Abstract:Aim To investigate the inhibition role and mechanism of adipose derived mesenchymal stem cell (ADMSC) exosomes (Exo) on adverse ventricular remodeling after myocardial infarction (MI). Methods The changes of autophagy and inflammasomes phenotype of cardiac fibroblasts after H2O2 treatment were observed. MI rats were injected with an equal volume of normal saline, adipose derived mesenchymal stem cell exosomes (MSC-Exo) or fibroblast exosomes (MEF-Exo) via a tail vein. The expression of autophagy related 16 like protein 1 (ATG16L1), autophagy related protein 7 (ATG7) and NOD-like receptor protein 3 (NLRP3), inflammatory response, the degree of myocardial fibrosis, and the cardiac function were observed in different groups. Results After treatment with H2O2 on cardiac fibroblasts, the expressions of ATG16L1 and ATG7 were significantly decreased (P＜0.001), NLRP3 was significantly increased (P＜0.001), and the levels of inflammatory cytokines interleukin-1β (IL-1β) and IL-18 were significantly elevated (P＜0.001). After MI rats were intervened with MSC-Exo, the expressions of autophagy related proteins ATG16L1 and ATG7 were significantly up-regulated (P＜0.001), NLRP3 was significantly down-regulated (P＜0.001), serum IL-1β and IL-18 levels were significantly decreased (P＜0.001), fibrosis-related proteins collagen Ⅰ and Ⅲ were significantly reduced (P＜0.001), myocardial fibrosis was significantly relieved (P＜0.001), and cardiac function was significantly improved (P＜0.001). Conclusion Adipose derived MSC-Exo play a role in inhibiting adverse ventricular remodeling after MI by regulating the balance of autophagy and NLRP3 inflammasomes.

Abstract:Aim To investigate the effect and possible mechanism of oxymatrine injection (OMT) on cardiac function and ventricular remodeling in doxorubicin-induced chronic heart failure (CHF) rats. Methods The rat model with CHF was established by intraperitoneal injection (ip) of adriamycin (1.5 mg/kg, twice a week for 6 weeks).The model group, captopril injection (CTP, 6.5 mg/kg) group and OMT low (25 mg/kg), medium (50 mg/kg), high (100 mg/kg) dose group were set up, and the control group was set up, with 10 rats in each group. The rats in each group were treated by intraperitoneal injection once a day. 4 weeks later, the cardiac function indexes (left ventricular end-systolic diameter (LVESD), left ventricular end-diastolic diameter (LVEDD), left ventricular fractional shortening (LVFS), stroke volume (SV)) were measured through animal ultrasound; the content of cardiac troponin I (cTnI), brain natriuretic peptide (BNP), stromelysin-2 (ST2) in serum were detected by enzyme-linked immunosorbent assay (ELISA); the left ventricular hypertrophy index (LVHI) was calculated; the morphological changes and fibrosis of myocardial tissue were observed by HE staining and Masson staining; the expression of collagen I (Coll-1), α smooth muscle actin (α-SMA), transforming growth factor-β1 (TGF-β1), Smad2, p-Smad2, Smad3, p-Smad3, Smad7 were detected by Western blot. Results Compared with the model group, the LVESD and LVEDD were decreased in CTP group and OMT low, medium, high dose groups; the LVFS, LVEF and SV were increased (all P＜0.05). The contents of cTnI, BNP and ST2 were decreased (all P＜0.05). The pathological changes and fibrosis of myocardial tissue were significantly improved, and the collagen volume fraction (CVF) were decreased (P＜0.05). The expressions of Coll-1, α-SMA and TGF-β1 were decreased; the ratio of p-Smad2/Smad2 and p-Smad3/Smad3 were decreased; the expression of Smad7 were increased (all P＜0.05). The effect of OMT on various indexes of CHF rats were dose-dependent, and the effect of OMT high-dose group on various indexes were significantly better than those of CTP group. Conclusion OMT can improve cardiac function and inhibit ventricular remodeling in CHF rats, which mechanism may be related to the inhibition of TGF-β1/Smads signaling pathway.

Abstract:Aim To observe the changes in indexes of ventricular remodeling and adverse drug reactions in patients with acute myocardial infarction (AMI) before and after treatment, and evaluate the efficacy and safety of different doses of sarcubatrix/valsartan in the treatment of heart failure patients after AMI. Methods 174 patients with acute ST-segment elevation myocardial infarction (STEMI) and subnormal left ventricular ejection fraction (LVEF) ＜50% from March 2018 to March 2022 were randomly allocated to receive maximal tolerated dose of sacubitril/valsartan (titrated up to maximal tolerated dose or 200 mg, Bid, n＝80) or low dose sacubitril/valsartan (50 mg, Bid, n＝94) treatment, they also received conventional treatment. The changes in echocardiographic parameters, serum N-terminal pro-brain natriuretic peptide(NT-proBNP) and adverse drug reactions (symptomatic hypotension, hyperkalemia, kidney function decline and angioedema, et al) from baseline to 12 months after discharge were assessed. Results After treatment, there was statistically significant difference in left atrial diameter (LAD) of maximum tolerated dose group and low dose group compared with baseline (P＜0.05), however, there was no statistically significant difference between the two groups (P＞0.05). The left ventricular end diastolic diameter (LVEDD) were significantly decreased in two groups compared with baseline (P＜0.05), but there was no statistically significant difference between the two groups (P＞0.05). The left ventricular ejection fraction(LVEF) were significantly increased in both groups compared with baseline (P＜0.05), but there was no statistically significant difference between the two groups (P＞0.05). The decrease of serum NT-proBNP levels was higher in maximum tolerated dose group than that in low dose group (P＜0.05). The incidence of drug-related adverse reactions was higher in the maximum tolerated group (17.5% vs 2.1%, P＜0.05). Conclusion Compared with low dose sacubitril/valsartan group, the maximum tolerated dose group did not show significant advantages in improving cardiac remodeling and LVEF. Although it may be possible to reduce cardiovascular events by further reducing NT-proBNP levels, strict titration of the maximum tolerable dose was closely related to frequent adverse drug reactions.

Abstract:Recent related studies suggest that osteopontin is related to the severity of cardiac insufficiency, and its mechanism is related to mediating the expression of extracellular matrix and the regulation of the renin angiotensin aldosterone system, which is expected to be a new biochemical indicator for clinical evaluation of patients with heart failure. This article reviews the structure and function of osteopontin and its mechanism and significance related to heart failure.

Abstract:Aim To investigate the protection effect of microRNA-22 on cardiac function and ventricular remodeling after myocardial infarction. Methods The study constructed mouse myocardial infarction model and transfected adenovirus containing microRNA-22 into peri-infarct area. It assessed cardiac function four weeks after myocardial infarction by using echocardiography. Mouse exercise ability was assessed by swimming. HE and Masson staining was applied to assess microstructure and fibrosis of myocardium. Results Over-expressing of microRNA-22 improved mouse left ventricular ejection fraction (LVEF) percentage (49.38%±2.51% vs 42.29%±2.74%, P<0.05) and fractional shortening (FS) percentage (24.24±0.64% vs 22.59%±0.73%, P<0.05) compared with adeno-null group. Mouse in adeno-microRNA-22 group showed longer swimming time and better exercise ability (8.13±1.01 min vs 7.02±1.32 min, P<0.05).HE and Masson staining also showed better cardiac microstructure and less fibrosis. Adeno-microRNA-22 group showed elevated microRNA-22 expression (6.66±2.01 vs 1.22±0.07, P<0.05) and down-regulated PTEN protein expression (0.63±0.19 vs 2.23±0.44, P<0.05). Conclusion Over-expression of microRNA-22 protected mouse cardiac function and reduced ventricular remodeling after myocardial infarction.

Abstract:Aim To investigate the effect of asiatic acid (AA) on angiogenesis and ventricular remodeling in acute myocardial infarction (AMI) rats and its mechanism, based on the changes of silent information regulator 3 (SIRT3)/β-catenin/peroxisome proliferator activated receptor γ (PPARγ) signaling pathway during the development of AMI. Methods A total of 72 SD rats was randomly divided into groups according to the principle of weight balance. 12 of them were in the blank control group, and the AMI model was made in the remaining rats. After successful modeling, according to the random number table method rats were randomly divided into 5 groups:model group, positive control group, AA high dose group, AA medium dose group and AA low dose group, 12 rats in each group. The blank control group and the model group were given normal saline, the positive control group was given aspirin enteric-coated tablets, and the drug intervention group was given different doses of AA. 28 days later, Doppler ultrasound was used to detect angiogenesis and ventricular remodeling in each group. Reverse transcription polymerase chain reaction (RT-PCR) was used to detect the expressions of SIRT3, β-catenin and PPARγ mRNA in rat myocardium. The levels of inflammatory factors interleukin-6 (IL-6), tumor necrosis factor α (TNF-α), nuclear factor κB (NF-κB) were detected by enzyme linked immunosorbent assay.Results Compared with the blank control group, the cardiac function was worse, the microvascular density (MVD) increased, the expressions of SIRT3, β-catenin, PPARγ mRNA and the serum levels of IL-6, TNF-α, NF-κB were all increased, in the model group (P＜0.05). Compared with the model group, the cardiac function was obviously improved, MVD increased, the expressions of SIRT3, β-catenin and PPARγ mRNA increased, and the levels of serum IL-6, TNF-α and NF-κB decreased, in each AA drug adiministration group (P＜0.05). Compared with the positive control group, the cardiac function was improved, the MVD increased, the expressions of SIRT3, β-catenin and PPARγ mRNA in the myocardium increased, and the levels of serum IL-6, TNF-α and NF-κB decreased, in the high, middle and low dose groups of AA (P＜0.05). Conclusion Asiatic acid inhibits SIRT3/β-catenin/PPARγ signaling pathway in infarcted myocardium of rats, and has protective effect on myocardial tissue of AMI rats.

Abstract:Aim To explore the effect of Baicalin on blood pressure and left ventricular remodeling in rats with renal hypertension. Methods Amogn 40 male Wistar rats 10 were randomly selected for sham operation group, which renal hypertensive rat model was established by using two kidney one clip method. The rats with renal hypertension were randomly divided into model group and Baicalin group after 6 weeks, eventually alive rats were devided into sham operation group (n=9), model group (n=10) and Baicalin group (n=11) for 4 weeks intervention. During the experiment, the general situation of rats was observed, and the blood pressure were detected before operation, operation after 6 weeks, and intervention for 4 weeks; high frequency echocardiography were detected after 4 weeks and the cardiac function indexes were measured. The rats were sacrificed and the heart was removed. The morphological changes of myocardial tissue was observed by using HE staining, Masson staining. The myocardial apoptosis was detected by TUNEL method and the expression of endoplasmic reticulum chaperone glucose regulated protein(GRP78), glucose regulated protein(GRP94) in myocardial cell of rats were also detected by real-time PCR and Western blot. The expression of CCAAT/enhancer binding protein homologous protein(CHOP) and Caspase 3 was monitored by Western blot. Results Compared with model group, there was significant change of blood pressure in Baicalin group (P<0.05), and the indexes of left ventricular remodeling were significantly improved after the echocardiography(P<0.05). Compared with model group, the integral of pathological myocardial fibrosis and fibrosis related factors matrix metalloprotein-9(MMP-9), matrix metalloprotein-2(MMP-2), connective tissue growth factor(CTGF) and transforming growth factor-β1(TGF-β1) expression was significantly decreased in Baicalin group(P<0.05). Compared with model group, the expression of GRP78, GRP94, CHOP, Caspase 3 and apoptosis of cardiomyocyte were significantly decreased in Baicalin group(P<0.05). Conclusion Baicalin had a certain antihypertensive effect, it could improve the left ventricular remodeling in renal hypertensive rats, reduce myocardial pathological changes, ease the endoplasmic reticulum stress and reduce apoptosis in myocardial cell.

Abstract:Aim To investigate the role of galectin-3 (Gal-3) in ventricular remodeling of heart insufficiency, via the pathway of Gal-3 specific competitive antagonist--modified citrus pectin (MCP) inhibiting Gal-3. Methods 30 rabbits were randomly divided into sham operation group, cardiac insufficiency group and MCP group. A model of cardiac dysfunction after myocardial infarction was made by ligating the anterior descending branch of coronary artery. After the model was successfully made, MCP group was treated with 75 g/L MCP allocated with normal saline, and intragastric administration for 4 weeks with 2 mL/(kg·d), and sham operation group and cardiac insufficiency group received the intragastric administration of 2 mL/(kg·d) normal saline for 4 weeks. Before operation and 2,4, 6 weeks after operation, cardiac function was measured by cardiac ultrasound, and serum levels of Gal-3 and brain natriuretic peptide (BNP) were detected by ELISA. The mRNA expressions of Gal-3, collagen Ⅰ and Ⅲ in myocardial tissue were detected by real-time quantitative PCR, and the ratio of Ⅰ/Ⅲ was calculated. 6 weeks after operation, Masson staining was used to observe the histopathology of myocardial infarction region, and the protein expressions of Gal-3, collagen Ⅰ and Ⅲ were detected by Western blot. Results After 4 weeks of administration, the heart function of the MCP group was significantly improved compared with the cardiac insufficiency group (P＜0.01). The serum Gal-3 in cardiac insufficiency group was higher than that in sham operation group (P＜0.05), and serum Gal-3 in MCP group was significantly lower than that in cardiac insufficiency group (P＜0.05). Correlation analysis showed that left ventricular ejection fraction was negatively correlated with serum Gal-3 (r＝－0.841, P＝0.009), and left ventricular end-diastolic diameter was positively correlated with serum Gal-3 (r＝0.905, P＝0.002), in cardiac insufficiency group. Compared with cardiac insufficiency group, the mRNA expression of Gal-3, collagen Ⅰ and Ⅲ in MCP group was significantly decreased (P＜0.05). Under optical microscope, cardiac insufficiency group showed myocardial cell disorder, part of myocardial cell necrosis, edema, acollagen deposition and inflammatory cell infiltration; MCP group showed myocardial fiber thickening, arranging in a slightly tidy order. Protein expressions of Gal-3, collagen Ⅰ and Ⅲ in the infarcted myocardium of cardiac insufficiency group were significantly higher than those in MCP group and sham operation group. Correlation analysis showed that Gal-3 in infarction region was positively correlated with collagen Ⅲ in cardiac insufficiency group (r＝0.793, P＝0.019). Conclusion Gal-3 plays a key role in the progressions of ventricular remodeling and myocardial fibrosis in heart failure.

Abstract:Aim To investigate the value of serum vascular endothelial growth factor-B (VEGF-B) in the prognosis evaluation of patients with acute myocardial infarction(AMI). Methods Sixty-two patients with AMI were selected as case group in the department of cardiology from March 2014 to October 2015, and the elbow venous blood of AMI patients were immediately drawn before discharge, and enzyme-linked immunosorbent assay (ELISA) method was used for determining the concentrations of serum VEGF-B. The increased values (ΔEDV, ΔM) of the left ventricular end diastolic volume(LVEDV), left ventricular mass(LVM) and the occurrence of major adverse cardiac events(MACE) of the AMI patients were followed up within sixty days after discharge. The AMI patients were divided into ΔEDV≤0 group and ΔEDV>0 group, ΔM≤0 group and ΔM>0 group respectively according to the ΔEDV level and ΔM level. According to MACE occurrence, the AMI patients were divided into the MACE group and non-MACE group. The predictive value of VEGF-B concentration before discharge was analysed to left ventricular remodeling(LVR) and MACE after discharge. The relationship between MACE and LVR in AMI patients after discharge was also analysed. Results According to the results of the follow-up, the concentration of serum VEGF-B of ΔEDV≤0 group ((110.61±38.29) μg/L, n=34) was significantly higher than that of ΔEDV>0 group ((67.74±24.32) μg/L, n=26), the concentration of serum VEGF-B of ΔM≤0 group ((112.46±39.91) μg/L, n=32) was significantly higher than that of ΔM>0 group ((70.24±23.17) μg/L, n=28), the concentration of serum VEGF-B of the MACE group ((53.73±15.70) μg/L, n=25) was significantly lower than that of non-MACE group ((111.95±33.16) μg/L, n=37), the differences were statistically significant (P<0.01). The incidence of MACE in LVR group (100%) was higher than that of non-LVR group (5.26%), the difference was statistically significant (P<0.01). Conclusion For AMI patients, the lower concentration of serum VEGF-B before discharge, the more LVR obviously after discharge. Low level of VEGF-B predicts LVR after AMI. For AMI patients, the lower concentration of serum VEGF-B before discharge, the higher incidence of MACE after discharge. The concentration of serum VEGF-B before discharge can be used as a prediction index of MACE occurrence after discharge.

Abstract:Aim To explore the effect of Nrf2 gene in silent bone marrow mesenchymal stem cells （MSC） that take siRNA as the vector on the myocardial fibrosis and ventricular remodeling after the treatment of rat myocardial infarction （MI） with its transplantation as well as to investigate the potential mechanism of this process.Methods The established MI rat models were randomly divided into MSC transplantation group with silent Nrf2 gene （MSCNrf2－/－）,MSC transplantation group with over expression of Nrf2 gene （MSCNrf2＋/＋）,and MSC transplantation group with PBS （control group）,12 rats in each group. At the 28 th day after cell transplantation,the collagen deposition and fibrosis degrees after MI were evaluated using myocardial tissue Masson staining,the expression levels of infarcted myocardium Nrf2 and heme oxygenase-1 （HO-1） proteins were detected using Western blot,LVEDD,LVESD and LVEF were evaluated using echocardiography.Results At the 28 th day after cell transplantation,Masson staining results showed that myocardial tissue fibrosis degree in MSCNrf2－/－ group was severer than that in control group （P<0.05）,but the MSCNrf2＋/＋group showed to decrease with control group （P<0.05）. Western blot results showed that the Nrf2 and HO-1 protein expression decreased in MSCNrf2－/－ group with a statistically significant difference compared with control group （P<0.05）,however,the Nrf2 and HO-1 protein expression in MSCNrf2＋/＋ group significantly increased compared with control group （P<0.05）. Echocardiography results showed that LVEDD and LVESD values increased and LVEF value decreased in MSCNrf2－/－ group with a statistically significant difference compared with control group （P<0.05）. While the comparison of control group,LVEDD and LVESD values decreased and LVEF value increased in MSCNrf2＋/＋ group.Conclusions Nrf2 siRNA can effectively interfere the expression of Nrf2 in MSC and reduce the repair ability of exogenous MSC for MI heart,which will increase the collagen deposition in infarcted area,thus contributing to ventricular remodeling and reducing cardiac function.