Exosomes derived from miR-133a-3p engineered mesenchymal stem cells promote myocardial repair in rats after acute myocardial infarction / 中华心血管病杂志

Objective: To investigate the effects of exosome derived from miR-133a-3p engineered human umbilical cord blood mesenchymal stem cells (ucMSC) on myocardial repair after acute myocardial infarction (AMI) in rats. Methods: UcMSC was amplified and cultured in vitro. Lentiviral carrying miR-133a-3p and negative control vectors were transfected into ucMSC. Exosomes secreted by the transfected ucMSC were named miR-133a-3p-Exo and miR-NC-Exo, respectively. The AMI model of rats was established by ligation of the left anterior descending coronary artery. MiR-133a-3p-Exo or miR-NC-Exo were then injected into the border zone of the infarct area. Cardiac function was assessed by echocardiography after twenty-eight days of intervention, and Masson staining was used to evaluate the area of myocardial fibrosis post-AMI. The myocardial apoptosis after infarction was evaluated by TUNEL staining and the angiogenesis after infarction was evaluated by immunofluorescence staining in the current study. Results: Compared with the miR-NC-Exo group, the left ventricular ejection fraction in the miR-133a-3p-Exo group was significantly increased ((47.4%±9.8%) vs. (64.2%±8.9%), P<0.05). While the myocardial fibrosis area ((31.2%±7.3%) vs. (18.0%±1.5%), P<0.01) and the percentage of apoptotic cardiomyocytes ((25.6%±3.6%) vs. (15.1%±4.4%), P<0.05) was significantly reduced in the miR-133a-Exo group. Besides, the expression of CD31 and α-smooth muscle actin (α-SMA) were also increased significantly in the miR-133a-3p-Exo group compared to the miR-NC-Exo group (CD31: (2.9±0.9) vs. (13.9±2.0), P<0.000 1, α-SMA: (3.5±0.9) vs. (11.0±1.6), P<0.000 1). Conclusion: Exosome derived from miR-133a-3p engineered ucMSC effectively inhibited myocardial apoptosis and promoted angiogenesis, thus improving the cardiac function after myocardial infarction in rats.

Exosomes derived from miR-133a-3p engineered mesenchymal stem cells promote myocardial repair in rats after acute myocardial infarction / 中华心血管病杂志

Objective: To investigate the effects of exosome derived from miR-133a-3p engineered human umbilical cord blood mesenchymal stem cells (ucMSC) on myocardial repair after acute myocardial infarction (AMI) in rats. Methods: UcMSC was amplified and cultured in vitro. Lentiviral carrying miR-133a-3p and negative control vectors were transfected into ucMSC. Exosomes secreted by the transfected ucMSC were named miR-133a-3p-Exo and miR-NC-Exo, respectively. The AMI model of rats was established by ligation of the left anterior descending coronary artery. MiR-133a-3p-Exo or miR-NC-Exo were then injected into the border zone of the infarct area. Cardiac function was assessed by echocardiography after twenty-eight days of intervention, and Masson staining was used to evaluate the area of myocardial fibrosis post-AMI. The myocardial apoptosis after infarction was evaluated by TUNEL staining and the angiogenesis after infarction was evaluated by immunofluorescence staining in the current study. Results: Compared with the miR-NC-Exo group, the left ventricular ejection fraction in the miR-133a-3p-Exo group was significantly increased ((47.4%±9.8%) vs. (64.2%±8.9%), P<0.05). While the myocardial fibrosis area ((31.2%±7.3%) vs. (18.0%±1.5%), P<0.01) and the percentage of apoptotic cardiomyocytes ((25.6%±3.6%) vs. (15.1%±4.4%), P<0.05) was significantly reduced in the miR-133a-Exo group. Besides, the expression of CD31 and α-smooth muscle actin (α-SMA) were also increased significantly in the miR-133a-3p-Exo group compared to the miR-NC-Exo group (CD31: (2.9±0.9) vs. (13.9±2.0), P<0.000 1, α-SMA: (3.5±0.9) vs. (11.0±1.6), P<0.000 1). Conclusion: Exosome derived from miR-133a-3p engineered ucMSC effectively inhibited myocardial apoptosis and promoted angiogenesis, thus improving the cardiac function after myocardial infarction in rats.

Promising roles of non-exosomal and exosomal non-coding RNAs in the regulatory mechanism and as diagnostic biomarkers in myocardial infarction / 浙江大学学报（英文版）（B辑：生物医学和生物技术）

Non-exosomal non-coding RNAs (non-exo-ncRNAs) and exosomal ncRNAs (exo-ncRNAs) have been associated with the pathological development of myocardial infarction (MI). Accordingly, this analytical review provides an overview of current MI studies on the role of plasma non-exo/exo-ncRNAs. We summarize the features and crucial roles of ncRNAs and reveal their novel biological correlations via bioinformatics analysis. The following contributions are made: (1) we comprehensively describe the expression profile, competing endogenous RNA (ceRNA) network, and "pre-necrotic" biomarkers of non-exo/exo-ncRNAs for MI; (2) functional enrichment analysis indicates that the target genes of ncRNAs are enriched in the regulation of apoptotic signaling pathway and cellular response to chemical stress, etc.; (3) we propose an updated and comprehensive view on the mechanisms, pathophysiology, and biomarker roles of non-exo/exo-ncRNAs in MI, thereby providing a theoretical basis for the clinical management of MI.

Mechanism of Buyang Huanwu Decoction in protecting ischemic myocardium by regulating platelet autophagy in rats with acute myocardial infarction / 中国中药杂志

This study explored the effects of Buyang Huanwu Decoction(BYHWD) on platelet activation and differential gene expression after acute myocardial infarction(AMI). SD rats were randomly divided into a sham-operated group, a model group, a positive drug(aspirin) group, and a BYHWD group. Pre-treatment was conducted for 14 days with a daily oral dose of 1.6 g·kg~(-1) BYHWD and 0.1 g·kg~(-1) aspirin. The AMI model was established using the high ligation of the left anterior descending coronary artery method. The detection indicators included myocardial infarct size, heart function, myocardial tissue pathology, peripheral blood flow perfusion, platelet aggregation rate, platelet membrane glycoprotein CD62p expression, platelet transcriptomics, and differential gene expression. The results showed that compared with the sham-operated group, the model group showed reduced ejection fraction and cardiac output, decreased peripheral blood flow, and increased platelet aggregation rate and CD62p expression, and activated platelets. At the same time, TXB_2 content increased and 6-keto-PGF1α content decreased in serum. Compared with the model group, BYHWD increased ejection fraction and cardiac output, improved blood circulation in the foot and tail regions and cardiomyocytes arrangement, reduced myocardial infarct size and inflammatory infiltration, down-regulated platelet aggregation rate and CD62p expression, reduced serum TXB_2 content, and increased 6-keto-PGF1α content. Platelet transcriptome sequencing results revealed that BYHWD regulated mTOR-autophagy pathway-related genes in platelets. The differential gene expression levels were detected using real-time quantitative PCR. BYHWD up-regulated mTOR, down-regulated autophagy-related FUNDC1 and PINK genes, and up-regulated p62 gene expression. The results demonstrated that BYHWD could regulate platelet activation, improve blood circulation, and protect ischemic myocardium in AMI rats, and its mechanism is related to the regulation of the mTOR-autophagy pathway in platelets.

Intervention effect of Chuanxiong-Chishao herb pair on circRNA/lncRNA expression profile in a myocardial infarction-atherosclerosis model / 中国中药杂志

This study aimed to explore the intervention effect of Chuanxiong-Chishao herb pair(CX-CS) on a myocardial infarction-atherosclerosis(MI-AS) mouse model and investigate its effect on the expression profile of circular RNAs(circRNAs)/long non-coding RNAs(lncRNAs) in ischemic myocardium and aorta. Sixty male ApoE~(-/-) mice were randomly assigned to a model group, high-, medium-, and low-dose CX-CS groups(7.8, 3.9, and 1.95 g·kg~(-1)), and a positive drug group(metoprolol 26 mg·kg~(-1) and simvastatin 5.2 mg·kg~(-1)), with 12 mice in each group. Male C57BL/6J mice were assigned to the sham group. The mice in the model group and the groups with drug intervention were fed on a high-fat diet for 10 weeks, followed by anterior descending coronary artery ligation. After that, the mice were fed on a high-fat diet for another two weeks to induce the MI-AS model. The mice in the sham group received normal feed, followed by sham surgery without coronary artery ligation. Mice in the groups with drug intervention received CX-CS or positive drug by gavage for four weeks from the 9th week of high-fat feeding, and those in the model group and the sham group received an equal volume of normal saline. Whole transcriptome sequencing was performed on the heart and aorta tissues of the medium-dose CX-CS group, the model group, and the sham group after administration. The results showed that the medium-and high-dose CX-CS groups showed improved cardiac function and reduced myocardial fibrosis area, and the medium-dose CX-CS group showed significantly reduced plaque area. CX-CS treatment could reverse the expression of circRNA＿07227 and circRNA＿11464 in the aorta of AS model and circRNA expression(such as circRNA＿11505) in the heart of the MI model. Differentially expressed circRNAs between the CX-CS-treated mice and the model mice were mainly enriched in lipid synthesis, lipid metabolism, lipid transport, inflammation, and angiogenesis in the aorta, and in angiogenesis, blood pressure regulation, and other processes in the heart. CX-CS treatment could reverse the expression of lncRNAs such as ENSMUST00000162209 in the aorta of the AS model and TCONS＿00002123 in the heart of the MI model. Differentially expressed lncRNAs between the CX-CS-treated mice and model mice were mainly enriched in lipid metabolism, angiogenesis, autophagy, apoptosis, and iron death in the aorta, and in angiogenesis, autophagy, and iron death in the heart. In summary, CX-CS can regulate the expression of a variety of circRNAs and lncRNAs, and its intervention mechanism in coronary heart disease may be related to the regulation of angiogenesis and inflammation in ischemic myocardium, as well as lipid metabolism, lipid transport, inflammation, angiogenesis in AS aorta.

Differential expression and implication of m6A methylation in mice with experimental myocardial infarction / 中华心血管病杂志

Objective: To define differentially expressed N6-adenylate methylation (m6A) genes in the myocardial tissue of mice with myocardial infarction (MI) and explore its potential impact on the pathological process of MI. Methods: The random number table method was used to divide the eighteen SPF C57BL/6J male mice aged from 8 to 10 weeks into MI group (MI group, n=9) and control group (control group, n=9). Modified m6A genes from the myocardial tissue were detected via methylated RNA immunoprecipitation with the next generation sequencing (MeRIP-seq). We explored methylation modified characteristics, verified mRNA expression and m6A modified level by bioinformatics analysis, qPCR and MeRIP-qPCR. Results: The Heatmap revealed that 901 differentially modified m6A genes between MI and control group, of which 537 genes were upregulated, and 364 genes were downregulated. The principal component analysis affirmed that two groups could be distinguished significantly in terms of m6A gene modification. The characteristic sequence of m6A modification was GGACU and mainly concentrated in the coding sequence. According to the conjoint analysis with RNA-seq and MeRIP-seq, 119 genes expressed simultaneous m6A modification difference and mRNA expression difference. The Venn diagram exhibited the positive and negative correlation between m6A modification and mRNA expression. Besides, the GO enrichment analysis indicated that the genes with m6A differential modification in MI group were mainly involved in heart development and other processes. qPCR verified that Gbp6 was up-regulated, while Dnaja1 and Dnajb1 were down-regulated. MeRIP-qPCR revealed that the m6A modification level of Hspa1b was downregulated. Conclusion: Myocardial infarction induces differential modification of m6A in the mice model. In addition, the genes with m6A modification may be affected by methylation related enzymes, thus participating the pathogenesis of MI by regulating apoptosis and inflammation.

Differential expression and implication of m6A methylation in mice with experimental myocardial infarction / 中华心血管病杂志

Objective: To define differentially expressed N6-adenylate methylation (m6A) genes in the myocardial tissue of mice with myocardial infarction (MI) and explore its potential impact on the pathological process of MI. Methods: The random number table method was used to divide the eighteen SPF C57BL/6J male mice aged from 8 to 10 weeks into MI group (MI group, n=9) and control group (control group, n=9). Modified m6A genes from the myocardial tissue were detected via methylated RNA immunoprecipitation with the next generation sequencing (MeRIP-seq). We explored methylation modified characteristics, verified mRNA expression and m6A modified level by bioinformatics analysis, qPCR and MeRIP-qPCR. Results: The Heatmap revealed that 901 differentially modified m6A genes between MI and control group, of which 537 genes were upregulated, and 364 genes were downregulated. The principal component analysis affirmed that two groups could be distinguished significantly in terms of m6A gene modification. The characteristic sequence of m6A modification was GGACU and mainly concentrated in the coding sequence. According to the conjoint analysis with RNA-seq and MeRIP-seq, 119 genes expressed simultaneous m6A modification difference and mRNA expression difference. The Venn diagram exhibited the positive and negative correlation between m6A modification and mRNA expression. Besides, the GO enrichment analysis indicated that the genes with m6A differential modification in MI group were mainly involved in heart development and other processes. qPCR verified that Gbp6 was up-regulated, while Dnaja1 and Dnajb1 were down-regulated. MeRIP-qPCR revealed that the m6A modification level of Hspa1b was downregulated. Conclusion: Myocardial infarction induces differential modification of m6A in the mice model. In addition, the genes with m6A modification may be affected by methylation related enzymes, thus participating the pathogenesis of MI by regulating apoptosis and inflammation.

Study of senescence protein p66Shc on myocardial tissue repair in adult mice / 生理学报

Our previous study has shown that p66Shc plays an important role in the process of myocardial regeneration in newborn mice, and p66Shc deficiency leads to weakened myocardial regeneration in newborn mice. This study aims to explore the role of p66Shc protein in myocardial injury repair after myocardial infarction in adult mice, in order to provide a new target for the treatment of myocardial injury after myocardial infarction. Mouse myocardial infarction models of adult wild-type (WT) and p66Shc knockout (KO) were constructed by anterior descending branch ligation. The survival rate and heart-to-body weight ratio of two models were compared and analyzed. Masson's staining was used to identify scar area of injured myocardial tissue, and myocyte area was determined by wheat germ agglutinin (WGA) staining. TUNEL staining was used to detect the cardiomyocyte apoptosis. The protein expression of brain natriuretic peptide (BNP), a common marker of myocardial hypertrophy, was detected by Western blotting. The results showed that there was no significant difference in survival rate, myocardial scar area, myocyte apoptosis, and heart weight to body weight ratio between the WT and p66ShcKO mice after myocardial infarction surgery. Whereas the protein expression level of BNP in the p66ShcKO mice was significantly down-regulated compared with that in the WT mice. These results suggest that, unlike in neonatal mice, the deletion of p66Shc has no significant effect on myocardial injury repair after myocardial infarction in adult mice.

Triatriatum sinistrum em adulto assintomático: relato de caso / Cor triatriatum sinistrum in an asymptomatic adult: a case report

Cor triatriatum é um anomalia cardíaca congênita rara frequentemente diagnosticada na primeira infância. Este estudo de caso apresenta um adulto com um achado acidental de cor triatriatum sinistrum. Com base na apresentação clínica, o paciente foi tratado de forma conservadora. São apresentados achados de imagens ecocardiográficas de cor triatriatum sinistrum deste paciente juntamente de revisão narrativa da literatura sobre essa doença.(AU)

Cor triatriatum is a rare congenital heart anomaly often diagnosed in early childhood. This case study features an adult with an incidental finding of cor triatriatum sinistrum. Based on the clinical presentation, the patient was treated conservatively. Cor triatriatum sinistrum echocardiographic image findings of this patient are presented along with a narrative review of the literature about this disease. (AU)

Exercise Testing, Family History, and Subclinical Atherosclerosis Markers for Cardiovascular Risk Reclassification in Middle-Aged Women

Abstract Background Cardiovascular diseases are the main cause of death in women and the accuracy of currently available risk scores is questionable. Objective To reclassify the risk estimated by the Framingham Risk Score (FRS) in asymptomatic middle-aged women by incorporating family history, exercise testing variables, and subclinical atherosclerosis markers. Methods This cross-sectional study included 509 women (age range, 46-65 years) without cardiovascular symptoms. Those at low or intermediate risk by the FRS were reclassified to a higher level considering premature family history of acute myocardial infarction and/or sudden death; four variables from exercise testing; and two variables related to subclinical atherosclerosis markers. The homogeneity of these variables according to the FRS was verified by Pearson chi-square test (p<0.05). Results According to the FRS, 80.2%, 6.2%, and 13.6% of the women were classified as low (<5%), intermediate (5-10%), and high (>10%) risks, respectively. The intermediate-risk stratum showed the highest increase (from 6.2% to 33.3%) with addition of family history; followed by addition of chronotropic index <80% (to 24.2%); functional capacity <85% (22.2%), coronary calcium score >0 (20.6%); decreased one-minute heart rate recovery ≤12 bpm (15.2%); carotid intima-media thickness >1 mm and/or carotid plaque (13.8%) and ST-segment depression (9.0%). The high-risk stratum increased to 14.4% with the addition of reduced heart rate recovery and to 17.1% with the coronary calcium score. Conclusion Incorporation of premature family history of cardiovascular events, exercise testing abnormal parameters, and subclinical atherosclerosis markers into the FRS led to risk reclassification in 3.0-29.7% of asymptomatic middle-aged women, mainly by an increase from low to intermediate risk.

Mechanism of Xuefu Zhuyu Decoction in treatment of myocardial infarction based on network pharmacology and molecular docking / 中国中药杂志

To explore the action mechanism of Xuefu Zhuyu Decoction in treating myocardial infarction based on network pharmaco-logy and molecular docking. Active components and corresponding targets of Xuefu Zhuyu Decoction were obtained through Traditional Chinese Medicine Systems Pharmacology Database(TCMSP), and related targets of myocardial infarction were obtained through GeneCards, DisGeNET, and OMIM databases. Then the intersection targets were obtained by integrating the drug targets and disease targets. The "active component-target" network was constructed by Cytoscape software, and protein-protein interaction(PPI) network was drawn using STRING platform. Protein cluster analysis was carried out using MCODE. GO enrichment analysis and KEGG pathway analysis were carried out using DAVID database and ClueGO, and molecular docking was carried out using Autodock Vina and Pymol. Finally, 226 active components of Xuefu Zhuyu Decoction were obtained, 257 corresponding targets, 1 340 targets of myocardial infarction, and 109 drug and disease intersection targets were obtained. From GO enrichment analysis, 208 biological process terms, 38 molecular function terms, and 33 cellular component terms were obtained. From KEGG pathway analysis, NF-κB signaling pathway, IL-17 signaling pathway, HIF-1 signaling pathway, and other related pathways were obtained. The molecular docking results showed that the main active components(quercetin, kaempferol, β-sitosterol, luteolin, stigmasterol and baicalein) of Xuefu Zhuyu Decoction in the treatment of myocardial infarction had good binding properties with the core proteins IL6, ALB, VEGFA, TNF, MAPK3 and CASP3. The results suggested that Xuefu Zhuyu Decoction may play a role in the treatment of myocardial infarction by reducing the inflammatory response, reducing oxidative stress, inhibiting cell apoptosis, and promoting angiogenesis.

Association of CYP2C19 and CYP3A5 gene polymorphisms with myocardial infarction / 中华医学遗传学杂志

OBJECTIVE@#To assess the association of CYP2C19 and CYP3A5 gene polymorphisms with the risk of myocardial infarction.@*METHODS@#Five hundred patients with myocardial infarction and 500 healthy controls were randomly selected. Fluorescent PCR and Sanger sequencing were used to detect the CYP2C19 and CYP3A5 gene polymorphisms. Logistic regression was used to analyze the correlation between the polymorphisms and myocardial infarction. Quanto software was used to evaluate the statistical power.@*RESULTS@#The two groups had significant difference in the frequency of AG, GG genotypes and A allele of the CYP2C19 gene rs4986893 locus and the AA, AG, GG genotypes and G allele of the CYP3A5 gene rs776746 locus ( P<0.05), but not in the frequency of genotypes and alleles of CYP2C19 gene rs4244285 and rs12248560 loci, and the AA genotype of the rs4986893 locus. After correction for age, gender, and body mass index, Logistic regression indicated that the AG genotype and A allele of the CYP2C19 gene rs4986893 locus, and the GG genotype and G allele of CYP3A5 gene rs776746 locus are associated with susceptibility of myocardial infarction, while rs4986893 GG genotype and AA and AG genotypes of rs776746 may confer a protective effect. Based on the sample size and allele frequency, analysis with Quanto software suggested that the result of this study has a statistical power of 99%.@*CONCLUSION@#CYP2C19 and CYP3A5 gene polymorphisms may increase the risk for myocardial infarction.

Quantification of DNA Damage in Different Tissues in Rats with Heart Failure / Quantificação de Dano em DNA em Diferentes Tecidos em Ratos com Insuficiência Cardíaca

Abstract Background: Chronic heart failure (CHF) is a complex syndrome which comprises structural and functional alterations in the heart in maintaining the adequate blood demand to all tissues. Few investigations sought to evaluate oxidative DNA damage in CHF. Objective: To quantify the DNA damage using the comet assay in left ventricle (LV), lungs, diaphragm, gastrocnemius and soleus in rats with CHF. Methods: Twelve male Wistar rats (300 to 330 g) were selected for the study: Sham (n = 6) and CHF (n = 6). The animals underwent myocardial infarction by the ligation of the left coronary artery. After six weeks, the animals were euthanized. It was performed a cell suspension of the tissues. The comet assay was performed to evaluate single and double strand breaks in DNA. Significance level (p) considered < 0.05. Results: The CHF group showed higher values of left ventricle end-diastolic pressure (LVEDP), pulmonary congestion, cardiac hypertrophy and lower values of maximal positive and negative derivatives of LV pressure, LV systolic pressure (p < 0.05). CHF group showed higher DNA damage (% tail DNA, tail moment and Olive tail moment) compared to Sham (p < 0.001). The tissue with the highest damage was the soleus, compared to LV and gastrocnemius in CHF group (p < 0.05). Conclusion: Our results indicates that the CHF affects all tissues, both centrally and peripherically, being more affected in skeletal muscle (soleus) and is positively correlated with LV dysfunction.

Resumo Fundamento: A insuficiência cardíaca crônica (ICC) é uma síndrome complexa que compreende alterações estruturais e funcionais no coração, mantendo demanda sanguínea adequada a todos os tecidos. Poucas investigações procuraram avaliar o dano oxidativo ao DNA na ICC. Objetivo: Quantificar o dano ao DNA utilizando o ensaio cometa no ventrículo esquerdo (VE), pulmões, diafragma, gastrocnêmio e sóleo em ratos com ICC. Métodos: Doze ratos Wistar machos (300 a 330 g) foram selecionados para o estudo: placebo (n = 6) e ICC (n = 6). Os animais foram submetidos a infarto do miocárdio através de ligadura da artéria coronária esquerda. Após seis semanas, os animais foram sacrificados. Foi realizada uma suspensão celular dos tecidos. O ensaio cometa foi realizado para avaliar as quebras de fita simples e dupla no DNA. Nível de significância (p) < 0,05. Resultados: O grupo ICC apresentou maiores valores de pressão diastólica final do ventrículo esquerdo (PDFVE), congestão pulmonar, hipertrofia cardíaca e menores valores de derivados máximos positivos e negativos da pressão do VE, pressão sistólica do VE (p < 0,05). O grupo ICC apresentou maior dano ao DNA (% de DNA da cauda, momento da cauda e momento da cauda de Olive) em comparação ao placebo (p < 0,001). O tecido com maior dano foi o sóleo, comparado ao VE e ao gastrocnêmio no grupo ICC (p < 0,05). Conclusão: Nossos resultados indicam que a ICC afeta todos os tecidos, de maneira central e periférica, sendo mais afetada no músculo esquelético (sóleo) e está positivamente correlacionada com a disfunção do VE.

The branched-chain amino acid transaminase 1 -23c/g polymorphism confers protection against acute coronary syndrome

ABSTRACT Background: Previous studies have shown an association between polymorphisms of the BAT1-NF-κB inhibitor-like-1 (NFKBIL1)-LTA genomic region and susceptibility to myocardial infarction and acute coronary syndrome (ACS). Objective: The objective of the study was to study the role of three polymorphisms in the BAT1, NFKBIL1, and LTA genes on the susceptibility or protection against ACS; we included a group of cases-controls from Central Mexico. Methods: The BAT1 rs2239527C/G, NFKBIL1 rs2071592T/A, and LTA rs1800683G/A polymorphisms were genotyped using a 5' TaqMan assay in a group of 625 patients with ACS and 617 healthy controls. Results: Under a recessive model, the BAT1 -23C/G (rs2239527) polymorphism showed an association with protection against ACS (odds ratio = 0.56, and p-corrected = 0.019). In contrast, the genotype and allele frequencies of the NFKBIL1 rs2071592T/A and LTA rs1800683G/A polymorphisms were similar between ACS patients and controls and no association was identified. Conclusion: Our data suggest an association between the BAT1 -23C/G polymorphism and protection against ACS in Mexican patients.

Clinical significance and correlation of microRNA-21 expression and the neutrophil-lymphocyte ratio in patients with acute myocardial infarction

OBJECTIVES: To explore the clinical significance and correlation of microRNA-21 (miR-21) and the neutrophil-lymphocyte ratio (NLR) in patients with acute myocardial infarction (AMI). METHODS: The observation group contained 184 patients, while the control group contained 150 patients. The expression of miR-21 in the serum of each group was detected by qRT-PCR. RESULTS: A total of 184 patients and their family members were followed-up for 30 days, among which 35 patients died and 149 patients survived, resulting in a survival rate of 80.97%. According to univariate analysis, there were significant differences in age, cardiac troponin (cTn), heart rate, Killip grade, percutaneous coronary intervention (PCI) operation rate, miR-21 and NLR. In the receiver operating characteristic (ROC) analysis, the area under the curve (AUC) values of miR-21 and NLR for the diagnosis of AMI were 0.909 and 0.868, respectively, and the area under the combined detection curve was 0.960. In the Kaplan-Meier survival analysis, the survival of patients with high miR-21 expression and NLR was significantly higher than that of patients with low miR-21 expression and NLR (p=0.027; p=0.001). The correlation showed that miR-21 expression in serum was positively correlated with the NLR in the observation group (r=0.528, p<0.05). cTn, heart rate, Killip classification, PCI operation rate, miR-21, NLR are independent risk factors for AMI. CONCLUSION: miR-21 and NLR play a role in the diagnosis of AMI and can be used as predictors for the survival of AMI.

Lactate-upregulation of lactate oxidation complex-related genes is blunted in left ventricle of myocardial infarcted rats

Lactate modulates the expression of lactate oxidation complex (LOC)-related genes and cardiac blood flow under physiological conditions, but its modulatory role remains to be elucidated regarding pathological cardiac stress. The present study evaluated the effect of lactate on LOC-related genes expression and hemodynamics of hearts submitted to myocardial infarction (MI). Four weeks after MI or sham operation, isolated hearts of male Wistar rats were perfused for 60 min with Na+-lactate (20 mM). As expected, MI reduced cardiac contractility and relaxation with no changes in perfusion. The impaired cardiac hemodynamics were associated with increased reactive oxygen species (ROS) levels (Sham: 19.3±0.5 vs MI: 23.8±0.3 µM), NADPH oxidase (NOX) activity (Sham: 42.2±1.3 vs MI: 60.5±1.5 nmol·h−1·mg−1) and monocarboxylate transporter 1 (mct1) mRNA levels (Sham: 1.0±0.06 vs MI: 1.7±0.2 a.u.), but no changes in superoxide dismutase (SOD), catalase, NADH oxidase (NADox), and xanthine oxidase activities. Lactate perfusion in MI hearts had no additional effect on ROS levels, NADox, and NOX activity, however, it partially reduced mct1 mRNA expression (MI-Lactate 1.3±0.08 a.u.). Interestingly, lactate significantly decreased SOD (MI-Lactate: 54.5±4.2 µmol·mg−1·min−1) and catalase (MI: 1.1±0.1 nmol·mg−1·min−1) activities in MI. Collectively, our data suggest that under pathological stress, lactate lacks its ability to modulate the expression of cardiac LOC-related genes and the perfused pressure in hearts submitted to chronic MI. Together, these data contribute to elucidate the mechanisms involved in the pathogenesis of heart failure induced by MI.

Serum Klotho (but not haplotypes) associate with the post-myocardial infarction status of older adults

OBJECTIVES: The number of deaths from vascular diseases is incredibly high worldwide, and reliable markers for major events are still needed. The current cross-sectional study investigated the association of Klotho haplotypes and Klotho serum levels with classic risk factors and a clinical history of vascular events. METHODS: Clinical, anthropometric, biochemical and nutritional assessments were conducted with 168 older adults, complemented by genotyping (rs9536314 and rs9527025) and the detection of serum Klotho (ELISA). RESULTS: Klotho levels and haplotypes did not associate with most classic risk factors for vascular events, including markers such as C-reactive protein and homocysteine. A positive association was only found between Klotho levels and the previous occurrence of a myocardial infarction by both correlational (p=0.006) and variance analyses (p<0.001), and these associations were independent of the context. CONCLUSION: Our results suggest that serum Klotho is higher in individuals with a clinical history of myocardial infarction but not with a history of coronary artery disease or stroke. None of the Klotho haplotypes were associated with the variables investigated herein.

Hypomethylation of Interleukin-6 Promoter is Associated with the Risk of Coronary Heart Disease / Hipometilação do Promotor de Interleucina-6 Associada com Risco de Doença Arterial Coronariana

Abstract Background: Interleukin-6 (IL-6) is implicated in the pathogenesis of coronary heart disease (CHD), and IL-6 expression has associated with reduced DNA methylation of its gene promoter. However, there are no data on IL-6 promoter methylation and the risk of CHD. Objective: To examine whether IL-6 promoter methylation measured in blood leukocyte DNA is associated with CHD risk. Methods: A total of 212 cases with CHD and 218 controls were enrolled. Methylation at two CpG sites in IL-6 promoter was measured by bisulfite pyrosequencing, and the mean IL-6 methylation was calculated by averaging the methylation measures of the two CpGs. Results: Mean methylation level in IL-6 promoter in CHD cases was significantly lower than that in controls (p = 0.023). Logistic regression analysis showed that IL-6 methylation was inversely associated with the risk of CHD. The odds ratios (ORs) of CHD for subjects in the second and first (lowest) tertile of IL-6 methylation were 1.87 (95% CI = 1.10‑3.20) and 2.01 (95% CI = 1.19-3.38) (ptrend = 0.013), respectively, compared to subjects in the third (highest) tertile. The IL-6 hypomethylation-related risk estimates tended to be stronger for acute myocardial infarction (ptrend = 0.006). CpG position-specific analysis showed that hypomethylation of position 1 conferred a more pronounced increase in CHD risk than that of position 2. Conclusion: These findings suggest that DNA hypomethylation of IL-6 promoter is associated with the increased risk for CHD, especially for acute myocardial infarction. The two distinct CpGs in IL-6 may contribute differently to the development of CHD.

Resumo Fundamento: Interleucina-6 (IL-6) está implicada na patogênese de doença arterial coronariana (DAC), sendo sua expressão associada com redução da metilação de DNA do promotor do seu gene. Entretanto, não há dados sobre metilação do promotor de IL-6 e risco de DAC. Objetivo: Verificar se a metilação do promotor de IL-6 medida no DNA de leucócitos sanguíneos acha-se associada com risco de DAC. Métodos: este estudo arrolou 212 casos com DAC e 218 controles. Metilação em dois sítios de CpG no promotor de IL-6 foi medida por pirosequenciamento de bissulfito, sendo a metilação média de IL-6 calculada pela média das medidas de metilação dos dois CpGs. Resultados: A média do nível de metilação no promotor de IL-6 nos casos de DAC foi significativamente mais baixa do que nos controles (p = 0,023). Análise de regressão logística mostrou associação inversa entre metilação de IL-6 e risco de DAC. As razões de chance (OR) de DAC para indivíduos no segundo e no primeiro (mais baixo) tercis de metilação de IL-6 foram 1,87 (IC 95%: 1,10-3,20) e 2,01 (IC 95%: 1,19-3,38) (ptrend = 0,013), respectivamente, comparadas à de indivíduos no terceiro (mais alto) tercil. As estimativas de risco relacionado à hipometilação de IL-6 tenderam a ser mais fortes para infarto agudo do miocárdio (ptrend = 0,006). Análise com especificidade de posição de CpG mostrou que hipometilação na posição 1 conferiu maior elevação no risco de DAC do que na posição 2. Conclusão: Tais achados sugerem que a hipometilação de DNA do promotor de IL-6 está associada com elevado risco de DAC, especialmente para infarto agudo do miocárdio. Os dois CpGs distintos no promotor de IL-6 podem contribuir de modo diferente para o desenvolvimento de DAC.

Comparing the diagnostic values of circulating microRNAs and cardiac troponin T in patients with acute myocardial infarction

OBJECTIVE: Recent studies have shown that circulating microRNAs might be useful, novel biomarkers for the diagnosis of acute myocardial infarction. The aims of this study were to evaluate the expression of cardiac-specific miRNAs (miR-1, -133a, -208b, and -499) in patients with acute myocardial infarction and to compare the diagnostic values of these miRNAs with that of cardiac troponin T. METHODS: Sixty-seven plasma samples obtained from patients with acute myocardial infarction and 32 plasma specimens collected from healthy volunteers were analyzed in this study. The levels of cardiac-specific miRNAs (miR-1, -133a, -208b, and -499) were measured by quantitative reverse transcription-polymerase chain reaction, and the concentrations of plasma cardiac troponin T were measured using electrochemiluminescence-based methods and an Elecsys 2010 Immunoassay Analyzer. RESULTS: The levels of plasma miR-1, -133a, -208b, and -499 were significantly higher in acute myocardial infarction patients (all p<0.001) than in healthy volunteers. The expression of the cardiac-specific miRNAs in acute myocardial infarction patients decreased to close to the baseline levels at the time of hospital discharge (all p>0.05). There were no correlations between the levels of the four circulating miRNAs and the clinical characteristics of the study population (all p>0.05). Furthermore, receiver operating characteristic curve analyses showed that the four plasma miRNAs were not superior to cardiac troponin T for the diagnosis of acute myocardial infarction (all p>0.05). CONCLUSION: Our results demonstrate that circulating miR-1, -133a, -208b, and -499 may be useful biomarkers in acute myocardial infarction patients but that these miRNAs are not superior to cardiac troponin T for the diagnosis of acute myocardial infarction.