Inclisiran, the first small interfering RNA (siRNA) lipid lowering drug, has reported muscle adverse events (MAEs), but long-term safety is unclear. This study is based on data obtained from the Food and Drug Administration Adverse Event Reporting System (FAERS) database, covering the period from December 22, 2021, to December 31, 2024. MAEs signals of inclisiran were mined by calculating reporting odds ratios (ROR) and the Bayesian confidence propagation neural network (BCPNN). Stratification analysis, serious, and nonserious cases were compared, and signals were prioritized using a rating scale. In addition, we used Mendelian randomization (MR) to investigate the causal relationship between inclisiran and musculoskeletal system diseases. Among 4685 adverse event reports of inclisiran, 523 MAEs reports were found. Inclisiran has potential signals in terms of MAEs (ROR: 7.51, 95% CI, 6.86-8.23; IC: 2.75, IC 025 : 2.60). Inclisiran-related MAEs signal intensity was lower than statins (ROR: 0.40, 95% CI, 0.37-0.44), but higher than other PCSK9 inhibitors (ROR: 5.85, 95% CI, 5.26-6.50). Combination with statins/fibrates rarely increased MAE risk or signal strength. Notably, the signal between inclisiran and MAEs can still be detected when stratified by sex, age, reporter type, and serious report. Among the 7 PTs identified, muscle spasms and myalgia are of moderate clinical priority signals and should be given particular attention. MR analysis further validated that inclisiran may be potentially associated with an increased risk of musculoskeletal system diseases. This study revealed that MAEs associated with inclisiran. Additional laboratory and clinical monitoring should be considered for patients taking inclisiran for timely diagnosis and management of MAEs.

Preeclampsia is a hypertensive disorder of pregnancy associated with substantial maternal morbidity and long-term cardiovascular risk, but the consistency of echocardiographic remodeling remains unclear. We conducted a mega-meta-analysis of left ventricular function and geometry, enabled by a large language model based suite of tools. A PROSPERO-registered review (CRD420251109103) searched PubMed, Scopus, and Embase without date limits. Synthesa AI screened more than 138,000 abstracts, extracted data, assessed risk of bias, and generated Bayesian analytic code, with all outputs validated by human reviewers. Seventy-five studies including met eligibility criteria. Preeclampsia was associated with a small but statistically significant reduction in ejection fraction (mean difference -0.87%, 95% CrI -1.58 to -0.16) and a clinically meaningful impairment in global longitudinal strain (-3.08%, 95% CrI -4.13 to -2.06). Left ventricular mass index was substantially higher in the preeclampsia group (+13.10 g/m 2 , 95% CrI 10.06 to 16.21), as was relative wall thickness (+0.062, 95% CrI 0.042 to 0.081), whereas fractional shortening showed no significant difference (-0.60%, 95% CrI -2.15 to +0.86). Moderator analyses revealed that BMI and parity significantly influenced strain, while gestational age at diagnosis accounted for nearly all variance in ventricular mass. This mega-meta-analysis defines a remodeling phenotype of preserved ejection fraction, impaired strain, and hypertrophic adaptation consistent with subclinical systolic dysfunction. Equally, it demonstrates the transformative role of LLM-based tools, showing that evidence syntheses of this magnitude can be automated, scaled, and standardized in ways previously unattainable.

Heart failure (HF), with varied symptoms caused by cardiac strain or damage, has high morbidity and mortality. Protein lactylation, a post-translational modification, regulates immune and cardiovascular processes, but its role in HF's immune microenvironment remains underexplored. Differentially expressed lactylation-related genes (LacRGs) were identified by intersecting HF differentially expressed genes with LacRG data sets. Unsupervised clustering categorized patients with HF into LacRG-based subgroups. An LacRG diagnostic model was developed to assess associations with immune cell infiltration, immunotherapy potential, and single-cell RNA sequencing expression patterns. HF mouse models were constructed and verified for LacRG expression. In 200 HF versus 166 non-HF samples, 38 differentially expressed LacRGs were identified, revealing distinct immune landscapes. Two LacRG clusters exhibited unique functional enrichment and immunologic features. A 14-gene LacRG signature distinguished HF from controls with high accuracy (area under the curve: 0.999, 1.000, 0.744). Single-cell RNA sequencing (GSE145154) revealed reduced lactylation scores in fibroblast, macrophage, T-cell, and NK-cell subsets in HF, alongside characterization of altered cellular subtypes and activated signaling pathways within these populations. External data sets (GSE46224, GSE116250) identified 6 hub genes-HBB, EXT1, CENPA, NT5E, STAT4, and CAPN5, which were validated in HF mouse models. In addition, analysis of HF dataset further indicated higher LacRG scores in heart failure with preserved ejection fraction than in reduced ejection fraction. Lactylation modification is closely linked to HF's immune microenvironment. A 14-gene LacRG signature and 6 hub genes provide novel insights into HF pathophysiology and potential therapeutic avenues. Further studies are warranted to validate their regulatory roles in HF through immune microenvironmental mechanisms.

Although selective SGLT2 inhibitors improve heart failure (HF) outcomes, they do not consistently reduce atherothrombotic events (myocardial infarctions and strokes). Clinical trials with sotagliflozin, the first dual SGLT1/2 inhibitor, have shown significant reductions in both HF outcomes and atherothrombotic events: an effect not seen with highly selective SGLT2 inhibitors such as empagliflozin. This effect may be related to SGLT1 inhibition, because SGLT1 is widely expressed in the myocardium, platelets, and endothelial cells, suggesting a potential antithrombotic mechanism. The SOTA-THROMBOSIS trial is a randomized, cross-over study in healthy volunteers (n = 16) comparing the antithrombotic effects of dual SGLT1/2 inhibition with sotagliflozin and selective SGLT2 inhibition with empagliflozin. All participants will receive each treatment for 4 weeks, separated by a 1-month washout. Blood thrombogenicity under high and low shear rate conditions will be assessed using the Badimon perfusion chamber. Additional assessments include platelet aggregation (Multiplate Analyzer) and clot formation kinetics using thromboelastometry (RoTEM). Measurements will be performed at baseline (pretreatment) and at the end of each treatment period. The cross-over design-where each participant receives both study treatments and serves as his/her own control-significantly reduces both, intrasubject and intragroup variability. We hypothesize that both treatments will reduce blood thrombogenicity compared with baseline, with sotagliflozin offering a more marked antithrombotic effect than empagliflozin. This trial will provide novel mechanistic insights into the antithrombotic activity of SGLT1/2 inhibition. If confirmed, these findings may explain the additional cardiovascular protection observed with sotagliflozin and support its use in patients with HF at high thrombotic risk.

Cardiovascular diseases are life-threatening conditions with multifactorial causes. As the most abundant cells in the vascular wall, vascular smooth muscle cells (VSMCs) play a crucial role in regulating vascular tone. Under physiologic conditions, VSMCs predominantly demonstrate a contractile phenotype. However, this phenotype can be altered in response to microenvironmental stimuli, particularly during injury or pathologic conditions. We performed a systematic literature review to examine the phenotypic switching of VSMCs from a contractile state to a dedifferentiated state, and the role of senescence in VSMC dysfunction. Special attention was given to the impact of microenvironmental stress on VSMCs transdifferentiation into multiple phenotypes, including macrophage-like cells, foam cells, and mesenchymal stem cells. Prolonged or excessive phenotypic switching of VSMCs leads to cellular senescence, characterized by decreased proliferative capacity, increased secretion of inflammatory factors (senescence-associated secretory phenotype), and a tendency toward calcification. Senescent VSMCs undergo transdifferentiation into multiple phenotypes, which promote arterial calcification and fibrosis, thereby exacerbating cardiovascular disease progression. Emerging evidence reveals that VSMC phenotypic switching and senescence share common molecular pathways, offering new opportunities for developing dual-target therapies against age-related cardiovascular diseases by simultaneously modulating cellular plasticity and aging processes.

The global burden of mortality is largely attributable to cardiovascular diseases (CVDs), where altered metabolic homeostasis plays a critical role. The identification of lactylation as an epigenetic modification mediated by lactate has transformed the conventional view of this glycolysis byproduct from a mere metabolic intermediate to a multifaceted signaling molecule. This review comprehensively reveals the mechanistic insights underlying lactylation in CVDs, particularly in myocardial ischemia, atherosclerosis, and heart failure, highlighting its pivotal role in disease pathogenesis through modulation of transcriptional regulation, metabolic adaptation, and cellular differentiation. Considering the enzyme-regulated reversibility of lactylation, this work systematically evaluates its druggable targets, thereby establishing a conceptual foundation for combined metabolism-epigenetic therapeutics.

Berberine, the primary active compound in Coptis chinensis Franch, is well known for its anti-infective, hypoglycemic, lipid-lowering, antitumor, and anti-inflammatory effects. This review summarizes the physicochemical and pharmacokinetic characteristics of berberine, its intraintestinal pharmacology involving gut microbiota cross-talk to heart failure (gut-cardiac axis), extraintestinal pharmacology in heart failure, and network pharmacology. Berberine enhances the intestinal barrier, reducing endotoxin entry into the bloodstream. It also regulates the intestinal flora composition, notably altering the Bacillota/Bacteroidota ratio. Importantly, berberine promotes beneficial bacteria while inhibiting pathogenic bacteria. In addition, it influences gut microbiota metabolites, decreasing trimethylamine and trimethylamine N-oxide while increasing short-chain fatty acids. Berberine addresses extraintestinal direct mechanisms by mitigating heart failure risk factors such as atherosclerosis, hyperglycemia, and hyperlipidemia. It also decreases cardiac oxygen consumption, oxidative stress, and endoplasmic reticulum stress, thereby reducing chronic cardiac inflammation, apoptosis, and remodeling, while enhancing myocardial energy to improve cardiac function. Network pharmacology analysis has identified the top 10 hub genes for berberine in heart failure therapy: STAT3, TNF, MTOR, NFKB1, HIF1A, ESR1, BCL2, PTGS2, PPARG, and MMP9. Notably, TNF, HIF1A, and PPARG are key targets for berberine in heart failure with preserved ejection fraction treatment. Berberine shows promise for heart failure treatment, but its bioavailability needs improvement. In addition, the efficacy and safety of berberine in clinical heart failure management, especially in heart failure with preserved ejection fraction, require further evaluation through large-scale, multicenter clinical trials.