Cluster-Based Phenotyping in an HFpEF Population Identifies a Biomarker-High, Atrial-Dysfunction Phenotype with Impaired Quality of Life, Reduced Exercise Capacity and Higher Healthcare Utilization

Background/Objectives: Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous syndrome. Atrial remodeling represents an important dimension of HFpEF beyond the presence of atrial fibrillation (AF). We aimed to identify clinically meaningful atrial phenotypes using unsupervised clustering. Methods: Overall, 153 patients were analyzed from a prospective HFpEF registry who underwent clinical assessment, laboratory testing, electrocardiography, resting and stress echocardiography and cardiopulmonary exercise testing. Consensus k-means clustering across multiply imputed datasets integrated markers of atrial structure and function, biomarkers, and hemodynamic burden. Clinical characteristics, functional capacity, quality of life and 12-month healthcare utilization were compared between clusters. Sensitivity analyses assessed cluster robustness. Results: Two phenotypes were identified. Cluster 1 (n = 66) was characterized by higher biomarker and hemodynamic burden, impaired renal function, larger left atrial volume index, and reduced left atrial reservoir strain. Variables not included in cluster generation also differed between phenotypes: Cluster 1 showed poorer exercise capacity, shorter six-minute walking distance, worse quality of life, and a higher observed all-cause hospitalization burden. The hospitalization finding was considered exploratory. The principal cluster structure was preserved in sensitivity analyses, including complete-case analysis. Conclusions: The clustering approach identified an HFpEF phenotype characterized by biomarker elevation and advanced atrial remodeling. The phenotype was associated with greater functional impairment and adverse patient-reported characteristics. These clinical associations support the potential relevance of multidimensional atrial phenotyping, although the findings remain hypothesis-generating and require validation in independent cohorts.