Palmitic acid in type 2 diabetes mellitus promotes atherosclerotic plaque vulnerability via macrophage Dll4 signaling.

Patients with Type 2 Diabetes Mellitus are increasingly susceptible to atherosclerotic plaque vulnerability, leading to severe cardiovascular events. In this study, we demonstrate that elevated serum levels of palmitic acid, a type of saturated fatty acid, are significantly linked to this enhanced vulnerability in patients with Type 2 Diabetes Mellitus. Through a combination of human cohort studies and animal models, our research identifies a key mechanistic pathway: palmitic acid induces macrophage Delta-like ligand 4 signaling, which in turn triggers senescence in vascular smooth muscle cells. This process is critical for plaque instability due to reduced collagen synthesis and deposition. Importantly, our findings reveal that macrophage-specific knockout of Delta-like ligand 4 in atherosclerotic mice leads to reduced plaque burden and improved stability, highlighting the potential of targeting this pathway. These insights offer a promising direction for developing therapeutic strategies to mitigate cardiovascular risks in patients with Type 2 Diabetes Mellitus.

Role of advanced glycation end products in diabetic vascular injury: molecular mechanisms and therapeutic perspectives.

BACKGROUND: In diabetic metabolic disorders, advanced glycation end products (AGEs) contribute significantly to the development of cardiovascular diseases (CVD). AIMS: This comprehensive review aims to elucidate the molecular mechanisms underlying AGE-mediated vascular injury. CONCLUSIONS: We discuss the formation and accumulation of AGEs, their interactions with cellular receptors, and the subsequent activation of signaling pathways leading to oxidative stress, inflammation, endothelial dysfunction, smooth muscle cell proliferation, extracellular matrix remodeling, and impaired angiogenesis. Moreover, we explore potential therapeutic strategies targeting AGEs and related pathways for CVD prevention and treatment in diabetic metabolic disorders. Finally, we address current challenges and future directions in the field, emphasizing the importance of understanding the molecular links between AGEs and vascular injury to improve patient outcomes.

AGEs induce high expression of Dll4 via endoplasmic reticulum stress PERK signaling-mediated internal ribosomal entry site mechanism in macrophages.

Background and aim: Advanced glycation end products (AGEs)- exposed macrophages was characterized by Delta-like ligand 4 (Dll4) high expressed and has been shown to participate in diabetes-related atherosclerosis. This study was aimed to investigate the translational regulatory mechanism of Dll4 high expression in macrophages exposed to AGEs. Methods: Human Dll4 5' untranslated region (5'UTR) sequence was cloned and inserted into a bicistronic reporter plasmid. Human THP-1 macrophages transfected with the bicistronic reporter plasmids were exposed to AGEs. Dual-luciferase assay was used to detect internal ribosome entry site (IRES) activity contained in Dll4 5'UTR. Small interference RNA transfection was used to knock-down specific gene expression. Localization of protein was analyzed. Results: AGEs exposure significantly induced IRES activity in Dll4 5' UTR in human macrophages. Internal potential promoter and ribosome read-through mechanisms were excluded. Inhibition of endoplasmic reticulum stress and specific silencing of protein kinase R-like endoplasmic reticulum kinase (PERK)/eukaryotic initiation factor 2α (eIF2α) signaling pathway activation reduced IRES activity in Dll4 5' UTR in human macrophages. Dll4 5' UTR IRES activity was also inhibited by targeted silencing of heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1). Moreover, specific inhibition of PERK/eIF2α signaling pathway led to deactivation of hnRNPA1, resulting to reduction of AGEs- induced Dll4 5' UTR IRES activity in human macrophages. Conclusions: AGEs induced Dll4 5' UTR IRES activity in human macrophages which was dependent on endoplasmic reticulum stress PERK/eIF2α signaling pathway. hnRNPA1 acted the role as an ITAF was also indispensable for AGEs-induced Dll4 5'UTR IRES activity in human macrophages.

Delta- like ligand 4- expressing macrophages and human diseases: Insights into pathophysiology and therapeutic opportunities.

Macrophages are key players in the immune response and have been implicated in various human diseases, including atherosclerosis, cancer, and chronic inflammatory disorders. While numerous studies have delved into the nuances of macrophage behavior in these conditions, there remains a gap in understanding the specific role of Delta-like ligand 4 (Dll4)-expressing macrophages and their overarching implications across these diseases. Among the plethora of factors expressed by macrophages, Dll4 has emerged as a molecule of particular interest. Recent studies have highlighted its unique role in modulating macrophage functions and its potential implications in various diseases. This review seeks to consolidate existing knowledge, address this gap, and present a comprehensive overview of Dll4-expressing macrophages in the context of these disorders and highlight their potential as therapeutic targets. We examined the involvement of Dll4-expressing macrophages in multiple human diseases such as atherosclerosis, cancer and chronic inflammatory diseases, emphasizing their influence on disease progression. We also discussed the challenges, limitations, and emerging research areas in targeting Dll4-expressing macrophages and provide an outlook on potential therapeutic strategies for the treatment of these diseases. By addressing the previously existing research gap, we've provided a roadmap that brings together fragmented insights, paving the way for more holistic research and potentially more effective therapeutic strategies centered on Dll4-expressing macrophages.

Study on development methods of different types of gas wells in tight sandstone gas reservoirs.

Reasonable production allocation of tight sandstone gas reservoirs is an important basis for efficient development of gas wells. Taking Block XX in Ordos Basin as an example, the modified flowing material balance equation was established considering the variation of gas viscosity and compression coefficient, the advantages and disadvantages of the method were discussed, and a reasonable production allocation process for gas wells was developed. The results show that: ① The commonly used flow material balance method ignores the change of natural gas compression coefficient, viscosity and deviation coefficient in the production process. The slope of the relationship curve between bottom hole pressure and cumulative production and the slope of the relationship curve between average formation pressure and cumulative production are not equal After considering this change. Compared with the results calculated by the material balance method, the results calculated by the flow material balance method are smaller. ② The production of 660 gas wells in the study area during stable production period is verified. Compared with the open flow method, the dynamic reserve allocation method is better, with an error of 0.06%. ③ The new method in this paper is used to allocate production for different types of gas wells. The cumulative production of different types of gas wells shows different degrees of increase. The I, II, III and IV types of gas wells increase by 32.26%, 30.29%, 23.58% and 25.07% respectively. This study provides technical support for dynamic reserve calculation and reasonable production allocation of gas wells in the study area, and has important guiding significance for the formulation of reasonable development plan and economic and efficient development of tight sandstone gas reservoirs.

Hydroxychloroquine Attenuates hERG Channel by Promoting the Membrane Channel Degradation: Computational Simulation and Experimental Evidence for QT-Interval Prolongation with Hydroxychloroquine Treatment.

INTRODUCTION: The coronavirus disease 2019 (COVID-19) pandemic has led to millions of confirmed cases and deaths worldwide and has no approved therapy. Currently, more than 700 drugs are tested in the COVID-19 clinical trials, and full evaluation of their cardiotoxicity risks is in high demand. METHODS: We mainly focused on hydroxychloroquine (HCQ), one of the most concerned drugs for COVID-19 therapy, and investigated the effects and underlying mechanisms of HCQ on hERG channel via molecular docking simulations. We further applied the HEK293 cell line stably expressing hERG-wild-type channel (hERG-HEK) and HEK293 cells transiently expressing hERG-p.Y652A or hERG-p.F656A mutants to validate our predictions. Western blot analysis was used to determine the hERG channel, and the whole-cell patch clamp was utilized to record hERG current (IhERG). RESULTS: HCQ reduced the mature hERG protein in a time- and concentration-dependent manner. Correspondingly, chronic and acute treatment of HCQ decreased the hERG current. Treatment with brefeldin A (BFA) and HCQ combination reduced hERG protein to a greater extent than BFA alone. Moreover, disruption of the typical hERG binding site (hERG-p.Y652A or hERG-p.F656A) rescued HCQ-mediated hERG protein and IhERG reduction. CONCLUSION: HCQ can reduce the mature hERG channel expression and IhERG via enhancing channel degradation. The QT prolongation effect of HCQ is mediated by typical hERG binding sites involving residues Tyr652 and Phe656.

Comparison of outcomes between transcatheter tricuspid valve repair and surgical tricuspid valve replacement or repair in patients with tricuspid insufficiency.

BACKGROUND: Tricuspid regurgitation is associated with significant morbidity and mortality, but with limited treatment options. The objective of this study is to compare the demographic characteristics, complications, and outcomes of transcatheter tricuspid valve repair (TTVr) versus surgical tricuspid valve replacement (STVR) or surgical tricuspid valve repair (STVr), using real-world data from the National Inpatient Sample (NIS) database. METHODS AND RESULTS: Our study analyzed data from the National Inpatient Sample (NIS) database from 2016 to 2018 and identified 92, 86, and 84 patients with tricuspid insufficiency who underwent STVr, STVR, and TTVr, respectively. The mean ages of patients who received STVr, STVR, and TTVr were 65.03 years, 66.3 years, and 71.09 years, respectively, with TTVr patients significantly older than those who received STVr (P < 0.05). Patients who received STVr or STVR had higher mortality rates (8.7% and 3.5%, respectively) compared to those who received TTVr (1.2%). Patients who underwent STVr or STVR were also more likely to experience perioperative complications, including third-degree atrioventricular block (8.7% STVr vs. 1.2% TTVr, P = 0.329; 38.4% STVR vs. 1.2% TTVr, P < 0.05), respiratory failure (5.4% STVr vs. 1.2% TTVr, P = 0.369; 15.1% STVR vs. 1.2% TTVr, P < 0.05), respiratory complications (6.5% STVr vs. 1.2% TTVr, P = 0.372; 19.8% STVR vs. 1.2% TTVr, P < 0.05), acute kidney injury (40.2% STVr vs. 27.4% TTVr, P = 0.367; 34.9% STVR vs. 27.4% TTVr, P = 0.617), and fluid and electrolyte disorders (44.6% STVr vs. 22.6% TTVr, P = 0.1332; 50% STVR vs. 22.6% TTVr, P < 0.05). In addition, the average cost of care and the average length of hospital stay were higher for patients who underwent STVr or STVR than for those who received TTVr (USD$37995 ± 356008.523 STVr vs. USD$198397 ± 188943.082 TTVr, P < 0.05; USD$470948 ± 614177.568 STVR vs. USD$198397 ± 188943.082 TTVr, P < 0.05; 15.4 ± 15.19 STVr vs. 9.6 ± 10.21 days TTVr, P = 0.267; 24.7 ± 28.81 STVR vs. 9.6 ± 10.21 days TTVr, P < 0.05). CONCLUSION: TTVr has shown to have favorable outcomes compared to STVr or STVR, but more research and clinical trials are required to help formulate evidence-based guidelines for the role of catheter-based management in tricuspid valve disease.

Advanced glycation end products induce skeletal muscle atrophy and insulin resistance via activating ROS-mediated ER stress PERK/FOXO1 signaling.

Skeletal muscle atrophy is often found in patients with type 2 diabetes mellitus (T2DM), which is characterized by insulin resistance. As the largest tissue in the body, skeletal muscle plays important roles in insulin resistance. Advanced glycation end products (AGEs) are a type of toxic metabolite that are representative of multiple pathophysiological changes associated with T2DM. Mice were exposed to AGEs. Forkhead box O1 (FOXO1) was silenced by using a constructed viral vector carrying siRNA. Skeletal muscle atrophy was evaluated by using hematoxylin-eosin (H&E), oil red O, myosin skeletal heavy chain (MHC), and laminin immunofluorescent stains. Reactive oxygen species (ROS) generation was assessed by using the dihydroethidium (DHE) stain. Western blotting was used to evaluate protein expression and phosphorylation. Insulin resistance was monitored via the insulin tolerance test and the glucose infusion rate (GIR). Mice exposed to AGEs showed insulin resistance, which was evidenced by reduced insulin tolerance and GIR. H&E and MHC immunofluorescent stains suggested reduced cross-sectional muscle fiber area. Laminin immunofluorescent and oil red O stains indicated increased intramuscular fibrosis and lipid deposits, respectively. Exposure to AGEs induced ROS generation, increased phosphorylation of protein kinase RNA-like endoplasmic reticulum kinase (PERK) and FOXO1, facilitated FOXO1 nuclear translocation, and elevated expression of muscle atrophy F-box (MAFbx) in gastrocnemius muscle. foxo1 silencing significantly suppressed skeletal muscle atrophy and insulin resistance without affecting ROS production. AGEs exacerbated skeletal muscle atrophy and insulin resistance by activating the PERK/FOXO1 signaling pathway in skeletal muscle.NEW & NOTEWORTHY In this study, we proposed a molecular mechanism underlying the skeletal muscle atrophy-associated insulin resistance in type 2 diabetes mellitus (T2DM). Our investigation suggests that exposure to AGEs, which are characteristic metabolites of T2DM pathology, induces the activation of reactive oxygen species (ROS)-mediated endoplasmic reticulum (ER) stress, leading to the upregulation of the protein kinase RNA-like ER kinase (PERK)/forkhead box O1 (FOXO1)/muscle atrophy F-box pathway and subsequent skeletal muscle atrophy, ultimately resulting in insulin resistance.

Transcatheter Mitral Valve Repair Versus Transcatheter Mitral Valve Replacement in Patients with Mitral insufficiency.

AIMS: Mitral regurgitation (MR) is the most prevalent form of valvular heart disease. Transcatheter mitral valve repair (TMVr) and transcatheter mitral valve replacement (TMVR) have recently emerged as alternatives to open heart surgical repair or replacement. However, studies on the comparative outcomes of TMVr and TMVR are limited. This study aims to compare the demographics, complications and outcomes of TMVr and TMVR based on a real-world investigation of the National Inpatient Sample (NIS) database. METHODS AND RESULTS: From 2016-2018 in the NIS database, a total of 210 and 3370 patients who underwent TMVR and TMVr, respectively, were selected. The mean age of the patients was 75.99 years (TMVr) and 69.6 years (TMVR) (p <0.01). The mortality of patients who received TMVR was higher compared to that of patients who were treated with TMVr (8.1 vs. 1.9%, p <0.01). The patients who underwent TMVR were more likely to suffer perioperative complications including blood transfusions (16.2 vs. 5.0%, p <0.01) and acute kidney injury (22.9 vs. 13.3%, p <0.01). The average cost of treatment was higher (USD $278864 vs. USD $216845, p <0.01), and the average duration of hospitalization was longer (8.73 vs. 4.17 d, p <0.01) for TMVR compared to TMVr. When taking into account perioperative comorbidities and other factors, TMVR was associated with a worse adjusted in-hospital mortality (odds ratio [OR], 3.307 [95% CI, 1.533-7.136]; p <0.01). CONCLUSION: TMVr is associated with lower mortality, peri-procedural morbidity, and resource use compared to TMVR. A patient-centered approach can help guide decision-making about the choice of intervention for the individual patient and more studies evaluating the long-term outcomes and durability of TMVR are needed at present.

Host-derived bacillus spp. as probiotic additives for improved growth performance in broilers.

In recent years, the utilization of antibiotics in animal feed has been restricted, probiotics have been increasingly used to replace antibiotics in maintaining animal health. The aim of this study was to screen and evaluate probiotics with excellent probiotic potential from the gut of healthy goslings for clinical application. Thirteen strains of Bacillus (named AH-G201 to AH-G2013), including 2 strains of Bacillus subtilis (B. subtilis), 6 strains of Bacillus licheniformis (B. licheniformis) and 5 strains of Bacillus amyloliquefaciens (B. amyloliquefaciens), were isolated and identified. Then, acid and bile salts tolerance tests were performed to screen probiotics strains that could survive under different environments. The effects of screened probiotics on the growth of pathogenic Escherichia coli (E. coli) and Salmonella were assessed. Furthermore, we performed the drug resistance tests and safety tests in animals. The results showed that B. Subtilis AH-G201, B. licheniformis AH-G202 and AH-G204 exhibited higher gastrointestinal resistance under in vitro conditions, and showed a moderate level of resistance to the tested antibiotics. Importantly, AH-G201 and AH-G202 showed 24 to 60% inhibition rate against pathogenic E. coli and Salmonella. Moreover, the safety analysis of AH-G201 and AH-G202 suggested that the 2 probiotics strains have no adverse effects on body weight gain and feed intake in the broilers, and in addition, they have significantly improved growth performance. Finally, we analyzed effects of B. Subtilis AH-G201and B. licheniformis AH-G202 on growth performance, immune organ index and the feces microbes of broilers. The results showed that broilers fed with high doses (5 × 109 CFU/mL, for single strain) of a mixture of AH-G201 and AH-G202 exhibited good growth performance, and exhibited the greatest gain in spleen weight and the highest lactic acid bacteria counts. These findings indicate that the combined addition of B. Subtilis AH-G201 and B. licheniformis AH-G202 has the potential to replace antibiotics and to improve the growth performance of broilers.

Uric Acid Predicts Recovery of Left Ventricular Function and Adverse Events in Heart Failure With Reduced Ejection Fraction: Potential Mechanistic Insight From Network Analyses.

Background and Aims: Heart failure with reduced ejection fraction (HFrEF) still carries a high risk for a sustained decrease in left ventricular ejection fraction (LVEF) even with the optimal medical therapy. Currently, there is no effective tool to stratify these patients according to their recovery potential. We tested the hypothesis that uric acid (UA) could predict recovery of LVEF and prognosis of HFrEF patients and attempted to explore mechanistic relationship between hyperuricemia and HFrEF. Methods: HFrEF patients with hyperuricemia were selected from the National Inpatient Sample (NIS) 2016-2018 database and our Xianyang prospective cohort study. Demographics, cardiac risk factors, and cardiovascular events were identified. Network-based analysis was utilized to examine the relationship between recovery of LVEF and hyperuricemia, and we further elucidated the underlying mechanisms for the impact of hyperuricemia on HFrEF. Results: After adjusting confounding factors by propensity score matching, hyperuricemia was a determinant of HFrEF [OR 1.247 (1.172-1.328); P < 0.001] of NIS dataset. In Xianyang prospective cohort study, hyperuricemia is a significant and independent risk factor for all-cause death (adjusted HR 2.387, 95% CI 1.141-4.993; P = 0.021), heart failure readmission (adjusted HR 1.848, 95% CI 1.048-3.259; P = 0.034), and composite events (adjusted HR 1.706, 95% CI 1.001-2.906; P = 0.049) in HFrEF patients. UA value at baseline was negatively correlated to LVEF of follow-ups (r = -0.19; P = 0.046). Cutoff UA value of 312.5 µmmol/L at baseline can work as a predictor of LVEF recovery during follow-up, with the sensitivity of 66.7%, the specificity of 35.1%, and the accuracy of 0.668 (95% CI, 0.561-0.775; P = 0.006). Moreover, gene overlap analysis and network proximity analysis demonstrated a strong correlation between HFrEF and Hyperuricemia. Conclusion: Lower baseline UA value predicted the LVEF recovery and less long-term adverse events in HFrEF patients. Our results provide new insights into underlying mechanistic relationship between hyperuricemia and HFrEF.

Matrine inhibits advanced glycation end products-induced macrophage M1 polarization by reducing DNMT3a/b-mediated DNA methylation of GPX1 promoter.

Advanced glycation end products (AGEs) are characterized diabetic metabolites inducing macrophage M1 polarization which is crucial in diabetes-exacerbated atherosclerosis. Matrine was proved anti-atherosclerotic. The current study was aimed to investigate the inhibitory effects of matrine on AGEs- induced macrophage M1 polarization and underlying molecular mechanisms. Primary mouse macrophages were exposed to AGEs. Receptor for AGEs (RAGE) and toll-like receptor 4 (TLR4) were over-expressed by vectors. Matrine was used to treat these cells. Inducible nitric oxide synthase (iNOS) expression and pro-inflammatory cytokine production were used to evaluate macrophage M1 polarization. Oxidative stress was assessed by intracellular reactive oxygen species (ROS) generation, total antioxidant capacity (TAC) and malondialdehyde (MDA) contents. Relative mRNA expression level was determined by real-time PCR. Western blotting was used to evaluate protein and protein phosphorylation levels. Bisulfite sequencing PCR (BSP) was used to evaluate DNA methylation. Matrine reduced AGEs exposure-elevated expressions of DNA methyltransferase (DNA MTase, DNMT)3a and DNMT3b in macrophages which were not affected by RAGE or TLR4 over expressions. DNA methylation rate of GPX1 promoter was reduced from 97.22% to 66.67% in AGEs- exposed macrophages treated by matrine. GPX1 expression was up-regulated by matrine, which further suppressed AGEs/RAGE-mediated oxidative stress. Thus, the activation of down-stream TLR4/STAT1 signaling pathway was inhibited by matrine treatment which eventually suppressed AGEs- induced macrophage M1 polarization. However, these effects of matrine were impaired by RAGE and TLR4 overexpression. Results from this study suggested that matrine inhibited AGEs- induced macrophage M1 polarization by suppressing RAGE-induced oxidative stress-mediated TLR4/STAT1 signaling pathway. Matrine exerted anti-oxidant effects via increasing GPX1 expression by inhibiting DNMT3a/b-induced GPX1 promoter DNA methylation.

Selenium Supplementation Improved Cardiac Functions by Suppressing DNMT2-Mediated GPX1 Promoter DNA Methylation in AGE-Induced Heart Failure.

Objective: Advanced glycation end products (AGEs) are featured metabolites associated with diabetic cardiomyopathy which is characterized by heart failure caused by myocyte apoptosis. Selenium was proved cardioprotective. This study was aimed at investigating the therapeutic effects and underlying mechanisms of selenium supplementation on AGE-induced heart failure. Methods: Rats and primary myocytes were exposed to AGEs. Selenium supplementation was administrated. Cardiac functions and myocyte apoptosis were evaluated. Oxidative stress was assessed by total antioxidant capacity (TAC), reactive oxygen species (ROS) generation, and GPX activity. Expression levels of DNA methyltransferases (DNMTs) and glutathione peroxidase 1 (GPX1) were evaluated. DNA methylation of the GPX1 promoter was analyzed. Results: AGE exposure elevated intracellular ROS generation, induced myocyte apoptosis, and impaired cardiac functions. AGE exposure increased DNMT1 and DNMT2 expression, leading to the reduction of GPX1 expression and activity in the heart. Selenium supplementation decreased DNMT2 expression, recovered GPX1 expression and activity, and alleviated intracellular ROS generation and myocyte apoptosis, resulting in cardiac function recovery. DNA methylation analysis in primary myocytes indicated that selenium supplementation or DNMT inhibitor AZA treatment reduced DNA methylation of the GPX1 gene promoter. Selenium supplementation and AZA administration showed synergic inhibitory effect on GPX1 gene promoter methylation. Conclusions: Selenium supplementation showed cardioprotective effects on AGE-induced heart failure by suppressing ROS-mediated myocyte apoptosis. Selenium supplementation suppressed ROS generation by increasing GPX1 expression via inhibiting DNMT2-induced GPX1 gene promoter DNA methylation in myocytes exposed to AGEs.

Development of a potential diagnostic monoclonal antibody against capsid spike protein VP27 of the novel goose astrovirus.

Goose astrovirus (GAstVs) is an emerging pathogen of goslings that causes fatal gout, kidney hemorrhages, renomegaly, and high mortality. The GAstVs VP27 protein is an important capsid protein and a candidate for the development of diagnostic reagents. The aim of this study was to clone and express the VP27 gene for preparation of a specific monoclonal antibody (mAb). The VP27 protein was expressed and purified in the supernatant of Escherichia coli BL21. Then, the mAb was obtained with the hybridoma technique and named 2AF11. It was differentiated as IgG1 with the help of immunoglobulin subclass tests. This mAb can specifically recognize the VP27 protein in GAstVs-infected cells, as evidenced by western blot analysis and immunofluorescent assay. Furthermore, this mAb could also detect the VP27 protein in GAstVs-infected tissues, as demonstrated by immunohistochemistry. These findings indicate that this mAb has high diagnostic potential. Therefore, the newly produced anti-VP27 mAb, 2AF11, could be a useful tool as a specific diagnostic marker for GAstVs.

Outcomes of transcatheter edge-to-edge mitral valve repair with percutaneous coronary intervention vs. surgical mitral valve repair with coronary artery bypass grafting.

Aims: Patients with severe ischemic mitral regurgitation (IMR) may receive concurrent coronary artery bypass graft (CABG) with surgical mitral valve repair (SMVr) or percutaneous coronary stent implantation (PCI) with transcatheter edge-to-edge mitral valve repair (TMVr). However, there is no consensus on the management of severe IMR in this setting. We aimed to compare the outcomes of combined SMVr with CABG to concurrent TMVr with PCI among patients with IMR in the National Inpatient Sample (NIS) database. Methods and results: The National Inpatient Sample was queried for all patients diagnosed with IMR who underwent SMVr with CABG or TMVr with PCI during the years 2016-2018. Study outcomes included all-cause in-hospital mortality, periprocedural complications, and resources used. A total of 1,360 potentially eligible patients were included in the study. After 1:5 propensity score matching, 133 patients were classified in the SMVr + CABG group and 29 patients in the TMVr + PCI group. Adjusted mortality was higher in the TMVr + PCI group compared with the SMVr + CABG group (13.8% vs. 4.5%, P = 0.034). Perioperative complications were higher among patients who underwent SMVr + CABG including blood transfusions (29.3% vs. 6.9%, P = 0.01) and post-procedural cardiogenic shock (11.3% vs. 0%, P = 0.044). The cost of care was higher (USD$783548.80 vs. USD$331846.523, P = 0.001) and the length of stay was longer (17.9 vs. 15.44 days, P < 0.001) in the TMVr + PCI group. On multivariable analysis, age (OR, 1.039 [95% CI, 1.006-1.072]; P = 0.032), renal failure (OR, 3.465 [95% CI, 1.867-6.433]; P < 0.001), and liver disease (OR, 5.012 [95% CI, 2.578-9.686]; P < 0.001) were associated with in-hospital mortality. Conclusion: TMVr + PCI was associated with higher resource use and in-hospital mortality but with improved perioperative complications compared with SMVr + CABG.

Targeting the Autophagy-Lysosome Pathway in a Pathophysiologically Relevant Murine Model of Reversible Heart Failure.

The key biological "drivers" that are responsible for reverse left ventricle (LV) remodeling are not well understood. To gain an understanding of the role of the autophagy-lysosome pathway in reverse LV remodeling, we used a pathophysiologically relevant murine model of reversible heart failure, wherein pressure overload by transaortic constriction superimposed on acute coronary artery (myocardial infarction) ligation leads to a heart failure phenotype that is reversible by hemodynamic unloading. Here we show transaortic constriction + myocardial infarction leads to decreased flux through the autophagy-lysosome pathway with the accumulation of damaged proteins and organelles in cardiac myocytes, whereas hemodynamic unloading is associated with restoration of autophagic flux to normal levels with incomplete removal of damaged proteins and organelles in myocytes and reverse LV remodeling, suggesting that restoration of flux is insufficient to completely restore myocardial proteostasis. Enhancing autophagic flux with adeno-associated virus 9-transcription factor EB resulted in more favorable reverse LV remodeling in mice that had undergone hemodynamic unloading, whereas overexpressing transcription factor EB in mice that have not undergone hemodynamic unloading leads to increased mortality, suggesting that the therapeutic outcomes of enhancing autophagic flux will depend on the conditions in which flux is being studied.

Global, Regional, and National Burden of Myocarditis From 1990 to 2017: A Systematic Analysis Based on the Global Burden of Disease Study 2017.

Objective: The global trends in myocarditis burden over the past two decades remain poorly understood and might be increasing during the coronavirus disease 2019 (COVID-19) worldwide pandemic. This study aimed to provide comprehensive estimates of the incidence, mortality, and disability-adjusted life years (DALYs) for myocarditis globally from 1990 to 2017. Methods: Data regarding the incidence, mortality, DALY, and estimated annual percentage change (EAPC) between 1990 and 2017 for myocarditis worldwide were collected and calculated from the 2017 Global Burden of Disease study. We additionally calculated the myocarditis burden distribution based on the Socio-Demographic Index (SDI) quintile and Human Development Index (HDI). Results: The incidence cases of myocarditis in 2017 was 3,071,000, with a 59.6% increase from 1990, while the age-standardized incidence rate (ASIR) was slightly decreased. The number of deaths due to myocarditis increased gradually from 27,120 in 1990 to 46,490 in 2017. The middle SDI quintile showed the highest number of myocarditis-related deaths. On the contrary, the global age-standardized death rate (ASDR) decreased with an overall EAPC of -1.4 [95% uncertainty interval (UI) = -1.8 to -1.0]. Similar to ASDR, the global age-standardized DALY rate also declined, with an EAPC of -1.50 (95% UI = -2.30 to -0.8) from 1990 to 2017. However, there was a 12.1% increase in the number of DALYs in the past 28 years; the middle SDI and low-middle SDI quintiles contributed the most to the DALY number in 2017. We also observed significant positive correlations between the EPAC of age-standardized rate and HDI for both death and DALY in 2017. Conclusions: Globally, the ASIR, ASDR, and age-standardized DALY rate of myocarditis decreased slightly from 1990 to 2017. The middle SDI quintile had the highest level of ASIR, ASDR, and age-standardized DALY rate, indicating that targeted control should be developed to reduce the myocarditis burden especially based on the regional socioeconomic status. Our findings also provide a platform for further investigation into the myocarditis burden in the era of COVID-19.

Global burden of cardiovascular diseases attributable to hypertension in young adults from 1990 to 2019.

BACKGROUND: Hypertension grows into a serious public health problem among young adults, linking to a set of life-threatening cardiovascular diseases (CVDs). Young adults are not well represented in current knowledge about the CVDs burden attributable to hypertension. METHODS: In this analysis of data from the GBD (Global Burden of Disease) study 2019, we focus on young adults and provide the first comprehensive and comparative assessment of the hypertension attributable CVDs burden, in terms of its mortality and years of living with disability (YLD) from 1990 to 2019, stratified by location, sex, and development status. RESULTS: Globally in 2019, the death and YLD numbers caused by hypertension-related CVDs were 640 239 and 2 717 474 in young adults, marking a 43.0 and 86.6% increase from 1990, respectively. The corresponding mortality rate dropped by 10.5%, whereas the YLD rate increased by 16.8% during the same period. V-shaped association between CVDs burden and social development status was observed. The largest burden and the most pronounced increase were borne by middle-income countries, while high-income countries had the lowest death/YLD rate with a quicker annual decline. Men largely outpaced women in hypertension attributable CVDs mortality. Ischemic heart disease and stroke were the leading cause for death and YLD burden, correspondingly. CONCLUSIONS: Hypertension attributable CVDs burden in young adults has greatly increased from 1990 to 2019, with considerably spatiotemporal and sexual heterogeneity. The largest burden was borne by middle-income countries, especially by men. Establishment of geographically and sexually tailored strategies were needed to prevent hypertension-related CVDs in young adults.

Global Burden of Aortic Aneurysm and Attributable Risk Factors from 1990 to 2017.

Background: To date, our understanding of the global aortic aneurysm (AA) burden distribution is very limited. Objective: To assess a full view of global AA burden distribution and attributable risk factors from 1990 to 2017. Methods: We extracted data of AA deaths, disability-adjusted life years (DALYs), and their corresponding age-standardized rates (ASRs), in general and by age/sex from the 2017 Global Burden of Disease (GBD) study. The current AA burden distribution in 2017 and its changing trend from 1990 to 2017 were separately showed. The spatial divergence was discussed from four levels: global, five social-demographic index regions, 21 GBD regions, and 195 countries and territories. We also estimated the risk factors attributable to AA related deaths. Results: Globally, the AA deaths were 167,249 with an age-standardized death rate (ASDR) of 2.19/100,000 persons in 2017, among which the elderly and the males accounted for the majority. Although reductions in ASRs were observed in developed areas, AA remained an important health issue in those relatively underdeveloped areas and might be much more important in the near future. AA may increasingly affect the elderly and the female population. Similar patterns of AA DALYs burden were noted during the study period. AA burden attributable to high blood pressure and smoking decreased globally and there were many heterogeneities in their distribution. Discussion: AA maintained an incremental public health issue worldwide. The change pattern of AA burden was heterogeneous across locations, ages, and sexes and it is paramount to improve resource allocation for more effective and targeted prevention strategies. Also, prevention of tobacco consumption and blood pressure control should be emphasized.