Clinical Phenogroups in Heart Failure With Preserved Ejection Fraction: Detailed Phenotypes, Prognosis, and Response to Spironolactone

Abstract

Objectives: This study sought to assess if clinical phenogroups differ in comprehensive biomarker profiles, cardiac and arterial structure/function, and responses to spironolactone therapy.

Background: Previous studies identified distinct subgroups (phenogroups) of patients with heart failure with preserved ejection fraction (HFpEF).

Methods: Among TOPCAT (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist Trial) participants, we performed latent-class analysis to identify HFpEF phenogroups based on standard clinical features and assessed differences in multiple biomarkers measured from frozen plasma; cardiac and arterial structure/function measured with echocardiography and arterial tonometry; prognosis; and response to spironolactone.

Results: Three HFpEF phenogroups were identified. Phenogroup 1 (n = 1,214) exhibited younger age, higher prevalence of smoking, preserved functional class, and the least evidence of left ventricular (LV) hypertrophy and arterial stiffness. Phenogroup 2 (n = 1,329) was older, with normotrophic concentric LV remodeling, atrial fibrillation, left atrial enlargement, large-artery stiffening, and biomarkers of innate immunity and vascular calcification. Phenogroup 3 (n = 899) demonstrated more functional impairment, obesity, diabetes, chronic kidney disease, concentric LV hypertrophy, high renin, and biomarkers of tumor necrosis factor-alpha-mediated inflammation, liver fibrosis, and tissue remodeling. Compared with phenogroup 1, phenogroup 3 exhibited the highest risk of the primary endpoint of cardiovascular death, heart failure hospitalization, or aborted cardiac arrest (hazard ratio [HR]: 3.44; 95% confidence interval [CI]: 2.79 to 4.24); phenogroups 2 and 3 demonstrated similar all-cause mortality (phenotype 2 HR: 2.36; 95% CI: 1.89 to 2.95; phenotype 3 HR: 2.26, 95% CI: 1.77 to 2.87). Spironolactone randomized therapy was associated with a more pronounced reduction in the risk of the primary endpoint in phenogroup 3 (HR: 0.75; 95% CI: 0.59 to 0.95; p for interaction = 0.016). Results were similar after excluding participants from Eastern Europe.

Conclusions: We identified important differences in circulating biomarkers, cardiac/arterial characteristics, prognosis, and response to spironolactone across clinical HFpEF phenogroups. These findings suggest distinct underlying mechanisms across clinically identifiable phenogroups of HFpEF that may benefit from different targeted interventions.

Keywords: HFpEF; TOPCAT; arterial stiffness; biomarkers; phenogroups.

Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Figures

Figure 1.. Differences in biomarkers across clinical phenogroups.

Red boxes surrounding the biomarker title on the radar plot represent biomarkers that met statistical significance accounting for multiplicity correction based on the number of underlying principal components

Figure 2.. Differences in echocardiographic findings and tonometry across clinical phenogroups.

Red boxes surrounding the measurement title on the radar plot represent parameters that met statistical significance accounting for multiplicity correction based on the number of underlying principal components

Figure 3.

Kaplan-Meier curves for patient outcomes by clinical phenogroup

Figure 4.

Kaplan-Meier curves for the primary outcome by spironolactone treatment status, stratified by clinical phenogroup

Figure 5.. Summary of biomarker, echocardiographic, vascular, and clinical differences across the three identified phenogroups.

Phenogroups were identified using LCA based on age, sex, race, diabetes status, history of AF, obesity, severe heart failure symptoms, and CKD status

Central Illustration. Clinical phenogroups in HFpEF.

Three clinical phenogroups were identified in TOPCAT. Biomarkers of key pathways were measured in available frozen samples from trial participants. Key circulating biomarker, cardiac and vascular features were found, indicating distinct patterns. The phenogroups exhibited different prognosis and differential response to spironolactone.