Συστηματική φλεγμονή και οξειδωτικό stress Σύνδρομο απνοιών στον ύπνο – ειδικά θέματα Συστηματική φλεγμονή και οξειδωτικό stress Κ. Θ. Κωστίκας, MD, FCCP Πνευμονολόγος

Σύνδρομο Απνοιών στον Ύπνο Συστηματική Φλεγμονή και Οξειδωτικό Stress Καρδιαγγειακός κίνδυνος Μεσολαβητές φλεγμονής Οξειδωτικό stress Θεραπευτικές αναζητήσεις

Σύνδρομο Απνοιών στον Ύπνο Συστηματική Φλεγμονή και Οξειδωτικό Stress Καρδιαγγειακός κίνδυνος Μεσολαβητές φλεγμονής Οξειδωτικό stress Θεραπευτικές αναζητήσεις

ΣΑΥ και Καρδιαγγειακές Παθήσεις Οι καρδιαγγειακές παθήσεις αποτελούν το κύριο αίτιο νοσηρότητας και θνησιμότητας στο ΣΑΥ Υπέρταση Ισχαιμική καρδιοπάθεια Αγγειακά εγκεφαλικά επεισόδια Οι μηχανισμοί που τις συνδέουν με το ΣΑΥ είναι πολυπαραγοντικοί McNicholas WT, ERS 2009

Κίνδυνος Αιφνίδιου Καρδιαγγειακού Θανάτου Somers J, NEJM 2005

Παθοφυσιολογικοί Μηχανισμοί PNA=parasympathetic nervous system activity. PO2=partial pressure of oxygen. PCO2=partial pressure of carbon dioxide. SNA=sympathetic nervous system activity. HR=heart rate. BP=blood pressure. LV=left ventricular. Bradley TD, Floras J, Lancet 2009

Inflammation, Atherosclerosis, and Coronary Artery Disease Hansson GK, NEJM 2005

OSA and the Vessel Wall Gozal D, AJRCCM 2008

OSA and Cardiovascular Disease Ryan S, Thorax 2009

Σύνδρομο Απνοιών στον Ύπνο Συστηματική Φλεγμονή και Οξειδωτικό Stress Καρδιαγγειακός κίνδυνος Μεσολαβητές φλεγμονής Οξειδωτικό stress Θεραπευτικές αναζητήσεις

CRP and IL-6 in Severe OSAHS: The Effect of CPAP 30 patients with OSAS and 14 obese control subjects Patients with moderate-to-severe OSAS were treated with CPAP for 1 month Yokoe T, Circulation 2003

CRP and SDB: the Wisconsin Cohort We investigated potential associations between circulating CRP, sleep duration, and SDB. Design: Cross-sectional Study. CRP was measured after overnight polysomnography. The relationships between CRP and sleep parameters were evaluated using multiple linear regression with and without controlling for age, sex, and body mass index (BMI) and other potential confounders. CRP was found to be higher for women and had a strong positive correlation with age and BMI. CRP showed a significant positive association with current smoking, waist-hip ratio (WHR), LDL-cholesterol, triglycerides, leptin, and insulin, independent of age, sex, and BMI. Significant independent negative associations for CRP were observed with HDL-cholesterol (HDL), insulin sensitivity (quantitative insulin sensitivity check index [QUICKI]), and hours of exercise. There was a significant positive association between CRP levels and the apnea-hypopnea index (AHI, the measure of SDB), but these relationships were not significant after adjustment for age, sex, and BMI. No significant association between CRP levels and measures of sleep duration (polysomnographic and selfreported) were found. Conclusion: There was no significant association between CRP levels and sleep duration. The lack of an independent association between CRP levels and SDB suggests that the reported relationship between these 2 variables may be primarily driven by their association with obesity. 907 adults from the Wisconsin Sleep Cohort Study (WSCS) Taheri S, Sleep 2007

CRP and OSAHS: the role of obesity No correlation with sleep parameters # significant with obesity (!) Background: High C-reactive protein (CRP) and homocysteine levels are risk factors for cardiovascular disease. Methods: CRP and homocysteine levels were measured in 110 subjects following polysomnography (PSG). Non-OSAS patients (group 1) were compared with two patient groups (mild/moderate OSAS (group 2) and severe OSAS (group 3)) group-matched for body mass index (BMI), and a fourth group of patients with severe OSAS who were more obese (group 4). All were free of other disease and similar in age, smoking habits and cholesterol levels. 50 suitable patients were commenced on continuous positive airway pressure (CPAP) treatment after PSG and 49 were reassessed 6 weeks later. Results: CRP levels were similar in groups 1, 2 and 3 (median (interquartile range (IQR)) 1.11 (0.76–2.11) mg/l vs 1.82 (1.20–3.71) mg/l vs 2.20 (1.16–3.59) mg/l; p = 0.727, Kruskal-Wallis test), but were significantly higher in group 4 than in the other groups (5.36 (2.42–9.17) mg/l, p,0.05 by individual group comparisons). In multivariate analysis of all subjects, BMI was an independent predictor for CRP levels (b = 0.221; p = 0.006) but apnoea-hypopnoea index and other measures of OSAS were not. There was no difference in homocysteine levels between all four groups (p = 0.1). CPAP did not alter CRP (2.29 (1.32–4.10) vs 2.84 (1.13–5.40) mg/l; p = 0.145) or homocysteine levels (8.49 (3.66) vs 9.90 (4.72) mmol/l; p = 0.381). Conclusion: CRP and homocysteine levels are not associated with OSAS severity in men but CRP is independently associated with obesity. 110 subjects, including 22 age and BMI-matched normal controls Before and after 6 weeks CPAP Ryan S, Thorax 2007

Soluble IL-6 Receptor in SDB A total of 385 adult participants (18 years of age) in the Cleveland Family Study, Cleveland, Ohio, underwent sleep studies and determination of IL-6 and sIL-6R levels in samples obtained in the evening and morning of polysomnography. Morning sIL-6R levels demonstrated stronger associations with moderate to severe SRBD than morning IL-6 levels. Associations with SRBD and morning sIL-6R levels persisted even after adjustment for waist circumference, cardiovascular disease, and evening sIL-6R levels, suggesting the potential utility of sIL-6R as a marker for measuring overnight SRBD stresses. 385 adult participants n the Cleveland Family Study Mehra R, Arch Intern Med 2006

TNF-α and IL-8 in OSA Ryan S, AJRCCM 2006 Background: Circulating nuclear factor-B (NF-B)–dependent genes, particularly tumor necrosis factor-α (TNF-α), are elevated in obstructive sleep apnea syndrome (OSAS) and likely contribute to cardiovascular disease. Furthermore, TNF-α is associated with excessive daytime sleepiness. We investigated the predictors of TNF-α and related genes in large, well-selected cohorts of subjects with OSAS and control subjects. Methods: We performed a prospective study of 30 subjects who did not have OSAS (22 non-sleepy normal control subjects and 8 sleepy non-apneic subjects who snored), 36 subjects with mild to moderate OSAS, and 31 subjects with severe OSAS; all subjects were male. Groups were matched for age, body mass index, and other relevant variables. Subjects had no other disease and were not regularly taking medication. All had serum for TNF-α and related assays drawn after polysomnography. A total of 49 suitable subjects were treated with continuous positive airway pressure (CPAP); sleep studies together with serum assays were repeated 6 wk later. Results: TNF-α levels were higher in subjects with OSAS than in subjects without OSAS (p 0.001). In multivariate analysis, TNF-α was independently associated with the desaturation index (r=0.399, p<0.001), Epworth Sleepiness Score (r=0.243, p=0.005), and cholesterol (r=0.216, p=0.018). Furthermore, TNF-α levels were higher in sleepy non-apneic subjects who snored than in normal control subjects (p=0.002) but lower than in subjects with OSAS (p=0.03). CPAP therapy lowered TNF-α levels (p=0.004). Another NF-B–dependent cytokine, interleukin-8 (IL-8), showed similar differences between groups and after CPAP therapy, but a range of other mediators of inflammation, including IL-1, IL-6, IL-10, and IL-12, showed no differences. Conclusion: Intermittent hypoxia is the strongest predictor of TNF-α levels, supporting a role for inflammation in the cardiovascular pathophysiology of OSAS. Furthermore, TNF-α levels are independently associated with excessive daytime sleepiness. Ryan S, AJRCCM 2006

TNF-α and IL-8 in OSA Both IL-8 and TNF-α suppressed by 6 wks of CPAP Intermittent hypoxia (DI) is the strongest predictor of TNF-α levels TNF-α levels are independently associated with excessive daytime sleepiness (ESS) Ryan S, AJRCCM 2006

Increased Carotid Intima-Media Thickness and Serum Inflammatory Markers in OSA IL-18 Controls: obese control subjects Increased carotid intima-media thickness (IMT) and increased serum levels of inflammatory markers, such as C-reactive protein (CRP), interleukin (IL)-6, and IL-18, are associated with an increased risk of cardiovascular and cerebrovascular diseases. The aim of this study was to evaluate whether carotid IMT, a useful marker for early atherosclerosis, is associated with these inflammatory markers in patients with obstructive sleep apnea (OSA). Carotid IMT was investigated with ultrasonography in 36 patients with OSA and 16 obese control subjects. Serum levels of CRP, IL-6, and IL-18 were measured at 5:00 A.M. Carotid IMT (p 0.001) and serum levels of CRP (p 0.003), IL-6 (p 0.005), and IL-18 (p 0.03) of patients with OSA were significantly higher than those of obese control subjects. Carotid IMT was significantly correlated with serum levels of CRP (r 0.61, p 0.0001), IL-6 (r 0.41, p 0.01), and IL-18 (r 0.45, p 0.005), duration of OSA-related hypoxia (r 0.60, p 0.0001), and severity of OSA (r 0.50, p 0.002). In addition, the primary factor influencing carotid IMT was duration of hypoxia during total sleep time (p 0.036). These results suggest that OSA-related hypoxia and systemic inflammation might be associated with the progression of atherosclerosis and thus might increase the risks of cardiovascular and cerebrovascular morbidity in patients with OSA. PLUS: increased CRP, IL-6, IL-18 IMT related to duration of OSA-related hypoxia, and severity of OSA Minoguchi K, AJRCCM 2005

Selective activation of inflammatory over adaptive pathways by intermittent hypoxia In vitro model of intermittent hypoxia/reoxygenation (IHR) Increase in luciferase activity comparing HELA cells treated with normoxia, following exposure to 2, 4, 8 or 16 cycles of intermittent hypoxia (IH) or 24-hour sustained hypoxia (SH) Ryan S, Circulation 2005

Selective activation of inflammatory over adaptive pathways by intermittent hypoxia In vitro model of intermittent hypoxia/reoxygenation (IHR) Ryan S, Circulation 2005

Hypoxia, Inflammation and CVD in OSA Ryan S, Thorax 2009

Elevated IL-8 and ICAM-1 Levels and CPAP Intercellular adhesion molecule-1 (ICAM-1) Apnea Index AI (A) and DM (B) desaturation magnitude (DM) 20 OSAS pts and 10 controls Ohga E, J Appl Physiol 2003

Σύνδρομο Απνοιών στον Ύπνο Συστηματική Φλεγμονή και Οξειδωτικό Stress Καρδιαγγειακός κίνδυνος Μεσολαβητές φλεγμονής Οξειδωτικό stress Θεραπευτικές αναζητήσεις

Αυξημένη παραγωγή ROS από ουδετερόφιλα ασθενών με ΣΑΥ Obstructive sleep apnea (OSA) is associated with increased cardiovascular morbidity and mortality. Free oxygen radicals have been implicated in the pathogenesis of cardiovascular disorders. Therefore, we aimed to test the hypothesis that increased oxidative stress constitutes one underlying mechanism for the connection between OSA and cardiovascular disease. In 18 patients with OSA the release of superoxide from polymorphonuclear neutrophils was determined after stimulation with the bacterial tripeptide formylmethionylleucylphenylalanine (fMLP) and the calcium ionophore A23. Superoxide production was measured as superoxide dismutase-inhibitable reduction of cytochrome c. Blood samples were obtained before and after two nights of CPAP therapy and after 4.8 ± 0.6 mo of follow-up. Ten healthy young volunteers and 10 lung cancer patients without OSA but a similar spectrum of comorbidity served as controls. Before CPAP, neutrophil superoxide generation was markedly enhanced in OSA when compared with both control groups. Effective CPAP therapy led to a rapid and long-lasting decrease of superoxide release in OSA. In conclusion, OSA is linked with a “priming” of neutrophils for enhanced respiratory burst. The increased superoxide generation, which might have major impact on the development of cardiovascular disorders, is virtually fully reversed by effective CPAP therapy. Schulz R, AJRCCM 2000

Lipid peroxidation and OSA Increased lipid peroxidation is a surrogate marker of atherosclerosis and cardiovascular morbidity AHI-dependent Minoguchi K, ERJ 2006

DNA oxidation in OSA Urinary excretion of 8-hydroxy-2-deoxyguanosine (8-OHdG) After adjustments for BMI, current smoke, sex, DBP, age, T-chol, HbA1c, medication, only ODI was significantly correlated with urinary 8-OHdG excretion Yamaouchi M, Chest 2005

Reduced Antioxidant Capacity in OSA 47 male patients with OSAS and 37 healthy control subjects were studied Barcelo A, ERJ 2006

Οξειδωτικό stress και φλεγμονή στο αγγειακό ενδοθήλιο ασθενών με ΣΑΑΥ Background Indirect evidence implicates endothelial dysfunction in the pathogenesis of vascular diseases associated with obstructive sleep apnea (OSA). We investigated directly whether dysfunction and inflammation occur in vivo in the vascular endothelium of patients with OSA. The effects of continuous positive airway pressure (CPAP) therapy on endothelial function and repair capacity were assessed. Methods and Results Thirty-two patients with newly diagnosed OSA and 15 control subjects were studied. Proteins that regulate basal endothelial nitric oxide (NO) production (endothelial NO synthase [eNOS] and phosphorylated eNOS) and inflammation (cyclooxygenase-2 and inducible NOS) and markers of oxidative stress (nitrotyrosine) were quantified by immunofluorescence in freshly harvested venous endothelial cells before and after 4 weeks of CPAP therapy. Vascular reactivity was measured by flow-mediated dilation. Circulating endothelial progenitor cell levels were quantified to assess endothelial repair capacity. Baseline endothelial expression of eNOS and phosphorylated eNOS was reduced by 59% and 94%, respectively, in patients with OSA compared with control subjects. Expression of both nitrotyrosine and cyclooxygenase-2 was 5-fold greater in patients with OSA than in control subjects, whereas inducible NOS expression was 56% greater. Expression of eNOS and phosphorylated eNOS significantly increased, whereas expression of nitrotyrosine, cyclooxygenase-2, and inducible NOS significantly decreased in patients who adhered to CPAP 4 hours daily. Baseline flow-mediated dilation and endothelial progenitor cell levels were lower in patients than in control subjects, and both significantly increased in patients who adhered to CPAP 4 hours daily. Conclusions OSA directly affects the vascular endothelium by promoting inflammation and oxidative stress while decreasing NO availability and repair capacity. Effective CPAP therapy is associated with the reversal of these alterations. freshly harvested venous endothelial cells Jelic S, Circulation 2008

Oxidative Stress, Inflammation and Endothelial Dysfunction in Obesity and OSA Untreated OSA rather than obesity is a major determinant of vascular endothelial dysfunction, inflammation, and elevated oxidative stress in obese patients After 4 weeks of continuous positive airway pressure therapy, flow-mediated dilation and expression of eNOS and phosphorylated eNOS significantly increased whereas expression of nitrotyrosine and nuclear factor-B significantly decreased in OSA patients who adhered to continuous positive airway pressure 4 hours daily freshly harvested venous endothelial cells Jelic S Circulation 2010

Σύνδρομο Απνοιών στον Ύπνο Συστηματική Φλεγμονή και Οξειδωτικό Stress Καρδιαγγειακός κίνδυνος Μεσολαβητές φλεγμονής Οξειδωτικό stress Θεραπευτικές αναζητήσεις

The Effect of CPAP on Inflammatory Biomarkers in Patients with OSAHS 1: good compliance, 2: poor compliance, 3: CPAP denial A: good compliance B: poor compliance 6-months CPAP treatment A: good compliance, B: poor compliance 1: good compliance, 2: poor compliance, 3: CPAP denial Steiropoulos P, Chest 2007; Steiropoulos P, Sleep 2009

CPAP on Inflammatory Biomarkers A Randomized Controlled Trial Oxford: John Stradling 100 men with moderate–severe OSAS were Randomised to therapeutic (n=51) or subtherapeutic (n=49) CPAP treatment for 4 weeks Negative also for IFN-γ and adiponectin Kohler M, Thorax 2009

Effect of CPAP on oxidative stress Christou K, Sleep Med 2009

Effect of CPAP on Antioxidant Capacity in OSA 47 male patients with OSAS and 37 healthy control subjects were studied Barcelo A, ERJ 2006

IV Vitamin C Improves Endothelial Dysfunction n=10, p<0.01 measured flow-mediated dilation (FMD) of the brachial artery by ultrasound in 10 otherwise healthy, untreated patients with OSA and 10 age-and sex-matched control subjects without sleep-disordered breathing before and after intravenous injection of the antioxidant vitamin C (500 mg) intravenous injection of vitamin C (500 mg) Grebe M, AJRCCM 2006

ΣΑΑΥ: Καρδιαγγειακή Νοσηρότητα και Θνητότητα Marin J, Lancet 2005

Μείωση καρδιαγγειακού κινδύνου με CPAP και στο ήπιο-μέτριο ΣΑΑΥ Mild-to-moderate OSA All Methods: Consecutive sleep laboratory patients with all degrees of OSA were included. Endpoints were nonfatal (myocardial infarction, stroke, and acute coronary syndrome requiring revascularization procedures) and fatal (death from myocardial infarction or stroke) cardiovascular events. Measurements and Main Results: Comparison of event-free survival rates in treated versus untreated patients (Kaplan-Meier estimates, log-rank test). Of 449 patients enrolled (age, 56.0610.5 years; body mass index, 30.865.4kg/m2), 364 patients received OSA treatment, and 85 patients remained untreated. Median follow-up was 72.0 months (range, 1–156). Mean apnea–hypopnea index before treatment was 30.9 6 21.8/hour in treated and 15.3 6 13.0/hour in untreated patients, but there were no differences in cardiovascular comorbidities or risk factors. In patients with mild–moderate OSA (n 5 288), events were more frequent in untreated patients (estimated event-free survival at 10 yr, 51.8 vs. 80.3% [P <0.001]; absolute risk reduction, 28.5%; number needed to treat to prevent one event/10 yr, 3.5). After adjustment for age, gender, cardiovascular risk factors, and comorbidities at baseline, OSA treatment was an independent predictor for events (hazard ratio, 0.36; 95% confidence interval, 0.21–0.62; P , 0.001). Conclusions: OSA treatment was associated with a cardiovascular risk reduction of 64% independent from age and preexisting cardiovascular comorbidities. OSA treatment should be considered for primary and secondary cardiovascular prevention, even in milder OSA. Number needed to treat 3.5 Buchner NJ, AJRCCM 2007

ΣΑΑΥ και Καρδιαγγειακές Παθήσεις Obstructive sleep apnoea (OSA) is a common disorder in which repetitive apnoeas expose the cardiovascular system to cycles of hypoxia, exaggerated negative intrathoracic pressure, and arousals. These noxious stimuli can, in turn, depress myocardial contractility, activate the sympathetic nervous system, raise blood pressure, heart rate, and myocardial wall stress, depress parasympathetic activity, provoke oxidative stress and systemic infl ammation, activate platelets, and impair vascular endothelial function. Epidemiological studies have shown signifi cant independent associations between OSA and hypertension, coronary artery disease, arrhythmias, heart failure, and stroke. In randomised trials, treating OSA with continuous positive airway pressure lowered blood pressure, attenuated signs of early atherosclerosis, and, in patients with heart failure, improved cardiac function. Current data therefore suggest that OSA increases the risk of developing cardiovascular diseases, and that its treatment has the potential to diminish such risk. However, large-scale randomised trials are needed to determine, defi nitively, whether treating OSA improves cardiovascular outcomes. Bradley TD, Floras J, Lancet 2009

Hypoxia, Inflammation and CVD in OSA Activation and interaction of inflammatory pathways in response to intermittent hypoxia in obstructive sleep apnoea syndrome (OSAS). Proposed mechanisms by which OSAS predisposes to the development of endothelial dysfunction and cardiovascular disease include sympathetic excitation, vascular endothelial dysfunction, oxidative stress and inflammation. Intermittent hypoxia, the characteristic feature of OSAS, activates inflammatory mechanisms directly through the hypoxia-sensitive transcription factors nuclear factor (NF)-kB and hypoxia-inducible factor (HIF)-1. The co-existence of obesity in many OSAS patients augments the pro-inflammatory state through increased production of interleukin (IL)-6 and C-reactive protein (CRP) by adipose tissue. There are differences in the response to intermittent hypoxia between body tissues, with NF-kB having its largest apparent influence in endothelial cells, and adipocytes and HIF-1 playing a key role in the carotid body response. Activation of leukocytes and nitric oxide (NO) involvement in the inflammatory response to intermittent hypoxia in OSAS may be regulated by cross-talk between the NF-kB and HIF-1 pathways. Garvey JF, ERJ 2009

Oxidative Stress in OSA: Mechanisms Lavie L, Lavie P, Eur Respir J 2009

Significant Confounders: Smoking and Obesity

Συμπεράσματα Υπάρχουν ισχυρές ενδείξεις ότι το ΣΑΥ σχετίζεται με παρουσία συστηματικής φλεγμονής και συστηματικού οξειδωτικού stress Πολλές από τις κλινικές μελέτες έχουν προβλήματα και γι' αυτό το λόγο έχουν αντιφατικά αποτελέσματα Μικρός αριθμός ασθενών Συγχυτικοί παράγοντες (κάπνισμα, παχυσαρκία) Συμμετοχή ασθενών με καρδιαγγειακές παθήσεις Οι μακροχρόνιες τυχαιοποιημένες μελέτες με CPAP δεν είναι εύκολο να πραγματοποιηθούν για ηθικούς λόγους Χρειάζονται μεγάλες πολυκεντρικές μελέτες με καλά επιλεγμένους πληθυσμούς Η μελλοντική αντιμετώπιση του ΣΑΥ μπορεί να στοχεύσει και σε έλεγχο της συστηματικής φλεγμονής και του οξειδωτικού stress

Literature suggestions Ryan S , Taylor CT, Mc Nicholas WT. Thorax 2009;64;631-636 Systemic inflammation: a key factor in the pathogenesis of cardiovascular complications in obstructive sleep apnoea syndrome? Gozal D, Kheirandish-Gozal L. AJRCCM 2008; 177: 369-375 Cardiovascular Morbidity in Obstructive Sleep Apnea: Oxidative Stress, Inflammation, and Much More. Pulmonary Perspective Lavie L, Lavie P. Eur Respir J 2009; 33: 1467–1484 Molecular mechanisms of cardiovascular disease in OSAHS: the oxidative stress link. Bradley TD, Floras JS. Lancet 2009; 373: 82-93 Obstructive sleep apnoea and its cardiovascular consequences