Utilizing machine learning for early screening of thyroid nodules: a dual-center cross-sectional study in China.

Background: Thyroid nodules, increasingly prevalent globally, pose a risk of malignant transformation. Early screening is crucial for management, yet current models focus mainly on ultrasound features. This study explores machine learning for screening using demographic and biochemical indicators. Methods: Analyzing data from 6,102 individuals and 61 variables, we identified 17 key variables to construct models using six machine learning classifiers: Logistic Regression, SVM, Multilayer Perceptron, Random Forest, XGBoost, and LightGBM. Performance was evaluated by accuracy, precision, recall, F1 score, specificity, kappa statistic, and AUC, with internal and external validations assessing generalizability. Shapley values determined feature importance, and Decision Curve Analysis evaluated clinical benefits. Results: Random Forest showed the highest internal validation accuracy (78.3%) and AUC (89.1%). LightGBM demonstrated robust external validation performance. Key factors included age, gender, and urinary iodine levels, with significant clinical benefits at various thresholds. Clinical benefits were observed across various risk thresholds, particularly in ensemble models. Conclusion: Machine learning, particularly ensemble methods, accurately predicts thyroid nodule presence using demographic and biochemical data. This cost-effective strategy offers valuable insights for thyroid health management, aiding in early detection and potentially improving clinical outcomes. These findings enhance our understanding of the key predictors of thyroid nodules and underscore the potential of machine learning in public health applications for early disease screening and prevention.

Apolipoprotein O modulates cholesterol metabolism via NRF2/CYB5R3 independent of LDL receptor.

Apolipoprotein O (APOO) plays a critical intracellular role in regulating lipid metabolism. Here, we investigated the roles of APOO in metabolism and atherogenesis in mice. Hepatic APOO expression was increased in response to hyperlipidemia but was inhibited after simvastatin treatment. Using a novel APOO global knockout (Apoo-/-) model, it was found that APOO depletion aggravated diet-induced obesity and elevated plasma cholesterol levels. Upon crossing with low-density lipoprotein receptor (LDLR) and apolipoprotein E (APOE) knockout hyperlipidemic mouse models, Apoo-/- Apoe-/- and Apoo-/- Ldlr-/- mice exhibited elevated plasma cholesterol levels, with more severe atherosclerotic lesions than littermate controls. This indicated the effects of APOO on cholesterol metabolism independent of LDLR and APOE. Moreover, APOO deficiency reduced cholesterol excretion through bile and feces while decreasing phospholipid unsaturation by inhibiting NRF2 and CYB5R3. Restoration of CYB5R3 expression in vivo by adeno-associated virus (AAV) injection reversed the reduced degree of phospholipid unsaturation while decreasing blood cholesterol levels. This represents the first in vivo experimental validation of the role of APOO in plasma cholesterol metabolism independent of LDLR and elucidates a previously unrecognized cholesterol metabolism pathway involving NRF2/CYB5R3. APOO may be a metabolic regulator of total-body cholesterol homeostasis and a target for atherosclerosis management. Apolipoprotein O (APOO) regulates plasma cholesterol levels and atherosclerosis through a pathway involving CYB5R3 that regulates biliary and fecal cholesterol excretion, independently of the LDL receptor. In addition, down-regulation of APOO may lead to impaired mitochondrial function, which in turn aggravates diet-induced obesity and fat accumulation.

Performance of 99mTc-PYP scintigraphy in the diagnosis of hereditary transthyretin cardiac amyloidosis.

OBJECTIVE: Most reported research has primarily investigated wild-type transthyretin cardiac amyloidosis (ATTRwt-CA). However, the application of bone scintigraphy for hereditary transthyretin cardiac amyloidosis (ATTRv-CA) has not been systematically investigated. Therefore, in this study, we aimed to evaluate the diagnostic value of 99mTc-PYP scintigraphy in ATTRv-CA. METHODS: Fifty-four patients were enrolled in a highly suspected cardiac amyloidosis cohort. Transthyretin (TTR) gene characteristics were summarized in the ATTRv-CA group. In 99mTc-PYP scintigraphy, the diagnostic efficiency of the visual score (VGS) and heart-to-contralateral chest (H/CL) ratio were evaluated. Furthermore, the interobserver consistency among the diagnosticians was investigated. RESULTS: Twenty-eight patients were diagnosed with ATTRv-CA with eight genotypes. The Ala97Ser genotype accounts for 46% (n = 13) with a mean age of disease onset, definite diagnosis, and interval of 61.6 ± 1.9, 66.5 ± 1.3, and 4.0 (3.0, 6.2) years, respectively. Their VGS is Grade 3, and their H/CL ratio is higher than that of the non-Ala97Ser group, but no statistical significance exists (mean H/CL: 1.95 ± 0.06 vs. 1.87 ± 0.02, p = 0.844). Additionally, ATTRv-CA patients showed VGS ≥ 2, and mean H/CL ratio of 2.09 ± 0.06. The sensitivity and specificity of VGS were 100% and 65%, respectively. And the interobserver consistency analysis of VGS showed the intraclass correlation coefficient is 0.522. The best cutoff value of H/CL ratio was 1.51 (AUC = 0.996), and the diagnostic consistency of H/CL (bias: 0.018) was high. CONCLUSIONS: Ala97Ser is the most common genotype in ATTRv-CA in our cohort, with characteristics of later onset and rapid progression, but delayed diagnosis and extensive 99mTc-PYP uptake. Overall, ATTRv-CA patients showed moderate-to-extensive myocardial 99mTc-PYP uptake. Additionally, VGS carries subjectivity, low specialty and interobserver consistency. But H/CL exhibit high diagnostic efficacy and interobserver consistency. The H/CL ratio is more useful than VGS.

Macrophage-specific deletion of MIC26 (APOO) mitigates advanced atherosclerosis by increasing efferocytosis.

BACKGROUND AND AIMS: Recent studies have suggested that MIC26 (apolipoprotein O, APOO), a novel mitochondrial inner membrane protein, is involved in inflammation. Thus, the role of macrophage MIC26 in acute inflammation and chronic inflammatory disease atherosclerosis was investigated. METHODS: Macrophage-specific MIC26 knockout mice (MIC26LysM) were generated by crossing Apooflox/flox and LysMcre+/- mice. An endotoxemia mouse model was generated to explore the effects of macrophage MIC26 deficiency on acute inflammation, while an atherosclerosis mouse model was constructed by crossing MIC26LysM mice with Apoe-/- mice and challenged with a Western diet. Atherosclerotic plaques, primary macrophage function, and mitochondrial structure and function were analyzed. RESULTS: MIC26 knockout did not affect the median survival time and post-injection serum interleukin 1ß concentrations in mice with endotoxemia. Mice with MIC26 deficiency in an Apoe-/- background had smaller atherosclerotic lesions and necrotic core than the control group. In vitro studies found that the loss of MIC26 did not affect macrophage polarization, apoptosis, or lipid handling capacity, but increased efferocytosis (the ability to clear apoptotic cells). An in situ efferocytosis assay of plaques also showed that the ratio of macrophage-associated apoptotic cells to free apoptotic cells was higher in the MIC26-deficient group than in the control group, indicating increased efferocytosis. In addition, an in vivo thymus efferocytosis assay indicated that MIC26 deletion promoted efferocytosis. Mechanistically, the loss of MIC26 resulted in an abnormal mitochondrial inner membrane structure, increased mitochondrial fission, and decreased mitochondrial membrane potential. Loss of MIC26 reduced mitochondria optic atrophy type 1 (OPA1) protein, and OPA1 silencing in macrophages promoted efferocytosis. Overexpression of OPA1 abolished the increase in efferocytosis produced by MIC26 deficiency. CONCLUSIONS: Macrophage MIC26 deletion alleviated advanced atherosclerosis and necrotic core expansion by promoting efferocytosis. This mechanism may be related to the increased mitochondrial fission caused by reduced mitochondrial OPA1.

Serum soluble TREM2 is an independent biomarker associated with coronary heart disease.

BACKGROUND: Triggering receptor expressed on myeloid cells 2 (TREM2) is a unique receptor expressed by macrophages in atherosclerotic plaque and is involved in the progression of atherosclerosis. Whether serum soluble TREM2 (sTREM2) levels has a relationship with coronary heart disease (CHD) remains unclear. METHODS: The cross-sectional study included 86 patients with CHD and 86 controls matched with age and sex. Demographic information, medication history, and laboratory data were collected. sTREM2 concentrations were detected by enzyme-linked immunosorbent assay. We compared the sTREM2 levels in two groups and constructed stepwise linear regression analysis for factors related to the sTREM2 level in patients with CHD; we further used the logistic regression model to evaluate the relationship between sTREM2 and CHD. The diagnostic value of sTREM2 and other biomarkers in CHD was evaluated by the receiver operating characteristic curve (ROC). RESULTS: The serum level of sTREM2 in CHD patients is higher than that in controls. In CHD patients, the stepwise linear regression analysis found that sTREM2 levels were correlated with triglyceride (TG), high-density lipoprotein cholesterols (HDL-C), apolipoprotein B (ApoB) and smoking status. Logistic regression models showed that sTREM2 was associated independently with CHD after adjusted confounders. The ROC curve showed a sensitivity of 59.3% and specificity of 81.4% with an area under the curve of 0.781 (95% CI: 0.711-0.852) for the diagnosis of CHD with serum sTREM2 at a cut-off value of > 1104.894 pg/ml, indicating a higher diagnostic value than high sensitivity C reaction protein (hs-CRP) and apolipoprotein B (ApoB). CONCLUSION: In this study, we provide evidence that sTREM2 levels are elevated in CHD patients and are associated with various cardiovascular risk factors. Additionally, sTREM2 demonstrates better diagnostic performance compared to traditional indicators in identifying CHD. These findings suggest that sTREM2 may serve as a potential biomarker for coronary heart disease.

Prediction of Fatty Liver Disease in a Chinese Population Using Machine-Learning Algorithms.

BACKGROUND: Fatty liver disease (FLD) is an important risk factor for liver cancer and cardiovascular disease and can lead to significant social and economic burden. However, there is currently no nationwide epidemiological survey for FLD in China, making early FLD screening crucial for the Chinese population. Unfortunately, liver biopsy and abdominal ultrasound, the preferred methods for FLD diagnosis, are not practical for primary medical institutions. Therefore, the aim of this study was to develop machine learning (ML) models for screening individuals at high risk of FLD, and to provide a new perspective on early FLD diagnosis. METHODS: This study included a total of 30,574 individuals between the ages of 18 and 70 who completed abdominal ultrasound and the related clinical examinations. Among them, 3474 individuals were diagnosed with FLD by abdominal ultrasound. We used 11 indicators to build eight classification models to predict FLD. The model prediction ability was evaluated by the area under the curve, sensitivity, specificity, positive predictive value, negative predictive value, and kappa value. Feature importance analysis was assessed by Shapley value or root mean square error loss after permutations. RESULTS: Among the eight ML models, the prediction accuracy of the extreme gradient boosting (XGBoost) model was highest at 89.77%. By feature importance analysis, we found that the body mass index, triglyceride, and alanine aminotransferase play important roles in FLD prediction. CONCLUSION: XGBoost improves the efficiency and cost of large-scale FLD screening.

Independent association of PCSK9 with platelet reactivity in subjects without statin or antiplatelet agents.

Background and aims: Proprotein convertase subtilisin/kexin type 9 (PCSK9) levels could predict cardiovascular event in patients with well-controlled LDL-C levels, suggesting an LDL-independent mechanism of PCSK9 on the cardiovascular system. Accumulating evidence suggests PCSK9 might be associated with increased platelet reactivity. This study aimed to assess the relationship between PCSK9 levels and platelet reactivity in subjects not taking statins or antiplatelet agents. Methods: A cross-sectional study was conducted to investigate the independent contribution of PCSK9 to platelet activity by controlling for the potential confounding factors. The study population included 89 subjects from a health examination centre who underwent routine annual health check-ups or had an examination before a selective operation. Subjects taking statins or antiplatelet agents were excluded. Adenosine diphosphate (ADP)-induced platelet aggregation was determined by PL-11 platelet analyzer using impedance aggregometry and plasma PCSK9 levels were determined using an ELISA. Serum Lipid profile was assessed by measuring the concentration of total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and triglyceride (TG), with low-density lipoprotein cholesterol (LDL-C) being directly measured using enzymatic techniques. The association between PCSK9 and platelet reactivity was investigated. Results: The study subjects were composed of 53 males and 36 females with an average age of 55 (±11) years old. The univariate correlation analysis showed significant correlation between ADP-induced maximal aggregation rate (MAR) and PCSK9 (r = 0.55, p < 0.001) as well as TC (r = 0.23, p = 0.028), LDL-C (r = 0.27, p < 0.001), and PLT (r = 0.31, p = 0.005). Being male (41.2% vs. 46.6, p = 0.04) and smoking (37.4 vs. 46.2%, p = 0.016) were associated with lower ADP-induced MAR than being female and non-smoking. However, there is no correlation between PCSK9 and AA-induced platelet maximal aggregation rate (r = 0.17, p = 0.12). Multiple regression analysis suggested that PCSK9 contributed independently to ADP-induced maximal aggregation rate (ß = 0.08, p = 0.004) after controlling for the effect of TC, LDL-C, PLT, being male, and smoking. Conclusions: PCSK9 is positively associated with platelet reactivity, which may partly account for the beneficial effect of PCSK9 inhibition in reducing the risk of major adverse cardiovascular events after acute coronary syndrome (ACS).

Clinical Profile and Prognosis of Hereditary Transthyretin Amyloid Cardiomyopathy: A Single-Center Study in South China.

Background: Hereditary transthyretin amyloid cardiomyopathy (ATTR-CM) is a genotypically heterogeneous disorder with a poor prognosis. There is limited literature describing the variants responsible for ATTRv in areas outside the United State, the United Kingdom and Europe. This study was performed to describe the clinical characteristics and genotypic profiles of this disease in South China. Methods: This was a single-center retrospective study that evaluated 29 patients with a confirmed diagnosis of hereditary transthyretin amyloid cardiomyopathy enrolled from January 2016 to November 2021. Results: 93.1% patients were male and the median age of symptom onset was 53 (46, 62.5) years old. The initial manifestations of ATTR-CM were cardiovascular symptoms (55.2%), neuropathy (41.4%) and vitreous opacity (3.4%). Phenotypes at diagnosis were mixed (82.8%), predominant cardiac (6.9%), neurological (6.9%) and ophthalmic (3.4%). Poor R-wave progression (41%), pseudo-infarct (31%) and low-voltage (31%) patterns were common findings on electrocardiogram. Unexplained increased wall thickness was observed in all 29 patients, with mean septal and posterior wall thicknesses of 14.25 ± 6.26 mm and 15.34 ± 2.84 mm, respectively. Diastolic dysfunction was also seen in all 29 patients, and 17 (58%) had a restrictive fill pattern at diagnosis. Nine different missense mutations of the TTR gene were found in 29 patients from 23 families, with c.349G>T (p.Ala117Ser) the most common mutation. The median survival time after diagnosis was 47.6 (95% CI 37.9-57.4) months, with 1, 3 and 5-year survival rates of 91.2%, 74% and 38% respectively. Patients with advanced heart failure (National Amyloidosis Staging stage II/III) had worse survival than stage I [Breslow (Generalized Wilcoxon), χ2 = 4.693, P = 0.03)]. Conclusions: ATTR amyloidosis genotypes and phenotypes are highly heterogeneous. Advanced heart failure predicts a poor prognosis. Understanding the different clinical profiles of ATTR cardiac amyloidosis with different genotype is important to its early recognition.

Improvements in High-Density Lipoprotein Quantity and Quality Contribute to the Cardiovascular Benefits by Anti-tumor Necrosis Factor Therapies in Rheumatoid Arthritis: A Systemic Review and Meta-Analysis.

Objective: Inflammation plays important role in atherosclerotic cardiovascular diseases (CVDs), but the interaction between the inflammation and lipid profile is largely unrevealed in humans. Patients with rheumatoid arthritis (RA) suffer from a higher risk of CVDs. Decreased total cholesterol (TC) and high-density lipoprotein (HDL) were prevalent in patients with RA. Anti-tumor necrosis factor (TNF) therapies relieve disease activity and decrease CVDs risk in RA, but their comprehensive effects on the lipid profile are unclear. This study aims to investigate the changes in blood lipid profile along time in the patients with RA accepting anti-TNF therapies by meta-analysis. Methods: The MEDLINE, the Embase, and the Cochrane Central Register of Controlled Trials (CENTRAL) were searched for eligible literature. Data of lipids were classified into short-, mid-, and long-term according to treatment duration. Meta-analyses were performed to compare the lipid levels before and after treatments. Results: A total of 44 records and 3,935 patients were included in the meta-analyses. Anti-TNF therapies were associated with significant increase in TC [mean difference (MD): +0.14, +0.23, and +0.26 mmol/l, respectively] and HDL (MD): +0.11, +0.12, and +0.11 mmol/l, respectively) in the short-, mid-, and long-term; anti-TNF therapies were associated with increased low-density lipoprotein (LDL) (MD: +0.06 mmol/l) and apolipoprotein A1 (ApoA1) (MD: +0.07 g/l) in the short-term, but not in the mid-term and long-term; triglyceride (TG) and apolipoprotein B (ApoB) do not change significantly in all the periods; proatherosclerotic indexes (TC/HDL, ApoB/ApoA1, and LDL/HDL) tend to decrease in the short- and mid-term, but return to baseline in the long-term after TNF inhibition. Conclusion: Anti-TNF therapies were related to a long-term raised HDL level, which, together with evidence of improved HDL function, may contribute partially to the decreased CVDs risk by TNF inhibition.

Progressive Heart Failure and Death as the Initial Manifestation of NK/T-Cell Lymphoma: A Case Report and Literature Review.

Natural killer/T-cell (NK/T-cell) lymphoma is a rare-type non-Hodgkin lymphoma derived from NK cells or cytotoxic T cells. Here, we present a case of a 40-year-old woman who experienced quick-developed global heart failure and then was diagnosed with NK/T-cell lymphoma through lymphoid biopsy. Neither transthoracic echocardiography nor any radiological images detected a mass in her heart or pericardium. Elevated plasma troponin level and diffused patchy areas of gadolinium late enhancement on cardiac magnetic resonance were compatible with myocarditis. Considering the persistently elevated cytokine level, systemic inflammation symptoms, acute respiratory distress syndrome, and cardiac dysfunction, a cytokine storm secondary to NK/T-cell lymphoma was considered. Due to the refractory malignant arrhythmia, the patient died soon after being admitted to our hospital.

New Insight Into Metformin-Induced Cholesterol-Lowering Effect Crosstalk Between Glucose and Cholesterol Homeostasis via ChREBP (Carbohydrate-Responsive Element-Binding Protein)-Mediated PCSK9 (Proprotein Convertase Subtilisin/Kexin Type 9) Regulation.

[Figure: see text].

Pericardial Sarcoma: "Invisible" on Radiology.

Primary pericardial tumour is an extremely rare disease and an aggressive carcinoma. Its main presenting symptoms are a large recurrent hemorrhagic pericardial effusion. Imaging is the significant tool in the evaluation of pericardial lesions and of tumours. We report the case of a 17-year-old patient with recurrent hemorrhagic pericardial effusion who was diagnosed with primary pericardial fibrosarcoma. However, multiple radiological examinations, including computed tomography and fludeoxyglucose/positron emission tomography-computed tomography ([18F] FDG/PET-CT) suggested the presence of fluid and no sign of tumour. Actually, when a patient presents with recurrent hemorrhagic pericardial effusions, pericardial tumours must be taken into account as part of the differential diagnosis.

Effects of metformin on blood lipid profiles in nondiabetic adults: a meta-analysis of randomized controlled trials.

PURPOSE: To evaluate the effects of metformin on serum lipid profiles in nondiabetic adults through a comprehensive meta-analysis. METHODS: In the present meta-analysis, randomized and controlled trials were collected by searching PubMed, Embase, and Cochrane Libraries from inception to April 2019. Compared with placebos, the effects of metformin treatment on lipid profiles in nondiabetic adults were evaluated. RESULTS: Forty-seven studies from 45 articles including 5731 participants were enrolled. Pooled results showed that metformin had significant effects on total cholesterol (mean change -6.57 mg/dl; 95% CI -9.66, -3.47; P = 0.000) and LDL-c (mean change -4.69 mg/dl; 95% CI -7.38, -2.00; P = 0.001), but insignificant effects on HDL-c (mean change -4.33 mg/dl; 95% CI -9.62, 0.96; P = 0.109) and triglyceride (mean change -0.85 mg/dl; 95% CI -0.36, 2.06; P = 0.169). Significant heterogeneities were found for all lipid profiles (HDL-c = 85.5%; LDL-c = 59.9%; total cholesterol = 75.3% and triglyceride = 67.1%). Different from the pooled data, in a subgroup analysis, the effect of metformin on triglyceride in patients with polycystic ovarian syndrome (PCOS) was significant with a mean reduction of 8.15 mg/dl. In addition, sensitivity analysis showed that the pooled effects of metformin on serum lipid profiles were stable. Publication bias derived from funnel plots or Begg's tests (P = 0.933, 0.860, 0.904, and 0.567 for HDL-c, LDL-c, total cholesterol, and triglyceride, respectively) was not significant. CONCLUSION: This meta-analysis revealed that metformin could reduce total cholesterol and LDL-c in nondiabetic adults. In addition, metformin might exert a triglyceride-lowering effect in nondiabetics with PCOS status.

New Insights into Apolipoprotein A5 and the Modulation of Human Adipose-derived Mesenchymal Stem Cells Adipogenesis.

BACKGROUND: The hallmark of obesity is the excessive accumulation of triglyceride (TG) in adipose tissue. Apolipoprotein A5 (ApoA5) has been shown to influence the prevalence and pathogenesis of obesity. However, the underlying mechanisms remain to be clarified. METHODS: Human adipose-derived mesenchymal stem cells (AMSCs) were treated with 600 ng/ml human recombinant ApoA5 protein. The effect of ApoA5 on intracellular TG content and adipogenic related factors expression were determined. Furthermore, the effect of ApoA5 on CIDE-C expression was also observed. RESULTS: During the process of adipogenesis, ApoA5 treatment reduced the intracellular accumulation of lipid droplets and the TG levels; meanwhile, ApoA5 down-regulated the expression levels of adipogenic related factors, including CCAAT enhancer-binding proteins α/ß (C/EBPα/ß), fatty acid synthetase (FAS), and fatty acid-binding protein 4 (FABP4). Furthermore, the suppression of adipogenesis by ApoA5 was mediated through the inhibition of CIDE-C expression, an important factor which promotes the process of adipogenesis. However, over-expressing intracellular CIDE-C could lead to the loss-of-function of ApoA5 in inhibiting AMSCs adipogenesis. CONCLUSIONS: In conclusion, ApoA5 inhibits the adipogenic process of AMSCs through, at least partly, down-regulating CIDE-C expression. The present study provides novel mechanisms whereby ApoA5 prevents obesity via AMSCs in humans.

New insights into different adipokines in linking the pathophysiology of obesity and psoriasis.

Psoriasis is a chronic, systemic, hyper-proliferative immune-mediated inflammatory skin disease. The results of epidemiological investigations have shown that psoriasis affects around 2% of the general population worldwide, and the total number of psoriasis patients is more than 6 million in China. Apart from the skin manifestations, psoriasis has been verified to associate with several metabolic comorbidities, such as insulin resistance, diabetes and obesity. However, the underlying mechanism is still not elucidated. Adipocytes, considered as the active endocrine cells, are dysfunctional in obesity which displays increased synthesis and secretion of adipokines with other modified metabolic properties. Currently, growing evidence has pointed to the central role of adipokines in adipose tissue and the immune system, providing new insights into the effect of adipokines in linking the pathophysiology of obesity and psoriasis. In this review, we summarize the current understanding of the pathological role of adipokines and the potential mechanisms whereby different adipokines link obesity and psoriasis. Furthermore, we also provide evidence which identifies a potential therapeutic target aiming at adipokines for the management of these two diseases.

The negative effect of ANGPTL8 on HDL-mediated cholesterol efflux capacity.

BACKGROUND: It is well known that angiopoietin-like protein 8 (ANGPTL8) exerts its effects on lipid metabolism through the inhibition of lipoprotein lipase and subsequent elevation of plasma triglyceride. However, it is not clear whether ANGPTL8 could affect lipid metabolism via other pathways. The study was aimed to investigate the effects of ANGPTL8 on the function of high-density lipoprotein (HDL), which plays a protective role in atherosclerosis progression. METHODS: Two hundred and ten subjects were recruited. Plasma ANGPTL8 was measured by enzyme-linked immunosorbent assays. Cholesterol efflux capacity was chosen as the biomarker of HDL function and measured via H3-cholesterol loading THP-1 cell models. RESULTS: ANGPTL8 exhibited no significant difference between CAD group and nonCAD group, but ANGPTL8 in DM group was significantly higher than that in the nonDM group [568.3 (406.2-836.8) vs 458.2 (356.8-755.6), P = 0.023]. Compared to controls, subjects in CAD group and DM group exhibited significantly lower cholesterol efflux capacity [CAD: 14.58 ± 2.06 vs 12.51 ± 2.83%, P < 0.0001; DM: 13.62 ± 2.57 vs 12.34 ± 3.16%, P = 0.0099]. ANGPTL8 was inversely correlated with cholesterol efflux capacity (r = - 0.188, P < 0.01). Regression analysis revealed that plasma ANGPTL8 was an independent contributor to cholesterol efflux capacity (standardized ß = - 0.143, P = 0.023). CONCLUSION: ANGPTL8 presents a negative effect on HDL-mediated cholesterol efflux capacity.

Krüppel-like factor 14, a coronary artery disease associated transcription factor, inhibits endothelial inflammation via NF-κB signaling pathway.

BACKGROUND AND AIMS: Human genetic studies indicated that variations near the transcription factor Krüppel-like factor 14 (KLF14) gene locus are highly associated with coronary artery disease. Activation of endothelial cells (ECs) by pro-inflammatory molecules and pathways is a primary step in atherosclerosis development. We aimed to investigate the effects and mechanism of KLF14 on inflammatory responses in ECs. METHODS: Adenovirus-mediated overexpression of human KLF14 and EC specific Klf14 knockout mice were applied to study the role of KLF14 in EC inflammation. Intravital microscopy was used to examine leukocyte-endothelial cell interactions in vivo. RESULTS: The expression of Klf14 was markedly decreased in mouse aortic ECs in both acute and chronic inflammatory conditions. Overexpression of KLF14 inhibited inflammatory activation of human ECs stimulated by interleukin 1ß and tumor necrosis factor α. Primary pulmonary ECs from Klf14 knockout mice showed increased expression of adhesion molecules under IL-1ß stimuli. Mechanistically, KLF14 inhibited NF-κB signaling pathway by transcriptionally suppressing the expression of p65, resulting in significantly decreased leukocyte adhesion to activated ECs. Using intravital microscopy, an increased leukocyte-endothelial cell interaction was observed in endothelial specific Klf14 knockout mice compared to wild type control mice. Additionally, perhexiline, a KLF14 activator, induces KLF14 expression in ECs and reduced leukocyte-endothelial cell interactions in vitro and in vivo. CONCLUSIONS: The data revealed that KLF14 inhibited the inflammatory response in ECs and the protective effects were mediated by transcriptional inhibition of NF-κB signaling pathway. Endothelial KLF14 could be a potential therapeutic target for cardiovascular diseases.

Apolipoprotein CIII may mediate the impacts of angiopoietin-like protein 8 on triglyceride metabolism.

BACKGROUND: Angiopoietin-like protein 8(ANGPTL8) and apolipoprotein CIII (apoCIII) were found to inhibit the activity of lipoprotein lipase (LPL) and disrupt the clearance of triglyceride-rich lipoproteins (TRLs), leading to hypertriglyceridemia. Whether any relationship exists between these two important modulators of triglyceride metabolism has not been reported. Besides, whether ANGPTL8 concentration is altered in the patients with coronary artery disease (CAD) is still unclear. METHODS: A hospital-based case-control study was conducted. Sixty-eight CAD subjects and fifty-two nonCAD controls were recruited. Plasma apoCIII, ANGPTL8 was measured. RESULTS: ANGPTL8 and apoCIII concentration exhibited no significant difference between CAD group and nonCAD group. Both ANGPTL8 and apoCIII were significantly correlated with triglyceride level(r = - 0.243, P = 0.008; r = 0.335, P < 0.001, respectively). Regression analysis revealed that apoCIII was an independent contributor to triglyceride level independent of ANGPTL8 concentration (standardized ß = 0.230, P < 0.01). CONCLUSION: ApoCIII may mediate the effects of ANGPTL8 on triglyceride metabolism.

Primary aortoesophageal fistula: A fatal outcome.

Aortoesophageal fistula is a rare but life-threatening cause of massive gastrointestinal bleeding. We reported a case of primary aortoesophageal fistula associated with thoracic aortic pseudoaneurysm. Esophagogastroduodenoscopy demonstrated a bulging erosive lesion coated with fibrin. The patient was therefore diagnosed as malignant esophageal mesenchymoma initially. An emergency contrast-enhanced computed tomography revealed an out-pouching saccular aneurysm protruding toward the esophagus at the level of T8-9. The patient expired rapidly due to intractable massive bleeding. Assumptive diagnosis of esophageal malignancy leads to a loss of the most optimal time-point for operation thus negatively affecting the patient survival.

Combined use of metformin and atorvastatin attenuates atherosclerosis in rabbits fed a high-cholesterol diet.

Statins are widely used to reduce cardiovascular risk. Unfortunately, some patients still experience cardiovascular events though prescribed with high-intensity statins. Metformin, an anti-diabetic drug, was reported to possess anti-atherosclerotic effects. Therefore, the experiments were designed to evaluate whether combined use of metformin and atorvastatin can achieve additional benefits. In rabbits fed a high-cholesterol diet, we evaluated the effects of the combination therapy on atherosclerotic plaques, lipid profiles, blood glucose levels, liver and kidney functions. Effects of combination therapy on cholesterol efflux and the expression of related transporters were studied in vitro. Our results showed that the combination therapy induced a more significant decrease in atherosclerotic lesion area than atorvastatin without additional lipid-lowering effect. The combination therapy significantly increased the percentage of large high-density lipoprotein subfraction. The intravenous glucose tolerance test showed that atorvastatin-treated rabbits had an increased area under the curve for time-dependent glucose levels after a bolus injection of glucose, which was completely reversed by metformin treatment. In cultured macrophages, co-treatment with metformin and atorvastatin promoted cholesterol efflux and up-regulated expression of ATP-binding cassette transporters A1 and G1. Taken together, our results suggest that atorvastatin/metformin combination therapy may achieve additional anti-atherosclerotic benefits likely through increasing cholesterol efflux in macrophages.