Circulating mediators linking cardiometabolic diseases to HFpEF: a mediation Mendelian randomization analysis

Abstract

Background: Heart failure with preserved ejection fraction (HFpEF) is an increasingly prevalent clinical syndrome with high morbidity and mortality. Although HFpEF frequently coexists with cardiometabolic diseases, the causal mechanisms and potential mediators remain poorly understood.

Objectives: This study aimed to identify cardiometabolic risk factors specifically driving HFpEF and to determine their underlying circulating mediators.

Methods: We used two-sample Mendelian Randomization (MR) to analyze the effects of obesity, Type 2 diabetes, hypertension, chronic kidney disease (CKD), and dyslipidemia on HFpEF and heart failure with reduced ejection fraction (HFrEF) in large European-ancestry GWAS datasets. We then performed mediation MR to identify plasma proteins and metabolites that mediate the transition from each cardiometabolic disease to HFpEF, respectively. We applied multivariable MR to assess the impact of risk confounding on the results. Bioinformatic analyses were conducted to delineate mechanisms.

Results: Cardiometabolic diseases had heterogeneous effects on HFpEF and HFrEF. Obesity and type 2 diabetes showed adjusted causal effects with HFpEF, hypertension showed potential relevance to HFpEF, whereas dyslipidemia and CKD did not. MR analysis identified 5 proteins that mediate obesity to HFpEF; 5 proteins that mediate type 2 diabetes to HFpEF. Further mediation MR analysis of obesity and T2D on HFrEF revealed heterogeneity in circulating mediators between metabolic HFpEF and HFrEF. Comprehensive bioinformatics analyses showed that IL1R1, together with other proteins such as TP53 and FGF19, orchestrates the inflammatory and fibrotic processes underlying HFpEF.

Conclusions: These findings suggest that metabolic HFpEF has distinct etiological features compared with HFrEF and is driven by complex, condition-specific mediators. IL1R1 mediates HFpEF in multiple metabolic risk states, suggesting a potential therapeutic target. Further translational studies are warranted to evaluate anti-inflammatory strategies targeting IL1R1 in HFpEF.

Keywords: Cardiometabolic diseases; Circulating mediators; HFpEF; IL1R1; Type 2 diabetes.

Fig. 1

Effects of cardiometabolic diseases on HFpEF and HFrEF IVW were used to investigate the association between cardiometabolic diseases and Heart failure. When the OR value is greater than 1, we believe that this exposure is acting as a risk factor and has a causal effect. If it is less than 1, it may act as a protective factor. BMI: body mass index; T2D: type 2 diabetes mellitus; HBP: high blood pressure; eGFR: estimated glomerular filtration rate; HDL: high-density lipoprotein; LDL: low-density lipoprotein; TG: triglycerides; TC: total cholesterol; HFpEF: heart failure with preserved ejection fraction; HFrEF: heart failure with reduced ejection fraction; OR: Odds ratio; IVW, Inverse-variance weighting; 95% CI, 95% confidence interval. P value < 0.05 was considered statistically significant

Fig. 2

Cardiometabolic disease-induced plasma mediator heatmaps show the impact of cardiometabolic disease to plasma proteins and plasma metabolites. When the IVW beta value > 0, it indicates a positive causal relationship, and when the IVW beta value < 0, it indicates a negative causal relationship, “*” indicates that the IVW analysis results are statistically significant: (A): Effect of plasma protein expression and concentrations by BMI. (B): Effects of plasma protein expression and concentrations by T2D. (C): Effects of plasma metabolites expression and concentrations by BMI. (D): Effects of plasma metabolites expression and concentrations by T2D

Fig. 3

Identification of causal mediators in HFpEF or HFrEF Forest plot of plasma mediators with causal effects on HFpEF or HFrEF. When the OR value is greater than 1.0, we believe that this medium is acting as a risk factor and has a causal effect. If it is less than 1.0, it may act as a protective mediator. The FDR adjusted P < 0.1 indicates causal effect is significant

Fig. 4

The mediated effect of circulating mediators (A): Bootstrap method to calculate the mediator effect proportion of plasma mediators between BMI, T2D and HFpEF. (B): Bootstrap method to calculate the mediator effect proportion of plasma mediators between BMI, T2D and HFrEF

Fig. 5

Circulating mediators in HFpEF Circulating mediators mediate HFpEF and HFrEF in BMI and T2D, playing both promoting and compensatory protective roles

Fig. 6

Protein–Protein Interaction and Pathway Enrichment Analyses Discover the causal mediators’ interaction networks and biological functions: (A): Protein–protein-metabolite interaction network of BMI circulating mediators with causal effects on HFpEF; (B): GO enrichment analysis and KEGG pathway enrichment analysis of causal circulating mediators and their interacting proteins. (C): Protein–protein-metabolite interaction network of T2D circulating mediators with causal effects on HFpEF; (D): GO enrichment analysis and KEGG pathway enrichment analysis of causal circulating mediators and their interacting proteins. (E): Protein–protein-metabolite interaction network of key IL1R1 with causal effects on HFpEF; (F): GO enrichment analysis and KEGG pathway enrichment analysis of causal circulating mediators and their interacting proteins. MF: Molecular function. BP: Biological process. CC: Cellular component. KEGG: Kyoto Encyclopedia of Genes and Genomes