Dapagliflozin and sacubitril on myocardial microperfusion in patients with post-acute myocardial infarction heart failure and type 2 diabetes

BACKGROUND Coronary heart disease and type 2 diabetes mellitus(T2DM)frequently coexist,creating a complex and challenging clinical scenario,particularly when complicated with acute myocardial infarction(AMI).AIM To examine the effects of dapagliflozin combined with sakubactrovalsartan sodium tablets on myocardial microperfusion.METHODS In total,98 patients were categorized into control(n=47)and observation(n=51)groups.The control group received noxital,while the observation group was treated with dapagliflozin combined with noxital for 6 months.Changes in myocardial microperfusion,blood glucose level,cardiac function,N-terminal prohormone of brain natriuretic peptide(NT-proBNP)level,growth differentiation factor-15(GDF-15)level,and other related factors were compared between the two groups.Additionally,the incidence of major adverse cardiovascular events(MACE)and adverse reactions were calculated.RESULTS After treatment,in the observation and control groups,the corrected thrombolysis in myocardial infarction frame counts were 37.12±5.02 and 48.23±4.66,respectively.The NT-proBNP levels were 1502.65±255.87 and 2015.23±286.31 pg/mL,the N-terminal pro-atrial natriuretic peptide(NT-proANP)levels were 1415.69±213.05 and 1875.52±241.02 ng/mL,the GDF-15 levels were 0.87±0.43 and 1.21±0.56 g/L,and the high-sensitivity C-reactive protein(hs-CRP)levels were 6.54±1.56 and 8.77±1.94 mg/L,respectively,with statistically significant differences(P<0.05).The cumulative incidence of MACEs in the observation group was significantly lower than that in the control group(P<0.05).The incidence of adverse reactions was 13.73%(7/51)in the observation group and 10.64%(5/47)in the control group,with no statistically significant difference(P>0.05).CONCLUSION Dapagliflozin combined with nocinto can improve myocardial microperfusion and left ventricular remodeling and reduce MACE incidence in patients with post-AMI heart failure and T2DM.The underlying mechanism may be related to the reduction in the expression levels of NT-proANP,GDF-15,and hs-CRP.

Electroacupuncture improves myocardial fibrosis in heart failure rats by attenuating ECM collagen deposition through modulation of TGF-β1/Smads signaling pathway

Background: To explore the effects of electroacupuncture on cardiac function and myocardial fibrosis in rat models of heart failure, and to elucidate the underlying mechanism of electroacupuncture in heart failure treatment. Methods: Healthy male Sprague-Dawley rats were allocated into three groups: Sham group, Model group, and electroacupuncture (Model + EA) group, with each group comprising 8 rats. The model underwent a procedure involving the ligation of the left anterior descending coronary artery to induce a model of heart failure. The Model + EA group was used for 7 consecutive days for electroacupuncture of bilateral Shenmen (HT7) and Tongli (HT5), once a day for 30 min each time. Left ventricular parameters in rats were assessed using a small-animal ultrasound machine to analyze changes in left ventricular end-diastolic volume, left ventricular end-systolic volume, left ventricular ejection fraction, and left ventricular fractional shortening. Serum interleukin-1β (IL-1β), cardiac troponin (cTn), and N-terminal brain natriuretic peptide precursor levels were measured using ELISA. Histopathological changes in rat myocardium were observed through HE staining, while collagen deposition in rat myocardial tissue was assessed using the Masson staining method. Picro sirius red staining, immunohistochemical staining, and RT-qPCR were utilized to distinguish between the various types of collagen deposition. The expression level of TGF-β1 and SMAD2/3/4/7 mRNA in rat myocardial tissues was determined using RT-qPCR. Additionally, western blot analysis was conducted to assess the protein expression levels of TGF-β1, SMAD3/7, and p-SMAD3 in rat myocardial tissues. Results: Compared with the Sham group, the left ventricular ejection fraction and left ventricular fractional shortening values of the Model group were significantly decreased (P < 0.01);the left ventricular end-diastolic volume and left ventricular end-systolic volume values were remarkably increased (P < 0.01);serum N-terminal brain natriuretic peptide precursor content was increased (P < 0.01);serum IL-1β and cTn levels were increased (P < 0.01);myocardial collagen volume fraction were increased (P < 0.01);and those of the expression of TGF-β1 and SMAD2/3/4 mRNA was increased (P < 0.01);the expression of SMAD7 mRNA was decreased (P < 0.01);the protein expression levels of TGF-β1, SMAD3, and p-Smad3 were increased (P < 0.01);the protein expression level of SMAD7 was decreased (P < 0.01) in the Model group. Compared to the Model group, the expression levels of the proteins TGF-β1, SMAD3, and p-Smad3 in myocardial tissue were found to be decreased (P < 0.01), and the expression level of the protein SMAD7 was found to be increased (P < 0.01) in the Model + EA group;the collagen volume fraction and deposition of type Ⅰ /Ⅲ collagen were decreased (P < 0.01) in the Model + EA group. Conclusion: Electroacupuncture alleviates myocardial fibrosis in rats with heart failure, and this effect is likely due to attributed to the modulation of the TGF-β1/Smads signaling pathway, which helps reduce collagen deposition in the extracellular matrix.

Metabolic dysfunction-associated steatotic liver disease-associated fibrosis and cardiac dysfunction in patients with type 2 diabetes

BACKGROUND Metabolic dysfunction-associated steatotic liver disease(MASLD),particularly in the presence of liver fibrosis,increases the risk of cardiovascular morbidity and mortality,but the nature of the cardio-hepatic interaction in the context type 2 diabetes mellitus(T2DM)is not fully understood.AIM To evaluate the changes in cardiac morphology and function in patients with T2DM and MASLD-associated liver fibrosis.METHODS T2DM patients with MASLD underwent a medical evaluation that included an assessment of lifestyle,anthropometric measurements,vital signs,an extensive laboratory panel,and a standard echocardiography.Liver fibrosis was evaluated using two scores[Fibrosis-4(FIB4)and Non-alcoholic fatty liver disease-Fibrosis Score(NFS)],and subjects were classified as having advanced fibrosis,no fibrosis,or an indeterminate risk.The correlations between structural and functional cardiac parameters and markers of liver fibrosis were evaluated through bivariate and multiple regression analyses.Statistical significance was set at P<0.05.RESULTS Data from 267 T2DM-MASLD subjects with complete assessment was analyzed.Patients with scores indicating advanced fibrosis exhibited higher interventricular septum and left ventricular(LV)posterior wall thickness,atrial diameters,LV end-systolic volume,LV mass index(LVMi),and epicardial adipose tissue thickness(EATT).Their mean ejection fraction(EF)was significantly lower(49.19%±5.62%vs 50.87%±5.14%vs 52.00%±3.25%;P=0.003),and a smaller proportion had an EF≥50%(49.40%vs 68.90%vs 84.21%;P=0.0017).Their total and mid LV wall motion score indexes were higher(P<0.05).Additionally,they had markers of diastolic dysfunction,with a higher E/e’ratio[9.64±4.10 vs 8.44(2.43-26.33)vs 7.35±2.62;P=0.026],and over 70%had lateral e’values<10 cm/second,though without significant differences between groups.In multiple regression analyses,FIB4 correlated with left atrium diameter(LAD;β=0.044;P<0.05),and NFS with both LAD(β=0.039;P<0.05)and right atrium diameter(β=0.041;P<0.01),Moreover,LVMi correlated positively with age and EATT(β=1.997;P=0.0008),and negatively with serum sex-hormone binding protein(SHBP)concentrations(β=-0.280;P=0.004).SHBP also correlated negatively with LAD(β=-0.036;P<0.05).CONCLUSION T2DM patients with markers of MASLD-related liver fibrosis exhibit lower EF and present indicators of diastolic dysfunction and cardiac hypertrophy.Additionally,LVMi and LAD correlated negatively with serum SHBP concentrations.

Atorvastatin ameliorated myocardial fibrosis in db/db mice by inhibiting oxidative stress and modulating macrophage polarization

BACKGROUND People with diabetes mellitus(DM)suffer from multiple chronic complications due to sustained hyperglycemia,especially diabetic cardiomyopathy(DCM).Oxidative stress and inflammatory cells play crucial roles in the occurrence and progression of myocardial remodeling.Macrophages polarize to two distinct phenotypes:M1 and M2,and such plasticity in phenotypes provide macrophages various biological functions.AIM To investigate the effect of atorvastatin on cardiac function of DCM in db/db mice and its underlying mechanisms.METHODS DCM mouse models were established and randomly divided into DM,atorvastatin,and metformin groups.C57BL/6 mice were used as the control.Cardiac function was evaluated by echocardiography.Hematoxylin and eosin and Masson staining was used to examine the morphology and collagen fibers in myocardial tissues.The expression of transforming growth factor-β1(TGF-β1),tumor necrosis factor-α(TNF-α),interleukin-1β(IL-1β),M1 macrophages(iNOS^(+)),and M2 macrophages(CD206^(+))were demonstrated by immunohistochemistry and immunofluorescence staining.The levels of TGF-β1,IL-1β,and TNF-αwere detected by ELISA and real-time quantitative polymerase chain reaction.Malondialdehyde(MDA)concentrations and superoxide dismutase(SOD)activities were also measured.RESULTS Treatment with atorvastatin alleviated cardiac dysfunction and decreased db/db mice. The broken myocardialfibers and deposition of collagen in the myocardial interstitium were relieved especially by atorvastatin treatment.Atorvastatin also reduced the levels of serum lactate dehydrogenase, creatine kinase isoenzyme, and troponin;lowered the levels of TGF-β1, TNF-α and IL-1β in serum and myocardium;decreased the concentration of MDAand increased SOD activity in myocardium of db/db mice;inhibited M1 macrophages;and promoted M2macrophages.CONCLUSION Administration of atorvastatin attenuates myocardial fibrosis in db/db mice, which may be associated with theantioxidative stress and anti-inflammatory effects of atorvastatin on diabetic myocardium through modulatingmacrophage polarization.

Liraglutide Suppresses Myocardial Fibrosis Progression by Inhibiting the Smad Signaling Pathway

Objective Liraglutide is a commonly used hypoglycemic agent in clinical practice,and has been demonstrated to have protective effects against the development of cardiovascular disease.However,its potential role in myocardial fibrosis remains unexplored.The present study aims to assess the impact of liraglutide on the activation of cardiac fibroblasts.Methods Primary rat adult fibroblasts were isolated,cultured,and randomly allocated into 4 groups:control group,transforming growth factor beta1(TGFβ1)stimulation group,liraglutide group,and TGFβ1+liraglutide group.Fibroblast activation was induced by TGFβ1.Cell proliferation activity was assessed using the CKK-8 kit,and cellular activity was determined using the MTT kit.Reverse transcrition-quantitative polymerase chain reaction(RT-qPCR)was utilized to quantify the level of collagen transcription,immunofluorescence staining was performed to detect the expression level of type III collagen andα-smooth muscle protein(α-SMA),and immunoblotting was conducted to monitor alterations in signal pathways.Results The addition of 10,25,50 and 100 nmol/L of liraglutide did not induce any significant impact on the viability of fibroblasts(P>0.05).The rate of cellular proliferation was significantly higher in the TGFβl stimulation group than in the control group.However,the treatment with 50 and 100 nmol/L of liraglutide resulted in the reduction of TGFβl-induced cell proliferation(P<0.05).The RT-qPCR results revealed that the transcription levels of type I collagen,type III collagen,andα-SMA were significantly upregulated in the TGFβl stimulation group,when compared to the control group(P<0.05).However,the expression levels of these aforementioned factors significantly decreased in the TGFβl+liraglutide group(P<0.05).The immunofluorescence staining results revealed a significant increase in the expression levels of type III collagen andα-SMA in the TGFβl stimulation group,when compared to the control group(P<0.05).However,these expression levels significantly decreased in the TGFβl+liraglutide group,when compared to the TGFβl stimulation group(P<0.05).The Western blotting results revealed that the expression levels of phosphorylated smad2 and smad3 significantly increased in the TGFβl stimulation group,when compared to the control group(P<0.05),while these decreased in the TGFβl+liraglutide group(P<0.05).Conclusion Liraglutide inhibits myocardial fibrosis development by suppressing the smad signaling pathway,reducing the activation and secretion of cardiac fibroblasts.

Dapagliflozin in heart failure and type 2 diabetes:Efficacy,cardiac and renal effects,safety

BACKGROUND Heart failure(HF),especially HF with reduced ejection fraction(HFrEF),presents complex challenges,particularly in the aging population where it often coexists with type 2 diabetes mellitus(T2DM).AIM To analyze the effect of dapagliflozin treatment on cardiac,renal function,and safety in patients with HFrEF combined with T2DM.METHODS Patients with T2DM complicated with HFrEF who underwent treatment in our hospital from February 2018 to March 2023 were retrospectively analyzed as the subjects of this study.The propensity score matching method was used,and a total of 102 eligible samples were scaled.The clinical efficacy of the two groups was evaluated at the end of the treatment,comparing the results of blood glucose,insulin,cardiac function,markers of myocardial injury,renal function indexes,and 6-min walk test(6MWT)before and after the treatment.We compared the occurrence of adverse effects on the treatment process of the two groups of patients.The incidence of adverse outcomes in patients within six months of treatment was counted.RESULTS The overall clinical efficacy rate of patients in the study group was significantly higher than that of patients in the control group(P=0.013).After treatment,the pancreatic beta-cell function index,left ventricular ejection fraction,and glomerular filtration rate of patients in the study group were significantly higher than control group(P<0.001),while their fasting plasma glucose,2-h postprandial glucose,glycosylated hemoglobin,insulin resistance index,left ventricular end-systolic diameter,left ventricular end-diastolic diameter,cardiac troponin I,creatine kinase-MB,N-terminal pro b-type natriuretic peptide,serum creatinine,and blood urea nitrogen were significantly lower than those of the control group.After treatment,patients in the study group had a significantly higher 6MWT than those in the control group(P<0.001).Hypoglycemic reaction(P=0.647),urinary tract infection(P=0.558),gastrointestinal adverse effect(P=0.307),respiratory disturbance(P=0.558),and angioedema(P=0.647)were not statistically different.There was no significant difference between the incidence of adverse outcomes between the two groups(P=0.250).CONCLUSION Dapagliflozin significantly enhances clinical efficacy,cardiac and renal function,and ambulatory capacity in patients with HFrEF and T2DM without an increased risk of adverse effects or outcomes.

Hyperglycemia-induced myocardial fibrosis may be associated with pyroptosis and apoptosis of cardiomyoctes in diabetic mice

Myocardial fibrosis is an important manifestation of diabetic cardiomyopathy.This study investigated the potential mechanism of diabetic myocardial fibrosis.Male C57BL/6J and db/db mice aged 8 weeks were randomly divided into the diabetic(DB)and control groups.At 20 weeks,the mouse heart was harvested and subjected to hematoxylin-eosin staining(HE)and Masson staining to investigate the degree of fibrosis.The expressions of transforming growth factor-beta 1(TGF-β1),collagen-III,B-cell lymphoma-2(Bcl2),Bcl2-associated X protein(Bax),cleaved gasdermin D(GSDMD),cysteinyl aspartate specific proteinase-1(caspase-1),apoptosis-associated speck-like protein containing a CARD(ASC),and nucleotide-binding oligomerization domain(NOD)-like receptor 3(NLRP3)were measured by western blotting.Immunohistochemistry and TdT-mediated dUTP nick end labeling(TUNEL)staining were performed to analyze the development of apoptosis and pyroptosis.A significant increase in body weight and blood glucose in the DB group was observed.Myocardial pathological injury,fibrosis,apoptosis,and pyroptosis were more obvious and serious in the DB group.The expression of anti-apoptotic Bcl2 significantly decreased,while the expression levels of pro-apoptotic Bax,caspase-3,and pyroptosis-related proteins,such as cleaved GSDMD,and caspase-1 in the DB group were significantly increased.Pyroptosis and apoptosis were probably the main mechanisms that caused myocardial fibrosis in mice with diabetes.

Long-term quality-of-care score for predicting the occurrence of acute myocardial infarction in patients with type 2 diabetes mellitus

BACKGROUND Cardiovascular disease(CVD)is the leading cause of death globally,and diabetes mellitus(DM)is a well-established risk factor.Among the risk factors for CVD,DM is a major modifiable factor.In the fatal CVD outcomes,acute myocardial infarction(AMI)is the most common cause of death.AIM To develop a long-term quality-of-care score for predicting the occurrence of AMI among patients with type 2 DM on the basis of the hypothesis that good quality of care can reduce the risk of AMI in patients with DM.METHODS Using Taiwan’s Longitudinal Cohort of Diabetes Patients Database and the medical charts of a medical center,we identified incident patients diagnosed with type 2 DM from 1999 to 2003 and followed them until 2011.We constructed a summary quality-of-care score(with values ranging from 0 to 8)with process indicators(frequencies of HbA1c and lipid profile testing and urine,foot and retinal examinations),intermediate outcome indicators(low-density lipoprotein,blood pressure and HbA1c),and co-morbidity of hypertension.The associations between the score and the incidence of AMI were evaluated using Cox regression models.RESULTS A total of 7351 patients who had sufficient information to calculate the score were enrolled.In comparison with participants who had scores≤1,those with scores between 2 and 4 had a lower risk of developing AMI[adjusted hazard ratio(AHR)=0.71;95% confidence interval(95%CI):0.55-0.90],and those with scores≥5 had an even lower risk(AHR=0.37;95%CI:0.21-0.66).CONCLUSION Good quality of care can reduce the risk of AMI in patients with type 2 DM.The quality-of-care score developed in this study had a significant association with the risk of AMI and thus can be applied to guiding the care for these patients.

Network-pharmacology-based research on protective effects and underlying mechanism of Shuxin decoction against myocardial ischemia/reperfusion injury with diabetes

BACKGROUND Patients with diabetes mellitus are at higher risk of myocardial ischemia/reperfusion injury(MI/RI).Shuxin decoction(SXT)is a proven recipe modification from the classic herbal formula"Wu-tou-chi-shi-zhi-wan"according to the traditional Chinese medicine theory.It has been successfully used to alleviate secondary MI/RI in patients with diabetes mellitus in the clinical setting.However,the underlying mechanism is still unclear.AIM To further determine the mechanism of SXT in attenuating MI/RI associated with diabetes.METHODS This paper presents an ensemble model combining network pharmacology and biology.The Traditional Chinese Medicine System Pharmacology Database was accessed to select key components and potential targets of the SXT.In parallel,therapeutic targets associated with MI/RI in patients with diabetes were screened from various databases including Gene Expression Omnibus,DisGeNet,Genecards,Drugbank,OMIM,and PharmGKB.The potential targets of SXT and the therapeutic targets related to MI/RI in patients with diabetes were intersected and subjected to bioinformatics analysis using the Database for Annotation,Visualization and Integrated Discovery.The major results of bioinformatics analysis were subsequently validated by animal experiments.RESULTS According to the hypothesis derived from bioinformatics analysis,SXT could possibly ameliorate lipid metabolism disorders and exert anti-apoptotic effects in MI/RI associated with diabetes by reducing oxidized low density lipoprotein(LDL)and inhibiting the advanced glycation end products(AGE)-receptor for AGE(RAGE)signaling pathway.Subsequent animal experiments confirmed the hypothesis.The treatment with a dose of SXT(2.8 g/kg/d)resulted in a reduction in oxidized LDL,AGEs,and RAGE,and regulated the level of blood lipids.Besides,the expression of apoptosis-related proteins such as Bax and cleaved caspase 3 was down-regulated,whereas Bcl-2 expression was up-regulated.The findings indicated that SXT could inhibit myocardial apoptosis and improve cardiac function in MI/RI in diabetic rats.CONCLUSION This study indicated the active components and underlying molecular therapeutic mechanisms of SXT in MI/RI with diabetes.Moreover,animal experiments verified that SXT could regulate the level of blood lipids,alleviate cardiomyocyte apoptosis,and improve cardiac function through the AGE-RAGE signaling pathway.

Update on evidence-based clinical application of sodium-glucose cotransporter inhibitors:Insight to uncommon cardiovascular disease scenarios in diabetes

In this paper,we concentrate on updating the clinical research on sodium-glucose cotransporter inhibitors(SGLTis)for patients with type 2 diabetes who have heart failure with a preserved injection fraction,acute heart failure,atrial fibrillation,primary prevention of atherosclerotic cardiovascular disease/cardiovascular disease,and acute myocardial infarction.We searched the data of randomized controlled trials and meta-analyses of SGLTis in patients with diabetes from PubMed between January 1,2020 and April 6,2024 for our review.According to our review,certain SGLTis(empagliflozin,dapagliflozin,canagliflozin,and tofogliflozin),but not sodium-glucose cotransporter 1 inhibitor(SGLT1i),exhibit relatively superior clinical safety and effectiveness for treating the abovementioned diseases.Proper utilization of SGLTis in these patients can foster clinical improvement and offer an alternative medication option.However,clinical trials involving SGLTis for certain diseases have relatively small sample sizes,brief intervention durations,and conclusions based on weak evidence,necessitating additional data.These findings are significant and valuable for providing a more comprehensive reference and new possibilities for the clinical utilization and scientific exploration of SGLTis.

Paeoniflorin Attenuates Myocardial Fibrosis in Isoprenaline-induced Chronic Heart F ailure Rats via Inhibiting P38 MA PK Pathway

Paconiflorin(Pae)is a monoterpenoid glycoside compound and has many biological activitics,such as immunosuppression,anti-inflammation and anti-cell proliferation.However,the effects and mechanisms of Pae on chronic heart failure(CHF)remain unclear.This study was conducted to assess the effects and mechanisms of Pae on myocardial fibrosis in isoprenaline(Iso)-induced CHF rats.Pae(20 mgkg)was intragastrically administrated to CHF rats for 6 weeks.Cardiac structure and function were assessed.The protein and mRNA levels of transforming growth factorβ1(TGF-β1)and p38 were detected.C ompared to Iso group,Pae could alleviate myocardial fbrosis and improve cardiac function in CHF rats.The levels of collagen volume fraction(13.75%+3.77%vs.30.97%+4.22%,P<0.001)and perivascular collagen volume area(14.32%+2.50%v8.28.31%+3.16%,P<0.001)were significantly reduced in Pae group as compared with those in Iso group.The expression of TGF-BI protein(0.30+0.07 vs.0.66+0.07,P<0.05)and mRNA(3.51+0.44 vs.7.58+0.58,P<0.05)decreased significantly in Pac group as compared with that in Iso group.The expression of p38 protein(0.36+0.12 vs.0.81+0.38,P<0.05)and mRNA(3.84+0.05 vs.4.40+0.17,P<0.05)also decreased markedly in Pae group as compared with that in Iso group.Pae could attenuate myocardial fibrosis and improve cardiac function in CHF rats by down-regulating the p38 MAPK signaling pathway.

Taurine Inhibits Myocardial Fibrosis via PKC-ERK1/2 Signaling Pathways

Previous studies have demonstrated the important role of taurine in inhibiting proliferation of myofibrob lasts（myoFb） and myocardial fibrosis. However, the underlying mechanisms are unclear. The present study was de signed to shed light on this issue through exploring the signal pathways via in vitro experiments. Angiotension II （AngII） treatment significantly increased myoFb proliferation and the levels of collagens I and III（P〈0.05）, whereas taurine, PKCα（PKC： protein kinase C） specific inhibitor L-threo-dihydro-sphingosine（D4681）, ERK1/2 inhibitor （PD98095） abrogated myoFb proliferation and collagen levels（P〈0.05, P〈0.01, respectively）, and increased the G0/G1 phase rate and decreased S phase rate. Immunocytochemistry, confocal fluorescence staining and image analy sis showed that taurine could inhibit the translocation and expression of p-PKCαin membrane, and then inhibit nuc lear translocation and expression of p-ERK1/2. These results have statistically significant differences compared with those of AngII group（P〈0.01）. Western blot results also show that taurine could inhibit the protein expression of p-PKCα and p-ERK1/2. We used p-PKCα specific inhibitor D4681 in order to elucidate the relationship between p-PKCα and p-ERK1/2 in signal transduction pathways. Finally, the results show that the protein expression of p-ERK1/2 and nuclear translocation were suppressed in D4681 group.

The role of glycogen synthase kinase 3 beta in brain injury induced by myocardial ischemia/reperfusion injury in a rat model of diabetes mellitus

Myocardial ischemia/reperfusion injury can lead to severe brain injury.Glycogen synthase kinase 3 beta is known to be involved in myocardial ischemia/reperfusion injury and diabetes mellitus.However,the precise role of glycogen synthase kinase 3 beta in myocardial ischemia/reperfusion injury-induced brain injury is unclear.In this study,we observed the effects of glycogen synthase kinase 3 beta on brain injury induced by myocardial ischemia/reperfusion injury in diabetic rats.Rat models of diabetes mellitus were generated via intraperitoneal injection of streptozotocin.Models of myocardial ischemia/reperfusion injury were generated by occluding the anterior descending branch of the left coronary artery.Post-conditioning comprised three cycles of ischemia/reperfusion.Immunohistochemical staining and western blot assays demonstrated that after 48 hours of reperfusion,the structure of the brain was seriously damaged in the experimental rats compared with normal controls.Expression of Bax,interleukin-6,interleukin-8,terminal deoxynucleotidyl transferase d UTP nick end labeling,and cleaved caspase-3 in the brain was significantly increased,while expression of Bcl-2,interleukin-10,and phospho-glycogen synthase kinase 3 beta was decreased.Diabetes mellitus can aggravate inflammatory reactions and apoptosis.Ischemic post-conditioning with glycogen synthase kinase 3 beta inhibitor lithium chloride can effectively reverse these changes.Our results showed that myocardial ischemic post-conditioning attenuated myocardial ischemia/reperfusion injury-induced brain injury by activating glycogen synthase kinase 3 beta.According to these results,glycogen synthase kinase 3 beta appears to be an important factor in brain injury induced by myocardial ischemia/reperfusion injury.

Effects of Ligustrazine on Myocardial Fibrosis in Rats with Pressure Overload

Objective: To investigate the effects of ligustrazine (Li) on myocardial fibrosis in rats with pressure overload. Methods: Pressure overload rat models were established by constricting the abdominal a-orta. Sixty-three SD rats were divided into 3 groups: Sham operated group (SOG, n = 21), operated group (OG, n = 21) and operated combined with ligustrazine group (OG+Li, n = 21). Each group was randomly assigned to seven time points: The 1st, 2nd, 4th, 7th, 14th, 21st and 30th day after operation. Three rats were included in each time point. Serial sections of cardiac tissues were examined and the morphological or morphometric analysis of the SOG, OG and OG+Li done by histopathological and computer image analyzer technique. Results: (1) It showed that there were reactive fibrosis (from the 4th day on after operation) and reparative fibrosis (from the 21st day on after operation) in the OG, while myocardial fibrosis in the OG+Li was alleviated. Though reactive fibrosis (from the 21st day on after operation) was shown, reparative fibrosis wasn't seen. (2) Perivascular collagen area (PVCA) in the OG (2. 09±0. 45) was significantly higher than SOG (0. 83±0.06) from the 1st day on after operation and then steadily increased, while in the OG+Li (1.16±0.06), it was significantly lower than OG at the same time; collagen volume fraction (CVF) in the OG (3.08±0. 56) significantly increased compared with the SOG (2. 78±0. 64) from the 2nd day on after operation and showed a trend of rapid ascending from the 21st day on after operation; and in the OG + Li (4.69±0.85), it was significantly decreased compared with the OG (7.56±0.88) from the 21st day on after operation, with all P<0.05. Conclusion: Ligustrazine could alleviate and postpone the accumulation of myocardial collagen and has protective effects on the heart.

Association of electrocardiographic markers with myocardial fibrosis as assessed by cardiac magnetic resonance in different clinical settings

BACKGROUND Cardiac magnetic resonance(CMR)is a unique tool for non-invasive tissue characterization,especially for identifying fibrosis.AIM To present the existing data regarding the association of electrocardiographic(ECG)markers with myocardial fibrosis identified by CMR-late gadolinium enhancement(LGE).METHODS A systematic search was performed for identifying the relevant studies in Medline and Cochrane databases through February 2021.In addition,we conducted a relevant search by Reference Citation Analysis(RCA)(https://www.referencecitationanalysis.com).RESULTS A total of 32 studies were included.In hypertrophic cardiomyopathy(HCM),fragmented QRS(fQRS)is related to the presence and extent of myocardial fibrosis.fQRS and abnormal Q waves are associated with LGE in ischemic cardiomyopathy patients,while fQRS has also been related to fibrosis in myocarditis.Selvester score,abnormal Q waves,and notched QRS have also been associated with LGE.Repolarization abnormalities as reflected by increased Tp-Te,negative Twaves,and higher QT dispersion are related to myocardial fibrosis in HCM patients.In patients with Duchenne muscular dystrophy,a significant correlation between fQRS and the amount of myocardial fibrosis as assessed by LGE-CMR was observed.In atrial fibrillation patients,advanced inter-atrial block is defined as P-wave duration≥120 ms,and biphasic morphology in inferior leads is related to left atrial fibrosis.CONCLUSION Myocardial fibrosis,a reliable marker of prognosis in a broad spectrum of cardiovascular diseases,can be easily understood with an easily applicable ECG.However,more data is needed on a specific disease basis to study the association of ECG markers and myocardial fibrosis as depicted by CMR.

Study on key genes and pathways of myocardial fibrosis and prediction of effective traditional Chinese medicine

Objectives:Bioinformatics was applied to screen the key genes of Myocardial fibrosis,explore its pathogenesis and predict the potential traditional Chinese medicines for the treatment of Myocardial fibrosis.Methods:Based on raw data of gene chip GSE59437 from gene expression database(GEO),myocardial tissue samples from 3 control mice and 3 mice treated with angiotensin II-induced myocardial fibrosis were included.Using R language processing data and screening of gene express significant differences(DEG),use a database of DAVID and the R language finish Gene Ontology(GO)annotation and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway enrichment for differences gene,using the STRING database structure protein protein interactions(PPI)networks,using Cytoscape software visualization and use the MCODE plug-in screening key function modules in the network.Coremine Medical database was used to map the key genes,construct the gene-Chinese medicine network,and screen the traditional Chinese medicines for the treatment of myocardial fibrosis.Results:208 DEGs were screened,94 of which were up-regulated and 114 were down-regulated.DEGs is mainly involved in a variety of biological processes such as extracellular matrix remodeling,collagen fiber deposition and lipid metabolism disorders.KEGG pathway enrichment involves Platelet activation,Oxytocin signaling pathway,Insulin secretion,ECM-receptor interaction,GnRH signaling pathway,TNF signaling pathway and other signaling pathways.Key modules of PPI network including:CTGF,TIMP1,SPP1,SERPINE1,COL3A1,POSTN and FOS.The potential traditional Chinese medicines for the treatment of myocardial fibrosis are Astragalus membranaceus(Fisch.),Lepidium apetalum Willd and Salvia miltiorrhiza Bge.Conclusion:Myocardial fibrosis is a complex pathological process,and the genes related to the imbalance of extracellular matrix synthesis and degradation and excessive deposition of collagen fibers play an important role in this process.This study provides a scientific reference for further exploring the pathogenesis of myocardial fibrosis,looking for therapeutic targets and potential therapeutic traditional Chinese medicines.

Cystic fibrosis-related diabetes:The unmet need

Cystic fibrosis(CF)is a common autosomal recessive disease.Life expectancy of patients with CF continues to improve mainly driven by the evolving therapies for CF-related organ dysfunction.The prevalence of CF-related diabetes(CFRD)increases exponentially as patients’age.Clinical care guidelines for CFRD from 2010,recommend insulin as the mainstay of treatment.Many patients with CFRD may not require exogenous insulin due to the heterogeneity of this clinical entity.Maintenance of euglycemia by enhancing endogenous insulin production,secretion and degradation with novel pharmacological therapies like glucagonlike peptide-1 agonist is an option that remains to be fully explored.As such,the scope of this article will focus on our perspective of glucagon-like peptide-1 receptor agonist in the context of CFRD.Other potential options such as sodiumglucose cotransporter-2 and dipeptidyl peptidase 4 inhibitors and their impact on this patient population is limited and further studies are required.

Effect of Candesartan Combined with Rosuvastatin on Myocardial Fibrosis in Rats with Alcoholic Cardiomyopathy by Mediating LOX-1 Expression

Objective:To analyze the effect of candesartan and rosuvastatin on myocardial fibrosis in rats with alcoholic cardiomyopathy by mediating the expression of lectin-like oxidized low-density lipoprotein receptor-1(LOX-1).Methods:The rats were selected as experimental samples,and these rats were randomly divided into observation group and alcohol feeding group(abbreviated as"alcohol group")and desartan combined with rosuvastatin intervention+alcoholic cardiomyopathy group(Referred to as the"intervention group"),the observation group is fed normally,the alcohol group is fed with alcohol,and the intervention group uses two drugs on the basis of the alcohol group to intervene.After 16 weeks of the three groups of experiments,analyze the results of the three groups of experiments.Myocardial structure,myocardial fibrosis and myocardial function.Results:After 16 weeks,the left ventricular short axis shortening rate(FS)and left ventricular ejection fraction in the alcohol group were lower than those in the observation group,while the collagen volume fraction(CVF)and left ventricular end-diastolic diameter(LVEDd)were higher than those in the observation group,The expression of LOX-1 in the intervention group was lower than that in the alcohol group,and the degree of fibrosis was reduced.The expression of LOX-1 in the alcohol group was higher than that in the observation group,and the degree of fiber increased.At the same time,the expression of TN-X and smad-3 protein in the alcohol group(86%±7%,83%±9%)were higher than those in the observation group(32%±10%,30%±7%),while the expression of smad-7 protein(36%±8%)was lower than that in the observation group(78%±9%),P<0.05 among the three groups of experiments,and there is statistical significance among the groups.Conclusion:Candesartan combined with Rosuvastatin can reduce myocardial fibrosis in rats with alcoholic cardiomyopathy by mediating the expression of LOX-1.

Comparison between multiple logistic regression and machine learning methods in prediction of abnormal thallium scans in type 2 diabetes

BACKGROUND The prevalence of type 2 diabetes(T2D)has been increasing dramatically in recent decades,and 47.5%of T2D patients will die of cardiovascular disease.Thallium-201 myocardial perfusion scan(MPS)is a precise and noninvasive method to detect coronary artery disease(CAD).Most previous studies used traditional logistic regression(LGR)to evaluate the risks for abnormal CAD.Rapidly developing machine learning(Mach-L)techniques could potentially outperform LGR in capturing non-linear relationships.AIM To aims were:(1)Compare the accuracy of Mach-L methods and LGR;and(2)Found the most important factors for abnormal TMPS.METHODS 556 T2D were enrolled in the study(287 men and 269 women).Demographic and biochemistry data were used as independent variables and the sum of stressed score derived from MPS scan was the dependent variable.Subjects with a MPS score≥9 were defined as abnormal.In addition to traditional LGR,classification and regression tree(CART),random forest,Naïve Bayes,and eXtreme gradient boosting were also applied.Sensitivity,specificity,accuracy and area under the receiver operation curve were used to evaluate the respective accuracy of LGR and Mach-L methods.RESULTS Except for CART,the other Mach-L methods outperformed LGR,with gender,body mass index,age,low-density lipoprotein cholesterol,glycated hemoglobin and smoking emerging as the most important factors to predict abnormal MPS.CONCLUSION Four Mach-L methods are found to outperform LGR in predicting abnormal TMPS in Chinese T2D,with the most important risk factors being gender,body mass index,age,low-density lipoprotein cholesterol,glycated hemoglobin and smoking.

Clinical significance of diabetes on symptom and patient delay among patients with acute myocardial infarction——an analysis from China Acute Myocardial Infarction(CAMI) registry

Background Diabetes is frequently associated with poor prognosis among acute myocardial infarction(AMI)patients.Patients with these comorbidities often have atypical symptoms and subsequent delay in treatment.Few studies have reported detailed AMI symptoms in patients with diabetes.This study compared AMI symptoms and presentation characteristics between diabetics and non-diabetics.Methods We included patients from the China AMI registry diagnosed with AMI between January 2013 and September 2014.Baseline characteristics,symptomology,and delay in treatment were compared between diabetics and non-diabetics.Multivariable logistic regression analysis was used to explore independent predictors of atypical symptoms.Results A total of 4450(20.2%)patients had diabetes.They were older,more often women,higher in body mass index,and more likely to have non-ST segment elevation myocardial infarction.Fewer diabetic patients presented with persistent precordial chest pain(63.1%vs.68%,P<0.0001),diaphoresis(60.1%vs.65.6%,P<0.0001),fatigue(16.7%vs.18.3%,P=0.0123),and incontinence(0.4%vs.0.7%,P=0.0093).Time to hospital presentation was longer among patients with diabetes than those without.In multivariable analysis,diabetes was identified as an independent predictor of atypical symptoms(OR:1.112,95%CI:1.034?1.196).Conclusions Our study is the first large-scale study providing evidence that diabetics are less likely to present with typical chest pain and more likely to experience treatment delay when suffering from an AMI.Our results may increase clinician awareness of recognizing AMI patients rapidly to reduce diagnosis and treatment delay,particularly in the context of diabetes.