Short-term very low-calorie diet in obese females improves the haemostatic balance through the reduction of leptin levels, PAI-1 concentrations and a diminished release of platelet and leukocyte-derived microparticles.

BACKGROUND: In obesity, metabolic stress and inflammation in injured tissues could favour enhanced shedding of procoagulant microparticles (MPs). At sites of endothelium injury, the swift recruitment of procoagulant leukocyte-derived MPs enables the initiation of blood coagulation and thrombus growth. OBJECTIVES: In obese females, we sought to evaluate the impact of a very low-calorie diet (VLCD) on procoagulant MP levels, fibrinolytic status, inflammation and endothelium damage. METHODS: Circulating biomarkers of vascular damage, fibrinolytic status, platelet activation and inflammation were measured before, 30 and 90 days after starting a short-term VLCD. MPs were measured by flow cytometry and capture assays. Their procoagulant potential was quantified using functional prothrombinase assays and their cellular origin were determined using flow cytometry (endothelium, platelet, leukocyte, lymphocyte and erythrocyte-derived MP) or capture assays. RESULTS: A total of 24 obese females (39 ± 10 years) with a mean body mass index of 35 ± 4 kg m(-2) were prospectively enroled. Procoagulant leukocyte-derived MPs were associated with the waist circumference at baseline (r=0.534; P=0.010) and at 90 days follow-up (r=0.487; P=0.021). At 90 days, weight reduction (-9.8%) was associated with a lowering of blood pressure, improvement of metabolic parameters and a significant reduction of plasminogen activator inhibitor-1 (PAI-1) (-38%), procoagulant platelet-derived MPs (-43%), leukocyte-derived MPs (-28%) and leptin (-32%) levels. CONCLUSION: In obese females, a short-term VLCD results in an overall improvement of the haemostatic balance characterized by the reduction of PAI-levels, diminished release of platelet and leukocyte-derived MPs and a reduction in leptin levels, an adipocyte-derived cytokine.

[Value of left atrial dilation in the diagnosis of silent myocardial ischemia in diabetes mellitus patients]. / Facteurs prédictifs de l'existence d'une ischémie myocardique silencieuse chez le patient diabétique. Intérêt de l'évaluation de la surface de l'oreillette gauche.

BACKGROUND: Accelerated atherothrombosis is a common feature in diabetes mellitus patients (DM), which can be related to abnormalities in vascular cell apoptosis and activation leading to the release of procoagulant microparticles (MPs). In DM patients, we hypothesized that circulating levels of biomarkers involved in atherothrombosis processes as well as cardiac and carotid echocardiography variables could be useful in the detection of silent myocardial diagnosed by myocardial perfusion imaging. METHODS AND RESULTS: We investigated, in 55 patients with diabetes (mean age 62+/-10 years) and 15 nondiabetics (46+/-14 years) patients the prevalence of silent myocardial ischemia (SMI) detected by a treadmill exercise or dipyridamole (99m)Tc-sestamibi stress test. Echocardiographic and -carotid variables were obtained using standardized methods. Biomarkers assessing endothelial apoptosis or activation (CD31+-MPs, CD62+-MPs, VCAM-1), inflammatory status (CD11a +/- MPs, MCP-1, CRP), platelet activation (GPIb+/-MPs, CD40-L, P-selectin, GPV) ventricular stretch (BNP) were measured in the plasma. SMI was diagnosed in 23/55 (42%) diabetics patients and in 3/15 (20%) nondiabetics patients. Enhanced inflammatory status and leukocyte damage (CD11a+-MPs) were evidenced in diabetic patients. Within the diabetic population, biomarkers levels of atherothrombosis were not significantly associated to the detection of SMI. In multivariable analyses adjusted for LV hypertophy, left atrial surface (LA) remained independent predictor of silent myocardial ischemia (OR 4.14; IC [1.7-16.13]; P=0.039). CONCLUSIONS: In diabetes mellitus patients, LA surface independently predicted silent myocardial ischemia after adjustment for established echocardiographic, and inflammatory risk factors. This simple measure of LA dilation could be helpful in the identification of diabetes mellitus patients at heightened cardiovascular risk.

[Platelet responsiveness to clopidogrel in patients with coronary syndrome. Comparison of platelet aggregation induced by ADP and flow cytometric analysis of intraplatelet VASP phosphorylation]. / Evaluation de la réponse plaquettaire au clopidogrel au cours des syndromes coronariens. Comparaison de l'agrégométrie à l'ADP et de la méthode VASP.

UNLABELLED: Although antiplatelet therapy with ASA-clopidogrel reduces the risk of cardiovascular episodes after PCI, a substantial number of events occur during follow-up. Sustained platelet reactivity under dual antiplatelet therapy was recently associated with increased risk of recurrent atherothrombotic events after PCI. Whereas it appears significant to determine clopidogrel responsiveness, the accurate platelet function assay is still under investigation. OBJECTIVES: (i) to determine the proportion of "low-responders" or "resistants" patients during coronary syndrome (ii) to identify determinants of interindividual variability response to clopidogrel (iii) to compare aggregometry and VASP phosphorylation measured by flow cytometry. Patients were treated by clopidogrel (300 mg loading dose and 75 mg maintenance dose) and ASA (160 mg) (N=27). Additional treatment by GPIIbIIIa antagonists was given to high-risk patients (N=9). Platelet function was monitored by ADP aggregometry (5, 10, 20 microM) and VASP phosphorylation before any treatment by clopidogrel (d0) and at least five days after (d5). The platelet reactivity index (PRI), expressed as percentage, is the difference in VASP fluorescence intensity between resting (+ PGE1) and activated (ADP) platelets. At d5, low responsiveness to clopidogrel was defined by either (i) a PRI > 67.3% corresponding to the mean value -2SD measured in untreated patients (dO) (ii) or an absolute change (delta d0-d5) in aggregation (ADP 10 microM) < to 30%. RESULTS: PRI, platelet aggregometry to ADP was significantly reduced following clopidogrel treatment (P < 0.01). A wide inter-individual variability to clopidogrel was observed at d5 (PRI from 11 to 83%). Whatever the platelet function used, a large proportion of patients were detected as "low-responders" (37% by VASP, 44% by ADP aggregometry). Absolute change in ADP aggregation was correlated to the variation of PRI (R = 0.559; P = 0.02). Contrary to ADP aggregometry, PRI was not influenced by GPIIbIIIa antagonists or prior administration of ASA. However, the conformity of the two methods to evaluate clopidogrel responsiveness was only 66%. No differences in platelet aggregometry could be observed at d5 between "low" and "good-responders" defined by VASP analysis. At d5, a higher PRI value could be detected in male and patients with history of dyslipemia. CONCLUSION: During coronary syndrome, impaired platelet responsiveness to clopidogrel was observed in a large proportion of patients whatever the platelet function assay used. VASP analysis was found insensitive to GPIIbIIIa or aspirin administration. Possible mechanisms linking clopidogrel "resistance" measured by VASP assay and enhanced thrombogenicity remain to be characterized. Indeed, clopidogrel "resistance" defined by VASP analysis was not associated with higher platelet aggregation.

[Microparticles during sepsis and trauma. A link between inflammation and thrombotic processes]. / Microparticules circulantes au cours des traumatismes graves et des sepsis: un élément du couplage inflammation-thrombose.

Sepsis and trauma lead to a sustained activation of monocytes and endothelium. In the vascular compartment, stimulated cells release microparticles. Circulating MP provide an additional procoagulant phospholipid surface enabling the assembly of the clotting enzymes complexes and thrombin generation. Their procoagulant properties rely on the exposition of phosphatidylserine, made accessible after cell stimulation and on the possible presence of tissue factor, the main cellular initiator of blood coagulation. Microparticles constitute the main reservoir of blood-borne tissue factor activity. At sites of endothelium injury, enhanced release or recruitment of procoagulant MP through P-selectin-PSGL-1 pathway could concentrate TF activity above a threshold allowing blood coagulation to be triggered. Converging evidences from experimental or clinical data highlight a role for MP harboring tissue factor in the initiation of disseminated intravascular coagulopathy. In these settings, the pharmacological modulation of MP levels or biological functions through activated protein C or factor VIIa allows challenging issues.

Elevated levels of procoagulant microparticles in a patient with myocardial infarction, antiphospholipid antibodies and multifocal cardiac thrombosis.

Circulating procoagulant microparticles (MP) are pathogenic markers of enhanced coagulability associated to a variety of disorders and released from stimulated vascular cells. When derived from endothelial cells, MP were found characteristic of thrombotic propensity in primary antiphospholipid syndrome (APS). The prothrombotic status of a patient with antiphospholipid antibodies (APL), a past history of mesenteric vein thrombosis and presenting myocardial infarction and extensive intracardiac thrombosis was examined by measurement of circulating procoagulant MP. MP of platelet and endothelial origins were highly elevated with respect to values detectable in patients with myocardial infarction and no history of APS (6- and 3-fold elevation, respectively) or in healthy volunteers (13- and 25-fold elevation, respectively). In this particular patient, with moderate APL titer, a drastic release of procoagulant MP could have contributed to thrombus growth and the development of extensive intracardiac thrombosis.

[Microparticles and cardiovascular disease]. / Microparticules et pathologies cardiovasculaires.

Microparticles are membrane fragments liberated by activated or apoptopic cells. Thought for a long time to be cellular debris with no specific biologic function, in the vascular compartment they are a circulating reservoir of cellular effectors involved in thrombosis, inflammation, vascular remodelling and angiogenesis. High concentrations of circulating procoagulating microparticles found in many cardiovascular diseases indicate the importance of platelet, endothelial and monocytic activation and could contribute to the persistence of atherothrombotic disease. Pharmacological modulation of circulating microparticle concentrations could become a major therapeutic target in the future.

[The significance of circulating microparticles in physiology, inflammatory and thrombotic diseases]. / Les microparticules circulantes: rôles physiologiques et implications dans les maladies inflammatoires et thrombotiques.

BACKGROUND: In multicellular organisms, apoptosis and subsequent microparticle shedding play a key role in homeostasis. Having long been considered as << cellular dust >>, microparticles released in biological fluids upon cell activation or apoptosis appear as multifunctional bioeffectors involved in the modulation of key functions including immunity, inflammation, hemostasis and thrombosis, angiogenesis. MP constitute reliable markers of vascular damage, accessible to biological detection whilst the cells they originate from remain sequestered in tissues or are promptly submitted to phagocytosis. RECENT FINDINGS: MP modulate biological functions of target cells through the transfer of cytoplasmic content, lipids and membrane receptors. The pharmacological modulation of circulating levels of microparticles could be of particular interest in thrombotic or inflammatory diseases, cancer or hemophilia. CONCLUSION: MP can now be viewed not only as a hallmark of cell damage but also as a true biological tool.

[Variable extent of platelet responsiveness to clopidogrel inhibition: "clopidogrel resistance"?]. / Variabilité de la réponse plaquettaire au clopidogrel: "résistance" biologique?

During percutaneous coronary angioplasty, platelet inhibition by clopidogrel and aspirin has drastically decreased the risk of thrombotic occlusion of the stented vessels. However, despite the widespread use of these drugs, the incidence of acute or subacute stent thrombosis remains elevated, concerning 1 to 2% of the treated patients. Considerable differences in the responsiveness to clopidogrel could be observed, suggesting a possible underlying biological resistance. "Clopidogrel resistance" has recently been associated to an increased risk of thrombotic events following coronary angioplasty. Variations in enteric absorption, biotransformation in the liver by the CYP3A4, changes in the ADP receptor P2Y12, abnomalies of intraplatelet signal transduction, extent of platelet activation, class angina, diabetes mellitus may account for the considerable interindividual response variability widely reported. In this view, laboratory tests evaluating "clopidogrel resistance" might be useful tools for the identification and follow-up of patients at higher thrombotic risk. Indeed, in these patients, further platelet inhibition can be achieved by higher doses of clopidogrel.

Protective effects of vitamin C on endothelium damage and platelet activation during myocardial infarction in patients with sustained generation of circulating microparticles.

During myocardial infarction (MI), high levels of circulating procoagulant microparticles (MP) shed from endothelial cells and platelets diffuse prothrombotic and proinflammatory potentials crucial for the coronary prognosis. In addition to conventional treatments, we evaluated whether vitamin C treatment could modify circulating levels of procoagulant MP. Upon admission, 61 patients with MI were prospectively randomized for immediate additional vitamin C treatment. Circulating MP were quantified by functional prothrombinase assay before and after 5 days of vitamin C administration (1 g day-1). The cellular origin of MP was also assessed. In vitamin C-treated patients, the reduction in platelet-derived MP was 10% higher (P = 0.01). In patients with diabetes mellitus, dyslipidemia or more than two cardiovascular risk factors, vitamin C decreased endothelial and platelet-derived MP levels by approximately 70% and 13%, respectively. This early effect on circulating platelet and endothelial-derived MP, testifies to the importance of oxidative stress during MI. Vitamin C could prove beneficial for the outcome of patients at higher thrombotic risk.

Circulating procoagulant microparticles and soluble GPV in myocardial infarction treated by primary percutaneous transluminal coronary angioplasty. A possible role for GPIIb-IIIa antagonists.

Circulating procoagulant microparticles (MP) were measured as markers of vascular damage and prothrombotic risk in patients undergoing ST-segment myocardial infarction (STEMI) treated by primary percutaneous transluminal coronary angioplasty (PTCA) and additional GPIIb-IIIa antagonists. Cells possibly more responsive to GPIIb-IIIa (alpha(IIb)beta(3)) antagonists were evidenced through MP phenotypes by comparison with healthy volunteers (HV) and STEMI patients treated by PTCA without GPIIb-IIIa antagonist (CP). In 50 STEMI patients, blood samples were collected at day 1 and day 6. Circulating procoagulant MP were captured on annexin V and quantified by prothrombinase assay as nanomolar phosphatidylserine equivalents (nm PhtdSer). Platelet activation by thrombin was confirmed through independent measurement of soluble GPV (sGPV). With respect to HV, procoagulant MP levels were high in patients with STEMI or unstable angina, platelet-derived MP and elevated sGPV testifying to significant platelet activation. A substantial release of endothelial-derived MP was evidenced simultaneously. In abciximab-treated patients, procoagulant MP, mainly of platelet origin, decreased precociously at day 1 (4.2 +/- 0.6 vs. CP 15.5 +/- 2.1 nm PhtdSer; P = 0.001) together with sGPV (36 +/- 3 vs. CP 58 +/- 8 ng mL(-1); P = 0.02). Leukocyte-derived MP decreased at day 6 (0.12 +/- 0.04 vs. CP 0.56 +/- 0.12 nm PhtdSer; P = 0.01) suggesting a possible effect on underlying inflammatory status. In patients presenting cardiovascular events at 6-month follow-up, procoagulant MP levels at day 1 could be indicative of a worsened outcome. MP could constitute a relevant parameter for the follow-up of STEMI patients treated by GPIIb-IIIa antagonists.

[The implantable automatic defibrillator]. / Défibrillation automatique implantable. A propos de quelques avancées techniques récentes.

Technical advances in the design of implantable automatic defibrillators have been constant since the introduction of these devices in the mid 80s. The most obvious advance is the miniaturisation of the devices from which all components have benefited. The capacity of the batteries has improved inversely proportionally to their size, even if the longevity has not always lived up to expectations. The volumic energy of the condensers has improved and their technology also, and their size has decreased. Condensers are still usually made by the electrolytic/aluminium method but tantalum technology is bound to become more generalised because it presents so many advantages. Above all, the circuitry has benefited from the progress of micro-electronics, associating miniaturisation with an increase in more and more complex functions...but requiring more electrical current. Of these functions, algorithms to detect arrhythmias has reduced the number of inappropriate shocks but do not yet have excellent specificity either in single or in dual chamber sensing. Defibrillators incorporating a multisite anti-bradycardiac function are more and more popular because of the close relationship between cardiac failure and sudden death.

[Procoagulant membranous microparticles and atherothrombotic complications in diabetics]. / Microparticules membranaires procoagulantes et complications athérothrombotiques chez le patient diabétique.

Endothelial apoptosis and platelet activation play a key role in atherothrombotic event. These two mechanisms resulting membrane thickening leading to procoagulant microparticle (MP) liberation into the blood stream. In the vascular compartment, MP contribute to increased thrombin formation, to platelet activation, and prolong inflammation of the arterial wall by inducing the synthesis of cytokines and adhesion of glycoproteins by the endothelial cells. In diabetic patients, increased endothelial apoptosis associated with intense platelet and monocytic activation could contribute to accelerated atherothrombosis. Endothelial, platelet and monocytic derived MP, found in high concentrations in these patients, induce a prothrombotic, proadhesive and proinflammatory tendency in the vascular comportment which could directly impact on the vascular prognosis. In diabetes, increased platelet or monocytic MP is a marker for microvascular disease. Likewise, in acute coronary syndromes of diabetic patients, high concentrations of procoagulant MP could be associated with a poor cardiovascular prognosis. In these diabetic patients, many treatments (antioxidant, antiplatelet, lipid lowering, antihypertensive) significantly reduce the levels of MP and parameters associated with inflammation. MP are one of the key factors linking inflammation, oxidative stress, apoptosis and thrombosis in accelerated atherothrombotic disease of the diabetic. In future, the measurement of MP should help evaluate the efficacy of antioxidant and antiplatelet therapy, especially in diabetic patients.

Microparticles in atrial fibrillation: a link between cell activation or apoptosis, tissue remodelling and thrombogenicity.

Microparticles (MPs) are small membrane vesicles that are shed from virtually all cells in response to stress. Widely described in atherothrombotic diseases, recent data suggest a role for circulating MPs in the hypercoagulable state associated with supraventricular tachyarrhythmia. During atrial fibrillation, several mechanisms, such as high ventricular heart rate, low or oscillatory shear stress, stretch, hypoxia, inflammation and oxidative stress, are potent inducers of apoptotic cell death, which leads to the shedding of procoagulant MPs within the vasculature. As key regulators of cell-cell cross-talk and important mediators of inflammatory, thrombogenic and proteolytic pathways, MPs directly or indirectly contribute to the amplification loops involved in atrial fibrillation. Because high levels of platelets and endothelial-derived MPs are identified during stroke and are associated with infarct size and clinical outcome, they are proposed to be a potent marker of ischaemic risk. During pulmonary vein isolation, the additional increases of platelet and leukocyte MP levels suggest the extent of tissue damage and reflect a transient activation of the coagulation cascade that could favour ischaemic stroke. Conversely, the observed decreases of several apoptotic markers some months after the restoration of sinus rhythm suggest that the extent of apoptotic processes is reversible and might enable restoration of haemostasis. In this review, we will summarise the current evidence supporting the roles of apoptosis and cell activation in the development of the prothrombotic state observed in atrial fibrillation, with a particular focus on procoagulant MPs.

Prevalence, characteristics, and prognosis role of type 1 ST elevation in the peripheral ECG leads in patients with Brugada syndrome.

BACKGROUND: Despite isolated reports of Brugada syndrome (BrS) in the inferior or lateral leads, the prevalence and prognostic value of ST elevation in the peripheral electrocardiographic (ECG) leads in patients with BrS remain poorly known. OBJECTIVE: To study the prevalence, characteristics, and prognostic value of type 1 ST elevation and ST depression in the peripheral ECG leads in a large cohort of patients with BrS. METHODS: ECGs from 323 patients with BrS (age 47 ± 13 years; 257 men) with spontaneous (n = 141) or drug-induced (n = 182) type 1 ECG were retrospectively reviewed. Two hundred twenty-five (70%) patients were asymptomatic, 72 (22%) patients presented with unexplained syncope, and 26 (8%) patients presented with sudden death (12 patients) or appropriated implantable cardioverter-defibrillator therapies (14 patients) at diagnosis or over a mean follow-up of 48 ± 34 months. RESULTS: Thirty (9%) patients presented with type 1 ST elevation in at least 1 peripheral lead (22 patients in the aVR leads, 2 in the inferior leads, 5 in both aVR and inferior leads, and 1 in the aVR and VL leads). Patients with type 1 ST elevation in the peripheral leads more often had mutations in the SCN5A gene, were more often inducible, had slower heart rate, and higher J-wave amplitude in the right precordial leads. Twenty-seven percent (8 of 30) of the patients with type 1 ST elevation in the peripheral leads experimented sudden death/appropriate implantable cardioverter-defibrillator therapy, whereas it occurred in only 6% (18 of 293) of other patients (P < .0001). In multivariate analysis, type 1 ECG in the peripheral leads was independently associated with malignant arrhythmic events (odds ratio 4.58; 95% confidence interval 1.7-12.32; P = .0025). CONCLUSIONS: Type 1 ST elevation in the peripheral ECG leads can be seen in 10% of the patients with BrS and is an independent predictor for a malignant arrhythmic event.

Impaired inhibition of P2Y(12) by clopidogrel is a major determinant of cardiac death in diabetes mellitus patients treated by percutaneous coronary intervention.

OBJECTIVES: We sought to determine whether low platelet response (LR) to the P2Y(12) receptor antagonist as assessed by vasodilator-stimulated phosphoprotein flow cytometry (VASP-FCT) differentially affects outcome in patients with or without diabetes mellitus undergoing percutaneous coronary intervention. BACKGROUND: While both DM and LR to clopidogrel are known to predict an unfavorable outcome after PCI, the deleterious effect of their association is less well established. The VASP-FCT is specific for the P2Y(12) ADP receptor pathway. In this test, platelet activation is expressed as the platelet reactivity index (PRI). METHODS: Patients were assigned to four different groups according to the presence or not of DM (DM, NDM) and LR to clopidogrel (LR, R). LR was defined as a PRI of >61%, a threshold previously identified as the optimal cut-off value to predict cardiac death following PCI. RESULTS: A total of 436 consecutive patients (163 DM, 273 NDM) were enrolled. The proportion of LR patients was higher in DM (47.9% vs. 35.2% p=0.011). At 9±2 months follow-up, the rates of total and cardiac mortality and possible and overall stent thrombosis were higher in DM-LR patients. Conversely, the cardiovascular outcome of DM-R patients was comparable to that of NDM (-LR or -R) patients. In DM, a multivariate analysis identified LR to clopidogrel (HR 6.09 [1.27-29.08], p=0.023) as the sole independent predictor of cardiac mortality. CONCLUSIONS: In DM patients undergoing PCI, LR to clopidogrel is an independent predictor of cardiac death.

[Usefulness of diastolic deceleration time assessed by transthoracic Doppler measurement in the detection of sustained microvascular obstruction in STEMI patients treated by primary PTCA]. / Intérêt de la mesure du temps de décélération diastolique par Doppler transthoracique dans l'évaluation du phénomène de no-reflow au cours de l'infarctus du myocarde antérieur traité par angioplastie primaire.

AIMS: To assess the value of coronary flow measurement by transthoracic Doppler technique in the detection of "no-reflow" phenomenon. METHODS: Fourteen patients with first anterior wall infarction treated by successful (TIMI3) primary percutaneous angioplasty and left descending coronary artery stenting were investigated. Myocardial perfusion following PCI was assessed by (i) ST-segment resolution, (ii) MRI-detected microvascular obstruction (early hypoenhancement), (iii) coronary flow pattern measurement by transthoracic Doppler technique. RESULTS: Sustained impairment of myocardial perfusion following PCI was observed in a large proportion of the cohort (36% by MRI, 43% by ST regression analysis). Patients with a diastolic deceleration time inferior to 482 ms had higher troponin and CK peak value, higher wall motion index score, lower ST resolution and lower LVEF assessed by MRI. The concordance of the three methods was 80%. CONCLUSION: The measurement of diastolic deceleration time by transthoracic Doppler technique is a reliable technique to identify microvascular obstruction following PCI in acute anterior STEMI. A DDT inferior to 482 ms is associated with sustained "no-reflow" phenomenon.

Recurrent form of neurogenic stunned myocardium: is myocardial adrenergic receptor distribution a dynamic process?

Neurogenic stunned myocardium mediated by stress-induced catecholamine acute release is considered as the central causative mechanism of transient left ventricular dysfunction syndrome (TVLDS). Interindividual differences in both LV ß-adrenergic receptor density and sympathetic innervation were proposed to explain the atypical forms of TVLDS. Whether this distribution is independent of age or may vary during ageing still remains unclear. We report a recurrent form of TLVDS characterized by two different patterns. Whilst myocardial receptor distribution or sympathetic innervation appears to follow a dynamic process, the precise determinants of these variations remain largely unknown.