Growth-differentiation factor-15 is a robust, independent predictor of 11-year mortality risk in community-dwelling older adults: the Rancho Bernardo Study

Abstract

Background: Growth-differentiation factor-15 (GDF-15) is emerging as a prognostic marker in patients with cardiovascular disease (CVD), but its prognostic value in community-dwelling adults has not been reported. We hypothesized that GDF-15 would add incremental power for prediction of mortality in a population of community-dwelling older adults without known heart disease.

Methods and results: We measured plasma GDF-15, N-terminal pro-B-type natriuretic peptide (NT-proBNP), and C-reactive protein levels in 1391 Rancho Bernardo Study participants, mean age 70 years, with no history of CVD and followed them for a mean of 11 years. In models adjusted for traditional CVD risk factors, GDF-15 was a robust predictor of all-cause, cardiovascular, and noncardiovascular mortality. GDF-15 was a stronger predictor of all-cause mortality than either NT-proBNP or C-reactive protein (hazard ratio [95% confidence interval] per SD log(10) units 1.5 [1.3 to 1.8], P<0.0001 for GDF-15 versus 1.3 [1.2 to 1.5], P<0.0001 for NT-proBNP; C-reactive protein was not a significant predictor). Among biomarkers considered, only GDF-15 predicted noncardiovascular death (hazard ratio 1.6 [1.4 to 2.0], P<0.0001). Growth differentiation factor-15 improved discrimination and modestly but significantly improved reclassification for all-cause and noncardiovascular mortality with borderline improvement for cardiovascular mortality; NT-proBNP significantly improved reclassification for all-cause and for cardiovascular mortality; C-reactive protein did not improve reclassification for any end point tested. Participants in the highest quartile of both GDF-15 and NT-proBNP had an increased risk of death compared with participants with only NT-proBNP elevated (hazard ratio 1.5 [1.1 to 2.0], P=0.01).

Conclusions: Growth differentiation factor-15 is a strong predictor of all-cause, cardiovascular, and noncardiovascular mortality in community-dwelling older individuals, adding incremental value to traditional risk factors and to NT-proBNP and C-reactive protein levels.

Figure 1

Kaplan Meier curves adjusted for competing types of mortality, by GDF-15 quartile. Cut-points for GDF-15 quartiles are <962, 962–1268, 1269–1780, and >1780 ng/L. Log rank p-value <0.001 for each.

Figure 2

Reclassification based on GDF-15 levels. Individuals in the unshaded diagonal boxes did not change classification with the addition of GDF-15. Green shading indicates the number (percent) of individuals who were reclassified in a desirable direction when GDF-15 was added to the baseline model; red shading indicates individuals who were reclassified in an undesirable direction.

Figure 3

Forest plot of adjusted hazard ratio and 95% confidence interval (CI) for risk of death per 1-standard deviation increase in log₁₀GDF-15, log₁₀NT-proBNP, and log₁₀CRP level.

Figure 4

Kaplan Meier curves adjusted for competing type of mortality, based on GDF-15 and NT-proBNP levels. Four groups are compared: those with both GDF-15 and NT-proBNP in the highest quartile (n=171; 56 cardiovascular, 64 non-cardiovascular deaths), those with only GDF-15 in the highest quartile (n=176; 38 cardiovascular, 61 non-cardiovascular deaths), those with only NT-proBNP in the highest quartile (n=174; 35 cardiovascular, 41 non-cardiovascular deaths), and those with neither marker elevated (n=863; 39 cardiovascular, 101 non-cardiovascular deaths). Three participants did not have NT-proBNP measured. Log rank p-value <0.001 for each.