Xuewen Li

Obesity is a major and potentially modifiable risk factor for heart failure (HF); however, the biological mediators linking excess adiposity to adverse cardiac remodeling and HF progression remain incompletely defined. Among adipose‐derived factors, leptin has emerged as a candidate mediator because of its associations with neurohormonal activation, vascular dysfunction, inflammation, oxidative stress, and myocardial remodeling. This review synthesizes contemporary evidence regarding the role of leptin in the pathophysiology of obesity‐related heart failure and examines its clinical and translational ramifications. Data indicate that hyperleptinemia and leptin resistance may facilitate HF progression via interconnected mechanisms, including sympathetic nervous system activation, dysregulation of the renin–angiotensin–aldosterone system, endothelin‐1 and reactive oxygen species signaling, diminished nitric oxide bioavailability, endothelial dysfunction, and myocardial hypertrophy and fibrosis. These pathways may be particularly pertinent to obesity‐related HF phenotypes characterized by diastolic dysfunction and detrimental remodeling. Leptin may facilitate biomarker‐driven phenotyping and risk stratification, especially in obesity‐related heart failure with preserved ejection fraction (HFpEF). Nonetheless, the majority of mechanistic evidence is sourced from animal and cellular studies, with substantial human data still lacking. Taken together, current evidence supports leptin as a mechanistically informative biomarker candidate in obesity‐related HF, particularly HFpEF, rather than as an established causal mediator or therapeutic target.

Transient receptor potential (TRP) channels are non-selective cation channels with diverse physiological functions, widely expressed across various cell types. These channels play crucial roles in maintaining homeostasis and contribute to the progression of cardiovascular diseases, particularly atherosclerosis. Atherosclerosis is a chronic vascular inflammatory condition marked by lipid accumulation and fibrous tissue proliferation in the arterial intima. TRP channels regulate intracellular ionic gradients and activate downstream signaling pathways, thereby influencing the function of vascular endothelial and smooth muscle cells. Therefore, they are increasingly implicated in the pathogenesis of cardiovascular and cerebrovascular diseases. Emerging evidence has demonstrated that pharmacological modulation (antagonism or activation) of TRP channels regulates programmed cell death mechanisms, positioning these channels as key modulators of atherosclerotic plaque dynamics. Specifically, TRP channels modulate various cell death modalities, including apoptosis, autophagy, and necrosis, while also influencing inflammatory responses and oxidative stress-related pathways that potentiate cellular death. These interconnected mechanisms significantly contribute to the development of atherosclerotic lesions. This review systematically examined the mechanistic roles of TRP channels in atherosclerosis via regulation of cell death pathways, aiming to provide a comprehensive understanding of their pathophysiological functions and to support the development of targeted molecular therapies.

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.

Plaque destabilization and rupture are the primary triggers of acute coronary syndrome (ACS). Soluble growth stimulation expressed gene 2 (sST2) has been implicated in cardiovascular disease. We aimed to investigate the association between circulating sST2 levels and features of coronary plaque destabilization assessed by optical coherence tomography (OCT) in patients with unstable angina (UA). This study enrolled 122 patients admitted with UA and 107 age- and sex-matched healthy controls. All UA patients underwent standard coronary angiography and OCT imaging to identify features indicative of plaque destabilization. Plasma sST2 levels were measured in all participants using an immunofluorescence assay. Associations between sST2 levels, clinical characteristics, and factors predicting OCT-defined plaque destabilization were analyzed. sST2 levels were significantly higher in UA patients compared to healthy controls (p < 0.001). Among UA patients, sST2 levels were significantly elevated in those with OCT-defined plaque destabilization features compared to those without (p < 0.001). In multivariable logistic regression analysis, elevated sST2 levels emerged as an independent factor associated with the presence of OCT-defined plaque destabilization (p = 0.013). Circulating sST2 levels are elevated in UA patients and independently associated with features of coronary plaque destabilization identified by OCT. These findings suggest sST2 may be a novel biomarker reflecting plaque destabilization in patients with UA, potentially aiding in risk stratification.

Atrial fibrillation (AF) poses a serious health threat to human health and causes various adverse effects. It is currently the most common type of arrhythmia in adults. Long-term AF induces a series of heart-remodeling events, including mainly cardiac structural remodeling and electrical remodeling, which further exacerbates AF. The oxidative stress has been shown to play a role in inducing myocardial remodeling and the progression of AF. Recent studies have shown that ferroptosis occurs in the myocardium of patients with AF, which exacerbates oxidative stress and may constitute a new mechanism for the progression of AF. However, it is unknown to us how ferroptosis is involved in the initiation and maintenance of AF, so the purpose of this review is to elucidate the possible underlying mechanism of ferroptosis exacerbating AF. We reviewed the latest studies on myocardial ferroptosis and AF and speculate that the lipid peroxidation products isolevuglandins (IsoLGs), which are produced during myocardial ferroptosis, may be involved in the progression of AF through two pathways: (1) IsoLGs inhibit the degradation of myocardial collagen, worsening myocardial fibrosis; and (2) IsoLGs promote the occurrence of amyloidosis in the myocardium and increase the risk of AF. Consequently, we aim to prevent the progression of atrial fibrillation by either suppressing the production of IsoLGs or enhancing their clearance process to inhibit ferroptosis in the myocardium, improving the prognosis of patients with AF.

Background: This study evaluates changes in the burden of high body mass index (BMI) and its impact on atrial fibrillation and flutter (AF/AFL) using the 2021 Global Burden of Disease database. Methods: Mortality and disability-adjusted life years rates were analysed globally, considering age, sex, geography and the Socio-demographic Index (SDI). Decomposition and frontier analyses assessed the impact of epidemiological drivers and SDI on the burden. The nordpred model validated the predictions. Results: The burden of high BMI is now 2.5 times greater than 30 y ago and will continue to increase over the next 20 y, heavily impacting cardiovascular and metabolic diseases. High BMI–related AF/AFL also poses a significant burden, especially in developed regions. Men's burden grows faster than women's. Decomposition analysis shows epidemiological changes mainly drive burden increases, while in women, population growth is more significant. Frontier analysis indicates that the gap between actual burden and theoretical optimal value has widened with increasing SDI, except in countries such as Bulgaria and the Czech Republic. Conclusions: Over the past 30 y, the overall burden of high BMI and its impact on AF/AFL have increased significantly, highlighting the need for targeted public health strategies.

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.

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.