TL;DR
Insight is provided into metabolic heterogeneity in HF and OGDHL is identified as a potential regulator of cardiac metabolic remodeling, which was consistently downregulated in experimental HF models.
Introduction Cardiovascular–kidney–metabolic (CKM) syndrome represents an emerging systemic disorder characterized by intertwined metabolic dysfunction, chronic kidney disease, and cardiovascular injury, yet robust preclinical models and mechanistic insights remain limited. Methods Here, we established a progressive rat model of CKM syndrome by combining high-fat/high-sucrose exposure with adenine-induced renal stress, capturing temporal changes from early metabolic dysregulation to advanced multi-organ injury. Integrative multi-omics analyses incorporating network toxicology, single-cell RNA sequencing, and spatial transcriptomics were performed to investigate molecular features associated with CKM progression. Finally, AI-assisted virtual screening coupled with molecular docking was conducted to identify potential multi-target therapeutic candidates. Results Longitudinal phenotyping revealed a temporal pattern in which early metabolic abnormalities preceded more prominent renal and cardiovascular impairment. Integrative multi-omics analyses incorporating network toxicology, single-cell RNA sequencing, and spatial transcriptomics consistently converged on lipid metabolic dysregulation as a prominent molecular feature associated with CKM progression. PPARγ, ESR1, and FASN were identified as candidate regulatory nodes associated with CKM-related lipid remodeling. Single-cell analyses revealed enrichment of lipid metabolic programs in renal epithelial compartments, particularly proximal tubular cells, suggesting their potential involvement in CKM-associated renal metabolic remodeling. Spatial transcriptomics further revealed patterns consistent with ectopic adipocyte infiltration, lipid-associated niche remodeling, increased PPARγ/FASN expression, and reduced ESR1 expression in diseased kidneys. AI-assisted virtual screening coupled with molecular docking identified BRD-K26818574 as a potential multi-target therapeutic candidate. Discussion Collectively, this study establishes a translational CKM model and highlights renal lipotoxic remodeling as a potential therapeutic target in CKM progression.
To elucidate the molecular characteristics of synergistic interactions across the clinical stages of coronary heart disease (CHD)—specifically stable angina pectoris (SAP), unstable angina pectoris (UAP), and acute myocardial infarction (AMI)—through integrated metabolomic and proteomic analyses. Based on a cohort including SAP, UAP, AMI, and healthy controls, metabolomic and proteomic analyses were performed to identify differentially expressed molecules, followed by KEGG pathway enrichment analysis. Pathways co-enriched across both omics platforms were selected to construct metabolite-protein interaction networks. The number of pathways co-enriched in both metabolomic and proteomic analyses increased markedly with disease stage. Only two pathways (histidine metabolism and arginine and proline metabolism) were identified in the SAP stage; this number increased to five in the UAP stage (including ferroptosis and efferocytosis) and expanded to 25 in the AMI stage, encompassing three major functional modules: immune inflammation, metabolic reprogramming, and cell signaling. The core network exhibited a stepwise increase in connectivity, shifting from a sparse structure in the SAP stage to a highly interconnected architecture in the AMI stage, with L-glutamate and KNG1 identified as the central hubs in this cross-sectional network. In addition, CNDP1 exhibited a stage-dependent functional transition, shifting from downregulation in SAP to upregulation in AMI. In this cross-sectional analysis, metabolic dysregulation and immune activation exhibited stepwise increases in interconnectivity across the SAP, UAP, and AMI groups, with the most extensive crosstalk observed in the AMI stage—a network configuration consistent with a tightly coupled “molecular storm”. These findings provide novel insights into stage-associated molecular signatures of CHD and identify candidate hub molecules for stage-oriented therapeutic investigation.
Heart failure (HF) is a leading cause of morbidity and mortality. We conducted multi-ancestry genome-wide association studies of 345,687 HF cases (4,468,166 individuals), and 47,192 and 46,934 cases of HF with preserved (HFpEF) and reduced ejection fraction (HFrEF), respectively, integrating plasma proteomics and multi-tissue transcriptomics to identify druggable targets. Across HF, HFrEF, and HFpEF, we identified 383 loci (166 novel) and 568 genes (375 novel). Eleven novel genes are targets of approved or investigational cardiovascular therapies, supporting indication expansion of aldosterone synthase inhibitors (CYP11B2) and type-II activin receptor antagonists (ACVR2A) to HF. Six cardiomyopathy genes were novel for HF and associated with cardiac structure and function. We identified nearly 100 genes involved in food intake and energy expenditure; metabolism of fatty acids, glucose, and branched-chain amino acids; and mitochondrial proteome, sustaining myocardial energy production. Our findings highlight the primordial role of metabolic pathways and adipokines as therapeutic targets for HF management.
ARTICLE HIGHLIGHTS Previous studies have identified heterogeneity among prediabetes subgroups using clinical characteristics; however, biological and metabolic heterogeneity remains insufficiently captured. This study examined whether data-driven clustering based on metabolomic biomarkers could define distinct prediabetes subtypes with differential type 2 diabetes, cardiovascular disease, and chronic kidney disease risk. Using 16 metabolomic biomarkers, we identify three metabolically distinct clusters showing progressively higher risks of incident type 2 diabetes, cardiovascular disease, and chronic kidney disease. Differential diet-cluster associations across clusters were obtained, and Mendelian randomization supported potential causal roles for several metabolomic biomarkers. Metabolomics-based stratification may improve risk prevention and enable cluster-specific dietary interventions in prediabetes.
Background. Heart failure with preserved ejection fraction (HFpEF) accounts for more than half of heart failure cases and is characterized by substantial clinical and biological heterogeneity. Sex differences are central to HFpEF pathophysiology, yet current phenotyping approaches often aggregate women and men, potentially obscuring distinct molecular mechanisms of disease progression. Molecularly resolved, sex-specific stratification is therefore needed to identify divergent risk pathways and improve biological understanding of HFpEF heterogeneity. Methods. In 698 HFpEF participants from the prospective MyoVasc cohort (379 females, 319 males), we run separate analyses on sex-specific cohorts. For each cohort, we integrated 92 circulating proteins (Olink Inflammation panel) and 49 clinical variables using Similarity Network Fusion to construct sex-stratified patient-patient similarity networks. Spectral clustering identified sex-specific prognostic subgroups related to the primary endpoint, i.e. worsening of Heart Failure (WHF). XGBoost models characterizing cluster-defining features were validated in an independent cohort of 342 HFpEF patients from the Gutenberg Health Study (GHS; 194 females, 148 males). Results. Two clusters emerged in each sex, with high-risk and low-risk clusters, showing the difference in WHF risk (MyoVasc females: HR 2.45, 95% CI 1.32-4.54, p=0.005; males: HR 2.77, 95% CI 1.27-6.04, p=0.011; C-index 0.62-0.63). Kaplan-Meier analyses confirmed separation (p<0.02 females, p<0.01 males). Clusters were reproduced in GHS using MyoVasc-trained XGBoost (females p=0.0082, males p=0.037). Shared top-ranking features included VEGF-A, TNFRSF9, and TGF-. Females were characterized by inflammatory (CD40, HGF, TNF) and glycemic signatures, whereas males showed prominence of immune-regulatory markers (IL-10RB, PD-L1) and renal function indicators (eGFR, creatinine). Conclusions. Sex-stratified molecular-clinical networks define prognostically distinct HFpEF subgroups with robust external validation. Shared protein biomarkers alongside sex-specific drivers reveal complementary progression mechanisms, supporting precision medicine strategies targeting high-risk cluster patients in sex-specific manner.
Recent favourable clinical trials of sodium-glucose transporter 2 (SGLT2) inhibitors and glucagon-like-peptide-1 (GLP-1) agonists have substantially changed the management landscape for heart failure with preserved ejection fraction (HFpEF) patients. However, the organ-level metabolic mechanisms underpinning these benefits remain incompletely understood and it is unclear how these therapies reshape inter-organ metabolic crosstalk in HFpEF. In many patients, the HFpEF phenotype appears to result from an intersection between abnormal cardiovascular physiology together with metabolic and inflammatory changes. Experimental HFpEF was induced in 18-month-old female C57BL/6J mice with a high-fat diet for 12 weeks, an angiotensin II infusion beginning at week 6, with age-matched controls, to establish a cardiometabolic phenotype. Treatment with the SGLT2 inhibitor Dapagliflozin (Dapa) was administered for 6 weeks, concurrently with AngII administration. In addition to comprehensive cardiovascular and inflammatory phenotyping, we conducted metabolomic profiling of the heart, liver and plasma and performed 16S rRNA sequencing to characterise alterations in the gut microbiome. Characteristic cardiometabolic and inflammatory profiles were observed in experimental HFpEF, including obesity, hypertension, diastolic dysfunction, hepatic steatosis, and gut dysbiosis. Despite no detectable improvement in echocardiographic function at endpoint, Dapa induced distinct hepatic remodelling, with increased citraconate, restoration of succinate, modulation of branched-chain amino acid and ketone pathways and reduced oxidative stress markers. Aromatic amino acid metabolism and gut-derived metabolites were broadly disrupted across heart, liver, and plasma. HFpEF is defined by complex, tissue-specific metabolic derangements. SGLT2 inhibition primarily remodeled the hepatic metabolome, positioning the liver as a central hub of cardio-renal-liver crosstalk. These findings suggest that extra-cardiac metabolic pathways, particularly liver-centered mechanisms, may contribute to the therapeutic benefits of SGLT2 inhibitors in HFpEF and provide new insights into inter-organ metabolic regulation.