Lin Mingzhi, Guo Jiuqi, Tao Hongqian, Gu Zhilin, Tang Wenyi, Zhou Fuliang, Jiang Yanling, Zhang Ruyi, Jia Dalin, Sun Yingxian, Jia Pengyu
Department of Cardiology, The First Hospital of China Medical University, 155 Nanjing North Street, Heping District, Shenyang, 110001, People's Republic of China.
Key Laboratory of Environmental Stress and Chronic Disease Control and Prevention, Ministry of Education, China Medical University, Shenyang, Liaoning, China.
Cardiovasc Diabetol. 2025 May 12;24(1):201. doi: 10.1186/s12933-025-02738-0.
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.
This study aimed to identify cardiometabolic risk factors specifically driving HFpEF and to determine their underlying circulating mediators.
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.
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.
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.
射血分数保留的心力衰竭（HFpEF）是一种发病率和死亡率日益增高的临床综合征。尽管HFpEF常与心脏代谢疾病共存，但其因果机制和潜在介质仍知之甚少。
本研究旨在确定特异性驱动HFpEF的心脏代谢危险因素，并确定其潜在的循环介质。
我们使用两样本孟德尔随机化（MR）分析肥胖、2型糖尿病、高血压、慢性肾脏病（CKD）和血脂异常对大型欧洲裔全基因组关联研究（GWAS）数据集中HFpEF和射血分数降低的心力衰竭（HFrEF）的影响。然后进行中介MR分析，以分别确定介导每种心脏代谢疾病向HFpEF转变的血浆蛋白和代谢物。我们应用多变量MR评估风险混杂对结果的影响。进行生物信息学分析以阐明机制。
心脏代谢疾病对HFpEF和HFrEF有不同影响。肥胖和2型糖尿病显示出与HFpEF的校正因果效应，高血压显示出与HFpEF的潜在相关性，而血脂异常和CKD则不然。MR分析确定了5种介导肥胖向HFpEF转变的蛋白质；5种介导2型糖尿病向HFpEF转变的蛋白质。对肥胖和2型糖尿病对HFrEF的进一步中介MR分析显示，代谢性HFpEF和HFrEF之间的循环介质存在异质性。综合生物信息学分析表明，IL1R1与TP53和FGF19等其他蛋白质共同协调HFpEF潜在的炎症和纤维化过程。
这些发现表明，与HFrEF相比，代谢性HFpEF具有独特的病因特征，且由复杂的、特定疾病的介质驱动。IL1R1在多种代谢风险状态下介导HFpEF，提示其可能为潜在治疗靶点。有必要进行进一步的转化研究，以评估针对HFpEF中IL1R1的抗炎策略。
