טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
M.Sc Thesis
M.Sc StudentHefetz Aya
SubjectNitric Oxide (NO) and Vascular Endothelial Growth Factor
(VEGF) levels in Obstructive Sleep Apnea Syndrom
(OSAS): Relationship to Cardiovascular
Disease
DepartmentDepartment of Medicine
Supervisors Professor Emeritus Peretz Lavie
Dr. Lena Lavie


Abstract

Introduction: Obstructive sleep apnea syndrome (OSAS) is characterized by repeated breathing arrests during sleep, leading to repeated arterial oxygen desaturations. A strong independent association was established between OSAS and cardiovascular morbidity and mortality.

Nitric oxide (NO) mediates vascular relaxation, decreases aggregation of platelets and inhibits leukocyte/endothelial cell interactions.

Vascular endothelial growth factor (VEGF) promotes new blood vessel formation via mitogenesis, and regulates vascular permeability, and vascular tone.

Methods: Nitric oxide levels were measured by the chemiluminescent nitric oxide analyzer (NOA 280, SIEVERES, BOULDER, CO). VEGF levels were measured by a quantitative enzyme-linked immunoassay technique using a commercially available kit (R&D Systems, Abingdon, UK).

Results and Discussion : Experiment 1: There were no circadian rhythms for NO or VEGF in young healthy men. Experiment 2: Overnight NO levels were significantly lower in male OSAS patients in comparison to both control groups

( OSAS: 25.39±4.42 mM Age similar snorers: 36.46±7.41mM, p<0.01, Young healthy men: 38.86±12.87 mM). Overnight VEGF levels were significantly higher in OSAS patients in comparison to both control groups (OSAS: 1283.7 cm2 Age similar snorers: 918.44 cm2 Young healthy men: 389.92 cm2 , p<0.007).  Long term nasal Continuous Positive Air Pressure (nCPAP) treatment significantly increased NO levels (Before: 26.93±6.25 mM After: 37.4±10.31 mM, p<0.01). Morning L-arginine levels also showed a significant increase after nCPAP treatment (Before: 100.4±13.57 mM After: 116.04±12.84 mM, p<0.05, Control: 106.0±9.61 mM). VEGF levels decreased in OSAS patients after nCPAP treatment (Before: 1419.11 cm2 or 129.01±43.37 pg/ml After: 1208.47 cm2 or 19.86±22.59 pg/ml). Experiment 3: Removing nCPAP treatment for one night in otherwise treated patients resulted in an immediate decrease in morning NO levels in all patients (With: 26.76±16.69 mM Without: 15.54±8.53 mM, p<0.04). Similarly a decrease in L-arginine was noted (With: 96.7±13.4 mM Without: 90.3±11.6 mM, p<0.1). In contrast omitting nCPAP resulted in increased VEGF levels (With: 144.18±138.64 pg/ml Without: 171.03±141.55 pg/ml ).

It is reasonable to assume that the recurrent episodic hypoxia during sleep, which promotes free radical formation, impaired endothelial cell function in OSAS patients, and as a result NO and VEGF release by endothelial and vascular smooth muscle cells were altered. Endothelial dysfunction provides a possible mechanism for explaining the high rate of cardiovascular morbidity in patients with sleep apnea. On the other hand the increased VEGF levels may contribute to a long-term adaptation of sleep apnea patients to the recurrent nocturnal hypoxia.