Clinical Phenogroups in Heart Failure With Preserved Ejection Fraction
Open accessAbstract
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.
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In TOPCAT, three phenogroups were identified, one of which represented by 'Obese, diabetic with advanced symptoms'; these subjects exhibited the worst overall prognosis and the highest levels of biomarkers of TNF-α mediated inflammation.
“In a recent study in participants of TOPCAT (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist Trial), three phenogroups were identified, one of which represented by “Obese, diabetic with advanced symptoms”. These subjects exhibited the worst overall prognosis and the highest levels of biomarkers of TNF-α mediated inflammation [72].”
From Dysregulated epicardial adipose tissue as a risk factor and potential therapeutic target of heart failure with preserved ejection fraction in diabetes (2022) · cites this paper as [72]
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- Authors
- Cohen, J. B., Schrauben, S. J., Zhao, L., Basso, M. D., Cvijic, M. E., Li, Z., Yarde, M., Wang, Z., Bhattacharya, P. T., Chirinos, D. A., Prenner, S., Zamani, P., Seiffert, D. A., Car, B. D., Gordon, D. A., Margulies, K., Cappola, T., & Chirinos, J. A.
- Affiliations
- University of Pennsylvania (US)
- Bristol-Myers Squibb (United States) (US)
- Hospital of the University of Pennsylvania (US)
- Northwestern University (US)
- Corresponding author
- Chirinos, Julio A.
- ORCID
- Venue
- JACC Heart Failure
- Publisher
- Elsevier BV
- Published
- 2020-03
- Volume
- 8
- Issue
- 3
- Pages
- 172-184
- ISSN
- 2213-1779 (ISSN-L)
- PMC
- PMC7058514
- OpenAlex
- W3000089361
- Cited by
- 432
- References
- 31
- Citations by year
- 2026: 64 · 2025: 80 · 2024: 79 · 2023: 61 · 2022: 73 · 2021: 52 · 2020: 22
- FWCI
- 32.15
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- JACC Heart Failure (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- University of Pennsylvania
- AstraZeneca
- MyoKardia
- Bristol-Myers Squibb
- National Institutes of Health
- Sanofi
- Bayer
- Microsoft
- GlaxoSmithKline
- American College of Radiology Imaging Network
- Merck Sharp and Dohme
- National Heart, Lung, and Blood Institute
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Heart Failure Treatment and Management
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Function and Risk Factors
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Fibrosis and Remodeling
- Keywords
- heart failure with preserved ejection fraction, spironolactone, biomarker profiles, latent class analysis, TOPCAT trial, left ventricular hypertrophy, arterial stiffness, inflammation, vascular calcification, cardiovascular mortality, heart failure hospitalization, atrial fibrillation, left atrial enlargement, renin, TNF-α, liver fibrosis, arterial tonometry
- MeSH terms
- Aged, Mineralocorticoid Receptor Antagonists, Echocardiography, Female, Heart Failure, Humans, Male, Middle Aged, Phenotype, Prognosis, Spironolactone, Stroke Volume, Treatment Outcome, Ventricular Remodeling
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