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

Jordana B. Cohen, Sarah J. Schrauben, Lei Zhao, Michael D. Basso, Mary Ellen Cvijic, Zhuyin Li, Melissa Yarde, Zhaoqing Wang, Priyanka T. Bhattacharya, Diana A. Chirinos, Stuart Prenner, Payman Zamani, Dietmar A. Seiffert, Bruce D. Car, David A. Gordon, Kenneth Margulies, Thomas Cappola, Julio A. Chirinos*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

128 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)172-184
Number of pages13
JournalJACC: Heart Failure
Issue number3
StatePublished - Mar 2020


  • HFpEF
  • arterial stiffness
  • biomarkers
  • phenogroups

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine


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