Distinct Exercise Response Patterns in Patients With Heart Failure With Preserved Ejection Fraction

Abstract

Background Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous disease characterized by exercise intolerance. Defining pathophysiologically distinct subgroups allows more personalized therapy, but efforts mainly relied on resting examinations. This study aimed to define HFpEF phenotypes based on exercise limitations using combined cardiopulmonary exercise testing with stress echocardiography.Methods A total of 913 patients with HFpEF were recruited from 4 third-line centers and divided into derivation (n=623) and validation cohorts (n=290). Unsupervised graph-based clustering of 61 cardiopulmonary exercise testing with stress echocardiography variables was used to identify HFpEF exercise phenotypes. Pathophysiological characteristics, exercise capacity, and clinical outcomes were compared between phenotypes.Results In the derivation cohort, cluster analysis identified 5 distinct HFpEF exercise phenotypes characterized by specific exercise responses: mild diastolic dysfunction (phenotype 1), impaired peripheral oxygen extraction (phenotype 2), right ventricular-pulmonary artery uncoupling (phenotype 3), reduced left ventricular systolic reserve (phenotype 4), and chronotropic incompetence (phenotype 5). The composite outcome of all-cause death and unplanned cardiovascular hospitalization differed significantly across phenotypes, with phenotypes 2 (hazard ratio [HR], 1.76 [95% CI, 1.07-2.91]), 4 (HR, 2.15 [95% CI, 1.27-3.65]), and 5 (HR, 2.19 [95% CI, 1.33-3.61]) showing higher rates of the primary combined outcome compared with phenotype 1. All phenotypes were replicated in the validation cohort.Conclusions Deep phenotyping of the exercise response in patients with HFpEF revealed 5 distinct phenogroups with marked differences in pathophysiology, exercise performance, and clinical outcomes. This subclassification may support more personalized therapeutic strategies and improve risk stratification in HFpEF.