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OBJECTIVE@#To evaluate the feasibility and tolerability of metoprolol standard dosing pathway (MSDP) in Chinese patients with acute coronary syndrome (ACS).@*METHODS@#In this multicenter, prospective, open label, single-arm and interventional study that was conducted from February 2018 to April 2019 in fifteen Chinese hospitals. A total of 998 hospitalized patients aged ≥ 18 years and diagnosed with ACS were included. The MSDP was applied to all eligible ACS patients based on the standard treatment recommended by international guidelines. The primary endpoint was the percentage of patients achieving the target dose at discharge (V2). The secondary endpoints included the heart rate and blood pressure at V2 and four weeks after discharge (V4), and percentage of patients experiencing bradycardia (heart rate < 50 beats/min), hypotension (blood pressure < 90/60 mmHg) and transient cardiac dysfunction at V2 and V4.@*RESULTS@#Of the 998 patients, 29.46% of patients achieved the target dose (≥ 95 mg/d) at V2. The total population was divided into two groups: target group (patients achieving the target dose at V2) and non-target group (patients not achieving the target dose at V2). There was significant difference in the reduction of heart rate from baseline to discharge in the two groups (-4.97 ± 11.90 beats/min vs. -2.70 ± 9.47 beats/min, P = 0.034). There was no significant difference in the proportion of bradycardia that occurred in the two groups at V2 (0 vs. 0, P = 1.000) and V4 (0.81% vs. 0.33%, P = 0.715). There was no significant difference in the proportion of hypotension between the two groups at V2 (0.004% vs. 0.004%, P = 1.000) and V4 (0 vs. 0.005%, P = 0.560). No transient cardiac dysfunction occurred in two groups during the study. A total of five adverse events (1.70%) and one serious adverse event (0.34%) were related to the pathway in target group.@*CONCLUSIONS@#In Chinese ACS patients, the feasibility and tolerability of the MSDP have been proved to be acceptable.
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Objective To establish a modified induction method for differentiation of rat pancreatic ductal stem cells (rPDSCs) to form islet-like cells. Methods All-trans retinic acid(ATRA) was added at 2, 4, 6 and 8 jjimol/L in the basal culture medium DMEM/F12 + 10% FBS + 1% penicillin/1% streptomycin to induce the differentiation of rPDSCs to form islet-like cells in vitro, and the optimal induction concentration of ATRA was screened. Based on the optimal ATRA induction concentration, rPDSCs were then induced to form islet-like cells in vitro by matrigel culture, suspension culture or hanging drop culture, respectively, to screen the optimal induction culture method . Cell morphology, dithizone(DTZ) staining, cell immunofluorescence staining, Real-time PCR and ELISA were used to detect the induced islet-like cells. Results Compared with the control group, 6 (jumol/L ATRA and matrigel culture were the best in the basic culture medium. After 28 days of induction, the cells enriched and differentiated to form islet-like spherical cell clusters; DTZ staining was positive; Pancreatic duodenal homeobox-1 (Pdxl) and insulin were expressed at gene and protein levels, respectively; Glucose stimulation, release insulin and C-peptide, showed glucose concentration dependent. Conclusion The in vitro differentiation of rPDSCs to form islet-like cells could be successfully induced by using 6 |xmol/L ATRA + DMEM/F12+10% FBS+1% double antibody under matrigel culture method in the present study.
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<p><b>BACKGROUND</b>The cholesterol-lowering statin drugs have some non-lipid-lowering effects, such as inhibiting myocardial remodeling. However, the underlying mechanism is still unclear.</p><p><b>METHODS</b>The left anterior descending coronary artery was ligated to establish a rat model of heart failure, and the rats were divided into a sham operation (SO) group, myocardial infarction model (MI) group, and MI-atorvastatin group. Changes in hemodynamic parameters were recorded after the final drug administration. Histological diagnosis was made by reviewing hematoxylin and eosin (HE) stained tissue. Real-time quantitative polymerase chain reaction (PCR) was performed to determine the expressions of type I and type III collagen, matrix metalloproteinase-2 (MMP-2), and tissue matrix metalloproteinase inhibitor-2 (TIMP-2). Further, primary rat cardiac fibroblasts were cultured and the MTT assay was performed to determine the effect of atorvastatin on cardiac fibroblast proliferation.</p><p><b>RESULTS</b>The model of heart failure was established and the results of HE staining and Masson's trichrome staining revealed that the rats in the heart failure group showed obvious hyperplasia of fibrotic tissue, which was significantly reduced in the atorvastatin group. Real-time quantitative PCR showed that the MI group showed a significantly increased expression of type I and type III collagen, MMP-2, and TIMP-2, but a significantly reduced MMP-2/TIMP-2 ratio. Compared with the MI group, the atorvastatin group showed significantly reduced expression of type I and III collagen, unchanged expression of MMP-2, significantly reduced expression of TIMP-2, and an increased MMP-2/TIMP-2 ratio. We further found that atorvastatin significantly inhibited the Ang II-induced fibroblast proliferation and the expression of type I and type III collagen in cardiac fibroblasts while increasing the MMP-2/TIMP-2 ratio.</p><p><b>CONCLUSIONS</b>These data suggest that atorvastatin can inhibit cardiac fibroblast proliferation and enhance collagen degradation by increasing the MMP-2/TIMP-2 ratio, thereby inhibiting the formation of myocardial fibrosis in rats with heart failure after myocardial infarction.</p>
Subject(s)
Animals , Female , Rats , Atorvastatin , Collagen , Disease Models, Animal , Fibrosis , Heart Failure , Drug Therapy , Pathology , Heptanoic Acids , Pharmacology , Therapeutic Uses , Hydroxymethylglutaryl-CoA Reductase Inhibitors , Pharmacology , Matrix Metalloproteinase 2 , Genetics , Myocardial Infarction , Myocardium , Pathology , Pyrroles , Pharmacology , Therapeutic Uses , Rats, Wistar , Tissue Inhibitor of Metalloproteinase-2 , Genetics , Ventricular RemodelingABSTRACT
<p><b>BACKGROUND</b>Inflammation plays a pivotal role in cardiac remodeling, especially in myocardial fibrosis. Abnormal growth of cardiac fibroblasts is critically involved in the pathophysiology of cardiac hypertrophy/remodeling. Previous study has demonstrated that many inflammation stimulating factors trigger transforming growth factor-β (TGF-β) induction and reactive myocardial fibrosis. Activin A (ACT A) is a member of TGF-β superfamily, and follistatin (FS) is an activin-binding protein, i.e. an antagonist of ACT A. Our previous studies have shown that ACT A-FS imbalance occurs in rats with heart failure (HF), and overexpression of ACT A can lead to ventricular remodeling, and resultant HF. Low expression of FS after myocardial infarction further exacerbated HF. The pathogenic change resulting from overexpression of ACT A is consistent with that of overexpression of angiotensin II (AngII). Ventricular remodeling includes cardiocyte remodeling and myocardial interstitial collagen deposition and fibrosis. Therefore, the present study was designed to investigate the effects of inflammatory factors on the ACT A-FS and the secretions of cardiac fibroblasts in order to explore in depth the mechanism of myocardial fibrosis.</p><p><b>METHODS</b>A rat model with HF was established, and the results showed that there was a greater degree of cardiac fibrosis in HF rats. In addition, we found that there was an imbalance of the ACT A/FS system in HF rats, which was characterized by increased levels of ACT A. Further, primary rat cardiac fibroblasts were cultured and the MTT assay was performed to determine the effect of the inflammatory factor-bacterial endotoxin lipopolysaccharide (LPS) on cardiac fibroblast proliferation.</p><p><b>RESULTS</b>The results showed that LPS can stimulate the cardiac fibroblasts to proliferate in a dose-dependent manner. Cellular immunohistochemical staining showed that the rat cardiac fibroblasts themselves could express ACT A and FS proteins, and stimulation by LPS could apparently promote the cultured primary rat cardiac fibroblasts to secrete ACT A, but inhibit the secretion of FS. The results also showed that ACT A promoted, in a dose-dependent manner, the proliferation of the cultured primary rat cardiac fibroblasts, and the expression of collagen types I and III. Moreover, ACT A promoted, in a dose dependent manner, the cardiac fibroblasts to secrete nitric oxide (NO), and unregulated the expression of inducible nitric oxide synthase (iNOS) mRNA.</p><p><b>CONCLUSIONS</b>These results suggest that the inflammatory mediator LPS can promote ACT A-FS imbalance in cardiac fibroblasts, mainly overexpression of ACT A. Overexpression of ACT A promotes the proliferation and the secretion of collagens in cardiac fibroblasts through autocrine/paracrine stimulation of NO, and is involved in the pathological process of myocardial fibrosis.</p>