Transcriptional and functional analysis of plasma exosomal microRNAs in acute viral myocarditis.

AIM: To assess the differential expression profiles of exosome-derived microRNA (miRNA) and reveal their potential functions in patients with acute viral myocarditis (AVMC). MATERIALS & METHODS: Peripheral blood samples were collected from 9 patients diagnosed with AVMC and 9 healthy controls (HC) in the Affiliated Hospital of Qingdao University from July 2021 to September 2022. The exosomal miRNA expression were tested using RNA high-throughput sequencing. We conducted the GO and KEGG functional analysis to predict the potential molecular, biological functions and related signaling pathways of miRNAs in exosomes. Target genes of exosomal miRNAs were predicted and miRNA-target gene network was mapped using gene databases. Differentially expressed exosomal miRNAs were selected and their expression levels were detected by quantitative real-time polymerase chain reaction (qRT-PCR) to verify the sequencing results. RESULTS: P < 0.05 and Fold Change>2 were considered as cut-off value to screen miRNAs that were differently expressed. This study identified 14 upregulated and 14 downregulated exosome-derived miRNAs. GO and KEGG analysis showed that differentially expressed miRNAs may be related to ß-catenin binding, DNA transcription activities, ubiquitin ligase, PI3K-Akt, FoxO, P53, MAPK, and etc.. The target genes of differentially expressed miRNAs were predicted using gene databases. Real-time PCR confirmed the upregulation of hsa-miR-548a-3p and downregulation of hsa-miR-500b-5p in AVMC. CONCLUSIONS: Hsa-miR-548a-3p and hsa-miR-500b-5p could serve as a promising biomarker of AVMC. Exosomal miRNAs may have substantial roles in the mechanisms of AVMC.

MINOCA biomarkers: Non-atherosclerotic aspects.

Myocardial infarction in the absence of obstructive coronary artery disease (MINOCA) is an important subtype of myocardial infarction. Although comprising less than 50% stenosis in the main epicardial coronary arteries, it constitutes a severe health risk. A variety of approaches have been recommended, but definitive diagnosis remains elusive. In addition, the lack of a comprehensive understanding of underlying pathophysiology makes clinical management difficult and unpredictable. This review highlights ongoing efforts to identify relevant biomarkers in MINOCA to improve diagnosis, individualize treatment and better predict outcomes.

Glucose control independent mechanisms involved in the cardiovascular benefits of glucagon-like peptide-1 receptor agonists.

Patients with type 2 diabetes mellitus (T2DM) face a high risk of developing cardiovascular diseases. However, traditional hypoglycemic drugs have limited effects on macrovascular complications of the disease. Clinical trials have confirmed that glucagon-like peptide-1 receptor agonists (GLP-1RAs), in addition to their capability of controlling blood glucose, can also decrease the risk of cardiovascular events in T2DM. The protective influence of GLP-1RAs on coronary heart disease and heart failure has been proven in recent clinical studies. Therefore, the international guidelines recommend GLP-1 RAs as the first-line therapy for patients with T2DM having cardiovascular disease. Notwithstanding the widespread clinical application of GLP-1RAs, the underlying mechanisms through which GLP-1RAs exert cardiovascular benefits in patients with DM remain unclear. In this review, we systematically summarize the mechanisms of action of GLP-1RAs responsible for producing favorable effects on the cardiovascular system, beyond their capability of blood glucose regulation. GLP-1RA-mediated cardiovascular protection is manifested through multiple mechanisms, including oxidative stress, inflammation, endoplasmic reticulum stress, apoptosis, and vascular/cardiac remodeling. The understanding of these mechanisms will facilitate the development of new and promising therapeutic modalities for T2DM. Furthermore, we have identified several promising targets for future research in this area.

Impact of serum uric acid levels on the clinical prognosis and severity of coronary artery disease in patients with acute coronary syndrome and hypertension after percutaneous coronary intervention: a prospective cohort study.

OBJECTIVE: The impact of serum uric acid (sUA) levels on the clinical prognosis and severity of coronary artery disease in patients with acute coronary syndrome (ACS) and hypertension after percutaneous coronary intervention (PCI) is not fully clear. This study aimed to assess the association among sUA levels, clinical prognosis and severity of coronary artery disease in patients with ACS and hypertension after PCI. DESIGN: In this prospective cohort study, we followed-up patients with ACS and hypertension after PCI for 1 year to explore the risk factors for 1 year total major adverse cardiovascular events (MACEs) and multivessel coronary artery disease, the dose-effect relationship among sUA levels, MACEs and severity of coronary artery disease and correlation between sUA levels and severity of coronary artery disease (Gensini score). SETTING/PATIENTS: Several Chinese internists followed-up 422 patients who were diagnosed with ACS and hypertension after PCI in a large tertiary hospital of Qingdao during the period from 1 June 2019 to 1 December 2019. OUTCOME MEASURES: One-year follow-up MACEs results and coronary angiography results. RESULTS: In the coronary angiography results, multivessel coronary artery disease (28.5% vs 21.4%, p=0.006) and non-culprit lesion vascular occlusion (11.7% vs 5.3%, p=0.042) were more common in the hyperuricaemia group, and the Gensini score (26.69±13.46 vs 17.66±10.57, p<0.001) was also higher. In the results of 1-year MACEs, the incidence of all-cause mortality (3.5% vs 2.5%, p=0.037), PCI or coronary artery bypass grafting therapy due to myocardial infarction or angina pectoris (15.1% vs 7.6%, p=0.027), medication conservative therapy in hospital due to myocardial infarction or angina pectoris (12.9% vs 6.7%, p=0.041) and total MACEs (31.8% vs 16.9%, p=0.001) were higher in patients with hyperuricaemia. Univariate and multivariate logistic regression analysis models showed that hyperuricaemia was still an independent risk factor for total MACEs within 1 year (OR=2.618, 95% CI 1.656 to 4.139, p<0.001; OR=1.920, 95% CI 1.158 to 3.183, p=0.011, respectively) and multivessel coronary artery disease (OR=2.140, 95% CI 1.371 to 3.342, p=0.001; OR=1.688, 95% CI 1.051 to 2.710, p=0.030, respectively) after adjusting for confounding factors. The severity of coronary artery disease (non-culprit lesion vascular occlusion (4.7% vs 8.4% vs 9.6% vs 16.2%, p=0.041); multivessel coronary artery disease (17.9% vs 22.4% vs 29.8% vs 35.2%, p=0.022); Gensini score (16.96±10.35 vs 19.31±10.63 vs 26.12±11.48 vs 33.33±14.01, p<0.001)) and the incidence of total MACEs (13.2% vs 14.2% vs 34.6% vs 41%, p<0.001) increased significantly with the sUA levels increasing. Further, the Gensini score was positively correlated with uric acid levels (r=0.515, p<0.001). CONCLUSIONS: Hyperuricaemia is an independent risk factor for 1-year total MACEs and multivessel coronary artery disease in patients with ACS and hypertension after PCI.

The Molecular Mechanisms of Cardiotoxicity Induced by HER2, VEGF, and Tyrosine Kinase Inhibitors: an Updated Review.

AIM: In recent decades, there has been a revolutionary decrease in cancer-related mortality and an increase in survival due to the introduction of novel targeted drugs. Nevertheless, drugs targeting human epidermal growth factor receptor 2 (HER-2), angiogenesis, and other tyrosine kinases also come with unexpected cardiac side effects, including heart failure, hypertension, arterial thrombosis, and arrhythmias, and have mechanisms that are unlike those of classic chemotherapeutic agents. In addition, it is challenging to address some problems, as the existing guidelines need to be more specific, and further large-scale clinical trials and experimental studies are required to confirm the benefit of administering cardioprotective agents to patients treated with targeted therapies. Therefore, an improved understanding of cardiotoxicity becomes increasingly important to minimize the pernicious effects and maximize the beneficial effects of targeted agents. METHODS: "Cardiotoxicity", "targeted drugs", "HER2", "trastuzumab", "angiogenesis inhibitor", "VEGF inhibitor" and "tyrosine kinase inhibitors" are used as keywords for article searches. RESULTS: In this article, we report several targeted therapies that induce cardiotoxicity and update knowledge of the clinical evidence, molecular mechanisms, and management measures.

Valsartan Prevented Neointimal Hyperplasia and Inhibited SRSF1 Expression and the TLR4-iNOS-ERK-AT1 Receptor Pathway in the Balloon-injured Rat Aorta.

Valsartan has the potential to attenuate neointimal hyperplasia and to suppress the inflammatory response. This study aimed to evaluate the role of valsartan in neointimal hyperplasia and the toll-like receptor 4 (TLR4)-nitric oxide synthase (NOS) pathway in the balloon-injured rat aorta.Forty-eight Wistar rats were randomly allocated to three groups: sham control (control), balloon-injured group (surgery), and balloon-injured+valsartan-treated group (valsartan). Rats were killed at 14 and 28 days after balloon-injury, and then the aortic tissues were collected for morphometric analysis as well as for measurements of the mRNA or protein expression of angiotensin II, angiotensin II type 1 (AT1) receptor, angiotensin II type 2 (AT2) receptor, TLR4, endothelial nitric oxide synthase (eNOS), inducible NOS (iNOS), serine/arginine-rich splicing factor 1(SRSF1) and extracellular signal regulated kinase (ERK). Valsartan at a dose of 20 mg/kg/day markedly decreased neointimal hyperplasia in the aorta of balloon-injured rats, and significantly reduced the mRNA or protein expression of TLR4, AT1 receptor, SRSF1 and phosphorylated-ERK (p-ERK) as well as the aortic levels of iNOS (all p < 0.05). Moreover, valsartan increased the eNOS level and AT2 receptor mRNA and protein expression levels (all p < 0.05). Valsartan prevented neointimal hyperplasia and inhibited SRSF1 expression and the TLR4-iNOS-ERK-AT1 receptor pathway in the balloon-injured rat aorta.

Exploration of CYP21A2 and CYP17A1 polymorphisms and preeclampsia risk among Chinese Han population: a large-scale case-control study based on 5021 subjects.

BACKGROUND: Several genome-wide association studies have identified single-nucleotide polymorphisms (SNPs), such as rs4409766, rs1004467, and rs3824755 in CYP17A1 and rs2021783 in CYP21A2, as new hypertension susceptibility genetic variants in the Chinese population. This study aimed to look into the relationship between preeclampsia (PE) and these SNPs in Chinese Han women. METHODS: Overall, 5021 unrelated pregnant women were recruited, including 2002 patients with PE and 3019 normal healthy controls. The real-time PCR (TaqMan) method was applied to genotype these four polymorphisms. RESULTS: A statistically obvious difference in the allelic frequencies was observed in CYP21A2 rs2021783 between cases and controls (χ2 = 7.201, Pc = 0.028 by allele), and the T allele was associated with the occurrence and development of PE (OR = 1.151, 95% CI 1.039-1.275). We also found a significant association between rs2021783 and the development of early-onset PE (Pc = 0.008 by genotype, Pc = 0.004 by allele). For rs1004467 and rs3824755, the distribution of allelic frequencies differed markedly between mild PE and control groups (χ2 = 6.843, Pc = 0.036; χ2 = 6.869, Pc = 0.036), and patients with the TT genotype of rs1004467 were less easy to develop mild PE than were those carrying the CT or CC genotype (χ2 = 7.002, Pc = 0.032, OR = 1.306, 95% CI 1.071-1.593). The GG genotype of rs3824755 appeared to a protective effect on the occurrence of mild PE (OR = 0.766, 95% CI 0.629-0.934). CONCLUSIONS: CYP21A2 rs2021783 appears to be closely related to PE susceptibility, and CYP17A1 rs1004467 and rs3824755 seem to be closely associated with mild PE in Han women.

The effect of olmesartan on aortic intimal thickening after balloon injury through Apelin/APJ.

PURPOSE: Restenosis is the main complication after percutaneous coronary intervention. The proliferation of new intima contributes to the process. In this study, we aimed to explore the effect of olmesartan on intimal thickening after balloon injury and possible mechanism. METHODS: Aortic endothelial denudation model was made by a 2F balloon catheter. Thirty-six rats were randomly allocated into three groups: Control (n = 12) Surgery (n = 12, received vascular balloon injury) and Olmesartan (n = 12, received 3 mg.kg-1.d-1olmesartan after injury). Fourteen and 28 days after injury, HE staining was used to assess the aortic endothelial injury. Radioimmunological method was used to examine the level of angiotensin II (Ang II). Western blotting and reverse transcription polymerse chain reaction (RT-PCR) were employed to detect the protein and mRNA level of Apelin/APJ. RESULTS: After vascular balloon injury, the proliferation of vascular smooth muscle cells and the intimal thickening were increased. The mRNA and protein level of Ang II, AT1, Apelin and APJ mRNA were promoted by vascular balloon injury. Olmesartan decreased the proliferation of vascular smooth muscle cells and the intimal thickening. Olmesartan decreased the expression of Ang II and AT1, but further increased the expression of Apelin and APJ. Balloon injury also induced the activation of Extracellular signal-regulated kinase (ERK) signaling and olmesartan decreased the effect. CONCLUSION: Olmesartan inhibits the intimal thickening through activating Apelin/APJ and inhibiting AngII-AT1 and ERK pathway.

Comparison of Efficacy between Clopidogrel and Ticagrelor in Patients with Acute Coronary Syndrome after Interventional Treatment and Their Effects on IL-6.

BACKGROUND: We aimed to compare the efficacy between clopidogrel and ticagrelor in patients with acute coronary syndrome (ACS) after percutaneous coronary intervention (PCI) and their effects on IL-6. METHODS: A retrospective analysis and collection of 200 ACS patients diagnosed by the Department of Cardiology, Affiliated Hospital of Qingdao University, Qingdao, China in 2016 were performed. Patients were randomly divided into clopidogrel group and ticagrelor group. Data of left ventricular ejection fraction and ACS clinical classification before PCI, PCI treatment, IL-6, platelet aggregation status, maximum platelet aggregation rate (MPAR), P2Y12 response unit (PRU) and adverse reaction of patients were collected. After PCI, patients were followed up for 1 year to compare the ischemia after treatment between clopidogrel group and tigravilol group. RESULTS: MPAR and PRU after PCI of clopidogrel group were significantly higher than those of ticagrelor group (P<0.05). The expression of IL-6 in two groups peaked at 1 day after PCI and then decreased. That of ticagrelor group was consistently lower than that of clopidogrel group (P<0.05). The incidence of ischemic events after treatment in clopidogrel group was significantly higher than that in ticagrelor group (P<0.001). CONCLUSION: Compared with clopidogrel, tigerrilol had more significant inhibition of platelet aggregation after PCI in ACS patients, and tigerrilol had better effect after interventional treatment in ACS patients. In addition, compared with clopidogrel, tegrel can significantly inhibit the expression of IL-6 in patients with ACS and better alleviate the inflammatory response after PCI.

The effect of CYP2C19 genotype-guided antiplatelet therapy on outcomes of selective percutaneous coronary intervention patients: an observational study.

Aim: To observe if personalized antiplatelet therapy according to the CYP2C19 phenotype can improve the outcomes of patients receiving selective percutaneous coronary intervention (PCI). Methods: In this observational study, 677 Chinese patients undergoing selective PCI were divided into gene group (n = 369) and conventional group (n = 308), and given antiplatelet therapy according to the CYP2C19 genotype or clinical features, respectively. Incidence of MACE (death, non-fatal myocardial infarction, and unplanned repeat revascularization) and bleeding was compared between the two groups after 18 months. Results: Diabetes, heart dysfunction and SYNTAX score (>15), but not routinely CYP2C19 genotype test-guided antiplatelet therapy, were associated with MACE. The incidence of bleeding showed no difference. Conclusion:CYP2C19 phenotype-guided antiplatelet therapy may have no influence on the outcomes of selective PCI patients. Clinical features-guided antiplatelet therapy may be reasonable.

Cardio-protective effects of salvianolic acid B on oxygen and glucose deprivation (OGD)-treated H9c2 cells.

The morphological feature of apoptosis is induced by oxygen and glucose deprivation (OGD) in cardiomyocytes H9c2 cells. Salvianolic acid B (Sal-B) has been studied in several pathological progresses, whereas it is still unclear whether maternally expressed gene 3 (MEG3) is an intermediate regulator during this progress. After pre-incubation with Sal-B and stimulation with OGD, viability and apoptosis of were examined in MEG3-overexpressed H9c2 cells. Cyclin D1, apoptosis-correlated proteins and regulators of signalling pathways were quantified with Western blot assay. MEG3 was detected by quantitative reverse transcription PCR (qRT-PCR). Sal-B was implicated in the enhancement of cell viability and suppression of apoptosis in OGD-treated H9c2 cells by repressing MEG3. In addition, MEG3 overexpression exerted an inhibitory effect on murine double minute 2 (MDM2) expression while aggrandized p53 expression in OGD-treated H9c2 cells which were pre-incubated with Sal-B. Furthermore, MEG3 overexpression abolished the up-regulative effect of Sal-B on phosphorylation of adenosine monophosphate-activated protein kinase (AMPK) in OGD-treated H9c2 cells. These results indicated that cardio-protective function of Sal-B might be ascribed to its down-regulatory property on MEG3 expression which hence blocks p53 and triggers AMPK activation in OGD-treated cells.

Hypertension Is an Independent Predictor of Multivessel Coronary Artery Disease in Young Adults with Acute Coronary Syndrome.

BACKGROUND: Risk factors of multivessel coronary artery disease (CAD) among young acute coronary syndrome (ACS) patients remain elusive now. METHODS: This retrospective study analyzed data from 187 consecutive young (age ≤45 years) ACS patients (75 STEMI, 30 NSTEMI, and 72 unstable angina) hospitalized in our hospital from January 2012 to December 2016. Thirty-six young male patients with normal coronary angiography (CAG) findings (no-CAD), who underwent CAG due to suspected chest pain in this period, served as control group. There were 83 patients with single-vessel disease (SVD) and 104 patients with multiple-vessel disease (MVD) among ACS patients. Patients were followed up for a mean of 267±124 days by clinical visit or telephone calls. RESULTS: All included patients were male. Prevalence of hypertension (57.2% vs. 30.6%, p=0.002) and smoking (70.6% vs. 52.8%, p=0.049) was significantly higher in ACS patients than in no-CAD patients. Prevalence of hypertension (72.1% vs. 38.6%, p<0.001) and body mass index (BMI) were significantly higher in MVD group than in SVD group. Multivariable analysis revealed that hypertension was an independent risk factor for MVD after adjustment for age, gender, BMI, smoking, family history of premature CAD, hyperlipidemia, left ventricular ejection fraction, and brain natriuretic peptide (odds ratio=3.71, 95% confidence interval=1.84-7.46, p<0.001). Rate of major adverse cardiovascular events (MACE) during follow-up (20.2% vs. 4.8%) was significantly higher in MVD group compared with SVD group. CONCLUSIONS: Hypertension is an independent predictor of MVD and MVD is associated with increased MACE rate compared to SVD in young ACS patients during the short-term follow-up.

Comparison of Ticagrelor and Clopidogrel for Patients Undergoing Emergency Percutaneous Coronary Intervention.

BACKGROUND: We compared treatments with the antiplatelets ticagrelor and clopidogrel used in patients with acute myocardial infarction (AMI) during the perioperative period for emergency percutaneous coronary intervention (PCI). METHODS: A total of 120 patients were selected and randomly divided into control and observation groups (60 patients in each) from 2014-2016 at The Affiliated Hospital of Qingdao University. The patients in the control group received 300 mg clopidogrel and 300 mg aspirin for oral administration, while those in the observation group were given 180 mg ticagrelor and 300 mg aspirin orally prior to the PCI. During the operation, heparinization and a tirofiban micro-pump were used continuously. RESULTS: Coronary artery and peripheral venous blood were extracted from each patient to obtain various parameters of thrombelastogram (TEG), and the maximum platelet aggregation rates in order to compare antiplatelet effects. Major adverse cardiac events (MACE) were recorded during the following 6-month follow-up. Analysis of the data showed no differences in terms of the time span between medication intake and stent implantation, or the dosage of heparin and tirofiban used between the two groups. Before stent implantation, and 24 and 48 h after the procedure the average R and K values of TEG in coronary artery blood and peripheral venous blood samples in the observation group were longer than those in the control group, while the α angle, MA, CI, MARAA and MARADP values were lower (P<0.05). CONCLUSION: Ticagrelor can improve antiplatelet treatment for patients with AMI during the perioperative period of emergency PCI.

Chronic Kidney Disease Exacerbates Myocardial Ischemia Reperfusion Injury: Role of Endoplasmic Reticulum Stress-Mediated Apoptosis.

Chronic kidney disease (CKD) is known to exacerbate myocardial ischemia reperfusion (IR) injury. However, the underlying mechanisms are still not well understood. Despite various strategies for cardioprotection, limited studies have been focused on the prevention of CKD-induced myocardial susceptibility to IR injury. Here, we hypothesized that excessive endoplasmic reticulum (ER) stress-mediated apoptosis involved in myocardial IR injury in CKD mice and pretreatment with chemical ER chaperone rendered the heart resistant to myocardial IR injury in the setting of CKD. CKD was induced by 5/6 subtotal nephrectomy (SN) in mice, whereas sham-operated mice served as control (Sham). CKD significantly aggravated the cardiac injury after IR in SN group than Sham group as reflected by more severe cardiac dysfunction, increased myocardial infarct size and the ratio of myocardial apoptosis. The expression of ER stress-mediated apoptotic proteins (Bcl-2 associated X protein (Bax), glucose-regulated protein 78 (GRP78), CCAAT/enhancer-binding protein homologous protein (CHOP), caspase-12) was markedly upregulated after IR injury in SN group than Sham group, whereas the expression of anti-apoptotic protein, Bcl-2, was obviously downregulated. In addition, the chemical ER chaperone sodium 4-phenylbutyrate (4PBA) pretreatment ameliorated cardiac dysfunction and lessened the infarct size and myocardial apoptosis after IR injury in mice with CKD. Taken together, these findings demonstrated that excessive activation of ER stress-mediated apoptosis pathway involved in the CKD-induced myocardial susceptibility to IR injury, and chemical ER chaperone 4PBA alleviated myocardial IR injury in mice with CKD.

Assessment of aflatoxin B1 myocardial toxicity in rats: mitochondrial damage and cellular apoptosis in cardiomyocytes induced by aflatoxin B1.

Objective The number of deaths from heart disease is increasing worldwide. Aflatoxin B1 (AFB1), a toxin produced by the fungi Aspergillus flavus and Aspergillus parasiticus, is frequently detected in improperly processed/stored human food products. While AFB1 hepatotoxicity and carcinogenic properties have been well addressed, its myocardial toxicity is poorly documented. This study aimed to investigate myocardial toxic activity of AFB1. Methods Ten rats were fed with AFB1 at a dose that did not result in acute toxic reactions for 30 days and 10 vehicle-fed rats served as controls. Transmission electron microscopy was used to assess mitochondrial damage in cardiomyocytes. The terminal deoxynucleotidyl transferase-mediated UTP nick-end labelling assay was performed to detect apoptosis of cardiomyocytes. Western blotting was performed to measure apoptotic proteins (i.e., active caspase-3, Bax, and Bcl-2) in heart tissue. Results AFB1 treatment resulted in mitochondrial membrane disruption and disorganization of cristae, which are indicators of mitochondrial damage. Myocardial cell apoptosis was significantly higher after AFB1 treatment (22.07% ± 3.29%) compared with controls (6.27% ± 2.78%, P < 0.05). AFB1 treatment enhanced expression of active caspase-3, Bax, and Bcl-2 in cardiac tissue. Conclusion Various adverse effects are exerted by AFB1 on the heart, indicating AFB1 myocardial toxicity.

Acute Coronary Stent Thrombosis in Modern Era: Etiology, Treatment, and Prognosis.

Acute stent thrombosis (AST) is a rare but life-threatening complication of coronary artery stenting. AST remains a challenging task for cardiologists, despite the application of modern procedural techniques and dual-antiplatelet therapy strategies as well as improved understanding of the underlying pathophysiology. This review focuses on the prevalence, risk factors, prognosis, multiple potential underlying pathogenesis, knowledge gaps, and recommends diagnosis and individualized management strategies of AST.