Growth Differentiation Factor 15 Predicts Cardiovascular Events in Peripheral Artery Disease

Peripheral artery disease (PAD) is associated with an elevated risk of major adverse cardiovascular events (MACE). Despite this, few reliable biomarkers exist to identify patients at heightened risk of MACE. Growth differentiation factor 15 (GDF15), a stress-responsive cytokine implicated in inflammation, atherosclerosis, and thrombosis, has been broadly studied in cardiovascular disease but remains underexplored in PAD. This study aimed to evaluate the prognostic utility of GDF15 for predicting 2-year MACE in PAD patients using explainable statistical and machine learning approaches. We conducted a prospective analysis of 1192 individuals (454 with PAD and 738 without PAD). At study entry, patient plasma GDF15 concentrations were measured using a validated multiplex immunoassay. The cohort was followed for two years to monitor the occurrence of MACE, defined as stroke, myocardial infarction, or death. Baseline GDF15 levels were compared between PAD and non-PAD participants using the Mann-Whitney U test. A machine learning model based on extreme gradient boosting (XGBoost) was trained to predict 2-year MACE using 10-fold cross-validation, incorporating GDF15 and clinical variables including age, sex, comorbidities (hypertension, diabetes, dyslipidemia, congestive heart failure, coronary artery disease, and previous stroke or transient ischemic attack), smoking history, and cardioprotective medication use. The model's primary evaluation metric was the F1 score, a validated measurement of the harmonic mean of the precision and recall values of the prediction model. Secondary model performance metrics included precision, recall, positive likelihood ratio (LR+), and negative likelihood ratio (LR-). A prediction probability histogram and Shapley additive explanations (SHAP) analysis were used to assess model discrimination and interpretability. The mean participant age was 70 ± SD 11 years, with 32% (n = 386) female representation. Median plasma GDF15 levels were significantly higher in PAD patients compared to the levels in non-PAD patients (1.29 [IQR 0.77-2.22] vs. 0.99 [IQR 0.61-1.63] pg/mL; p < 0.001). During the 2-year follow-up period, 219 individuals (18.4%) experienced MACE. The XGBoost model demonstrated strong predictive performance for 2-year MACE (F1 score = 0.83; precision = 82.0%; recall = 83.7%; LR+ = 1.88; LR- = 0.83). The prediction histogram revealed distinct stratification between those who did vs. did not experience 2-year MACE. SHAP analysis identified GDF15 as the most influential predictive feature, surpassing traditional clinical predictors such as age, cardiovascular history, and smoking status. This study highlights GDF15 as a strong prognostic biomarker for 2-year MACE in patients with PAD. When combined with clinical variables in an interpretable machine learning model, GDF15 supports the early identification of patients at high risk for systemic cardiovascular events, facilitating personalized treatment strategies including multidisciplinary specialist referrals and aggressive cardiovascular risk reduction therapy. This biomarker-guided approach offers a promising pathway for improving cardiovascular outcomes in the PAD population through precision risk stratification.