Atherosclerosis and glycosaminoglycan metabolism defects: Frequent association of endothelial dysfunction in patients with mucopolysaccharidosis. S. Yano1, K. Moleley1, L. Wong1, C. Castelnovi1, C. Azen2, Z. Pavlova3 1) Genetics/Pediatrics, University of Southern California, Los Angeles, CA; 2) Clinical Trials Unit Children's Hospital Los Angeles, University of Southern California, Los Angeles, CA; 3) Pathology, Children's Hospital Los Angeles, University of Southern California, Los Angeles, CA.

   Cardiovascular lesions including coronary stenosis are frequently associated in patients with genetic defects of glycosaminoglycan (GAG) metabolism. Atherosclerosis is the result of a complex interaction between lipoproteins, extracellular matrix consisting of proteoglycans, and cells of the vessel wall. Inflammatory response of T cells to GAGs is involved in atherogenesis that is preceded by endothelial dysfunction (ED) as a key event. Decreased nitric oxide (NO) bioavailability is considered the hallmark of ED. Reduced endothelial NO synthase (eNOS) has been reported in atherosclerotic arteries. Histopathologic similarity between the atherosclerotic changes in adults and in patients with GAG metabolism defects has been known although reduced eNOS has not been reported in GAG metabolism defects. Although it is well recognized that early diagnosis of coronary artery (CA) involvement in patients with Mucopolysaccharidosis (MPS) is of extreme importance for proper clinical management, diagnosis of early CA changes is difficult. Even CA angiography has limited value since it can underestimate the extent of the stenotic vascular lesions. Hence, the prevalence of CA lesions in patients with MPS is not well known. Impairment in reactive hyperemia-digital peripheral arterial tonometry (RH-PAT) with EndoPAT has been validated to correlate coronary microvascular function in patients with atherosclerosis. RH-PAT is thought to reflect endothelial NO production. Objective: (1) To evaluate eNOS in the CA specimens from a patient with GAG metabolism defect to confirm presence of the pathophysiology similar to the atherosclerotic changes characterized by ED. (2) To evaluate endothelial function in patients with various GAG metabolism defects. Methods and Results: (1) Immunohistological staining revealed decreased eNOS in the CA in a 3-year-old patient with MPS-I who died due to ischemic heart attack. (2) Evaluation of endothelial function with EndoPAT in 30 patients with GAG metabolism defects revealed a significantly high incidence of ED compared with 12 controls. Conclusions: Decreased eNOS in the MPS-I patient suggested the common pathology in GAG metabolism defects and in atherosclerosis, and a high incidence of ED in patients with GAG metabolism defects diagnosed by RH-PAT with EndoPAT may suggests that this method can provide vital information of CA lesions in the clinical management of patients with GAG metabolism defects.

You may contact the first author (during and after the meeting) at