IL-37 ameliorates myocardial fibrosis by regulating mtDNA-enriched vesicle release in diabetic cardiomyopathy mice.

BACKGROUND: Diabetic cardiomyopathy (DCM), a serious complication of diabetes, leads to structural and functional abnormalities of the heart and ultimately evolves to heart failure. IL-37 exerts a substantial influence on the regulation of inflammation and metabolism. Whether IL-37 is involved in DCM is unknown. METHODS: The plasma samples were collected from healthy controls, diabetic patients and DCM patients, and the level of IL-37 and its relationship with heart function were observed. The changes in cardiac function, myocardial fibrosis and mitochondrial injury in DCM mice with or without IL-37 intervention were investigated in vivo. By an in vitro co-culture approach involving HG challenge of cardiomyocytes and fibroblasts, the interaction carried out by cardiomyocytes on fibroblast profibrotic activation was studied. Finally, the possible interactive mediator between cardiomyocytes and fibroblasts was explored, and the intervention role of IL-37 and its relevant molecular mechanisms. RESULTS: We showed that the level of plasma IL-37 in DCM patients was upregulated compared to that in healthy controls and diabetic patients. Both recombinant IL-37 administration or inducing IL-37 expression alleviated cardiac dysfunction and myocardial fibrosis in DCM mice. Mechanically, hyperglycemia impaired mitochondria through SIRT1/AMPK/PGC1α signaling, resulting in significant cardiomyocyte apoptosis and the release of extracellular vesicles containing mtDNA. Fibroblasts then engulfed these mtDNA-enriched vesicles, thereby activating TLR9 signaling and the cGAS-STING pathway to initiate pro-fibrotic process and adverse remodeling. However, the presence of IL-37 ameliorated mitochondrial injury by preserving the activity of SIRT1-AMPK-PGC1α axis, resulting in a reduction in release of mtDNA-enriched vesicle and ultimately attenuating the progression of DCM. CONCLUSIONS: Collectively, our study demonstrates a protective role of IL-37 in DCM, offering a promising therapeutic agent for this disease.

Characteristics, predictors and outcomes of new-onset QT prolongation in sepsis: a multicenter retrospective study.

BACKGROUND: Sepsis-induced myocardial injury is a serious complication of sepsis. QT prolongation is a proarrhythmic state which reflects myocardial injury in a group of heterogeneous disorders. However, the study on the clinical value of QT prolongation in sepsis is limited. METHODS: We aimed to investigate the clinical characteristics and predictors of new-onset QT prolongation in sepsis and its impact on the outcome in a multicenter retrospective cohort study. Electrocardiographic and clinical data were collected from patients with sepsis from the wards and intensive care units of four centers after exclusion of QT-influencing medications and electrolyte abnormalities. Clinical outcomes were compared between patients with and without QT prolongation (QTc > 450 ms). Multivariate analysis was performed to ascertain whether QT prolongation was an independent predictor for 30-day mortality. The factors predicting QT prolongation in sepsis were also analyzed. RESULTS: New-onset QT prolongation occurred in 235/1024 (22.9%) patients. The majority demonstrated similar pattern as type 1 long QT syndrome. Patients with QT prolongation had a higher 30-day in-hospital mortality (P < 0.001), which was also associated with increased tachyarrhythmias including paroxysmal atrial fibrillation or tachycardia (P < 0.001) and ventricular arrhythmia (P < 0.001) during hospitalization. QT prolongation independently predicted 30-day mortality (P = 0.044) after multivariate analysis. History of coronary artery disease (P = 0.001), septic shock (P = 0.008), acute respiratory (P < 0.001), heart (P = 0.021) and renal dysfunction (P = 0.013) were independent predictors of QT prolongation in sepsis. CONCLUSIONS: New-onset QT prolongation in sepsis was associated with increased mortality as well as atrial and ventricular arrhythmias, which was predicted by disease severity and organ dysfunction.

Subclinical cardiac involvement present as electrocardiographic abnormalities in various neuromuscular diseases.

Background: Cardiac involvement is commonly present in various neuromuscular diseases which may develop life-threatening consequences. The early manifestation is often asymptomatic which however has been insufficiently studied. Objectives: We aim to characterize electrocardiographic (ECG) changes in neuromuscular diseases without cardiac symptoms. Methods: Adults having genetically and/or pathologically confirmed type 1 myotonic dystrophy (DM1), Becker muscular dystrophy (BMD), limb girdle muscular dystrophies (LGMDs) and mitochondrial diseases (MtDs) but without history of heart diseases and cardiovascular symptoms were enrolled. The 12-lead ECG characteristics and other test results at diagnosis were retrieved and analyzed. Results: 196 patients with neuromuscular diseases (44 DM1, 25 BMD, 82 LGMDs, 45 MtDs) were consecutively enrolled. ECG abnormalities were identified in 107 (54.6%) patients with a prevalence of 59.1% in DM1, 76.0% in BMD, 40.2% in LGMDs and 64.4% in MtDs. Conduction block was more commonly present in DM1 than the other groups (P < 0.01), which had a longest PR interval and QRS duration of 186.1 ± 38.3 ms and 104.2 [90.0-108.0]ms, respectively. QT prolongation was most frequently seen in DM1 (P < 0.001). Left ventricular hypertrophy features were found in BMD, LGMDs and MtDs (P < 0.05) without intergroup difference, while a significantly higher right ventricular amplitude is observed in BMD than in other groups (P < 0.001). Conclusions: Subclinical cardiac involvement is commonly present as ECG abnormalities in multiple adult neuromuscular diseases before associated symptoms occur and show diversity in different groups.

Evaluation of the Interfacial Interaction Ability between Basalt Fibers and the Asphalt Mastic.

The interfacial properties between the asphalt mastic and fibers plays an essential role in the fiber-enhanced asphalt mixture properties. However, there is a lack of comprehensive studies on the indicators to evaluate the interfacial interaction ability of fibers with the asphalt mastic. Therefore, this paper selected three types of basalt fibers (denoted as A-BF, B-BF and C-BF) coated with different impregnating agents to prepare the fiber asphalt mastic. The Dynamic Shear Rheometer (DSR) test-based indicators, pull-out strength, and adhesion work were used to access the fiber asphalt mastic interfacial interaction ability. The differences between different indicators were compared and analyzed. The results show that all the selected indicators in this paper can effectively reflect the different fiber asphalt mastic interfacial properties. The evaluation results with different indicators are consistent. The interfacial interaction between fibers and the asphalt mastic increases with increasing temperature. The evaluation result with adhesion work is the most accurate. However, the pull-out strength test is simple, and the test result correlates well with adhesion work, which can be adopted daily to evaluate the fiber asphalt mastic interfacial properties.

IL-37 improves mice myocardial infarction via inhibiting YAP-NLRP3 signaling mediated macrophage programming.

OBJECTIVE: Myocardial infarction is the highest cause of cardiovascular death. Previous studies found that patients with myocardial infarction have elevated serum IL-37 and IL-37 treatment significantly alleviates adverse remodeling in myocardial infarction mice. However, the underlying mechanism of IL-37 in myocardial infarction is still unknown. Here we explored the underlying mechanism of IL-37 in attenuating myocardial infarction. METHODS: The myocardial infarction mice model was constructed by left anterior descending ligation and then submitted to recombinant IL-37 administration. The histology and cardiac function were detected by HE & Masson staining and echocardiography, respectively. The macrophage phenotypes were analyzed by flow cytometry and real-time PCR. The cytokines in serum and cell culture supernatant were determined by ELISA. In addition, THP-1 cells were used in vitro to investigate the underlying mechanisms. RESULTS: Infarcted mice showed increased inflammatory cell infiltration and impaired cardiac function. IL-37 treatment alleviated pro-inflammatory macrophage infiltration, tissue injury, and collagen deposition in hearts on day 3 and 7 after infarction in mice. In addition, IL-37 application modulated the balance between M1 and M2 macrophages in infarcted hearts. In vitro, THP-1 cell line polarization was also regulated by IL-37, companied by YAP phosphorylation and NLRP3 inactivation. Verteporfin, a YAP inhibitor, could abolish IL-37-induced NLRP3 inhibition and M2 macrophage polarization. CONCLUSION: Our results demonstrated that IL-37 achieves a favorable therapeutical function on myocardial infarction by modulating YAP-NLRP3 mediated macrophage programming, providing a promising drug for the treatment of myocardial infarction.

Nr2f2 Overexpression Aggravates Ferroptosis and Mitochondrial Dysfunction by Regulating the PGC-1α Signaling in Diabetes-Induced Heart Failure Mice.

Diabetes is well recognized to increase the risk of heart failure, which is associated with higher mortality and morbidity. It is important for the development of novel therapeutic methods targeting heart failure in diabetic patients. Ferroptosis, an iron-dependent regulated cell death, has been implicated in the progression of diabetes-induced heart failure (DIHF). This study was designed to investigate the contribution of Nr2f2 to the activation of ferroptosis and mitochondrial dysfunction in DIHF. We established a diabetic model by a high-fat feeding diet combined with an intraperitoneal injection of streptozotocin. After 16 weeks, Nr2f2 expression was increased in heart tissue of DIHF mice. In vivo, DIHF mice overexpressing Nr2f2 (AAV9-cTNT-Nr2f2) exhibited severe heart failure and enhanced cardiac ferroptosis compared with DIHF control mice (AAV9-cTNT-ctrl), accompanied by mitochondrial dysfunction and aggravated oxidative stress reaction. In vitro, Nr2f2 knockdown ameliorated ferroptosis and mitochondrial dysfunction by negatively regulating PGC-1α, a crucial metabolic regulator. PGC-1α knockdown counteracted the protective effect of Nr2f2 knockdown. These data suggest that Nr2f2 promotes heart failure and ferroptosis in DIHF by modulating the PGC-1α signaling. Our study provides a new idea for the treatment of diabetes-induced heart failure.

Anatomy-based characteristics of far-field SVC electrograms in right superior pulmonary veins after isolation.

Background. Far-field electrograms from superior vena cava (SVC) can be present in right superior pulmonary vein (RSPV) after pulmonary vein (PV) isolation. Objectives. To analyze the characteristics of far-field SVC potentials in RSPV after PV isolation and the local anatomy difference between patients with and without the potentials. Methods. Patients undergoing PV isolation were retrospectively reviewed, contrast-enhanced computed tomography (CT) was performed before procedure for observing the anatomical relationship between RSPV and SVC. The prevalence and characteristics of far-field SVC electrograms were described and compared to far-field left atrial potentials at the nearest point along the linear ablation lesion. The anatomical proximity of RSPV and SVC on a 2-dimensional horizontal CT view was compared between patients with and without far-field SVC potentials. Results. Far-field SVC electrograms were observed in 35/92(38%) patients with an amplitude of 0.24 ± 0.11 mV and a major deflection slope of 0.051 ± 0.036 mV, both significantly higher than far-field left atrial electrograms (p < .001). In patients with far-field SVC electrograms, 83% had connected RSPV-SVC, defined as distance between RSPV and SVC endocardium less than 3 mm at the layer of RSPV ostium roof, while in patients without far-field SVC electrograms, 70% had disconnected RSPV-SVC. Conclusions. Far-field SVC electrograms appeared in RSPV had a prevalence higher than previously reported and a sharper major deflection compared to far-field left atrial electrograms. Connected RSPV-SVC on CT was associated with the presence of far-field SVC electrograms.

RAGE Regulating Vascular Remodeling in Diabetes by Regulating Mitochondrial Dynamics with JAK2/STAT3 Pathway.

In this research, we will explore the role and modulation of mitochondrial dynamics in diabetes vascular remodeling. Only a few cell types express the pattern recognition receptor, also known as the AGE receptor (RAGE). However, it is triggered in almost all of the cells that have been investigated thus far by events that are known to cause inflammation. Here, Type 2 diabetes was studied in both cellular and animal models. Elevated Receptor for advanced glycation end products (RAGE), phosphorylated JAK2 (p-JAK2), phosphorylated STAT3 (p-STAT3), transient receptor potential ion channels (TRPM), and phosphorylated dynamin-related protein 1 (p-DRP1) were observed in the context of diabetes. In addition, we found that inhibition of RAGE was followed by a remarkable decrease in the expression of the above proteins. It has also been demonstrated by western blotting and immunofluorescence results in vivo and in vitro. Suppressing STAT3 and DRP1 phosphorylation produced effects similar to those of RAGE inhibition on the proliferation, cell cycle, migration, invasion, and expression of TRPM in VSMCs and vascular tissues obtained from diabetic animals. These findings indicate that RAGE regulates vascular remodeling via mitochondrial dynamics through modulating the JAK2/STAT3 axis in diabetes. The findings could be crucial in gaining a better understanding of diabetes-related vascular remodeling. It also contributes to a better cytopathological understanding of diabetic vascular disease and provides a theoretical foundation for novel targets that aid in the prevention and treatment of diabetes-related cardiovascular problems.

Influence of Basalt Fibers on the Crack Resistance of Asphalt Mixtures and Mechanism Analysis.

The paper aims to investigate the influence of basalt fiber (BF) on the crack resistance of the asphalt mixture and conduct a mechanical analysis. First, two typical asphalt mixtures, namely AC-13 and SMA-13, were designed. The impact of BF on the mixture design results was analyzed. Then, several macroscopic tests, namely the four-point bending test, indirect tensile test, and semicircular bending test (SCB), were conducted to assess the effect of BF on the cracking resistance of asphalt mixtures. Finally, the influence of BF on the cracking resistance of asphalt mixtures was analyzed based on an environmental scanning electron microscope (ESEM) observation. The results show that: (1) BF increases the optimal asphalt content of AC13 and decreases the optimal asphalt content of SMA-13, which is caused by the different asphalt-absorption capacity of BF and lignin fiber (LF). (2) BF enhances both the fatigue crack resistance and temperature crack resistance of asphalt mixtures. The enhancement on the SMA-13 is more significant, indicating that the enhancement of BF on asphalt mixtures is related to the type of aggregate gradation. (3) BFs in the asphalt mixture lap each other to form a spatial network structure. Such structure can effectively improve the crack resistance of the mixture by dispersing the load stress and preventing the flow of asphalt mastic. The study results provide an effective method to design crack-resistant asphalt mixtures.

Effects of Fiber Diameter on Crack Resistance of Asphalt Mixtures Reinforced by Basalt Fibers Based on Digital Image Correlation Technology.

It is now more popular to use basalt fibers in the engineering programs to reinforce the crack resistance of asphalt mixtures. However, research concerning the impact of the basalt fiber diameter on the macro performance of AC-13 mixtures is very limited. Therefore, in this paper, basalt fibers with three diameters, including 7, 13 and 25 µm, were selected to research the influences of fiber diameter on the crack resistance of asphalt mixtures. Different types of crack tests, such as the low temperature trabecular bending test (LTTB), the indirect tensile asphalt cracking test (IDEAL-CT), and the semi-circular bend test (SCB), were conducted to reveal the crack resistance of AC-13 mixtures. The entire cracking process was recorded through the digital image correlation (DIC) technique, and the displacement cloud pictures, strain, average crack propagation rate (V) and fracture toughness (FT) indicators were used to evaluate the crack inhibition action of the fiber diameter on the mixture. The results showed that the incorporation of basalt fiber substantially improved the crack resistance, slowed down the increase of the displacement, and delayed the fracture time. Basalt fiber with a diameter of 7 µm presented the best enhancement capability on the crack resistance of the AC-13 mixture. The flexibility index (FI) of the SCB test showed a good correlation with V and FT values of DIC test results, respectively. These findings provide theoretical advice for the popularization and engineering application of basalt fibers in asphalt pavement.

NOD2-mediated P2Y12 upregulation increases platelet activation and thrombosis in sepsis.

BACKGROUND: Platelets from septic patients exhibit increased reactivity. However, the underlying mechanism of sepsis-induced platelet hyperactivity is still not completely understood. OBJECTIVE: P2Y12 is a central receptor for platelet activation. In this study, we investigated the role of platelet P2Y12 in platelet hyperactivity during sepsis. METHODS: We measured platelet P2Y12 expression and aggregation in response to ADP in septic patients and cecal ligation and puncture (CLP)-treated mice. We also detected the downstream signaling of P2Y12 in resting platelets from patients and mice with sepsis. The role of nucleotide-binding oligomerization domain 2 (NOD2)/RIP2/NF-κB/P65 pathway in sepsis-induced platelet P2Y12 high expression was also investigated. Finally, we compared the antiplatelet and antithrombotic effects of clopidogrel, prasugrel, and ticagrelor in experimental sepsis in mice and rats. RESULTS: Compared to healthy subjects, platelets from septic patients exhibit P2Y12 hyperactivity and higher P2Y12 expression. pAkt is enhanced and pVASP is impaired in resting platelets from the patients, indicating the constitutive activation of platelet P2Y12 receptor. Mouse sepsis model recapitulates the findings in septic patients. NOD2 deficiency attenuates sepsis-induced platelet P2Y12 high expression, hyperactivity, and thrombosis. Prasugrel and ticagrelor are potent P2Y12 inverse agonists, and exhibit superior antiplatelet and antithrombotic efficacy over clopidogrel in mice and rats with sepsis. CONCLUSIONS: NOD2 activation upregulates platelet P2Y12 expression, which is constitutively activated and contributes to platelet hyperactivity in septic status. Compared to clopidogrel, prasugrel and ticagrelor are potent P2Y12 inverse agonists with superior antiplatelet and antithrombotic efficacy in experimental sepsis.

Evaluation of the Aging of Styrene-Butadiene-Styrene Modified Asphalt Binder with Different Polymer Additives.

A wide variety of polymer additives have been widely used in recent years. However, the effect of different polymer additives on the durability of asphalt binders has not been investigated thoroughly. To evaluate the aging property of styrene-butadiene-styrene (SBS) asphalt binder with different polymer additives, three polymer modifiers, namely high modulus modifier (HMM), anti-rutting agent (ARA), and high viscosity modifier (HVM), were added to it. First, the Thin Film Over Test (TFOT) and Pressure Aging Vessel (PAV) was performed on the asphalt binders. The rheological properties of the four asphalt binders before and after aging were then checked by the Dynamic Shear Rheometer Test (DSR). The chemical compositions of the asphalt binders were determined by the Fourier Transform Infrared Spectrometer (FTIR) test. Several aging indicators were adopted to reflect the aging degree of the asphalt binders. The results show that when polymer additives are added to the SBS asphalt binder, the complex modulus, storage modulus, loss modulus, and rutting factor substantially increase and the phase angle decreases. All the test parameters become higher after aging. The phase angle of the SBS asphalt binder is the highest at both unaged and aged states, while its other parameters values are the smallest. Moreover, the Carbonyl Aging Indicator (CAI) of SBS with polymer additives becomes lower under both TFOT and PAV conditions, indicating that polymer additives can improve the aging resistance of SBS asphalt, of which HVM modifies the aging resistance best. Complex Modulus Aging Indicator (CMAI) and Storage Modulus Aging Indicator (SMAI) have the best correlation coefficients with CAI, and the two aging indicators can be used to predict the aging degree of polymer modified asphalt binders.

Effect of Different Polymer Modifiers on the Long-Term Rutting and Cracking Resistance of Asphalt Mixtures.

To evaluate the long-term performances of different polymer-modified asphalt mixtures, three modifiers were chosen to modify AC-13 (defined as the asphalt concrete with the aggregate nominal maximum particle size of 13.2 mm); namely, high viscosity modifier (HVM), high modulus modifier (HMM), and anti-rutting agent (ARA). The deformation and cracking resistance of different polymer-modified mixtures were checked at different aging conditions (unaged, short-term aged, and long-term aged for 5, 10, and 15 days respectively). The results of the Hamburg wheel-track test and uniaxial penetration test (UPT) showed that the rutting resistance of all asphalt mixtures changed in a V-shape as the aging progressed. From the unaged stage to the long-term aging stage (5 days), the rutting resistance decreases gradually. While after the long-term aging stage (5 days), the rutting resistance increases gradually. Results from the semicircular bending test (SCB) and the indirect tensile asphalt cracking test (IDEAL-CT) indicated that the cracking resistance of all the mixtures gradually decline with the deepening of the aging degree, indicating that aging weakens the crack resistance of asphalt mixtures. Additionally, test results showed that the rutting resistance of ARA AC-13 (defined as AC-13 containing ARA) is the best, the cracking resistances of ARA AC-13, HMM AC-13 (defined as AC-13 containing HMM) and HVM AC-13 (defined as AC-13 containing HVM) have no significant difference, and different polymer modifiers had different sensitivities to aging due to the polymer content and the type of modifier. The conclusions of this study help to further understand the long-term performance of polymer-modified asphalt mixtures during service life and to help guide the selection of modifiers for mixtures.

Prediction of Crack Resistance of LFSMA-13 with and without Anti-Rut Agent Using Parameters of FTIR Spectrum under Different Aging Degrees.

This paper aims to better analyze the crack resistance of lignin fiber reinforced SMA-13 (LFSMA-13) asphalt mixtures, with and without polymer anti-rut agent (ARA), under different aging degrees. IDEAL-CT test and Fourier transform infrared (FTIR) spectroscopy were utilized to analyze the relationships between the crack resistance of LFSMA-13, with and without ARA, and the parameters of the FTIR spectrum of the asphalt extracted from the test samples. A convenient testing method to predict the anti-crack ability of the mixtures in a road was also derived in this study. The test samples were prepared using the specifications listed by AASHTO. The fracture formation work (Winitial) and cracking index (CTIndex) in the IDEAL-CT test were adopted to reflect the cracking ability of the asphalt mixtures in both the crack formation stage and the crack propagation stage. The peak areas of the FTIR spectrum were utilized to reveal the chemical properties of the asphalt material inside the SMA-13 asphalt mixtures, with and without ARA under different aging degrees. Grey correlation analysis was adopted to choose the most suitable FTIR spectrum parameters to derive the prediction models of Winitial and CTIndex under different aging degrees. After conducting a series of tests, the results showed that the aging process could well affect the crack resistance of the test samples and the peak areas of the asphalt extracted from the mixtures. The FTIR parameters selected from the grey correlation analysis could be used to well predict the anti-crack ability of the asphalt mixtures.

Pseudo normalization of H-V interval due to intra-His block in a patient with fasciculoventricular accessory pathway.

A 57-year-old male suffering from cardiogenic syncope was found to have preexcited QRS on surface ECG at admission. A dual-chamber ICD was implanted after discovering intermittent high degree A-V block and ventricular tachycardia during hospitalization. An EP study was performed 2 days later. Fasciculoventricular accessory pathway was diagnosed based on the fixed H-V interval with different A-H interval when atrial activation conducted to ventricle. However, the H-V interval was normal, which can be explained by intra-His block based on the findings of two split His potentials, the second of which was closely followed by local ventricular electrogram. The conduction delay in His bundle led to pseudo normalization of H-V interval.

Increased serum interleukin-6 level as a predictive biomarker for atrial fibrillation: A systematic review and meta-analysis.

BACKGROUND: Atrial fibrillation (AF) is related to a higher risk of thromboembolic events and mortality. Some studies have demonstrated that the inflammatory biomarker interleukin-6 (IL-6) is associated with a higher risk of higher thrombosis in AF patients, but the real effect of IL-6 remains a controversy. METHODS: We conducted a systematic review and meta-analysis to investigate the association between IL-6 and thromboembolic events, as well as bleeding events, acute coronary syndrome (ACS) events and all-cause mortality in AF. RESULTS: A total of five studies involving 22 928 patients met our inclusion criteria for the systematic review. The higher level of IL-6 in AF patients is related to long-term thromboembolic events including stroke (RR 1.44, CI 95% 1.09-1.90, p=0.01). IL-6 meant a higher risk of long-term bleeding risk (RR 1.36, CI 95% 1.06-1.74, p=0.02), ACS risk (RR 1.81, CI 95% 1.43-2.30, p<0.001) and all-cause mortality (RR 2.35, CI 95% 2.09-2.65, p<0.001). CONCLUSION: A higher level of IL-6 may predict a greater number of long-term thromboembolic events and bleeding events, ACS events and mortality in AF patients. Further studies such as the cut-off point of IL-6 need to be conducted in the future.

A stricter control of low-density lipoprotein is necessary for thrombosis reduction in "lower thrombosis risk" patients with atrial fibrillation: a multicenter retrospective cohort study.

Patients with atrial fibrillation (AF) are associated with increased thrombotic events. Our previous case-control study showed low-density lipoprotein cholesterol (LDL-C) was an independent predictor of ischemic stroke in AF patients. To investigate the risks of thrombosis in relation to LDL-C among AF patients at different stroke risks by long-time follow-up. Atrial fibrillation patients without history of thrombosis enrolled from five hospitals were classified into low-risk (LR) and high-risk (HR) group according to CHA2DS2VASc score and followed up with a median period of 26 months. Univariate and multivariate logistic regression analysis were performed in each group. The best cut-off value calculated by receiver operating characteristic (ROC) analysis was used to divide patients into low LDL-C (L-LDL) and high LDL-C (H-LDL) subgroups. Propensity score matching (PSM) and inverse probability of treatment weighted (IPTW) were utilized in both subgroups, after which Kaplan-Meier curves for thrombosis were performed. Univariate and multivariate analysis showed LDL-C was significantly related to thrombosis in LR, but less significantly in HR group. The best cut-off value was 2.155 mmol/L in LR and 2.795 mmol/L in HR group. Lower LDL-C was associated with decreased thrombosis in both groups by PSM and IPTW. Kaplan-Meier curves displayed that H-LDL subgroup was at higher thrombosis risk with significant difference at 24th month in LR patients. LDL-C independently predicts thrombosis with different cut-off values in AF patients at different risks. A stricter control of LDL-C level is necessary for thrombosis reduction in patients with lower score.

Up-regulating autophagy by targeting the mTOR-4EBP1 pathway: a possible mechanism for improving cardiac function in mice with experimental dilated cardiomyopathy.

BACKGROUND: Autophagy plays a crucial role in the pathological process of cardiovascular diseases. However, little is known about the pathological mechanism underlying autophagy regulation in dilated cardiomyopathy (DCM). METHODS: We explored whether up-regulating autophagy could improve cardiac function in mice with experimental DCM through the mTOR-4EBP1 pathway. Animal model of DCM was established in BALB/c mice by immunization with porcine cardiac myosin. Both up- or down-regulation of autophagy were studied by administration of rapamycin or 3-MA in parallel. Morphology, Western blotting, and echocardiography were applied to confirm the pathological mechanisms. RESULTS: Autophagy was activated and autophagosomes were significantly increased in the rapamycin group. The collagen volume fraction (CVF) was decreased in the rapamycin group compared with the DCM group (9.21 ± 0.82% vs 14.38 ± 1.24%, P < 0.01). The expression of p-mTOR and p-4EBP1 were significantly decreased in rapamycin-induced autophagy activation, while the levels were increased by down-regulating autophagy with 3-MA. In the rapamycin group, the LVEF and FS were significantly increased compared with the DCM group (54.12 ± 6.48% vs 45.29 ± 6.68%, P < 0.01; 26.89 ± 4.04% vs 22.17 ± 2.82%, P < 0.05). As the inhibitor of autophagy, 3-MA aggravated the progress of maladaptive cardiac remodeling and declined cardiac function in DCM mice. CONCLUSIONS: The study indicated a possible mechanism for improving cardiac function in mice with experimental DCM by up-regulating autophagy via the mTOR-4EBP1 pathway, which could be a promising therapeutic strategy for DCM.