Risk Factors of Heart Failure: New Insights from Mendelian Randomization

Heart failure (HF) causes a heavy disease burden globally. Identifying etiological risk factors is essential for informing disease prevention and developing new treatment strategies. This review synthesizes insights from published Mendelian randomization (MR) studies on risk factors associated with HF. MR analyses support potential causal associations between various risk factors and HF, including lifestyle habits (e.g., physical activity, smoking, sleep patterns), cardiometabolic factors (e.g., obesity, hypertension, type 2 diabetes, dyslipidemia), nutritional exposures (e.g., 25-hydroxyvitamin D, sodium intake, diet), emerging biomarkers (e.g., fibroblast growth factor 23), gut microbiota, and potential druggable targets. These studies uncover molecular processes that may contribute to HF pathogenesis and provide leads for therapeutic intervention. However, findings are not always consistent across studies, and discrepancies may arise from differences in study design, genetic instruments, population characteristics, and analytical methods. Key assumptions, including the absence of horizontal pleiotropy and the validity of instrumental variables, may not always be fully satisfied, since the interpretation of MR results requires caution. Future MR studies integrating multi-omics data, advanced methodologies and diverse populations will be essential to refine causal inference and enhance translational relevance. Overall, MR provides valuable insights into the potential causal determinants of HF and may contribute to improved prevention strategies and identification of therapeutic targets, although further validation and integration with clinical evidence are required.