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

Figures

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  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

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  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

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  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

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  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

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  Fig. 5. Circulating mediators in HFpEF Circulating mediators mediate HFpEF and HFrEF in BMI and T2D, playing both promoting and compensatory protective roles

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  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