Optimized new Shengmai powder inhibits myocardial fibrosis in heart failure by regulating the rat sarcoma/rapidly accelerated fibrosarcoma/mitogen-activated protein kinase kinase/extracellular regulated protein kinases signaling pathway.

OBJECTIVE: Exploring the effect of Optimized New Shengmai powder (, ONSMP) on myocardial fibrosis in heart failure (HF) based on rat sarcoma (RAS)/rapidly accelerated fibrosarcoma (RAF)/mitogen-activated protein kinase kinase (MEK)/extracellular regulated protein kinases (ERK) signaling pathway. METHODS: Randomized 70 Sprague-Dawley rats into sham (n = 10) and operation (n = 60) groups, then established the HF rat by ligating the left anterior descending branch of the coronary artery. We randomly divided the operation group rats into the model, ONSMP [including low (L), medium (M), and high (H) dose], and enalapril groups. After the 4-week drug intervention, echocardiography examines the cardiac function and calculates the ratios of the whole/left heart to the rat's body weight. Finally, we observed the degree of myocardial fibrosis by pathological sections, determined myocardium collagen (COL) I and COL Ⅲ content by enzyme-linked immunosorbent assay, detected the mRNA levels of COL I, COL Ⅲ, α-smooth muscle actin (α-SMA), and c-Fos proto-oncogene (c-Fos) by universal real-time, and detected the protein expression of p-RAS, p-RAF, p-MEK1/2, p-ERK1/2, p-ETS-like-1 transcription factor (p-ELK1), p-c-Fos, α-SMA, COL I, and COL Ⅲ by Western blot. RESULTS: ONSMP can effectively improve HF rat's cardiac function, decrease cardiac organ coefficient, COL volume fraction, and COL I/Ⅲ content, down-regulate the mRNA of COL I/Ⅲ, α-SMA and c-Fos, and the protein of p-RAS, p-RAF, p-MEK1/ 2, p-ERK1/2, p-ELK1, c-Fos, COL Ⅰ/Ⅲ, and α-SMA. CONCLUSIONS: ONSMP can effectively reduce myocardial fibrosis in HF rats, and the mechanism may be related to the inhibition of the RAS/RAF/MEK/ERK signaling pathway.

Genetic associations between Rapid Eye Movement (REM) sleep behavior disorder and cardiovascular diseases.

BACKGROUND: Previous studies revealed that sleep disorders are potential risk factors for cardiovascular diseases, such as obstructive sleep apnea and rapid eye movement (REM) sleep behavior disorder (RBD). However, the causal associations between RBD and cardiovascular diseases remained unknown. MATERIALS AND METHODS: We used the latest and largest summary-level genome-wide association studies of RBD, stroke and its subtypes, coronary artery disease (CAD), myocardial infarction (MI), and heart failure (HF) to select genetic variants as the instrumental variables. Mendelian randomization (MR) analysis was performed to test the causal associations between RBD and the cardiovascular diseases above. Inverse variance weighted method was used as the main analysis. RESULTS: After multiple comparisons, genetically predicted RBD was significantly associated with the risk of HF [odds ratio (OR) = 1.033, 95% CI 1.013-1.052, p = 0.001]. Leave-one-out analysis further supported the robustness of the causal association. Furthermore, we identified a suggestive association between genetically predicted MI and RBD (OR = 0.716, 95% CI 0.546-0.940, p = 0.016). However, in our study no associations were identified of RBD with CAD or stroke and its subtypes. CONCLUSION: Our study highlighted the potential associations between RBD and cardiovascular diseases at genetic level, including HF and MI. More studies were required to clarify the biological mechanisms involved the associations.

A combined observational and Mendelian randomization investigation reveals NMR-measured analytes to be risk factors of major cardiovascular diseases.

Dyslipidaemias is the leading risk factor of several major cardiovascular diseases (CVDs), but there is still a lack of sufficient evidence supporting a causal role of lipoprotein subspecies in CVDs. In this study, we comprehensively investigated several lipoproteins and their subspecies, as well as other metabolites, in relation to coronary heart disease (CHD), heart failure (HF) and ischemic stroke (IS) longitudinally and by Mendelian randomization (MR) leveraging NMR-measured metabolomic data from 118,012 UK Biobank participants. We found that 123, 110 and 36 analytes were longitudinally associated with myocardial infarction, HF and IS (FDR < 0.05), respectively, and 25 of those were associated with all three outcomes. MR analysis suggested that genetically predicted levels of 70, 58 and 7 analytes were associated with CHD, HF and IS (FDR < 0.05), respectively. Two analytes, ApoB/ApoA1 and M-HDL-C were associated with all three CVD outcomes in the MR analyses, and the results for M-HDL-C were concordant in both observational and MR analyses. Our results implied that the apoB/apoA1 ratio and cholesterol in medium size HDL were particularly of importance to understand the shared pathophysiology of CHD, HF and IS and thus should be further investigated for the prevention of all three CVDs.

Upregulated dual oxidase 1-induced oxidative stress and caspase-1-dependent pyroptosis reflect the etiologies of heart failure.

BACKGROUND: Oxidative stress is implicated in the pathogenesis of heart failure. Dual oxidase 1 (DUOX1) might be important in heart failure development through its mediating role in oxidative stress. This study was designed to evaluate the potential role of DUOX1 in heart failure. MATERIALS AND METHODS: AC16 cells were treated with 2 µmol/L of doxorubicin (DOX) for 12, 24, and 48 h to construct a heart failure model. DUOX1 overexpression and silencing in AC16 cell were established. DUOX1 expression was detected by Quantitative real-time polymerase chain reaction (qRT-PCR) and western blot. Pyroptosis and reactive oxygen species (ROS) production were measured by flow cytometry. RESULTS: Increased DUOX1 expression levels were observed after DOX treatment for 24 h in AC16 cells. DUOX1 silencing inhibited DOX-induced pyroptosis and ROS production. The release of IL-1ß, IL-18, and lactate dehydrogenase (LDH), and expression levels of pyroptosis-related proteins were also decreased. DUOX1 overexpression increased pyroptosis, ROS production, IL-1ß, IL-18, and LDH release, and pyroptosis-related protein expression. N-acetyl-cysteine (NAC) significantly reversed DUOX1-induced pyroptosis, ROS, and related factors. CONCLUSION: These results suggest that DUOX1-derived genotoxicity could promote heart failure development. In the process, oxidative stress and pyroptosis may be involved in the regulation of DUOX1 in heart failure.

miR-200b-3p relieved inflammation in patients with heart failure by regulating ZEB1 expression.

BACKGROUND: MicroRNA-200b-3p (miR-200b-3p) plays a pivotal role in inflammatory responses and is implicated in various inflammatory disorders. In this study, we aim to explore the role of miR-200b-3p in the inflammatory response in heart failure (HF). METHODS: Patients diagnosed with heart failure and age-matched healthy controls were studied. Peripheral blood samples from participants were collected for RNA-seq analysis to explore the expression profile of miR-200b-3p. The predictive value of miR-200b-3p and ZEB1 in the prognosis of heart failure was evaluated by analyzing the receiver operating characteristic (ROC) curve. Bioinformatics analysis and double luciferase reporter gene analysis were used to confirm the interaction between miR-200b-3p and ZEB1. Real-time quantitative polymerase chain reaction (QRT-PCR) was used to detect the expression levels of miR-200b-3p and ZEB1 in cardiopulmonary bypass. Additionally, the effects of miR-200b-3p on myocardial cell line (H9c2) injury were evaluated by enzyme-linked immunosorbent assay (ELISA). RESULTS: In the extracardiac circulation of HF patients, miR-200b-3p expression was significantly reduced, while ZEB1 levels were notably elevated. Analysis of the ROC curve revealed that miR-200b-3p and ZEB1 have predictive value in the prognosis of HF patients. The double luciferase reporter experiment demonstrated that miR-200b-3p binds to ZEB1 and inhibits its expression. Overexpression of miR-200b-3p demonstrated a remarkable ability to alleviate inflammation and inhibit the damage to myocardial cells in vivo. CONCLUSION: MiR-200b-3p can target and inhibit ZEB1, reducing the inflammatory reaction of myocardial cells. The miR-200b-3p/ZEB1 network may be helpful in preventing and treating HF.

Relationship Between Genotype Status and Clinical Outcome in Hypertrophic Cardiomyopathy.

BACKGROUND: The genetic basis of hypertrophic cardiomyopathy (HCM) is complex, and the relationship between genotype status and clinical outcome is incompletely resolved. METHODS AND RESULTS: We assessed a large international HCM cohort to define in contemporary terms natural history and clinical consequences of genotype. Consecutive patients (n=1468) with established HCM diagnosis underwent genetic testing. Patients with pathogenic (or likely pathogenic) variants were considered genotype positive (G+; n=312; 21%); those without definite disease-causing mutations (n=651; 44%) or variants of uncertain significance (n=505; 35%) were considered genotype negative (G-). Patients were followed up for a median of 7.8 years (interquartile range, 3.5-13.4 years); HCM end points were examined by cumulative event incidence. Over follow-up, 135 (9%) patients died, 33 from a variety of HCM-related causes. After adjusting for age, all-cause and HCM-related mortality did not differ between G- versus G+ patients (hazard ratio [HR], 0.78 [95% CI, 0.46-1.31]; P=0.37; HR, 0.93 [95% CI, 0.38-2.30]; P=0.87, respectively). Adverse event rates, including heart failure progression to class III/IV, heart transplant, or heart failure death, did not differ (G- versus G+) when adjusted for age (HR, 1.20 [95% CI, 0.63-2.26]; P=0.58), nor was genotype independently associated with sudden death event risk (HR, 1.39 [95% CI, 0.88-2.21]; P=0.16). In multivariable analysis, age was the only independent predictor of all-cause and HCM-related mortality, heart failure progression, and sudden death events. CONCLUSIONS: In this large consecutive cohort of patients with HCM, genotype (G+ or G-) was not a predictor of clinical course, including all-cause and HCM-related mortality and risk for heart failure progression or sudden death. G+ status should not be used to dictate clinical management or predict outcome in HCM.

Circular RNAs: a small piece in the heart failure puzzle.

Cardiovascular disease, specifically heart failure (HF), remains a significant concern in the realm of healthcare, necessitating the development of new treatments and biomarkers. The RNA family consists of various subgroups, including microRNAs, PIWI-interacting RNAs (piRAN) and long non-coding RNAs, which have shown potential in advancing personalized healthcare for HF patients. Recent research suggests that circular RNAs, a lesser-known subgroup of RNAs, may offer a novel set of targets and biomarkers for HF. This review will discuss the biogenesis of circular RNAs, their unique characteristics relevant to HF, their role in heart function, and their potential use as biomarkers in the bloodstream. Furthermore, future research directions in this field will be outlined. The stability of exosomal circRNAs makes them suitable as biomarkers, pathogenic regulators, and potential treatments for cardiovascular diseases such as atherosclerosis, acute coronary syndrome, ischemia/reperfusion injury, HF, and peripheral artery disease. Herein, we summarized the role of circular RNAs and their exosomal forms in HF diseases.

Associations between varicose veins and heart failure: A genetic correlation and mendelian randomization study.

Varicose veins and heart failure (HF) are increasingly prevalent. Although numbers of observational studies have indicated that varicose veins might contribute to the risk of HF, the causal relationship between them remains unclear due to the uncontrolled confounding factors and reverse causation bias. Therefore, this study aimed to explore the potential causal relationship between varicose veins and HF. Based on publicly released genome-wide association studies (GWAS), gene correlation was assessed using linkage disequilibrium score (LDSC) regression, and we conducted a two-sample Mendelian randomization (TSMR) analysis to infer the causal relationship. We performed the Inverse variance weighted (IVW) method as the primary analysis, and used Weighted median, MR-Egger, weighted mode, simple mode, and MR-pleiotropy residual sum and outlier (MR-PRESSO) methods to detect and correct for horizontal pleiotropy. LDSC revealed there was a positive genetic correlation between varicose veins and HF (rg = 0.1726184, Se = 0.04511803, P = .0001). The results of the IVW method indicated that genetically predicted varicose veins were associated with an increased risk of HF (odds ratio (OR) = 1.03; 95% confidence interval (CI): 1.01-1.06; P = .009). Our findings illustrated the significant causal effect of varicose veins on HF, suggesting that people with varicose veins might have a higher risk of HF. The results provided a novel and important perspective into the development mechanism of HF.

Improved integration of single-cell transcriptome data demonstrates common and unique signatures of heart failure in mice and humans.

BACKGROUND: Cardiovascular research heavily relies on mouse (Mus musculus) models to study disease mechanisms and to test novel biomarkers and medications. Yet, applying these results to patients remains a major challenge and often results in noneffective drugs. Therefore, it is an open challenge of translational science to develop models with high similarities and predictive value. This requires a comparison of disease models in mice with diseased tissue derived from humans. RESULTS: To compare the transcriptional signatures at single-cell resolution, we implemented an integration pipeline called OrthoIntegrate, which uniquely assigns orthologs and therewith merges single-cell RNA sequencing (scRNA-seq) RNA of different species. The pipeline has been designed to be as easy to use and is fully integrable in the standard Seurat workflow.We applied OrthoIntegrate on scRNA-seq from cardiac tissue of heart failure patients with reduced ejection fraction (HFrEF) and scRNA-seq from the mice after chronic infarction, which is a commonly used mouse model to mimic HFrEF. We discovered shared and distinct regulatory pathways between human HFrEF patients and the corresponding mouse model. Overall, 54% of genes were commonly regulated, including major changes in cardiomyocyte energy metabolism. However, several regulatory pathways (e.g., angiogenesis) were specifically regulated in humans. CONCLUSIONS: The demonstration of unique pathways occurring in humans indicates limitations on the comparability between mice models and human HFrEF and shows that results from the mice model should be validated carefully. OrthoIntegrate is publicly accessible (https://github.com/MarianoRuzJurado/OrthoIntegrate) and can be used to integrate other large datasets to provide a general comparison of models with patient data.

[Acute heart failure in a neonate]. / æ–°ç”Ÿå„¿æ€¥æ€§å¿ƒåŠŸèƒ½ä¸å ¨1例.

The male patient, one day old, was admitted to the hospital due to hypoglycemia accompanied by apnea appearing six hours after birth. The patient had transient hypoglycemia early after birth, and acute heart failure suddenly occurred on the eighth day after birth. Laboratory tests showed significantly reduced levels of adrenocorticotropic hormone and cortisol, and pituitary magnetic resonance imaging was normal. Genetic testing results showed that the patient had probably pathogenic compound heterozygous mutations of the TBX19 gene (c.917-2A>G+c.608C>T), inherited respectively from the parents. The patient was conclusively diagnosed with congenital isolated adrenocorticotropic hormone deficiency caused by mutation of the TBX19 gene. Upon initiating hydrocortisone replacement therapy, cardiac function rapidly returned to normal. After being discharged, the patient continued with the hydrocortisone replacement therapy. By the 18-month follow-up, the patient was growing and developing well. In neonates, unexplained acute heart failure requires caution for possible endocrine hereditary metabolic diseases, and timely cortisol testing and genetic testing should be conducted.

Familial dilated cardiomyopathy in a child: a case report.

BACKGROUND: Dilated cardiomyopathy (DCM) commonly leads to heart failure (HF) and represents the most common indication for cardiac transplantation in the pediatric population. Clinical manifestations of DCM are mainly the symptoms of heart failure; it is diagnosed by EKG, chest x-ray and echocardiography. For the idiopathic and familial diseases cases of DCM, there are no definite guidelines for treatment in children as they are treated for prognostic improvement. CASE PRESENTATION: We report the case of a 2-year-old girl diagnosed with dilated cardiomyopathy associated with homozygous mutation in the Myosin Light Chain 3 gene admitted for edema in lower extremities, muscle weakness, lethargy and vomiting, and she was found to be in cardiogenic shock. Chest x-ray showed cardiomegaly and EKG showed first degree atrioventricular block. Echocardiogram showed severe biventricular systolic and diastolic dysfunction. After 70 days of hospitalization, the patient went into cardiac arrest with cessation of electrical and mechanical activity of the heart, despite cardiopulmonary resuscitative efforts. CONCLUSION: Although rare, pediatric DCM carries a high risk of morbidity and mortality and a lack of curative therapy.

Statins improve cardiac endothelial function to prevent heart failure with preserved ejection fraction through upregulating circRNA-RBCK1.

Heart failure with preserved ejection fraction (HFpEF) is associated with endothelial dysfunction. We have previously reported that statins prevent endothelial dysfunction through inhibition of microRNA-133a (miR-133a). This study is to investigate the effects and the underlying mechanisms of statins on HFpEF. Here, we show that statins upregulate the expression of a circular RNA (circRNA-RBCK1) which is co-transcripted with the ring-B-box-coiled-coil protein interacting with protein kinase C-1 (RBCK1) gene. Simultaneously, statins increase activator protein 2 alpha (AP-2α) transcriptional activity and the interaction between circRNA-RBCK1 and miR-133a. Furthermore, AP-2α directly interacts with RBCK1 gene promoter in endothelial cells. In vivo, lovastatin improves diastolic function in male mice under HFpEF, which is abolished by loss function of endothelial AP-2α or circRNA-RBCK1. This study suggests that statins upregulate the AP-2α/circRNA-RBCK1 signaling to suppress miR-133a in cardiac endothelial cells and prevent diastolic dysfunction in HFpEF.

HAPLN1 knockdown inhibits heart failure development via activating the PKA signaling pathway.

BACKGROUND: Heart failure (HF) is a heterogeneous syndrome that affects millions worldwide, resulting in substantial health and economic burdens. However, the molecular mechanism of HF pathogenesis remains unclear. METHODS: HF-related key genes were screened by a bioinformatics approach.The impacts of HAPLN1 knockdown on Angiotensin II (Ang II)-induced AC16 cells were assessed through a series of cell function experiments. Enzyme-linked immunosorbent assay (ELISA) was used to measure levels of oxidative stress and apoptosis-related factors. The HF rat model was induced by subcutaneous injection isoprenaline and histopathologic changes in the cardiac tissue were assessed by hematoxylin and eosin (HE) staining and echocardiographic index. Downstream pathways regulated by HAPLN1 was predicted through bioinformatics and then confirmed in vivo and in vitro by western blot. RESULTS: Six hub genes were screened, of which HAPLN1, FMOD, NPPB, NPPA, and COMP were overexpressed, whereas NPPC was downregulated in HF. Further research found that silencing HAPLN1 promoted cell viability and reduced apoptosis in Ang II-induced AC16 cells. HAPLN1 knockdown promoted left ventricular ejection fraction (LVEF) and left ventricular fraction shortening (LVFS), while decreasing left ventricular end-systolic volume (LVESV) in the HF rat model. HAPLN1 knockdown promoted the levels of GSH and suppressed the levels of MDA, LDH, TNF-α, and IL-6. Mechanistically, silencing HAPLN1 activated the PKA pathway, which were confirmed both in vivo and in vitro. CONCLUSION: HAPLN1 knockdown inhibited the progression of HF by activating the PKA pathway, which may provide novel perspectives on the management of HF.

Single-cell transcriptomics in MI identify Slc25a4 as a new modulator of mitochondrial malfunction and apoptosis-associated cardiomyocyte subcluster.

Myocardial infarction (MI) is the leading cause of premature death. The death of cardiomyocytes (CMs) and the dysfunction of the remaining viable CMs are the main pathological factors contributing to heart failure (HF) following MI. This study aims to determine the transcriptional profile of CMs and investigate the heterogeneity among CMs under hypoxic conditions. Single-cell atlases of the heart in both the sham and MI groups were developed using single-cell data (GSE214611) downloaded from Gene Expression Omnibus (GEO) database ( https://www.ncbi.nlm.nih.gov/geo/ ). The heterogeneity among CMs was explored through various analyses including enrichment, pseudo time, and intercellular communication analysis. The marker gene of C5 was identified using differential expression analysis (DEA). Real-time polymerase chain reaction (RT-PCR), bulk RNA-sequencing dataset analysis, western blotting, immunohistochemical and immunofluorescence staining, Mito-Tracker staining, TUNEL staining, and flow cytometry analysis were conducted to validate the impact of the marker gene on mitochondrial function and cell apoptosis of CMs under hypoxic conditions. We identified a cell subcluster named C5 that exhibited a close association with mitochondrial malfunction and cellular apoptosis characteristics, and identified Slc25a4 as a significant biomarker of C5. Furthermore, our findings indicated that the expression of Slc25a4 was increased in failing hearts, and the downregulation of Slc25a4 improved mitochondrial function and reduced cell apoptosis. Our study significantly identified a distinct subcluster of CMs that exhibited strong associations with ventricular remodeling following MI. Slc25a4 served as the hub gene for C5, highlighting its significant potential as a novel therapeutic target for MI.

A Meta-Analysis Approach to Gene Regulatory Network Inference Identifies Key Regulators of Cardiovascular Diseases.

Cardiovascular diseases (CVDs) represent a major concern for global health, whose mechanistic understanding is complicated by a complex interplay between genetic predisposition and environmental factors. Specifically, heart failure (HF), encompassing dilated cardiomyopathy (DC), ischemic cardiomyopathy (ICM), and hypertrophic cardiomyopathy (HCM), is a topic of substantial interest in basic and clinical research. Here, we used a Partial Correlation Coefficient-based algorithm (PCC) within the context of a meta-analysis framework to construct a Gene Regulatory Network (GRN) that identifies key regulators whose activity is perturbed in Heart Failure. By integrating data from multiple independent studies, our approach unveiled crucial regulatory associations between transcription factors (TFs) and structural genes, emphasizing their pivotal roles in regulating metabolic pathways, such as fatty acid metabolism, oxidative stress response, epithelial-to-mesenchymal transition, and coagulation. In addition to known associations, our analysis also identified novel regulators, including the identification of TFs FPM315 and OVOL2, which are implicated in dilated cardiomyopathies, and TEAD1 and TEAD2 in both dilated and ischemic cardiomyopathies. Moreover, we uncovered alterations in adipogenesis and oxidative phosphorylation pathways in hypertrophic cardiomyopathy and discovered a role for IL2 STAT5 signaling in heart failure. Our findings underscore the importance of TF activity in the initiation and progression of cardiac disease, highlighting their potential as pharmacological targets.

Cardiomyocyte-specific deletion of the mitochondrial transporter Abcb10 causes cardiac dysfunction via lysosomal-mediated ferroptosis.

Heart function is highly dependent on mitochondria, which not only produce energy but also regulate many cellular functions. Therefore, mitochondria are important therapeutic targets in heart failure. Abcb10 is a member of the ABC transporter superfamily located in the inner mitochondrial membrane and plays an important role in haemoglobin synthesis, biliverdin transport, antioxidant stress, and stabilization of the iron transporter mitoferrin-1. However, the mechanisms underlying the impairment of mitochondrial transporters in the heart remain poorly understood. Here, we generated mice with cardiomyocyte-specific loss of Abcb10. The Abcb10 knockouts exhibited progressive worsening of cardiac fibrosis, increased cardiovascular risk markers and mitochondrial structural abnormalities, suggesting that the pathology of heart failure is related to mitochondrial dysfunction. As the mitochondrial dysfunction was observed early but mildly, other factors were considered. We then observed increased Hif1α expression, decreased NAD synthase expression, and reduced NAD+ levels, leading to lysosomal dysfunction. Analysis of ABCB10 knockdown HeLa cells revealed accumulation of Fe2+ and lipid peroxides in lysosomes, leading to ferroptosis. Lipid peroxidation was suppressed by treatment with iron chelators, suggesting that lysosomal iron accumulation is involved in ferroptosis. We also observed that Abcb10 knockout cardiomyocytes exhibited increased ROS production, iron accumulation, and lysosomal hypertrophy. Our findings suggest that Abcb10 is required for the maintenance of cardiac function and reveal a novel pathophysiology of chronic heart failure related to lysosomal function and ferroptosis.

Bi-directional association of body size and composition with heart failure: A Mendelian randomization study.

PURPOSE: The effect of obesity on the development of heart failure (HF) has received attention, and this study intends to further explore the bidirectional association between body size or composition and HF by using Mendelian Randomization (MR) approach. DESIGN: We performed a two-sample bidirectional MR study to investigate the association between body size or composition and the risk of HF using aggregated data from genome-wide association studies. Univariable MR analysis was used to investigate the causal relationship, and multivariable MR analysis was used to explore the mediating role of general and central obesity in the relationship between body size or composition and HF. RESULTS: This forward MR study found that body mass index (BMI), waist circumference (WC), waist-hip ratio (WHR), fat mass (FM) and fat-free mass (FFM) were risk factors for the development of HF with the strength of causal association BMI > FM > WC > FFM > WHR. After adjusting for BMI, the observed associations between the remaining indicators and heart failure attenuated to null. After adjusting for WC, only BMI (OR = 1.59, 95%CI: 1.32-1.92, P = 9.53E-07) and FM (OR = 1.39, 95%CI: 1.20-1.62, P = 1.35E-0.5) kept significantly related to the risk of HF. Reverse MR analysis showed no association of changes in body size or composition with the onset of HF. CONCLUSION: The two-sample bidirectional MR study found that general obesity, measured by BMI, was an independent indicator of the development of HF, while other related indicators were associated with HF incidence dependent on BMI, besides, no association was observed between HF diagnosis and the body size or composites.

Heart failure potentially affects the cortical structure of the brain.

BACKGROUND: Heart failure (HF) has been reported to affect cerebral cortex structure, but the underlying cause has not been determined. This study used Mendelian randomization (MR) to reveal the causal relationship between HF and structural changes in the cerebral cortex. METHODS: HF was defined as the exposure variable, and cerebral cortex structure was defined as the outcome variable. Inverse-variance weighted (IVW), MR-Egger regression and weighted median (WME) were performed for MR analysis; MR-PRESSO and Egger's intercept was used to test horizontal pleiotropy; and "leave-one-out" was used for sensitivity analysis. RESULTS: Fifty-two single nucleotide polymorphisms (SNPs) were defined as instrumental variables (IVs), and there was no horizontal pleiotropy in the IVs. According to the IVW analysis, the OR and 95% CI of cerebral cortex thickness were 0.9932 (0.9868-1.00) (P=0.0402), and the MR-Egger intercept was -15.6× 10-5 (P = 0.7974) and the Global test pval was 0.078. The P-value of the cerebral cortex surface was 0.2205, and the MR-Egger intercept was -34.69052 (P= 0.6984) and the Global Test pval was 0.045. HF had a causal effect on the surface area of the caudal middle frontal lobule (P=0.009), insula lobule (P=0.01), precuneus lobule (P=0.049) and superior parietal lobule (P=0.044). CONCLUSIONS: HF was potentially associated with changes in cortical thickness and in the surface area of the caudal middle frontal lobule, insula lobule, precuneus lobule and superior parietal lobule.

Large-scale cross-ancestry genome-wide meta-analysis of serum urate.

Hyperuricemia is an essential causal risk factor for gout and is associated with cardiometabolic diseases. Given the limited contribution of East Asian ancestry to genome-wide association studies of serum urate, the genetic architecture of serum urate requires exploration. A large-scale cross-ancestry genome-wide association meta-analysis of 1,029,323 individuals and ancestry-specific meta-analysis identifies a total of 351 loci, including 17 previously unreported loci. The genetic architecture of serum urate control is similar between European and East Asian populations. A transcriptome-wide association study, enrichment analysis, and colocalization analysis in relevant tissues identify candidate serum urate-associated genes, including CTBP1, SKIV2L, and WWP2. A phenome-wide association study using polygenic risk scores identifies serum urate-correlated diseases including heart failure and hypertension. Mendelian randomization and mediation analyses show that serum urate-associated genes might have a causal relationship with serum urate-correlated diseases via mediation effects. This study elucidates our understanding of the genetic architecture of serum urate control.