ADAM8 deficiency in macrophages promotes cardiac repair after myocardial infarction via ANXA2-mTOR-autophagy pathway.

INTRODUCTION: A disintegrin and metalloproteinase 8 (ADAM8), a crucial regulator in macrophages, is closely associated with cardiovascular disease progression. OBJECTIVES: This study aimed to explore how ADAM8 regulates macrophage function to inhibit cardiac repair after myocardial infarction (MI). METHODS: Macrophage-specific ADAM8 knockout mice (ADAM8flox/flox, Lyz2-Cre, KO) and corresponding control mice (ADAM8flox/flox, Flox) were established using the CRISPR/Cas9 system. Bone marrow transplantation was performed, and macrophage-specific ADAM8-overexpressing adeno-associated virus (AAV6-CD68-Adam8) was produced. Finally, proteomics, RNA sequencing, and co-immunoprecipitation/mass spectrometry (COIP/MS) were used to explore the underlying mechanisms involved. RESULTS: ADAM8 was highly expressed in the plasma of patients with acute myocardial infarction (AMI) and in cardiac macrophages derived from AMI mice. ADAM8 KO mice exhibited enhanced angiogenesis, suppressed inflammation, reduced cardiac fibrosis, and improved cardiac function during AMI, which were reversed by overexpressing macrophage-specific ADAM8 and intervention with the clinical anti-angiogenic biologic bevacizumab. Bone marrow transplantation experiments produced ADAM8 KO phenotypes. RNA sequencing showed that autophagy was activated in bone marrow-derived macrophages (BMDMs) with ADAM8 KO, which was confirmed via p-mTOR Ser2448/mTOR, p62, and LC3II/I detection. Autophagy inactivation suppressed angiogenic factor release and promoted inflammation in BMDMs with ADAM8 KO. Mechanistically, ADAM8 could bind to ANXA2 and promote phosphorylation of the ANXA2 Ser26 site. ADAM8 KO impeded ANXA2 phosphorylation, inhibited mTOR Ser2448 site phosphorylation, and activated autophagy, which were demonstrated using the activation or inactivation of ANXA2 phosphorylation. CONCLUSIONS: ADAM8 was increased in cardiac macrophages after AMI. The ADAM8-ANXA2-mTOR-autophagy axis in macrophages is responsible for regulating angiogenesis and inflammation following MI. Thus, ADAM8 may be a new target in MI treatment.

Prognostic value of a disintegrin and metalloproteinase Domain-8 in heart failure.

Background: Heart failure (HF) is a severe disease threatening people's health. The aim of this study is to find a significant biomarker inducive to predicting the prognosis of HF. Methods: GSE135055 and GSE161472 datasets were reanalyzed for exploring key genes related to HF. This single-center, prospective, observational cohort study enrolled 298 patients with or without HF from the Cardiology Department of Zhongda Hospital. Levels of ADAM8 were measured using ELISA kits. Major adverse cardiovascular events (MACEs) were defined as the composite end points of the first occurrence of rehospitalization because of HF or cardiac-related death during one-year follow-up. Results: (1) Bioinformatics analysis showed that ADAM8 was a key gene in HF via mainly regulating the mechanisms of extracellular matrix (ECM) organization. (2) Levels of ADAM8 were significantly increased in the HF group, compared to the non-failing (NF) group (p < 0.001), especially in patients with HFrEF (p < 0.05), and HFmEF (p < 0.05). The prevalence of HF in the high ADAM8 group (≧472.916 pg/mL) was significantly higher than in the low ADAM8 group (<472.916 pg/mL) (41.95 % vs 30.54 %, p < 0.01). (3) Correlation analysis revealed that ADAM8 was negatively correlated to the left ventricular ejection fraction (LVEF) (r = -0.272, p < 0.001). ROC analysis showed that the AUC of ADAM8 in predicting HF and predicting the MACE were 0.701 (p < 0.0001) and 0.683 (p < 0.0001), respectively. (4) Logistic and Cox regression both indicated that high ADAM8 expression can predict adverse prognosis of HF. Conclusions: ADAM8 may be a risk factor for HF, especially in cases of HFrEF and HFmEF. High ADAM8 expression in plasma was related to the decreased heart function, and can predict the adverse prognosis of HF.

Identification of potential crucial cuproptosis-related genes in myocardial ischemia-reperfusion injury through the bioinformatic analysis.

BACKGROUND: Cuproptosis is known to regulate diverse physiological functions in many diseases, but its role in regulating Myocardial Ischemia-Reperfusion Injury (MI/RI) remains unclear. METHODS: For this purpose, the MI/RI microarray datasets GSE61592 were downloaded from the Gene Expression Omnibus (GEO) database, and the Differently Expressed Genes (DEGs) in MI/RI were identified using R software. Moreover, the MI/RI mice model was established to confirm further the diagnostic value of Pyruvate Dehydrogenase B (Pdhb), Dihydrolipoamide S-acetyltransferase (Dlat), and Pyruvate dehydrogenase E1 subunit alpha 1 (Pdhα1). RESULTS: The analysis of microarray datasets GSE61592 revealed that 798 genes were upregulated and 768 were downregulated in the myocardial tissue of the ischemia-reperfusion injury mice. Furthermore, Dlat, Pdhb, Pdhα1, and cuproptosis-related genes belonged to the downregulated genes. The receiver operating characteristics curve analysis results indicated that the Dlat, Pdhb, and Pdhα1 levels were downregulated in MI/RI and were found to be potential biomarkers for MI/RI diagnosis and prognosis. Similarly, analysis of Dlat, Pdhb, and Pdhα1 levels in the MI/RI mice revealed Pdhb being the key diagnostic marker. CONCLUSIONS: This study demonstrated the prognostic value of cuproptosis-related genes (Dlat, Pdhb, and Pdhα1), especially Pdhb, MI/RI, providing new insight into the MI/RI treatment.

Macrophage-driven cardiac inflammation and healing: insights from homeostasis and myocardial infarction.

Early and prompt reperfusion therapy has markedly improved the survival rates among patients enduring myocardial infarction (MI). Nonetheless, the resulting adverse remodeling and the subsequent onset of heart failure remain formidable clinical management challenges and represent a primary cause of disability in MI patients worldwide. Macrophages play a crucial role in immune system regulation and wield a profound influence over the inflammatory repair process following MI, thereby dictating the degree of myocardial injury and the subsequent pathological remodeling. Despite numerous previous biological studies that established the classical polarization model for macrophages, classifying them as either M1 pro-inflammatory or M2 pro-reparative macrophages, this simplistic categorization falls short of meeting the precision medicine standards, hindering the translational advancement of clinical research. Recently, advances in single-cell sequencing technology have facilitated a more profound exploration of macrophage heterogeneity and plasticity, opening avenues for the development of targeted interventions to address macrophage-related factors in the aftermath of MI. In this review, we provide a summary of macrophage origins, tissue distribution, classification, and surface markers. Furthermore, we delve into the multifaceted roles of macrophages in maintaining cardiac homeostasis and regulating inflammation during the post-MI period.

Impact of calcification on Murray law-based quantitative flow ratio for physiological assessment of intermediate coronary stenoses.

BACKGROUND: To investigate the influence of coronary calcification on the diagnostic performance of Murray law-based quantitative flow ratio (µQFR) in identifying hemodynamically significant coronary lesions referenced to fractional flow reserve (FFR). METHODS: A total of 571 intermediate lesions from 534 consecutive patients (66.1 ± 10.0 years, 67.2% males) who underwent coronary angiography and simultaneous FFR measurement were included. Calcific deposits were graded by angiography as none or mild (spots), moderate (involving ≤ 50% of the reference vessel diameter), and severe (> 50%). Performance of µQFR to detect functional ischemia (FFR ≤ 0.80) was evaluated, including diagnostic parameters and areas under the receiver-operating curves (AUCs). RESULTS: The discrimination of ischemia by µQFR was comparable between none/mild and moderate/severe calcification (AUC: 0.91 [95% confidence interval: 0.88-0.93] vs. 0.87 [95% confidence interval: 0.78-0.94]; p = 0.442). No statistically significant difference was observed for µQFR between the two categories in sensitivity (0.70 vs. 0.69, p = 0.861) and specificity (0.94 vs. 0.90, p = 0.192). Moreover, µQFR showed significantly higher AUCs than quantitative coronary angiographic diameter stenosis in both vessels with none/mild (0.91 vs. 0.78, p < 0.001) and moderate/severe calcification (0.87 vs. 0.69, p < 0.001). By multivariable analysis, there was no association between calcification and µQFR-FFR discordance (adjusted odds ratio: 1.529, 95% confidence interval: 0.788-2.968, p = 0.210) after adjustment for other confounding factors. CONCLUSIONS: µQFR demonstrated robust and superior diagnostic performance for lesion-specific ischemia compared with angiography alone regardless of coronary calcification.

Sex Differences in Murray Law-Based Quantitative Flow Ratio Among Patients With Intermediate Coronary Lesions.

Background The Murray law-based quantitative flow ratio (µQFR) is a novel technique that simulates fractional flow reserve (FFR) from a single angiographic view. However, the impact of sex differences on the diagnostic performance of µQFR has not been investigated. Methods and Results In this study, FFR and µQFR were assessed in 497 intermediate stenoses (30%-70% by visual estimation) from 460 patients (34.3% female). Physiological significance was defined as FFR ≤0.80 or µQFR ≤0.80. After adjusting for potential confounders, female sex was independently associated with higher FFR (P=0.048 and 0.026, respectively) and µQFR (P=0.001 for both) in both fully adjusted and stepwise backward models. µQFR provided superior diagnostic accuracy compared with angiography alone for detecting FFR ≤0.80 in both women (area under the curve, 0.93 [95% CI, 0.88-0.97] versus 0.80 [95% CI, 0.73-0.86]; P=0.001) and men (area under the curve, 0.88 [95% CI, 0.84-0.92] versus 0.73 [95% CI, 0.68-0.78]; P<0.001), with comparable performance between the sexes (P=0.175). In the multivariable analysis, sex was not a significant factor contributing to the overall disagreement between FFR and µQFR. Conclusions Regardless of angiographic stenosis severity, women tend to have higher FFR and µQFR values than men. Furthermore, µQFR performs similarly well in both sexes and offers improved diagnostic accuracy over angiography alone, indicating its potential as a reliable, wire-free tool to identify functional ischemia.

Inhibition of miR-195-3p protects against cardiac dysfunction and fibrosis after myocardial infarction.

Cardiac fibrosis following myocardial infarction is a major risk factor for heart failure. Recent evidence suggests that miR-195-3p is up-regulated in fibrotic diseases, including kidney and liver fibrosis. However, its function and underlying mechanisms in cardiac fibrosis after MI remain unknown. To investigate the role of miR-195-3p in MI-induced cardiac fibrosis, we established acute MI models by ligating adult C57B/L6 mice LAD coronary artery while sham-operated mice were used as controls. In vivo inhibition of miR-195-3p was conducted by intramyocardial injection of AAV9-anti-miR-195-3p. In vitro overexpression and inhibition of miR-195-3p were performed by transfecting cultured Cardiac Fibroblasts (CFs) with synthetic miRNA mimic and inhibitor. Our results showed that MI induced the expression of miR-195-3p and that inhibition of miR-195-3p reduced myofibroblast differentiation and collagen deposition and protected cardiac function. In vitro stimulation of CFs with TGF-ß1 resulted in a significant increase in miR-195-3p expression. Inhibition of miR-195-3p attenuated the TGF-ß1-induced expression of ECM proteins, migration, and proliferation. PTEN expression was significantly reduced in the hearts of MI mice, in activated CFs, and in CFs transfected with miR-195-3p mimic. Inhibition of miR-195-3p markedly restored PTEN expression in MI mice and TGF-ß1-treated CFs. In conclusion, this study highlights the crucial role of miR-195-3p in promoting cardiac fibrosis and dysfunction after MI. Inhibiting miR-195-3p could be a promising therapeutic strategy for preventing cardiac fibrosis and preserving cardiac function after MI. Additionally, the study sheds light on the mechanisms underlying the effects of miR-195-3p on fibrosis, including its regulation of PTEN/AKT pathway.

Association between dietary intake of anthocyanidins and heart failure among American adults: NHANES (2007-2010 and 2017-2018).

Background: Despite anthocyanidins have anti-inflammatory and antioxidant properties, no studies have researched association between dietary intake of anthocyanidins and heart failure. Methods: We enrolled 15,869 participants from the National Health and Nutrition Examination Survey (NHANES) (2007-2010 and 2017-2018) in this cross-sectional study. We examined baseline data and prevalence of heart failure in different quartile groups of anthocyanin intake (Q1-4). Three models were established through logistic regression to evaluate the protective effect of Q4 (highest anthocyanidins intake) on heart failure. The protective effect of high anthocyanidins intake on heart failure was further evaluated in different subgroups. Results: Participants with the highest anthocyanidins intake (Q4) had the lowest prevalence of heart failure (Q1:2.54%, Q2:2.33%, Q3:2.43%, Q4:1.57%, p = 0.02). After adjusting for possible confounding factors, compared with the Q1 group, the highest anthocyanidins intake (Q4) was independently related to lower presence of heart failure (Q4: OR 0.469, 95%CI [0.289, 0.732], p = 0.003). And this association was still stable in subgroups of female, ≥45 years, smoker, non-Hispanic White or without diabetes, stroke and renal failure. Conclusion: Dietary intake of anthocyanidins had negative association with the presence of heart failure.

Upregulation of Biomarker Limd1 Was Correlated with Immune Infiltration in Doxorubicin-Related Cardiotoxicity.

Doxorubicin is one of the most common antitumor drugs. However, cardiotoxicity's side effect limits its clinical applicability. In the present study, Gene Expression Omnibus (GEO) datasets were applied to reanalyze differentially expressed genes (DEGs) and construct weighted correlation network analysis (WGCNA) modules of doxorubicin-induced cardiotoxicity in wild-type mice. Several other bioinformatics analyses were performed to pick out the hub gene, and then the correlation between the hub gene and immune infiltration was evaluated. In total, 120 DEGs were discovered in a mouse model of doxorubicin-induced cardiotoxicity, and PF-04217903, propranolol, azithromycin, etc. were found to be potential drugs against this pathological condition. Among all the DEGs, 14 were further screened out by WGCNA modules, of which Limd1 was upregulated and finally regarded as the hub gene after being validated in other GEO datasets. Limd1 was upregulated in the peripheral blood mononuclear cell (PBMC) of the rat model, and the area under curve (AUC) of the receiver operating characteristic curve (ROC) in diagnosing cardiotoxicity was 0.847. The GSEA and PPI networks revealed a potential immunocyte regulatory role of Limd1 in cardiotoxicity. The proportion of "dendritic cells activated" in the heart was significantly elevated, while "macrophage M1" and "monocytes" declined after in vivo doxorubicin application. Finally, Limd1 expression was significantly positively correlated with "dendritic cells activation' and negatively correlated with "monocytes" and "macrophages M1'. In summary, our results suggested that limd1 is a valuable biomarker and a potential inflammation regulator in doxorubicin-induced cardiotoxicity.

Visceral adipose tissue-directed human kallistatin gene therapy improves adipose tissue remodeling and metabolic health in obese mice.

OBJECTIVE: Adipose tissue remodeling is a dynamic process that is pathologically expedited in the obese state and is closely related to obesity-associated disease progression. This study aimed to explore the effects of human kallistatin (HKS) on adipose tissue remodeling and obesity-related metabolic disorders in mice fed with a high-fat diet (HFD). METHODS: Adenovirus-mediated HKS cDNA (Ad.HKS) and a blank adenovirus (Ad.Null) were constructed and injected into the epididymal white adipose tissue (eWAT) of 8-weeks-old male C57B/L mice. The mice were fed normal or HFD for 28 days. The body weight and circulating lipids levels were assessed. Intraperitoneal glucose tolerance test (IGTT) and insulin tolerance test (ITT) were also performed. Oil-red O staining was used to assess the extent of lipid deposition in the liver. Immunohistochemistry and HE staining were used to measure HKS expression, adipose tissue morphology, and macrophage infiltration. Western blot and qRT-PCR were used to evaluate the expression of adipose function-related factors. RESULTS: At the end of the experiment, the expression of HKS in the serum and eWAT of the Ad.HKS group was higher than in the Ad.Null group. Furthermore, Ad.HKS mice had lower body weight and decreased serum and liver lipid levels after four weeks of HFD feeding. IGTT and ITT showed that HKS treatment maintained balanced glucose homeostasis. Additionally, inguinal white adipose tissue (iWAT) and eWAT in Ad.HKS mice had a higher number of smaller-size adipocytes and had less macrophage infiltration than Ad.Null group. HKS significantly increased the mRNA levels of adiponectin, vaspin, and eNOS. In contrast, HKS decreased RBP4 and TNFα levels in the adipose tissues. Western blot results showed that local injection of HKS significantly upregulated the protein expressions of SIRT1, p-AMPK, IRS1, p-AKT, and GLUT4 in eWAT. CONCLUSIONS: HKS injection in eWAT improves HFD-induced adipose tissue remodeling and function, thus significantly improving weight gain and dysregulation of glucose and lipid homeostasis in mice.

Identification of major hub genes involved in high-fat diet-induced obese visceral adipose tissue based on bioinformatics approach.

High-fat diet (HFD) can cause obesity, inducing dysregulation of the visceral adipose tissue (VAT). This study aimed to explore potential biological pathways and hub genes involved in obese VAT, and for that, bioinformatic analysis of multiple datasets was performed. The expression profiles (GSE30247, GSE167311 and GSE79434) were downloaded from Gene Expression Omnibus. Overlapping differentially expressed genes (ODEGs) between normal diet and HFD groups in GSE30247 and GSE167311 were selected to run protein-protein interaction network, GO and KEGG analysis. The hub genes in ODEGs were screened by Cytoscape software and further verified in GSE79434 and obese mouse model. A total of 747 ODEGs (599 up-regulated and 148 down-regulated) were screened, and the GO and KEGG analysis showed that the up-regulated ODEGs were significantly enriched in inflammatory response and extracellular matrix receptor interaction pathways. On the other hand, the down-regulated ODEGs were involved in metabolic pathways; however, there were no significant KEGG pathways. Furthermore, six hub genes, Mki67, Rac2, Itgb2, Emr1, Tyrobp and Csf1r were acquired. These pathways and genes were verified in GSE79434 and VAT of obese mice. This study revealed that HFD induced VAT expansion, inflammation and fibrosis, and the hub genes could be used as therapeutic biomarkers in obesity.

The triglycerides-glucose index and the triglycerides to high-density lipoprotein cholesterol ratio are both effective predictors of in-hospital death in non-diabetic patients with AMI.

Background: The triglycerides-glucose index (TyG) and the triglycerides to high-density lipoprotein cholesterol (TG/HDL-C) are simple indicators for assessing insulin resistance in epidemiological studies. We aimed to clarify the relationship between indicators of insulin resistance and prognosis in non-diabetic acute myocardial infarction (AMI) patients. Methods: A total of 1,648 AMI patients without diabetes were enrolled from the Department of Cardiology, Zhongda Hospital, between 2012.03 and 2018.12. The medical history, laboratory and imaging data of patients were collected through the medical record system, and all-cause death events were recorded. Pearson analysis was used to study the correlation among different variables. Logistic regression analysis was used to analyze the predictive effect of TyG and TG/HDL-C in in-hospital death of AMI patients. Results: 1. In AMI group, the TyG index was significantly increased in death groups compared to no-death groups (P = 0.025). TG/HDL-C was not significantly increased in the death group of AMI patients (P = 0.588). The patients were respectively divided into Q1-Q4 groups and T1-T4 groups according to the quartiles of TyG and TG/HDL-C. The trends of in-hospital mortality in the Q4 group of TyG and T4 group of TG/HDL-C were higher than in other groups, although these differences were not significant. 2. Pearson correlation analysis showed that TyG was positively correlated with lipid-related markers, including ApoB (r = 0.248, P < 0.001), total cholesterol (TC) (r = 0.270, P < 0.001), low-density lipoprotein cholesterol (LDL-C) (r = 0.238, P < 0.001). Spearman analysis showed that TG/HDL-C was also positively associated with TC (r = 0.107, P < 0.001), ApoB (r = 0.180, P < 0.001) and LDL-C (r = 0.164, P < 0.001). 3. Logistic regression analysis showed that TyG (OR = 3.106, 95% CI [2.122-4.547], P < 0.001) and TG/HDL-C (OR = 1.167, 95% CI [1.062-1.282], P = 0.001) were both important factors to predict the in-hospital death of AMI patients without diabetes. Conclusions: TyG index and TG/HDL-C, as emerged simple markers of insulin resistance, were both important predictors of in-hospital death in AMI patients without diabetes.

Upregulation of key genes Eln and Tgfb3 were associated with the severity of cardiac hypertrophy.

BACKGROUND: Hypertension-induced cardiac hypertrophy is one of the most common pre-conditions that accompanies heart failure. This study aimed to identify the key pathogenic genes in the disease process. METHODS: GSE18224 was re-analyzed and differentially expressed genes (DEGs) were obtained. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were carried out. Networks of transcription factor (TF)-mRNA, microRNA (miRNA)-mRNA and Protein-Protein interaction (PPI) were constructed, and a key module was further screened out from PPI network. GSE36074 dataset and our transverse aortic constriction (TAC) mouse model were used to validate gene expression in the module. Finally, the correlation between the genes and biomarkers of cardiac hypertrophy were evaluated. RESULTS: Totally, there were 348 DEGs in GSE18224, which were mainly enriched in biological processes including collagen fibril organization, cellular response to transforming growth factor-beta stimulus and were involved in ECM-receptor interaction and Oxytocin signaling pathway. There were 387 miRNAs targeted by 257 DEGs, while 177 TFs targeted 71 DEGs. The PPI network contained 222 nodes and 770 edges, with 18 genes screened out into the module. After validation, 8 genes, which were also significantly upregulated in the GSE36074 dataset, were selected from the 18 DEGs. 2 of the 8 DEGs, including Eln and Tgfb3 were significantly upregulated in our mouse model of myocardial hypertrophy. Finally, the expression of Eln and Tgfb3 were found to be positively correlated with the level of the disease biomarkers. CONCLUSIONS: Upregulated key genes Eln and Tgfb3 were positively correlated with the severity of cardiac hypertrophy, which may provide potential therapeutic targets for the disease.

METTL3 mediates Ang-II-induced cardiac hypertrophy through accelerating pri-miR-221/222 maturation in an m6A-dependent manner.

BACKGROUND: METTL3 is the core catalytic enzyme in m6A and is involved in a variety of cardiovascular diseases. However, whether and how METTL3 plays a role during angiotensin II (Ang-II)-induced myocardial hypertrophy is still unknown. METHODS: Neonatal rat cardiomyocytes (NRCMs) and C57BL/6J mice were treated with Ang-II to induce myocardial hypertrophy. qRT-PCR and western blots were used to detect the expression of RNAs and proteins. Gene function was verified by knockdown and/or overexpression, respectively. Luciferase and RNA immunoprecipitation (RIP) assays were used to verify interactions among multiple genes. Wheat germ agglutinin (WGA), hematoxylin and eosin (H&E), and immunofluorescence were used to examine myocardial size. m6A methylation was detected by a colorimetric kit. RESULTS: METTL3 and miR-221/222 expression and m6A levels were significantly increased in response to Ang-II stimulation. Knockdown of METTL3 or miR-221/222 could completely abolish the ability of NRCMs to undergo hypertrophy. The expression of miR-221/222 was positively regulated by METTL3, and the levels of pri-miR-221/222 that bind to DGCR8 or form m6A methylation were promoted by METTL3 in NRCMs. The effect of METTL3 knockdown on hypertrophy was antagonized by miR-221/222 overexpression. Mechanically, Wnt/ß-catenin signaling was activated during hypertrophy and restrained by METTL3 or miR-221/222 inhibition. The Wnt/ß-catenin antagonist DKK2 was directly targeted by miR-221/222, and the effect of miR-221/222 inhibitor on Wnt/ß-catenin was abolished after inhibition of DKK2. Finally, AAV9-mediated cardiac METTL3 knockdown was able to attenuate Ang-II-induced cardiac hypertrophy in mouse model. CONCLUSIONS: Our findings suggest that METTL3 positively modulates the pri-miR221/222 maturation process in an m6A-dependent manner and subsequently activates Wnt/ß-catenin signaling by inhibiting DKK2, thus promoting Ang-II-induced cardiac hypertrophy. AAV9-mediated cardiac METTL3 knockdown could be a therapeutic for pathological myocardial hypertrophy.

High-density lipoprotein cholesterol to apolipoprotein A-1 ratio is an important indicator predicting in-hospital death in patients with acute coronary syndrome.

BACKGROUND: Dyslipidemia plays a pivotal role in the pathogenesis of acute coronary syndrome (ACS). This study aims to investigate the value of two indices associated with lipid metabolism, low-density lipoprotein cholesterol to apolipoprotein B ratio (LBR) and high-density lipoprotein cholesterol to apolipoprotein A-1 ratio (HAR), to predict in-hospital death in patients with ACS. METHODS: This single-center, retrospective, observational study included 3,366 consecutive ACS patients in Zhongda Hospital, Southeast University from July 2013 to January 2018. The clinical and laboratory data were extracted, and the in-hospital death and hospitalization days were also recorded. RESULTS: All patients were equally divided into four groups according to quartiles of HAR: Q1 (HAR < 1.0283), Q2 (1.0283 ≤ HAR < 1.0860), Q3 (1.0860 ≤ HAR < 1.1798), and Q4 (HAR ≥ 1.1798). Overall, HAR was positively associated with the counts of neutrophils and monocytes, whereas negatively correlated to lymphocyte counts. HAR was negatively correlated to left ventricular ejection fraction (LVEF). Compared to other three groups, in-hospital mortality (vs. Q1, Q2, and Q3, p < 0.001) and hospitalization length (vs. Q1, Q2, and Q3, p < 0.001) were significantly higher in the Q4 group. When grouped by LBR, however, there was no significant difference in LVEF, in-hospital mortality, and hospitalization length among groups. After adjusting potential impact from age, systolic blood pressure, creatine, lactate dehydrogenase, albumin, glucose, and uric acid, multivariate analysis indicated that HAR was an independent factor predicting in-hospital death among ACS patients. CONCLUSIONS: HAR had good predictive value for patients' in-hospital death after the occurrence of acute coronary events, but LBR was not related to in-hospital adverse events.

Serpina3c regulates adipose differentiation via the Wnt/ß-catenin-PPARγ pathway.

OBJECTIVE: The Serpin protein family plays an important role in regulating the functioning of the adipose tissue. This study aimed to study the underlying mechanisms of Serpina3c in regulating adipogenesis. METHODS: We developed a Serpina3c knockout (Serpina3c-/-) mouse model and Serpina3c knockdown and overexpression 3T3-L1 preadipocyte models to evaluate the role of Serpina3c in adipose differentiation. Mice were fed on ND for 12-month or HFD for one month. The body weight, glucose tolerance, and insulin tolerance of the mice were subsequently measured. Lipid depositions and adipose tissue morphology were then detected using Oil red O staining and HE staining. qRT-PCR and Western blot were used to detect the expression of adipose differentiation transcription factors. RESULTS: Serpina3c-/- mice exhibited lower body weight and white adipose tissue (WAT) weight than WT mice after 12 months of being fed on ND. Additionally, there was an increase in serum and hepatic triglyceride (TG) levels in Serpina3c-/- mice, without changes in glucose metabolism. Wnt/ß-catenin was upregulated while PPARγ expression was decreased in knockout mice WAT. Impaired adipocyte differentiation caused by Serpina3c knockdown was reversed by IWR-1 and kallistatin through an increase in PPARγ expression. Serpina3c-/- mice fed on HFD for one month had a lower body weight and WAT than WT, accompanied by increased lipid depositions in the liver and muscles and severe insulin resistance. CONCLUSION: Serpina3c promotes adipogenesis and maintains normal fat function by inhibiting the Wnt/ß-catenin pathway.

Age-Related Utilization of Thrombus Aspiration in Patients With ST-Segment Elevation Myocardial Infarction: Findings From the Improving Care for Cardiovascular Disease in China Project.

Background: There are some controversies on the utilization and benefits of thrombus aspiration in patients with ST-segment elevation myocardial infarction (STEMI). However, a few studies investigated this issue and the age-associated effects among the large population in China. Hence, we aimed to figure out the age-associated utilization and in-hospital outcomes of thrombus aspiration to improve therapeutic decisions in clinical routine. Methods: We retrospectively recruited 13,655 eligible STEMI patients from the database of the Improving Care for Cardiovascular Disease in China-Acute Coronary Syndrome project. These subjects were allocated into primary percutaneous coronary intervention (PPCI)-only group and thrombus aspiration group after being subdivided into three age groups (G21-50, G51-75, and G76-95). After 1:1 propensity score matching for PPCI-only and thrombus aspiration groups, a total of 8,815 matched patients were enrolled for the subsequent analysis. The primary outcome was in-hospital cardiovascular death, and the key safety outcome was in-hospital stroke. Results: We observed that the ratio of STEMI patients undergoing thrombus aspiration to PPCI-only reduced with aging. For patients ≤ 75 years, the culprit lesion suffered from thrombus aspiration was mainly located in the left anterior descending branch, and left-ventricular ejection fraction (LVEF) was lower (G21-50: 54.9 ± 8.9 vs. 56.0 ± 8.7%, P = 0.01; G51-75: 53.9 ± 9.6 vs. 54.8 ± 9.0%, P = 0.001) and the rate of regional wall motion abnormality was higher (G21-50: 75.7 vs. 66.5%, P < 0.001; G51-75: 75.4 vs. 69.1%, P < 0.001) in the thrombus aspiration group. By contrast, for patients > 75 years, the right coronary artery was the predominant culprit lesion undergoing thrombus aspiration, LVEF (63.1 ± 10.5 vs. 53.1 ± 9.5%, P = 0.985) and the regional wall motion abnormality (79.2 vs. 74.2%, P = 0.089) were comparable between the two treatment groups. Thrombus aspiration neither reduced the in-hospital risk of cardiovascular death, all-cause death, recurrent myocardial infarction, acute stent thrombosis, heart failure, cardiogenic shock, and sudden cardiac arrest nor increased stroke risk compared with the PPCI-only group. However, after adjustment for age, thrombus aspiration presented the tendency to reduce the incidence of sudden cardiac arrest (4.9 vs. 2.5%, P = 0.06) and in-hospital cardiovascular death at 3 days (hazard ratio 0.46; 95% CI, 0.20-1.06; log-rank P = 0.08) in G76-95 group and tended to increase the incidence of heart failure in G51-75 (5.7 vs. 6.9%, P = 0.07). Conclusion: The thrombus aspiration neither significantly reduced the in-hospital incidence of major adverse cardiac events nor increased stroke risk. However, it might play a protective role in reducing in-hospital sudden cardiac arrest and increasing survival from cardiovascular death at 3 days for the elderly.

Exosomal miR-17-3p Alleviates Programmed Necrosis in Cardiac Ischemia/Reperfusion Injury by Regulating TIMP3 Expression.

OBJECTIVE: Myocardial ischemia/reperfusion (I/R) injury can aggravate myocardial injury. Programmed necrosis plays a crucial role in this injury. However, the role of exosomal miRNAs in myocardial I/R injury remains unclear. Therefore, this study is aimed at exploring the function and mechanism of exosomal miR-17-3p in myocardial I/R injury. METHODS: The myocardial I/R injury animal model was established in C57BL/6 mice. Exosomes were identified using transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), and Western blotting. Programmed necrosis was detected by PI staining. Heart function and myocardial infarct size were evaluated using echocardiography and triphenyl tetrazolium chloride (TTC) staining, respectively. Histopathological changes were visualized by hematoxylin and eosin (H&E) and Masson staining. The regulation of TIMP3 expression by miR-17-3p was verified using a dual-luciferase reporter assay. Lactate dehydrogenase (LDH) and tumor necrosis factor-α (TNF-α) levels were measured by enzyme-linked immunosorbent assays (ELISA). TIMP3 expression was measured by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and Western blotting. RESULTS: We demonstrated that miR-17-3p was significantly downregulated in peripheral blood exosomes after cardiac I/R injury. Further analysis indicated that exosomal miR-17-3p attenuated H2O2-induced programmed necrosis in cardiomyocytes in vitro. Moreover, TIMP3 was a target for miR-17-3p. TIMP3 affected H2O2-induced programmed necrosis in cardiomyocytes. This effect was modulated by miR-17-3p in vitro. Furthermore, exosomal miR-17-3p greatly alleviated cardiac I/R injury in vivo. CONCLUSIONS: The present study demonstrated that exosomal miR-17-3p alleviated the programmed necrosis associated with cardiac I/R injury by regulating TIMP3 expression. These findings could represent a potential treatment for I/R injury.

Albumin to globulin ratio was associated with in-stent restenosis and revascularization events after percutaneous coronary intervention.

In-stent restenosis is a common complication after percutaneous coronary intervention (PCI) for coronary heart disease requiring revascularization. We performed a retrospective analysis to assess the value of inflammatory biomarker albumin to globulin ratio (AGR) in clinical prognosis of PCI. In total, 992 patients with coronary heart disease who underwent the first drug-eluting stent implantation and re-examination angiography in our hospital were enrolled in this study. The AGR was measured. At mean follow-up of 11.2 ± 4 months, the in-stent restenosis (ISR) and revascularization events (including target lesion revascularization, target vessel revascularization, and revascularization of de novo lesions) occurred in 127 and 284 patients, respectively. Compared with the non-ISR or non-event group, AGR was significantly lower in the ISR group and the events group. Beyond that, albumin was significantly lower, whereas urea nitrogen, glucose, and Gensini score, as well as the proportions of a history of diabetes and peripheral vascular diseases were significantly higher in the ISR group and the events group. Age, heart rate, white blood cell, neutrophils, lymphocyte, monocyte, and incidence of ischemic stroke were significantly higher in the events group. Multivariate Cox regression analysis showed that AGR was independently associated with ISR (p = 0.032) and events (p = 0.024). Besides, Kaplan-Meier analysis indicated that the higher quartile of AGR had a lower rate of ISR (p = 0.038) and events (p ≤ 0.001). Finally, the receiver operating characteristic curve for AGR in diagnosing ISR and events indicated that the area under the curve were 0.56 and 0.57, respectively. Therefore, AGR is one of the most important factors that independently associate with the ISR and revascularization events after PCI.

Inflammatory activation and immune cell infiltration are main biological characteristics of SARS-CoV-2 infected myocardium.

The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) can target cardiomyocytes (CMs) to directly invade the heart resulting in high mortality. This study aims to explore the biological characteristics of SARS-CoV-2 infected myocardium based on omics by collecting transcriptome data and analyzing them with a series of bioinformatics tools. Totally, 86 differentially expressed genes (DEGs) were discovered in SARS-CoV-2 infected CMs, and 15 miRNAs were discovered to target 60 genes. Functional enrichment analysis indicated that these DEGs were mainly enriched in the inflammatory signaling pathway. After the protein-protein interaction (PPI) network was constructed, several genes including CCL2 and CXCL8 were regarded as the hub genes. SRC inhibitor saracatinib was predicted to potentially act against the cardiac dysfunction induced by SARS-CoV-2. Among the 86 DEGs, 28 were validated to be dysregulated in SARS-CoV-2 infected hearts. Gene Set Enrichment Analysis (GSEA) analysis of Kyoto Encyclopedia of Genes and Genomes (KEGG) showed that malaria, IL-17 signaling pathway, and complement and coagulation cascades were significantly enriched. Immune infiltration analysis indicated that 'naive B cells' was significantly increased in the SARS-CoV-2 infected heart. The above results may help to improve the prognosis of patients with COVID-19.