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OBJECTIVE: To compare neoadjuvant chemotherapy (nCT) with CAPOX alone versus neoadjuvant chemoradiotherapy (nCRT) with capecitabine in locally advanced rectal cancer (LARC) with uninvolved mesorectal fascia (MRF). BACKGROUND DATA: nCRT is associated with higher surgical complications, worse long-term functional outcomes, and questionable survival benefits. Comparatively, nCT alone seems a promising alternative treatment in lower-risk LARC patients with uninvolved MRF. METHODS: Patients between June 2014 and October 2020 with LARC within 12 cm from the anal verge and uninvolved MRF were randomly assigned to nCT group with 4 cycles of CAPOX (Oxaliplatin 130 mg/m2 IV day 1 and Capecitabine 1000 mg/m2 twice daily for 14 d. Repeat every 3 wk) or nCRT group with Capecitabine 825 mg/m² twice daily administered orally and concurrently with radiation therapy (50 Gy/25 fractions) for 5 days per week. The primary end point is local-regional recurrence-free survival. Here we reported the results of secondary end points: histopathologic response, surgical events, and toxicity. RESULTS: Of the 663 initially enrolled patients, 589 received the allocated treatment (nCT, n=300; nCRT, n=289). Pathologic complete response rate was 11.0% (95% CI, 7.8-15.3%) in the nCT arm and 13.8% (95% CI, 10.1-18.5%) in the nCRT arm ( P =0.33). The downstaging (ypStage 0 to 1) rate was 40.8% (95% CI, 35.1-46.7%) in the nCT arm and 45.6% (95% CI, 39.7-51.7%) in the nCRT arm ( P =0.27). nCT was associated with lower perioperative distant metastases rate (0.7% vs. 3.1%, P =0.03) and preventive ileostomy rate (52.2% vs. 63.6%, P =0.008) compared with nCRT. Four patients in the nCT arm received salvage nCRT because of local disease progression after nCT. Two patients in the nCT arm and 5 in the nCRT arm achieved complete clinical response and were treated with a nonsurgical approach. Similar results were observed in subgroup analysis. CONCLUSIONS: nCT achieved similar pCR and downstaging rates with lower incidence of perioperative distant metastasis and preventive ileostomy compared with nCRT. CAPOX could be an effective alternative to neoadjuvant therapy in LARC with uninvolved MRF. Long-term follow-up is needed to confirm these results.
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Terapia Neoadjuvante , Neoplasias Retais , Humanos , Terapia Neoadjuvante/métodos , Resultado do Tratamento , Capecitabina/uso terapêutico , Neoplasias Retais/patologia , Quimiorradioterapia/métodos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Estadiamento de NeoplasiasRESUMO
PURPOSE: Given the beneficial effects of sacubitril/valsartan on blood pressure generally, this study investigates its antihypertension effects in diabetes mellitus (DM) patients with primary hypertension specifically, and the effect of sacubitril/valsartan on glycolipid metabolism. METHODS: We conducted a randomized, open-label, active-controlled study to compare the antihypertension effects of sacubitril/valsartan in DM individuals with primary hypertension. The primary end point was reduction in mean systolic blood pressure (SBP) from baseline with sacubitril/valsartan vs. olmesartan at week 8. The secondary endpoints included the changes in diastolic blood pressure (DBP), daytime SBP/DBP, nighttime SBP/DBP, BP achievement (office sitting BP < 130/80 mmHg), and lipid profile. The trial was registered with chictr.org.cn (ChiCTR2200066428) on Dec 22, 2022. RESULTS: A total of 124 patients were included in the final analysis. SBP decreased to a greater extent in the sacubitril/valsartan group from baseline to 8 weeks [between-treatment difference: 3.51 mm Hg, 95% confidence interval (95% CI) 0.41 to 6.62 mm Hg, P = 0.03]. Furthermore, more patients achieved the blood pressure goal with sacubitril/valasartan (74.60% vs. 54.70%, P = 0.03). Multiple logistical regression analysis showed that sacubitril/valsartan was associated with BP achievement [odds ratio (OR) 0.33, 95% CI 0.14-0.73, P = 0.007], but the difference in SBP, DBP, day time SBP/DBP, and night time SBP/DBP reduction did not approach statistical significance. HbA1C1, total cholesterol, and low-density lipoprotein-cholesterol were lower than baseline in both groups (P < 0.05); however, there was no difference in the effects on glucose and lipid metabolism from sacubitril/valsartan compared to olmesartan. CONCLUSIONS: Sacubitril/valsartan not only provided superior BP reduction compared to olmesartan, it did so without adverse effects on glycemic control and lipid parameters in DM patients with primary hypertension.
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Based on the air pollutant emission inventory of Jinan in 2020, the VOCs emission status and existing problems of typical industries including the chemical industry, industrial coating, printing, and furniture manufacturing were investigated and analyzed, and two emission reduction scenarios were designed to estimate the emission reduction potential according to the enterprise scales and the end-of-pipe treatment techniques. The results showed that the VOCs emissions of the typical industries from large to small were the chemical industry(7947.92 t), industrial coating(2383.29 t), printing(792.87 t), and furniture manufacturing(143.79 t). The chemical industry and industrial painting were dominated by large enterprises, accounting for 46.45% and 50.89% of VOCs emissions, whereas printing and furniture manufacturing were dominated by medium-sized enterprises, accounting for 51.76% and 42.37% of VOCs emissions, respectively. The end-of-pipe treatment was dominated by a single inefficient treatment technique, and the utilization rate of efficient treatment techniques such as combustion techniques and combination techniques was only 7.46%. The on-site investigation reported some problems in some enterprises, including incomplete source substitution, inadequate management of fugitive emissions, and unsuitable end-of-pipe treatment facilities. Therefore, VOCs emissions of typical industries had a certain reduction potential. Under the two designed emission reduction scenarios, the chemical industry had the greatest emission reduction potential, with emission reduction rates of 69.58%-84.99%, and the emission reduction rates of industrial coating, printing, and furniture manufacturing industries were 26.98%-34.74%, 36.96%-59.74%, and 8.55%-40.45%, respectively. Among the four industries, large and medium-sized enterprises had greater emission reduction potential, with average emission reduction rates of 70.00% and 44.23%, respectively. Under the scenario of a higher emission reduction target, the average emission reduction rates of small and micro enterprises were greatly increased, reaching 87.49% and 79.65%, respectively. The results of this study could provide scientific basis for developing VOCs governance in typical industries and enterprises.
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This study aimed to analyze the main factors influencing air quality in Tangshan during COVID-19, covering three different periods: the COVID-19 period, the Level I response period, and the Spring Festival period. Comparative analysis and the difference-in-differences (DID) method were used to explore differences in air quality between different stages of the epidemic and different years. During the COVID-19 period, the air quality index (AQI) and the concentrations of six conventional air pollutants (PM2.5, PM10, SO2, NO2, CO, and O3-8h) decreased significantly compared to 2017-2019. For the Level I response period, the reduction in AQI caused by COVID-19 control measures were 29.07%, 31.43%, and 20.04% in February, March, and April of 2020, respectively. During the Spring Festival, the concentrations of the six pollutants were significantly higher than those in 2019 and 2021, which may be related to heavy pollution events caused by unfavorable meteorological conditions and regional transport. As for the further improvement in air quality, it is necessary to take strict measures to prevent and control air pollution while paying attention to meteorological factors.
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Poluentes Atmosféricos , Poluição do Ar , COVID-19 , Poluentes Ambientais , Humanos , Poluição do Ar/análise , Poluentes Atmosféricos/análise , China , Poluentes Ambientais/análise , Material Particulado/análise , Monitoramento Ambiental/métodosRESUMO
Background: For the patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI), dual antiplatelet therapy (DAPT) for at least 1 year is recommended in the guidelines to minimize the risk of stent thrombosis. Persistently uncovered stent strut means delayed neointima formation and extend the window of time in which the stent is prone to thrombosis. Previous studies showed that statins could improve post-stenting strut endothelial coverage for patients undergoing PCI. However, there are lack of evidences on whether early initiation of proprotein convertase subtilisin/Kexin type 9 monoclonal antibody (PCSK9mAb) after PCI in ACS patients can further improve the rate of stent strut coverage on the background of oral lipid-lowering therapy (LLT). Methods: This is a single-center, randomized trial to enroll 36 patients undergoing PCI with a clinical diagnosis of non-ST-segment elevation ACS. The baseline level of low-density lipoprotein cholesterol (LDL-C) of these patients are between 1.4 mmol/L and 3.4 mmol/L. Patients will be assigned to intensive lipid-lowering therapy (LLT) with PCSK9mAb group and conventional LLT without PCSK9mAb group for 12 weeks in a clinical follow-up setting according to 1: 1 randomization. the rate of stent strut endothelial coverage by optical coherence tomography (OCT) examination at 12 weeks after enrollment between the groups will be compared. Conclusion: This will be the first study to investigate changes in the rate of stent strut endothelial coverage under intensive LLT with PCSK9mAb by OCT examination in ACS patients undergoing PCI. The finding of this study will provide clinical evidence for future research about the hypothesis of a novel strategy of "intensive LLT (PCSK9mAb + statin ± ezetimibe) combined with shortened DAPT duration" for ACS patients undergoing PCI.Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: ChiCTR2200063395.
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OBJECTIVE: To investigate whether ischemic preconditioning (IP) can reduce myocardial no-reflow by activating endothelial (e-) nitric oxide synthase (NOS) via the protein kinase A (PKA) pathway. METHODS AND RESULTS: In a 90-min ischemia and 3-h reperfusion model, minipigs were assigned into sham, ischemia-reperfusion (IR), IR+IP, IR+IP+L-NNA (an eNOS inhibitor, 10mg·kg(-1)), IR+IP+H-89 (a PKA inhibitor, 1.0µg·kg(-1)·min(-1)), IR+L-NNA, and IR+H-89 groups. IP pretreatment improved cardiac function and coronary blood flow, decreased the activities of creatine kinase by 36.6% after 90 min of ischemia and by 32.8% after 3 h of reperfusion (P<0.05), reduced the no-reflow areas from 49.9% to 11.0% (P<0.01), and attenuated the infarct size from 78.2% to 35.4% (P<0.01). IP stimulated myocardial PKA activities and the expression of PKA and Ser(133) phosphorylated (p-) cAMP response element-binding protein (CREB) in the reflow and no-reflow myocardium, and enhanced the activities of constitutive NOS and the phosphorylation of eNOS at Ser(1179) and Ser(635) in the no-reflow myocardium. IP suppressed the expression of tumor necrosis factor-α and P-selectin, and attenuated cardiomyocytes apoptosis by regulating the expression of Bcl-2 and caspase-3 in the reflow and no-reflow myocardium. The eNOS inhibitor L-NNA completely canceled these beneficial effects of IP without any influence on PKA activity, whereas the PKA inhibitor H-89 partially blocked the IP cardioprotective effects and eNOS phosphorylation at the same time. CONCLUSION: IP attenuates myocardial no-reflow and infarction after ischemia and reperfusion by activating the phosphorylation of eNOS at Ser(1179) and Ser(635) in a partly PKA-dependent manner.
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Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Precondicionamento Isquêmico , Traumatismo por Reperfusão Miocárdica/patologia , Miocárdio Atordoado/patologia , Óxido Nítrico Sintase Tipo III/metabolismo , Fenômeno de não Refluxo/patologia , Animais , Apoptose , Biomarcadores/metabolismo , Hemodinâmica , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Miocárdio Atordoado/metabolismo , Miocárdio Atordoado/fisiopatologia , Miocárdio/enzimologia , Miocárdio/patologia , Fenômeno de não Refluxo/metabolismo , Fenômeno de não Refluxo/fisiopatologia , Fosforilação , Suínos , Porco MiniaturaRESUMO
AIM: The cholesterol-lowering drugs statins could enhance the activities of endothelial nitric oxide synthase (eNOS) and protect myocardium during ischemia and reperfusion. The aim of this study was to examine whether protein kinase A (PKA) was involved in statin-mediated eNOS phosphorylation and cardioprotection. METHODS: 6-Month-old Chinese minipigs (20-30 kg) underwent a 1.5-h occlusion and 3-h reperfusion of the left anterior descending coronary artery (LAD). In the sham group, the LAD was encircled by a suture but not occluded. Hemodynamic and cardiac function was monitored using a polygraph. Plasma activity of creatine kinase and the tissue activities of PKA and NOS were measured spectrophotometrically. p-CREB, eNOS and p-eNOS levels were detected using Western blotting. Sizes of the area at risk, the area of no-reflow and the area of necrosis were measured morphologically. RESULTS: Pretreatment of the animals with simvastatin (SIM, 2 mg/kg, po) before reperfusion significantly decreased the plasma activity of creatine kinase, an index of myocardial necrosis, and reduced the no-reflow size (from 50.4%±2.4% to 36.1%±2.1%, P<0.01) and the infarct size (from 79.0%±2.7% to 64.1%±4.5%, P<0.01). SIM significantly increased the activities of PKA and constitutive NOS, and increased Ser(133) p-CREB protein, Ser(1179) p-eNOS, and Ser(635) p-eNOS in ischemic myocardium. Intravenous infusion of the PKA inhibitor H-89 (1 µg·kg(-1)·min(-1)) partially abrogated the SIM-induced cardioprotection and eNOS phosphorylation. In contrast, intravenous infusion of the eNOS inhibitor L-NNA (10 mg·kg(-1)) completely abrogated the SIM-induced cardioprotection and eNOS phosphorylation during ischemia and reperfusion, but did not affect the activity of PKA. CONCLUSION: Pretreatment with a single dose of SIM 2.5 h before reperfusion attenuates myocardial no-reflow and infarction through increasing eNOS phosphorylation at Ser(1179) and Ser(635) that was partially mediated via the PKA signaling pathway.
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Anticolesterolemiantes/uso terapêutico , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Infarto do Miocárdio/prevenção & controle , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Óxido Nítrico Sintase Tipo III/metabolismo , Sinvastatina/uso terapêutico , Animais , Creatina Quinase/sangue , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Coração/efeitos dos fármacos , Hemodinâmica/efeitos dos fármacos , Infarto do Miocárdio/enzimologia , Infarto do Miocárdio/patologia , Traumatismo por Reperfusão Miocárdica/enzimologia , Traumatismo por Reperfusão Miocárdica/patologia , Miocárdio/enzimologia , Miocárdio/patologia , Fosforilação/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Suínos , Porco MiniaturaRESUMO
OBJECTIVE: Myocardial edema plays an important role in the development of myocardial no-reflow and reperfusion injury after the revascularization of acute myocardial infarction (AMI). The present study investigated whether the effect of ischemic preconditioning (IPC) against myocardial no-reflow and reperfusion injury was related to the reduction of myocardial edema through the protein kinase A (PKA) pathway. METHODS: Twenty-four minipigs were randomized into sham, AMI, IPC, and IPC + H-89 (PKA inhibitor, 1.0 µg · kg(-1) · min(-1)) groups. The area of no-reflow (ANR), area of necrosis (AN), and water content in left ventricle and ischemic-myocardium and non-ischemic area were determined by pathological studies. Microvascular permeability was determined by FITC-labeled dextran staining. Cardiomyocyte cross-sectional area (CSA) and mitochondria cross-sectional area (MSA) were evaluated by histological analysis. Myocardial expression of aquaporins (AQPs) was detected by Western blot. RESULTS: Compared with the MI group, the sizes of no-reflow and infarct were reduced by 31.9% and 46.6% in the IPC group (all P < 0.01), water content was decreased by 5.7% and 4.6% in the reflow and no-reflow myocardium of the IPC group (all P < 0.05), microvascular permeability and cardiomyocytes swelling in the reflow area were inhibited by 29.8% and 21.3% in the IPC group (all P < 0.01), mitochondrial water accumulation in the reflow and no-reflow areas of the IPC group were suppressed by 45.5% and 34.8% respectively (all P < 0.01), and the expression of aquaporin-4, -8, and -9 in the reflow and no-reflow myocardium were blocked in the IPC group. However, these beneficial effects of IPC were partially abolished in the IPC + H-89 group. CONCLUSIONS: The cardioprotective effects of IPC against no-reflow and reperfusion injury is partly related to the reduction of myocardial edema by inhibition of microvascular permeability and aquaporins up-regulation via PKA pathway.
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Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Precondicionamento Isquêmico , Infarto do Miocárdio/metabolismo , Traumatismo por Reperfusão Miocárdica/metabolismo , Animais , Aquaporinas/metabolismo , Permeabilidade Capilar , Edema/metabolismo , Edema/patologia , Infarto do Miocárdio/patologia , Traumatismo por Reperfusão Miocárdica/patologia , Miocárdio/metabolismo , Miocárdio/patologia , Suínos , Porco MiniaturaRESUMO
INTRODUCTION AND OBJECTIVES: Ischemia and ischemia/reperfusion can dephosphorylate and redistribute connexin 43 (Cx43). But it is unknown whether no-reflow phenomenon has an effect on the expression and distribution of Cx43 after acute infarction and reperfusion. METHODS: 21 open-chest pigs were divided into three groups. Left anterior descending artery (LAD) occlusion for 90 min before 180 min of reperfusion was made in ischemia/reperfusion group. The pigs in ischemia groups were either subjected to LAD ligation for 90 min or for 270 min. No-reflow and risk regions were determined pathologically by dye staining. Cx43 expression was measured by western blotting and quantitative RT-PCR analysis. Cx43 spatial distribution was shown by immunofluorescence examination. RESULTS: The content of phosphorylated and mRNA of Cx43 were higher in reflow region than in the no-reflow or sustained ischemic region. The distribution of Cx43 was also altered in no-reflow region. CONCLUSIONS: There are some differences in synthesis, expression and distribution of myocardial Cx43 at microvascular level after ischemia/reperfusion. Cx43 is partially rephosphorylated with reperfusion only in the reflow myocardium.
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Conexina 43/metabolismo , Isquemia Miocárdica/terapia , Reperfusão Miocárdica/efeitos adversos , Miocárdio/metabolismo , Fenômeno de não Refluxo/metabolismo , Animais , Western Blotting , Conexina 43/genética , Circulação Coronária , Modelos Animais de Doenças , Hemodinâmica , Microscopia de Fluorescência , Isquemia Miocárdica/metabolismo , Isquemia Miocárdica/fisiopatologia , Fenômeno de não Refluxo/genética , Fenômeno de não Refluxo/fisiopatologia , Fosforilação , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Suínos , Fatores de TempoRESUMO
The objective of the present study was to investigate whether pretreatment with single low loading dose of tongxinluo (TXL), a traditional Chinese medicine, 1 h before myocardial ischemia could attenuate no-reflow and ischemia-reperfusion injury by regulating endothelial nitric oxide synthase (eNOS) via the PKA pathway. In a 90-min ischemia and 3-h reperfusion model, minipigs were randomly assigned to the following groups: sham, control, TXL (0.05 g/kg, gavaged 1 h before ischemia), TXL + H-89 (a PKA inhibitor, intravenously infused at a dose of 1.0 µg·kg(-1)·min(-1) 30 min before ischemia), and TXL + N(ω)-nitro-L-arginine (L-NNA; an eNOS inhibitor, intravenously administered at a dose of 10 mg/kg 30 min before ischemia). TXL decreased creatine kinase (CK) activity (P < 0.05) and reduced the no-reflow area from 48.6% to 9.5% and infarct size from 78.5% to 59.2% (P < 0.05), whereas these effects of TXL were partially abolished by H-89 and completely reversed by L-NNA. TXL elevated PKA activity and the expression of PKA, Thr(198) phosphorylated PKA, Ser(1179) phosphorylated eNOS, and Ser(635) phosphorylated eNOS in the ischemic myocardium. H-89 repressed the TXL-induced enhancement of PKA activity and phosphorylation of eNOS at Ser(635), and L-NNA counteracted the phosphorylation of eNOS at Ser(1179) and Ser(635) without an apparent influence on PKA activity. In conclusion, pretreatment with a single low loading dose of TXL 1 h before ischemia reduces myocardial no-reflow and ischemia-reperfusion injury by upregulating the phosphorylation of eNOS at Ser(1179) and Ser(635), and this effect is partially mediated by the PKA pathway.
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Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Medicamentos de Ervas Chinesas/uso terapêutico , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Óxido Nítrico Sintase Tipo III/metabolismo , Transdução de Sinais/fisiologia , Animais , Creatina Quinase/sangue , Proteínas Quinases Dependentes de AMP Cíclico/antagonistas & inibidores , Relação Dose-Resposta a Droga , Medicamentos de Ervas Chinesas/farmacologia , Isoquinolinas/farmacologia , Modelos Animais , Traumatismo por Reperfusão Miocárdica/metabolismo , Fosforilação , Inibidores de Proteínas Quinases/farmacologia , Transdução de Sinais/efeitos dos fármacos , Sulfonamidas/farmacologia , Suínos , Porco MiniaturaRESUMO
BACKGROUND: An association between admission plasma glucose levels and an increased risk of no-reflow has been well documented. Although HMG-CoA reductase inhibitor (statin) therapy can reduce no-reflow, little is known about its effect on no-reflow in patients with hyperglycemia. In the present study, we investigated whether pretreatment with a statin could reduce no-reflow in patients with hyperglycemia, who underwent primary coronary intervention for acute myocardial infarction (AMI). METHODS: A total of 259 consecutive patients who underwent primary angioplasty for a first AMI were studied. Blood glucose and creatinine kinase levels were measured on admission. All patients underwent 2-dimensional echocardiography and electrocardiographic analysis just after admission. No-reflow was defined as a Thrombolysis in Myocardial Infarction (TIMI) flow grade <3. Hyperglycemia was defined as a blood glucose level >or=10 mmol/L. Statin administration prior to admission was determined by detailed interview or information in the medical records. RESULTS: Hyperglycemia was diagnosed in 154 patients on admission. The no-reflow phenomenon was found in 31 of the 154 patients with hyperglycemia. The incidence of no-reflow was significantly greater in patients with hyperglycemia compared with no hyperglycemia. A multivariable logistic regression analysis showed that hyperglycemia on admission was an independent predictor of no-reflow. Among the 154 patients with hyperglycemia, there were no significant differences in baseline clinical characteristics between patients who received statin pretreatment and those who did not; however, hyperlipidemia occurred in a greater number of the patients who did not receive statin pretreatment. The 40 patients with hyperglycemia who received statins before admission had a lower incidence of no-reflow than those who did not receive statin pretreatment (5% and 25.4%; p < 0.05). Multivariable logistic regression analysis revealed that absence of statin pretreatment was a significant predictor of no-reflow in patients with hyperglycemia, along with ejection fraction on admission, initial TIMI 0 flow, number of Q waves, and anterior AMI. CONCLUSION: The results of our study show that pretreatment with statins could attenuate no-reflow after AMI in patients with acute hyperglycemia.
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Angioplastia Coronária com Balão , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hiperglicemia/tratamento farmacológico , Fenômeno de não Refluxo/prevenção & controle , Doença Aguda , Glicemia/metabolismo , Angiografia Coronária , Circulação Coronária/efeitos dos fármacos , Ecocardiografia , Eletrocardiografia , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Hiperglicemia/complicações , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/diagnóstico por imagem , Infarto do Miocárdio/terapia , Fenômeno de não Refluxo/complicações , Valor Preditivo dos TestesRESUMO
OBJECTIVE: To assess the effects of tongxinluo on vascular endothelial integrity and myocardial no-reflow in early reperfusion of acute myocardial infarction. METHODS: Forty mini-swines were divided into five groups randomly, sham group, control group, low dose (0.1 g/kg), medium dose (0.2 g/kg) and high dose (0.4 g/kg) groups of Tongxinluo. It was administered at 2 hours pre-reperfusion. Animals except in sham group were subjected to 1.5 hour of coronary occlusion followed by 3 hours of reperfusion. Content of VE-cadherin, beta-catenin, matrix metalloproteinase (MMP)-2 and 9 in myocardium were evaluated; no-reflow area was examined with myocardial contrast echocardiography (MCE) at 1.5 hour of AMI and 3 hours of reperfusion. RESULTS: (1) Compared with that of normal myocardium, content of VE-cadherin and beta-catenin decreased in reperfusion and no-reflow myocardium while MMP-2 and 9 increased significantly (all P < 0.05); (2) Compared with that of control group, a high dose of Tongxinluo could increase significantly the content of VE-cadherin in both reperfusion and no-reflow myocardium, (22.2 +/- 3.2)% vs (32.0 +/- 3.9)% and (14.5 +/- 2.8)% vs (28.3 +/- 2.2)% respectively, beta-catenin, (20.5 +/- 3.5)% vs (27.3 +/- 2.9)% and (13.3 +/- 2.1)% vs (20.6 +/- 2.4)%, while reduce MMP-2, (48.3 +/- 4.1)% vs (29.4 +/- 3.5)% and (57.3 +/- 4.3)% vs (38.2 +/- 4.0)% respectively, MMP-9, (55.6 +/- 4.0)% vs (34.3 +/- 3.5)% and (62.4 +/- 4.8)% vs (44.4 +/- 4.1)%, all P < 0.05; (3) Compared with that of control group, a high dose of Tongxinluo could reduce significantly both no-reflow area, (6.6 +/- 1.7) cm2 vs (4.7 +/- 1.5) cm2, P < 0.05, and percentage (90.8 +/- 3.8)% vs (71.4 +/- 4.1)%, P < 0.05, at 3 hours of reperfusion. CONCLUSION: A high dose of tongxinluo could effectively maintain the integrity of vascular endothelium and attenuate no-reflow area in early reperfusion of acute myocardial infarction.
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Capilares/patologia , Medicamentos de Ervas Chinesas/uso terapêutico , Infarto do Miocárdio/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Fitoterapia , Animais , Medicamentos de Ervas Chinesas/farmacologia , Endotélio Vascular/efeitos dos fármacos , Feminino , Precondicionamento Isquêmico , Masculino , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Infarto do Miocárdio/patologia , Traumatismo por Reperfusão Miocárdica/patologia , Miocárdio , Suínos , Porco MiniaturaRESUMO
UNLABELLED: It has been verified that adenosine can attenuate myocardial no-reflow. However, the effects of adenosine on adenosine triphosphate-sensitive K+ (KATP) channel and endothelin-1 (ET-1) are unknown. METHODS: Forty mini-swines were randomized into 5 study groups: 8 in the control group, 8 in the adenosine pretreatment group, 8 in the glibenclamide (K(ATP) channel blocker)-treated group, 8 in the adenosine and glibenclamide-pretreated group and 8 in the sham-operated group. An acute myocardial infarction and reperfusion model was created with three-hour occlusion of the left anterior descending coronary artery followed by a one-hour reperfusion. RESULTS: Compared with the control group, adenosine significantly decreased the area of no-reflow (myocardial contrast echocardiography: from 78.5 +/- 4.5% to 20.7 +/- 4.1%, pathological means: from 82.3 +/- 1.9% to 21.5 +/- 4.3% of ligation area, respectively; all P < 0.01), reduced necrosis size from 98.5 +/- 1.3% to 75 +/- 4.7% of ligation area, P < 0.05). It also decreased plasma ET-1 and myocardial tissue ET-1. However, glibenclamide abrogated the protective effect of adenosine. CONCLUSION: The beneficial effect of adenosine on myocardial no-reflow could be due to its effect on ET-1 via the activation of K(ATP) channel.
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Adenosina/administração & dosagem , Circulação Coronária/efeitos dos fármacos , Endotelina-1/sangue , Canais KATP/metabolismo , Infarto do Miocárdio/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Vasodilatadores/administração & dosagem , Animais , Modelos Animais de Doenças , Ecocardiografia , Endotelina-1/efeitos dos fármacos , Injeções Intravenosas , Canais KATP/efeitos dos fármacos , Infarto do Miocárdio/diagnóstico , Infarto do Miocárdio/metabolismo , Traumatismo por Reperfusão Miocárdica/diagnóstico , Traumatismo por Reperfusão Miocárdica/metabolismo , Miocárdio/metabolismo , Miocárdio/patologia , Radioimunoensaio , Distribuição Aleatória , Suínos , Porco Miniatura , Resultado do TratamentoRESUMO
UNLABELLED: Simvastatin can prevent cardiac remodelling after myocardial infarction, though the exact mechanisms are uncertain. Myocardial no-reflow is associated with progressive cardiac remodelling. However, it remains unknown whether post-infarction treatment with simvastatin can also reduce myocardial no-reflow for which suppression of adenosine triphosphate-sensitive K+ (K(ATP)) channel opening is an important mechanism. METHODS: Area at risk and the area of no-reflow were determined by myocardial contrast echocardiography (MCE) and by pathology in 45 mini-swine randomised into 5 groups: 10 control, 9 simvastatin, 9 glibenclamide, 9 simvastatin plus glibenclamide and 8 sham-operated. A myocardial infarction and reperfusion model was created by 3-h occlusion of the coronary artery followed by 4 weeks of reperfusion. RESULTS: Compared with the control group, simvastatin significantly increased coronary blood volume (P<0.01) and decreased the area of no-reflow measured by MCE (78.5+/-4.5% to 43.7+/-4.3%) and pathological evaluation (82.3+/-1.9% to 45.2+/-3.8%) of area at risk (P<0.01). Simvastatin also increased the levels of K(ATP) channel proteins (SUR2 and Kir6.2) (P<0.05), but had no effect on necrosis area. The combination of simvastatin and glibenclamide had no significant effect on the above parameters. CONCLUSIONS: Post-infarction treatment with simvastatin can reduce myocardial no-reflow. This beneficial effect is due to activation of the K(ATP) channel.
Assuntos
Infarto do Miocárdio/tratamento farmacológico , Canais de Potássio Corretores do Fluxo de Internalização/fisiologia , Sinvastatina/uso terapêutico , Animais , Antígenos CD , Caderinas , Débito Cardíaco/efeitos dos fármacos , Colesterol/sangue , Modelos Animais de Doenças , Eletrocardiografia , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Canais KATP , Infarto do Miocárdio/patologia , Suínos , Porco Miniatura , Função Ventricular Esquerda/efeitos dos fármacosRESUMO
BACKGROUND: In animal models, pretreatment with angiotensin-converting enzyme inhibitor (ACEI) can reduce no-reflow. In the present study, we investigated whether pretreatment with ACEI may prevent no-reflow in patients who underwent primary coronary intervention for AMI. METHOD AND RESULTS: A total of 259 consecutive patients who underwent primary angioplasty for a first AMI were studied. No-reflow was defined as a TIMI flow grade < 3. The no-reflow phenomenon was found in 33 of 259 patients. There were no significant differences in clinical characteristics between the patients with and without ACEI pretreatment. However, the 47 patients receiving chronic ACEI treatment before admission had lower incidence of the no-reflow than those without it (4.2 and 14.6%, p<0.05). Multivariable logistic regression analysis revealed that absence of ACEI pretreatment was a significant predictor of the no-reflow along with absence of preinfarction angina, complete occlusion of the culprit lesion, high-burden thrombus, ejection fraction on admission, number of Q-waves, absence of statin pretreatment, and anterior AMI. CONCLUSION: Pretreatment with ACEI could preserve the microvascular integrity after acute myocardial infarction in humans.
Assuntos
Angioplastia Coronária com Balão , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Circulação Coronária/efeitos dos fármacos , Infarto do Miocárdio/fisiopatologia , Infarto do Miocárdio/terapia , Adulto , Idoso , Análise de Variância , Velocidade do Fluxo Sanguíneo/efeitos dos fármacos , Captopril/uso terapêutico , Angiografia Coronária , Eletrocardiografia , Enalapril/uso terapêutico , Feminino , Fosinopril/uso terapêutico , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/diagnóstico por imagem , Valor Preditivo dos Testes , Projetos de Pesquisa , Volume Sistólico/efeitos dos fármacos , Fatores de Tempo , Resultado do TratamentoRESUMO
OBJECTIVE: To evaluate the efficacy and safety of long-term treatment with arotinolol in patients with idiopathic dilated cardiomyopathy (IDCM). METHODS: Sixty-three patients with IDCM were evaluated at baseline and after 12-month therapy with arotinolol. The conventional therapy for congestive heart failure was continued throughout the study with arotinolol as the only beta-blocker. Left ventricular function was assessed with the New York Heart Association functional class and two-dimensional echocardiography. RESULTS: After 12-month arotinolol treatment, there was a significant improvement in left ventricular systolic function. Left ventricular end-systolic dimension significantly decreased from 59.52 +/- 8.83 mm to 50.89 +/- 8.17 mm (P < 0.001). Left ventricular ejection fraction significantly increased from 27.39% +/- 7.94% to 41.13% +/- 9.45% ( P < 0.001). Left ventricular mass index decreased from 150.47 +/- 42.42 g/m2 to 141.58 +/- 34.36 g/m2 (P < 0.01). No adverse events leading to premature discontinuation of study drug occurred. CONCLUSION: In this preliminary study, 12-month arotinolol treatment has a favorable effect on left ventricular function in patients with IDCM, and it is safe and well tolerated.
Assuntos
Antagonistas Adrenérgicos beta/farmacologia , Cardiomiopatia Dilatada/tratamento farmacológico , Propanolaminas/farmacologia , Função Ventricular Esquerda/efeitos dos fármacos , Antagonistas Adrenérgicos beta/efeitos adversos , Antagonistas Adrenérgicos beta/uso terapêutico , Adulto , Cardiomiopatia Dilatada/fisiopatologia , Ecocardiografia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Propanolaminas/efeitos adversos , Propanolaminas/uso terapêuticoRESUMO
INTRODUCTION: It has been found that nicorandil can attenuate myocardial no-reflow. However, the exact cause of this beneficial effect has remained unclear. We investigated whether the beneficial effect of nicorandil on myocardial no-reflow could be partly due to its protection against endothelial dysfunction. METHODS: Ligation area and area of no-reflow were determined echocardiographically and pathologically in sixty-two animals randomized into 7 study groups: 9 controls, 9 nicorandil-treated, 8 glibenclamide (K(ATP) channel blocker)-treated, 10 N(G)-monomethyl-L-arginine (L-NMMA, nonselective nitric oxide synthase antagonist)-treated, 10 nicorandil and glibenclamide-treated, 8 nicorandil and L-NMMA-treated and 8 sham-operated. The acute myocardial infarction and reperfusion model was created with one 3-h occlusion of the left anterior descending coronary artery followed by 2 h of reperfusion. Constitutive nitric oxide synthase (cNOS) activity and inducible nitric oxide synthase (iNOS) activity were also quantified. RESULTS: Compared with the control group, nicorandil significantly improved ventricular function, increased coronary blood flow volume (P<0.01), decreased area of no-reflow and reduced necrosis area. Nicorandil also increased the cNOS activity and decreased iNOS activity (P<0.05). L-NMMA and glibenclamide abrogated the effects of nicorandil on ventricular function, coronary blood flow volume, area of no-reflow, necrosis area and cNOS activity, but not iNOS activity. CONCLUSIONS: The beneficial effect of nicorandil on myocardial no-reflow could be due to its protection of endothelial function via the activation of K(ATP) channel.
Assuntos
Circulação Coronária/efeitos dos fármacos , Células Endoteliais/efeitos dos fármacos , Endotélio Vascular/efeitos dos fármacos , Infarto do Miocárdio/tratamento farmacológico , Nicorandil/farmacologia , Canais de Potássio/metabolismo , Animais , Anti-Hipertensivos/farmacologia , Células Endoteliais/metabolismo , Endotélio Vascular/fisiopatologia , Glibureto/farmacologia , Infarto do Miocárdio/fisiopatologia , Óxido Nítrico Sintase/análise , Tamanho do Órgão/efeitos dos fármacos , Suínos , Porco Miniatura , Regulação para CimaRESUMO
BACKGROUND: Both fosinopril and valsartan are effective in protecting endothelial function. We hypothesized that they may also reduce myocardial no-reflow. In addition, suppression of adenosine triphosphate-sensitive K (KATP) channel opening is an important mechanism for myocardial no-reflow. Therefore, this study sought to assess the effect of fosinopril and valsartan on myocardial no-reflow and explore the possible mechanism. METHODS: Coronary ligation area and the area of no-reflow were determined with both myocardial contrast echocardiography in vivo and pathological means in 56 mini-swine randomized into seven study groups: eight in control, eight in fosinopril-pretreated (1 mg/kg/day) for 3 days, eight in fosinopril and glibenclamide (KATP channel blocker)-pretreated, eight in valsartan-pretreated (2 mg/kg/day) for 3 days, eight in valsartan and glibenclamide-pretreated, eight in glibenclamide-treated and eight in sham-operated. An acute myocardial infarction and reperfusion model was created with a 3-h occlusion of the coronary artery followed by a 2-h reperfusion. The levels of KATP channel proteins (SUR2, Kir6.1, and Kir6.2) in the reflow and no-reflow myocardium were quantified by Western blotting. RESULTS: Compared with the control group, both fosinopril and valsartan significantly improved ventricular function, decreased area of no-reflow (myocardial contrast echocardiography: from 78.5+/-4.5 to 24.5+/-2.7 and 24.3+/-3.6%, pathological means: from 82.3+/-1.9 to 25.2+/-3.2 and 24.9+/-4.4% of ligation area, respectively; all P<0.01), reduced necrosis size from 98.5+/-1.3 to 88.9+/-3.6 and 89.1+/-3.1% of ligation area, respectively (both P<0.05). They also increased the levels of SUR2 and Kir6.2 (P<0.01), but had no effect on the level of Kir6.1 (P>0.05). A combination of fosinopril or valsartan with glibenclamide significantly increased area of no-reflow (P<0.05) and decreased the levels of SUR2 and Kir6.2 (P<0.01). CONCLUSIONS: Pretreatment with fosinopril or valsartan can reduce myocardial no-reflow. This beneficial effect is due to activation of the KATP channel.
Assuntos
Anti-Hipertensivos/farmacologia , Fosinopril/farmacologia , ATPase Trocadora de Hidrogênio-Potássio/efeitos dos fármacos , Infarto do Miocárdio/prevenção & controle , Reperfusão Miocárdica , Tetrazóis/farmacologia , Valina/análogos & derivados , Doença Aguda , Animais , Anti-Hipertensivos/uso terapêutico , Velocidade do Fluxo Sanguíneo/efeitos dos fármacos , Quimioprevenção , Endotélio/efeitos dos fármacos , Fosinopril/uso terapêutico , Modelos Animais , Miocárdio , Suínos , Tetrazóis/uso terapêutico , Fatores de Tempo , Valina/farmacologia , Valina/uso terapêutico , ValsartanaRESUMO
OBJECTIVE: To evaluate the effect of adenosine on endothelin-1 (ET-1) after acute myocardial infarction (AMI) and reperfusion and explore the possible mechanism of no-reflow. METHODS: Twenty-four mini-swine were randomized into three study groups: control group (n=8), adenosine treated group (n=8), and sham-operated group (n=8). The mini-swine in the groups were subjected to 3 hours of coronary occlusion, followed by 60 minutes of reperfusion except those in the sham-operated group. The levels of ET-1 in blood sample, normal, infracted reflow and no-reflow myocardium were evaluated by radioimmuno-assay (RIA). The gene expressions of ET-1 in normal, infracted reflow and no-reflow myocardium were quantified by reverse transcription-polymerase chain reaction. RESULTS: In both control group and adenosine group, compared with that at the baseline, ET-1 in blood sample significantly increased at 5 minutes and 180 minutes of left anterior descending coronary artery occlusion, as well as 5 and 60 minutes of reperfusion (all P < 0.01). In adenosine group, the levels of ET-1 were significantly lower than those in the control group (P < 0.05, P < 0.01). In both control group and adenosine group, compared with that in normal myocardium, ET-1 levels in both infarcted reflow and no-reflow myocardium significantly increased (both P < 0.01), with the level of ET-1 in no-reflow myocardium significantly higher than that in infarcted reflow myocardium (P < 0.01). In adenosine group, the level of ET-1 in infarcted reflow myocardium was significantly lower than that in the control group (P < 0.01). In both control and adenosine groups, compared with that in normal myocardium, the gene expression of ET-1 in infarcted reflow myocardium was significantly up-regulated (P < 0.01), while that of ET-1 in. no-reflow myocardium significantly down-regulated (P < 0.01). In adenosine group, the level of ET-1 in infarcted reflow myocardium was significantly lower than that in the control group (P < 0.01). CONCLUSION: The endothelium injury may be one of the important mechanisms for no-reflow phenomenon. Adenosine cay prevent endothelium from injury to reduce no-reflow.
Assuntos
Adenosina/uso terapêutico , Endotelina-1/metabolismo , Infarto do Miocárdio/fisiopatologia , Adenosina/farmacologia , Animais , Modelos Animais de Doenças , Endotelina-1/genética , Feminino , Masculino , Infarto do Miocárdio/tratamento farmacológico , Reperfusão Miocárdica , Suínos , Porco MiniaturaRESUMO
OBJECTIVE: To evaluate the beneficial effects of diltiazem on myocardial no-reflow. METHODS: Twenty-four mini-swine were randomized into 3 equal groups: diltiazem-treated group subjected to 3 hours of coronary occlusion to cause acute myocardial infarction (AMI), followed by 60 minutes of reperfusion and injected with diltiazem into the coronary artery 1 minute before reperfusion, control group undergoing coronary occlusion followed by 60 minutes of reperfusion and injected with normal saline, and sham operation group. 5 minutes before AMI in all groups and 180 minutes after AMI and 60 minutes after re-perfusion in the diltiazem and control groups, hemodynamic data, such as heart rate (HR), left ventricular systolic pressure (LVSP). Left ventricular end diastolic pressure (LVEDP), +/- dp/dt(max), cardiac output (CO), and coronary blood volume (CBV) were measured. Myocardial contrast echography (MCE) was used to measure the left ventricle wall area (LVWA) and ligation area (LA) so as to calculate LA and to measure the area of no-reflow (ANR) so as to calculate ANR. 60 minutes after reperfusion thioflavin-S was injected into left ventricle so as to color the reperfused area and then the descending anterior branch was re-ligated and Evan's blue was injected into the left ventricle to color the area outside the ligation area. The heart was taken out to undergo histological examination. RESULTS: (1) In comparison with the values before AMI the LVSP, +/- dp/dt(max), and CO of the control group significantly declined (P < 0.05, 0.01), while the LVEDP significantly increased (P < 0.01) by the end of 3 hours after LAD occlusion; and the LVSP significantly increased and the +/- dp/dt(max) further significantly declined (both P < 0.05) 60 minutes after reperfusion. In the diltiazem group, the changes of LVSP, +/- dp/dt(max), CO, and LVEDP were the same as those in the control group after 3 hours of AMI, while the +/- dp/dt(max), CO, and LVEDP recovered significantly, more significantly than those in the control group, 60 minutes after reperfusion (all P < 0.05). (2) In the control group, the sizes of coronary ligation area (LA) measured by both MCE in vivo and histopathological evaluation were similar (P > 0.05), and the values of area of no-reflow (ANR) measured by MCE in vivo and histopathological evaluation were 78.5% and 82.3% respectively with the final necrosis area (NA) reaching 99% of the LA. There was no significant difference in LA measured by both MCE and histopathological evaluation between the control and diltiazem groups, while the values of ANR measured by both methods was significantly decreased to 19.9% and 20.6% that before AMI respectively in the diltiazem group (both P < 0.01). There was no significant difference in NA between the control and diltiazem groups (P > 0.05). The CBV of the control group was significantly declined to 45.8% and 50.6% of the baseline value respectively immediately and 60 minutes after reperfusion (both P < 0.01), while the CBV of the diltiazem group became 80.4% and 79.3% of the baseline value respectively immediately and 60 minutes after reperfusion (both P < 0.05), both significantly higher than those of the control group (both P < 0.01). CONCLUSION: Diltiazem is effective both in preventing myocardial no-reflow and improving left ventricular function, but not in reducing MI size during AMI and reperfusion.