The causal relationship between metabolic syndrome and its components and cardiovascular disease: A mendelian randomization study.

AIM: To investigate the causal relationship between metabolic syndrome (MetS) and its components and 14 cardiovascular diseases using Mendelian randomization (MR). METHODS: We used summary statistics from large-scale genome-wide association studies of MetS, its components, and cardiovascular diseases. We performed a two-sample MR analysis using the inverse-variance weighted method and other sensitivity methods. We also performed multivariate MR to adjust for potential risk factors. RESULTS: Our study found that MetS was causally associated with an increased risk of ischemic stroke, abdominal aortic aneurysm, pulmonary embolism, coronary heart disease, heart failure, and peripheral artery disease. Waist circumference was causally associated with an increased risk of 6 cardiovascular diseases. Type 2 diabetes mellitus, diastolic blood pressure, systolic blood pressure, triglycerides, and high-density lipoprotein cholesterol were all causally associated with coronary heart disease, with varying causal relationships with the remaining 5 cardiovascular diseases. Multivariate MR showed that, except for ischaemic stroke, waist circumference remained causally associated with the remaining five cardiovascular diseases after adjusting for potential confounders. CONCLUSION: Our study provides evidence that metabolic syndrome is causally associated with 6 cardiovascular diseases. Waist circumference is the most important component of these relationships. These findings have implications for the prevention and management of metabolic syndrome and cardiovascular diseases.

MicroRNA-338-3p as a therapeutic target in cardiac fibrosis through FGFR2 suppression.

BACKGROUND: The development of cardiac fibrosis involves the activation of cardiac fibroblasts (CFs) and their differentiation into myofibroblasts, which leads to the disruption of the extracellular matrix network. In the past few years, microRNAs (miRNA) have been described as potential targets for treating cardiac diseases. Although miR-338-3p has been shown to participate in the development of carcinoma, whether it affects cardiac fibrosis is unclear. METHODS: We examined the expression profiles of microRNAs in left ventricular samples of heart failure mice established by thoracic aortic constriction (TAC). Real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to detect the expression of miR-338-3p. CCK-8 assay/Transwell migration assay was used to measure the proliferation rate/migration of CFs. Luciferase reporter gene assay was used to test the binding between miR-338-3p and FGFR2. RESULTS: This study demonstrated that miR-338-3p was significantly decreased in thoracic aortic constriction mice. Cardiac miR-338-3p amounts were also reduced in patients with dilated cardiomyopathy (DCM). Interestingly, miR-338-3p overexpression inhibited α-SMA, COL1A1, and COL3A1 expression, as well as cell proliferation and migration in CFs. Bioinformatics analysis and dual-luciferase reporter assays revealed FGFR2 was targeted by miR-338-3p, whose antifibrotic effect could be alleviated by overexpression of FGFR2. Moreover, in DCM cases, serum miR-338-3p levels were markedly elevated in individuals with worse outcomes. CONCLUSIONS: The present study provides evidence that miR-338-3p suppresses cardiac fibroblast activation, proliferation, and migration by directly targeting FGFR2 in mice. Besides, serum miR-338-3p might constitute a potential prognostic biomarker of dilated cardiomyopathy.

The Prognostic Significance of Chronic Kidney Disease on the All-Cause Death of Ischemic Heart Failure in the Chinese Population: A Prospective Cohort Study.

OBJECTIVE: Our team tried to explore the impact of chronic kidney disease (CKD) on all-cause death among ischemic heart failure (IHF) patients. METHODS: From December 2015 to June 2019, IHF patients were continuously recruited in the Department of Cardiology, Guangdong Provincial People's Hospital. Participants were tracked through telephone interviews until October 15, 2020, or until the clinical endpoints appeared. The clinical endpoints were defined as all-cause death. The date of death or the last follow-up date minus the discharge date was used to calculate the follow-up time. RESULTS: A total of 1568 IHF patients (mean age 63.5 ± 11.0 years old, 85.8% male) were included in this study. Using the estimated glomerular filtration rate (eGFR) of 60 mL/min/1.73 m2 as the dividing line, IHF patients were divided into non-CKD group (n = 1,134) and CKD group (n = 434). After a median follow-up of 2.1 years, the all-cause death of non-CKD and CKD patients was 6.1/100 person-years and 13.7/100 person-years, respectively, and the incidence rate ratio was 2.24 (95% CI: 1.75-2.88; p value <0.001). The cumulative all-cause death of non-CKD and CKD patients were 19.4% and 40.7%, respectively (p value <0.001). CKD was an independent predictor of all-cause death in IHF patients (HR: 1.35, 95% CI: 1.03-1.76, p value = 0.029). Among IHF patients, in 8 subgroups, the all-cause death of CKD patients was consistently higher than that of non-CKD patients. Among IHF patients, the risk of all-cause death gradually increased when eGFR gradually decreased. CONCLUSION: Among IHF patients, CKD is a significant risk factor for all-cause death.

Tissue-Specific Hydrogels for Three-Dimensional Printing and Potential Application in Peripheral Nerve Regeneration.

Decellularized extracellular matrix hydrogel (dECM-G) has demonstrated its significant tissue-specificity, high biocompatibility, and versatile utilities in tissue engineering. However, the low mechanical stability and fast degradation are major drawbacks for its application in three-dimensional (3D) printing. Herein, we report a hybrid hydrogel system consisting of dECM-Gs and photocrosslinkable gelatin methacrylate (GelMA), which resulted in significantly improved printability and structural fidelity. These premixed hydrogels retained high bioactivity and tissue-specificity due to their containing dECM-Gs. More specifically, it was realized that the hydrogel containing dECM-G derived from porcine peripheral nerves (GelMA/pDNM-G) effectively facilitated neurite growth and Schwann cell migration from two-dimensional cultured dorsal root ganglion explants. The nerve cells were also encapsulated in the GelMA/pDNM-G hydrogel for 3D culture or underwent cell-laden bioprinting with high cell viability. The preparation of such GelMA/dECM-G hydrogels enabled the recapitulation of functional tissues through extrusion-based bioprinting, which holds great potential for applications in regenerative medicine. Impact statement Tissue-derived decellularized matrices have drawn broad interests for their versatile applications in tissue engineering and regenerative medicine, especially the decellularized peripheral nerve matrix, which can effectively facilitate axonal extension, remyelination, and neural functional restoration after peripheral nerve injury. However, neither decellularized porcine nerve matrix (pDNM) nor pDNM hydrogel (pDNM-G) can be directly used in three-dimensional printing for personalized nerve constructs or cell transplantation. This work developed a hybrid hydrogel consisting of decellularized extracellular matrix hydrogel (dECM-G) and photocrosslinkable gelatin methacrylate (GelMA), which resulted in significantly improved printability and structural fidelity. The GelMA/pDNM-G hydrogel retained high bioactivity and tissue-specificity due to its dECM-G content. Such hybrid hydrogel systems built up a springboard in advanced biomaterials for neural tissue engineering, as well as a promising strategy for dECM containing bioprinting.

Recent Applications of Pillar[n]arene-Based Host-Guest Recognition in Chemosensing and Imaging.

Pillar[n]arene is a novel kind of synthetic supramolecular macrocyclic host characterized by its particular pillar-shaped structure consisting of an electron-rich cavity and two finely adjustable rims. Benefiting from its rigid structure, facile synthesis, ease of functionalization, and outstanding host-guest chemistry, pillar[n]arene shows great potential for diverse applications. Significantly, the host-guest recognition of pillar[n]arene provides a novel approach for chemosensing and imaging. Herein, this Review critically and comprehensively reviews the applications of pillar[n]arene-based host-guest recognition in chemosensing and imaging. The sensing and imaging mechanisms as well as the unique roles and advantages of pillar[n]arene-based host-guest recognition are summarized. In addition, preparations of hybrid materials based on pillar[n]arene and inorganic materials are also introduced comprehensively in the light of chemosensing and imaging. Finally, current challenges and perspectives on pillar[n]arene-based host-guest recognition in chemosensing and imaging are outlined.

The association of lipoprotein(a) and intraplaque neovascularization in patients with carotid stenosis: a retrospective study.

BACKGROUND: Lipoprotein(a) is genetically determined and increasingly recognized as a major risk factor for arteriosclerotic cardiovascular disease. We examined whether plasma lipoprotein(a) concentrations were associated with intraplaque neovascularization (IPN) grade in patients with carotid stenosis and in terms of increasing plaque susceptibility to haemorrhage and rupture. METHODS: We included 85 patients diagnosed with carotid stenosis as confirmed using carotid ultrasound who were treated at Guangdong General Hospital. Baseline data, including demographics, comorbid conditions and carotid ultrasonography, were recorded. The IPN grade was determined using contrast-enhanced ultrasound through the movement of the microbubbles. Univariate and multivariate binary logistic regression analyses were used to evaluate the association between lipoprotein(a) and IPN grade, with stepwise adjustment for covariates including age, sex, comorbid conditions and statin therapy (model 1), total cholesterol, triglyceride, low-density lipoprotein cholesterol calculated by Friedwald's formula, high-density lipoprotein cholesterol, apolipoprotein A and apolipoprotein B (model 2), maximum plaque thickness and total carotid maximum plaque thickness, degree of carotid stenosis and internal carotid artery (ICA) occlusion (model 3). RESULTS: Lipoprotein(a) was a significant predictor of higher IPN grade in binary logistic regression before adjusting for other risk factors (odds ratio [OR] 1.238, 95% confidence interval [CI] (1.020, 1.503), P = 0.031). After adjusting for other risk factors, lipoprotein(a) still remained statistically significant in predicting IPN grade in all model. (Model 1: OR 1.333, 95% CI 1.074, 1.655, P = 0.009; Model 2: OR 1.321, 95% CI 1.059, 1.648, P = 0.014; Model 3: OR 1.305, 95% CI 1.045, 1.628, P = 0.019). Lp(a) ≥ 300 mg/L is also significantly related to IPN compare to < 300 mg/L (OR 2.828, 95% CI 1.055, 7.580, P = 0.039) as well as in model 1, while in model 2 and model 3 there are not significant difference. CONCLUSIONS: Plasma lipoprotein(a) concentrations were found to be independently associated with higher IPN grade in patients with carotid stenosis. Lowering plasma lipoprotein(a) levels may result in plaque stabilization by avoiding IPN formation.

Thiol-Rich Multifunctional Macromolecular Crosslinker for Gelatin-Norbornene-Based Bioprinting.

Extrusion-based bioprinting is an emerging and most frequently used technique for the fabrication of cell-laden constructs. A suitable hydrogel-based bioink for cell encapsulation and protection is critical for printability, structural stability, and post-printing cell viability. The thiol-ene chemistry-based gelatin-norbornene (GelNB) hydrogels have drawn much attention as a promising substitution of gelatin methacryloyl (GelMA), owing to the fast and controllable step-growth polymerization mechanism, as well as a significant reduction in reactive oxygen species (ROS) accumulation. Herein, thiolated heparin (HepSH) was synthesized and used as a macromolecular crosslinker for GelNB-based bioprinting, so that GelNB gelation became less sensitive to the thiol/ene ratio. The mechanical stability and moduli of GelNB/HepSH hydrogels were easily manipulated by the concentration and/or degree of thiol substitution. The GelNB/HepSH hydrogel allowed little intracellular ROS for encapsulated cells but provided vascular endothelial growth factor binding affinity for potential facilitation of neovascularization. Finally, the GelNB/HepSH bioink enabled a convenient printing process for both complex-structured bioscaffolds and cell-laden constructs, and resulted in good printability and high post-crosslinking cell viability. The crosslinker HepSH may serve as a multifunctional macromolecule that enables GelNB-based bioprinting in broad applications in regenerative medicine.

Genetic analysis using targeted next-generation sequencing of sporadic Chinese patients with idiopathic dilated cardiomyopathy.

BACKGROUND: Inherited dilated cardiomyopathy (DCM) contributes to approximately 25% of idiopathic DCM cases, and the proportion is even higher in familial DCM patients. Most studies have focused on familial DCM, whereas the genetic profile of sporadic DCM in Chinese patients remains unknown. METHODS: Between June 2018 and September 2019, 24 patients diagnosed with idiopathic DCM without a family history were included in the present study. All patients underwent genetic screening for 80 DCM-related genes using targeted next-generation sequencing. RESULTS: By in silico analysis, 10 of 99 detected variants were considered pathogenic or likely-pathogenic, including seven TTN truncating variants (TTNtv), one in-frame deletion in TNNT2, one missense mutation in RBM20, and one frameshift deletion variant in FLNC. Of these variants, eight are reported for the first time. CONCLUSIONS: Using targeted next-generation sequencing, potential genetic causes of idiopathic DCM were identified. Sarcomere mutations remained the most common genetic cause of inherited DCM in this cohort of sporadic Chinese DCM.

Association of anaemia and all-cause mortality in patients with ischaemic heart failure varies by renal function status.

AIMS: The aims of the current study were to evaluate the association between anaemia and all-cause mortality according to chronic kidney disease (CKD) status and to explore at what level of haemoglobin concentration would the all-cause mortality risk increase prominently among CKD and non-CKD patients, respectively. METHODS AND RESULTS: This is a prospective cohort study, and 1559 patients with ischaemic heart failure (IHF) were included (mean age of 63.5 ± 11.0 years, 85.8% men) from December 2015 to June 2019. Patients were divided into the CKD (n = 481) and non-CKD (n = 1078) groups based on the estimated glomerular filtration rate of 60 mL/min/1.73 m2 . In the CKD group, the incidence rate of all-cause mortality in anaemic and non-anaemic patients was 15.4 per 100 person-years and 10.8 per 100 person-years, respectively, with an incidence rate ratio of 1.42 (95% confidence interval: 1.00-2.02; P-value = 0.05). In the non-CKD group, the incidence rate of all-cause mortality in anaemic and non-anaemic patients was 9.8 per 100 person-years and 5.5 per 100 person-years, respectively, with an incidence rate ratio of 1.78 (95% confidence interval: 1.20-2.59; P-value = 0.005). After a median follow-up of 2.1 years, the cumulative incidence rate of all-cause mortality in anaemic and non-anaemic patients was 41.5% and 44.1% (P-value = 0.05) in the CKD group, and 30.9% and 18.1% (P-value < 0.0001) in the non-CKD group. In the CKD group, cumulative incidence rate of all-cause mortality increased prominently when haemoglobin concentration was below 100 g/L, which was not observed in the non-CKD group. CONCLUSIONS: Results of the current study indicated that among IHF patients, the association between anaemia and all-cause mortality differed by the renal function status. These findings underline the importance to assess mortality risk and manage anaemia among IHF patients according to the renal function status.

Mechanically strengthened hybrid peptide-polyester hydrogel and potential applications in spinal cord injury repair.

ADA16 peptide hydrogels have been broadly used in tissue engineering due to their good biocompatibility and nanofibrous structure mimicking the native extracellular matrix (ECM). However, the low mechanical strength often fails them as implantable scaffolds. To improve the mechanical stability of the RADA16 peptide hydrogel, a photocrosslinkable diacrylated poly(ϵ-caprolactone)-b-poly(ethylene glycol)-b-poly(ϵ-caprolactone) triblock copolymer (PCECDA) was physically combined with RADA16 peptide pre-modified with cell adhesive Arg-Gly-Asp sequence (RADA16-RGD). Consequently, an interpenetrating network, RADA16-RGD/PCECDA, was formed with highly enhanced mechanical property. The storage modulus (G') of RADA16-RGD/PCECDA (6% w/v, mass ratio mRADA16-RGD/mPCECDA = 1:5) hybrid hydrogel was elevated to ∼2000 Pa, compared to the RADA16-RGD (1% w/v) hydrogel alone (∼700 Pa). Furthermore, this hybrid hydrogel retained the nanofibrous structure from RADA16-RGD peptide, but underwent much slower degradation than RADA16-RGD alone. In vitro, the hybrid hydrogel exhibited excellent cytocompatibility and promoted the differentiation of the seeded neural stem cells. Finally, the RADA16-RGD/PCECDA hydrogel demonstrated capability in reducing cavitation, glial scar formation and inflammation at the lesion sites of hemi-sectioned spinal cord injury model in rats, which holds great potential for application in neural tissue engineering and regenerative medicine.