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Ischemic stroke (IS) is a leading cause of death and disability worldwide. Identification of novel blood-based biomarkers that aid in the early identification of high-risk patients and in the classification and diagnosis of IS may facilitate patient management and improve the understanding of stroke etiologies. In 3,904 men and women from the Atherosclerosis Risk In Communities study, we investigated the association of 245 serum metabolites measured at the baseline examination via untargeted metabolomic profiling with incident IS. First IS events occurring between the baseline examination and December 31, 2012 were ascertained by annual telephone interview and hospital surveillance, followed case adjudication by a committee of experienced physicians. Cox proportional hazard models were used to estimate the hazard ratio (HR) for IS per standard deviation of the standardized serum level of each metabolites, adjusting for baseline age, sex, race and field center (model 1); and additionally for diabetes, hypertension, current smoking, body mass index, and estimated glomerular filtration rate (model 2). Over a median follow-up of 23 years, 306 incident IS were observed. After correcting for multiple testing, we identified 12 serum metabolites associated with IS in model 1 (P<0.0002). Two long-chain dicarboxylic acids, tetradecanedioate and hexadecanedioate, remained significantly associated with IS in model 2 (HR [95%CI] = 1.13 [1.08-1.18] and 1.15 [1.09-1.20], respectively). Serum levels of these two metabolites were strongly correlated (r2=0.88). Analyses by IS subtypes suggested that this association is specific to cardioembolic stroke. In summary, we identified two long-chain dicarboxylic acids associated with cardioembolic stroke independently of known risk factors. These compounds are metabolic products of fatty acids produced by ω-oxidation, a normally minor catabolic pathway, which becomes more prominent when β-oxidation is defective. These results are consistent with recent metabolomics studies of carotid plaque tissue implicating β-oxidation dysfunction in plaque instability. Further studies are needed to confirm the relationships uncovered here and shed light on possible mechanisms for these associations.