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. Objec...
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BMC
2025-05-01
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| Series: | Cardiovascular Diabetology |
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| Online Access: | https://doi.org/10.1186/s12933-025-02738-0 |
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| author | Mingzhi Lin Jiuqi Guo Hongqian Tao Zhilin Gu Wenyi Tang Fuliang Zhou Yanling Jiang Ruyi Zhang Dalin Jia Yingxian Sun Pengyu Jia |
| author_facet | Mingzhi Lin Jiuqi Guo Hongqian Tao Zhilin Gu Wenyi Tang Fuliang Zhou Yanling Jiang Ruyi Zhang Dalin Jia Yingxian Sun Pengyu Jia |
| author_sort | Mingzhi Lin |
| collection | DOAJ |
| description | 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. Graphical Abstract |
| format | Article |
| id | doaj-art-dcbeffa143464960a028ea29e9cc9490 |
| institution | Kabale University |
| issn | 1475-2840 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | BMC |
| record_format | Article |
| series | Cardiovascular Diabetology |
| spelling | doaj-art-dcbeffa143464960a028ea29e9cc94902025-08-20T03:53:58ZengBMCCardiovascular Diabetology1475-28402025-05-0124111710.1186/s12933-025-02738-0Circulating mediators linking cardiometabolic diseases to HFpEF: a mediation Mendelian randomization analysisMingzhi Lin0Jiuqi Guo1Hongqian Tao2Zhilin Gu3Wenyi Tang4Fuliang Zhou5Yanling Jiang6Ruyi Zhang7Dalin Jia8Yingxian Sun9Pengyu Jia10Department of Cardiology, The First Hospital of China Medical UniversityDepartment of Cardiology, The First Hospital of China Medical UniversityDepartment of Cardiology, The First Hospital of China Medical UniversityDepartment of Cardiology, The First Hospital of China Medical UniversityDepartment of Cardiology, The First Hospital of China Medical UniversityDepartment of Cardiology, The First Hospital of China Medical UniversityDepartment of Cardiology, The First Hospital of China Medical UniversityDepartment of Cardiology, The First Hospital of China Medical UniversityDepartment of Cardiology, The First Hospital of China Medical UniversityDepartment of Cardiology, The First Hospital of China Medical UniversityDepartment of Cardiology, The First Hospital of China Medical UniversityAbstract 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. Graphical Abstracthttps://doi.org/10.1186/s12933-025-02738-0HFpEFCardiometabolic diseasesCirculating mediatorsType 2 diabetesIL1R1 |
| spellingShingle | Mingzhi Lin Jiuqi Guo Hongqian Tao Zhilin Gu Wenyi Tang Fuliang Zhou Yanling Jiang Ruyi Zhang Dalin Jia Yingxian Sun Pengyu Jia Circulating mediators linking cardiometabolic diseases to HFpEF: a mediation Mendelian randomization analysis Cardiovascular Diabetology HFpEF Cardiometabolic diseases Circulating mediators Type 2 diabetes IL1R1 |
| title | Circulating mediators linking cardiometabolic diseases to HFpEF: a mediation Mendelian randomization analysis |
| title_full | Circulating mediators linking cardiometabolic diseases to HFpEF: a mediation Mendelian randomization analysis |
| title_fullStr | Circulating mediators linking cardiometabolic diseases to HFpEF: a mediation Mendelian randomization analysis |
| title_full_unstemmed | Circulating mediators linking cardiometabolic diseases to HFpEF: a mediation Mendelian randomization analysis |
| title_short | Circulating mediators linking cardiometabolic diseases to HFpEF: a mediation Mendelian randomization analysis |
| title_sort | circulating mediators linking cardiometabolic diseases to hfpef a mediation mendelian randomization analysis |
| topic | HFpEF Cardiometabolic diseases Circulating mediators Type 2 diabetes IL1R1 |
| url | https://doi.org/10.1186/s12933-025-02738-0 |
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