HF作为心血管疾病终末期综合征，已成为全球主要公共卫生挑战，其发病机制复杂且尚未完全阐明。据美国心脏协会2024年最新统计数据，全球HF患者数量已突破6400万，五年生存率与多种癌症相当。随着人口老龄化加深，HF的流行病学特征显示发病率及死亡率呈上升趋势，尤其在65-70岁年龄组中，患病率预计将达到8.5%。目前研究面临三方面主要局限：缺乏整合血管新生通路与免疫微环境的系统研究；传统观察性研究难以区分免疫改变是HF的原因还是结果；缺乏将转录组特征、血管新生分析与遗传工具变量相结合的研究策略。本研究旨在系统探索HF中的"血管新生-免疫轴"及其潜在机制，通过整合转录组数据分析与孟德尔随机化因果推断深入研究免疫系统与HF之间的关系。

本研究通过两个主要方向展开：一是利用孟德尔随机化方法进行免疫细胞-HF因果关系分析；二是进行HF免疫微环境与血管新生特征分析。研究一通过严格的孟德尔随机化分析，确认了14个免疫细胞特征与HF之间的因果关系，包括多种具有保护作用的免疫细胞特征与增加HF风险的免疫特征。通过反向MR分析和Steiger方向性检验，大致确立了免疫细胞特征到HF的单向因果关系。多变量MR分析则确认免疫细胞特征对HF的因果影响独立于传统危险因素（糖尿病、肥胖、高血压）。研究二则通过整合四个GEO数据集（GSE26887、GSE84796、GSE29819、GSE21610），构建了统一的HF转录组特征谱，成功识别了29个与HF相关的血管新生特异性基因，并筛选出11个具有高诊断价值的标志物，据此构建了性能良好的HF诊断模型。

研究发现血管新生基因与免疫微环境之间存在密切关联，特定的血管新生基因（如SMOC2、PTN和FAP）与免疫细胞呈显著正相关，而另一组基因（如E2F8、BMP7和ADAMTS8）则与免疫细胞呈显著负相关，这支持了"血管新生-免疫轴"在HF中的重要作用。基于血管新生基因的表达和免疫浸润特征，研究将HF患者分为两个分子亚型，这两个亚型在基因表达谱和免疫微环境方面存在显著差异，为HF的精准分型提供了新思路。同时，通过中介效应分析，研究发现IL-3受体α亚基（IL-3Rα）作为关键中介分子，在连接免疫细胞与HF过程中发挥重要作用。

本研究通过整合转录组特征分析与遗传因果推断，系统揭示了血管新生-免疫轴在HF发病机制中的双向调控作用，为HF的精准诊断与治疗提供了全新视角。研究成果不仅丰富了对HF发病机制的认识，还为免疫调节的精准靶点识别、血管新生标志物开发以及HF的分子分型和精准医疗提供了理论基础。通过此项系统研究，建立了从转录组特征到遗传因果推断的方法学框架，为HF的未来研究和临床实践提供了创新性思路和重要参考。

Heart failure, as an end-stage syndrome of cardiovascular disease, has become a major global public health challenge with complex pathogenesis that is not yet fully elucidated. According to the latest 2024 statistics from the American Heart Association, the number of heart failure patients worldwide has exceeded 64 million, with a five-year survival rate comparable to various cancers. As population aging deepens, epidemiological characteristics of heart failure show increasing incidence and mortality rates. Current research faces three main limitations: lack of systematic studies integrating angiogenesis pathways with the immune microenvironment; traditional observational studies that struggle to distinguish whether immune changes are causes or consequences of heart failure; and absence of research strategies combining transcriptomic characteristics, angiogenesis analysis, and genetic instrumental variables. This study aims to systematically explore the "angiogenesis-immune axis" in heart failure and its potential mechanisms through integrating transcriptomic data analysis with Mendelian randomization causal inference to deeply investigate the relationship between the immune system and heart failure.

This research is conducted through two main directions: first, using Mendelian randomization methods to analyze causal relationships between immune cells and heart failure; second, analyzing the immune microenvironment and angiogenesis characteristics in heart failure. Study one, through rigorous Mendelian randomization analysis, confirmed causal relationships between 14 immune cell traits and heart failure, including various immune cell characteristics with protective effects and immune features that increase heart failure risk. Through reverse MR analysis and Steiger directional testing, a predominantly unidirectional causal relationship from immune cell traits to heart failure was established. Multivariable MR analysis confirmed that the causal influence of immune cell traits on heart failure is independent of traditional risk factors （diabetes, obesity, hypertension）. Study two integrated four GEO datasets （GSE26887, GSE84796, GSE29819, GSE21610） to construct a unified heart failure transcriptome profile, successfully identifying 29 angiogenesis-specific genes associated with heart failure, and screening 11 markers with high diagnostic value, based on which a well-performing heart failure diagnostic model was constructed.

The research found close associations between angiogenesis genes and the immune microenvironment, with specific angiogenesis genes （such as SMOC2, PTN, and FAP） showing significant positive correlations with immune cells, while another group of genes （including E2F8, BMP7, and ADAMTS8） showed significant negative correlations with immune cells, supporting the important role of the "angiogenesis-immune axis" in heart failure. Based on angiogenesis gene expression and immune infiltration characteristics, the study classified heart failure patients into two molecular subtypes, which showed significant differences in gene expression profiles and immune microenvironments, providing new insights for precise classification of heart failure. Additionally, through mediation effect analysis, the study found that the IL-3 receptor α subunit （IL-3Rα） functions as a key mediator in connecting immune cells with heart failure progression.

This study systematically revealed the bidirectional regulatory role of the angiogenesis-immune axis in heart failure pathogenesis by integrating transcriptomic feature analysis and genetic causal inference, providing a new perspective for precise diagnosis and treatment of heart failure. The research findings not only enrich the understanding of heart failure pathogenesis but also provide a theoretical foundation for precise target identification in immune regulation, development of angiogenesis markers, and molecular classification and precision medicine for heart failure. Through this systematic study, a methodological framework from transcriptomic characteristics to genetic causal inference has been established, offering innovative ideas and important references for future research and clinical practice in heart failure.