The Evaluation of Flow-Mediated Vasodilation in the Brachial Artery Correlates With Endothelial Dysfunction Evaluated by Nitric Oxide Synthase Metabolites in Marfan Syndrome Patients

Abstract

Marfan syndrome (MS) is of the most common connective tissue disorders. Although most patients have mutations in the fibrillin-1 gene (FBN1) and more than 1,700 mutations have been described, there are no mutations in less than 10% of patients. Aortic dilation is the most important complication; it involves chronic inflammatory processes and endothelial dysfunction. Prospective study from March 2015 to January 2017, in a cohort of 32 patients of MS confirmed by Ghent criteria and 35 controls of both genders, with a median age of 26 years (18-56). Patients had no comorbidities such as diabetes, hypertension, and/or neoplasms. They were not being treated with statin, NSAIDs, calcium antagonists, oral nitrates, and/or beta-blockers during 7 days prior to the study and patients with smoking history in the last 4 years. Controls were matched by age and gender. We analyzed endothelial dysfunction by flow-mediated vasodilation in the brachial artery, determining the maximum peak flow in the reactive hyperemia phase with a Philips Envisor device with Doppler capability. Its correlation with serum levels of biological markers that could participate in endothelial dysfunction pathways such as ${\text{NO}}_3^{-}/{\text{NO}}_2^{-}$ ratio, ${\text{NO}}_2^{-}$ , citrulline, TNFα, IL-1, IL-6, IL-10, IL-8, osteopontin, ICAM, VCAM, and ${\text{NO}}_3^{-}/{\text{NO}}_2^{-}$ was determined. Endothelial dysfunction was found in 21 MS patients (65%). The aortic annulus (AAo) was of 27 mm (22-40) and 24 mm (22-30) (p = 0.04) in MS patients with and without dysfunction. The level of ${\text{NO}}_3^{-}/{\text{NO}}_2^{-}$ ratio, was of 108.95 ± 12.05 nM/ml in controls vs. 170.04 ± 18.76 nM/ml in MS (p = 0.002), ${\text{NO}}_2^{-}$ was of 33.78 ± 3.41 vs. 43.95 ± 2.59 nM/ml (p = 0.03), citrulline 62.65 ± 3.46 vs. 72.81 ± 4.35 μMol/ml (p = 0.06). VCAM median was 39 pg/ml (0-86) vs. 32 pg/ml (11-66) (p = 0.03), respectively. The correlation of VCAM with triglycerides (TG) was of 0.62 (p = 0.005). There were no differences in TNFα, IL-1, IL-6, IL-8, IL-10, and osteopontin. MS endothelial dysfunction is related to aortic diameters, and increased levels of VCAM, L-citrulline and ${\text{NO}}_3^{-}/{\text{NO}}_2^{-}$ ratio, ${\text{NO}}_2^{-}$ . VCAM-1 has a significant correlation with TG and could play a significant role in endothelial dysfunction.

Keywords: Marfan syndrome; endothelial dysfunction; flow-mediated vasodilation; inflammation; nitric oxide.