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.

A novel cartilage-targeting MOF-HMME-RGD sonosensitizer combined with sonodynamic therapy to enhance chondrogenesis and cartilage regeneration.

Articular cartilage regeneration is still a difficult task due to the cartilage's weak capacity for self-healing and the effectiveness of the available therapies. The engineering of cartilage tissue has seen widespread use of stem cell-based therapies. However, efficient orientation of line-specific bone marrow mesenchymal stem cells (BMSCs) to chondrogenesis and maintenance of chondrogenic differentiation challenged stem cell-based therapy. Herein, we developed a Fe-based metal-organic framework (MOF) loaded with hematoporphyrin monomethyl ether (HMME) and cartilage-targeting arginine-aspartate-glycine (RGD) peptide to form MOF-HMME-RGD sonosensitizer to regulate BMSCs chondrogenic differentiation for cartilage regeneration via the modulation of reactive oxygen species (ROS). By using sonodynamic therapy (SDT), the MOF-HMME-RGD demonstrated favorable biocompatibility, could generate a modest amount of ROS, and enhanced BMSCs chondrogenic differentiation through increased accumulation of glycosaminoglycan, an ECM component specific to cartilage, and upregulated expression of key chondrogenic genes (ACAN, SOX9, and Col2a1). Further, transplanted BMSCs loading MOF-HMME-RGD combined with SDT enhanced cartilage regeneration for cartilage defect repair after 8 weeks into treatment. This synergistic strategy based on MOF nanoparticles provides an instructive approach to developing alternative sonosensitizers for cartilage regeneration combined with SDT.

Inhibition of myocardial remodeling through miR-150/TET3 axis after AMI.

BACKGROUND: Current studies have suggested that miRNA is beneficial in inhibiting myocardial remodeling after myocardial infarction (AMI), however, its underlying mechanism is unclear. OBJECTIVES: We aimed to investigate whether miR-150 can inhibit myocardial remodeling after myocardial infarction and whether this process is regulated by the miR-150/TET3 pathway. METHODS: On the first day, C57BL/6 AMI mice(n = 15) were administrated with miR-150, and another 15 AMI mice were administrated with the same volume of control Agomir. Left ventricular ejection fraction (LVEF%) and myocardial remodeling were compared after one week; TET3 (ten-eleven translocation 3) and VEGF-α (vascular endothelial growth factor-α) were also determined in the infracted heart simultaneously. The neovascularization in the infarcted area at day 21 was compared through CD31 using fluorescence microscopy; Activated monocytes stimulated with LPS were transfected with miR-150. Laser scanning confocal microscopy was used to detect the intracytoplasmic imaging of miR-150 in Ly6Chigh monocytes. Expression of the miR-150 in the monocytes was measured using Q-PCR. After 48 h, the proportion of Ly6Chigh/low monocytes was determined using flow cytometry. Expression of TET3 in Ly6Chigh/low monocytes was measured using Q-PCR and Western blot. After the downregulation of TET3 specifically, the levels of Ly6Chigh/low monocytes were further determined. RESULTS: We first observed an increased trend of mice survival rate in the miR-150 injection group, but it didn't reach a statistical difference (66.7% vs. 40.0%, p = 0.272). However, AMI mice administrated with miR-150 displayed better LVEF% (51.78%±2.90% vs. 40.28%±4.20%, p<0.001) and decreased infarct size% (25.47 ± 7.75 vs. 50.39 ± 16.91, p = 0.002). After miR-150 was transfected into monocytes, the percentage of Ly6Clow monocytes increased significantly after 48 h (48.5%±10.1% vs. 42.5%±8.3%, p < 0.001). Finally, Western blot analysis (0.56 ± 0.10/ß-actin vs. 0.99 ± 0.12/ß-actin, p < 0.001) and real-time PCR (1.09 ± 0.09/GAPDH vs. 2.53 ± 0.15/GAPDH, p < 0.001, p < 0.001) both confirmed decreased expression of TET3 in monocytes after transfection with miR-150. After the downregulation of TET3 specifically, Ly6Clow monocytes showed a significant increase (16.73%±6.45% vs. 6.94%±2.99%, p<0.001, p < 0.001). CONCLUSIONS: miR-150 alleviated myocardial remodeling after AMI. Possible mechanisms are ascribed to the regulating of TET3 and VEGF-α in inflammatory monocytes.

Very high HDL-C (high-density lipoprotein cholesterol) is associated with increased cardiovascular risk in patients with NSTEMI (non-ST-segment elevation myocardial infarction) undergoing PCI (percutaneous coronary intervention).

BACKGROUND: Studies in populations with or without cardiovascular disease have shown that very high HDL-C levels are associated with an increased risk of cardiovascular events. However, the exact relationship between HDL-C levels and long-term prognosis remains unknown in patients with myocardial infarction (MI) undergoing percutaneous coronary intervention (PCI). METHODS: This was a post hoc secondary analysis of long-term follow-up results in patients undergoing PCI open-label, observational cohort study. Patients with MI who had undergone PCI were enrolled. Restricted cubic spline (RCS) analysis and logistic regression analysis were performed to assess the relationship between HDL-C levels and the risk of cardiovascular events. RESULTS: A total of 1934 patients with MI undergoing PCI were enrolled in our analysis and our population was divided in 3 groups according to the HDL-C plasma levels: HDL-C < 40 mg/dL (low HDL-C); HDL-C between 40 and 80 mg/ dL (medium HDL-C); and HDL-C > 80 mg/dL (high HDL-C). RCS analysis showed a nonlinear U-shaped association between HDL-C levels and major adverse cardiac and cerebrovascular events (MACCE) in patients with NSTEMI with adjusted variables. After adjusting for potential confounders, the follow-up analysis indicated that high risk group had elevated occurrence of MACCE than low risk group (HDL-C 35 and 55 mg/dL) (OR:1.645, P = 0.006). CONCLUSIONS: Our analysis demonstrated that there is a U-shaped association between HDL-C and MACCE in patients with NSTEMI undergoing PCI.

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.

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.

Photocrosslinkable, Injectable Locust Bean Gum Hydrogel Induces Chondrogenic Differentiation of Stem Cells for Cartilage Regeneration.

Due to the limited therapeutic efficacy of current treatments, articular cartilage regeneration is still challenging work. Scaffold-based tissue engineering provides a promising strategy for cartilage regeneration, but most scaffolds are limited by poor mechanical properties or unfavorable biocompatibility. Here, a novel photocrosslinkable, injectable locust bean gum (LBG)-methacrylate (MA) hydrogel is reported as a biomimetic extracellular matrix (ECM) for cartilage repair with minimal invasive operation. LBG-MA hydrogels show controllable degradation rate and improve mechanical properties and excellent biocompatibility. More importantly, LBG-MA hydrogel significantly induces bone mesenchymal stem cells to chondrogenic differentiation in vitro, as evidenced by high accumulation of cartilage-specific ECM components glycosaminoglycan and upregulated expression of key chondrogenic genes (collagen type II, aggrecan, and sex determining region Y-box9). Besides, the hydrogel is injectable, which can be in situ crosslinked via UV irradiation. Further, the photocrosslinkable hydrogels accelerate cartilage healing in vivo after 8 weeks of therapy. A strategy is provided here for photocrosslinkable, injectable, biodegradable scaffold fabrication based on native polysaccharide polymer for minimal invasive cartilage repair.

Quantification of patient-specific coronary material properties and their correlations with plaque morphological characteristics: An in vivo IVUS study.

BACKGROUND: A method using in vivo Cine IVUS and VH-IVUS data has been proposed to quantify material properties of coronary plaques. However, correlations between plaque morphological characteristics and mechanical properties have not been studied in vivo. METHOD: In vivo Cine IVUS and VH-IVUS data were acquired at 32 plaque cross-sections from 19 patients. Six morphological factors were extracted for each plaque. These samples were categorized into healthy vessel, fibrous plaque, lipid-rich plaque and calcified plaque for comparisons. Three-dimensional thin-slice models were constructed using VH-IVUS data to quantify in vivo plaque material properties following a finite element updating approach by matching Cine IVUS data. Effective Young's moduli were calculated to represent plaque stiffness for easy comparison. Spearman's rank correlation analysis was performed to identify correlations between plaque stiffness and morphological factor. Kruskal-Wallis test with Bonferroni correction was used to determine whether significant differences in plaque stiffness exist among four plaque groups. RESULT: Our results show that lumen circumference change has a significantly negative correlation with plaque stiffness (r = -0.7807, p = 0.0001). Plaque burden and calcification percent also had significant positive correlations with plaque stiffness (r = 0.5105, p < 0.0272 and r = 0.5312, p < 0.0193) respectively. Among the four categorized groups, calcified plaques had highest stiffness while healthy segments had the lowest. CONCLUSION: There is a close link between plaque morphological characteristics and mechanical properties in vivo. Plaque stiffness tends to be higher as coronary atherosclerosis advances, indicating the potential to assess plaque mechanical properties in vivo based on plaque compositions.

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.

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.

Novel Easy to Synthesize Benzonitrile Compounds with Mixed Carbazole and Phenoxazine Substituents Exhibiting Dual Emission and TADF Properties.

The photophysical and electrochemical properties of a new class of fluorinated benzonitrile compounds substituted with mixed phenoxazine and carbazole units have been investigated. When absorbing in a large range of the UV-vis spectrum due to both localized and charge-transfer absorptions, these compounds show dual broad emission in solution and intense emission in PMMA films, with photoluminescence quantum yields changing from a few percent in solution to 18% in a more rigid environment. The compounds also exhibit thermally activated delayed fluorescence demonstrated by the role of oxygen in the quenching of delayed fluorescence and by time-resolved luminescence studies, with an efficiency directly related to the number of phenoxazine substituents. Electrochemistry reveals dramatic changes in the reduction mechanisms according to the number of remaining fluorine atoms on the benzonitrile core. All these results demonstrate how it is possible to tune the photophysical and electrochemical properties of easily synthesizable derivatives by controlling the nature and relative number of the substituents on a simple aromatic platform.

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.

Quantifying Patient-Specific in vivo Coronary Plaque Material Properties for Accurate Stress/Strain Calculations: An IVUS-Based Multi-Patient Study.

Introduction: Mechanical forces are closely associated with plaque progression and rupture. Precise quantifications of biomechanical conditions using in vivo image-based computational models depend heavily on the accurate estimation of patient-specific plaque mechanical properties. Currently, mechanical experiments are commonly performed on ex vivo cardiovascular tissues to determine plaque material properties. Patient-specific in vivo coronary material properties are scarce in the existing literature. Methods: In vivo Cine intravascular ultrasound and virtual histology intravascular ultrasound (IVUS) slices were acquired at 20 plaque sites from 13 patients. A three-dimensional thin-slice structure-only model was constructed for each slice to obtain patient-specific in vivo material parameter values following an iterative scheme. Effective Young's modulus (YM) was calculated to indicate plaque stiffness for easy comparison purposes. IVUS-based 3D thin-slice models using in vivo and ex vivo material properties were constructed to investigate their impacts on plaque wall stress/strain (PWS/PWSn) calculations. Results: The average YM values in the axial and circumferential directions for the 20 plaque slices were 599.5 and 1,042.8 kPa, respectively, 36.1% lower than those from published ex vivo data. The YM values in the circumferential direction of the softest and stiffest plaques were 103.4 and 2,317.3 kPa, respectively. The relative difference of mean PWSn on lumen using the in vivo and ex vivo material properties could be as high as 431%, while the relative difference of mean PWS was much lower, about 3.07% on average. Conclusion: There is a large inter-patient and intra-patient variability in the in vivo plaque material properties. In vivo material properties have a great impact on plaque stress/strain calculations. In vivo plaque material properties have a greater impact on strain calculations. Large-scale-patient studies are needed to further verify our findings.

The Neutrophil-to-Lymphocyte Ratio Is an Important Indicator Predicting In-Hospital Death in AMI Patients.

Objective: To explore the role of neutrophil-to-lymphocyte ratio (NLR) in predicting the short-term prognosis of NSTEMI and STEMI. Methods: This study was a single-center, retrospective and observational study. 2618 patients including 1289 NSTMI and 1329 STEMI patients were enrolled from June 2013 to February 2018 in Zhongda Hospital, Southeast University. The demographic information, clinical characteristics, medical history, laboratory examination, treatment, and outcome of individuals at admission and during hospitalization were extracted from the electronic medical record system. Outcome was defined as the all-cause death during hospitalization. Results: (1) In the NSTEMI group, the ability of NLR in predicting in-hospital death (AUC = 0.746) was higher than the neutrophil-monocyte ratio (NMR) (AUC = 0.654), the platelet-lymphocyte ratio (PLR) (AUC = 0.603) and the lymphocyte-monocyte ratio (LMR) (AUC = 0.685), and also higher than AST (AUC = 0.621), CK (AUC = 0.595), LDH (AUC = 0.653) and TnI (AUC = 0.594). The AUC of NLR in the STEMI group was only 0.621. (2) The optimal cut-off value of NLR in NSTEMI group was 5.509 (Youden index = 0.447, sensitivity = 77.01%, specificity = 67.72%). After adjusting variables including age, sex, diabetes history, smoking history, LDL-C and Cr, the logistic regression showed that the patients with NLR>5.509 had higher hazard risk of death (HR4.356; 95%CI 2.552-7.435; P < 0.001) than the patients with NLR ≤ 5.509. (3) Stratification analysis showed that the in-hospital mortality of patients with NLR > 5.509 was 14.611-fold higher than those with NLR ≤ 5.509 in patients aged <76, much higher than the ratio in patients aged ≥ 76. For patients with creatinine levels ≤ 71, the in-hospital death risk in high NLR group was 10.065-fold higher than in low NLR group (95%CI 1.761-57.514, P = 0.009), while the HR was only 4.117 in patients with creatinine levels > 71. The HR in patients with or without diabetes were 6.586 and 3.375, respectively. The HR in smoking or no smoking patients were 6.646 and 4.145, respectively. The HR in patients with LDL-C ≥ 2.06 or <2.06 were 5.526 and 2.967 respectively. Conclusion: Compared to NMR, PLR, and LMR, NLR had the best ability in predicting in-hospital death after NSTEMI. Age, creatinine, LDL-C, diabetes and smoking history were all important factors affecting the predictive efficiency in NSTEMI. NLR had the limited predictive ability in STEMI.

Accuracy of triggering receptor expressed on myeloid cells 1 in diagnosis and prognosis of acute myocardial infarction: a prospective cohort study.

BACKGROUND: Acute myocardial infarction (AMI) is one of the fatal cardiac emergencies. The detection of triggering receptor expressed on myeloid cells 1 (TREM1), a cell surface immunoglobulin that amplifies pro-inflammatory responses, screened by bioinformatics was shown to be significant in diagnosing and predicting the prognosis of AMI. METHODS: GSE66360, GSE61144 and GSE60993 were downloaded from the Gene Expression Omnibus (GEO) database to explore the differentially expressed genes (DEGs) between AMI and control groups using R software. A total of 147 patients in total were prospectively enrolled from October 2018 to June 2019 and divided into two groups, the normal group (n = 35) and the AMI group (n = 112). Plasma was collected from each patient at admission and all patients received 6-month follow-up care. RESULTS: According to bioinformatic analysis, TREM1 was an important DEG in patients with AMI. Compared with the normal group, TREM1 expression was markedly increased in the AMI group (p < 0.001). TREM1 expression was positively correlated with fasting plasma glucose (FPG), glycosylated hemoglobin (HbAC), and the number of lesion vessels, although it had no correlation with Gensini score. TREM1 expression in the triple-vessels group was significantly higher than that of the single-vessel group (p < 0.05). Multiple linear regression showed that UA and HbAC were two factors influencing TREM1 expression. The ROC curve showed that TREM1 had a diagnostic significance in AMI (p < 0.001), especially in AMI patients without diabetes. Cox regression showed increased TREM1 expression was closely associated with 6-month major adverse cardiac events (MACEs) (p < 0.001). CONCLUSIONS: TREM1 is a potentially significant biomarker for the diagnosis of AMI and may be closely associated with the severity of coronary lesions and diabetes. TREM1 may also be helpful in predicting the 6-month MACEs after AMI.

Quantitative Assessment of Left and Right Atrial Strains Using Cardiovascular Magnetic Resonance Based Tissue Tracking.

Background: Left and right atrium (LA and RA) exert an essential and dynamic role in ventricular filling and hence affect heart performance. Strain quantification has been reported as a novel parameter to assess function. However, the assessment of bi-atrial strains with cardiovascular magnetic resonance (CMR) based techniques is still limited and gender- and age-specific normal values in a healthy population are missing. Methods: One hundred and fifty healthy volunteers (49.8 ± 17.3 years, 75 males) undergoing 1.5 Tesla CMR examination were retrospectively and consecutively recruited. LA and RA free wall (RAFW) radial and longitudinal strains (RS and LS) associated with atrial reservoir, conduit and booster pump functions were evaluated with CMR based tissue tracking (CMR-TT) technique. Results: The reservoir, conduit and pump LS resulted as 30.7 ± 10.2%, 19.5 ± 8.2%, 10.9 ± 3.7% for LA, and 52.2 ± 17.6%, 33.3 ± 14.2%, 19.1 ± 8.5% for RAFW, respectively. The amplitude of RA strains was significantly larger than that of LA strains, except for conduit RS. With the increase of age, the decrement of majority of reservoir and conduit strains were observed, while pump strains remained unaffected. Females presented with significantly larger RAFW strains compared with males, especially in the elderly. In addition to the positive correlation between atrial strains and emptying fraction, the negative correlation between atrial strains and volume index was also confirmed. Intra-observer reproducibility of LA strains was superior to RAFW strains (coefficient of variation: 10.12-17.04% vs. 10.80-27.36%, respectively), and the measurement of reservoir and conduit strains was more reproducible in comparison with pump strain. Conclusion: CMR-TT is a feasible and reproducible technique to quantify LA and RA strains and determine atrial phasic functions. The existence of age- and gender-related difference of strains suggests the necessity to establish specific normal values for individual populations.

The Association Between Quantitative Flow Ratio and Intravascular Imaging-defined Vulnerable Plaque Characteristics in Patients With Stable Angina and Non-ST-segment Elevation Acute Coronary Syndrome.

Background: This study aimed to examine whether quantitative flow ratio (QFR), an angiography-based computation of fractional flow reserve, was associated with intravascular imaging-defined vulnerable plaque features, such as thin cap fibroatheroma (TCFA) in patients with stable angina, and non-ST-segment elevation acute coronary syndrome. Methods: Patients undergoing optical coherence tomography (OCT) or intravascular ultrasound (IVUS) examinations were identified from two prospective studies and their interrogated vessels were assessed with QFR. Lesions in the OCT cohort were classified into tertiles: QFR-T1 (QFR ≤ 0.85), QFR-T2 (0.85 < QFR ≤ 0.93), and QFR-T3 (QFR > 0.93). Lesions in the IVUS cohort were classified dichotomously as low or high QFR groups. Results: This post-hoc analysis included 132 lesions (83 for OCT and 49 for IVUS) from 126 patients. The prevalence of OCT-TCFA was significantly higher in QFR-T1 (50%) than in QFR-T2 (14%) and QFR-T3 (19%) (p = 0.003 and 0.018, respectively). Overall significant differences were also observed among tertiles in maximum lipid arc, thinnest fibrous cap thickness, and minimal lumen area (p = 0.017, 0.040, and <0.001, respectively). Thrombus was more prevalent in QFR-T1 (39%) than in QFR-T2 (3%), and QFR-T3 (12%) (p = 0.001 and 0.020, respectively). In the multivariable analysis, QFR ≤ 0.80 remained as a significant determinant of OCT-TCFA regardless of the presence of NSTE-ACS and the level of low-density lipoprotein cholesterol (adjusted OR: 4.387, 95% CI 1.297-14.839, p = 0.017). The diagnostic accuracy of QFR was moderate in identifying lesions with OCT-TCFA (area under the curve: 0.72, 95% CI 0.58-0.86, p = 0.003). In the IVUS cohort, significant differences were found between two groups in minimal lumen area and plaque burden but not in the distribution of virtual histology (VH)-TCFA (p = 0.025, 0.036, and 1.000, respectively). Conclusions: Lower QFR was related to OCT-defined plaque vulnerability in angiographically mild-to-intermediate lesions. The QFR might be a useful tool for ruling out high-risk plaques without using any pressure wire or vasodilator.

Clinical prediction models of fractional flow reserve: an exploration of the current evidence and appraisal of model performance.

BACKGROUND: Invasive fractional flow reserve (FFR) is a standard indicator of coronary stenoses' hemodynamic severity. Clinical prediction models (CPMs) may help differentiate ischemic from non-ischemic lesions without using a pressure wire but by integrating related variables. This approach differs from that of physics-based models. However, it is not yet known which CPMs are the most reliable at detecting hemodynamic significance. METHODS: A systematic review was performed of relevant publications that developed or validated any FFR CPMs from inception to April 2019 in the PubMed, EMBASE, and Cochrane Library databases by two independent authors. The risk of bias and applicability were assessed using the prediction model risk of the bias assessment tool (PROBAST). RESULTS: A total of 11 unique CPMs and 5 subsequent external validation studies were identified. The prevalence of hemodynamically significant lesions (FFR ≤0.80) across the studies had a median of 37.1% (range: 20.7-68.0%). Lesion length, percent diameter stenosis, and minimal lumen diameter were the three most frequently used variables in the CPMs. Of the 11 FFR CPMs, 9 (82%) exhibited strong discrimination [area under the curve (AUC) >0.75], and 5 (45%) had been subject to external validation; however, calibration was only available for 3 models (27%). There was a high degree of applicability; however, none of the studies was assessed as having a low risk of bias. A CPM was identified that had undergone rigorous validation and calibration: the DILEMMA score (three validations; median AUC, 0.83). CONCLUSIONS: Almost half of the existing FFR CPMs had been externally validated. Due to their good discrimination abilities, these FFR CPMs are useful tools that could reduce the need for invasive hemodynamic measurements. Future research that adheres to methodological guidelines should be undertaken to develop high-quality models in this setting. (PROSPERO registration number: CRD42019125011).

Nanographene-Osmapentalyne Complexes as a Cathode Interlayer in Organic Solar Cells Enhance Efficiency over 18.

Interface engineering is a critical method by which to efficiently enhance the photovoltaic performance of nonfullerene solar cells (NFSC). Herein, a series of metal-nanographene-containing large transition metal involving dπ -pπ conjugated systems by way of the addition reactions of osmapentalynes and p-diethynyl-hexabenzocoronenes is reported. Conjugated extensions are engineered to optimize the π-conjugation of these metal-nanographene molecules, which serve as alcohol-soluble cathode interlayer (CIL) materials. Upon extension of the π-conjugation, the power conversion efficiency (PCE) of PM6:BTP-eC9-based NFSCs increases from 16% to over 18%, giving the highest recorded PCE. It is deduced by X-ray crystallographic analysis, interfacial contact methods, morphology characterization, and carrier dynamics that modification of hexabenzocoronenes-styryl can effectively improve the short-circuit current density (Jsc ) and fill factor of organic solar cells (OSCs), mainly due to the strong and ordered charge transfer, more matching energy level alignments, better interfacial contacts between the active layer and the electrodes, and regulated morphology. Consequently, the carrier transport is largely facilitated, and the carrier recombination is simultaneously impeded. These new CIL materials are broadly able to enhance the photovoltaic properties of OSCs in other systems, which provides a promising potential to serve as CILs for higher-quality OSCs.