PEX3 promotes regenerative repair after myocardial injury in mice through facilitating plasma membrane localization of ITGB3.

The peroxisome is a versatile organelle that performs diverse metabolic functions. PEX3, a critical regulator of the peroxisome, participates in various biological processes associated with the peroxisome. Whether PEX3 is involved in peroxisome-related redox homeostasis and myocardial regenerative repair remains elusive. We investigate that cardiomyocyte-specific PEX3 knockout (Pex3-KO) results in an imbalance of redox homeostasis and disrupts the endogenous proliferation/development at different times and spatial locations. Using Pex3-KO mice and myocardium-targeted intervention approaches, the effects of PEX3 on myocardial regenerative repair during both physiological and pathological stages are explored. Mechanistically, lipid metabolomics reveals that PEX3 promotes myocardial regenerative repair by affecting plasmalogen metabolism. Further, we find that PEX3-regulated plasmalogen activates the AKT/GSK3ß signaling pathway via the plasma membrane localization of ITGB3. Our study indicates that PEX3 may represent a novel therapeutic target for myocardial regenerative repair following injury.

Checkpoint Kinase 1 Stimulates Endogenous Cardiomyocyte Renewal and Cardiac Repair by Binding to Pyruvate Kinase Isoform M2 C-Domain and Activating Cardiac Metabolic Reprogramming in a Porcine Model of Myocardial Ischemia/Reperfusion Injury.

BACKGROUND: The regenerative capacity of the adult mammalian hearts is limited. Numerous studies have explored mechanisms of adult cardiomyocyte cell-cycle withdrawal. This translational study evaluated the effects and underlying mechanism of rhCHK1 (recombinant human checkpoint kinase 1) on the survival and proliferation of cardiomyocyte and myocardial repair after ischemia/reperfusion injury in swine. METHODS AND RESULTS: Intramyocardial injection of rhCHK1 protein (1 mg/kg) encapsulated in hydrogel stimulated cardiomyocyte proliferation and reduced cardiac inflammation response at 3 days after ischemia/reperfusion injury, improved cardiac function and attenuated ventricular remodeling, and reduced the infarct area at 28 days after ischemia/reperfusion injury. Mechanistically, multiomics sequencing analysis demonstrated enrichment of glycolysis and mTOR (mammalian target of rapamycin) pathways after rhCHK1 treatment. Co-Immunoprecipitation (Co-IP) experiments and protein docking prediction showed that CHK1 (checkpoint kinase 1) directly bound to and activated the Serine 37 (S37) and Tyrosine 105 (Y105) sites of PKM2 (pyruvate kinase isoform M2) to promote metabolic reprogramming. We further constructed plasmids that knocked out different CHK1 and PKM2 amino acid domains and transfected them into Human Embryonic Kidney 293T (HEK293T) cells for CO-IP experiments. Results showed that the 1-265 domain of CHK1 directly binds to the 157-400 amino acids of PKM2. Furthermore, hiPSC-CM (human iPS cell-derived cardiomyocyte) in vitro and in vivo experiments both demonstrated that CHK1 stimulated cardiomyocytes renewal and cardiac repair by activating PKM2 C-domain-mediated cardiac metabolic reprogramming. CONCLUSIONS: This study demonstrates that the 1-265 amino acid domain of CHK1 binds to the 157-400 domain of PKM2 and activates PKM2-mediated metabolic reprogramming to promote cardiomyocyte proliferation and myocardial repair after ischemia/reperfusion injury in adult pigs.

Monocyte-to-lymphocyte ratio predicts mortality and cardiovascular mortality in the general population.

BACKGROUND: Systemic chronic inflammation (SCI) is closely involved in the pathogenesis of many diseases. This study aims to investigate the association between MLR with mortality and cardiovascular disease (CVD) mortality in US adults. METHODS: 35,813 adults were enrolled from the 1999-2014 National Health and Nutrition Examination Survey (NHANES) cycle. Individuals were categorized according to MLR tertiles and followed until 31 December 2019. Kaplan-Meier plots and log-rank tests were utilized to explore survival differences among the MLR tertiles. Adjusted multivariable Cox analysis was employed to investigate the relationship of MLR with mortality and CVD mortality. Restricted cubic spline and subgroup analysis were further used to discern non-linear relationship and the relationship in categories. RESULTS: During a median follow-up of 134 months, 5865 (16.4%) all-cause deaths and 1602 (4.5%) cardiovascular deaths occurred. Kaplan-Meier plots revealed significant differences in all-cause and cardiovascular mortality among the MLR tertiles. In the fully-adjusted Cox regression model, individuals in the highest tertile of MLR had higher risk of mortality (HR = 1.26, 95% CI: 1.17-1.35) and CVD mortality (HR = 1.41, HR, 95% CI: 1.23-1.62) than those in the lowest tertile. The restricted cubic spline exhibited a J-shaped relationship between MLR with mortality and CVD mortality (P for non-linearity <0.001). The further subgroup analysis demonstrated a robust trend across categories. CONCLUSION: Our study demonstrated that increased baseline MLR was positively associated with a higher risk of death in US adults. MLR was a strong independent predictor of mortality and CVD mortality in the general population.

Mesenchymal stem cell-derived extracellular vesicles carrying miR-99b-3p restrain microglial activation and neuropathic pain by stimulating autophagy.

Neuropathic pain is a complex condition that seriously affects human quality of life. This study aimed to investigate the therapeutic mechanism of mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) and try to discover new targets for alleviating neuropathic pain. Extracellular vesicles were isolated and identified via ultracentrifugation. BV-2 microglial cells were stimulated with lipopolysaccharide (LPS) in the presence or absence of MSC-EVs. Further, microglial activation and neuroinflammation were evaluated by flow cytometry, RT-qPCR, and ELISA. High-throughput sequencing analysis was performed to reveal the differentially expressed (DE) miRNAs in BV-2 microglia. Autophagy-related regulators were assessed by Western blotting and Immunofluorescence staining. Chronic constriction injury (CCI) model was used to induce neuropathic pain in rats, and the mechanical withdrawal threshold (MWT) was measured. High-throughput sequencing analysis identified 17 DE miRNAs, which were mainly enriched in PI3K-AKT and mTOR signaling pathways. MSC-EVs inhibited the activation of PI3K/AKT/mTOR signaling pathway in LPS-stimulated microglia. Moreover, MSC-EVs treatment enhanced the autophagy level in activated microglia, whereas autophagy inhibitor 3-MA reversed the suppressing effects of MSC-EVs on microglial activation and neuroinflammation. The MSC-EV-mediated transfer of miR-99b-3p was verified to promote microglial autophagy, and miR-99b-3p overexpression suppressed the expression of pro-inflammatory factors in activated microglia. During in vivo studies, intrathecal injection of MSC-EVs significantly up-regulated the expression of miR-99b-3p, and alleviated mechanical allodynia caused by activated microglia in the spinal cord dorsal horn of CCI rats. Moreover, MSC-EVs treatment repaired CCI-induced autophagic impairment by stimulating autophagy in the spinal cord. Collectively, our findings demonstrated that MSC-EVs had an analgesic effect on neuropathic pain via promoting autophagy, and these antinociceptive effects were at least in part caused by MSC-EV-mediated transfer of miR-99b-3p, thereby inhibiting microglial activation and pro-inflammatory cytokines expression.

Huc-MSCs-derived exosomes attenuate neuropathic pain by inhibiting activation of the TLR2/MyD88/NF-κB signaling pathway in the spinal microglia by targeting Rsad2.

BACKGROUND: Mesenchymal stem cells (MSCs)-derived exosomes have shown promise as a cell-free therapeutic strategy for neuropathic pain. This study was conducted to explore the potential mechanisms underlying the analgesic effects of MSC-derived exosomes in treating neuropathic pain. METHODS: Human umbilical cord MSCs (huc-MSCs)-derived exosomes were isolated and identified. BV-2 microglia were stimulated with lipopolysaccharide (LPS) in the presence or absence of exosomes. Differentially expressed proteins were identified by tandem mass tag (TMT)-based proteomic analysis. The analgesic effects of huc-MSCs-derived exosomes were evaluated in a rat model of chronic constriction injury (CCI). The underlying mechanism was investigated by flow cytometry, RT-qPCR, Western blotting, immunofluorescent staining, and small interfering RNA transfection. RESULTS: In vitro, huc-MSCs-derived exosomes suppressed LPS-induced microglial activation and inhibited activation of the TLR2/MyD88/NF-κB signaling pathway. Based on the proteomic analysis, Rsad2 was identified and confirmed to be down-regulated by huc-MSCs-derived exosomes. Importantly, knockdown of Rsad2 also inhibited microglial activation and restrained activation of the TLR2/MyD88/NF-κB signaling pathway. In vivo, intrathecal injection of exosomes ameliorated CCI-induced mechanical allodynia, down-regulated Rsad2 expression and restrained TLR2/MyD88/NF-κB signaling activation in the spinal microglia. CONCLUSION: Huc-MSCs-derived exosomes exerted analgesic effects on neuropathic pain by inhibiting activation of the TLR2/MyD88/NF-κB signaling pathway in the spinal microglia. The mechanism underlying these antinociceptive effects involved exosome-mediated interference with Rsad2 expression, thereby inhibiting microglial activation.

The Association Between Vitamin D Levels and the 10-Year Risk of Atherosclerotic Cardiovascular Disease: A Population-Based Study.

BACKGROUND: The association between vitamin D levels and atherosclerotic cardiovascular disease (ASCVD) risk remains unclear. In this study, the association between serum 25(OH)D and 10-year ASCVD risk was examined in a national sample of middle-aged and older adults. METHODS: Cross-sectional data from the 2009-2014 National Health and Nutrition Examination Survey were analyzed. The Pooled Cohort Equations were used to estimate the risk of a first ASCVD event in 10 years. An adjusted multiple linear regression model was used to investigate the association between serum 25(OH)D and ASCVD risk. In addition, we performed sensitivity analysis and interactive analysis to assess the robustness of associations across different subgroups. RESULTS: A total of 3354 participants were included in this study. The linear regression model indicated that the risk of ASCVD decreased with the increase in serum 25(OH)D. When analyzed as a continuous variable, serum 25(OH)D was significantly associated with the estimated 10-year risk of ASCVD. In the fully adjusted model, each 10-nmol/L increase in serum 25(OH)D reduced the estimated 10-year ASCVD risk by 0.172% ( P < .001). Individuals in the moderate, insufficient, and sufficient vitamin D deficiency groups had a 0.449% ( P = .362), 0.957% ( P = .046), 1.475% ( P = .003) decrease in ASCVD risk, respectively, when a severe vitamin D deficiency group was set as a reference in the fully adjusted model. CONCLUSION: Our data suggest a negative association between vitamin D levels and the predicted 10-year risk of ASCVD. Further studies are required to investigate whether vitamin D supplements could reduce the risk of ASCVD.

Trends in general and abdominal obesity in US adults: Evidence from the National Health and Nutrition Examination Survey (2001-2018).

Aim: This study investigates the trend in general obesity and abdominal obesity in US adults from 2001 to 2018. Methods: We included 44,184 adults from the nine cycles of the continuous NHANES (2001-2002, 2003-2004, 2005-2006, 2007-2008, 2009-2010, 2011-2012, 2013-2014, 2015-2016, and 2017-2018). The age-adjusted mean body mass index and waist circumference were calculated, and the sex-specific annual change was estimated by the survey cycle. We used the weighted sex-specific logistic regression models to analyze the prevalence of general obesity and abdominal obesity from 2001 to 2018. The weighted adjusted odds ratio (OR) with a 95% confidence interval (CI) was calculated. Results: Our study showed that general obesity and abdominal obesity account for about 35.48 and 53.13% of the US population. From 2001-2002 to 2017-2018, the age-adjusted prevalence of general obesity increased from 33.09 to 41.36% in females and from 26.88 to 42.43% in males. During 2001-2018, the age-adjusted prevalence of abdominal obesity increased from 57.58 to 67.33% in females and from 39.07 to 49.73% in males. A significant time-dependent increase was observed in the prevalence of general obesity (adjusted OR, 1.007; 95% CI 1.005-1.009, P < 0.001) and abdominal obesity (adjusted OR, 1.006; 95% CI, 1.004-1.008; P < 0.001). Conclusion: General obesity and abdominal obesity are a heavy health burden among US adults, and the increasing trend remains in both males and females from 2001 to 2018.

High waist circumference is a risk factor for hypertension in normal-weight or overweight individuals with normal metabolic profiles.

This study aims to investigate the relationship between waist circumference and hypertension risk in normal-weight/overweight individuals with normal cardiometabolic profiles. The authors included 7217 normal-weight and overweight individuals with normal cardiometabolic profiles from the 2001 to 2014 US National Health and Nutrition Examination Survey. The authors summarized demographic characteristics, cardiometabolic profiles, and behavioral factors across waist circumference quartiles. Then, in the logistic regression analysis, the authors observed a positive and significant association between waist circumference (as a continuous variable) and the prevalence of hypertension in all three models (nonadjusted, minimally adjusted, and fully adjusted), with odds ratios (95% confidence intervals) of 1.76 (1.65-1.86), 1.29 (1.20-1.39), and 1.24 (1.09-1.40), respectively. When analyzed as a categorical variable, individuals in the highest waist circumference group had a 1.48-fold increased risk of hypertension than the lowest group in the fully adjusted model. Moreover, the Cox regression analysis revealed a positive and significant association between waist circumference and all-cause mortality in individuals with hypertension in the nonadjusted model (HR, 1.27; 95% CI, 1.10-1.47) and the fully adjusted model (HR, 1.59; 95% CI, 1.22-2.06). In conclusions, our results showed that, even in those with normal metabolic profiles, high waist circumference was significantly associated with the increased prevalence of hypertension. And once hypertension has been established, patients with high waist circumference showed elevated all-cause mortality. Therefore, waist circumference should be routinely measured and controlled regardless of metabolic profiles.

High waist circumference is a risk factor of new-onset hypertension: Evidence from the China Health and Retirement Longitudinal Study.

This study aims to investigate the association between waist circumference and the development of hypertension based on a nationwide cohort Chinese population. A total of 5330 individuals free of hypertension at baseline were collected from the China Health and Retirement Longitudinal Study. The association between waist circumference and the development of hypertension was analyzed by an adjusted cox regression model and visualized by restricted cubic splines. Further, we applied the supervised machine learning methods to evaluate the importance of multiple variates for new-onset hypertension. Additionally, the robustness of the association was assessed by a subgroup analysis. A total of 1490 individuals (28.0%) developed hypertension during a mean follow-up of 3.32 years. The new-onset hypertension was more observed in those with increased waist circumference (P for trend < .001). In the fully adjusted Cox regression, each 10 cm increase of waist circumference would result in an 18% elevated risk of hypertension. The random forest method and the Extreme Gradient Boosting method revealed waist circumference as an important feature to predict the development of hypertension. The sensitivity analysis indicated a consistent trend between waist circumference and new-onset hypertension in all BMI categories. This study suggested high waist circumference as an independent risk factor for new-onset hypertension based on a nationwide cohort of Chinese adults aged ≥45 years old. Our results supported that waist circumference should be routinely measured.

Clinical outcomes of bariatric surgery - Updated evidence.

Obesity has grown to become a major health problem over the past few decades. Obesity-related comorbidities, such as diabetes mellitus, hypertension, obstructive sleep apnea, and dyslipidemia, are inextricably linked with increased adverse clinical consequences and mortality. Compared with other strategies for obesity, bariatric surgery is efficient in weight loss and has been proved to exert positive effects on obesity-related risk factors. This broad improvement in risk factors has resulted in substantial remission or reductions of comorbidities and better performance on clinical outcomes, including cardiovascular diseases, cancer, and mortality. With the development of surgical procedures, the safety of bariatric surgery has been validated and the rate of peri-operative death is low all over the world. Nonetheless, surgeons ought to be careful about potential complications, such as nutrition deficiencies, psychological disorders, or new digestive tract tumors after surgery. For patients with obesity, bariatric surgery might be a precious and crucial tool to bring additional benefits including comorbidities protection and life span extension. All patients with obesity should be engaged in a union consultation group to select a suitable treatment.

Association Between Serum Calcium and the Prevalence of Hypertension Among US Adults.

Background: Hypertension is a significant risk factor of cardiovascular diseases, posing a serious threat to global health. Calcium plays an important role in regulating body homeostasis. The association of calcium with hypertension remains uncertain in the general population. Methods and Results: Cross-sectional data from the 2007-2018 National Health and Nutrition Examination Survey (NHANES) were analyzed. Adjusted multivariable logistic regression analysis and restricted cubic spline were used to investigate the association of serum calcium with the prevalence of hypertension. A total of 26,778 participants were included. The increase in calcium levels showed a positive association with the prevalence of hypertension in all three models with ORs of 1.347 (1.249-1.454), 1.522 (1.401-1.654), and 1.438 (1.306-1.583). The further subgroup analysis demonstrated a robust trend across all categories by sex, age, race, BMI, and eGFR. The restricted cubic spline plot exhibited an S-curve relationship between calcium and hypertension. Conclusion: Our cross-sectional study demonstrated a positive association between higher serum calcium level and the prevalence of hypertension. Our findings highlighted serum calcium level in hypertensive patients.

Serine/Threonine-Protein Kinase 3 Facilitates Myocardial Repair After Cardiac Injury Possibly Through the Glycogen Synthase Kinase-3ß/ß-Catenin Pathway.

Background The neonatal heart maintains its entire regeneration capacity within days after birth. Using quantitative phosphoproteomics technology, we identified that SGK3 (serine/threonine-protein kinase 3) in the neonatal heart is highly expressed and activated after myocardial infarction. This study aimed to uncover the function and related mechanisms of SGK3 on cardiomyocyte proliferation and cardiac repair after apical resection or ischemia/reperfusion injury. Methods and Results The effect of SGK3 on proliferation and oxygen glucose deprivation/reoxygenation- induced apoptosis in isolated cardiomyocytes was evaluated using cardiomyocyte-specific SGK3 overexpression or knockdown adenovirus5 vector. In vivo, gain- and loss-of-function experiments using cardiomyocyte-specific adeno-associated virus 9 were performed to determine the effect of SGK3 in cardiomyocyte proliferation and cardiac repair after apical resection or ischemia/reperfusion injury. In vitro, overexpression of SGK3 enhanced, whereas knockdown of SGK3 decreased, the cardiomyocyte proliferation ratio. In vivo, inhibiting the expression of SGK3 shortened the time window of cardiac regeneration after apical resection in neonatal mice, and overexpression of SGK3 significantly promoted myocardial repair and cardiac function recovery after ischemia/reperfusion injury in adult mice. Mechanistically, SGK3 promoted cardiomyocyte regeneration and myocardial repair after cardiac injury by inhibiting GSK-3ß (glycogen synthase kinase-3ß) activity and upregulating ß-catenin expression. SGK3 also upregulated the expression of cell cycle promoting genes G1/S-specific cyclin-D1, c-myc (cellular-myelocytomatosis viral oncogene), and cdc20 (cell division cycle 20), but downregulated the expression of cell cycle negative regulators cyclin kinase inhibitor P 21 and cyclin kinase inhibitor P 27. Conclusions Our study reveals a key role of SGK3 on cardiac repair after apical resection or ischemia/reperfusion injury, which may reopen a novel therapeutic option for myocardial infarction.

Association Between Waist Circumference and the Prevalence of (Pre) Hypertension Among 27,894 US Adults.

Aims: This study aimed to investigate the association between waist circumference and the prevalence of (pre) hypertension. Methods: Cross-sectional data from the 2007-2018 National Health and Nutrition Examination Survey were analyzed. The historical trend of abdominal obesity was assessed by the Cochran-Armitage trend test. After preprocessed by the multiple imputation strategy, we used generalized additive models to assess the association of waist circumference with systolic/diastolic blood pressure and performed correlation analysis by the Spearman correlation coefficient. Moreover, we used multivariable logistic regression (non-adjusted, minimally adjusted, and fully adjusted models), restricted cubic spline, and sensitivity analysis to investigate the association between waist circumference and (pre) hypertension. Results: A total of 27,894 participants were included in this study. In the fully adjusted model, waist circumference was positively associated with (pre) hypertension with odds ratios (95% confidence intervals) of 1.28 (1.18-1.40) in the young group and 1.23 (1.15-1.33) in the old group. Restricted cubic spline showed a higher prevalence of (pre) hypertension with the increase of waist circumference. In the subgroup analysis, waist circumference showed a robust trend across all BMI categories with odds ratios (95% confidence intervals) of 3.33 (1.29-8.85), 1.35 (1.17-1.57), 1.27 (1.13-1.41), and 1.09 (1.01-1.17) in underweight, normal weight, overweight, and obese individuals, respectively. Conclusion: This study highlighted waist circumference as a significant biomarker to evaluate the risk of (pre) hypertension. Our results supported the measure of waist circumference regardless of BMI when evaluating the cardiometabolic risk related to fat distribution.

Cardiotoxicity in cancer immune-checkpoint therapy: Mechanisms, clinical evidence, and management strategies.

Immune-checkpoint inhibitors (ICIs), a unique antibody-based therapeutic strategy, have revolutionized the treatment landscape of solid and hematological cancers. Despite the proven benefits of ICIs, the cardiotoxicity from unspecific immune activation (uncommon but potentially fatal) is a continuing concern. Accumulating preclinical research has demonstrated that ICIs initiate inflammation in the myocardium, while clinically significant cardiotoxicity were reported in few patients receiving ICI therapy, probably due to the low incidence and unspecific symptoms. The subtle signs and symptoms (e.g., chest pain, dizziness, and dyspnea) were likely attributed to cancer and/or non-cardiac events by previous studies, thus limiting the understanding of the incidence, outcomes, risk factors, and management of ICI-related cardiotoxicity. The heterogeneous clinical presentation and complex diagnostic procedure further make it challenging to accurately identify ICI-related cardiac events in clinical trials. Therefore, ICI-related cardiotoxicity, whose incidence is probably underestimated, has not been well recognized. In this article, we provide an overview of potential mechanisms underlying ICI-related cardiotoxicity and review accumulating clinical evidence of ICI-related cardiotoxicity, with a focus on myocarditis. Moreover, we discuss possible strategies to manage ICI-related cardiotoxicity and highlight the importance of developing cardio-oncology.

Identification of key genes in calcific aortic valve disease via weighted gene co-expression network analysis.

BACKGROUND: Calcific aortic valve disease (CAVD) is the most common subclass of valve heart disease in the elderly population and a primary cause of aortic valve stenosis. However, the underlying mechanisms remain unclear. METHODS: The gene expression profiles of GSE83453, GSE51472, and GSE12644 were analyzed by 'limma' and 'weighted gene co-expression network analysis (WGCNA)' package in R to identify differentially expressed genes (DEGs) and key modules associated with CAVD, respectively. Then, enrichment analysis was performed based on Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, DisGeNET, and TRRUST database. Protein-protein interaction network was constructed using the overlapped genes of DEGs and key modules, and we identified the top 5 hub genes by mixed character calculation. RESULTS: We identified the blue and yellow modules as the key modules. Enrichment analysis showed that leukocyte migration, extracellular matrix, and extracellular matrix structural constituent were significantly enriched. SPP1, TNC, SCG2, FAM20A, and CD52 were identified as hub genes, and their expression levels in calcified or normal aortic valve samples were illustrated, respectively. CONCLUSIONS: This study suggested that SPP1, TNC, SCG2, FAM20A, and CD52 might be hub genes associated with CAVD. Further studies are required to elucidate the underlying mechanisms and provide potential therapeutic targets.

The application of deep learning in electrocardiogram: Where we came from and where we should go?

Electrocardiogram (ECG) is a commonly-used, non-invasive examination recording cardiac voltage versus time traces over a period. Deep learning technology, a robust artificial intelligence algorithm, can imitate the data processing patterns of the human brain, and it has experienced remarkable success in disease screening, diagnosis, and prediction. Compared with traditional machine learning, deep learning algorithms possess more powerful learning capabilities and can automatically extract features without extensive data pre-processing or hand-crafted feature extraction, which makes it a suitable tool to analyze complex structures of high-dimensional data. With the advances in computing power and digitized data availability, deep learning provides us an opportunity to improve ECG data interpretation with higher efficacy and accuracy and, more importantly, expand the original functions of ECG. The application of deep learning has led us to stand at the edge of ECG innovation and will potentially change the current clinical monitoring and management strategies. In this review, we introduce deep learning technology and summarize its advantages compared with traditional machine learning algorithms. Moreover, we provide an overview on the current application of deep learning in ECGs, with a focus on arrhythmia (especially atrial fibrillation during normal sinus rhythm), cardiac dysfunction, electrolyte imbalance, and sleep apnea. Last but not least, we discuss the current challenges and prospect directions for the following studies.

The Safety and Efficacy of Rivaroxaban Compared with Warfarin in Patients with Atrial Fibrillation and Diabetes: A Systematic Review and Meta-analysis.

AIMS: This meta-analysis was conducted to compare the efficacy and safety of rivaroxaban with warfarin in patients with atrial fibrillation (AF) and diabetes mellitus. METHODS: PubMed, Embase, Cochrane Library, and Web of Science databases were systematically searched from the establishment of databases up to 15 October 2019. Studies on efficacy and safety outcomes of rivaroxaban and warfarin were included. Efficacy and safety outcomes, including stroke, ischemic stroke, stroke or systemic embolism, myocardial infarction, major adverse cardiac events, major bleeding, intracranial hemorrhage, and major gastrointestinal bleeding were collected for meta-analysis. RESULTS: Compared with warfarin, rivaroxaban could significantly reduce stroke (risk ratio [RR] 0.77; 95% confidence interval [CI] 0.63-0.95; P = 0.01), ischemic stroke (RR 0.74; 95% CI 0.63-0.87; P = 0.0004), stroke or systemic embolism (RR 0.73; 95% CI 0.60-0.89; P = 0.002), myocardial infarction (RR 0.68; 95% CI 0.56-0.82; P < 0.0001), and major adverse cardiac events (RR 0.71; 95% CI 0.53-0.94; P = 0.02) in patients with AF and diabetes. Moreover, rivaroxaban was associated with a lower risk of major bleeding (RR 0.79; 95% CI 0.65-0.96; P = 0.02), intracranial hemorrhage (RR 0.52; 95% CI 0.39-0.69; P < 0.00001), and major gastrointestinal bleeding (RR 0.74; 95% CI 0.56-0.98; P = 0.04). Similar results were obtained in stratified meta-analysis of cohort studies. CONCLUSION: Our study suggests a favorable risk-benefit profile of rivaroxaban, with superior efficacy and safety over warfarin in patients with AF and diabetes.

Epigenetic role of N6-methyladenosine (m6A) RNA methylation in the cardiovascular system.

As the most prevalent and abundant transcriptional modification in the eukaryotic genome, the continuous and dynamic regulation of N6-methyladenosine (m6A) has been shown to play a vital role in physiological and pathological processes of cardiovascular diseases (CVDs), such as ischemic heart failure (HF), myocardial hypertrophy, myocardial infarction (MI), and cardiomyogenesis. Regulation is achieved by modulating the expression of m6A enzymes and their downstream cardiac genes. In addition, this process has a major impact on different aspects of internal biological metabolism and several other external environmental effects associated with the development of CVDs. However, the exact molecular mechanism of m6A epigenetic regulation has not been fully elucidated. In this review, we outline recent advances and discuss potential therapeutic strategies for managing m6A in relation to several common CVD-related metabolic disorders and external environmental factors. Note that an appropriate understanding of the biological function of m6A in the cardiovascular system will pave the way towards exploring the mechanisms responsible for the development of other CVDs and their associated symptoms. Finally, it can provide new insights for the development of novel therapeutic agents for use in clinical practice.

Shenfu injection attenuates lipopolysaccharide-induced myocardial inflammation and apoptosis in rats.

Shenfu injection (SFI), a Chinese medicinal product, shows potent efficacy in treating sepsis. The aim of the present study was to clarify the protective effects of SFI against lipopolysaccharide (LPS)-induced myocardial inflammation and apoptosis. Experiments were carried out in Sprague-Dawley (SD) rats treated with LPS or LPS + SFI, and in H9C2 cardiomyocytes. The sepsis-associated myocardial inflammation and apoptosis was induced by the intraperitoneal injection of LPS (20 mg·kg-1). SFI attenuated the increased expression of tumor necrosis factor (TNF)-α and interleukin (IL)-1ß induced by LPS both in serum and heart. In LPS group, cell viability was reduced, and reversed after SFI administration. LPS treatment increased the expression levels of cleaved-caspase 3 and Bax, and those of Bcl2 and Bcl2/Bax. These two trends were reversed by SFI administration. The expression levels of phosphorylated mitogen-activated protein kinase kinase (p-MEK) and phosphorylated extracellular regulated protein kinases (p-ERK) were increased by LPS, and reversed by SFI. MEK inhibitor U0126 attenuated the apoptosis induced by LPS. These results indicate that SFI could treat LPS-induced cardiac dysfunction. In conclusion, SFI attenuates the inflammation and apoptosis induced by LPS via downregulating the MEK and ERK signaling pathways.