Abstract
OBJECTIVE: To determine whether altered metabolic profiles represent a link between atrial dysfunction and cardioembolic (CE) stroke, and thus whether underlying dysfunctional atrial substrate may contribute to thromboembolism risk in CE stroke. METHODS: A total of 144 metabolites were measured using liquid chromatography-tandem mass spectrometry in plasma samples collected within 9 hours of stroke onset in 367 acute stroke patients. Stroke subtype was assigned using the Causative Classification of Stroke System, and CE stroke (n = 181) was compared to non-CE stroke (n = 186). Markers of left atrial dysfunction included abnormal atrial function (P-wave terminal force in lead V1, PTFV(1) >4,000 μV·ms), left atrial enlargement on echocardiography, and frank atrial fibrillation on ECG. Stroke recurrence risk was assessed using CHADS(2) and CHA(2)DS(2)-VASc scores. Associations between metabolites and CE stroke, atrial dysfunction, and stroke recurrence risk were evaluated using logistic regression models. RESULTS: Three tricarboxylic acid metabolites-succinate (odds ratio [OR] 1.71, 95% confidence interval [CI] 1.36-2.15, p = 1.37 × 10(-6)), α-ketoglutarate (OR 1.62, 95% CI 1.29-2.04, p = 1.62 × 10(-5)), and malate (OR 1.58, 95% CI 1.26-1.97, p = 2.57 × 10(-5))-were associated with CE stroke. Succinate (OR 1.36, 95% CI 1.31-1.98, p = 1.22 × 10(-6)), α-ketoglutarate (OR 2.14, 95% CI 1.60-2.87, p = 2.08 × 10(-8)), and malate (OR 2.02, 95% CI 1.53-2.66, p = 1.60 × 10(-7)) were among metabolites also associated with subclinical atrial dysfunction. Of these, succinate was also associated with left atrial enlargement (OR 1.54, 95% CI 1.23-1.94, p = 1.06 × 10(-4)) and stroke recurrence based on dichotomized CHADS(2) (OR 2.63, 95% CI 1.68-4.13, p = 3.00 × 10(-6)) and CHA(2)DS(2)-VASc (OR 2.43, 95% CI 1.60-3.68, p = 4.25 × 10(-6)) scores. CONCLUSIONS: Metabolite profiling identified changes in succinate associated with CE stroke, atrial dysfunction, and stroke recurrence, revealing a putative underlying link between CE stroke and energy metabolism.