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

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 (&bgr; 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 (&bgr; 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 (&bgr; 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.

[1]  P. Sachdev,et al.  The Relationship of Serum Macrophage Inhibitory Cytokine – 1 Levels with Gray Matter Volumes in Community-Dwelling Older Individuals , 2015, PloS one.

[2]  M. Rousseau,et al.  Increased soluble ST2 is a stronger predictor of long-term cardiovascular death than natriuretic peptides in heart failure patients with reduced ejection fraction. , 2014, International journal of cardiology.

[3]  Y. Izumiya,et al.  Growth differentiation factor-15 is a useful prognostic marker in patients with heart failure with preserved ejection fraction. , 2014, The Canadian journal of cardiology.

[4]  M. Whooley,et al.  Growth differentiation factor 15 and cardiovascular events in patients with stable ischemic heart disease (The Heart and Soul Study). , 2014, American heart journal.

[5]  L. Lind,et al.  GDF-15 for Prognostication of Cardiovascular and Cancer Morbidity and Mortality in Men , 2013, PloS one.

[6]  D. Levy,et al.  Association of Novel Biomarkers of Cardiovascular Stress With Left Ventricular Hypertrophy and Dysfunction: Implications for Screening , 2013, Journal of the American Heart Association.

[7]  P. Wolf,et al.  Serum Brain–Derived Neurotrophic Factor and Vascular Endothelial Growth Factor Levels Are Associated With Risk of Stroke and Vascular Brain Injury: Framingham Study , 2013, Stroke.

[8]  P. Sachdev,et al.  Macrophage inhibitory cytokine‐1 is associated with cognitive impairment and predicts cognitive decline – the Sydney Memory and Aging Study , 2013, Aging cell.

[9]  D. Levy,et al.  Relations of arterial stiffness and endothelial function to brain aging in the community , 2013, Neurology.

[10]  Sohail Q Khan,et al.  Pre-discharge risk stratification in unselected STEMI: is there a role for ST2 or its natural ligand IL-33 when compared with contemporary risk markers? , 2013, International journal of cardiology.

[11]  R. Vasan,et al.  Soluble ST2 predicts elevated SBP in the community , 2013, Journal of hypertension.

[12]  R. Henning,et al.  Growth differentiation factor 15 impairs aortic contractile and relaxing function through altered caveolar signaling of the endothelium. , 2013, American journal of physiology. Heart and circulatory physiology.

[13]  R. Vasan,et al.  Distribution and clinical correlates of the interleukin receptor family member soluble ST2 in the Framingham Heart Study. , 2012, Clinical chemistry.

[14]  Andrew D. Johnson,et al.  Clinical and genetic correlates of growth differentiation factor 15 in the community. , 2012, Clinical chemistry.

[15]  D. Levy,et al.  Prognostic Utility of Novel Biomarkers of Cardiovascular Stress: The Framingham Heart Study , 2012, Circulation.

[16]  C. DeCarli,et al.  Multiple Biomarkers and Risk of Clinical and Subclinical Vascular Brain Injury: The Framingham Offspring Study , 2012, Circulation.

[17]  D. Laskowitz,et al.  Evolving role of biomarkers in acute cerebrovascular disease , 2012, Annals of neurology.

[18]  C. Wolf,et al.  Growth differentiation factor-15 in the early diagnosis and risk stratification of patients with acute chest pain. , 2012, Clinical chemistry.

[19]  R. Wachter,et al.  Growth-differentiation factor-15 and functional outcome after acute ischemic stroke , 2012, Journal of Neurology.

[20]  R. Lichtinghagen,et al.  Growth Differentiation Factor 15 Plasma Levels and Outcome after Ischemic Stroke , 2011, Cerebrovascular Diseases.

[21]  E. Barrett-Connor,et al.  Growth-Differentiation Factor-15 Is a Robust, Independent Predictor of 11-Year Mortality Risk in Community-Dwelling Older Adults: The Rancho Bernardo Study , 2011, Circulation.

[22]  Shijie Jin,et al.  Production and functions of IL-33 in the central nervous system , 2011, Brain Research.

[23]  K. Unsicker,et al.  Regulation of GDF-15, a distant TGF-β superfamily member, in a mouse model of cerebral ischemia , 2010, Cell and Tissue Research.

[24]  L. Lind,et al.  Growth-differentiation factor-15 is an independent marker of cardiovascular dysfunction and disease in the elderly: results from the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) Study. , 2009, European heart journal.

[25]  C. Choi,et al.  Estimating the probability of stroke in Korean hypertensive patients visiting tertiary hospitals using a risk profile from the framingham study , 2009, BMC neurology.

[26]  Henri A. Vrooman,et al.  Progression of Cerebral Small Vessel Disease in Relation to Risk Factors and Cognitive Consequences: Rotterdam Scan Study , 2008, Stroke.

[27]  L. Wallentin,et al.  Growth-differentiation factor-15 improves risk stratification in ST-segment elevation myocardial infarction. , 2007, European heart journal.

[28]  A. Siegbahn,et al.  Growth Differentiation Factor 15 for Risk Stratification and Selection of an Invasive Treatment Strategy in Non–ST-Elevation Acute Coronary Syndrome , 2007, Circulation.

[29]  P. Koudstaal,et al.  Silent brain infarcts: a systematic review , 2007, The Lancet Neurology.

[30]  D. Levy,et al.  Multiple biomarkers for the prediction of first major cardiovascular events and death. , 2006, The New England journal of medicine.

[31]  D. Heil.  Predicting Activity Energy Expenditure Using the Actical® Activity Monitor , 2006, Research quarterly for exercise and sport.

[32]  R. D'Agostino,et al.  Association of white matter hyperintensity volume with decreased cognitive functioning: the Framingham Heart Study. , 2006, Archives of neurology.

[33]  D. Harvey,et al.  Measures of brain morphology and infarction in the framingham heart study: establishing what is normal , 2005, Neurobiology of Aging.

[34]  R B D'Agostino,et al.  Stroke risk profile, brain volume, and cognitive function , 2004, Neurology.

[35]  Sudha Seshadri,et al.  Framingham Stroke Risk Profile and Lowered Cognitive Performance , 2004, Stroke.

[36]  A. Hofman,et al.  Silent brain infarcts and the risk of dementia and cognitive decline. , 2003, The New England journal of medicine.

[37]  W. D. Fairlie,et al.  Expression of growth differentiation factor‐15/ macrophage inhibitory cytokine‐1 (GDF‐15/MIC‐1) in the perinatal, adult, and injured rat brain , 2001, The Journal of comparative neurology.

[38]  K. Unsicker,et al.  Growth/Differentiation Factor-15/Macrophage Inhibitory Cytokine-1 Is a Novel Trophic Factor for Midbrain Dopaminergic Neurons In Vivo , 2000, The Journal of Neuroscience.

[39]  R B D'Agostino,et al.  Probability of stroke: a risk profile from the Framingham Study. , 1991, Stroke.

[40]  W. Kannel,et al.  An investigation of coronary heart disease in families. The Framingham offspring study. , 1979, American journal of epidemiology.

[41]  M. Rienstra,et al.  Relation between soluble ST2, growth differentiation factor-15, and high-sensitivity troponin I and incident atrial fibrillation. , 2014, American heart journal.

[42]  Richard T. Lee,et al.  Role of ST2 in non-ST-elevation acute coronary syndrome in the MERLIN-TIMI 36 trial. , 2012, Clinical chemistry.