Sleep Apnea induced Endothelial Dysfunction: could it be reversible?

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1 Orofacial Pain and Oral Medicine Course: OFPM #723 Motor/Sleep Disorders and Oral Physiology in OFPOM Lecture #3a Dr. Glenn Clark Professor of Diagnostic Sciences Assistant Dean of Distance Education Director of Masters Degree in Orofacial Pain and Oral Medicine Herman Ostrow School of Dentistry of USC Sleep Apnea induced Endothelial Dysfunction: could it be reversible? Q: What is Endothelial Dysfunction? 1

2 1. normal anatomy of blood vessels Dysfunction begins with a endothelial insult such as: increased shear stress damage bacterial adherance oxidative stress = reactive oxygen/nitrogen species expression of pro-inflammatory mediators Scanning Electron Microscope Macrophages sticking to endothelium 2

3 2. Artherosclerosis of blood vessels CVE Stroke Q: How can we measure Endothelial Dysfunction? 3

4 3. Markers of Endothelial Dysfunction A. Cardiovascular/Cardiac Function Hypertension HRV & Arrhythmia B. Serologic Markers C-reactive protein; Cytokines High Density Lipoproteins ROS (Peroxidase) C. Provocation Testing Flow Mediated Dilation (FMD) Peripheral Arterial Tonometry A. Hypertension, HRV & Arrhythmia B. Serologic Markers of Arterial Disease C-Reactive Protein (CRP) is a protein found in the blood that is produced in the liver in response to infection, cancer & inflammatory diseases. Proinflammatory cytokines promotes systemic inflammation (e.g. Il-1 or TNF-alpha) Peroxidases are a large family of enzymes that typically catalyze a reaction (e.g. lipid peroxides). High Density Lipoproteins Peroxidase C-Reactive Protein Cytokines 4

5 Click here to watch a 9 minute video on Flow Mediated Vasodilation Testing C.Provocation Testing (Brachial Artery Flow-Mediated Vasodilation) Baseline Post-Occlusion 5 Minutes of Blood Pressure Cuff Occlusion Takese B, Am J Cardiol 1998:82:1535 Comparison of Brachial and Coronary Flow-Mediated Vasodilation 5

6 CVE s Peripheral Arterial Tonometry Peripheral Arterial Tonometry Probe Endo-PAT 2000 Q: Does increased arterial stiffness predict cardiovascular disease? Schachinger V et al, Circulation 2000;101:1899 Rate of CVE s over 7.7 Years in 147 Subjects with CAD grouped by FMD 45% 40% 35% 30% 25% 20% 15% 10% 5% 0% FMD FMD >19% FMD 10-19% FMD <10% 6

7 Neuntfeufl T et al, Am J Cardiol 2000;86:207 CHD Events over 5 Years in 76 CAD Patients According to Brachial Artery FMD 50% 45% 40% 35% 30% 25% 20% 15% 10% 5% 0% PTCA CABG MI ANY EVENT FMD >10% FMD <10% Murakami T et al. J Am Coll Cardiol 2001;37:294A CVE s over 4 Years in 480 Patients with Suspected CAD According to Brachial Artery FMD 25% 20% 15% 10% CHD Events CV Events 5% 0% <4% 4%-8% >8% Q: Is Endothelial Dysfunction related to obstructive sleep apnea? 7

8 4. Association between SDB and ED Endothelial Dysfunction?? Three studies on hypertension, CV function & OSA: Data show that with OSA there is increased: 1) sympathetic nerve activity 2) serologic markers of endothelial activation 3) markers of carotid atherosclerosis 4) elevated heart rate variability 5) morning elevated diastolic blood pressure [Zhang J, et al. Zhonghua Jie He He Hu Xi Za Zhi Jun;30(6): ] [Drager LF, et al. Hypertension. 2009;53(1):64-9.] [Xu Q, et al. Zhonghua Yi Xue Za Zhi Jul 14;89(26): ] Three studies on serum inflammatory markers & OSA: Data show that with OSA there is increased: 1) C-reactive protein levels associated with ODI > 10 2) Untreated SDB (ODI>20/h) associated with CRP 3) Moderate/severe OSA associated with low HDLcholesterol serum levels in the elderly. [Roche F, et al. Eur Respir J Apr;33(4): ] [Yao M, et al. Sleep. 2006;29(5):661-5.] [Roche F, et al. Sleep Med Sep;10(8):882-6.] 8

9 Click here to watch a 6 minute video on CPAP Risk and Benefits Q: Does CPAP reverse endothelial dysfunction? 9

10 Vlachantoni IT, et al. Effects of continuous positive airway pressure (CPAP) treatment for obstructive sleep apnea in arterial stiffness: a meta-analysis. Sleep Med Rev Feb;17(1): Meta-analysis of CPAP effect on arterial stiffness in OSA studies (n=615) assessed arterial stiffness and CPAP 2. 5 different meta-analyses were performed Results: 1. significant improvement of all arterial stiffness after CPAP 2. Compliance with CPAP did not alter result Conclusion: meta-analyses showed significant improvements in all indices of arterial stiffness after CPAP treatment in patients with OSA. Q: Does a MAD reverse endothelial dysfunction? Five studies on MAD tx and HTN in OSA: Data show that with MAD tx: 1) MAD tx for 4 wks lowered 24 hr DBP slightly 2) MAD tx lowered daytime blood pressure. 3) MAD tx reduced DBP at 3-m and 3-yr point [Gotsopoulos H, et al. Sleep Aug 1;27(5): ] [Yoshida K. Int J Prosthodont Jan-Feb;19(1):61-6.] [Otsuka R, et al. Sleep Breath Mar;10(1):29-36.] [Andrén A, et al. J Oral Rehabil Oct;36(10): ] [Zhang LQ, et al. Zhonghua Yi Xue Za Zhi Jul 14;89(26): ] 10

11 Sarah Hezi ---Lena -- Peretz -- Glenn -- Giora 16 subjects (11m/5f). - mean age = 54.0±8.3/y - BMI = 28.0±3.1 kg/m2 Venous blood (10 ml) samples obtained from each patient after an overnight fast for purpose of testing the biochemical markers of oxidative stress 11

12 Peripheral Arterial Tonometry Probe Testing with PAT Normal Response Abnormal Response BASELINE OCCLUSION HYPEREMIA Kuvin et al, July 2003 Provocation testing (PAT) & MAD Tx: Data shows that the MAD (Herbst): 1. Reduces AHI, ODI and Sleepiness scores 2. Reduces Serologic Markers of Inflammation 3. Reduces Arterial Stiffness (at the 3 months and the 1 year tx point) [Itzhaki S, et al. Chest. 2007;131(3):740-9.] 12

13 Implication of Data Improved EF (back to normal levels) without a complete elimination of apneic events suggesting there is a threshold for episodic hypoxia on EF. Q: Since Itzhaki (2007) has this result been validated? Galic T, et al. Effects of mandibular advancement device treatment on arterial stiffness and glucose metabolism in patients with mild to moderate obstructive sleep apnea: a prospective 1 year study. Sleep Breath Mar;20(1): Study: MAD effect on arterial stiffness & inflammatory markers patients with mild to moderate OSA enrolled 2. MAD treatment effect at 3 months and 1 year 3. PSG, arterial stiffness and blood test for markers 4. 1 year data were compared to baseline values. Results: 1. Significant decrease in AHI at 1 yr (22.9±5.9 to 9.7±4.5) 2. Reduce fasting plasma glucose at 1 yr (5.3±0.5 to 4.9±0.5) 3. Plasma level of inflammatory marker fibrinogen decreased significantly from 3.4 ± 0.7 at baseline to 3.0 ± 0.9. Conclusions: MAD Tx improved arterial stiffness, glucose metabolism and fibrinogen levels in OSA patients at 1 year. 13

14 Conclusions 1. Atherogenic disease (in part) occurs due to oxidative stress associated with chronic intermittent hypoxia (OSA). 2. Finally arterial inflammation (evidenced by serologic markers of inflammation) is related to OSA because hypoxia reoxygenation during sleep produces reactive oxygen species (ROS) which damages the endothelium. 3. Treatment both with CPAP (>5hr/n) and MADs can reverse some of this damage. The End! [Hybrid Online Education] Master s Degree and Certificates? 41 14