Abstract
Introduction: Heart failure with preserved ejection fraction (HFpEF) is a heterogenous disease associated with low exercise capacity. Hypothesis: Unsupervised clustering of biomarker data can identify subgroups of individuals with HFpEF and differences in exercise capacity. Methods: The study included participants with chronic, stable HFpEF from the RELAX trial with available serum biomarker data. We used unsupervised hierarchical clustering analysis of 9 serum biomarkers to derive phenogroups of participants with HFpEF. Adjusted linear regression was used to assess the association between cluster membership with peak oxygen consumption (VO2), maximum exercise watts, and VO2 anaerobic threshold. Results: Among 211 participants in the RELAX trial, 3 phenogroups were identified based on the gain in within-inertia. No significant differences were observed in age, sex, or race across phenogroups. Phenogroup 1 (n=136) participants had the lowest burden of CV (cardiovascular) risk factors, including diabetes, anemia, and kidney disease as well as the lowest overall biomarkers levels ( Fig. A ). Phenogroup 2 (n=61) consisted of participants who were older with a higher burden of CV risk factors and fibrosis biomarkers, including galectin-3, collagen-I, and troponin-I levels. Phenogroup 3 (n=14) participants were younger with high burden of CV risk factors and inflammatory biomarkers including aldosterone, CRP, and uric acid. Compared with phenogroup 1, phenogroup 2 and 3 had significantly lower peak VO2, adjusted for traditional CV risk factors [estimate (95% CI): -1.99 (-2.83, -1.16) and -2.31 (-3.66, -0.95), respectively] (Fig. B ). Additionally, phenogroup 3 vs. 1 had lower exercise watts and VO2 anaerobic threshold. Conclusion: Using serum biomarkers, we identified 3 unique phenogroups of patients with chronic, stable HFpEF and significant differences in CV risk factor burden and exercise capacity.
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