Author + information
- Received August 22, 2019
- Accepted September 4, 2019
- Published online January 8, 2020.
- Jordana B. Cohen, MD, MSCEa,b,
- Sarah J. Schrauben, MD, MSCEa,b,
- Lei Zhao, MD, PhDc,
- Michael D. Basso, MSc,
- Mary Ellen Cvijic, PhDc,
- Zhuyin Li, PhDc,
- Melissa Yarde, MSc,
- Zhaoqing Wang, MSc,
- Priyanka T. Bhattacharya, MDb,d,
- Diana A. Chirinos, PhDe,
- Stuart Prenner, MDf,
- Payman Zamani, MD, MTRf,
- Dietmar A. Seiffert, MDc,
- Bruce D. Car, PhDc,
- David A. Gordon, PhDc,
- Kenneth Margulies, MDf,
- Thomas Cappola, MD, ScMf and
- Julio A. Chirinos, MD, PhDf,∗ ()
- aRenal-Electrolyte and Hypertension Division, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
- bCenter for Clinical Epidemiology and Biostatistics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
- cBristol-Myers Squibb Company, Lawrenceville, New Jersey
- dDivision of Hospital Medicine, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania
- eDepartment of Preventive Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
- fDivision of Cardiovascular Medicine, Hospital of the University of Pennsylvania and Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
- ↵∗Address for correspondence:
Dr. Julio A. Chirinos, South Tower, Room 11-138, Perelman Center for Advanced Medicine, 3400 Civic Center Blvd, Philadelphia, PA 19104.
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 Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist Trial (TOPCAT) 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.
This work was funded by a research grant from Bristol-Myers Squibb to Dr. Julio A. Chirinos. Dr. Cohen is supported by K23-HL133843. Dr. Zamani is supported by K23-HL-130551. Dr. Julio A. Chirinos has received consulting honoraria from Sanifit, Microsoft, Fukuda-Denshi, Bristol-Myers Squibb, OPKO Healthcare, Ironwood Pharmaceuticals, Pfizer, Akros Pharma, Merck, and Bayer; research grants from National Institutes of Health, American College of Radiology Network, Fukuda Denshi, Bristol-Myers Squibb, and Microsoft; and is named as inventor in a University of Pennsylvania patent application for the use of inorganic nitrates/nitrites for the treatment of HFpEF and a patent application for novel neoepitope biomarkers of tissue fibrosis in HFpEF. Dr. Margulies has received research funding from GlaxoSmithKline, AstraZeneca, Merck Sharp and Dohme, Sanofi-Aventis, and American Reagent Phamaceuticals (formerly Luitpold); and consulting honoraria from American Reagent and MyoKardia, Inc. Dr. Cappola has received research funding from BG Medicine. All other authors have reported that they have no relationships relevant to the contents of this paper to report.
- Received August 22, 2019.
- Accepted September 4, 2019.
- 2020 American College of Cardiology Foundation
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