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

doi:10.1016/j.jchf.2019.09.009

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

Preventive Medicine

Research output: Contribution to journal › Article › peer-review

253 Scopus citations

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.

Original language	English (US)
Pages (from-to)	172-184
Number of pages	13
Journal	JACC: Heart Failure
Volume	8
Issue number	3
DOIs	https://doi.org/10.1016/j.jchf.2019.09.009
State	Published - Mar 2020

Funding

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 & Dohme, Sanofi, 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. This manuscript was prepared using TOPCAT research materials obtained from the National Heart, Lung, and Blood Institute Biologic Specimen and Data Repository Information Coordinating Center and does not necessarily reflect the opinions or views of TOPCAT or the National Heart, Lung, and Blood Institute. The authors appreciate the technical support from Terrye Delmonte and Karl Kammerhoff from BMS Biorepository. 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 & Dohme, Sanofi, 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.

Keywords

HFpEF
TOPCAT
arterial stiffness
biomarkers
phenogroups

ASJC Scopus subject areas

Cardiology and Cardiovascular Medicine

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.jchf.2019.09.009

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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. (2020). Clinical Phenogroups in Heart Failure With Preserved Ejection Fraction: Detailed Phenotypes, Prognosis, and Response to Spironolactone. JACC: Heart Failure, 8(3), 172-184. https://doi.org/10.1016/j.jchf.2019.09.009

@article{ff28de3a171548308510ed03b4c9c1e8,

title = "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",

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

note = "Publisher Copyright: {\textcopyright} 2020 American College of Cardiology Foundation",

year = "2020",

month = mar,

doi = "10.1016/j.jchf.2019.09.009",

language = "English (US)",

volume = "8",

pages = "172--184",

journal = "JACC: Heart Failure",

issn = "2213-1779",

publisher = "Elsevier BV",

number = "3",

}

Cohen, JB, Schrauben, SJ, Zhao, L, Basso, MD, Cvijic, ME, Li, Z, Yarde, M, Wang, Z, Bhattacharya, PT, Chirinos, DA, Prenner, S, Zamani, P, Seiffert, DA, Car, BD, Gordon, DA, Margulies, K, Cappola, T & Chirinos, JA 2020, 'Clinical Phenogroups in Heart Failure With Preserved Ejection Fraction: Detailed Phenotypes, Prognosis, and Response to Spironolactone', JACC: Heart Failure, vol. 8, no. 3, pp. 172-184. https://doi.org/10.1016/j.jchf.2019.09.009

TY - JOUR

T1 - Clinical Phenogroups in Heart Failure With Preserved Ejection Fraction

T2 - Detailed Phenotypes, Prognosis, and Response to Spironolactone

AU - Cohen, Jordana B.

AU - Schrauben, Sarah J.

AU - Zhao, Lei

AU - Basso, Michael D.

AU - Cvijic, Mary Ellen

AU - Li, Zhuyin

AU - Yarde, Melissa

AU - Wang, Zhaoqing

AU - Bhattacharya, Priyanka T.

AU - Chirinos, Diana A.

AU - Prenner, Stuart

AU - Zamani, Payman

AU - Seiffert, Dietmar A.

AU - Car, Bruce D.

AU - Gordon, David A.

AU - Margulies, Kenneth

AU - Cappola, Thomas

AU - Chirinos, Julio A.

PY - 2020/3

Y1 - 2020/3

N2 - 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.

AB - 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.

KW - HFpEF

KW - TOPCAT

KW - arterial stiffness

KW - biomarkers

KW - phenogroups

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SN - 2213-1779

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

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