Incremental prognostic impact of peripheral microvascular endothelial dysfunction on the development of ischemic stroke

BACKGROUND: Peripheral microvascular endothelial dysfunction (PMED) has been linked to an increased risk of cardiovascular events, but there is a lack of information characterizing the predictive value of PMED for future risk of ischemic stroke (IS). METHODS AND RESULTS: This retrospective observational cohort study enrolled 637 patients who underwent non-invasive microvascular endothelial function assessment using reactive hyperemia peripheral arterial tonometry. Reactive hyperemia peripheral arterial tonometry index ≤2 was defined as PMED. Of 280 patients with PMED, 12 (4.3%) patients developed IS, compared with only 4 (1.1%) of 357 patients without PMED during a median follow-up of 5.3 years. Patients with PMED had lower IS-free survival compared with patients without PMED (log-rank P=0.03). Cox proportional hazard ratio (HR) analyses showed that PMED predicted the incidence of IS, with a HR of 3.43, 95% CI, 1.10–10.63 (P=0.03); adjusted HR of 3.70, 95% CI, 1.18–11.59 (P=0.02) after adjusting for sex, smoking history, and atrial fibrillation; adjusted HR of 3.45, 95% CI, 1.11–10.72 (P=0.03) after adjusting for CHA₂ DS₂-VASc score; adjusted HR of 5.70, 95% CI, 1.40–23.29 (P=0.02) after adjusting for revised Framingham Stroke Risk Score. Reactive hyperemia peripheral arterial tonometry index improved discrimination of risk for IS after adding reactive hyperemia peripheral arterial tonometry index to CHA₂ DS₂-VASc score and revised Framingham Stroke Risk Score. CONCLUSIONS: PMED was associated with a >3-fold increased risk of IS. These findings underscore the concept of the systemic nature of endothelial dysfunction, which could act as a potential marker to predict future risk of IS.