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BACKGROUND: It remained unclear whether the combination of the Canada Acute Coronary Syndrome Risk Score (CACS-RS) and N-terminal pro-brain natriuretic peptide (NT-pro-BNP) could have a better performance in predicting clinical outcomes in acute ST-elevation myocardial infarction (STEMI) patients with primary percutaneous coronary intervention. METHODS: A total of 589 consecutive STEMI patients were enrolled. The potential additional predictive value of NT-pro-BNP with the CACS-RS was estimated. Primary endpoint was in-hospital mortality and long-term poor outcomes. RESULTS: The incidence of in-hospital death was 3.1%. Patients with higher NT-pro-BNP and CACS-RS had a greater incidence of in hospital death. After adjustment for the CACS-RS, elevated NT-pro-BNP (defined as the best cutoff point based on the Youden's index) was significantly associated with in hospital death (odd ratio = 4.55, 95%CI = 1.52-13.65, p = 0.007). Elevated NT-pro-BNP added to CACS-RS significantly improved the C-statistics for in-hospital death, as compared with the original score (0.762 vs. 0.683, p = 0.032). Furthermore, the addition of NT-pro-BNP to CACS-RS enhanced net reclassification improvement (0.901, p < 0.001) and integrated discrimination improvement (0.021, p = 0.033), suggesting effective discrimination and reclassification. In addition, the similar result was also demonstrated for in-hospital major adverse clinical events (C-statistics: 0.736 vs. 0.695, p = 0.017) or 3-year mortality (0.699 vs. 0.604, p = 0.004). CONCLUSIONS: Both NT-pro-BNP and CACS-RS are risk predictors for in hospital poor outcomes in patients with STEMI. A combination of them could derive a more accurate prediction for clinical outcome s in these patients.
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Síndrome Coronario Agudo/sangre , Péptido Natriurético Encefálico/sangre , Fragmentos de Péptidos/sangre , Medición de Riesgo , Infarto del Miocardio con Elevación del ST/sangre , Síndrome Coronario Agudo/epidemiología , Síndrome Coronario Agudo/etiología , Biomarcadores/sangre , China/epidemiología , Electrocardiografía , Estudios de Seguimiento , Incidencia , Intervención Coronaria Percutánea , Valor Predictivo de las Pruebas , Pronóstico , Curva ROC , Estudios Retrospectivos , Infarto del Miocardio con Elevación del ST/cirugía , Tasa de Supervivencia/tendencias , Factores de TiempoRESUMEN
OBJECTIVE: Compared with genetic factors, drug interactions are largely unexplored in pharmacogenetic studies. This study sought to systematically investigate the effects of VKORC1, STX4A, CYP2C9, CYP4F2, CYP3A4, and GGCX gene polymorphisms and interacting drugs on warfarin maintenance dose. METHODS: A retrospective study of 845 Chinese patients after heart valve replacement receiving long-term warfarin maintenance therapy was conducted. Thirteen polymorphisms in the six genes were genotyped, and 36 drugs that may interact with warfarin were investigated. RESULTS: Single-nucleotide polymorphism association analysis showed that VKORC1, CYP2C9 and CYP4F2 variations were highly associated with the warfarin maintenance dose. Among 36 drugs that may interact with warfarin, fluconazole, amiodarone, and omeprazole were associated with the requirement for 45.8, 16.7, and 16.7% lower median warfarin dose (all P<0.05 with a false discovery rate <0.05). The final pharmacogenetic equation explained 43.65% of interindividual variation of warfarin maintenance dose with age, body surface area, VKORC1 g.3588G>A, CYP2C9*3, CYP4F2 c.1297G>A, amiodarone, fluconazole, and diltiazem accounting for 1.97, 2.74, 24.12, 3.94, 1.64, 5.92, 2.47, and 0.84% of variation. CONCLUSION: The present study indicated that VKORC1, CYP4F2, and CYP2C9 genotypes and interacting drugs had a significant impact on the warfarin maintenance dose in Chinese patients with heart valve replacement and demonstrated that integrating interacting drugs can largely improve the predictability of the dose algorithm.
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Anticoagulantes/uso terapéutico , Hidrocarburo de Aril Hidroxilasas/genética , Sistema Enzimático del Citocromo P-450/genética , Oxigenasas de Función Mixta/genética , Warfarina/administración & dosificación , Adulto , China , Citocromo P-450 CYP2C9 , Familia 4 del Citocromo P450 , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas/genética , Femenino , Estudios de Asociación Genética , Variación Genética , Genotipo , Implantación de Prótesis de Válvulas Cardíacas/métodos , Humanos , Masculino , Persona de Mediana Edad , Periodo Posoperatorio , Vitamina K Epóxido ReductasasRESUMEN
Diabetic patients continue to develop inflammation and cardiovascular complication even after achieving glycemic control, suggesting a "metabolic memory". Metabolic memory is a major challenge in the treatment of diabetic complication, and the mechanisms underlying metabolic memory are not clear. Recent studies suggest a link between chromatin histone methylation and metabolic memory. In this study, we tested whether histone 3 lysine-9 tri-methylation (H3K9me3), a key epigenetic chromatin marker, was involved in high glucose (HG)-induced inflammation and metabolic memory. Incubating cardiomyocyte cells in HG resulted in increased levels of inflammatory cytokine IL-6 mRNA when compared with myocytes incubated in normal culture media, whereas mannitol (osmotic control) has no effect. Chromatin immunoprecipitation (ChIP) assays showed that H3K9me3 levels were significantly decreased at the promoters of IL-6. Immunoblotting demonstrated that protein levels of the H3K9me3 methyltransferase, Suv39h1, were also reduced after HG treatment. HG-induced apoptosis, mitochondrial dysfunction and cytochrome-c release were reversible. However, the effects of HG on the expression of IL-6 and the levels of H3K9me3 were irreversible after the removal of HG from the culture. These results suggest that HG-induced sustained inflammatory phenotype and epigenetic histone modification, rather than HG-induced mitochondrial dysfunction and apoptosis, are main mechanisms responsible for metabolic memory. In conclusion, our data demonstrate that HG increases expression of inflammatory cytokine and decreases the levels of histone-3 methylation at the cytokine promoter, and suggest that modulating histone 3 methylation and inflammatory cytokine expression may be a useful strategy to prevent metabolic memory and cardiomyopathy in diabetic patients.
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Epigénesis Genética , Glucosa/metabolismo , Histonas/metabolismo , Lisina/metabolismo , Miocitos Cardíacos/metabolismo , Línea Celular , Células Cultivadas , Citocinas/genética , Citocinas/metabolismo , Epigénesis Genética/efectos de los fármacos , Regulación de la Expresión Génica/efectos de los fármacos , Glucosa/farmacología , Humanos , Inflamación/genética , Inflamación/metabolismo , Mediadores de Inflamación/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Metilación , Miocitos Cardíacos/efectos de los fármacos , Regiones Promotoras GenéticasRESUMEN
We investigated whether transplantation of bone marrow mesenchymal stem cells (BMSC) with induced BMSC (iBMSC) or uninduced BMSC (uBMSC) into the myocardium could improve the performance of post-infarcted rat hearts. BMSCs were specified by flowcytometry. IBMSCs were cocultured with rat cardiomyocyte before transplantation. Cells were injected into borders of cardiac scar tissue 1 week after experimental infarction. Cardiac performance was evaluated by echocardiography at 1, 2, and 4 weeks after cellular or PBS injection. Langendorff working-heart and histological studies were performed 4 weeks after treatment. Myogenesis was detected by quantitative PCR and immunofluorescence. Echocardiography showed a nearly normal ejection fraction (EF) in iBMSC-treated rats and all sham control rats but a lower EF in all PBS-treated animals. The iBMSC-treated heart, assessed by echocardiography, improved fractional shortening compared with PBS-treated hearts. The coronary flow (CF) was decreased obviously in PBS and uBMSC-treated groups, but recovered in iBMSC-treated heart at 4 weeks (P < 0.01). Immunofluorescent microscopy revealed co-localization of Superparamagnetic iron oxide (SPIO)-labeled transplanted cells with cardiac markers for cardiomyocytes, indicating regeneration of damaged myocardium. These data provide strong evidence that iBMSC implantation is of more potential to improve infarcted cardiac performance than uBMSC treatment. It will open new promising therapeutic opportunities for patients with post-infarction heart failure.
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Trasplante de Médula Ósea , Corazón/fisiología , Trasplante de Células Madre Mesenquimatosas , Infarto del Miocardio/terapia , Animales , Diferenciación Celular/fisiología , Cartilla de ADN/genética , Ecocardiografía , Citometría de Flujo , Masculino , Microscopía Fluorescente , Desarrollo de Músculos/fisiología , Miocitos Cardíacos/trasplante , Reacción en Cadena de la Polimerasa , Ratas , Ratas Sprague-DawleyRESUMEN
Gastric cancer is one of the most common malignant tumors causing death in Fujian Province, China. However, the mortality of gastric cancer is greatly varied in different areas in Fujian; for example, the mortality in Changle City is 7.4 times higher than that in Fuan City. In this study, we compared the differences in serological parameters, pepsinogen (PG) I, PG II, gastrin-17 (G-17), and Helicobacter pylori (H. pylori) antibody, between the two cities. It has been reported that low serum PG I is correlated with atrophic gastritis, a high-risk condition for developing gastric cancer, while high serum G-17 has been used for serological detection of atrophic corpus gastritis. We recruited 224 healthy subjects in Changle and 229 healthy subjects in Fuan, matched in age and sex. The serum levels of PG II and G-17 were significantly higher in Changle than those in Fuan. Importantly, the frequency of the subjects with low serum PG I (< 25 µg/L) was significantly higher in Changle than in Fuan, although the serum PG I levels were similar between the two cities. Moreover, the percentage of the subjects with high serum G-17 (≥ 2 pmol/L) and the positive rate of serum IgG antibody against H. pylori were significantly higher in Changle than those in Fuan. The detected differences in these serological parameters are consistent with the notion that the prevalence of atrophic gastritis may be higher in Changle than in Fuan, which results in a higher risk condition for developing gastric cancer in Changle.
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Anticuerpos Antibacterianos/sangre , Ciudades/epidemiología , Gastrinas/sangre , Helicobacter pylori/inmunología , Pepsinógenos/sangre , Neoplasias Gástricas/sangre , Neoplasias Gástricas/microbiología , Adulto , Anciano , Anticuerpos Antibacterianos/inmunología , China/epidemiología , Femenino , Geografía , Infecciones por Helicobacter/sangre , Infecciones por Helicobacter/epidemiología , Infecciones por Helicobacter/inmunología , Infecciones por Helicobacter/microbiología , Humanos , Inmunoglobulina G/sangre , Inmunoglobulina G/inmunología , Masculino , Persona de Mediana Edad , Pepsinógeno A/sangre , Pepsinógeno C/sangre , Características de la Residencia/estadística & datos numéricos , Neoplasias Gástricas/mortalidadRESUMEN
Macrophage migration inhibitory factor (MIF) is an inflammatory cytokine associated with the atherosclerotic process and atherosclerotic plaque stability. MIF was shown to be highly expressed in advanced atherosclerotic lesions. Neutralizing MIF with a blocking antibody induced a regression of established atherosclerotic lesions. In this study, we investigated the mechanism underlying the proangiogenic effect of MIF in human umbilical vein endothelial cells (HUVECs). We showed that MIF induced the expression of angiogenesis-related genes in HUVECs. We also showed that MIF induced tube formation of HUVECs in vitro and in vivo. Angiotensin II (Ang II) could specifically up-regulate MIF expression in HUVECs. Using a luciferase reporter assay, we demonstrated that the AP-1 response element in the 5'-UTR of the MIF gene played a role in Ang II-induced MIF expression. Small hairpin RNA (shRNA) targeting c-Jun, a component of AP-1, and the AP-1 inhibitor CHX both efficiently inhibited MIF expression. The consistent result of electrophoretic mobility shift assay (EMSA) showed that Ang II specifically increased AP-1 activation in HUVECs. Our results suggest that AP-1 mediates Ang II-induced MIF expression which contributes to atherosclerotic plaque destabilization in human endothelial cells.
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Inductores de la Angiogénesis/metabolismo , Angiotensina II/farmacología , Células Endoteliales/efectos de los fármacos , Células Endoteliales/metabolismo , Factores Inhibidores de la Migración de Macrófagos/metabolismo , Neovascularización Fisiológica/efectos de los fármacos , Factor de Transcripción AP-1/metabolismo , Animales , Secuencia de Bases , Extractos Celulares , Núcleo Celular/efectos de los fármacos , Núcleo Celular/metabolismo , Ensayo de Cambio de Movilidad Electroforética , Humanos , Factores Inhibidores de la Migración de Macrófagos/genética , Factores Inhibidores de la Migración de Macrófagos/farmacología , Datos de Secuencia Molecular , Ratas , Venas Umbilicales/citologíaRESUMEN
PURPOSE: Compared with genetic factors, drug interactions were largely unexplored in warfarin pharmacogenetic studies. This study sought to systematically investigate the effects of genetic polymorphisms of VKORC1, STX4A, CYP2C9, CYP3A4, and GGCX and interacting drugs on the initial responses to warfarin in Chinese patients with heart valve replacement (HVR). METHODS: A retrospective study was conducted in 809 patients starting warfarin therapy after HVR. The relationships between 12 polymorphisms plus 47 drugs and primary outcomes of the time to the first international normalized ratio (INR) ≥ 1.8 and the time to the first INR > 3.5 and the secondary outcomes of the proportion of time INR < 1.8, the proportion of time INR > 3.5, and the daily warfarin dose in the first 28 days after the initiation of warfarin treatment were analyzed. RESULTS: Genetic polymorphisms and interacting drugs could significantly affect the primary and secondary outcomes. The time to the first INR ≥ 1.8 was significantly influenced by the body surface area (BSA), VKORC1 g.3588G > A allele, and CYP2C9*3 allele, with hazard ratio (HR; 95% confidence interval [CI]) of 0.34 (0.17-0.66), 2.71 (2.2-3.35) and 1.43 (1.07-1.93) respectively. The time to the first INR > 3.5 was affected not only by BSA, VKORC1 g.3588G > A allele, and CYP2C9*3 allele with HR (95%CI) of 0.26 (0.07-0.99), 2.76 (1.61-4.72), and 3.09 (2.02-4.74) respectively, but also by age and interacting drugs, including fluconazole, amiodarone, and simvastatin with HR (95%CI) of 1.02 (1.01-1.04), 2.66 (1.16-6.08), 1.78 (1.17-2.73), and 5.33 (1.67-16.96) respectively. CONCLUSIONS: Not only VKORC1 and CYP2C9 genotypes, but also interacting drugs, had a significant impact on the variability of the initial response to warfarin.
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Anticoagulantes/uso terapéutico , Anuloplastia de la Válvula Cardíaca , Válvulas Cardíacas/cirugía , Polimorfismo de Nucleótido Simple , Warfarina/uso terapéutico , Adulto , Hidrocarburo de Aril Hidroxilasas/genética , Pueblo Asiatico/genética , Citocromo P-450 CYP2C9 , Sistema Enzimático del Citocromo P-450/genética , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Quimioterapia Combinada , Femenino , Genotipo , Haplotipos , Válvulas Cardíacas/efectos de los fármacos , Humanos , Relación Normalizada Internacional , Masculino , Persona de Mediana Edad , Oxigenasas de Función Mixta/genética , Polimorfismo Genético , Estudios RetrospectivosRESUMEN
Diabetic hyperglycemia result in cardiovascular complications, but the mechanisms by which high levels of glucose (HG) cause diabetic cardiomyopathy are not known. We investigate whether HG-induced repression of insulin-like growth factor 1 receptor (IGF-1R) mediated by epigenetic modifications is one potential mechanism. We found that HG resulted in decreased IGF-1 receptor (IGF-1R) mRNA levels, and IGF-1R protein when compared with H9C2 rat cardiomyocyte cells incubated in normal glucose. HG also induced apoptosis of H9C2 cells. The effects of HG on reduced expression of IGF-1R and increased apoptosis were blocked by silencing p53 with small interference RNA but not by non-targeting scrambled siRNA. Moreover, HG negatively regulated IGF-1R promoter activity as determined by ChIP analysis, which was dependent on p53 since siRNA-p53 attenuated the effects of HG on IGF-1R promoter activity. HG also increased the association of p53 with histone deacetylase 1 (HDAC1), and decreased the association of acetylated histone-4 with the IGF-1R promoter. Furthermore, HDAC inhibitor relieved the repression of IGF-1R following HG state. These results suggest that HG-induced repression of IGF-1R is mediated by the association of p53 with the IGF-1R promoter, and by the subsequent enhanced recruitment of chromatin-modifying proteins, such as HDAC1, to the IGF-1R promoter-p53 complex. In conclusion, our data demonstrate that HG decreases expression of IGF-1R and decreases the association of acetylated histone-4 with the IGF-1R promoter. These studies may help delineate the complex pathways regulating diabetic cardiomyopathy, and have implications for the development of novel therapeutic strategies to prevent diabetic cardiomyopathy by epigenetic regulation of IGF-1R.
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Apoptosis , Angiopatías Diabéticas/etiología , Epigénesis Genética , Hiperglucemia/patología , Miocitos Cardíacos/metabolismo , Receptores de Somatomedina/genética , Acetilación , Animales , Glucemia , Línea Celular , Histonas/metabolismo , Miocitos Cardíacos/citología , Regiones Promotoras Genéticas , Ratas , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
1. It has been reported that allitridi, an active compound extracted from garlic, has many cardiovascular effects. However, it remains unknown whether allitridi affects major repolarization currents, such as the transient outward K(+) current (I(to) ), ultrarapid delayed rectifier K(+) current (I(Kur)) and the L-type Ca(2+) current (I(Ca)), in human atrial myocytes. 2. In the present study, we investigated the effects of allitridi on I(to), I(Kur), I(Ca) and the action potential in human isolated atrial myocytes using the whole-cell patch recording technique. 3. Allitridi reversibly inhibited I(to), but not I(Kur) and I(Ca), in human atrial myocytes. These effects of allitridi on I(to) were concentration dependent (IC(50) = 44.9 µmol/L). Inactivation of I(to) was accelerated and the voltage-dependent inactivation potential was shifted towards the negative direction. Allitridi (30 µmol/L) significantly prolonged action potential duration in human atrial myocytes. 4. The results of the present study indicate that allitridi inhibits I(to), but not I(Kur) and I(Ca), and prolongs the action potential duration in human atrial myocytes.
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Compuestos Alílicos/farmacología , Atrios Cardíacos/efectos de los fármacos , Miocitos Cardíacos/efectos de los fármacos , Canales de Potasio/efectos de los fármacos , Sulfuros/farmacología , Potenciales de Acción/efectos de los fármacos , Adulto , Anciano , Función Atrial/efectos de los fármacos , Fármacos Cardiovasculares/farmacología , Evaluación Preclínica de Medicamentos , Electrofisiología , Atrios Cardíacos/citología , Atrios Cardíacos/metabolismo , Humanos , Potenciales de la Membrana/efectos de los fármacos , Persona de Mediana Edad , Miocitos Cardíacos/fisiología , Canales de Potasio/metabolismoRESUMEN
OBJECTIVE: To investigate distribution of CYP2C9, CYP3A4, VKORC1 and GGCX gene polymorphisms in the Han population of Guangdong. METHODS: The subjects included were 970 Chinese Han patients who received long-term warfarin anticoagulant therapy orally after valve replacement in Guangdong General Hospital between 2000 and 2008. By selecting and analyzing the 12 single nucleotide polymorphisms (SNPs) loci, rs12572351 G>A, rs9332146 G>A, rs4917639 G>T, rs1057910 A>C (CYP2C9*3), rs1934967 G>T, rs1934968 G>A, rs2242480 T>C, rs2246709 G>A, rs9923231 C>T (VKORC1-1639 G>A), rs2359612 G>A (VKORC1*2), rs10871454 C>T, and rs699664 T>C, in 4 genes including CYP2C9, CYP3A4, VKORC1 and GGCX that were possibly correlated with warfarin pharmacodynamics and pharmacokinetics through literature retrieval, the distribution of mutation frequencies of the 12 SNPs loci in Chinese Han population were obtained systematically. SNaPshot technique was used to detect gene SNPs, Hardy-Weinberg genetic equilibrium test was used to test population representativeness. RESULTS: The allelic mutation frequency at CYP2C9 gene rs12572351 G>A, rs9332146 G>A, rs4917639 C>A, rs1057910 A>C (*3), rs1934967 G>T and rs1934968 G>A loci was 32.53%, 2.16%, 8.25%, 3.61%, 19.18% and 37.37%, respectively; the allelic mutation frequency at CYP3A4 gene rs2242480 T>C and rs2246709 G>A loci was 29.07% and 40.41%, respectively; the allelic mutation frequency at VKORC1 gene rs9923231 C>T, rs2359612 G>A and rs10871454 C>T SNPs loci was 87.99%, 87.94% and 91.34%, respectively; the allelic mutation frequency at GGCX gene rs699664 T>C locus was 31.86%. CONCLUSION: It is of important clinical significance in individualized warfarin therapy to systematically study distribution of mutation frequencies at 12 polymorphisms loci in 4 genes including CYP2C9, CYP3A4 , VKORC1 and GGCX related to warfarin pharmacodynamics and pharmacokinetics in the Chinese Han population receiving valve replacement.
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Anticoagulantes/farmacocinética , Implantación de Prótesis de Válvulas Cardíacas , Polimorfismo de Nucleótido Simple , Warfarina/farmacocinética , Warfarina/uso terapéutico , Adulto , Alelos , Anticoagulantes/farmacología , Anticoagulantes/uso terapéutico , Hidrocarburo de Aril Hidroxilasas/genética , China/etnología , Citocromo P-450 CYP2C9 , Citocromo P-450 CYP3A/genética , Femenino , Enfermedades de las Válvulas Cardíacas/tratamiento farmacológico , Enfermedades de las Válvulas Cardíacas/genética , Enfermedades de las Válvulas Cardíacas/cirugía , Humanos , Masculino , Persona de Mediana Edad , Oxigenasas de Función Mixta/genética , Periodo Posoperatorio , Vitamina K Epóxido Reductasas , Warfarina/farmacología , Adulto JovenRESUMEN
OBJECTIVE: To compare the efficacy and safety between the interventional and conservative treatment options for borderline vulnerable plaque lesion in acute coronary syndrome (ACS) patients by intravascular ultrasound (IVUS). METHODS: A total of 100 ACS patients [78 male, age 43 - 74 (60.4 ± 14.1) years] undergoing coronary angiography (CAG) with borderline lesion (coronary artery stenosis between 50% - 70%) were enrolled in May 2007 to February 2009, who were randomly divided into PCI group (50 patients) and conservative therapy group (50 patients). According to minimal lumen area (MLA) detected by IVUS, patients were further divided into MLA ≥ 4.0 mm(2) sub-group and MLA < 4.0 mm(2) sub-groups. Outcomes during hospitalization and after 10 - 12 month follow-up were compared. RESULTS: IVUS was performed in 40 patients at 10 - 12 months post PCI, there was no in-stent thrombosis and the extent of stent neointimal hyperplasia was comparable as at the time of immediately post PCI. IVUS was performed in 35 patients at 10 - 12 months post conservative therapy, IVUS results showed that MLA increased significantly [(7.32 ± 1.42) mm(2) vs. (4.98 ± 0.89) mm(2), P < 0.01], while plaque area [(7.70 ± 2.09) mm(2) vs. (10.01 ± 2.55) mm(2), P < 0.05], plaque burden [(55.94 ± 8.36)% vs. (67.97 ± 9.36)%] and low echo area [(4.08 ± 0.80) mm(2) vs. (2.27 ± 0.79) mm(2)] were significantly decreased at follow up compared to those as baseline (all P < 0.01). There was one patient in PCI group with MLA ≥ 4.0 mm(2) developed acute in-stent thrombosis in left anterior descending artery two days after the procedure and 9 patients in conservative therapy and MLA < 4.0 mm(2) group received PCI due to recurrent angina pectoris during follow-up. CONCLUSIONS: For the borderline lesion with MLA ≥ 4.0 mm(2) detected by IVUS, adequate medication could effectively attenuate and or reverse the plaque progression and stabilize plaque.
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Síndrome Coronario Agudo/tratamiento farmacológico , Síndrome Coronario Agudo/terapia , Placa Aterosclerótica/diagnóstico , Ultrasonografía Intervencional , Adulto , Anciano , Ablación por Catéter , Angiografía Coronaria , Femenino , Humanos , Masculino , Persona de Mediana Edad , Resultado del TratamientoRESUMEN
OBJECTIVE: To investigate potential contributions of genetic variants of cytochrome P-450 2C9 (CYP2C9) and vitamin K expoxide reductase (VKORC1) to the anticoagulation response during the initiation of warfarin therapy in the Han Chinese population. METHODS: A total of 798 Han Chinese patients received long-term warfarin anticoagulant therapy orally after valve replacement in our hospital between 2000 and 2008 were included in this study. Nine single nucleotide polymorphism (SNP) loci [rs12572351 G > A, rs9332146 G > A, rs4917639 G > T, rs1057910 A > C (CYP2C9(*)3), rs1934967 G > T, rs1934968 G > A, rs9923231 C > T (VKORC1-1639 G > A), rs2359612 G > A and rs10871454 C > T] in 2 genes including CYP2C9 and VKORC1, which were possibly correlated with warfarin pharmacokinetics and pharmacodynamics through literature retrieval, were selected and analyzed. Warfarin steady-state dose requirement, time to the INR (the international normalized ratio) within the therapeutic range and percent of the INR of more than 3.5 were compared among genotype subgroups. SNaPshot technique was used to detect gene SNPs; Hardy-Weinberg genetic equilibrium test was used to test population representativeness. RESULTS: CYP2C9(*)3 genotype did not affect the required warfarin dose while it was associated with increased risk of bleeding when treated with routine dosage regimen during the initiation of treatment. The allelic mutation frequency at VKORC1 gene rs10871454G > A and VKORC1-1639G > A SNP loci was 92.04% and 88.03%, respectively and rs10871454 was in perfect linkage disequilibrium with-1639. Patients with VKORC1 rs10871454 genetic mutation required lower warfarin dose in the first 28 days of therapy. VKORC1-1639 genetic polymorphism was also associated with shorter time to the INR within the therapeutic range and increased risk of over-anticoagulation. CONCLUSION: Detecting genetic polymorphism of CYP2C9 and VKORC1 could guide clinical use of warfarin to reduce the risk of adverse reactions including bleeding in patients receiving chronic anticoagulation therapy.
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Anticoagulantes/farmacología , Citocromo P-450 CYP2C9/genética , Vitamina K Epóxido Reductasas/genética , Warfarina/farmacología , Anciano , Anticoagulantes/uso terapéutico , Hidrocarburo de Aril Hidroxilasas , Frecuencia de los Genes , Genes , Variación Genética , Genotipo , Hemorragia , Humanos , Relación Normalizada Internacional , Desequilibrio de Ligamiento , Oxigenasas de Función Mixta , Polimorfismo de Nucleótido Simple , Warfarina/uso terapéuticoRESUMEN
1. It is known that high glucose can induce cardiomyocyte apoptosis and that macrophage migration inhibitory factor (MIF) may be involved in the development of diabetes. However, the relationship between high glucose and MIF in diabetic cardiomyopathy remains unclear. 2. In the present study, AC16 human cardiomyocytes were cultured in the presence of 25 mmol/L glucose for 20, 30 and 60 min before being subjected to western blot analyses to determine MIF expression and c-Jun N-terminal kinase (JNK) activation. In addition, AC16 cells were pretreated with 2.5 µmol/L SP600125 (a JNK inhibitor), 40 µmol/L (s,r)-3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazole acetic acid methyl ester (ISO-1; an MIF antagonist) or 0.1% dimethylsulphoxide (DMSO; vehicle) for 1 h prior to exposure to 25 mmol/L glucose and culture for 72 h, followed by annexin V-fluorescein isothiocyanate/propidium iodide staining and flow cytometry analysis. Caspase 3 activity and phosphorylation of JNK were also analysed by western blotting. 3. The high concentration of glucose increased expression of endogenous MIF and JNK phosphorylation in AC16 cardiomyocytes. Pretreatment of cells with SP600125 and ISO-1 reduced glucose-induced apoptosis and caspase 3 activity. Furthermore, JNK phosphorylation was attenuated by inhibition of endogenous MIF. 4. In conclusion, myocardial cell apoptosis induced by high glucose involves the overexpression of MIF and activation of the JNK signalling pathway. The identification of a high glucose-MIF-JNK pathway will help determine potential new targets in the treatment of diabetic cardiomyopathy.
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Apoptosis/fisiología , Glucosa/administración & dosificación , Proteínas Quinasas JNK Activadas por Mitógenos/fisiología , Sistema de Señalización de MAP Quinasas/fisiología , Factores Inhibidores de la Migración de Macrófagos/fisiología , Miocitos Cardíacos/metabolismo , Apoptosis/efectos de los fármacos , Células Cultivadas , Humanos , Proteínas Quinasas JNK Activadas por Mitógenos/biosíntesis , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Factores Inhibidores de la Migración de Macrófagos/biosíntesis , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/enzimologíaRESUMEN
MicroRNAs (miRNAs) have been increasingly reported to have important roles in diverse biological and pathological processes. We investigated miR-1 and miR-206 expression and their potential roles in a rat model of myocardial infarction (MI). miR-1 and miR-206 expression were significantly increased, and insulin-like growth factor 1 (IGF-1) protein was markedly reduced without obvious change of its mRNA level after MI induction. Position 175-196 of rat IGF-1 3'-untranslated region was identified to be required for efficient downregulation by miR-1/miR-206. IGF-1 level was reduced without changing its transcript level in rat H9C2 myoblast cells modified with miR-1 (H9C2-miR-1). In the serum withdrawal and hypoxic condition, caspase-3 activity and mitochondrial potential were significantly increased in H9C2-miR-1 cells compared with the control group, respectively (p<0.05, p<0.01). Together, our results indicate that miR-1 and miR-206 are involved in apoptotic cell death in MI by post-transcriptional repression of IGF-1.
Asunto(s)
Factor I del Crecimiento Similar a la Insulina/metabolismo , MicroARNs/biosíntesis , Infarto del Miocardio/metabolismo , Animales , Apoptosis , Modelos Animales de Enfermedad , Factor I del Crecimiento Similar a la Insulina/genética , Infarto del Miocardio/genética , Infarto del Miocardio/patología , Ratas , Ratas Sprague-Dawley , Transcripción Genética , Regulación hacia ArribaRESUMEN
C-kit-positive neonatal cardiomyocytes (NCMs) contribute to myocardial regeneration. However, the myocardium itself cannot give rise to a robust regenerative response owing to the limited numbers of c-kit-positive resident stem cells present in the heart. It has been shown that mesenchymal stem cells (MSCs) can enhance cardiac repair via the release of paracrine factors such as insulin-like growth factor (IGF-1). We investigated whether the increased expression of c-kit in NCMs mediates the beneficial effects of MSCs on cardiac repair. MSCs and NCMs were prepared from Lewis rats and co-cultured in a Transwell system, which allowed the diffusion of secreted factors but prevented cell contact between the two cell types. The proliferation of NCMs was determined by BrdU assay. The expression of c-kit was assessed by real-time PCR and flow cytometry. The apoptosis rate of NCMs in response to hypoxia was determined by flow cytometry. We found that the expression of c-kit in NCMs was increased by paracrine factors released by MSCs. The effect of paracrine factors on c-kit expression was attenuated by IGF-1 receptor-neutralizing antibody. Furthermore, we found that increased c-kit expression requires IGF-1 receptor activation via the phosphatidylinositol 3 kinase/Akt-mediated pathway. These findings provide a new paradigm for the biological effects of IGF-1 and have significant implications for understanding the beneficial effects of MSCs on myocardial regeneration.
Asunto(s)
Ciclo Celular , Células Madre Mesenquimatosas/metabolismo , Miocitos Cardíacos/metabolismo , Proteínas Proto-Oncogénicas c-kit/metabolismo , Receptor IGF Tipo 1/metabolismo , Animales , Animales Recién Nacidos , Anticuerpos Neutralizantes/farmacología , Apoptosis , Western Blotting , Médula Ósea/metabolismo , Proliferación Celular , Células Cultivadas , Ensayo de Inmunoadsorción Enzimática , Citometría de Flujo , Factor I del Crecimiento Similar a la Insulina/farmacología , Fosfatidilinositol 3-Quinasas/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Proto-Oncogénicas c-kit/genética , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ratas , Ratas Endogámicas Lew , Receptor IGF Tipo 1/genética , Receptor IGF Tipo 1/inmunología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de Señal , Regulación hacia ArribaRESUMEN
OBJECTIVE: To evaluate the effects of amlodipine-based antihypertensive combination regimen on blood pressure control and impact on cardiovascular events. METHODS: From Oct. 2007 to Oct. 2008, a total of 13 542 hypertensive patients from 180 centers in China were included in this multi-centre randomized, controlled, blind-endpoint assessment clinical trial. Inclusion criteria were: essential hypertension, 50 - 79 years of age with at least one cardiovascular risk factor and signed consent forms. Patients were randomly assigned to receive low-dose amlodipine + diuretics (group A) or low-dose amlodipine + telmisartan (group T). The primary endpoints are composite of non-fatal stroke/myocardial infarction and cardiovascular death. All patients will be followed-up for 4 years. RESULTS: The characteristics of patients between the two groups were similar: mean age (61.5 +/- 7.7) Yrs with 19% history of cerebrovascular diseases, 12% coronary diseases, 18% diabetes, 42% dyslipidemia, mean initial blood pressure 157/93 mm Hg. After 8-week treatment, mean blood pressure in group A and B were reduced to (133.0 +/- 11.0)/(81.0 +/- 7.6) mm Hg, (132.9 +/- 11.6)/(80.6 +/- 7.9) mm Hg respectively. Blood pressure control rates reached 72.1% and 72.6% in group A and T, respectively. CONCLUSION: Amlodipine-based antihypertensive combination regimens achieved satisfactory blood pressure control rate in patients with essential hypertension in this patient cohort.
Asunto(s)
Amlodipino/administración & dosificación , Antihipertensivos/administración & dosificación , Bencimidazoles/administración & dosificación , Benzoatos/administración & dosificación , Hipertensión/tratamiento farmacológico , Anciano , Presión Sanguínea , Quimioterapia Combinada , Femenino , Humanos , Hipertensión/fisiopatología , Masculino , Persona de Mediana Edad , TelmisartánRESUMEN
Glucose toxicity is an important initiator of cardiovascular disease, contributing to the development of cardiomyocyte death and diabetic complications. The present study investigated whether high glucose state could induce apoptosis of rat cardiomyocyte cell line H9C2 through microRNA regulated insulin-like growth factor (IGF-1) signaling pathway. Our data showed that H9C2 cells exposed to high glucose have increased miR-1 expression level, decreased mitochondrial membrane potential, increased cytochrome-c release, and increased apoptosis. Glucose induced mitochondrial dysfunction, cytochrome-c release and apoptosis was blocked by IGF-1. Using prediction algorithms, we identified 3'-untranslated regions of IGF-1 gene are the target of miR-1. miR-1 mimics, but not mutant miR-1, blocked the capacity of IGF-1 to prevent glucose-induced mitochondrial dysfunction, cytochrome-c release and apoptosis. In conclusion, our data demonstrate that IGF-1 inhibits glucose-induced mitochondrial dysfunction, cytochrome-c release and apoptosis and IGF-1's effect is regulated by miR-1.
Asunto(s)
Apoptosis , Regulación de la Expresión Génica , Glucosa/toxicidad , Factor I del Crecimiento Similar a la Insulina/genética , MicroARNs/metabolismo , Miocitos Cardíacos/efectos de los fármacos , Regiones no Traducidas 3'/genética , Regiones no Traducidas 3'/metabolismo , Animales , Apoptosis/genética , Secuencia de Bases , Línea Celular , Citocromos c/metabolismo , Factor I del Crecimiento Similar a la Insulina/metabolismo , Potencial de la Membrana Mitocondrial/genética , MicroARNs/genética , Mitocondrias Cardíacas/enzimología , Mitocondrias Cardíacas/metabolismo , Mutación , Miocitos Cardíacos/citología , Miocitos Cardíacos/metabolismo , RatasRESUMEN
1. Ketamine is widely used for the induction of anaesthesia in high-risk patients with cardiovascular instability or severe hypovolaemia. However, the ionic mechanisms involved in the effects of ketamine at therapeutically relevant concentrations in human cardiac myocytes are unclear. The present study was designed to investigate the effects of ketamine on L-type Ca2+ (I(Ca)), transient outward K+ (I(to)), ultra-rapid delayed rectifier K+ (I(Kur)) and inward rectifier potassium (I(K1)) currents, as well as on action potentials, in human isolated atrial myocytes. 2. Atrial myocytes were isolated enzymatically from specimens of human atrial appendage obtained from patients undergoing coronary artery bypass grafting. The action potential and membrane currents were recorded in both current- and voltage-clamp modes using the patch-clamp technique. 3. Ketamine inhibited I(Ca) with an IC(50) of 1.8 micromol/L. In addition, 10 micromol/L ketamine decreased the I(Ca) peak current at +10 mV from 5.1 +/- 0.3 to 2.1 +/- 0.4 pA/pF (P < 0.01), but did not change the threshold potential, peak current potential and reverse potential. 4. Ketamine had no effect on I(to), I(Kur) or I(K1), but it reversibly shortened the duration of the action potential in human atrial myocytes. 5. In conclusion, ketamine, at a clinically relevant concentration, shortens the action potential duration of the human atrial myocytes, probably by inhibiting I(Ca).
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Ketamina/farmacología , Ketamina/uso terapéutico , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/fisiología , Potenciales de Acción/efectos de los fármacos , Potenciales de Acción/fisiología , Adulto , Anciano , Relación Dosis-Respuesta a Droga , Técnicas Electrofisiológicas Cardíacas , Atrios Cardíacos/citología , Atrios Cardíacos/efectos de los fármacos , Humanos , Persona de Mediana Edad , Miocitos Cardíacos/citología , Factores de Tiempo , Adulto JovenRESUMEN
A rapid and sensitive quantitative assay method was developed for determining ribavirin pharmacokinetic in human plasma. The chromatographic separation was achieved within 4.5 min using a SinoChrom ODS-BP column (4.6 x 150 mm, 5 microm) with acetonitrile-water (1 mmol/L ammonium acetate buffer, 0.1% formic acid; 15:85, v/v) at a constant flow rate of 0.8 mL/min. The MRM pairs were m/z 245.2 --> m/z 113.1 for ribavirin and m/z 226.1 --> m/z 152.1 for acyclovir (internal standard), respectively, with dwell times of 200 ms for each transition. The results showed calibration curve for ribavirin was linear over a concentration range of 1-1000 ng/mL. The lower limit of quantification (LLOQ) was 1 ng/mL ribavirin. Twenty healthy volunteers received a 300 mg oral dose of ribavirin. Blood samples were then collected up to 120 h postdosing. All plasma data were comodeled for ribavirin by using noncompartmental modeling. The single dose of ribavirin was well tolerated and no serious adverse effects occurred. The mean time to maximum concentration was about 1.25 h. The mean maximum concentration of drug in plasma for oral ribavirin was 250 ng/mL. The mean elimination half-life was 43.6 h. The present study describes a simple, specific, sensitive HPLC-MS/MS method for measuring plasma drug concentration and analyzing human pharmacokinetics of ribavirin.
Asunto(s)
Cromatografía Líquida de Alta Presión/métodos , Ribavirina/sangre , Espectrometría de Masas en Tándem/métodos , Administración Oral , Antivirales/administración & dosificación , Antivirales/sangre , Antivirales/farmacocinética , Pueblo Asiatico , China , Humanos , Reproducibilidad de los Resultados , Ribavirina/administración & dosificación , Ribavirina/farmacocinéticaRESUMEN
OBJECTIVE: To investigate the ability of human bone marrow mesenchymal stem cells (hBMSCs), cocultured with semi-permeable membrane separated neonatal rat ventricular myocytes, to differentiate into cardiomyocytes. METHODS: hBMSCs were isolated and purified by density gradient centrifugation and adherence screening method. Cells were expanded as undifferentiated cells in culture for more than 3 passages and their phenotypes were identified with flow cytometer. hBMSCs were cocultured with neonatal rat ventricular myocytes in a rate of 1:10 separated by semi-permeable membrane. GATA4 mRNA was detected by RT-PCR; Immunocytochemistry, and Immunostaining were used to detect sarcomeric alpha-actinin, desmin, cTnT, and cTnI protein level. RESULTS: CD29 (98.64% +/- 0.80%) and CD44 (96.70% +/- 1.50%) were the major surface markers of hBMSCs. After coculturing with semi-permeable membrane separated neonatal rat ventricular myocytes, the first contraction of single cells was noted at day 7 and GATA4 expression was detected on these cells by RT-PCR after 1 to 3 weeks coculture. Desmin, sarcomeric alpha-actinin, cTnI and cTnT could be detected by immunocytochemistry and immunostaining on some of these cells. CONCLUSION: hBMSCs possess the potential to differentiate into myocardial cell phenotype in the cardiac microenvironment. Direct contact with cardiomyocytes was not necessary required for hBMSCs differentiation.