miR-202-5p protects rat against myocardial ischemia reperfusion injury by downregulating the expression of Trpv2 to attenuate the Ca 2+ overload in cardiomyocytes.

BACKGROUND: This study was aimed to unveil micro RNA (miRNA) expression profiles in myocardial ischemia-reperfusion (MI/R) rats and explore whether and how dysregulated miRNAs were involved in the initiation and progression of MI/R in a calcium-dependent manner. METHOD AND RESULTS: Rat model of MI/R was established and cardiomyocytes isolated from neonatal rats cardiomyocytes were induced. Both miRNA and messenger RNA expression profiles were analyzed by Microarray. Quantitative reverse-transcription polymerase chain reaction, immunoblotting, bioinformatics analysis, dual-luciferase reporter gene assay, hematoxylin and eosin, Evans blue, and triphenyl tetrazolium chloride were also used in this study. Serum concentrations of myocardial enzymes (phosphocreatine kinase [CK], creatine kinase [CK-MB], lactate dehydrogenase [LDH]), cardiomyocytes loadage of Ca2+ , as well as the expression level of inositol 1,4,5-trisphosphate receptors (IP3R) and sarcoplasmic reticulum Ca2+ -ATPase 2a (SERCA2a) were measured, respectively. Effects of upregulation or downregulation of miR-202-5p or Trpv2 on these indicators were investigated in vivo and in vitro. In MI/R rats and hypoxia/reoxygenation-induced NCMs, miR-202-5p was downregulated, while Trpv2 was upregulated. Trpv2 was a promising target of miR-202-5p and negatively regulated by miR-202-5p. Upregulation of miR-202-5p or downregulation of Trpv2 significantly reduced the serum concentration of myocardial enzymes, as well as cardiomyocyte-produced reactive oxygen species, but inhibition of miR-202-5p or overexpression of Trpv2 brought the worsening situation for these indicators. Besides, upregulation of miR-202-5p upregulation or downregulation of Trpv2 also inhibited Ca2+ overload in cardiomyocytes, accompanied with the increase of SERCA2a and suppression of IP3R. The reduced damage degree and infarct size in myocardial tissue were contrarily worsened by miR-202-5p inhibitor. CONCLUSION: Overexpression of miR-202-5p or downregulation of its downstream Trpv2 presented the cardioprotective effects to MI/R rats.

An application of RASER technique in the treatment of chronic total occlusion accompanied with stent fracture in right coronary artery: a case report.

BACKGROUND: The interventional treatment of chronic total occlusion (CTO) with stent fracture as well as severe calcification was extremely difficult and no effective technique has been reported. CASE PRESENTATION: A 50-year-old woman was hospitalized for angina, angiography revealed triple vessel disease, CTO accompanied with stent fracture in right coronary artery (RCA). Treatment using conventional coronary intervention was expected to be difficult. Therefore, we performed RASER technique, which was a combination of excimer laser coronary atherectomy (ELCA) with rotational atherectomy (RA), followed by the deployment of drug-eluting stents. Intravascular ultrasound (IVUS) revealed well attachment of the stents, the patient was discharged 3 days after the procedure and no recurrent chest discomfort was reported in a follow-up time of 10 months. CONCLUSION: This case report provided a first report of RASER technique in the treatment of CTO with stent fracture and severe calcification.

Evaluation of Short- and Long-Term Efficacy of Combined Intracoronary Administration of High-Dose Adenosine and Tirofiban during Primary Percutaneous Coronary Intervention.

BACKGROUND: To assess the influence of combined intracoronary application of high-dose adenosine and tirofiban in primary percutaneous coronary intervention (PCI) on clinical events and cardiac function. METHODS: Our study evaluated consecutive patients with acute ST-segment elevation myocardial infarction undergoing primary PCI, who were randomly divided into adenosine group (n = 130) and control group (n = 128). Combined with thrombus aspiration and then intracoronary tirofiban, the adenosine group received intracoronary adenosine (2 mg) through the aspiration catheter 2 times. After thrombus aspiration and stenting of the infarct- related artery, the control group received placebo. The primary endpoint of our investigation was major adverse cardiac events (MACE) at the 1-year and 3-year marks. The secondary endpoint comprised left ventricular remodeling (LVR) at 6 months, myocardial blush grade (MBG), thrombolysis in myocardial infarction (TIMI) flow grade and corrected TIMI frame count (CTFC) after PCI. RESULTS: Our study found that TIMI flow grade post-PCI did not differ significantly between the 2 groups, while CTFC favored the adenosine-treated patients (21.6 ± 6.5 vs. 25.1 ± 7.8, p = 0.001). Although the adenosine group achieved a higher rate of MBG 3 (45.1% vs. 32.0%, p = 0.035) and MBG 2-3 (76.2% vs. 62.3%, p = 0.018) than the control group, the incidences of MACE at 1 year (20.0% vs. 25.0%, p = 0.373) and 3 years (26.9% vs. 32.0%, p = 0.413) were comparable. LVR occurred in 23.1% (27/117) of adenosine-treated patients and in 29.8% (43/114) of the controls (p = 0.296). CONCLUSIONS: Intracoronary administration of high-dose adenosine combined with intracoronary tirofiban and thrombus aspiration may further improve myocardial perfusion after primary PCI.

Association of autoantibodies against the M2-muscarinic receptor with perinatal outcomes in women with severe preeclampsia.

BACKGROUND: The goal of this study was to test the hypothesis that autoantibodies against M2-muscarinic acetylcholine receptor (M2-AAB) are associated with severe preeclampsia and increased risk of adverse perinatal outcomes. METHODS: We conducted a case-control study comparing 60 women with severe preeclampsia to 60 women with normal pregnancy and 60 non-pregnant controls. A peptide, corresponding to amino acid sequences of the second extracellular loops of the M2 receptor, was synthesized as antigen to test for the presence of autoantibodies, using an enzyme-linked immunosorbent assay. The frequency and titer of M2-AAB were compared in the 3 groups. The risk of adverse perinatal outcomes among women with severe preeclampsia in the presence of M2-AAB was estimated. RESULTS: M2-AAB were positive in 31.7% (19/60) of patients with severe preeclampsia, in 10.0% (6/60) (p=0.006) of normal pregnant women and in 8.3% (5/60) (p=0.002) of non-pregnant controls. The presence of M2-AAB was associated with increased risk of adverse pregnancy complications (OR, 3.6; 95%CI, 1.0-12.6; p=0.048), fetal growth restriction (OR, 6.8; 95% CI, 2.0-23.0; p=0.002), fetal distress (OR, 6.7; 95% CI, 1.7-26.6; p=0.007), low Apgar score (OR, 5.3; 95% CI, 1.4-20.7; p=0.017), and perinatal death (OR, 4.3; 95% CI, 1.0-17.6; p=0.044) among women with severe preeclampsia. CONCLUSIONS: This study demonstrates, for the first time, an increase in M2-AAB in patients with severe preeclampsia. Women with severe preeclampsia who are M2-AAB positive are at increased risk for neonatal mortality and morbidity. We posit that M2-AAB may be involved in the pathogenesis of severe preeclampsia.

[Efficacy comparison of combined intracoronary administration of high-dose adenosine and tirofiban versus intracoronary tirofiban during primary percutaneous coronary intervention in patients with acute myocardial infarction].

OBJECTIVE: To compare the efficacy of intracoronary administration of combined high-dose adenosine and tirofiban versus intracoronary tirofiban during primary percutaneous coronary intervention (PCI) in patients with acute myocardial infarction. METHODS: Consecutive 258 patients with acute ST-segment elevation myocardial infarction (STEMI) underwent primary PCI, treated with thrombus aspiration and then intracoronary tirofiban, were randomly divided into adenosine group (n = 130) and control group (n = 128). Adenosine group received 2 times intracoronary adenosine (2 mg) after thrombus aspiration and after stenting of the infarct-related artery through the aspiration catheter. Control group received placebo. The primary end point was myocardial blush grade (MBG) after PCI. Secondary end points were thrombolysis in myocardial infarction (TIMI) flow grade and corrected TIMI frame count (CTFC) after PCI, ST-segment elevation resolution (STR), and major adverse cardiac events (MACE) at 30 days and 12 months. RESULTS: TIMI flow grade post PCI did not differ between the 2 groups, while CTFC favored the adenosine-treated patients [(21.6 ± 6.5) frames] compared with the placebo-treated patients [(25.1 ± 7.8) frames, P = 0.001]. MBG 3 was more frequently observed in the adenosine compared to the control group [45.1% (55/122) vs.32.0% (39/122), P = 0.035]. Patients in the adenosine group had a trend of higher rate of compete STR after the procedure compared patients in the control group [53.6% (67/125) vs. 41.9% (52/124), P = 0.065]. The incidence of MACE was comparable between patients randomized to adenosine and placebo at 30 days [12.3% (16/130) vs. 17.2% (22/128), P = 0.295] and at 12 months [12.3% (16/130) vs. 18.0% (23/128), P = 0.227]. CONCLUSION: Intracoronary administration of high-dose adenosine combined with tirofiban provides further improvement on myocardial perfusion after primary PCI but does not affect the clinical outcomes in patients with STEMI.

Effects of losartan in patients with NAFLD: A meta-analysis of randomized controlled trial.

Losartan has become a hot spot in the treatment of non-alcoholic fatty liver disease (NAFLD) among angiotensin receptor blocker drugs. We sought to conduct a systematic examination and meta-analysis to examine the effects of losartan on patients with NAFLD. We searched for potentially randomized controlled trials in PubMed, Embase, China National Knowledge Infrastructure, Wanfang, and the Cochrane database up to October 09, 2022. We used the Cochrane risk of bias tool to evaluate the study quality. Analysis of subgroups, sensitivity analysis, and publishing bias were explored. The quality of the included studies was moderate to high. Six trials involving 408 patients were included. The meta-analysis demonstrated that aspartate transaminase was significantly affected by losartan therapy (mean difference [MD] = -5.34, 95% confidence interval [CI] [-6.54, -4.13], Z = 8.70, P < 0.01). The meta-analysis subgroup showed that losartan 50 mg once daily could lower the level of alanine aminotransferase (MD = -18.92, 95% CI [-21.18, -16.66], Z = 16.41, P < 0.01). There was no statistically significant difference in serum total cholesterol, triglyceride, low-density lipoprotein, and high-density lipoprotein.

Aspirin versus LMWH for VTE prophylaxis after orthopedic surgery.

Low molecular weight heparin (LMWH) is often used to prevent perioperative venous thrombosis after surgery, but aspirin is also recommended by academics. Studies were searched in electronic databases until February 24, 2023. We performed a meta-analysis to evaluate the safety and efficacy of aspirin and LMWH for venous thromboembolism (VTE) prophylaxis in patients after orthopedic surgery. The outcomes were death from any causes, deep vein thrombosis (DVT), pulmonary embolism (PE), etc. This study was registered with INPLASY, number 202320117. Six randomized controlled trials enrolled 13,851 patients with postoperative joint surgery. The risk of DVT was comparable between the two groups when aspirin was combined with mechanical devices (RR 0.61 [95% CI 0.27-1.39], I² = 62%, P = 0.24). No significant differences in all cause death, PE, wound infection, and wound complication were found between the aspirin and LMWH groups. In this meta-analysis, the mortality rate was comparable between the aspirin and LMWH groups. However, aspirin alone had a higher risk of DVT than LMWH. Based on the results of this meta-analysis, we suggest aspirin combined with mechanical devices for VTE prophylaxis in patients after orthopedic surgery.

Efficacy and safety of baricitinib for the treatment of hospitalized adults with COVID-19: a systematic review and meta-analysis.

OBJECTIVES: Several clinical trials have evaluated the efficacy and safety of baricitinib in COVID-19 patients. Recently, there have been reports on critical patients, which are different from previous research results. The meta-analysis was performed to investigate the effects of baricitinib in COVID-19, by pooling data from all clinically randomized controlled trials (RCTs) available to increase power to testify. METHODS: Studies were searched in PubMed, Embase, and Cochrane Library databases on January 31, 2023. We performed a meta-analysis to estimate the efficacy and safety of baricitinib for the treatment of hospitalized adults with COVID-19. This study is registered with INPLASY, number 202310086. RESULTS: A total of 3010 patients were included in our analyses. All included studies were randomized controlled trials or prospective study. There was no difference in 14-day mortality between the two groups [OR 0.23 (95% CI 0.03-1.84), I2 = 72%, P = 0.17]. In subgroup analyses we found that baricitinib did not seem to improve significantly in 24-day mortality critically ill patients [OR 0.60 (95% CI 0.35-1.02), I2 = 0%, P = 0.06]. Fortunately, baricitinib have led to faster recovery and shorter hospital stays for COVID-19 patients. There were no difference in infections and infestations, major adverse cardiovascular events, deep vein thrombosis and pulmonary embolism. CONCLUSIONS: Baricitinib did not increase the incidence of adverse reactions. At the same time, we can find that it reduces the mortality of COVID-19 patients, not including the critically ill.

miR-190-5p Alleviates Myocardial Ischemia-Reperfusion Injury by Targeting PHLPP1.

OBJECTIVE: Myocardial ischemia-reperfusion (I/R) injury (MIRI) refers to the more serious myocardial injury after blood flow recovery, which seriously affects the prognosis of patients with ischemic cardiomyopathy. This study explored the new targets for MIRI treatment by investigating the effects of miR-190-5p and its downstream target on the structure and function of myocardial cells. METHODS: We injected agomir miR-190-5p into the tail vein of rats to increase the expression of miR-190-5p in rat myocardial cells and made an I/R rat model by coronary artery occlusion. We used 2,3,5-triphenyl tetrazolium chloride staining, lactate dehydrogenase (LDH) detection, echocardiography, and hematoxylin-eosin (HE) staining to determine the degree of myocardial injury in I/R rats. In addition, we detected the expression of inflammatory factors and apoptosis-related molecules in rat serum and myocardial tissue to determine the level of inflammation and apoptosis in rat myocardium. Finally, we determined the downstream target of miR-190-5p by Targetscan system and dual luciferase reporter assay. RESULTS: The expression of miR-190-5p in an I/R rat myocardium was significantly lower than that in normal rats. After treatment of I/R rats with agomir miR-190-5p, the ischemic area of rat myocardium and the concentration of LDH decreased. The results of echocardiography and HE staining also found that overexpression of miR-190-5p improved the structure and function of rat myocardium. miR-190-5p was also found to improve the viability of H9c2 cells in vitro and reduce the level of apoptosis of H9c2 cells. The results of Targetscan system and dual luciferase reporter assay found that miR-190-5p targeted to inhibit pleckstrin homology domain leucine-rich repeat protein phosphatase 1 (PHLPP1). In addition, inhibition of PHLPP1 was found to improve the viability of H9c2 cells. CONCLUSION: Therefore, miR-190-5p can reduce the inflammation and apoptosis of myocardium by targeting PHLPP1, thereby alleviating MIRI.

The prognostic role of high-sensitivity cardiac troponin T over time in ischemic and non-ischemic heart failure.

INTRODUCTION: High-sensitivity cardiac troponin T (hs-cTnT) as a prognostic biomarker can be detected in patients with heart failure (HF). AIM: This study focuses on hs-cTnT to evaluate its prognostic role in ischemic heart failure (IHF) and non-ischemic heart failure (NIHF). MATERIAL AND METHODS: One hundred and sixty patients with HF were divided into IHF and NIHF groups. Hs-cTnT measured at baseline, 2-5 h, 6-24 h and 24 h-7 d after admission was analyzed by generalized estimating equations. Patients were followed up for 1 year at the endpoint events of re-hospitalization for HF and all-cause death that was tested by the Kaplan-Meier method and the Cox regression method. RESULTS: Hs-cTnT varied significantly over time, first increasing and then decreasing in IHF while showing a continuously elevated trend in NIHF. Patients with hs-cTnT levels > 0.014 ng/ml had a significantly higher re-hospitalization rate compared with those with hs-cTnT levels ≤ 0.014 ng/ml (23.7% vs. 7.0%, p < 0.05). Adjusted for age, New York Heart Association class, N-terminal pro-B-type natriuretic peptide, and left ventricular ejection fraction, baseline hs-cTnT was independently associated with re-hospitalization and all-cause death in HF (p < 0.05). Optimal hs-cTnT cut-off of 0.0275 ng/ml was derived to predict the re-hospitalization and death in IHF (AUC = 0.709, 95% CI: 0.561-0.856, sensitivity: 76.9%, specificity: 63.5%, p < 0.05). CONCLUSIONS: Hs-cTnT varying over time is an important risk factor for the prognosis of patients with IHF and NIHF.

The Effect of Echocardiography Based on Lipid Nano Contrast Agent on Cardiology Patients with Heart Failure and Atrial Fibrillation.

This paper discusses the effect and evaluation of echocardiography based on lipid nano contrast agent on patients with heart failure and atrial fibrillation in cardiology department, providing reference for clinical diagnosis and treatment. Fifty two patients with diastolic heart failure diagnosed by echocardiography were selected for routine echocardiographic examination after optimizing the drug treatment scheme, and then the patients underwent treadmill exercise test and stress echocardiography evaluation. The results of conventional echocardiography and stress echocardiography after treatment were compared with those before treatment, and the clinical parameters and biochemical indexes before and after treatment were compared. Results after treatment, the clinical symptoms of the patients improved, the level of NT proBNP in the N-terminal forebrain decreased significantly, and the exercise tolerance increased significantly. Compared with the conventional echocardiography before and after treatment, the left ratio and e' value of stress echocardiography after treatment increased significantly, while E/e' decreased significantly. There was no significant difference in the indexes of general echocardiography before and after treatment. After treatment, positively correlated with the ratio of peak a to peak E. The results show that the sensitivity of stress echocardiography to evaluate ischemic diastolic heart failure has been improved, and some indexes have clinical significance. Compared with conventional echocardiography, it can effectively evaluate the therapeutic effect of drugs.

Prevalence and Prognostic Value of Heart Failure Stages: An Elderly Inpatient Based Cohort Study.

Background: The prevalence and prognostic value of heart failure (HF) stages among elderly hospitalized patients is unclear. Methods: We conducted a prospective, observational, multi-center, cohort study, including hospitalized patients with the sample size of 1,068; patients were age 65 years or more, able to cooperate with the assessment and to complete the echocardiogram. Two cardiologists classified all participants in various HF stages according to 2013 ACC/AHA HF staging guidelines. The outcome was rate of 1-year major adverse cardiovascular events (MACE). The Kaplan-Meier method and Cox proportional hazards models were used for survival analyses. Survival classification and regression tree analysis were used to determine the optimal cutoff of N-terminal pro-brain natriuretic peptide (NT-proBNP) to predict MACE. Results: Participants' mean age was 75.3 ± 6.88 years. Of them, 4.7% were healthy and without HF risk factors, 21.0% were stage A, 58.7% were stage B, and 15.6% were stage C/D. HF stages were associated with worsening 1-year survival without MACE (log-rank χ2 = 69.62, P < 0.001). Deterioration from stage B to C/D was related to significant increases in HR (3.636, 95% CI, 2.174-6.098, P < 0.001). Patients with NT-proBNP levels over 280.45 pg/mL in stage B (HR 2; 95% CI 1.112-3.597; P = 0.021) and 11,111.5 pg/ml in stage C/D (HR 2.603, 95% CI 1.014-6.682; P = 0.047) experienced a high incidence of MACE adjusted for age, sex, and glomerular filtration rate. Conclusions : HF stage B, rather than stage A, was most common in elderly inpatients. NT-proBNP may help predict MACE in stage B. Trial Registration: ChiCTR1800017204; 07/18/2018.

Cardioprotective Role of SIRT5 in Response to Acute Ischemia Through a Novel Liver-Cardiac Crosstalk Mechanism.

Protein posttranslational modifications play important roles in cardiovascular diseases. The authors' previous report showed that the abundance of succinylated and glutarylated proteins was significantly lower in the serum of patients with acute myocardial infarction (AMI) than in that of healthy volunteers, suggesting a potential relationship between protein acylation and AMI. Sirtuin 5 (SIRT5) facilitates the removal of malonyl, succinyl, and glutaryl modification; however, its effects on AMI remain unknown. In this study, the levels of SIRT5 in AMI mouse model was compared. Results showed elevated hepatic SIRT5 after myocardial infarction. Hepatocyte-specific SIRT5 overexpressing mice (liver SIRT5 OE) were generated to address the possible involvement of hepatic SIRT5 in AMI. The areas of myocardial infarction, myocardial fibrosis, and cardiac function in a model of experimental myocardial infarction were compared between liver SIRT5 OE mice and wild-type (WT) mice. The liver SIRT5 OE mice showed a significantly smaller area of myocardial infarction and myocardial fibrosis than the WT mice. The fibroblast growth factor 21 (FGF21) in the blood and myocardium of liver SIRT5 OE mice after AMI was markedly elevated compared with that in WT mice. The results of mass spectrometry showed increased levels of proteins regulating tricarboxylic acid cycle, oxidative phosphorylation, and fatty acid ß-oxidation pathways in the liver mitochondria of liver SIRT5 OE mice. These findings showed that SIRT5 may exhibit a cardioprotective effect in response to acute ischemia through a liver-cardiac crosstalk mechanism, probably by increasing the secretion of FGF21 and the improvement of energy metabolism.

Adding high-sensitivity C-reactive protein to frailty assessment to predict mortality and cardiovascular events in elderly inpatients with cardiovascular disease.

OBJECTIVE: Chronic inflammation is associated with major adverse cardiovascular events (MACEs), mortality, and frailty. Our aim was to add high-sensitivity C-reactive protein (hsCRP) to the frailty assessment to predict its association with prognosis of older adults with cardiovascular disease (CVD). METHODS: A comprehensive geriatric assessment was conducted at baseline in 720 in-patients aged ≥65 years with CVD. We divided the population into frailty and non-frailty groups according to the Fried phenotype, and hsCRP was further combined with frailty to stratify all patients into c-frailty and non-c-frailty groups. Predictive validity was tested using Cox proportional hazards regression model analysis and the discriminative ability was evaluated by receiver operating characteristic (ROC) curves. RESULTS: Of all the subjects enrolled, 51.0% were male and the mean age was 75.32 ± 6.52 years. The all-cause death and MACE rate was 6.4% at the 1-year follow-up. Frailty and c-frailty were independent predictors of all-cause death and MACE (hazard ratio [HR]: 2.55, 95% confidence interval [CI]: 1.35-4.83, p = 0.004; HR: 3.67, 95% CI: 1.83-7.39, p < 0.001). Adding hsCRP to the frailty model resulted in a significant increase in the area under the ROC curve from 0.74 (95% CI: 0.70-0.77) to 0.77 (95% CI: 0.71-0.84) (p = 0.0132) and a net reclassification index of 7.9% (95% CI: 1.96%-12.56%, p = 0.012). CONCLUSION: Adding hsCRP to the frailty assessment is helpful to identify a subgroup of older CVD patients with a higher risk of death and MACE over a period of 1 year. TRIAL REGISTRATION: ChiCTR1800017204; date of registration: 07/18/2018. URL: http://www.chictr.org.cn/showproj.aspx?proj=28931.

Long Non-coding RNA GAS5 Worsens Coronary Atherosclerosis Through MicroRNA-194-3p/TXNIP Axis.

It is formerly conducted that long non-coding RNA growth arrest-specific 5 (GAS5) is involved in the process of coronary atherosclerosis (AS). The regulatory effects of GAS5 on the microRNA (miR)-194-3p/thioredoxin-interacting protein (TXNIP) axis in AS have been insufficiently explored yet. Thereafter, this work is started from GAS5/miR-194-3p/TXNIP axis in AS. AS rats were modeled to obtain their coronary vascular tissues and endothelial cells (ECs), in which GAS5, miR-194-3p, and TXNIP expression were tested. ECs were identified by immunohistochemistry. The mechanism among GAS5, miR-194-3p, and TXNIP was determined. ECs were transfected with inhibited GAS5 or overexpressed miR-194-3p to decipher their functions in proliferation and apoptosis of ECs in AS. Raised GAS5 and TXNIP and degraded miR-194-3p expression levels exhibited in AS. GAS5 bound to miR-194-3p while miR-194-3p targeted TXNIP. Depleting GAS5 or restoring miR-194-3p enhanced proliferation and depressed apoptosis of ECs in AS. This work clearly manifests that inhibited GAS5 facilitates the growth of ECs through miR-194-3p-targeted TXNIP in AS, consolidating the basal reference to the curing for AS.

Age-related up-regulation of beta3-adrenergic receptor in heart-failure rats.

Stimulation of beta1- and beta2-adrenergic receptors (ARs) in the heart results in positive inotropy. In contrast, it has been reported that the beta3-AR is also expressed in the heart and that its stimulation leads to negative inotropic effects. The aim of this study was to investigate the expression of beta3-AR in age-related heart-failure rats and its relevance to left ventricular dysfunction. Aging male Wistar rats were divided into young and aging groups according to age, and each group included sham-operation and heart-failure subgroups. Left ventricular end-diastolic pressure (LVEDP) and the ratio of left ventricular weight to body weight (LV/BW) were significantly higher for the aging heart-failure versus young heart-failure and the heart-failure versus sham-operation groups (P < 0.01, respectively). However, the left ventricular end-systolic pressure (LVESP) and the maximal rate of rise or fall of left ventricular pressure were all significantly lower for the aging heart-failure versus young heart-failure and the heart-failure versus sham-operation groups (P < 0.01, respectively). beta3-AR protein levels increased significantly when heart failure worsened in aging rats. These results suggest that beta3-AR expression in age-related heart-failure rats and left ventricular function were highly correlated.

A missense mutation in the CHRM2 gene is associated with familial dilated cardiomyopathy.

Circulating autoantibodies against the M2-muscarinic acetylcholine receptor (CHRM2) have been detected in patients with dilated cardiomyopathy (DCM). However, it has yet to be determined whether the pathogenesis of familial DCM may be linked to the genetic variability of the CHRM2 gene. The coding regions of the CHRM2 gene were examined by direct DNA sequencing. Plasma concentrations of autoantibodies against CHRM2 were determined by ELISA in 7 unrelated DCM families. Linkage analysis demonstrated cosegregation of the microsatellite markers, D7S509 and D7S495 that flank the CHRM2 gene, with the familial form of DCM. A novel missense mutation (C722G) replacing cysteine with tryptophane (Cys176Trp) was identified in the CHRM2 gene in all affected members but was absent in unaffected members. Additionally, 139 sporadic DCM patients and 450 normal volunteers were screened for the same mutation, but none were identified. Among the 12 affected members with familial DCM, 5 patients had died suddenly and 7 experienced ventricular arrhythmia, atrioventricular conduction block, and heart failure. All mutation carriers were positive for autoantibodies against CHRM2. Survival analysis disclosed that prognosis in patients who were mutation carriers with familial DCM was poorer than that seen in patients who were noncarriers with sporadic DCM ((P<0.05). We have identified a novel missense mutation (C722G) in the CHRM2 gene associated with familial DCM. We also show that this variant correlates with the presence of autoantibodies against CHRM2. Patients with C722G mutation have more progressive disease, characterized by sudden death, arrhythmia, and heart failure.

Identification of Malonylation, Succinylation, and Glutarylation in Serum Proteins of Acute Myocardial Infarction Patients.

PURPOSE: To identify protein malonylation, succinylation, and glutarylation in human and rat serum. EXPERIMENTAL DESIGN: Immunoprecipitation coupled with MS/MS is employed to compare the relative abundance of malonylation, succinylation, and glutarylation of serum protein in acute myocardial infarction human and rat. RESULTS: One hundred thirty and 48 unique malonylated, succinylated, or glutarylated peptides are found in human and rat serum, respectively. Succinylation is the most predominant modification. The most modified protein is albumin. Abundance of serum protein succinylation and glutarylation is significantly (p < 0.05) lower in the peripheral serum of ST-segment elevation myocardial infarction patients compared with healthy volunteers, which is also observed in acute myocardial infarction rats. CONCLUSIONS AND CLINICAL RELEVANCE: Malonylation, succinylation, and glutarylation widely exist in mammalian serum proteins, and may reveal novel mechanism of acute myocardial infarction.

Transplantation of Endothelial Progenitor Cells in the Treatment of Coronary Artery Microembolism in Rats.

As the impairment of myocardial microenvironments due to coronary microembolization (CME) compromises the treatment effect of percutaneous coronary intervention and leads to adverse prognosis, we hypothesized that endothelial progenitor cells (EPCs) transplantation could improve cardiac function in the condition of CME. Low- (2 × 105) and high- (2 × 106) dose rat bone marrow-derived EPCs were transplanted in a model of CME. To develop a CME model, rats were injected with autologous micro-blood-clots into the left ventricle. Echocardiograph was examined before and 1, 7, and 28 days after EPC transplantation; serum cardiac troponin I (cTNI), von Willebrand factor (vWF), and cardiac microRNA expression were examined one day after EPCs transplantation. Heart morphology and vascular endothelial growth factor (VEGF), vWF, and basic fibroblast growth factor (bFGF) expression were examined one day after EPC transplantation. After 10 days of culture inductions, BM-EPCs have high purity as confirmed by flow cytometry. Cardiac function reflected by left ventricular ejection fraction significantly decreased after CME treatment and rescued by low-dose EPC. Compared to the sham group, cTNI and vWF serum levels increased significantly after CME treatment and rescued by low-dose EPC and high-dose EPC. Low-dose EPC treatment decreased myocardial necrosis and fibrosis and elevated cardiac expression of VEGF and vWF, while decreasing the cardiac expression of bFGF. Low-dose EPC treatment significantly suppressed cardiac expression of microRNA-19a but significantly enhanced microRNA-21, microRNA-214, and microRNA-486-3p expression. In conclusion, our results indicate that low-dose EPC transplantation may play a proangiogenic, antifibroblast, antifibrosis, and antinecrosis role and enhance cardiac function in a rat model of CME through a microRNA-related pathway.

Bone marrow mesenchymal stem cells-derived exosomal microRNA-185 represses ventricular remolding of mice with myocardial infarction by inhibiting SOCS2.

OBJECTIVE: Recently, the function of microRNAs (miRNAs) has been clarified in human diseases, we aimed to identify the role of miR-185 in myocardial infarction (MI). METHODS: Bone marrow mesenchymal stem cells (BMSCs) were cultured, from which the exosomes were extracted. MI mice models were established by coronary artery ligation and injected with transfected BMSCs. The echocardiographic and ventricle indicators, and hemodynamics of mice were measured. Moreover, the ultrastructure and apoptosis of cardiomyocytes were determined, and expression of miR-185, suppressor of cytokine signaling 2 (SOCS2), collagens, and apoptotic proteins in myocardial tissues were evaluated. RESULTS: MiR-185 was poorly expressed in myocardial tissues of MI mice. BMSCs-Exo could shuttle miR-185 to promote cardiac function and attenuate myocardial injury of myocardial tissues in MI mice, and also could protect cardiomyocytes from apoptosis in MI mice by reducing the expression of SOCS2. SOCS2 was determined to be the direct target gene of miR-185. Overexpressed SOCS2 could block the cardioprotective effect of BMSCs-derived exosomal miR-185 in MI mice. CONCLUSION: We have found in this study that BMSCs-derived exosomal miR-185 could repress ventricular remolding of MI mice by inhibiting SOCS2. This study may provide new method for MI treatment.