Machine Learning Identification of Patient Phenoclusters in Aortic Regurgitation

Background: Current treatment paradigms assume aortic regurgitation (AR) patients to be a homogenous population, but varied courses of disease progression and outcomes are observed clinically. Objectives: The aim of this study was to first use unsupervised machine learning to identify unique patient phenoclusters in AR, and subsequently evaluate their prognostic relevance. Methods: Clinical and cardiac magnetic resonance (CMR) characterization of moderate or severe AR patients was performed across 4 U.S. centers. Data from 2 centers were used for derivation of phenoclusters and validation was performed in the other 2. The outcome was all-cause death. An unsupervised clustering pipeline, Partition Around Medoids, used 23 clinical and CMR variables to derive patient clusters independent of outcomes. Results: Included were 972 patients with mean age 62 ± 23.2 years, 754 (78%) male, 680 (70%) trileaflet valve, and 330 (34%) underwent valve surgery. Over a median follow-up of 2.58 years (Q1-Q3: 1.03-5.50 years), the overall mortality rate was 12%. Four clusters were derived: 1) a younger predominantly male phenotype with majority of bicuspid aortic valve and high extent of left ventricular (LV) remodeling (1% mortality); 2) older male patients with predominantly tricuspid valves and intermediate outcomes (10% mortality); 3) older predominantly male patients with the highest burden of comorbidities, LV scarring, and dysfunction (22% mortality); and 4) a phenotype of predominantly female patients with high mortality and relatively higher symptoms burden, relatively lower extent of LV remodeling, and rate of aortic valve replacement (20% mortality). The clustering algorithm was independently associated with survival after adjustment for time-dependent aortic valve replacement and traditional risk markers of prognosis in patients with AR (C statistic 0.77 vs 0.75; P = 0.009 in the validation cohort). Conclusions: Unique patient phenoclusters of AR are described using a machine learning approach leveraging comprehensive CMR and clinical characterization. This approach may be an opportunity for a precision medicine approach to enhance risk stratification of patients with AR. Female patients with AR pose a unique phenotype with high mortality, which deserves greater attention.