Vascular Electrical Stimulation with Wireless, Battery-Free, and Fully Implantable Features Reduces Atherosclerotic Plaque Formation Through Sirt1-Mediated Autophagy.

Electrical stimulation (ES) is a safe and effective procedure in clinical rehabilitation with few adverse effects. However, studies on ES for atherosclerosis (AS) are scarce because ES does not provide a long-term intervention for chronic disease processes. Battery-free implants and surgically mounted them in the abdominal aorta of high-fat-fed Apolipoprotein E (ApoE-/- ) mice are used, which are electrically stimulated for four weeks using a wireless ES device to observe changes in atherosclerotic plaques. Results showed that there is almost no growth of atherosclerotic plaque at the stimulated site in AopE-/- mice after ES. RNA-sequencing (RNA-seq) analysis of Thp-1 macrophages reveal that the transcriptional activity of autophagy-related genes increase substantially after ES. Additionally, ES reduces lipid accumulation in macrophages by restoring ABCA1- and ABCG1-mediated cholesterol efflux. Mechanistically, it is demonstrated that ES reduced lipid accumulation through Sirtuin 1 (Sirt1)/Autophagy related 5 (Atg5) pathway-mediated autophagy. Furthermore, ES reverse autophagic dysfunction in macrophages of AopE-/- mouse plaques by restoring Sirt1, blunting P62 accumulation, and inhibiting the secretion of interleukin (IL)-6, resulting in the alleviation of atherosclerotic lesion formation. Here, a novel approach is shown in which ES can be used as a promising therapeutic strategy for AS treatment through Sirt1/Atg5 pathway-mediated autophagy.

The synergy between diurnal temperature range and calcium concentration help to predict hospital mortality in patients with acute myocardial infarction.

Epidemiological studies have suggested that cold is an important contributor to acute cardiovascular events and mortality. However, little is known about the Diurnal Temperature Range (DTR) impact on mortality of the patients with myocardial infarction. Calcium ions (Ca2+) play a vital role in the human body, such as cardiac electrophysiology and contraction. To investigate whether DTR on admission moderates the association between serum calcium and in-hospital mortality in patients with acute myocardial infarction (AMI). This retrospective study enrolled consecutive adult patients with AMI at a single center in China (2003-2012). Patients were divided into four groups (Ca-Q1-4) according to serum calcium concentration quartiles. Multivariate logistic regression modeling was used to assess whether DTR moderated the association between serum calcium and in-hospital mortality. The predictive value of serum calcium was evaluated by receiver operating characteristic (ROC) curve and net reclassification improvement (NRI) analyses. The study included 3780 patients. In-hospital mortality was 4.97% (188/3780). DTR moderated the association between serum calcium and in-hospital mortality (P-interaction = 0.020). Patients with low serum calcium in the highest DTR quartile exhibited an increased risk of in-hospital mortality (odds ratio for Ca-Q4 vs. Ca-Q1, 0.03; 95% confidence interval [95% CI], 0.01-0.20). In the highest DTR quartile, adding serum calcium concentration to the risk factor model increased the area under the ROC curve (0.81 vs. 0.76; P < 0.001) and increased NRI by 20.2% (95% CI 7.5-32.9; P = 0.001). Low serum calcium was an independent risk factor for in-hospital mortality in patients with AMI, and this association was moderated by DTR. Careful attention should be paid to patients with low serum calcium who experience a higher DTR on admission.

Hypermethylation of miR-181b in monocytes is associated with coronary artery disease and promotes M1 polarized phenotype via PIAS1-KLF4 axis.

BACKGROUND: Dysregulated microRNAs are involved in the macrophage polarization and atherosclerotic development. Apart from microRNAs, alteration in DNA methylation is considered as one of the most frequent epigenetic changes. The purpose of the research is to investigate the altered methylation status of miR-181b in the circulating monocytes from patients with coronary artery disease (CAD) and explore the underlying mechanisms. METHODS: We examined the methylation status of miR-181b in purified circulating monocytes from patients with CAD and healthy controls. We then transfected monocytes with miR-181b mimics and determined the role of miR-181b on the phenotypic switch of macrophages and inflammatory response. DNA methylation levels determined by MethyLight PCR and pyrosequencing at the promoter of miR-181b significantly increased in CAD patients. Based on TargetScan database, we identified PIAS1 as the target gene of miR-181b and explored the interaction of miR-181b and PIAS1 by Dual-Luciferase assay, quantitative PCR and immunoblots. We also investigated the role of miR-181b and PIAS1 on macrophage polarization and inflammation. RESULTS: Hypermethylation at the promoter of miR-181b directly contributed to the decrease of miR-181b activity and expression. Overexpression of miR-181b reduced M1 polarization and facilitated M2 polarization determined by quantitative PCR. While knockdown of PIAS1 induced KLF4 degradation and SUMOylation in monocytes, miR-181b mimics reverse the KLF4 SUMOylation via suppression of PIAS1. Moreover, KLF4 SUMOylation by PIAS1 reversed M1 polarization induced by depletion of miR-181b in monocytes. CONCLUSIONS: Hypermethylation of miR-181b induces M1 polarization and promotes atherosclerosis through activation of PIAS1 and KLF4 SUMOylation in macrophages.

Comparison of Ticagrelor with Clopidogrel in Reducing Interleukin-17 and Myeloperoxidase Expression in Thrombus and Improving Postprocedural Coronary Flow in ST-segment Elevation Myocardial Infarction Patients.

PURPOSE: This study aimed to explore the effects of ticagrelor (a P2Y12 receptor inhibitor) on interleukin (IL)-17 and myeloperoxidase (MPO) expression in coronary thrombus as well as on the coronary blood flow in ST-segment elevation myocardial infarction (STEMI) patients following percutaneous coronary intervention (PCI). METHODS: Forty STEMI patients who were admitted to the First Affiliated Hospital of Harbin Medical University between August 1, 2014 and December 30, 2014 were enrolled in this study according to a set inclusion criteria. They were randomized to ticagrelor and clopidogrel groups and treated with 180 mg ticagrelor and 600 mg clopidogrel before PCI, respectively. Intracoronary thrombus aspiration was performed by a physician during PCI. Immunohistochemistry and Western blot analysis were carried out to detect the expression of IL-17 and MPO in the thrombus. Corrected thrombolysis in myocardial infarction frame count (CTFC) was used to evaluate blood flow after PCI. RESULTS: Immunohistochemistry results showed that the average positive staining area percentage of IL-17 and MPO in the clopidogrel group was significantly higher than that in the ticagrelor group. Western blot analysis also showed similar results for IL-17 (clopidogrel 0.71 ± 0.036, ticagrelor 0.50 ± 0.56) and MPO (clopidogrel 0.50 ± 0.040; ticagrelor 0.38 ± 0.06). CTFC was lower in the ticagrelor group than that in the clopidogrel group (P < 0.05). CONCLUSIONS: Ticagrelor is more effective than clopidogrel in reducing inflammation thrombosis and improving postprocedural PCI blood flow in STEMI patients. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.

miRNA-21 Expression in the Serum of Elderly Patients with Acute Myocardial Infarction.

BACKGROUND The aims of this study were to examine the expression of miRNA-21 in the serum of elderly patients (>65 years) with acute myocardial infarction (AMI) and to investigate the potential role of serum miRNA-21 as a marker of early cardiac myocyte damage. MATERIAL AND METHODS Thirty-eight elderly patients with recent AMI, 27 elderly patients with unstable angina pectoris, and 25 healthy elderly individuals were included in the study. Serum miRNA-21 expression was determined following total RNA extraction and reverse-transcribed into cDNA, followed by reverse transcription-polymerase chain reaction (RT-PCR). Serum creatine kinase MB isoenzyme (CK-MB) and cardiac troponin I (cTnI) levels were analyzed by electrochemiluminescence. Apoptosis of human cardiac myocytes (HCM) was analyzed using fluorescence-activated cell sorting (FACS), and protein expression of caspase-3 was detected using Western blot. RESULTS Expression levels of miRNA-21 in the serum of elderly patients with AMI were positively correlated with serum levels of CK-MB (r=0.3683, P=0.0229) and cTnI (r=0.5128, P=0.009). Following tumor necrosis factor (TNF)-α induction, the apoptosis rates of HCM transfected with the miRNA-21 mimic short hairpin RNA (shRNA) were downregulated by 39.1% compared with control HCM cells, and protein expression of c-Jun N-terminal kinases (JNK) and p38 were unchanged (P>0.05); protein expression of p-JNK, p-p38 and caspase-3 were downregulated by 37.1%, 35.8%, and 36.0%, respectively. CONCLUSIONS Expression of miRNA-21 was upregulated in the serum of elderly patients with AMI, which inhibited TNF-a induced apoptosis in HCM by activating the JNK/p38/caspase-3 signaling pathway.

Application of neutrophil/lymphocyte ratio in predicting coronary blood flow and mortality in patients with ST-elevation myocardial infarction undergoing percutaneous coronary intervention.

BACKGROUND: To investigate the potential correlation of neutrophil/lymphocyte ratio (NLR) to coronary blood flow and in-hospital along with long-term mortality in patients with ST-elevation myocardial infarction (STEMI) undergoing percutaneous coronary intervention (PCI). METHODS: In the current study, 636 consecutive patients with STEMI were recruited and stratified into three tertiles by NLRs upon admission (tertile I<3.0, tertile II 3.0-6.40, tertile III>6.40). The coronary blood flow was expressed by corrected TIMI frame count (CTFC). The in-hospital mortality and 12-month long follow-up data were collected. Receiver operating characteristic (ROC) curves were also constructed. RESULTS: Our analysis demonstrated that NLR was positively correlated to CTFC and in-hospital mortality (r=0.517, p<0.001; r=0.439, p<0.001). In the multiple logistic regression analysis, NLR was testified as an independent risk factor for coronary blood flow after PCI and in-hospital mortality [odds ratio (OR)=2.031, 95% confidence interval (CI): 1.627-2.435, p<0.001; OR=1.176, 95% CI: 1.025-1.351, p=0.021]. During the 12-month follow-up, there were a total of 43 deaths and statistically significant increase in long-term mortality was observed in patients from tertile I to III (p=0.005). In the ROC curves analysis, the area under the curve (AUC=0.607, 95% CI: 0.475-0.739, p=0.253), with threshold value of 5.9 (sensitivity: 63.7%, specificity: 61.1%) for predicting in-hospital mortality. CONCLUSIONS: NLR, an indicator that can be tested in the laboratory with low cost and time consumption, is independently correlated to coronary blood flow and acts as an independent risk factor for in-hospital mortality in patients with STEMI undergoing PCI.

Apoptosis of THP-1 derived macrophages induced by sonodynamic therapy using a new sonosensitizer hydroxyl acetylated curcumin.

Curcumin is extracted from the rhizomes of the traditional Chinese herb Curcuma longa. Our previous study indicated curcumin was able to function as a sonosensitizer. Hydroxyl acylated curcumin was synthesized from curcumin to eliminate the unstable hydroxy perssad in our group. The potential use of Hydroxyl acylated curcumin as a sonosensitizer for sonodynamic therapy (SDT) requires further exploration. This study investigated the sonodynamic effect of Hydroxyl acylated curcumin on THP-1 macrophage. THP-1 macrophages were cultured with Hydroxyl acylated curcumin at a concentration of 5.0 µg/mL for 4 hours and then exposed to pulse ultrasound irradiation (0.5 W/cm2 with 1.0 MHz ) for 5 min, 10 min and 15 min. Six hours later, cell viability decreased significantly by CCK-8 assay. After ultrasound irradiation, the ratio of apoptosis and necrosis in SDT group was higher than that in control, Hydroxyl acylated curcumin alone and ultrasound alone. Moreover, the apoptotic rate was higher than necrotic rate with the flow cytometry analysis. Furthermore, Hydroxyl acylated curcumin-SDT induced reactive oxygen species (ROS) generation in THP-1 macrophages immediately after the ultrasound treatment while ROS generation was reduced significantly with the scavenger of singlet oxygen Sodium azide (NaN3). Hydroxyl acylated curcumin-SDT led to a conspicuous loss of mitochondrial membrane potential (MMP) compared with other groups, while MMP was increased significantly with the scavenger of singlet oxygen Sodium azide (NaN3), ROS inhibitor N-acetyl cysteine (NAC) and Mitochondrial Permeability Transition Pore (MPTP) inhibitor Cyclosporin A (CsA). The cytochrome C, cleaved-Caspase-9, cleaved-Caspase-3 and cleaved-PARP upregulated after SDT through Western blotting. These findings suggested that Hydroxyl acylated curcumin under low-intensity ultrasound had sonodynamic effect on THP-1 macrophages via generation of intracellular singlet oxygen and mitochondria-caspase signaling pathway, indicating that Hydroxyl acylated curcumin could be used as a novel sonosensitizer in SDT for atherosclerosis.

Effect of percutaneous thrombectomy on echocardiographic measures of myocardial microcirculation in elderly patients with acute myocardial infarction.

OBJECTIVES: To study the efficacy of percutaneous thrombectomy (PT) in improving myocardial microcirculation in elderly acute myocardial infarction (AMI) patients. METHODS: A total of 104 patients (> or = 65 years) with AMI and coronary thrombus shown by angiography were randomly divided into a group of percutaneous coronary intervention (PCI) (n=52) and a group of PCI plus PT (n=52). At 24 h and 1 week after PCI, real-time myocardial contrast echocardiography was performed by contrast pulse sequencing technology. Contrast score index, contrast defect length/left ventricle length [CDL/LVL (%)], wall motion score index and wall motion abnormal length/LVL (%) were calculated. RESULTS: At each time point, in patients treated with PCI plus PT, contrast score index, CDL/LVL (%), wall motion score index and wall motion abnormal length/LVL (%) were significantly lower than that in the PCI group. CONCLUSION: Thrombectomy reduces the noreflow and the extent of microvascular obstruction, thus it was a feasible therapy in elderly patients with AMI.

[The prognostic value of hyponatremia in patients with acute myocardial infarction].

OBJECTIVE: To evaluate the prognostic significance of hyponatremia in patients with AMI. METHODS: The study population consisted of 670 patients with AMI in coronary care unit in our hospital from January 2003 to December 2004. The patients were designed into three groups according to serum sodium concentration within twenty four to forty eight hours following the onset of AMI: Group A. Na(+) > or = 135 mmol/L; Group B. Na(+) 120-135 mmol/L; Group C. Na(+) < or = 120 mmol/L. The data of myocardial enzymes, myocardial infarction size, heart function and inhospital mortality were analyzed retrospectively. RESULTS: 1. The inhospital mortality of each group: group A was 7.6% (17/225), group B was 8.1% (34/421), group C was 33.3% (8/24). The difference between group C and group B or group A was significant. The P value was little than 0.05. 2. Activities of serum creatine phosphatase kinase and serum creatine phosphatase kinase isoenzymes and myocardial infarction sizes in each group were different (P < 0.05). 3. 59 cases of all died and 611 cases of all recovered in duration of hospital stay. Serum sodium concentrations of the recovered group were (133.00 +/- 5.25) mmol/L, and that of the died group were (122.00 +/- 7.25) mmol/L (P < 0.01). 4. In a multivariate logistic regression analysis, hyponatremia was associated with 30-day mortality in patients with AMI. In analysis of the association between the degree of hyponatremia and outcome, we observed that the risk of 30-day mortality increased with the severity of hyponatremia. CONCLUSION: Hyponatremia may be one of the important markers that predict a worse prognosis in patients with AMI.