Submitted to: Circulation
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 3/12/2012
Publication Date: 3/28/2012
Citation: Pikula, A., Beiser, A.S., Decarli, C., Himali, J.J., Debette, S., Au, R., Selhub, J., Toffler, G.H., Wang, T.J., Meigs, J.B. 2012. Multiple biomarkers and risk of clinical and subclinical vascular brain injury: the framingham offspring study. Circulation. 125(17):21000-2107. Interpretive Summary: Stroke, the loss of brain function that occurs when blood flow to brain stops for longer than a few seconds, is the fourth leading cause of death and is a major cause of long-term disability in America. Despite progress in acute treatment protocols, prevention remains the most effective approach to reduce the personal and public health impact of stroke. Subclinical brain injuries (that do not demonstrate characteristic clinical symptoms of an injury) are associated with increased risk of a subsequent stroke. The objective of this study was to determine if biomarkers present in blood and urine can be used to determine the risk for subclinical brain injury in the stroke-free, middle-aged (average age 59 years) participants of Framingham Heart Offpsring Study. A panel of 8 biologically plausible biomarkers were found to be involved. These include inflammation (C-reactive protein), blood clot formation (D-dimer and plasminogen activator inhibitor-1), function of lining of heart and blood vessels (total homocysteine and ratio of urinary albumin to creatinine) and brain hormonal activity (ratio of aldosterone to renin, B-type natriuretic peptide and N-terminal proatrial natriuretic peptide), were tested was found to be associated with the risk of stroke. Whether these biomarkers can be used to target individuals at risk of stroke for more intense primary prevention or monitoring requires further investigation.
Technical Abstract: Several biomarkers have been individually associated with vascular brain injury, but no prior study has explored the simultaneous association of a biologically plausible panel of biomarkers with the incidence of stroke/transient ischemic attack and the prevalence of subclinical brain injury. In 3127 stroke-free Framingham offspring (age, 59+/-10 years; 54% female), we related a panel of 8 biomarkers assessing inflammation (C-reactive protein), hemostasis (D-dimer and plasminogen activator inhibitor-1), neurohormonal activity (aldosterone-to-renin ratio, B-type natriuretic peptide, and N-terminal proatrial natriuretic peptides), and endothelial function (homocysteine and urinary albumin/creatinine ratio) measured at the sixth examination (1995-1998) to risk of incident stroke/transient ischemic attack. In a subset of 1901 participants with available brain magnetic resonance imaging (1999-2005), we further related these biomarkers to total cerebral brain volume, covert brain infarcts, and large white-matter hyperintensity volume. During a median follow-up of 9.2 years, 130 participants experienced incident stroke/transient ischemic attack. In multivariable analyses adjusted for stroke risk factors, the biomarker panel was associated with incident stroke/transient ischemic attack and with total cerebral brain volume (P<0.05 for both) but not with covert brain infarcts or white-matter hyperintensity volume (P>0.05). In backward elimination analyses, higher log-B-type natriuretic peptide (hazard ratio, 1.39 per 1-SD increment; P=0.002) and log-urinary albumin/creatinine ratio (hazard ratio, 1.31 per 1-SD increment; P=0.004) were associated with increased risk of stroke/transient ischemic attack and improved risk prediction compared with the Framingham Stroke Risk Profile alone; when the <5%, 5% to 15%, or >15% 10-year risk category was used, the net reclassification index was 0.109 (P=0.037). Higher C-reactive protein (beta=-0.21 per 1-SD increment; P=0.008), D-dimer (beta=-0.18 per 1-SD increment; P=0.041), total homocysteine (beta=-0.21 per 1-SD increment; P=0.005), and urinary albumin/creatinine ratio (beta=-0.15 per 1-SD increment; P=0.042) were associated with lower total cerebral brain volume. In a middle-aged community sample, we identified multiple biomarkers that were associated with clinical and subclinical vascular brain injury and could improve risk stratification.