Exercise Stress Echocardiography-Based Phenotyping of Heart Failure with Preserved Ejection Fraction

Background Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous syndrome requiring improved phenotypic classification. Previous studies have identified subphenotypes of HFpEF, but the lack of exercise assessment is a major limitation. This study sought to identify distinct pathophysiologic clusters of HFpEF based on clinical characteristics, and resting and exercise assessments. Methods A total of 265 patients with HFpEF underwent ergometry exercise stress echocardiography with simultaneous expired gas analysis. Cluster analysis was performed by the K-prototype method with 21 variables (10 clinical and resting echocardiographic variables and 11 exercise echocardiographic parameters). Pathophysiological features, exercise tolerance, and prognosis were compared among phenogroups. Results Three distinct phenogroups were identified: Phenogroup 1 (n=112, 42%) was characterized by preserved biventricular systolic reserve and cardiac output augmentation. Phenogroup 2 (n=58, 22%) was characterized by a high prevalence of atrial fibrillation, increased pulmonary arterial and right atrial pressures, depressed RV systolic functional reserve, and impaired right ventricular-pulmonary artery coupling during exercise. Phenogroup 3 (n=95, 36%) was characterized by the smallest body mass index, ventricular and vascular stiffening, impaired LV diastolic reserve, and worse exercise capacity. Phenogroups 2 and 3 had higher rates of composite outcomes of all-cause mortality or HF events than phenogroup 1 (log-rank p=0.02). Conclusion Exercise echocardiography-based cluster analysis identified three distinct phenogroups of HFpEF, with unique exercise pathophysiological features, exercise capacity, and clinical outcomes.