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.

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.

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.

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.

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.

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.

Impact of diabetes mellitus on the relationship between a Poiseuille-based index and fractional flow reserve in intermediate coronary lesions.

BACKGROUND: The ratio of lesion length (LL) to the fourth power of minimal lumen diameter (MLD) (LL/MLD4) is a Poiseuille-based index with good diagnostic accuracy for the detection of coronary lesions with abnormal fractional flow reserve (FFR). We aimed to evaluate the impact of diabetes mellitus (DM) on its performance in intermediate coronary stenoses. METHODS: We performed quantitative coronary angiography and simultaneous FFR measurement in 324 patients (234 non-DM and 90 DM) with 335 coronary lesions. The area under the receiver-operating characteristic curve (AUC) for angiographic parameters was determined, using an FFR value ≤0.80 to indicate the physiological significance of coronary stenoses. RESULTS: In the non-DM group, FFR was significantly related to percent diameter stenosis (%DS) (R = -0.238) and LL/MLD4 ratio (R = -0.301; P < 0.001 for both). In the DM group, there was no correlation between %DS and FFR, whereas a close-to-threshold correlation was observed for the LL/MLD4 ratio (R = -0.205; P = 0.048). The AUC of LL/MLD4 ratio was significantly different between non-diabetic and diabetic subjects (0.738 vs. 0.540; P = 0.024). Moreover, the LL/MLD4 ratio showed higher AUCs than %DS (0.738 vs. 0.635; P = 0.017) and LL (0.738 vs. 0.634; P = 0.024) in non-diabetic population but this superiority did not exist in diabetic population. CONCLUSION: We showed good diagnostic accuracy of LL/MLD4 ratio for identifying ischemic lesions in patients without DM. However, there was an impaired performance in diabetic patients and thus FFR measurement is essential to determine their hemodynamic status.

An RGD modified water-soluble fluorophore probe for in vivo NIR-II imaging of thrombosis.

Venous thrombosis leads to severe symptoms and death through pulmonary embolism. There is a great need for high sensitivity imaging methods to identify acute patients who would benefit from thrombolysis. We designed a novel, organic near-infrared second-window (NIR-II) probe, which targets the glycoprotein IIb/IIIa receptor (GPIIb/IIIa) on activated platelets. The probe's structure was characterized by MALDI-TOF-MS, TEM, UV-visible absorption and NIR-II fluorescent spectroscopy. The probe's specificity for activated platelets was investigated in vitro and in vivo. Thrombosis in mice was induced by administration of FeCl3 in the external jugular vein and imaged by using a NIR-II imager. The donor-acceptor-donor fluorescent core TTQ was prepared from donor and acceptor units. TTQ-PEG-NH2 was synthesized by sequential modification of PEGylated TTQ, followed by c(RGD) condensation. Signal strength was continuously monitored for 24 h following TTQ-PEG-c(RGD) or non-specific fluorescent dye injection. The contralateral external jugular vein, sham surgery and a competitive inhibition experiment served as controls. TTQ-PEG-c(RGD) presented high NIR-II intensity, good stability and excellent affinity for activated platelets. The NIR-II fluorescence signal of TTQ-PEG-c(RGD) injected mice significantly increased at the thrombus site and peaked at 4 h, whereas there was no significant change in the control mice, and the competitive inhibition of the RGD antagonist suppressed the enhancement of the NIR-II fluorescence signal. Comparison between fresh and old thrombi confirmed that TTQ-PEG-c(RGD) could be used to distinguish a fresh thrombus from an old thrombus. TTQ-PEG-c(RGD) can specifically target thrombosis in vitro and in vivo, providing a potential tool for noninvasive diagnosis of early thrombi.

Plasma concentrations of tissue kallikrein in normal and preeclamptic pregnancies.

Objective: To investigate maternal plasma concentrations of tissue kallikrein (TK) in normal and preeclamptic pregnancies.Methods: 96 women with singleton pregnancies were categorized into normal, mild preeclampsia and preeclampsia with severe features. Plasma levels of TK were quantified by ELISA and left lateralrecumbencyposition BP measured.Results: Maternal plasma TK concentrations were significantly lower in preeclampsia with severe features compared with mild preeclampsia and normal pregnant. Plasma TK concentrations were negatively correlated with systolic and diastolic blood pressure, and 24-hour urine protein.Conclusion: Lower maternal plasma TK may be a risk marker that reflects the severity of preeclampsia.