Utility of Growth Differentiation Factor-15, A Marker of Oxidative Stress and Inflammation, in Chronic Heart Failure: Insights From the HF-ACTION Study

Abhinav Sharma, Susanna R. Stevens, Joseph Lucas, Mona Fiuzat, Kirkwood F. Adams, David J. Whellan, Mark P. Donahue, Dalane W. Kitzman, Ileana L. Pina, Faiez Zannad, William E. Kraus, Christopher M. O'Connor, G. Michael Felker

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

Objectives This study sought to determine the relationship between growth differentiation factor (GDF)-15 and clinical outcomes in ambulatory patients with heart failure and reduced ejection fraction (HFrEF). Background The prognostic utility of GDF-15, a member of the transforming growth factor-β cytokine family, among patients with HF is unclear. Methods We assessed GDF-15 levels in 910 patients enrolled in the HF-ACTION (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training) trial, a randomized clinical trial of exercise training in patients with HFrEF. Median follow-up was 30 months. Cox proportional hazard models assessed the relationships between GDF-15 and clinical outcomes. Results The median GDF-15 concentration was 1,596 pg/ml. Patients in the highest tertile of GDF-15 were older and had measurements of more severe HF (higher N-terminal pro–B-type natriuretic peptide [NT-proBNP] concentrations and lower peak oxygen uptake on cardiopulmonary exercise testing [CPX]). GDF-15 therapy was a significant predictor of all-cause death (unadjusted hazard ratio [HR]: 2.03 when GDF-15 was doubled; p < 0.0001). This association persisted after adjustment for demographic and clinical and biomarkers including high sensitivity troponin T (hs-TnT) and NT-proBNP (HR: 1.30 per doubling of GDF-15; p = 0.029). GDF-15 did not improve discrimination (as measured by changes in c-statistics and the integrated discrimination improvement) in addition to baseline variables, including hs-TnT and NT-proBNP or variables found in CPX testing. Conclusions In demographically diverse, well-managed patients with HFrEF, GDF-15 therapy provided independent prognostic information in addition to established predictors of outcomes. These data support a possible role for GDF-15 in the risk stratification of patients with chronic HFrEF. (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training [HF-ACTION]; NCT00047437)

Original languageEnglish (US)
Pages (from-to)724-734
Number of pages11
JournalJACC: Heart Failure
Volume5
Issue number10
DOIs
StatePublished - Oct 1 2017

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Growth Differentiation Factor 15
Oxidative Stress
Heart Failure
Exercise
Inflammation
Natriuretic Peptides
Troponin T
Transforming Growth Factors
Proportional Hazards Models

Keywords

  • B-type natriuretic peptide
  • BNP
  • heart failure
  • N-terminal pro–B-type natriuretic peptide

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Utility of Growth Differentiation Factor-15, A Marker of Oxidative Stress and Inflammation, in Chronic Heart Failure : Insights From the HF-ACTION Study. / Sharma, Abhinav; Stevens, Susanna R.; Lucas, Joseph; Fiuzat, Mona; Adams, Kirkwood F.; Whellan, David J.; Donahue, Mark P.; Kitzman, Dalane W.; Pina, Ileana L.; Zannad, Faiez; Kraus, William E.; O'Connor, Christopher M.; Felker, G. Michael.

In: JACC: Heart Failure, Vol. 5, No. 10, 01.10.2017, p. 724-734.

Research output: Contribution to journalArticle

Sharma, A, Stevens, SR, Lucas, J, Fiuzat, M, Adams, KF, Whellan, DJ, Donahue, MP, Kitzman, DW, Pina, IL, Zannad, F, Kraus, WE, O'Connor, CM & Felker, GM 2017, 'Utility of Growth Differentiation Factor-15, A Marker of Oxidative Stress and Inflammation, in Chronic Heart Failure: Insights From the HF-ACTION Study', JACC: Heart Failure, vol. 5, no. 10, pp. 724-734. https://doi.org/10.1016/j.jchf.2017.07.013
Sharma, Abhinav ; Stevens, Susanna R. ; Lucas, Joseph ; Fiuzat, Mona ; Adams, Kirkwood F. ; Whellan, David J. ; Donahue, Mark P. ; Kitzman, Dalane W. ; Pina, Ileana L. ; Zannad, Faiez ; Kraus, William E. ; O'Connor, Christopher M. ; Felker, G. Michael. / Utility of Growth Differentiation Factor-15, A Marker of Oxidative Stress and Inflammation, in Chronic Heart Failure : Insights From the HF-ACTION Study. In: JACC: Heart Failure. 2017 ; Vol. 5, No. 10. pp. 724-734.
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abstract = "Objectives This study sought to determine the relationship between growth differentiation factor (GDF)-15 and clinical outcomes in ambulatory patients with heart failure and reduced ejection fraction (HFrEF). Background The prognostic utility of GDF-15, a member of the transforming growth factor-β cytokine family, among patients with HF is unclear. Methods We assessed GDF-15 levels in 910 patients enrolled in the HF-ACTION (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training) trial, a randomized clinical trial of exercise training in patients with HFrEF. Median follow-up was 30 months. Cox proportional hazard models assessed the relationships between GDF-15 and clinical outcomes. Results The median GDF-15 concentration was 1,596 pg/ml. Patients in the highest tertile of GDF-15 were older and had measurements of more severe HF (higher N-terminal pro–B-type natriuretic peptide [NT-proBNP] concentrations and lower peak oxygen uptake on cardiopulmonary exercise testing [CPX]). GDF-15 therapy was a significant predictor of all-cause death (unadjusted hazard ratio [HR]: 2.03 when GDF-15 was doubled; p < 0.0001). This association persisted after adjustment for demographic and clinical and biomarkers including high sensitivity troponin T (hs-TnT) and NT-proBNP (HR: 1.30 per doubling of GDF-15; p = 0.029). GDF-15 did not improve discrimination (as measured by changes in c-statistics and the integrated discrimination improvement) in addition to baseline variables, including hs-TnT and NT-proBNP or variables found in CPX testing. Conclusions In demographically diverse, well-managed patients with HFrEF, GDF-15 therapy provided independent prognostic information in addition to established predictors of outcomes. These data support a possible role for GDF-15 in the risk stratification of patients with chronic HFrEF. (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training [HF-ACTION]; NCT00047437)",
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T2 - Insights From the HF-ACTION Study

AU - Sharma, Abhinav

AU - Stevens, Susanna R.

AU - Lucas, Joseph

AU - Fiuzat, Mona

AU - Adams, Kirkwood F.

AU - Whellan, David J.

AU - Donahue, Mark P.

AU - Kitzman, Dalane W.

AU - Pina, Ileana L.

AU - Zannad, Faiez

AU - Kraus, William E.

AU - O'Connor, Christopher M.

AU - Felker, G. Michael

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N2 - Objectives This study sought to determine the relationship between growth differentiation factor (GDF)-15 and clinical outcomes in ambulatory patients with heart failure and reduced ejection fraction (HFrEF). Background The prognostic utility of GDF-15, a member of the transforming growth factor-β cytokine family, among patients with HF is unclear. Methods We assessed GDF-15 levels in 910 patients enrolled in the HF-ACTION (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training) trial, a randomized clinical trial of exercise training in patients with HFrEF. Median follow-up was 30 months. Cox proportional hazard models assessed the relationships between GDF-15 and clinical outcomes. Results The median GDF-15 concentration was 1,596 pg/ml. Patients in the highest tertile of GDF-15 were older and had measurements of more severe HF (higher N-terminal pro–B-type natriuretic peptide [NT-proBNP] concentrations and lower peak oxygen uptake on cardiopulmonary exercise testing [CPX]). GDF-15 therapy was a significant predictor of all-cause death (unadjusted hazard ratio [HR]: 2.03 when GDF-15 was doubled; p < 0.0001). This association persisted after adjustment for demographic and clinical and biomarkers including high sensitivity troponin T (hs-TnT) and NT-proBNP (HR: 1.30 per doubling of GDF-15; p = 0.029). GDF-15 did not improve discrimination (as measured by changes in c-statistics and the integrated discrimination improvement) in addition to baseline variables, including hs-TnT and NT-proBNP or variables found in CPX testing. Conclusions In demographically diverse, well-managed patients with HFrEF, GDF-15 therapy provided independent prognostic information in addition to established predictors of outcomes. These data support a possible role for GDF-15 in the risk stratification of patients with chronic HFrEF. (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training [HF-ACTION]; NCT00047437)

AB - Objectives This study sought to determine the relationship between growth differentiation factor (GDF)-15 and clinical outcomes in ambulatory patients with heart failure and reduced ejection fraction (HFrEF). Background The prognostic utility of GDF-15, a member of the transforming growth factor-β cytokine family, among patients with HF is unclear. Methods We assessed GDF-15 levels in 910 patients enrolled in the HF-ACTION (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training) trial, a randomized clinical trial of exercise training in patients with HFrEF. Median follow-up was 30 months. Cox proportional hazard models assessed the relationships between GDF-15 and clinical outcomes. Results The median GDF-15 concentration was 1,596 pg/ml. Patients in the highest tertile of GDF-15 were older and had measurements of more severe HF (higher N-terminal pro–B-type natriuretic peptide [NT-proBNP] concentrations and lower peak oxygen uptake on cardiopulmonary exercise testing [CPX]). GDF-15 therapy was a significant predictor of all-cause death (unadjusted hazard ratio [HR]: 2.03 when GDF-15 was doubled; p < 0.0001). This association persisted after adjustment for demographic and clinical and biomarkers including high sensitivity troponin T (hs-TnT) and NT-proBNP (HR: 1.30 per doubling of GDF-15; p = 0.029). GDF-15 did not improve discrimination (as measured by changes in c-statistics and the integrated discrimination improvement) in addition to baseline variables, including hs-TnT and NT-proBNP or variables found in CPX testing. Conclusions In demographically diverse, well-managed patients with HFrEF, GDF-15 therapy provided independent prognostic information in addition to established predictors of outcomes. These data support a possible role for GDF-15 in the risk stratification of patients with chronic HFrEF. (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training [HF-ACTION]; NCT00047437)

KW - B-type natriuretic peptide

KW - BNP

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KW - N-terminal pro–B-type natriuretic peptide

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