RESUMO
BACKGROUND: The capacity of high-density lipoprotein cholesterol (HDL) to acquire free cholesterol (FC) from triglyceride-rich lipoproteins during lipoprotein lipase-dependent lipolysis in a process of reverse remnant cholesterol transport, has been proposed as a key biological function of HDL particles that underlies the U-shaped relationship between HDLcholesterol and cardiovascular diseases. Although reverse remnant cholesterol transport has been evaluated in a fasting state, it has never been explored under nonfasting conditions. METHODS AND RESULTS: FC transfer was evaluated in healthy men (n=78) before and throughout the postprandial phase up to 8 hours after consumption of a test meal. Postprandially, the capacity of HDL to acquire FC increased progressively, reaching a maximal mean value of 98.5%±22.5% 6 hours after meal intake (P<0.05). Analysis of the study population according to tertiles of postprandial variation of FC transfer identified subjects exhibiting reduced capacity of HDL to acquire FC (tertile 1), those for whom the capacity of HDL to acquire FC remained unchanged (tertile 2), and subjects characterized by an enhanced FC transfer during the postprandial phase (tertile 3). Across the tertiles, we found an inverse relationship between the maximal postprandial change in FC transfer to HDL and the degree of postprandial triglyceride response. CONCLUSIONS: Healthy individuals exhibiting exacerbated postprandial triglyceride response and reduced HDL cholesterol levels feature reduced FC transfer to HDL during the postprandial state. These data suggest that to normalize postprandial triglyceride response, 2 conditions need to be fulfilled: notably elevated FC transfer to HDL in the postprandial phase and increased levels of acceptor HDL particles.
Assuntos
Hipertrigliceridemia , Período Pós-Prandial , Triglicerídeos , Humanos , Masculino , Período Pós-Prandial/fisiologia , Triglicerídeos/sangue , Hipertrigliceridemia/sangue , Adulto , Lipoproteínas/sangue , Voluntários Saudáveis , Pessoa de Meia-Idade , HDL-Colesterol/sangue , Colesterol/sangue , Adulto Jovem , Lipoproteínas HDL/sangue , Biomarcadores/sangue , Fatores de TempoRESUMO
BACKGROUND: Patients with systemic lupus erythematosus (SLE) exhibit a high risk for cardiovascular diseases (CVD) which is not fully explained by the classical Framingham risk factors. SLE is characterized by major metabolic alterations which can contribute to the elevated prevalence of CVD. METHODS: A comprehensive analysis of the circulating metabolome and lipidome was conducted in a large cohort of 211 women with SLE who underwent a multi-detector computed tomography scan for quantification of coronary artery calcium (CAC), a robust predictor of coronary heart disease (CHD). FINDINGS: Beyond traditional risk factors, including age and hypertension, disease activity and duration were independent risk factors for developing CAC in women with SLE. The presence of coronary calcium was associated with major alterations of circulating lipidome dominated by an elevated abundance of ceramides with very long chain fatty acids. Alterations in multiple metabolic pathways, including purine, arginine and proline metabolism, and microbiota-derived metabolites, were also associated with CAC in women with SLE. Logistic regression with bootstrapping of lipidomic and metabolomic variables were used to develop prognostic scores. Strikingly, combining metabolic and lipidomic variables with clinical and biological parameters markedly improved the prediction (area under the curve: 0.887, p < 0.001) of the presence of coronary calcium in women with SLE. INTERPRETATION: The present study uncovers the contribution of disturbed metabolism to the presence of coronary artery calcium and the associated risk of CHD in SLE. Identification of novel lipid and metabolite biomarkers may help stratifying patients for reducing CVD morbidity and mortality in SLE. FUNDING: INSERM and Sorbonne Université.
RESUMO
While low concentrations of high-density lipoprotein-cholesterol (HDL-C) are widely accepted as an independent cardiovascular risk factor, HDL-C-rising therapies largely failed, suggesting the importance of both HDL functions and individual subspecies. Indeed HDL particles are highly heterogeneous, with small, dense pre-beta-HDLs being considered highly biologically active but remaining poorly studied, largely reflecting difficulties for their purification. We developed an original experimental approach allowing the isolation of sufficient amounts of human pre-beta-HDLs and revealing the specificity of their proteomic and lipidomic profiles and biological activities. Pre-beta-HDLs were enriched in highly poly-unsaturated species of phosphatidic acid and phosphatidylserine, and in an unexpectedly high number of proteins implicated in the inflammatory response, including serum paraoxonase/arylesterase-1, vitronectin and clusterin, as well as in complement regulation and immunity, including haptoglobin-related protein, complement proteins and those of the immunoglobulin class. Interestingly, amongst proteins associated with lipid metabolism, phospholipid transfer protein, cholesteryl ester transfer protein and lecithin:cholesterol acyltransferase were strongly enriched in, or restricted to, pre-beta-HDL. Furthermore, pre-beta-HDL potently mediated cellular cholesterol efflux and displayed strong anti-inflammatory activities. A correlational network analysis between lipidome, proteome and biological activities highlighted 15 individual lipid and protein components of pre-beta-HDL relevant to cardiovascular disease, which may constitute novel diagnostic targets in a pathological context of altered lipoprotein metabolism.
Assuntos
Doenças Cardiovasculares , Humanos , Proteômica , HDL-Colesterol , Fatores de Risco de Doenças Cardíacas , Metabolismo dos LipídeosRESUMO
BACKGROUND: Inhibition of the interleukin (IL)-1ß innate immunity pathway is associated with anti-inflammatory effects and a reduced risk of recurrent cardiovascular events in stable patients with previous myocardial infarction (MI) and elevated high-sensitivity C-reactive protein (hs-CRP). OBJECTIVES: This study assessed the association between IL-1ß level with all-cause mortality in patients with acute ST-segment elevation MI who underwent primary percutaneous coronary intervention and the interplay between IL-1ß and hs-CRP concentrations on the risk of premature death. METHODS: IL-1ß concentration was measured in 1,398 patients with ST-segment elevation MI who enrolled in a prospective cohort. Crude and hazard ratios for all-cause and cardiovascular mortality were analyzed at 90 days and 1 year using multivariate Cox proportional regression analysis. Major adverse cardiovascular events (MACEs) were analyzed. RESULTS: IL-1ß concentration measured at admission was associated with all-cause mortality at 90 days (adjusted hazard ratio [adjHR]: 1.47 per 1 SD increase; 95% confidence interval [CI]: 1.16 to 1.87; p < 0.002). The relation was nonlinear, and the highest tertile of IL-1ß was associated with higher mortality rates at 90 days (adjHR: 2.78; 95% CI: 1.61 to 4.79; p = 0.0002) and at 1 year (adjHR: 1.93; 95% CI: 1.21 to 3.06; p = 0.005), regardless of the hs-CRP concentration. Significant relationships were equally observed when considering cardiovascular mortality and MACEs at 90 days (adjHR: 2.42; 95% CI: 1.36 to 4.28; p = 0.002, and adjHR: 2.29; 95% CI: 1.31 to 4.01; p = 0.004, respectively) and at 1 year (adjHR: 2.32; 95% CI: 1.36 to 3.97; p = 0.002, and adjHR: 2.35; 95% CI: 1.39 to 3.96; p = 0.001, respectively). CONCLUSIONS: IL-1ß measured at admission in patients with acute MI was independently associated with the risk of mortality and recurrent MACEs.
Assuntos
Interleucina-18/sangue , Infarto do Miocárdio/mortalidade , Medição de Risco/métodos , Idoso , Biomarcadores/sangue , Angiografia Coronária , Feminino , Seguimentos , França/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Mortalidade Prematura/tendências , Infarto do Miocárdio/sangue , Infarto do Miocárdio/diagnóstico , Estudos Prospectivos , Fatores de Risco , Taxa de Sobrevida/tendênciasRESUMO
Elevation of nonfasting triglyceride (TG) levels above 1.8 g/L (2 mmol/L) is associated with increased risk of cardiovascular diseases. Exacerbated postprandial hypertriglyceridemia (PP-HTG) and metabolic context both modulate the overall efficacy of the reverse cholesterol transport (RCT) pathway, but the specific contribution of exaggerated PP-HTG on RCT efficacy remains indeterminate. Healthy male volunteers (n = 78) exhibiting no clinical features of metabolic disorders underwent a postprandial exploration following consumption of a typical Western meal providing 1200 kcal. Subjects were stratified according to maximal nonfasting TG levels reached after ingestion of the test meal into subjects with a desirable PP-TG response (GLow, TG < 1.8 g/L, n = 47) and subjects with an undesirable PP-TG response (GHigh, TG > 1.8 g/L, n = 31). The impact of the degree of PP-TG response on major steps of RCT pathway, including cholesterol efflux from human macrophages, cholesteryl ester transfer protein (CETP) activity, and hepatic high-density lipoprotein (HDL)-cholesteryl ester (CE) selective uptake, was evaluated. Cholesterol efflux from human macrophages was not significantly affected by the degree of the PP-TG response. Postprandial increase in CETP-mediated CE transfer from HDL to triglyceride-rich lipoprotein particles, and more specifically to chylomicrons, was enhanced in GHigh vs GLow. The hepatic HDL-CE delivery was reduced in subjects from GHigh in comparison with those from GLow. Undesirable PP-TG response induces an overall reduction in RCT efficacy that contributes to the onset elevation of both fasting and nonfasting TG levels and to the development of cardiometabolic diseases.
Assuntos
Proteínas de Transferência de Ésteres de Colesterol/metabolismo , Colesterol/metabolismo , Hipertrigliceridemia/metabolismo , Período Pós-Prandial , Triglicerídeos/metabolismo , Adulto , Ésteres do Colesterol/metabolismo , Quilomícrons/metabolismo , Humanos , Lipoproteínas HDL/metabolismo , Fígado/metabolismo , Macrófagos/metabolismo , Masculino , Triglicerídeos/sangueRESUMO
BACKGROUND: The aim was to compare the peri-procedural biomarkers of coagulation and platelet activation in patients randomly allocated to intravenous enoxaparin or unfractionated heparin (UFH) in the ATOLL randomized trial (NCT00718471). METHODS AND RESULTS: A total of 129 patients (n = 58 enoxaparin and n = 71 UFH) admitted for ST-segment elevation myocardial infarction (STEMI) treated by percutaneous coronary intervention (PCI) were included in this substudy of the ATOLL trial. Activated partial thromboplastin time ratio, anti-Xa activity, von Willebrand factor antigen, prothrombin fragment 1 + 2 (F1 + 2), thrombin-antithrombin complex (TAT), tissue factor pathway inhibitor and soluble CD40 ligand were measured at sheath insertion (T1) and at the end of the PCI (T2) and correlated with 1-month clinical outcomes. Target anticoagulation levels at T2 were more readily achieved in patients receiving enoxaparin compared to those receiving UFH (80.3 vs 18.2%, p < 0.0001). Increased levels of F1 + 2 and TAT measured at T2 were associated with the incidence of the composite ischemic endpoint (p = 0.04 and p = 0.03) and all-cause mortality (p < 0.0001 and p = 0.002). Release of F1 + 2 between T1 and T2 also predicted the composite ischemic endpoint (312 ± 513 vs 37 ± 292, p = 0.04) and net clinical outcome (185 ± 405 vs 3.2 ± 278, p = 0.03). CONCLUSIONS: During primary PCI, enoxaparin achieved therapeutic levels more frequently than UFH. Higher level of thrombin generation measured at the end of the PCI procedure was associated with more frequent ischemic events.
Assuntos
Anticoagulantes/uso terapêutico , Enoxaparina/uso terapêutico , Heparina/uso terapêutico , Intervenção Coronária Percutânea/métodos , Infarto do Miocárdio com Supradesnível do Segmento ST/sangue , Infarto do Miocárdio com Supradesnível do Segmento ST/cirurgia , Idoso , Anticoagulantes/administração & dosagem , Anticoagulantes/efeitos adversos , Antitrombina III , Biomarcadores , Ligante de CD40/sangue , Enoxaparina/administração & dosagem , Enoxaparina/efeitos adversos , Fator Xa/análise , Feminino , Heparina/administração & dosagem , Heparina/efeitos adversos , Humanos , Lipoproteínas/análise , Masculino , Pessoa de Meia-Idade , Tempo de Tromboplastina Parcial , Peptídeo Hidrolases/sangue , Protrombina/análise , Infarto do Miocárdio com Supradesnível do Segmento ST/mortalidade , Fator de von Willebrand/análiseRESUMO
AIM: To explore platelet reactivity on dual antiplatelet therapy (DAPT) of acute coronary syndrome (ACS) patients infected with HIV. METHODS AND RESULTS: Acute coronary syndrome patients infected with HIV (n = 80) were matched to ACS patients without HIV (n = 160) on age, sex, diabetes, and DAPT (aspirin 100%, clopidogrel 68%, prasugrel 31%, ticagrelor 1%). Platelet reactivity was evaluated after ACS (>30 days) by measuring residual platelet aggregation (RPA) to aspirin and to P2Y12 inhibitors with light transmission aggregometry (LTA), VerifyNow aspirin assay (ARU), and P2Y12 assay (PRU) and with the VASP platelet reactivity index (VASP-PRI). Proportion of patients with high residual platelet reactivity (HPR) was evaluated. HIV-infected ACS patients had higher levels of platelet reactivity in response to P2Y12 inhibitors (RPA: 23.8 ± 2.7% vs. 15.3 ± 1.3%; P = 0.001; PRU: 132 ± 10 vs. 107.4 ± 6.6; P = 0.04; and VASP-PRI: 45.2 ± 2.6% vs. 32.0 ± 2.0%; P < 0.001) and to aspirin (RPA: 3.6 ± 1.5% vs. 0.4 ± 0.1%; P = 0.004 and ARU: 442 ± 11 vs. 407 ± 5; P = 0.002) compared with non-HIV. HIV-infection was independently associated with increased platelet reactivity regardless of the test used (RPA: P = 0.005; PRU: P < 0.001 and VASP-PRI: P < 0.001) and a higher proportion of HPR (OR = 7.6; P < 0.001; OR = 2.06; P = 0.06; OR = 2.91; P = 0.004, respectively) in response to P2Y12 inhibitors. Similar results were found with aspirin. Protease inhibitors use was associated with increased platelet reactivity and higher rate of HPR. CONCLUSIONS: Acute coronary syndrome patients infected with HIV have increased levels of platelet reactivity and higher prevalence of HPR to P2Y12 inhibitors and aspirin than non-HIV patients. These results could provide potential explanations for the observed increase risk of recurrent ischemic events in the HIV-infected population.
Assuntos
Síndrome Coronariana Aguda/tratamento farmacológico , Infecções por HIV/complicações , Inibidores da Agregação Plaquetária/administração & dosagem , Antagonistas do Receptor Purinérgico P2Y/administração & dosagem , Adenosina/administração & dosagem , Adenosina/análogos & derivados , Fármacos Anti-HIV/uso terapêutico , Aspirina/administração & dosagem , Plaquetas/efeitos dos fármacos , Clopidogrel , Estudos Transversais , Quimioterapia Combinada , Feminino , Infecções por HIV/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-Idade , Agregação Plaquetária/efeitos dos fármacos , Cloridrato de Prasugrel/administração & dosagem , Estudos Prospectivos , Recidiva , Fatores de Risco , Ticagrelor , Ticlopidina/administração & dosagem , Ticlopidina/análogos & derivadosRESUMO
BACKGROUND: The extent of P2Y12 inhibition during coronary intervention is an important determinant of ischemic complications. The currently available oral P2Y12 inhibitors are limited by a relatively slow onset of action and variable on-treatment response. OBJECTIVE: Our objective was to determine the pharmacodynamic (PD) dose-antiplatelet response relationship and the pharmacokinetics of MDCO-157, an intravenous formulation of clopidogrel complexed with sulphobutylether betacyclodextrin, and to identify the dose level of MDCO-157 that matches the PD effect of oral clopidogrel 300 mg. METHODOLOGY: A randomized open-label crossover study was performed in 33 healthy adult volunteers to determine the pharmacokinetic (clopidogrel and clopidogrel H4 thiol active metabolite) and the PD (vasodilator-stimulated phosphoprotein [VASP]) effects of MDCO-157 at doses of 75, 150, and 300 mg and of oral clopidogrel 300 mg. RESULTS: Data are presented as %, mean (standard deviation). The maximum effect of P2Y12 receptor inhibition assessed by flow cytometry using VASP was 70.42 (6.7), 69.45 (7.1), and 65.58 (12.6) for intravenous MDCO-157 at doses of 75, 150, and 300 mg, respectively, compared with 56.6 (17.5) with oral clopidogrel 300 mg administration (p < 0.0001). Intravenous administration of MDCO-157 led to a stepwise increase in plasma exposure of clopidogrel, higher than with administration of an oral dose of 300 mg (p < 0.0001). Plasma exposure of H4-thiol also increased with intravenous dose (3.6 ± 2.6, 6.9 ± 4.6, and 12.4 ± 9.1 h·ng/ml for intravenous 75, 150, and 300 mg, respectively) but was lower than with oral administration of a 300-mg dose (34.0 ± 16.0 h.ng/ml; pairwise p < 0.0001). CONCLUSIONS: MDCO-157, an intravenous formulation of clopidogrel complexed with sulphobutylether betacyclodextrin, did not show significant platelet inhibition when administered at doses up to 300 mg. Higher doses with longer infusion may be needed to reach a sufficient threshold of active metabolite generation. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01860105.
Assuntos
Inibidores da Agregação Plaquetária/administração & dosagem , Agregação Plaquetária/efeitos dos fármacos , Antagonistas do Receptor Purinérgico P2Y/administração & dosagem , Ticlopidina/análogos & derivados , Administração Oral , Adulto , Clopidogrel , Estudos Cross-Over , Relação Dose-Resposta a Droga , Feminino , Citometria de Fluxo , Humanos , Infusões Intravenosas , Masculino , Inibidores da Agregação Plaquetária/farmacocinética , Inibidores da Agregação Plaquetária/farmacologia , Antagonistas do Receptor Purinérgico P2Y/farmacocinética , Antagonistas do Receptor Purinérgico P2Y/farmacologia , Ticlopidina/administração & dosagem , Ticlopidina/farmacocinética , Ticlopidina/farmacologia , Adulto Jovem , beta-Ciclodextrinas/químicaRESUMO
BACKGROUND: Recent studies have suggested that ticagrelor 90mg twice daily provides stronger platelet inhibition than prasugrel 10mg once daily in acute coronary syndrome patients undergoing percutaneous coronary intervention. OBJECTIVES: To compare the effects of ticagrelor 90 mg twice daily and prasugrel 10mg once daily on platelet reactivity in patients with ST-segment elevation myocardial infarction (STEMI), using: the VerifyNow(®) P2Y12 (VN-P2Y12) assay, expressed in P2Y12 reaction units (PRU); measurement of the vasodilator-stimulated phosphoprotein platelet reactivity index (VASP-PRI; %); and light transmission aggregometry (LTA), expressed as residual platelet aggregation (RPA; %). METHODS: Platelet reactivity was evaluated prospectively using the three assays 30 days after primary PCI in 118 patients with STEMI on a maintenance dose of prasugrel 10mg once daily (n=60) or ticagrelor 90mg twice daily (n=58). RESULTS: On-treatment platelet reactivity, assessed by the VN-P2Y12 assay, was lower for ticagrelor compared with prasugrel (20.91 ± 4.59 PRU vs. 43.50±6.98 PRU; P=0.008) but was not significantly different when using the more specific VASP-PRI assay (13.05 ± 1.61% vs. 17.44 ± 1.97%; P=0.09) or RPA assessed by LTA (10.49 ± 1.44% vs. 7.20 ± 1.27%; P=0.09). CONCLUSIONS: The difference in platelet reactivity between ticagrelor and prasugrel varies according to the platelet function test in patients with STEMI. The differences observed may be related more to the tests than to the drugs used.
Assuntos
Adenosina/análogos & derivados , Plaquetas/efeitos dos fármacos , Infarto do Miocárdio/terapia , Intervenção Coronária Percutânea , Inibidores da Agregação Plaquetária/administração & dosagem , Cloridrato de Prasugrel/administração & dosagem , Antagonistas do Receptor Purinérgico P2Y/administração & dosagem , Adenosina/administração & dosagem , Plaquetas/metabolismo , Moléculas de Adesão Celular/sangue , Esquema de Medicação , Feminino , Humanos , Masculino , Proteínas dos Microfilamentos/sangue , Pessoa de Meia-Idade , Infarto do Miocárdio/sangue , Infarto do Miocárdio/diagnóstico , Intervenção Coronária Percutânea/efeitos adversos , Fosfoproteínas/sangue , Agregação Plaquetária/efeitos dos fármacos , Testes de Função Plaquetária , Valor Preditivo dos Testes , Estudos Prospectivos , Receptores Purinérgicos P2Y12/sangue , Receptores Purinérgicos P2Y12/efeitos dos fármacos , Ticagrelor , Fatores de Tempo , Resultado do TratamentoRESUMO
AIMS: The potential negative metabolic interaction between proton pump inhibitors and clopidogrel is an unsolved issue. We hypothesized that doubling the clopidogrel maintenance dose (150 mg) would be less effective than switching to prasugrel 10 mg maintenance dose (MD) to overcome this negative interaction. METHOD AND RESULTS: In a randomized study with a factorial design, 82 stable coronary artery disease patients treated with 75 mg clopidogrel MD and aspirin were assigned to receive in a double blind fashion lansoprazole (30 mg/day) or placebo and to receive in an open fashion 150 mg clopidogrel MD or 10 mg prasugrel MD. The primary endpoint was the relative change in residual platelet reactivity over the 14-day study period [(RPA14day-RPAbaseline)/RPAbaseline]. The effect of doubling the clopidogrel MD on relative change in RPA was neutralized by lansoprazole (-53.6±48.4% versus +0.8±53.7% without and with lansoprazole, respectively, p = 0.02) whereas 10 mg of prasugrel MD dramatically reduced RPA irrespective of lansoprazole co-administration (-81.8 %±24.8% vs. -72.9%±32.9% without and with lansoprazole, respectively, p = NS). Lansoprazole exposure was the only parameter with a significant interaction with RPA among subgroups. CONCLUSION: The higher platelet inhibitory effect obtained by doubling the clopidogrel MD was totally neutralized by the co-administration of lansoprazole. This drug interaction was not observed with prasugrel 10 mg.
Assuntos
Antiulcerosos/administração & dosagem , Lansoprazol/administração & dosagem , Piperazinas/administração & dosagem , Inibidores da Agregação Plaquetária/administração & dosagem , Antagonistas do Receptor Purinérgico P2Y/administração & dosagem , Tiofenos/administração & dosagem , Ticlopidina/análogos & derivados , Adulto , Idoso , Aspirina/administração & dosagem , Clopidogrel , Doença da Artéria Coronariana/tratamento farmacológico , Método Duplo-Cego , Interações Medicamentosas , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Ativação Plaquetária/efeitos dos fármacos , Cloridrato de Prasugrel , Receptores Purinérgicos P2Y12 , Ticlopidina/administração & dosagemRESUMO
OBJECTIVES: This study sought to determine whether red blood cell (RBC) transfusion increases in vivo platelet aggregation and inflammation in coronary and noncoronary patients. BACKGROUND: RBC transfusion increases in vitro platelet activation and aggregation in healthy volunteers, providing a possible explanation for the increase in recurrent ischemic events and mortality reported after RBC transfusion in patients with acute coronary syndromes (ACS). METHODS: Platelet reactivity was measured before and after RBC transfusion in 61 patients (33 with ACS patients and 28 without ACS). Relative changes between baseline and post-transfusion measurements of maximal and residual platelet aggregation were considered with different agonists as well as changes in vasodilator-stimulated phosphoprotein platelet reactivity index and P-selectin expression. Inflammatory and thrombotic biomarkers were also measured before and after transfusion. RESULTS: After RBC transfusion, platelet reactivity was increased when measured using adenosine diphosphate-induced light transmission aggregometry (11.6% relative increase in maximal platelet aggregation, p = 0.004; 10.8% increase in residual platelet aggregation, p = 0.005) and vasodilator-stimulated phosphoprotein platelet reactivity index (20.7% relative increase, p = 0.002), and there was a nonsignificant trend toward an increase in P-selectin expression. Similar results were found with the nonspecific agonist thrombin receptor-activated peptide (relative increases of 11.7% for maximal platelet aggregation, p = 0.04, and 12.7% for residual platelet aggregation, p = 0.02) but not with collagen or arachidonic acid agonists. There were no significant differences in inflammatory and thrombotic biomarkers before and after transfusion. CONCLUSIONS: After RBC transfusion, there is an increase in platelet reactivity, especially with tests measuring the adenosine diphosphate-P2Y12 receptor pathway, without significant variations in inflammatory or thrombotic biomarkers. This in vivo effect may account for the excess of ischemic events observed in the context of patients with ACS treated using percutaneous coronary intervention and P2Y12 inhibitors.
Assuntos
Anemia/terapia , Doença da Artéria Coronariana/complicações , Transfusão de Eritrócitos/métodos , Citometria de Fluxo/métodos , Agregação Plaquetária/fisiologia , Idoso , Anemia/sangue , Anemia/complicações , Doença da Artéria Coronariana/sangue , Estudos Transversais , Feminino , Seguimentos , Humanos , Masculino , Ativação Plaquetária , Testes de Função Plaquetária , Estudos Prospectivos , Resultado do TratamentoRESUMO
The FXIII-A Leu34 genetic variant increases and accelerates fibrin stabilisation; however, its association with premature coronary artery disease (CAD) and thrombotic events remains controversial. FXIII Val34Leu genotype was determined in 242 young individuals (<45 years old) who survived a myocardial infarction (MI) and 242 healthy controls matched for age and gender. We evaluated its effect on long-term clinical outcome defined as a composite of cardiovascular death, recurrent MI and urgent revascularisation. In addition, fibrin clot stiffness (elastic modulus or EM) and response to rt-PA-mediated fibrinolysis (fibrinolysis rate) were measured ex vivo using the Hemodyne analyser and confocal microscopy as surrogate endpoint. FXIII-A Leu34 genetic variant was not associated with premature CAD (adj. odds ratio 0.83 [0.49-1.4]) nor did it influence clinical outcome in patients, during a median follow-up of 6.3 (± 2.4) years. Patients produced stiffer fibrin clots (median [IQR] EM = 20.3 [14.9-28.1] vs. 12.8 [9.6-17.1] kdynes/cm²; p<0.0001) and displayed reduced response to fibrinolysis with lower fibrinolysis rate (6.7 [3.4-11.0] vs. 9.0 [5.0-16.7] sec-¹ x 10(-4); p<0.0001) than healthy controls. Carriage of factor XIII-A Leu34 led to a stepwise decrease in fibrinolysis rate with a significant gene-dose-effect in patients (7.7 [4.1-12.2] vs. 4.8 [3.0-8.5] vs. 4.3 [2.4-8.1] sec-¹ x 10(-4), for wild-type, heterozygous and homozygous, p for trend = 0.003) and a non-significant trend in controls (p = 0.01). In conclusion, FXIII-A Leu34 is a polymorphism which provides a strong resistance to fibrinolysis with a gene-dose effect, but does not relate to premature CAD or to recurrent coronary events in this study.
Assuntos
Fatores Etários , Doença da Artéria Coronariana/genética , Fator XIII/genética , Adulto , Estudos de Casos e Controles , Doença da Artéria Coronariana/epidemiologia , Doença da Artéria Coronariana/mortalidade , Doença da Artéria Coronariana/fisiopatologia , Trombose Coronária , Análise Mutacional de DNA , Feminino , Seguimentos , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Hemodinâmica , Humanos , Leucina/genética , Masculino , Infarto do Miocárdio , Polimorfismo Genético , Recidiva , Análise de SobrevidaRESUMO
OBJECTIVES: This study sought to determine whether the pharmacokinetic (PK) and pharmacodynamic (PD) responses to high or standard clopidogrel loading doses (LDs) differ according to CYP2C19*2 allele. BACKGROUND: CYP2C19 loss-of-function alleles are associated with reduced responsiveness to standard clopidogrel doses. METHODS: Young post-myocardial infarction patients heterozygous (wild type [wt]/*2, n = 43) or homozygous (*2/*2, n = 8) for the CYP2C19*2 genetic variant were matched with patients not carrying the variant (wt/wt, n = 58). All patients were randomized to a 300- or 900-mg clopidogrel LD. The relative reduction in residual platelet aggregation (RR-RPA, %) and the area under the plasma concentration time curve of active metabolite from baseline to 6 h after loading (AUC(0-6)) were compared according to both LD and CYP2C19*2 carriage. RESULTS: The 300-mg LD led to a gene-dose effect for RR-RPA (-65.7% ± 35.9% in wt/wt vs. -48.0% ± 38.4% in wt/*2 vs. -14.6% ± 32.4% in *2/*2; overall p value = 0.003, p = 0.03 for wt/wt versus wt/*2, p = 0.04 for wt/*2 versus *2/*2) with minor effect in *2/*2 carriers. After the 900-mg LD, the effect of the CYP2C19*2 variant on platelet inhibition was fully compensated in wt/*2 carriers but not in *2/*2 carriers (-83.6% ± 25.8% in wt/wt vs.-77.2% ± 26.9% in wt/*2 vs. -29.5% ± 26.8% in *2/*2; overall p value = 0.0003, p = 0.20 for wt/wt versus wt/*2, p < 0.001 for wt/*2 versus *2/*2). A similar pattern was observed for the active metabolite AUC(0-6) according to carriage of CYP2C19*2 for both LDs. There was a significant correlation between PK and PD responses irrespective of the LD. CONCLUSIONS: Carriers of CYP2C19*2 display significantly lower responses to clopidogrel with a gene-dose effect. Clopidogrel resistance can be overcome by increasing the dose in heterozygous carriers but not in homozygous carriers. (Clopidogrel and Response Variability Investigation Study 2 [CLOVIS-2]; NCT00822666).
Assuntos
Angioplastia Coronária com Balão , Hidrocarboneto de Aril Hidroxilases/metabolismo , Ponte de Artéria Coronária , Resistência a Medicamentos , Infarto do Miocárdio/terapia , Inibidores da Agregação Plaquetária/administração & dosagem , Agregação Plaquetária/efeitos dos fármacos , Ticlopidina/análogos & derivados , Difosfato de Adenosina , Adulto , Angioplastia Coronária com Balão/efeitos adversos , Hidrocarboneto de Aril Hidroxilases/genética , Clopidogrel , Ponte de Artéria Coronária/efeitos adversos , Estudos Cross-Over , Citocromo P-450 CYP2C19 , Relação Dose-Resposta a Droga , Resistência a Medicamentos/genética , Feminino , França , Dosagem de Genes , Heterozigoto , Homozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/sangue , Fenótipo , Inibidores da Agregação Plaquetária/farmacocinética , Testes de Função Plaquetária , Valor Preditivo dos Testes , Estudos Prospectivos , Sistema de Registros , Medição de Risco , Fatores de Risco , Ticlopidina/administração & dosagem , Ticlopidina/farmacocinética , Resultado do TratamentoRESUMO
OBJECTIVES: This study evaluated the ability of the bedside test Hemochron Jr. Hemonox (International Technidyne Corporation, Edison, New Jersey) to identify patients with insufficient anti-Xa activity level in the catheterization laboratory. BACKGROUND: Inadequate anticoagulation in patients undergoing percutaneous coronary intervention (PCI) is associated with increased periprocedural ischemic events. METHODS: In 296 unselected patients undergoing catheterization and/or PCI, whole blood Hemonox clotting time (CT) and activated partial thromboplastin time (aPTT) were measured at baseline (T1) and 10 min after the intravenous administration of enoxaparin (T2) in patients receiving additional enoxaparin and compared with plasma chromogenic anti-Xa activity level. RESULTS: Median values were 0.1 IU/ml (interquartile range [IQR]: 0.1 to 0.1 IU/ml) and 0.87 IU/ml (IQR: 0.74 to 1.03 IU/ml) for anti-Xa; 74 s (IQR: 70 to 81 s) and 143 s (IQR: 114 to 206 s) for Hemonox CT; and 44 s (IQR: 39 to 50 s) and 72 s (IQR: 58 to 93 s) for aPTT at T1 and T2, respectively. When using Hemonox CT to discriminate patients with anti-Xa level <0.5 IU/ml, the area under the receiver operating characteristic curve was 0.95 +/- 0.01 (95% confidence interval [CI]: 0.93 to 0.97) versus 0.89 +/- 0.01 (95% CI: 0.86 to 0.92) for aPTT. The threshold value of 120 s was associated with a 94.9% (95% CI: 91.1% to 97.4%) sensitivity and a 73.3% (95% CI: 67.6% to 78.5%) specificity to detect patients with inadequate anti-Xa level (<0.5 IU/ml) and positive predictive and negative predictive values of 73.9% (95% CI: 68.7% to 79.0%) and 94.78% (95% CI: 91.8% to 97.8%), respectively. CONCLUSIONS: Hemonox CT appears to be a fast and reliable bedside test for detecting patients insufficiently anticoagulated and needing adjustment of anticoagulation therapy with enoxaparin before PCI.