Association of growth differentiation factor-15 with coronary atherosclerosis and mortality in a young, multiethnic population: observations from the Dallas Heart Study

Abstract

Background: Growth differentiation factor 15 (GDF-15) is produced by cardiomyocytes and atherosclerotic lesions under stress conditions. Although higher circulating GDF-15 concentrations are associated with mortality across a spectrum of cardiovascular conditions, the relationship of GDF-15 with atherosclerosis and mortality in the general population remains undefined.

Methods: We measured plasma GDF-15 in 3219 participants of the Dallas Heart Study, a population sample of adults ages 30-65 years (55% women, 49% black). GDF-15 was analyzed in prespecified categories (<1200; 1200-1799; and ≥1800 ng/L) and continuously. End points included prevalent coronary artery calcium (CAC>10 Agatston units), increased CAC (CAC≥100 Agatston units) by electron beam computed tomography, and mortality through a median 7.3 years of follow-up (120 deaths, 48 cardiovascular deaths).

Results: Increasing GDF-15 associated with older age, black race, hypertension, diabetes, smoking, left ventricular (LV) mass/body surface area, and worse renal function (P<0.0001 for each). In multivariable models adjusted for traditional risk factors, renal function, and LV mass/body surface area, GDF-15≥1800 ng/L was associated with CAC>10 (odds ratio 2.1; 95% CI 1.2-3.7; P=0.01), CAC≥100 (odds ratio 2.6; 95% CI 1.4-4.9; P=0.002), all-cause mortality (hazard ratio 3.5; 95% CI 2.1-5.9, P<0.0001), and cardiovascular mortality (hazard ratio 2.5; 95% CI 1.1-5.8, P=0.03). Adding log GDF-15 to fully adjusted models modestly improved the c statistic (P=0.025), the integrated discrimination index (0.028; P<0.0001) and the category-less net reclassification index (0.42; P=0.002). These findings remained significant with further adjustment for high-sensitivity C-reactive protein, N-terminal pro-B-type natriuretic peptide, and cardiac troponin T.

Conclusions: GDF-15 is independently associated with subclinical coronary atherosclerosis and mortality, and its potential role for risk stratification in the general population merits further evaluation.

Fig. 1. Prevalent coronary calcium by GDF-15 groups

Adjusted odds ratios calculated for GDF-15 groups compared with GDF-15 <1200 ng/L, from logistic regression models for CAC >10 and CAC ≥ 100 in the general population and in those without cardiovascular disease, adjusting for age, sex, hypertension, diabetes, smoking, hypercholesterolemia, low HDL cholesterol, BMI, black or Hispanic race, eGFR, and LV mass/body surface area. Model for general population additionally adjusted for history of cardiovascular disease. CVD, self-reported history of MI, CHF, or stroke or evidence of median sternotomy or coronary stent on EBCT.

Fig. 2. GDF-15 groups and mortality in the general population

(A), All-cause mortality. (B), Cardiovascular mortality. Unadjusted hazard ratios calculated for GDF-15 groups compared with GDF-15 <1200 ng/L, from Cox proportional hazards models for all-cause death (120/2754) and cardiovascular death (48/2754) in the general population.

Fig. 3. GDF-15 groups and mortality in those without cardiovascular disease

(A), All-cause mortality. (B), Cardiovascular mortality. Unadjusted hazard ratios calculated for GDF-15 groups compared with GDF-15 <1200 ng/L, from Cox proportional hazards models for all-cause death (77/2288) and cardiovascular death (26/2288) in those without cardiovascular disease.