Machine Learning Identifies Metabolic Signatures that Predict the Risk of Recurrent Angina in Remitted Patients after Percutaneous Coronary Intervention: A Multicenter Prospective Cohort Study

Recurrent angina (RA) after percutaneous coronary intervention (PCI) has few known risk factors, hampering the identification of high-risk populations. In this multicenter study, plasma samples are collected from patients with stable angina after PCI, and these patients are followed-up for 9 months for angina recurrence. Broad-spectrum metabolomic profiling with LC-MS/MS followed by multiple machine learning algorithms is conducted to identify the metabolic signatures associated with future risk of angina recurrence in two large cohorts (n = 750 for discovery set, and n = 775 for additional independent discovery cohort). The metabolic predictors are further validated in a third cohort from another center (n = 130) using a clinically-sound quantitative approach. Compared to angina-free patients, the remitted patients with future RA demonstrates a unique chemical endophenotype dominated by abnormalities in chemical communication across lipid membranes and mitochondrial function. A novel multi-metabolite predictive model constructed from these latent signatures can stratify remitted patients at high-risk for angina recurrence with over 89% accuracy, sensitivity, and specificity across three independent cohorts. Our findings revealed reproducible plasma metabolic signatures to predict patients with a latent future risk of RA during post-PCI remission, allowing them to be treated in advance before an event.