comparisons. Changes in lipids did not correlate with C-IMT regression either when considered singly or when combined in a lipid score. Changes in soluble markers correlated poorly with C-IMT regression when analyzed singly, but strongly when combined in relevant composite scores (inflammation/coagulation score, endothelial activation score, soluble markers score and total score). CONCLUSION: In patients with stable coronary artery disease treated with moderate doses of atorvastatin, carotid IMT regression correlated with changes of inflammation, thrombosis and endothelial activation profiles.

E-selectin and TFPI are associated with carotid intima-media thickness in stable IHD patients: the baseline findings of the MIAMI study.

OBJECTIVE: MIAMI was a prospective multicenter clinical study designed to investigate the relationship between changes in carotid intima-media thickness (C-IMT) and those in the levels of circulating markers of inflammation, thrombosis and endothelial dysfunction. The study was performed in a group of stable coronary patients treated for two years with a moderate dosage of atorvastatin (20mg/day). In this paper the cross-sectional relationship between C-IMT and the same circulating markers of inflammation, thrombosis and endothelial dysfunction measured at baseline was investigated. METHODS: Eighty-five subjects that had not used statins for at least two months were enrolled in the study. At time of enrollment, the levels of vascular cell adhesion molecule-1 (VCAM-1), intracellular adhesion molecule-1 (ICAM-1), E-selectin, interleukin (IL)-6, IL-8, tumor necrosis factor (TNF)-alpha, high-sensitivity C-reactive protein (hs-CRP), tissue factor (TF), tissue factor pathway inhibitor (TFPI), von Willebrand factor (vWF), fibrinogen, total cholesterol (TC), high-density lipoprotein (HDL) and low-density lipoprotein (LDL), and triglycerides were measured, in parallel with C-IMT assessment. RESULTS: In cross-sectional analyses, markers of endothelial perturbation (i.e. E-selectin) and TFPI were more strongly correlated with arherosclerotic burden than markers of inflammation. The baseline picture in this study indicates that E-selectin and TFPI are linked with atherosclerotic burden.

Beneficial effects of fluvastatin following percutaneous coronary intervention in patients with unstable and stable angina: results from the Lescol intervention prevention study (LIPS).

AIMS: To investigate the effect on risk of major adverse cardiac events (MACE) of lipid lowering treatment with fluvastatin 80 mg/day after a first percutaneous coronary intervention in patients with stable and unstable angina. METHOD AND RESULTS: This prespecified subgroup analysis of the LIPS (Lescol intervention prevention study) analysed 1658 patients with documented diagnosis; 824 had unstable angina (417 randomly assigned to fluvastatin, 407 to placebo) and 834 had stable angina (including silent ischaemia; fluvastatin, 418; placebo, 416). Median follow up was 3.9 years. There was no significant effect of anginal status on long term risk of MACE. Fluvastatin treatment reduced the risk of MACE by 28% compared with placebo (p = 0.03) among patients with unstable angina, with no difference between patients with stable and patients with unstable angina (relative risk 1.07, 95% confidence interval 0.87 to 1.30, p = 0.53). Fluvastatin reduced coronary atherosclerotic events (MACE excluding restenosis) by 36% (p = 0.006) among patients with unstable angina and 31% (p = 0.02) among patients with stable angina. Fluvastatin caused similar reductions in total cholesterol and low density lipoprotein cholesterol concentrations in both patient groups. CONCLUSION: Treatment with fluvastatin 80 mg/day produced significant reductions in MACE and coronary atherosclerotic events after percutaneous coronary intervention in patients with average cholesterol concentrations. The beneficial effects of fluvastatin are observed in patients with unstable or stable angina alike.

Effects of fluvastatin and bezafibrate combination on plasma fibrinogen, t-plasminogen activator inhibitor and C reactive protein levels in coronary artery disease patients with mixed hyperlipidaemia (FACT study). Fluvastatin Alone and in Combination Treatment.

AIM OF THE STUDY: We studied the effects of fluvastatin and bezafibrate in monotherapy and in combination on plasma fibrinogen, t-plasminogen activator inhibitor (PAI-1) and C reactive protein (CRP) in patients with coronary artery disease (CAD) and mixed hyperlipidaemia. DESIGN: In this randomised, double blind, multicentre trial 333 patients with stable angina pectoris or previous myocardial infarction or coronary revascularisation and mixed hyperlipidaemia (LDL-cholesterol 135-250 mg/dl and triglycerides (TG) 180-400 mg/dl) were randomised to fluvastatin 40 mg, bezafibrate 400 mg, fluvastatin 20 mg + bezafibrate 400 mg or fluvastatin 40 mg + bezafibrate 400 mg treatments for 24 weeks. RESULTS: Plasma fibrinogen significantly decreased after treatment with the combinations fluvastatin+bezafibrate (-14 and -16%) and with bezafibrate monotherapy (-9%). No significant reduction was observed after fluvastatin monotherapy (-4%). No significant changes were observed in PAI-1 and CRP plasma levels. Combination therapy significantly decreased both LDL-C and TG, and significantly increased HDL-C. CONCLUSIONS: The combined effects on fibrinogen and plasma lipids achieved by fluvastatin and bezafibrate combination treatment might be more useful than the simple reduction of cholesterol in preventing ischaemic cardiovascular disease.

Preoperative plasma levels of prothrombin fragment 1 + 2 correlate with the risk of venous thrombosis after elective hip replacement.

Better preoperative identification of those patients at high risk of developing a deep vein thrombosis (DVT) after hip surgery could reduce the incidence of this postoperative complication, which still occurs despite prophylaxis. One hundred fifty-nine patients undergoing elective total hip replacement and given anticoagulant prophylaxis, were investigated, looking for the presence of a hypercoagulable state, that represents one element of Virchow's triad predisposing to DVT. Plasma levels of three markers of coagulation activation, namely prothrombin fragment 1 + 2 (F1 + 2), thrombin-antithrombin III complexes (TAT) and D-dimer were measured using ELISA procedures and were correlated with the results of the postoperative phlebography. A high correlation (p < 0.001) between the preoperative plasma levels of F1 + 2 and the risk of postoperative venous thromboembolism was detected. The performance of TAT and D-dimer levels in predicting DVT was lower. These findings support the hypothesis that preoperative measurement of coagulation activation markers might be useful in predicting DVT following a total hip replacement.

Clinical utility of prothrombin fragment 1+2, thrombin antithrombin III complexes and D-dimer measurements in the diagnosis of deep vein thrombosis following total hip replacement.

BACKGROUND: Measurements of prothrombin fragment 1+2 (F1+2), thrombin antithrombin III complexes (TAT) and D-dimer plasma levels have been proposed as non-invasive screening tests to exclude postoperative deep venous thrombosis (DVT). We investigated the diagnostic efficacy of these coagulation activation markers to rule out postoperative DVT in patients undergoing hip surgery under antithrombotic prophylaxis. METHODS: In this substudy of a randomized double-blind thrombosis prophylaxis trial comparing three doses of desirudin (10, 15 or 20 mg b.i.d.) with unfractionated heparin (5000 IU t.i.d.) we used ELISA procedures to measure F1+2, TAT and D-dimer in 159 patients undergoing total hip replacement at baseline (day 0) and on postoperative days 1, 3 and 6. Bilateral venography was performed in all cases 8-11 days after surgery. RESULTS: For the F1+2 assay sensitivity ranged from 73 to 83% in the three postoperative days investigated, and negative predictive value (NPV) from 68 to 74%. For TAT and D-dimer sensitivity ranged from 71 to 73% and from 71 to 83% and NPV from 61 to 65% and from 61 to 74% respectively. INTERPRETATION: In terms of sensitivity and NPV F1+2 and D-dimer are equivalent and are superior to TAT. However, their accuracy is too low to rule out the presence of DVT after hip surgery under antithrombotic prophylaxis.

Coagulation activation markers in the prediction of venous thrombosis after elective hip surgery.

BACKGROUND: Despite prophylaxis, deep vein thrombosis (DVT) after hip surgery continues to occur frequently. Thus it would be helpful if before surgery patients at higher risk of DVT could be identified and more adequate prophylaxis given. As part of an international study on the prevention of DVT after total hip replacement, we investigated whether preoperative levels of three coagulation activation markers, prothrombin fragment F1 + 2 (F1 + 2), thrombin-antithrombin III complexes (TAT) and D-dimer, correlate with results of postoperative venography. METHODS: 159 patients undergoing total hip replacement were randomized to receive 10, 15 or 20 mg desirudin bid or 5000 IU unfractionated heparin tid immediately before surgery and then for 11 days, until bilateral venography was performed. Preoperative F1 + 2, TAT and D-dimer plasma levels were measured using ELISA procedures. As no difference among anticoagulant treatments or in the interaction between treatments and DVT was detected for any of the three variables, results are reported as pooled data. FINDINGS: The frequency of DVT was 18.8% in the low (0.75-1.33 nM) vs 65.7% in the high third of distribution (1.77-3.47 nM) of F1 + 2 (p < .001), 27.3% in the low (2.00-2.50 micrograms/l) vs 57% in the high third (5.10-61.00 micrograms/l) of TAT (p = .042), and 29.4% in the low (39-59 micrograms/l) vs 57.1% in the high third (129-651 micrograms/l) of D-dimer (p = .051). INTERPRETATION: Preoperative F1 + 2, TAT and D-dimer levels are associated with the risk of development of DVT after total hip replacement.

Markers of hemostatic system activation during thromboprophylaxis with recombinant hirudin in total hip replacement.

Coagulation activation markers were studied in 148 patients undergoing total hip replacement under recombinant-hirudin (Desirudin, Revasc) prophylaxis with the aim of investigating the efficacy and safety of this anticoagulant compared with heparin in terms of biological effects on coagulation variables and bleeding. Hirudin (10, 15 or 20 mg s.c. b.i.d.) or unfractionated heparin (5000 IU s.c. t.i.d.) was administered immediately before surgery and continued for 8-12 days. Activated partial thromboplastin time (aPTT), prothrombin activation fragment F1 + 2 (F1 + 2), thrombin-antithrombin III complexes (TAT) and D-dimer were measured at baseline and on postoperative days 1,3 and 6, immediately before the morning injection. In comparison with baseline values, heparin had little effect on aPTT whereas the three hirudin doses prolonged aPTT significantly with no differences among the three doses. Moreover, there were no group differences in perioperative or cumulative blood loss or transfusion requirements. F1 + 2 fragment, TAT and D-dimer plasma levels were higher than at baseline during the entire postoperative period, with different trends (F1 + 2 increasing, TAT decreasing, D-dimer increasing, decreasing and then increasing again), but without significant differences among the four treatment groups. Our findings suggest that specific inhibition of thrombin seems a safe and efficacious mode of blocking thrombin activity after hip surgery although it does not prevent thrombin generation.

Relation between hemostatic variables and increase of common carotid intima-media thickness in patients with peripheral arterial disease.

BACKGROUND AND PURPOSE: Increases in common carotid intima-media thickness (CC-IMT), as measured by B-mode ultrasonography, have been widely used in both population studies and clinical trials in the search for risk factors for early atherosclerosis progression and have been found to correlate with age and with high concentrations of low-density lipoprotein cholesterol, leukocytes, and hemoglobin. We have now investigated the relation between several baseline hemostatic and conventional risk factors and CC-IMT changes over 16 months in 64 patients with peripheral arterial disease randomly selected from the prospective PLAT study series. METHODS: Samples from 24 patients (37.5%) who showed increases in CC-IMT during the follow-up period were compared with those from 40 (62.5%) in whom CC-IMT remained unchanged. RESULTS: Baseline conventional risk factors and coagulation variables were similar in the two groups except for higher plasma concentrations of von Willebrand factor (vWF) (178.3 +/- 53.6% versus 141.2 +/- 53.7%, P=.01) and factor VII (FVII) (133.9 +/- 36.4% versus 107.0 +/- 27.3%, P=.001) in the patients with increased CC-IMT. CC-IMT increase correlated positively with plasma levels of FVII (r=.31, P<.01) and vWF (r=.31, P<.01). Multiple stepwise regression analysis identified FVII as the only independent variable associated with an increase in CC-IMT (beta=.83, P=.01). CONCLUSIONS: High plasma concentration of FVII and vWF may be associated with the progression of early carotid atherosclerosis in patients with peripheral arterial disease.

Association of lipoprotein(a) with atherothrombotic events and fibrinolytic variables. A case-control study.

Elevated plasma levels of lipoprotein(a) [Lp(a)] have been associated with an increased risk of cardiovascular disease. The aim of the present study was to investigate whether Lp(a) plasma levels were associated with subsequent ischemic events and with fibrinolytic variables in patients with established atherosclerotic disease enrolled in the prospective PLAT study. Lp(a) levels and fibrinolytic variables in 37 atherosclerotic patients who subsequently developed an atherothrombotic event during the first year of follow-up (cases) were compared with those in paired controls, matched for age, sex, diagnosis at enrollment and lipid pattern, who remained free from vascular events during the same time frame. Median and mean Lp(a) levels were similar in cases (6.05 mg/dl; 13.8 +/- 19.4 mg/dl) and controls (6.05 mg/dl; 17.1 +/- 21.6 mg/dl). In the whole group plasma Lp(a) levels correlated significantly with the increase of t-PA antigen (r = 0.368; p = 0.002) and fibrinolytic activity (r = 0.410; p = 0.001) induced by venous stasis but not with baseline fibrinolytic variables. These findings indicate that in patients with established atherosclerotic disease Lp(a) may interfere in vivo with the fibrinolytic process but is not predictive of subsequent ischemic events.

Association of increased fibrin turnover and defective fibrinolytic capacity with leg atherosclerosis. The PLAT Group.

Patients with peripheral arterial disease have a high risk of death from cardiovascular events. As defective fibrinolysis associated with leg atherosclerosis has been suggested as a predisposing factor, we sought a relation among decreased fibrinolysis, the presence of leg atherosclerosis and the incidence of thrombotic events in a case-control study nested in the PLAT. Fifty-eight patients with coronary and/or cerebral atherothrombotic disease, free of leg atherosclerosis at Doppler examination, were compared with 50 atherosclerotic patients with leg involvement. High D-dimer (153.0 vs 81.3 ng/ml, p < 0.001) and tPA antigen before venous stasis (14.4 vs 11.8 ng/ml, p < 0.03), and low tPA antigen (6.7 vs 15.6 ng/ml, p < 0.01) and fibrinolytic activity released after venous stasis (fibrinolytic capacity: 113.2 vs 281.4 mm2, p < 0.001) were found in patients with leg atherosclerosis. D-dimer and fibrinolytic capacity, in addition to age, were selected by stepwise discriminant analysis as characterizing patients with leg atherosclerosis. Moreover, higher D-dimer and tPA inhibitor characterized patients with leg atherosclerosis who subsequently experienced thrombotic events. These findings constitute evidence of high fibrin turnover and impaired fibrinolytic potential in patients with leg atherosclerosis. Thus impaired fibrinolysis may contribute to the prothrombotic state in these patients.

Dermatan sulphate for the treatment of disseminated intravascular coagulation (DIC) in acute leukemia: a randomised, heparin-controlled pilot study.

Efficacy and safety of i.v. dermatan sulphate (DS) and heparin (H) in controlling laboratory alterations due to DIC were compared in 10 patients with acute leukaemia, in a prospective, randomised pilot study. The time courses of the coagulation and fibrinolysis markers for DIC were similar in the two treatment groups except for activated partial thromboplastin time and thrombin time, which were prolonged in the H but not in the DS group. Blood product support tended to be greater in the H than in the DS group. DS appears to be as effective as H in controlling thrombin production during leukaemic cytolysis and may represent a safer alternative to H in the management of DIC in acute leukaemia.

Idarubicin in the therapy of acute myeloid leukemia: final analysis in 57 previously untreated patients.

Fifty-seven previously untreated adult acute myeloid leukemia patients received idarubicin (IDA) in sequential combination with cytarabine as induction therapy; post-remission treatment included two courses of IDA and cytarabine alternating with two courses of VP-16 and cytarabine. As late intensification, patients received either high-dose cytarabine or, in 10 cases, autologous bone marrow transplantation. Complete remission (CR) was achieved in 48 patients (84.2%), 41 after one induction course and seven after two courses. Median length of disease-free survival (DFS) was 26 months. Univariate analysis did not identify any of the investigated variables as having prognostic significance in predicting DFS. On the other hand, patients achieving CR after one induction course had a better DFS than those requiring two courses. Furthermore, the analysis of DFS slightly favors autologous bone marrow transplantation. In conclusion, the antileukemic activity of the present IDA protocol is testified by the high CR rate and by the possibility of minimizing the role of prognostic factors. The better outcome of patients achieving CR after one induction course further supports the opinion that the intensity of the induction treatment, offered by an agent as potent as IDA, might significantly influence DFS.

Increased fibrin turnover and high PAI-1 activity as predictors of ischemic events in atherosclerotic patients. A case-control study. The PLAT Group.

A case-control comparison within the framework of the prospective, multidisciplinary PLAT Study was performed to assess whether altered baseline fibrinolytic variables were associated with an elevated risk of ischemic thrombotic events in patients with documented coronary, cerebral, and/or peripheral atherosclerotic disease. Fibrinogen, D-dimer, tissue plasminogen activator (t-PA) antigen, and fibrinolytic activity before and after venous stasis (delta = difference between the two values), t-PA inhibitor, and lipid levels in 60 atherosclerotic patients with a thrombotic event during the first year of follow-up were compared with those in 94 atherosclerotic patients without such events, who were matched for age, sex, and diagnosis at enrollment. Events were associated with a higher release of delta t-PA antigen (P = .047), higher D-dimer (P = .024), and higher t-PA inhibitor (P = .001) levels. delta Fibrinolytic activity was correlated inversely with t-PA inhibitor (P < .01) and triglycerides (P < .05). D-Dimer was also correlated with systolic blood pressure (P < .01). Atherosclerotic patients at higher risk of thrombotic ischemic events are characterized by increased fibrin turnover and impaired fibrinolytic activity due to high t-PA inhibitor levels. This hemostatic disequilibrium may participate with conventional risk factors such as elevated triglyceride levels and systolic blood pressure in the multifactorial mechanism of ischemic sequelae in patients with preexisting vascular atherothrombotic disease.

Evidence of clonal progression in a case of Richter syndrome.

BACKGROUND: The debate continues as to whether Richter syndrome should be defined as non-Hodgkin lymphoma (NHL) because of a more malignant clone of neoplastic cells superimposed on preexisting chronic lymphocytic leukemia (CLL) or as the chance occurrence of two unrelated tumors. The cellular characteristics of the neoplastic clone involved in the CLL phase and the subsequent NHL were investigated in a patient in whom Richter syndrome developed. METHODS: Cell analysis was performed with immunofluorescence, histologic analysis, DNA extraction, and Southern blot analysis. RESULTS: The separated CLL and NHL B-cells from blood and bone marrow, as well as the neoplastic cells in autopsy specimens of the organs affected by NHL, particularly the brain, were found to express the same light chain of surface immunoglobulin (SIg). The change MD-->M in the SIg heavy-chain expression and the appearance of cytoplasmic IgMk suggested isotype switching simulating that observed on the final phases of primary B-cell differentiation. This hypothesis was confirmed by Southern blot analysis of DNA from blood cells in the CLL phase and in Richter transformation, which showed that the two cell populations had identical Ig gene rearrangement. CONCLUSIONS: The NHL in the patient in this study represented a malignant progression of CLL, not a second lymphoid malignancy.

The PLAT Study: hemostatic function in relation to atherothrombotic ischemic events in vascular disease patients. Principal results. PLAT Study Group. Progetto Lombardo Atero-Trombosi (PLAT) Study Group.

The Progetto Lombardo Atero-Trombosi (PLAT) Study was a prospective, multicenter, multidisciplinary study of the association among hemostatic variables, conventional risk factors, and atherothrombotic events in four groups of patients with preexisting vascular ischemic disease (335 myocardial infarction survivors, 123 patients with stable angina pectoris, 160 with transient ischemic attacks, and 335 with peripheral vascular disease). In the myocardial infarction group, univariate analysis showed that atherothrombotic events were associated with high fibrinogen (p = 0.001), factor VIII:C (p less than 0.001), and von Willebrand factor antigen (vWF:Ag) (p = 0.004) levels and with low high density lipoprotein cholesterol (p = 0.043), factor VII (p = 0.019), and protein C (p = 0.044) levels; multivariate analysis produced associations with high fibrinogen and factor VIII:C levels and low protein C levels. By both univariate and multivariate analysis, events in the angina pectoris group were associated with high vWF:Ag (p = 0.026) and leukocyte (p = 0.033) levels and the presence of carotid arterial stenosis (p = 0.063); associations with high leukocyte (p = 0.037) and factor VIII:C (p = 0.186) levels, family history (p = 0.031), and diabetes (p = 0.061) were also found in the group with transient ischemic attacks. In those with peripheral vascular disease, events were associated with Fontaine stage greater than or equal to IIB (p = 0.024), high factor VIII:C levels (p = 0.073), and low protein C (p = 0.028), fibrinogen (p = 0.030), antithrombin III (p = 0.054), and factor VII (p = 0.057) levels by univariate analysis and with Fontaine stage and low fibrinogen levels by multivariate analysis.(ABSTRACT TRUNCATED AT 250 WORDS)