Inflammation plays a pivotal role in the pathogenesis of heart failure (HF). This study was aimed to the potential association between complete blood cell count (CBC)-derived inflammatory biomarkers and HF. Data from the National Health and Nutrition Examination Survey (NHANES) 2009-2018 were utilised. We evaluated the associations between HF and five systemic inflammation markers derived from CBC: systemic immune-inflammation index (SII), systemic inflammatory response index (SIRI), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and monocyte-to-lymphocyte ratio (MLR). Demographic characteristics, physical examinations, and laboratory data were systematically collected for comparative analysis between HF and non-HF individuals. Fitted smoothing curves and threshold effect analysis delineated the relationship. In addition, Spearman correlation and subgroup analyses were further conducted. A total of 26,021 participants were categorised into HF (n = 858) and non-HF (n = 25,163) groups. After adjusting for confounding variables, SIRI, NLR, and MLR had significant positive correlations with the risk of HF. Participants in the highest quarter groups of SIRI, NLR, and MLR showed a increased risk of developing HF compared to those in the lowest quarter group. Furthermore, subgroup and sensitivity analyses indicated that SIRI, NLR, and MLR had a stronger correlation to HF (all p < 0.05). Smoothing curve fitting highlighted a nonlinear relationship between CBC-derived inflammatory biomarkers and HF. Our results illustrated a significant association between elevated levels of SIRI, NLR, and MLR and an increased risk of HF. SIRI, NLR, and MLR could potentially serve as systemic inflammation hazard markers for HF.

Introduction: Eplerenone is approved for the treatment of hypertension as well as symptomatic heart failure with reduced ejection fraction (HFrEF) following an acute myocardial infarction. However, the adverse events (AEs) have not been systematically analyzed. The aim of this study was to identify adverse drug reactions (ADRs) related to eplerenone using the FDA Adverse Event Reporting System (FAERS) database. By identifying previously unreported AEs, the study could potentially contribute to updating the drug’s label.Methods: In order to find significant AEs, four algorithms, including Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN) and Empirical Bayesian Geometric Mean (EBGM), were used to analyze the signal strength of the ADRs connected to eplerenone that were gathered from the FAERS database over the previous 20 years.Results: From 2004Q1 to 2023Q4, a total of 20, 629, 811 reported cases were gathered from the FAERS database for this study. After processing the data and filtering, 1,874 case reports were analyzed. Of these cases, 1,070 AEs were identified, 128 of which were eplerenone-related ADRs. We investigated the occurrence of ADRs induced by eplerenone in 27 organ systems. Our study showed that the AEs listed in the medication’s package insert correspond with those listed in the literature, including hyperkalemia and increased creatinine. Additionally, the prescription label for eplerenone does not include all system organ class (SOC) terms, like Vascular disorders, hepatobiliary Disorders, etc.Discussion: The study used multiple algorithms to quantify the signal strength and then identified any previously unrecognized ADRs, further studies are needed to confirm the association of ADRs with eplerenone. The findings of this study may provide important insights into the safety profile of eplerenone, ensure that healthcare providers have up-to-date information about their potential risks and help guide them in the correct use of the drug.

Aims: Heart failure (HF) and non-alcoholic fatty liver disease (NAFLD) are significant global health issues with a complex interrelationship. This study investigates their shared biomarkers and causal relationships using bioinformatics and Mendelian randomization (MR) approaches. Methods: We analysed NAFLD and HF datasets from the Gene Expression Omnibus (GEO). The GSE126848 dataset included 57 liver biopsy samples [14 healthy individuals, 12 obese subjects, 15 NAFL patients and 16 non-alcoholic steatohepatitis (NASH) patients]. The GSE24807 dataset comprised 12 NASH samples and 5 healthy controls. The GSE57338 dataset included 313 cardiac muscle samples [177 HF patients (95 ischaemic heart disease patients and 82 idiopathic dilated cardiomyopathy patients) and 136 healthy controls]. The GSE84796 dataset consisted of 10 end-stage HF patients and 7 healthy hearts procured from organ donors. We identified differentially expressed genes (DEGs) and constructed a protein–protein interaction (PPI) network. Functional pathways were elucidated through enrichment analyses using Gene Ontology (GO), the Kyoto Encyclopedia of Genes and Genomes (KEGG) and GeneMANIA annotation. Single nucleotide polymorphism (SNP) data for HF and NAFLD were sourced from genome-wide association studies (GWAS). The HF dataset included 486 160 samples (14 262 experimental and 471 898 control), and the NAFLD dataset comprised 377 988 samples (4761 experimental and 373 227 control). MR analysis investigates the causal interrelations. Results: Our analysis revealed 4032 DEGs from GSE126848 and 286 DEGs from GSE57338. The top 10 hub genes (CD163, VSIG4, CXCL10, FCER1G, FPR1, C1QB, CCR1, C1orf162, MRC1 and CD38) were significantly enriched in immune response, calcium ion concentration regulation and positive regulation of monocyte chemotaxis. CIBERSORT analysis indicated associations between these hub genes and natural killer (NK) cells and macrophages. Transcription factor (TF) target prediction for CD38, CXCL10 and CCR1 highlighted related TFs. A two-sample MR analysis confirmed a bidirectional causal relationship between NAFLD and HF. The main method [inverse variance weighted (IVW)] demonstrated a significant positive causal relationship between NAFLD and HF [P = 0.037; odds ratio (OR) = 1.024; 95% confidence interval (CI): 1.001 to 1.048]. Similarly, HF was associated with an increase in the risk of NAFLD (P < 0.001; OR = 1.117; 95% CI: 1.053 to 1.185). Conclusions: Our findings reveal novel molecular signatures common to NAFLD and HF and confirm their bidirectional causality, highlighting the potential for targeted therapeutic interventions and prompting further investigation into their intricate relationship.

GLP-1 is a new type of antidiabetic agent that possesses many beneficial effects. Although its cardiovascular actions have been widely examined, little is known about GLP-1’s effects on the rat coronary artery (RCA) or about the mechanisms underpinning these effects. Here, we report that GLP-1 inhibits depolarization- or thromboxane receptor agonist (U46619)-induced RCA contraction in a dosage-dependent manner. Vasorelaxation was attenuated by denuding the endothelium, L-NAME (nitric oxide synthase inhibitor), and glyburide (K_ATP channel blocker) but was not affected by indomethacin (cyclooxygenase inhibitor), iberiotoxin [Ca²⁺-activated K⁺ channel (K_Ca) blocker], or 4-aminopyridine (K_V channel blocker). Furthermore, GLP-1 increased outward K⁺ currents by enhancing the K_ATP channel in rat coronary arterial smooth muscle cells (RCASMCs). These results show that GLP-1 is an endothelial-dependent vasospasmolytic agent in the RCA and imply that the relaxant effect is regulated by enhancing K_ATP rather than K_V or K_Ca currents in RCASMCs.

The AMP-activated protein kinase (AMPK) alpha (AMPKα) subunit is the catalytic subunit in the AMPK complex and includes both α1 and α2 isoforms. Phosphorylation of upstream kinases at the Thr172 site in the α-subunit is critical for AMPK activation. The kinases upstream of AMPK include liver kinase B1 (LKB1), calcium/calmodulin-dependent protein kinase kinase β (CaMKKβ), and transforming growth factor β-activated kinase 1 (TAK1). LKB1 predominantly regulates the AMPKα2 isoforms, whereas the phosphorylating roles of CaMKK and TAK1 in different isoforms of AMPKα have yet to be properly defined. Moreover, the understanding of the roles of AMPKα1 and α2 remains limited. Significant differences exist between the AMPKα1 and AMPKα2 isoforms regarding tissue distribution, cellular localization, and cardiac-unique roles, with AMPKα2 being the predominant catalytic isoform in the heart. During heart failure (HF), activated AMPKα isoforms, particularly AMPKα2, promote the remodeling of energy metabolism, ameliorate mitochondrial dysfunction, activate mitophagy, attenuate oxidative stress, and reduce cardiomyocyte death, thereby protecting cardiac function and delaying HF progression. Thus, drugs that selectively activate AMPK complexes containing specific α2 isoforms may help treat HF. However, AMPK activators are not currently very subtype-selective, direct agonists remain in clinical trials, and indirect agonists, although widely used in the clinic, have some non-AMPK-dependent effects. Therefore, a compelling need exists to develop subtype-selective activator drugs with greater specificity and efficacy and fewer side effects.