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Published on: February 20, 2017
Prognostic significance of growth differentiation factor-15 across age in chronic heart failure
Kanako Teramoto1, Kotaro Nochioka2, Yasuhiko Sakata3
1Department of Biostatistics, National Cerebral and Cardiovascular Center, Osaka, Japan.
Insights
Growth Differentiation Factor 15 (GDF15) levels increase with age in chronic heart failure (CHF) patients. GDF15 predicts cardiovascular events, especially in older adults, with a consistent additive value across all ages.
Area of Science:
- Cardiology
- Biomarkers
- Geriatrics
Background:
- Growth Differentiation Factor 15 (GDF15) is a cytokine elevated in stress, inflammation, and heart failure (HF).
- The prognostic significance and age-specific role of GDF15 in chronic heart failure (CHF) are not well understood.
Purpose of the Study:
- To investigate the age-specific characteristics and prognostic value of GDF15 in patients with CHF.
- To explore the association of GDF15 with clinical factors and cardiovascular outcomes across different age groups.
Main Methods:
- Serum GDF15 levels were measured in 942 hypertensive CHF patients across four age groups.
- Clinical correlates and interactions with age were analyzed using regression models (stepwise, LASSO).
- Association with the composite outcome of HF hospitalization or all-cause death was assessed over a mean follow-up of 8.6 years.
Main Results:
- GDF15 levels significantly increased with age, from 691 pg/mL (under 50) to 1516 pg/mL (70-79 years).
- GDF15 was independently associated with higher risk of HF hospitalization or death (aHR 1.84), with a heightened risk around age 70.
- Significant interactions between age and diabetes history/NT-proBNP were observed, particularly in the 60-70 age range.
Conclusions:
- GDF15 correlates show age interactions, and GDF15 is a key predictor of cardiovascular endpoints, especially in patients around 70 years old.
- The additive prognostic value of GDF15 is consistent across ages, supporting a universal cut-off value of 1400 pg/mL.
Aims:
Growth differentiation factor-15 (GDF15), a cytokine in the transforming growth factor family, is up-regulated in stress and inflammatory conditions and is elevated in patients with heart failure (HF). However, the age-specific attributes and prognostic significance of GDF15 across age remain unknown in chronic HF (CHF).
Methods And Results:
Serum levels of GDF15 were examined in 942 hypertensive patients (median 68 years) with CHF from the SUPPORT trial across the four age groups [under 50 (n = 73), 51-59 (n = 158), 60-69 (n = 296), and 70-79 years (n = 415)] and in the continuous spectrum. Clinical correlates of GDF15 were explored using the classic stepwise and LASSO (least absolute shrinkage and selection operator) regression approaches. Interaction terms with age were tested in the LASSO regression approach. The associations with the composite outcome of HF hospitalization or all-cause death were investigated across ages. Median GDF15 levels (pg/mL) increased along with aging, from 691 in under 50 years to 855 in 51-59 years, 1114 in 60-69 years, and 1516 in 70-79 years (trend P < 0.001). Age, sex, systolic blood pressure, history of diabetes, ischaemic heart disease, left ventricular (LV) end-systolic dimension, LV ejection fraction, estimated glomerular filtration rate, haemoglobin, N-terminal pro-brain natriuretic peptide (NT-proBNP), troponin, C-reactive protein, and the use of angiotensin-converting enzyme inhibitors, diuretics, and statins were mutually selected as clinical covariates of GDF15. The LASSO regression analysis identified significant interactions between age and the history of diabetes and NT-proBNP, with particularly robust associations in patients aged between 60 and 70 years. During the mean follow-up of 8.6 years, 474 composite endpoints of HF hospitalization or death occurred. GDF15 was associated with a higher risk of HF hospitalization or all-cause death [adjusted hazard ratio 1.84 (95% confidence interval 1.45-2.33)], with a particularly heightened risk in patients aged around 70 years (Pinteraction = 0.0008). The model with GDF15 on top of other established risk factors yielded marginally higher C-statistics compared with the model without GDF15 (0.803 and 0.796, P = 0.045). The additive value of GDF15 on top of other established risk factors appeared similar across ages. A universal cut-off value of 1400 pg/mL performed well in discriminating between those with and without HF hospitalization or death.
Conclusions:
Some clinical correlates of GDF15 have an interaction with age. GDF15 is an important determinant of cardiovascular endpoints, particularly in patients aged around 70 years. The additive value of GDF15 appeared consistent across ages, suggesting the use of a universal cut-off value.
