Associations of Circulating Growth Differentiation Factor-15 and ST2 Concentrations With Subclinical Vascular Brain Injury and Incident Stroke

Abstract

Background and Purpose— Growth differentiation factor-15 (GDF-15) and soluble (s)ST2 are markers of cardiac and vascular stress. We investigated the associations between circulating concentrations of these biomarkers and incident stroke and subclinical vascular brain injury in a sample from the Framingham Offspring cohort. Methods— We followed 3374 stroke- and dementia-free individuals (mean age, 59.0±9.7 years; 53% women) attending the Framingham Offspring sixth examination cycle 11.8±3.0 years for incident stroke. A subsample of 2463 individuals underwent brain magnetic resonance imaging and neuropsychological testing ≈4.0±1.7 years after the sixth examination. Results— After adjustment for traditional cardiovascular risk factors, B-type natriuretic peptide, high-sensitivity C-reactive protein, and urine albumin levels, higher stress biomarker levels were associated cross-sectionally with lower brain volumes ( β coefficients for intracranial volume comparing fourth [Q4] versus first biomarker [Q1] quartiles: −0.71% for GDF-15; P =0.002 and 0.47% for sST2; P =0.02) and worse performance on the visual reproduction test ( β coefficients for Q4 versus Q1: −0.62 for GDF-15; P =0.009 and −0.40 for sST2; P =0.04). Higher GDF-15 concentrations were also associated with greater log-transformed white-matter hyperintensity volumes ( β for Q4 versus Q1=0.19; P =0.01). Prospectively, a total of 203 (6%) individuals developed incident stroke/transient ischemic attack during follow-up. After multivariable adjustment, sST2 remained significantly associated with stroke/transient ischemic attack, hazard ratio for Q4 versus Q1 of 1.76, 95% confidence interval of 1.06 to 2.92, and P =0.03. Conclusions— Circulating GDF-15 and sST2 are associated with subclinical brain injury and cognitive impairment. Higher sST2 concentrations are also associated with incident stroke, suggesting potential links between cardiac stress biomarkers and brain injury.