RESUMO
BACKGROUND: Effective treatments for patients with primary biliary cholangitis are limited. Seladelpar, a peroxisome proliferator-activated receptor delta agonist, has potential benefits. METHODS: In this phase 3, 12-month, double-blind, placebo-controlled trial, we randomly assigned (in a 2:1 ratio) patients who had had an inadequate response to or who had a history of unacceptable side effects with ursodeoxycholic acid to receive oral seladelpar at a dose of 10 mg daily or placebo. The primary end point was a biochemical response, which was defined as an alkaline phosphatase level less than 1.67 times the upper limit of the normal range, with a decrease of 15% or more from baseline, and a normal total bilirubin level at month 12. Key secondary end points were normalization of the alkaline phosphatase level at month 12 and a change in the score on the pruritus numerical rating scale (range, 0 [no itch] to 10 [worst itch imaginable]) from baseline to month 6 among patients with a baseline score of at least 4 (indicating moderate-to-severe pruritus). RESULTS: Of the 193 patients who underwent randomization and treatment, 93.8% received ursodeoxycholic acid as standard-of-care background therapy. A greater percentage of the patients in the seladelpar group than in the placebo group had a biochemical response (61.7% vs. 20.0%; difference, 41.7 percentage points; 95% confidence interval [CI], 27.7 to 53.4, P<0.001). Normalization of the alkaline phosphatase level also occurred in a greater percentage of patients who received seladelpar than of those who received placebo (25.0% vs. 0%; difference, 25.0 percentage points; 95% CI, 18.3 to 33.2, P<0.001). Seladelpar resulted in a greater reduction in the score on the pruritus numerical rating scale than placebo (least-squares mean change from baseline, -3.2 vs. -1.7; least-squares mean difference, -1.5; 95% CI, -2.5 to -0.5, P = 0.005). Adverse events were reported in 86.7% of the patients in the seladelpar group and in 84.6% in the placebo group, and serious adverse events in 7.0% and 6.2%, respectively. CONCLUSIONS: In this trial involving patients with primary biliary cholangitis, the percentage of patients who had a biochemical response and alkaline phosphatase normalization was significantly greater with seladelpar than with placebo. Seladelpar also significantly reduced pruritus among patients who had moderate-to-severe pruritus at baseline. The incidence and severity of adverse events were similar in the two groups. (Funded by CymaBay Therapeutics; RESPONSE ClinicalTrials.gov number, NCT04620733; EudraCT number, 2020-004348-27.).
Assuntos
Acetatos , Fármacos Gastrointestinais , Cirrose Hepática Biliar , Humanos , Acetatos/administração & dosagem , Acetatos/efeitos adversos , Acetatos/uso terapêutico , Fosfatase Alcalina/sangue , Método Duplo-Cego , Cirrose Hepática Biliar/sangue , Cirrose Hepática Biliar/complicações , Cirrose Hepática Biliar/tratamento farmacológico , Prurido/etiologia , Prurido/tratamento farmacológico , Resultado do Tratamento , Ácido Ursodesoxicólico/efeitos adversos , Ácido Ursodesoxicólico/uso terapêutico , PPAR delta/agonistas , Administração Oral , Bilirrubina/sangue , Fármacos Gastrointestinais/administração & dosagem , Fármacos Gastrointestinais/efeitos adversos , Fármacos Gastrointestinais/uso terapêutico , Colagogos e Coleréticos/administração & dosagem , Colagogos e Coleréticos/efeitos adversos , Colagogos e Coleréticos/uso terapêuticoRESUMO
AIMS: Huntington's disease (HD) is a neurodegenerative disease with cognitive, motor and psychiatric symptoms. Toxic accumulation of misfolded mutant huntingtin protein induces mitochondrial dysfunction, leading to a bioenergetic insufficiency in neuronal and muscle cells. We evaluated the safety, pharmacokinetics and pharmacodynamics of SBT-020, a novel compound to improve mitochondrial function, in a 2-part study in early stage HD patients. METHODS: Part 1 consisted of 7-day multiple ascending dose study to select the highest tolerable dose for Part 2, a 28-day multiple dose study. Mitochondrial function was measured in the visual cortex and calf muscle, using phosphorous magnetic resonance spectroscopy, and in circulating peripheral blood mononuclear cells. RESULTS: Treatment-emergent adverse events were mild and more present in the SBT-020 group. Injection site reactions occurred in 91% in Part 1 and 97% in Part 2. Mitochondrial function in calf muscle, peripheral blood mononuclear cells or visual cortex was not changed overall due to treatment with SBT-020. In a posthoc analysis, patients with a higher degree of mitochondrial dysfunction (below the median [∆Ψm < 3412 and τPCr > 42.5 s]) showed more improvement than patients with a relatively lower level of mitochondrial dysfunction. CONCLUSION: SBT-020 was safe at all doses, but no significant differences in any of the pharmacodynamic measurements between the treatment groups and placebo group could be demonstrated. The data suggest that the better than expected mitochondrial function in our patient population at baseline might explain the lack of effect of SBT-020.
Assuntos
Doença de Huntington , Doenças Neurodegenerativas , Humanos , Doença de Huntington/tratamento farmacológico , Leucócitos Mononucleares , Imageamento por Ressonância MagnéticaRESUMO
Late-acquired stent malapposition (LASM) is a common finding after sirolimus-eluting stent (SES) implantation and may be the cause for late stent thrombosis. Inflammation may play a pivotal role in LASM just as it plays in stent restenosis. We have therefore investigated seven polymorphisms involved in inflammatory processes, related in previous reports to restenosis, on the risk of LASM in SES patients. Patients with ST-elevation myocardial infarction who underwent SES implantation and had intravascular ultrasonography (IVUS) data available for both immediate post-intervention and 9-month follow-up were included in the present study. In total, 104 patients from the MISSION! Intervention Study were genotyped for the caspase-1 5352 G/A, eotaxin 1382 A/G, CD14 260 A/G, colony stimulating factor 2 1943 C/T, IL10 -1117 C/T, IL10 4251 C/T, and the tumor necrosis factor alpha 1211 C/T polymorphisms. LASM occurred in 26/104 (25%) of patients. We found a significantly higher risk for LASM in patients carrying the caspase-1 (CASP1) 5352 A allele (RR = 2.32; 95% CI 1.22-4.42). In addition, mean neointimal growth was significantly lower in patients carrying this LASM risk allele (1.6 vs. 4.1%, p = 0.014). The other six polymorphisms related to inflammation were not significantly related to the risk of LASM. In conclusion, carriers of the 5352 A allele in the caspase-1 gene are at increased risk of developing LASM after SES implantation. If this is confirmed in larger studies, then screening for this polymorphism in patients undergoing percutaneous coronary interventions could eventually help cardiologists to better select between commercially available stents.
Assuntos
Angioplastia Coronária com Balão/efeitos adversos , Angioplastia Coronária com Balão/instrumentação , Fármacos Cardiovasculares/administração & dosagem , Caspase 1/genética , Stents Farmacológicos , Mediadores da Inflamação , Inflamação/genética , Infarto do Miocárdio/terapia , Sirolimo/administração & dosagem , Idoso , Distribuição de Qui-Quadrado , Feminino , Frequência do Gene , Predisposição Genética para Doença , Humanos , Inflamação/diagnóstico por imagem , Inflamação/enzimologia , Inflamação/imunologia , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/diagnóstico por imagem , Infarto do Miocárdio/enzimologia , Infarto do Miocárdio/genética , Países Baixos , Estudos Prospectivos , Medição de Risco , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Ultrassonografia de IntervençãoRESUMO
AIMS: Late stent malapposition (LSM) may be acquired (LASM) or persistent. LSM may play a role in patients who develop late stent thrombosis (ST). Our objective was to compare the risk of LASM in bare metal stents (BMS) with drug-eluting stents (DES) and to investigate the possible association of both acquired and persistent LSM with (very) late ST. METHODS AND RESULTS: We searched PubMed and relevant sources from January 2002 to December 2007. Inclusion criteria were: (a) intra-vascular ultrasonography (IVUS) at both post-stent implantation and follow-up; (b) 6-9-month-follow-up IVUS; (c) implantation of either BMS or the following DES: sirolimus, paclitaxel, everolimus, or zotarolimus; and (d) follow-up for LSM. Of 33 articles retrieved for detailed evaluation, 17 met the inclusion criteria. The risk of LASM in patients with DES was four times higher compared with BMS (OR = 4.36, CI 95% 1.74-10.94) in randomized clinical trials. The risk of (very) late ST in patients with LSM (five studies) was higher compared with those without LSM (OR = 6.51, CI 95% 1.34-34.91). CONCLUSION: In our meta-analysis, the risk of LASM is strongly increased after DES implantation compared with BMS. Furthermore, LSM seems to be associated with late and very late ST.
Assuntos
Falha de Prótese/efeitos adversos , Stents/efeitos adversos , Idoso , Doença da Artéria Coronariana/terapia , Stents Farmacológicos/efeitos adversos , Feminino , Oclusão de Enxerto Vascular , Humanos , Masculino , Pessoa de Meia-Idade , Paclitaxel/administração & dosagem , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de Risco , Sirolimo/administração & dosagem , Moduladores de Tubulina/administração & dosagemRESUMO
OBJECTIVES: Our aim was to evaluate the effects of early abciximab administration in the ambulance on immediate, short, and long term outcomes. BACKGROUND: Early abciximab administration before primary percutaneous coronary intervention (PPCI) for ST-segment elevation myocardial infarction (STEMI) is recommended in practice guidelines. However, optimal timing of administration remains indistinct. METHODS: Within a fixed protocol for PPCI, December 2006 was the cut-off point for this prospective study. A total of 179 consecutive patients with STEMI were enrolled, 90 patients received abciximab bolus in the hospital (in-hospital group), and 89 patients received abciximab bolus in the ambulance (in-ambulance group). RESULTS: The two groups were comparable for baseline and angiographic characteristics. The in-ambulance group received abciximab within the golden period (median 63 min). The infarct related artery (IRA) patency at onset of the PCI was four times higher in the in-ambulance group compared to in-hospital group (odds ratio = 4.9, 95% CI 2.4-10.1). Enzymatic infarct size was smaller in the in-ambulance group (cumulative 48-h CK release 8011 vs. 11267 U/L, P = 0.004). This was associated with higher left ventricular ejection fraction (LVEF) at 90 days post-PPCI measured by myocardial scintigraphy (59% vs. 54%, P = 0.01), and lower incidence of heart failure through a median of 210 days of clinical follow-up (3% vs.11%, P = 0.04). CONCLUSION: Early abciximab administration in the ambulance significantly improves early reperfusion in STEMI patients treated with PPCI. Moreover this is associated with a smaller infarct size, improved LV function and a lower risk of heart failure on clinical follow-up.
Assuntos
Ambulâncias , Angioplastia Coronária com Balão , Anticorpos Monoclonais/administração & dosagem , Serviços Médicos de Emergência , Insuficiência Cardíaca/prevenção & controle , Fragmentos Fab das Imunoglobulinas/administração & dosagem , Infarto do Miocárdio/terapia , Miocárdio/patologia , Inibidores da Agregação Plaquetária/administração & dosagem , Função Ventricular Esquerda/efeitos dos fármacos , Abciximab , Idoso , Protocolos Clínicos , Angiografia Coronária , Esquema de Medicação , Eletrocardiografia , Feminino , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/patologia , Insuficiência Cardíaca/fisiopatologia , Hospitalização , Humanos , Incidência , Infusões Intravenosas , Injeções Intravenosas , Modelos Lineares , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/complicações , Infarto do Miocárdio/patologia , Infarto do Miocárdio/fisiopatologia , Imagem de Perfusão do Miocárdio , Países Baixos/epidemiologia , Razão de Chances , Avaliação de Programas e Projetos de Saúde , Estudos Prospectivos , Medição de Risco , Volume Sistólico/efeitos dos fármacos , Fatores de Tempo , Resultado do Tratamento , Grau de Desobstrução VascularRESUMO
OBJECTIVES: Stent thrombosis is a life-threatening complication associated with sudden death and acute myocardial infarction. Histopathologic studies have linked the occurrence of very late stent thrombosis in drug-eluting stents (DES) with delayed endothealisation and stent malapposition. Our aim was to investigate if late stent malapposition in DES could be predicted by immediate postintervention intra-vascular ultrasonography (IVUS). METHODS AND RESULTS: From our MISSION! database of 184 consecutive patients with ST-elevation myocardial infarction (STEMI) who had immediate post-intervention and nine-month follow-up IVUS examinations we prospectively identified three patients with very late (> 365 days) and definite (with angiographic evidence) in-stent thrombosis in DES. Patients had completed the twelve-month clopidogrel-aspirin dual treatment period, two of them were under aspirin therapy while the third patient had aspirin temporarily discontinued before planned surgery. When assessed by serial documentary (immediate post-intervention and nine-month) IVUS, all three patients demonstrated stent malapposition at nine months: in two cases the malapposition was acquired (immediate post-intervention IVUS showed a well apposed stent) and one case presented persistent malapposition (the stent was found malapposed both at immediate post-intervention and nine-month follow-up IVUS). CONCLUSIONS: Immediate post-intervention IVUS showing no malapposition does not guarantee an uneventful course after DES implantation.
Assuntos
Angioplastia Coronária com Balão/efeitos adversos , Trombose Coronária/diagnóstico por imagem , Stents Farmacológicos/efeitos adversos , Infarto do Miocárdio/cirurgia , Ultrassonografia de Intervenção/métodos , Adulto , Idoso de 80 Anos ou mais , Angiografia Coronária , Trombose Coronária/etiologia , Eletrocardiografia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/diagnóstico , Valor Preditivo dos Testes , Falha de Prótese , Fatores de TempoRESUMO
AIM: To examine whether the velocity of saccadic eye movements in internuclear ophthalmoparesis (INO) improves with fampridine treatment in patients with multiple sclerosis (MS). METHODS: Randomized, double-blind, placebo-controlled, cross-over trial with fampridine in patients with MS and INO. Horizontal saccades were recorded at baseline and at multiple time points post-dose. Main outcome measures were the change of peak velocity versional dysconjugacy index (PV-VDI) and first-pass amplitude VDI (FPA-VDI). Both parameters were compared between fampridine and placebo using a mixed model analysis of variance taking patients as their own control. Pharmacokinetics was determined by serial blood sampling. RESULTS: Thirteen patients had a bilateral and 10 had a unilateral INO. One patient had an INO of abduction (posterior INO of Lutz) and was excluded. Fampridine significantly reduced both PV-VDI (-17.4%, 95% CI: -22.4%, -12.1%; P < 0.0001) and FPA-VDI (-12.5%, 95% CI: -18.9%, -5.5%; P < 0.01). Pharmacokinetics demonstrated that testing coincided with the average tmax at 2.08 hours (SD 45 minutes). The main adverse event reported after administration of fampridine was dizziness (61%). CONCLUSION: Fampridine improves saccadic eye movements due to INO in MS. Treatment response to fampridine may gauge patient selection for inclusion to remyelination strategies in MS using saccadic eye movements as primary outcome measure.
Assuntos
4-Aminopiridina/uso terapêutico , Esclerose Múltipla/complicações , Oftalmoplegia/tratamento farmacológico , Bloqueadores dos Canais de Potássio/uso terapêutico , 4-Aminopiridina/sangue , 4-Aminopiridina/farmacocinética , Adulto , Idoso , Estudos Cross-Over , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/sangue , Esclerose Múltipla/tratamento farmacológico , Oftalmoplegia/sangue , Oftalmoplegia/etiologia , Bloqueadores dos Canais de Potássio/sangue , Bloqueadores dos Canais de Potássio/farmacocinética , Movimentos Sacádicos/efeitos dos fármacos , Resultado do TratamentoRESUMO
Serum troponin within the normal range is an emerging predictor of cardiovascular mortality. We aimed to determine how rapidly high-sensitivity troponin-I (hs-cTnI) levels are lowered by statin therapy in patients with stable cardiovascular disease. In the RADAR substudy, patients were randomized to atorvastatin 20 mg/day (n = 39) or rosuvastatin 10 mg/day (n = 39) and up-titrated at 6-week intervals to 80 mg of atorvastatin or 40 mg of rosuvastatin. Hs-cTnI concentrations were measured at baseline and at 6 and 18 weeks of follow-up. Statin treatment resulted in a mean change of serum hs-cTnI of -8.2% (P = 0.010) after 6 weeks and -12.3% (P = 0.001) after 18 weeks. After 18 weeks, hs-cTnI levels were lowered by 21.8% with atorvastatin and by 4.1% with rosuvastatin (P = 0.001 and P = 0.133, respectively). During statin therapy, serum hs-cTnI levels decreased rapidly within weeks of treatment, suggesting an effect beyond long-term atherosclerosis regression. Mechanisms that mediate this effect require further study.
Assuntos
Atorvastatina/uso terapêutico , Doenças Cardiovasculares/tratamento farmacológico , Dislipidemias/tratamento farmacológico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Rosuvastatina Cálcica/uso terapêutico , Troponina I/sangue , Idoso , Atorvastatina/efeitos adversos , Biomarcadores/sangue , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/diagnóstico , Regulação para Baixo , Dislipidemias/sangue , Dislipidemias/diagnóstico , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Masculino , Pessoa de Meia-Idade , Países Baixos , Estudos Prospectivos , Rosuvastatina Cálcica/efeitos adversos , Fatores de Tempo , Resultado do TratamentoRESUMO
Biomarkers for primary or secondary risk prediction of cardiovascular disease (CVD) are urgently needed to improve individual treatment and clinical trial design. The vast majority of biomarker discovery studies has concentrated on plasma/serum as an easily accessible source. Although numerous markers have been identified, their added predictive value on top of traditional risk factors has been limited, as the biological specimen does not specifically reflect expression profiles related with CVD progression and because the signal is often diluted by marker release from other organs. In contrast to serum markers, circulating cells serve as indicators of the actual disease state due to their active role in the pathogenesis of CVD and are responsible for the majority of secreted biomarkers. Therefore, the CIRCULATING CELLS study was initiated, focusing on the cellular effectors of atherosclerosis in the circulation. In total, 714 patients with coronary artery disease (CAD) symptoms were included. Blood cell fractions (monocytes, T-lymphocytes, platelets, granulocytes, PBMC) of all individual patients were isolated and stored for analysis. Concomitantly, extensive flow cytometric characterization of these populations was performed. From each patient, a detailed clinical profile together with extensive questionnaires about medical history and life style was obtained. Various high-throughput -omics approaches (protein, mRNA, miRNA) are currently being undertaken. Data will be integrated with advanced bioinformatics for discovery and validation of secondary risk markers for adverse events. Overall, the CIRCULATING CELLS study grants the interesting possibility that it will both identify novel biomarkers and provide useful insights into the pathophysiology of CAD in patients.
Assuntos
Aterosclerose/fisiopatologia , Células Sanguíneas/citologia , Doenças Cardiovasculares/fisiopatologia , Doença da Artéria Coronariana/fisiopatologia , Idoso , Biomarcadores/metabolismo , Feminino , Citometria de Fluxo , Seguimentos , Ensaios de Triagem em Larga Escala , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de RiscoRESUMO
AIMS: Different biodegradable-polymer drug-eluting stents have not yet been systematically analysed. We sought to; 1) evaluate the risk of target lesion revascularisation (TLR) and definite stent thrombosis (DST) among different groups of biodegradable-polymer (BioPol) DES, and 2) to compare them with permanent polymer (PermPol) DES. METHODS AND RESULTS: We searched PubMed and relevant sources from January 2005 until October 2010. Inclusion criteria were (a) Implantation of a drug-eluting stent with biodegradable polymer; (b) available follow-up data for at least one of the clinical end-points (TLR/DST) at short term (30 days) and/or mid-term (one year). A total of 22 studies, including randomised and observational studies, with 8264 patients met the selection criteria; nine studies (2042 patients) in whom biodegradable-polymer sirolimus eluting stents (BioPol-SES) were implanted, eight studies (1731 patients) in whom biodegradable-polymer paclitaxel eluting stents (BioPol-PES) were implanted, and seven studies (4491 patients) in whom biodegradable-polymer biolimus-A9 eluting stents (BioPol-BES) were implanted. At 30 days, there was a higher risk of DST (p=0.04) and subsequently TLR (p=0.006) in the BioPol-BES compared to BioPol-SES, with no significant difference in the other stent comparisons. At 1-year, there was higher risk of TLR in the BioPol-PES (p=0.01), and the BioPol-SES (p=0.04) compared to BioPol-BES. One-year stent thrombosis was not statistically different between the studied groups (overall p=0.2). In another analysis comprising seven randomised trials comparing BioPol-DES (3778 patients) and PermPol-DES (3291 patients), the risks of TLR and stent thrombosis at 1-year were not significantly different (p=0.5 for both). CONCLUSIONS: Performance of different BioPol-DES seems to vary from each other. The short- and mid-term success rates may not be superimposable. Furthermore, they may not be necessarily better than PermPol-DES.
Assuntos
Angioplastia Coronária com Balão/instrumentação , Materiais Revestidos Biocompatíveis , Stents Farmacológicos , Polímeros , Idoso , Angioplastia Coronária com Balão/efeitos adversos , Animais , Medicina Baseada em Evidências , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Desenho de Prótese , Medição de Risco , Fatores de Risco , Trombose/etiologia , Fatores de Tempo , Resultado do TratamentoRESUMO
High Asymmetric Dimethylarginine (ADMA) levels are associated with increased platelet activity, elevated blood pressure, vasoconstriction and impaired vascular relaxation. We hypothesized that the myocardial infarction morning peak of occurrence is closely related to a morning peak of ADMA levels. We performed a cross-sectional study among patients with documented myocardial infarction who had been enrolled in the prospective MISSION! Intervention Study. In total, serum ADMA levels were measured in their acute setting of myocardial infarction in 120 patients. The frequency of myocardial infarction onset of symptoms and emergency coronary catheterization and the ADMA levels displayed a similar daily pattern with a morning peak between 06:00-11:59 h. The absolute ADMA levels peak was between 06:00-07:59 h with a median (interquartile range) peak value of 1.01 (0.84-1.21) µmol/L for the n=9 patients vs. 0.75 (0.61-0.89) µmol/L for the remaining 111 patients admitted throughout the rest of the 24-hour interval (p=0.003 for between groups comparison). The amplitude (95% 0.08 µmol/L (0.004-0.16) with p=0.042 for statistic model significance. In conclusion, ADMA levels display a 24-hour variation with a significant morning peak in patients with acute myocardial infarction. These findings may relate ADMA levels to the acute onset of thrombotic cardiovascular events.
Assuntos
Arginina/análogos & derivados , Ritmo Circadiano , Infarto do Miocárdio/metabolismo , Idoso , Arginina/sangue , Arginina/metabolismo , Biomarcadores/metabolismo , Pressão Sanguínea , Índice de Massa Corporal , Estudos Transversais , Feminino , Humanos , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/sangue , Óxido Nítrico Sintase/antagonistas & inibidores , Óxidos de Nitrogênio/metabolismo , Ativação Plaquetária , Fatores de TempoRESUMO
UNLABELLED: This paper contains detailed results of a sub-population of the prospective randomized RADAR (Rosuvastatin and Atorvastatin in different Dosages And Reverse cholesterol transport) study. OBJECTIVE: Statin treatment results in substantially decreased incidence of cardiovascular events but the exact pathophysiological mechanism of their beneficial effect is yet unclear. We aimed to examine the effects of up-titrated doses of two widely used statins (atorvastatin (ATOR) and rosuvastatin (ROSU)) on parameters involved in lipoprotein metabolism, in patients with low high density lipoprotein cholesterol values (HDL-C). RESEARCH DESIGN AND METHODS: In this RADAR substudy, 80 patients, aged 40-80 years, with known cardiovascular disease and low HDL-C (<1.0 mmol/l), were randomized to receive, after an initial 6 week dietary run-in phase, either ATOR 20 mg (n = 41) or ROSU 10 mg (n = 39). The doses were up-titrated (in 6 week intervals) to 80 mg of ATOR or 40 mg of ROSU at 12 weeks. Serum lipoproteins and lipoprotein metabolism parameters were measured at baseline and at 6 and 18 weeks of follow up. RESULTS: Both statins significantly reduced total cholesterol (TChol) and non-HDL-C values with ROSU being more effective for the doses studied (p < 0.05). No statistically significant effect on HDL-C was observed for either statin. Apolipoproteins (apo) B, CI, CIII, AV and E were significantly reduced in both groups (p < 0.05), while the ratio of HDL particles containing both apoAI and apoAII (LpAI-AII) over HDL containing apoAI alone (LpAI) was changed for both statins with the decrease of LpAI being more prominent in the ATOR group (p = 0.028). Cholesterol ester transfer protein (CETP) mass and activity, phospholipid transfer protein (PLTP) activity and lipoprotein-associated phospholipase A2 (Lp-PLA2) mass and activity were all significantly reduced in both treatment groups over the follow-up period (p < 0.001). ATOR displayed a more prominent decrease of PLTP activity compared to ROSU (p = 0.043), while ROSU displayed a more prominent decrease of Lp-PLA2 activity compared to ATOR (p = 0.04). Both statins effectively reduced, in a dose-dependent way, high sensitivity C-reactive protein values over time, while no effect on the levels of circulating inter cellular adhesion molecule 1 (cICAM-1) was observed. CONCLUSIONS: The effects of statin treatment extend further and beyond a mere TChol and LDL cholesterol reduction, as demonstrated by the aforementioned alterations of lipoproteins, enzymes and lipid transfer proteins involved in lipoprotein metabolism and pro-atherogenic and inflammatory molecules. ROSU and ATOR displayed a similar pattern of effect on lipid metabolism with discrete differences in the magnitude of this effect in certain variables. Despite the limitations of small population size and lack of clinical end points, reported data provide an insight for the possible pathophysiological mechanisms implicated in the effect of increasing dosages of different statin treatments.
Assuntos
Apolipoproteínas/sangue , Proteínas de Transporte/metabolismo , Enzimas/metabolismo , Fluorbenzenos/farmacologia , Ácidos Heptanoicos/farmacologia , Inflamação/metabolismo , Lipoproteínas/metabolismo , Pirimidinas/farmacologia , Pirróis/farmacologia , Sulfonamidas/farmacologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticolesterolemiantes/administração & dosagem , Anticolesterolemiantes/farmacologia , Apolipoproteínas/metabolismo , Atorvastatina , Relação Dose-Resposta a Droga , Feminino , Fluorbenzenos/administração & dosagem , Ácidos Heptanoicos/administração & dosagem , Humanos , Inflamação/sangue , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Pirimidinas/administração & dosagem , Pirróis/administração & dosagem , Rosuvastatina Cálcica , Sulfonamidas/administração & dosagemRESUMO
In acute myocardial infarction cardiac troponin-T (cTnT) is the preferred biomarker to detect myocardial necrosis. Our aim was to investigate the prognostic value of peak plasma cTnT in patients with ST-elevation myocardial infarction treated by primary percutaneous coronary intervention (PCI). Patients were eligible if ST-elevation myocardial infarction symptoms started <9 hours before the primary PCI. During the first 48 hours after primary PCI, cTnT and creatine kinase were measured repeatedly. Main outcome measures were left ventricular ejection fraction assessed by myocardial scintigraphy at 90 days, and clinical outcomes through 1-year follow-up after primary PCI in a dedicated outpatient clinic; 168 consecutive patients (79% men) with first ST-elevation myocardial infarction were studied. Mean age +/- SD was 59 +/- 12 years. Peak cTnT values were reached within 24 hours after primary PCI in all patients. The enzymatic infarct size, measured by cumulative 48-hours creatine kinase release, correlated positively with peak cTnT (r = 0.73, p <0.001). Left ventricular ejection fraction at 3 months was negatively correlated with peak cTnT (r = -0.52, p <0.001). A peak plasma cTnT > or = 6.5 microg/L predicted a left ventricular ejection fraction < or = 40% at follow-up with 86% sensitivity and 74% specificity. Multivariable Cox regression analysis identified peak cTnT as an independent predictor of major adverse cardiac events (hazard ratio 1.07, 95% confidence limits 1.01 to 1.12) and heart failure (hazard ratio 1.12, 95% confidence limits 1.05 to 1.20) during follow-up. In conclusion, peak cTnT after primary PCI for ST-elevation myocardial infarction offers a good estimation of infarct size and is a prognostic indicator in patients with first acute myocardial infarction.
Assuntos
Angioplastia Coronária com Balão , Infarto do Miocárdio/sangue , Infarto do Miocárdio/terapia , Troponina T/sangue , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/patologia , Valor Preditivo dos Testes , Prognóstico , Volume Sistólico , Resultado do TratamentoRESUMO
AIMS: To evaluate effects of sirolimus-eluting stents (SES) compared to bare-metal stents (BMS) at stent edges in patients with acute myocardial infarction (AMI). METHODS AND RESULTS: Clinical, angiographic, intravascular ultrasound (lVUS) and virtual histology (VH)-IVUS results were obtained and analysed in 20 SES and 20 BMS AMI patients at the index procedure and at nine months follow-up. Quantitative angiography and IVUS showed a trend toward decreases in mean lumen diameter, vessel volume, minimum lumen area and mean lumen area at both stent edges of BMS, and at the proximal edge of SES. At the distal stent edge, a significant difference between BMS and SES treated patients in mean lumen area was found (D-0.8+/-1.6 mm2 versus D0.2+/-0.8 mm2 respectively, p=0.04). Furthermore, in-stent SES had a larger lumen volume (SES: 167.7+/-59.2 mm3 versus BMS: 125.1+/-43.8 mm3; p=0.02) and less neointima volume (7.3+/-9.1 mm3 versus 53.2+/-35.1 mm3; p<0.001). Neither SES nor BMS demonstrated a significant effect on plaque composition at follow-up VH-IVUS analysis. CONCLUSIONS: A significant difference between SES and BMS treated patients was observed with respect to mean lumen diameter distal to the stented segment which suggests a downstream effect of sirolimus elution.
Assuntos
Angioplastia Coronária com Balão/instrumentação , Fármacos Cardiovasculares/administração & dosagem , Doença da Artéria Coronariana/terapia , Stents Farmacológicos , Metais , Infarto do Miocárdio/terapia , Sirolimo/administração & dosagem , Stents , Ultrassonografia de Intervenção , Adulto , Idoso , Angioplastia Coronária com Balão/efeitos adversos , Angiografia Coronária , Doença da Artéria Coronariana/complicações , Doença da Artéria Coronariana/diagnóstico por imagem , Feminino , Humanos , Hiperplasia , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/diagnóstico por imagem , Infarto do Miocárdio/etiologia , Desenho de Prótese , Fatores de Tempo , Resultado do TratamentoRESUMO
PAI-1 expression is regulated by a 4G/5G promoter polymorphism. The 4G allele is associated with greater circadian variation of PAI-1 levels. We hypothesized that the 24 h variation of cardiac risk is more pronounced among persons with the 4G4G genotype than among ones with 4G5G and 5G5G genotypes. We assessed the time of onset of symptoms in 623 consecutive patients with acute myocardial infarction (AMI) enrolled in the MISSION! Study between February 1, 2004, and October 29, 2006. All of the patients were genotyped for the PAI-1 4G/5G polymorphism. We quantified the amplitude of the 24 h variation of AMI with a generalized linear model with Poisson distribution. A morning peak, between 06:00-11:59 h (n = 197; 32% of all cases), in the onset of symptoms of AMI was observed. The group composed of patients with the 4G4G genotype did not have a more pronounced morning peak than the groups composed of other genotypes; the 24 h variation was 38% (95% confidence interval 12-70%) in the group of 4G4G patients and 34% (14-58%) and 56% (20-100%) in the 4G5G and 5G5G groups of patients, respectively. Our findings show that 24 h variation of cardiac risk is not more pronounced among the 4G4G genotype of PAI-1.
Assuntos
Ritmo Circadiano/genética , Infarto do Miocárdio/fisiopatologia , Inibidor 1 de Ativador de Plasminogênio/genética , Polimorfismo Genético , Ritmo Circadiano/fisiologia , Estudos de Coortes , Feminino , Genótipo , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/genética , Estudos RetrospectivosRESUMO
OBJECTIVE: Lipid profiling (lipidomics) may be useful in revealing detailed information with regard to the effects on lipid metabolism, the cardiovascular risk and to differentiate between therapies. The aims of the present study were to: (1) analyze in depth the lipid changes induced by rosuvastatin and atorvastatin at different dosages; (2) compare differences between the two drugs with respect to the lipid profile change; (3) relate the findings with meaningful pathological mechanisms of coronary artery disease. RESEARCH DESIGN AND METHODS: Liquid chromatography-mass spectrometry was applied to obtain the metabolite profiles of plasma samples taken from a prospectively defined subset (n=80) of participants in the RADAR study where a randomly assigned treatment with rosuvastatin or atorvastatin in increasing dosages was administered during an 18-week period. RESULTS: A number of sphingomyelins (SPMs) and phosphatidylcholines (PCs) correlate with the different effects of the two statins on the LDL-C/HDL-C ratio. Rosuvastatin increased the plasma concentration of PCs after 6 and 18 weeks, while atorvastatin reduced the plasma concentrations of PCs at both timepoints and dosages (p<0.01 for between-treatment comparison). Both atorvastatin and rosuvastatin lowered plasma SPMs concentrations, but atorvastatin demonstrated a more pronounced effect with the highest dose (p=0.03). Rosuvastatin resulted in a significantly more effective lowering of the [SPMs/(SPMs + PCs)] ratio than atorvastatin at any dose/timepoint (p<0.05), a ratio reported to be of clinical importance in coronary artery disease. CONCLUSIONS: The lipidomic technique has revealed that statins are different with regards to the effect on detailed lipid profile. The observed difference in lipids may be connected with different clinical outcomes as suggested by the [SPMs/(SPMs + PCs)] ratio.
Assuntos
Fluorbenzenos/uso terapêutico , Ácidos Heptanoicos/uso terapêutico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Lipídeos/classificação , Pirimidinas/uso terapêutico , Pirróis/uso terapêutico , Sulfonamidas/uso terapêutico , Atorvastatina , Cromatografia Líquida , Relação Dose-Resposta a Droga , Fluorbenzenos/administração & dosagem , Ácidos Heptanoicos/administração & dosagem , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Lipídeos/sangue , Espectrometria de Massas , Estudos Prospectivos , Pirimidinas/administração & dosagem , Pirróis/administração & dosagem , Rosuvastatina Cálcica , Sulfonamidas/administração & dosagemRESUMO
OBJECTIVES: Acute and late stent malapposition (SM) after bare-metal stents (BMS) and sirolimus-eluting stents (SES) in ST-segment elevation myocardial infarction patients were studied. BACKGROUND: Stent thrombosis may be caused by SM after primary percutaneous coronary intervention in ST-segment elevation myocardial infarction patients. METHODS: Post-procedure and follow-up intravascular ultrasound data were available in 184 out of 310 patients (60%; 104 SES, 80 BMS) included in the MISSION! Intervention Study. To determine the contribution of remodeling and changes in plaque burden to the change in lumen cross-sectional area (CSA) at SM sites, the change in lumen CSA (follow-up minus post-lumen CSA) was related to the change in external elastic membrane CSA (remodeling) and change in plaque and media CSA (plaque burden). RESULTS: Acute SM was found in 38.5% SES patients and 33.8% BMS patients (p = 0.51), late SM in 37.5% SES patients and 12.5% BMS patients (p < 0.001). Acquired SM was found in 25.0% SES patients and 5.0% BMS patients (p < 0.001). Predictors of acute SM were reference diameter (SES: odds ratio [OR] 3.49, 95% confidence interval [CI] 1.29 to 9.43; BMS: OR 28.8, 95% CI 4.25 to 94.5) and balloon pressure (BMS: OR 0.74, 95% CI 0.58 to 0.94). Predictors of late SM were diabetes mellitus (SES: OR 0.16, 95% CI 0.02 to 1.35), reference diameter (BMS: OR 19.2, 95% CI 2.64 to 139.7), and maximum balloon pressure (BMS: OR 0.74, 95% CI 0.55 to 1.00). Change in lumen CSA was related to change in external elastic membrane CSA (R = 0.73, 95% CI 0.62 to 0.84) after SES implantation and to change in plaque and media CSA (R = -0.62, 95% CI -0.77 to -0.46) after BMS implantation. After SES implantation, acquired SM was caused by positive remodeling in 84% and plaque reduction in 16% of patients. CONCLUSIONS: Acute SM was common after SES and BMS stent implantation in ST-segment elevation myocardial infarction patients. After SES implantation, late acquired SM is common and generally caused by positive remodeling.