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OSA is a systemic disease OSA is a systemic disease Presentation Transcript

  • OBSTRUCTIVE SLEEP APNEA IS A SYSTEMIC DISEASE Iman Galal, MD Assistant Professor Pulmonary Medicine Ain Shams University
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  • Page  47#, Verse25#Furqan, Chapter-Al View slide
  • Page  Obstructive Sleep Apnea Syndrome & Metabolic Syndrome. Obstructive Sleep Apnea Syndrome & Cardiovascular Diseases. Effect of Continuous Positive Airway Pressure treatment. Content: View slide
  • Page  Obstructive Sleep Apnea:
  • Page  Obstructive Sleep Apnea Memory Problems Increased Insulin Resistance Stroke Increased Traffic Accidents Cardiac Problems Hypertension
  • Page  Introduction: Obstructive sleep apnea, a highly prevalent disease, affecting 4% of men & 2% of women, is a disorder characterized by recurrent episodes of upper airway obstruction, & is associated with reductions in ventilation, resulting in recurrent arousals & episodic oxyhemoglobin desaturations during sleep.
  • Page  A variety of phenomena are implicated in OSAS such as modifications in the autonomic nervous system, hypoxemia–reoxygenation cycles, inflammation, & coagulation–fibrinolysis imbalance. OSAS patients also present increased levels of certain biomarkers linked to endocrine-metabolic & cardiovascular alterations among other systemic consequences. Introduction:
  • Page  Metabolic Syndrome: The National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) report recommended the use of 5 variables: 1) Abdominal Obesity: waist circumference (≥102 cm in , ≥88 cm in ) 2) ↑ TG (≥150 mg/dL or drug treatment) 3) ↓ HDL (<40 mg/dL in , <50 mg/dL in , or drug treatment) 4) Hypertension: BP (systolic BP ≥130 mmHg, or diastolic BP ≥ 85 mmHg, or drug treatment for hypertension) 5) Glucose Intolerance: fasting glucose (≥100 mg/dL or drug treatment) Subjects meeting 3 of these 5 criteria are classified as having Metabolic Syndrome. Grundy et al. Circulation 2005; 112: 285-90
  • Page  Metabolic Syndrome: International Diabetes Federation (IDF) Consensus Definition 2005 Criteria for Identification of the MS: Alberti, Lancet 2005 Abdominal Obesity: (waist circumference)  ethnicity specific  for Europids: Men >94 cm Women >80 cm Plus any Two of the following Triglycerides ≥150 mg/dL HDL cholesterol Men <40 mg/dL Women <50 mg/dL Blood Pressure ≥130 / ≥85mmHg Fasting Glucose ≥100mg/dL or Type II Diabetes
  • Page  The metabolic disturbances in patients with obstructive sleep apnea syndrome (OSAS) include insulin resistance & elevated levels of pro-inflammatory cytokines & vascular adhesion molecules, as well as an elevation of hormones derived from the adipose tissue as leptin. OSA & Metabolic Syndrome “Syndrome Z”
  • Page  OSA & MS in Adults Reference Design Results Coughlin et al.,2004 Case controlled (matched for BMI) OSA: AHI > 15 Control subjects: AHI < 5 MS: NCEP (ATP III) criteria Independent* associations between: 1. OSA & MS 2. OSA& systolic and diastolic blood pressure, fasting insulin, triglyceride, HDL, total/HDL cholesterol Gruber et al., 2006 Case controlled OSA: AHI criteria not given MS: International Diabetes Federation criteria Independent* association between: 1. OSA & MS 2. No independent association between OSA & insulin resistance (assessed by HOMA) Lam et al., 2006 Community based OSA: AHI > 5 MS: NCEP (ATP III) criteria OSA and MS Independent association between OSA & waist, diastolic blood pressure*, fasting glucose*, MS* Independent determinants of OSA: age, gender, BMI, MS Sasanabe et al.,2006 OSA: AHI > 15 Control subjects: AHI < 5 MS: criteria for Japanese population Independent* association between OSA & MS in not in Parish et al., 2007 Retrospective PSG & chart review Higher prevalence of MS in patients with OSA (60 vs.40%) Coughlin et al., 2007 Randomized, controlled study MS: NCEP (ATP III) criteria No change in proportion of subjects with MS with CPAP Significant ↓ in blood pressure
  • Page  OSA & Obesity: OSAS often coexists with obesity. OSAS is present in approximately 40% of obese individuals, & about 70% of OSAS patients are obese. In recent years, much attention has been focused on the interaction between OSAS & products released by adipose tissue such as Leptin, Adiponectin, Resistin & Ghrelin.
  • Page  OSA & Obesity: Gate et al., J Nutr 2004
  • Page  Leptin is an adipocyte-derived hormone that suppresses appetite & promotes satiety. Several studies have shown increased levels of Leptin in OSAS, suggesting resistance to the metabolic effects of leptin (Leptin Resistance). Obesity is a major confounding factor in the association between Leptin & OSA. Treatment with CPAP reduces leptin levels & also may be associated with decreased visceral fat accumulation. OSA & Obesity:
  • Page  Sleep Apnea & Visceral Fat AHI Visceral Fat (cm2) SaO2nadir% 0 20 40 60 80 100 50 150 250 350 450 r = .70 p = .00 0 20 40 60 80 100 50 150 250 350 450 r = -.61 p = .001 0 100 200 300 400 OSA Obese Controls * AbdominalFat Distribution(cm2) Subcutaneous Fat Visceral Fat Vgontzas et al. J Clin Endocrin Metab 2000; 85: 1151-8
  • Page  Effect of CPAP on Visceral Fat Fataccumulation(cm2) BW= BW 0 BW= BW 100 200 300 * * * Visceral Subcutaneous Chin et al., Circulation 1999; 100: 706-12
  • Page  OSA & Obesity: Increased Leptin: Chin et al., Circulation 1999; 100: 706-12. Ip et al., Chest 2000; 118: 580-6. Schafer et al., Chest 2002; 122: 829-39 (Obesity+) Shimizu et al., Thorax 2002; 57: 429-34. Ozturk et al., Arch Otolaryngol Head Neck Surg 2003; 129: 538-40. Sanner et al., Eur Respir J 2004; 23: 601-4. Shimura et al., Chest 2005; 127: 543-9 (Hypercapnia+) Barcelo et al., Am J Respir Crit Care Med 2005; 171: 183-7 (Obesity+) Tatsumi et al., Chest 2005; 127: 716-21. Ulukavak Ciftci et al., Respiration 2005; 72: 395-401.
  • Page  Adiponectin is an adipocyte-derived cytokine with regulatory functions in both glucose & lipid metabolism. In addition, Adiponectin has profound anti-inflammatory & antiatherogenic effects. Plasma levels of Adiponectin decreases in obesity & metabolic syndromes e.g., OSAS. CPAP treatment of OSAS does not effectively normalize Adiponectin levels. OSA & Obesity: Harsch et al, Respiration 2004; 10: 710-580-6 Zhang et al, Chin Med J 2004; 117: 1603-1606
  • Page  Resistin is a white adipose tissue hormone whose physiological function has not yet been established. In a study of 20 obese OSA patients, there was a weak link between Resistin & Insulin Sensitivity. CPAP treatment of OSA had no significant influence on Resistin levels. OSA & Obesity: Harsch et al, Med Sci Monit 2004; 10: 510-5
  • Page  OSA & Obesity: Adiponectin: variable results Zhang et al., Chin Med J 2004; 117: 1603-1606 Harsch et al., Respiration 2004; 71: 580-586 (obesity+) Wolk et al., Obes Res 2005; 13: 186-190 Zhang et al., Respiration 2006; 73: 73-77 Makino et al., Clin Endocrinol 2006; 64:12-19 Resistin: Harsch et al., Med Sci Monit 2004; 10: 510-5 (insulin sensitivity , inflammation+) Ghrelin: variable results Harsch et al., Eur Respir J 2003; 22:251-257 Ulukavak et al., Respiration 2005; 72: 395-401 =
  • Page  OSA & Obesity: OSA is less prevalent in than , yet this difference diminishes after menopause 2ry to the decline in estrogen & progesterone. Accordingly, estrogen replacement therapy in menopausal lessens the prevalence of OSAS. OSAS in causes reduced pituitary-gonadal function (possibly 2ry to obesity) → decline in morning serum testosterone levels, reduced androgen secretion & libido. In addition, ↑ leptin → impaired testicular Leyding cell function. Anttalainen et al., Acta Obstet Gynecol Scand 2006; 85: 1381-8 Wesstrom et al., Acta Obstet Gynecol Scand 2005; 84: 54-7 Teloken et al., Urology2006; 76:1033-7 Luboshitzky et al., Obes Res2005;13:780-6 Ishikawa et al., Andrologia2007;39:22-7
  • Page  Insulin Resistance Kasuga, J Clin Invest 2006 Normal Normal Increased Normal or IGT Diabetes mellitus Decreased Pancreatic Islets cell compensation cell failure Insulin secretion by cells Blood glucose
  • Page  Insulin Signaling in Cells Kasuga, J Clin Invest 2006
  • Page  Relation between OSA, MS & Type II DM Tasali & Ip, he Proceedings of the American Thoracic Society 2008;5:207-17
  • Page  OSA & Diabetes Mellitus: In 2001, El Masry & co-workers proved that the prevalence of severe OSA was significantly higher in diabetic patients than in normoglycaemic subject independent of BMI. Although obesity is the main risk factor for diabetes, yet coexistent severe OSA may add to this risk . El Masry et al., J Intern Med. 2001; 249: 153-61
  • Page  Reference TTT Period Study Population Measures of Glucose Main Results Brooks et al.,1994 4 ms 10 severely obese pts with DM with OSA Hyperinsulinemic euglycemic clamp Improvement in insulin sensitivity Harsh et al.2004 3 ms 40 Pts without DM with OSA Hyperinsulinemic euglycemic clamp Improvement in insulin sensitivity Harsh et al.2004 3 ms 9 Pts with DM with OSA Hyperinsulinemic euglycemic clamp Improvement in insulin sensitivity Babu et al.,2005 3 ms 25 Pts with DM with OSA 72-h interstitial glucoseHemoglobin A1c Improvement in 1h postprandial glucose & decrease in hemoglobin A1c Hassaballa et al.,2005 3-4 ms 38 Pts with DM with OSA Hemoglobin A1c Slight decrease in hemoglobin A1c Lindberg et al.,2006 3 wks 28 with OSA 28 Matched control Fasting insulin & HOMA Reductions in fasting insulin levels & IR Effect of CPAP on Glucose Metabolism:
  • Page  Reference TTT Period Study Population Measures of Glucose Main Results Saini et al.,1993 1 Night 8 pts with OSA Profiles of glucose & insulin at night No change in nocturnal glucose & insulin profiles Cooper et al.1995 1 Night 6 Obese Pts without DM with OSA Profiles of glucose & insulin at night No change in nocturnal glucose & insulin profiles Stoohs et al.2004 2 ms 5 Pts with OSA Fasting glucose & insulin Profiles of glucose & insulin at night ↑ in fasting & nocturnal glucose levels No change in fasting or nocturnal insulin levels Saarlainen et al.,1997 3 ms 7 Pts with OSA Hyperinsulinemic euglycemic clamp No improvement in insulin sensitivity Ip et al.,2000 6 ms 9 Pts with OSA Fasting glucose & insulin No change in fasting glucose & insulin levels Sumurra et al.,2006 2 ms 16 pts with OSA Hyperinsulinemic euglycemic clamp OGTT No change in insulin sensitivity & glucose tolerance Czupryniak et al.,2005 1 Night 9 pts without DM with OSA Nocturnal Intestinal glucose Fasting insulin & HOMA ↑ in nocturnal glucose No difference in fasting insulin levels & IR Coughlin et al.,2007 6 wks 34 Obese pts with OSA HOMA No change in insulin sensitivity with therapeutic CPAP vs. with placebo CPAP Effect of CPAP on Glucose Metabolism:
  • Page  OSA & Cardiovascular System: The association of OSAS & cardiovascular consequences can be addressed by 3 key questions: First: Is OSA an independent cardiovascular risk factor? Second: If so, does treatment of OSA reduce cardiovascular risk, morbidity & mortality? Third: Is screening for OSAS indicated for patients at risk for cardiovascular disease?
  • Page  Cardiovascular Events In OSA: Abu et al, JAMA. 2003;290:1906-1914
  • Page  OSA & Cardiovascular System: Somers et al, N Engl J Med. 1993;328:303-307 In healthy individuals, physiologic normal sleep is associated with distinct sleep stage–related changes in cardiovascular regulation. Sympathetic nerve traffic to muscles, as well as HR, BP, SV, COP, & SVR, all decrease progressively during deeper stages of NREM sleep. However, REM sleep is accompanied by striking increases in sympathetic drive.
  • Page  OSA & Cardiovascular System: Narkiewicz et al, Circulation 1998;97:943–945 The mechanism for increased sympathetic activation is not known. One possibility is that increased chemoreflex gain in OSA results in tonic chemoreflex activation even during normoxia, with consequent increased sympathetic activity. Administration of 100% oxygen (to eliminate tonic chemoreflex drive) significantly lowers sympathetic activity, HR, & BP in OSA patients during daytime wakefulness.
  • Page  Neural & Circulatory Changes in OSA: Somers et al, J Clin Invest. 1995;96:1897-1904
  • Page  Somers et al, J Clin Invest 1995 Neural & Circulatory Changes in OSA:
  • Page  Impaired Cardiovascular Variability: Narkiewicz et al, Circulation 1998;98:1071–77 Singh et al, Hypertension 1998;32:293–97 Fratolla et al, J Hypertens 1993;11:1133–37 Compared with similarly obese control subjects, resting awake OSA patients have diminished heart rate variability & increased BP variability. The Framingham Heart Study has implicated lower HR variability as a precursor to the development of future hypertension, & increased BP variability has been implicated in increased risk of end-organ damage in patients with hypertension.
  • Page  Heart Rate Variability in OSA: Thurnbeer, Swiss Med Wkly 2007; 137: 217-22 Var: HR variability, variability of > 6 bpm
  • Page  In OSA, the combination of repetitive hypoxemia & sleep deprivation may be associated with increased levels of plasma cytokines e.g., IL-6, α-TNF, CAMs, serum amyloid A, & CRP. CRP contribute to vascular disease & dysfunction by inhibiting nitric oxide synthase & increasing expression of cell adhesion molecules. Adhesion of circulating leukocytes to the endothelial cells is considered one of the initial steps in the pathogenesis of atherosclerosis. OSA & Inflammation: Vgontzas et al, J Clin Endocrinol Metab. 1997;82:1313-16 Shamsuzzaman et al, Circulation. 2002;105:2462-64 Venugopa et al, Circulation. 2002;106:1439-41 Ross et al, Nature;1993;362:801-809
  • Page  0 0.5 1 1.5 2 2.5 3 pg/mL Normal OSA Narcolepsy Idiopathic Hypersomnia TNF IL-6 ** Normal OSA Narcolepsy Idiopathic Hypersomnia Cytokines & Disorders of EDS: Vgontzas et.al., 1997
  • Page  OSA & Adhesion Molecules: Galal IH (2007) 0 100 200 300 400 500 600 700 0 1 2 3 4 sICAM-1 ng/mL 0 500 1000 1500 2000 2500 3000 3500 0 1 2 3 4 sVCAM-1 ng/mL
  • Page  In OSA, the hypoxia/reoxygenation phenomenon that occurs in response to apneas followed by hyperventilation, may elicit increased vascular oxidative stress. Low oxygen tension is a trigger for activation of polymorphonuclear neutrophils, which adhere to the endothelium & release free oxygen radicals. Prevention of OSA by CPAP reduces production of superoxide. OSA & Oxidative Stress: Schulz et al, Am J Respir Crit Care Med. 2000;162:566-70 Prabhakar et al, Am J Respir Crit Care Med. 2002;165:859-60
  • Page  Hypercoagulability in OSAS results from the imbalance between coagulation & fibrinolysis. Increases in hematocrit, nocturnal & daytime levels of fibrinogen, platelet aggregation, blood viscosity, FVIIa, FXIIa, VWF, D-dimer & fibrinolysis- inhibiting enzyme plasminogen inhibitor (PAI-1) in OSA, likely contribute to predisposition to clot formation & atherosclerosis. CPAP therapy can alleviate some of these abnormalities & can reduce factor VII clotting activity. OSA & Hpercoagulability: Hoffstein al, Chest. 1994;106:787-91 Chin et al, Am J Resp Crit Care Med. 1996;153:1972-76 Nobil et al, Clin Hemorheol Microcirc. 2000;22:21-27 Wessendorf et al, Am J Resp Crit Care Med. 2000;162:2039-42
  • Page  OSA & Endothelial Dysfunction: The hypoxia, hypercapnia, & pressor surges accompanying obstructive apneic events serve as potent stimuli for ↑ in the release of endothelin & ↓ in NO → endothelial dysfunction. Endothelial dysfunction is often seen with OSA comorbidites e.g., HTN, hyperlipidemia, DM, or smoking → ↑ risk of cardiovascular events. In addition, OSA itself may be an independent risk factor for the development of endothelial dysfunction. CPAP treatment plays an important role in the improvement & protection of vascular endothelial dysfunction. Zhang et al, Chin Med J. 200;116:844-7 Zamarron et al., Eur J Inten Med.2008;19:390-8
  • Page  Cardiovascular Events In OSA: Abu et al, JAMA. 2003;290:1906-14
  • Page  It is estimated that 50% of OSA patients are hypertensive, & 30% of hypertensive patients also have OSA, often undiagnosed. OSA & Hypertension: Silverberg et al, Curr Opin Nephrol Hypertens. 1998;7:353–7 Fletcher et al., Ann Intern Med. 1985;103:190 –5
  • Page  OSAS is identified as an independent risk factor for the onset of arterial hypertension. A clear dose-effect is evident: the more apneas/ hr of sleep, the higher the chance for becoming hypertensive. In 2003, the “Joint National Council on High Blood Pressure” listed OSA as the first identifiable cause of arterial hypertension. Harsch et al, Med Sci Monit 2004; 10: 510-5 OSA & Hypertension:
  • Page  Potential mechanisms linking OSA with HTN: Hoffmann et al, Minerva Med. 2004;95:281-90 Obstructive Sleep Apnea HYPERTENSION Chemoreflex activation Baroreflex dysfunction Arousals Intrathoracic pressure changes Sympathetic activation Leptin R Insulin R Inflammation Oxidative stress Obesity RAS activation Endothelial dysfunction
  • Page  Drug-Resistant Hypertension: (clinical blood pressure of >140/90mmHg while taking a sensible combination of ≥ antihypertensive drugs) a high prevalence of OSAS has been reported. (Fletcher EC 1985, Isaksson H, 1991) In a group of 41 patients taking a mean of 3.6 different antihypertensive medications daily: 96% of the men & 65% of the women had OSAS, with men suffering from more severe OSAS (AHI 32 vs. 14). (Logan AG, 2001) OSA & Hypertension:
  • Page  60 80 100 120 140 MAP(mmHg) baseline effective nCPAP 715 pm 1115 pm 315 am 715 am315 pm 1115 am Becker, Circulation 2003 Effect of nCPAP on Blood Pressure in OSA: -25 -20 -15 -10 -5 0 5 10 15 mmHg * * * MAP systolic diastolic
  • Page  OSA & Heart Failure: Marin et al., Lancet. 2005; 365:1 046 –53 OSA contribute to the progression of heart failure through several pathological mechanisms: 1) by eliciting greater sympathetic outflow to the heart, kidney, & resistance vessels during wakefulness & sleep. 2) by increasing left ventricular afterload both acutely & chronically. 3) by inducing hypoxia & 2ry increases in right ventricular afterload. 4) by increasing the risk of myocardial infarction. However, yet to be established is whether OSA can cause heart failure. In addition, whether the presence of OSA in Heart failure accelerates mortality remains unclear.
  • Page  Heart failure patients with CPAP-treated OSA have low mortality rate compared with untreated OSA. Effect of treatment on OSA on HF: Wang et al., J Am Coll Cardiol. 2007;49:1625-31
  • Page  Epidemiological data suggest that OSA is overrepresented in patients with CAD. Conversely, the clinical course of CAD is initiated (or) accelerated by the presence of OSA. More than half of sudden cardiac deaths in patients with proven OSA occur during the sleeping hours (between 10 PM & 6 AM). Thus, OSA appears to affect the timing of sudden cardiac death. OSA & CAD: Hedner et al., 2005 Somers et al., JACC 2008;52:686–717
  • Page  In patients with combined OSA & CAD, treatment of OSA was associated with a decrease in the occurrence of new cardiovascular events. Repots from patients’ spouses describe marked changes in sleep patterns, snoring severity, & witnessed apneas after bypass surgery and sometimes even after angioplasty. Effect of treatment on OSA & CAD: Milleron et al., Eur Heart J. 2004;25:728 –34 Somers et al., JACC 2008;52:686–717
  • Page  OSA & Arrhythmia: Zwillich et al, J Clin Invest. 1982;69:1286-92 Somers et al., JACC 2008;52:686–717 Nocturnal arrhythmias have been reported in up to 50% of patients with OSA even in absence of pre-existing cardiac disease. The most common arrhythmias include 2nd degree heart block, AF, ventricular extrasystole & sinus bradycardia, representing in part the diving reflex response to apnea & hypoxia
  • Page  Recurrence of AF After Cardioversion: 0 10 20 30 40 50 60 70 80 90 100 Controls (n=79) Treated OSA (n=12) Untreated Osa (n=27) % Recurrence at 12 Months ** Kanagola et al, Circ 107:2589, 2003
  • Page  In small series of patients with OSA (without clinical history of chronic obstructive pulmonary disorder) the reported daytime pulmonary arterial hypertension was found in 20- 42% of cases The most likely primary mechanism OSA-related PAH is hypoxemia, which is known to reflexively induce an acute increase in PAP. OSA & PAH: Yamakawa et al, Psychiatry Clin Neurosci.,2002;56:311–12 Voelkel, Am Rev Respir Dis. 1986;133:1186 –95
  • Page  Buchner et al. AJRCCM 2007 CPAP Treatment & Cardiovascular Risk:
  • Page  * Cardiovascular Disease & Mortality in OSAS: Doherty et al. Chest 2005; 127: 2076-84
  • Page  Memories are formed in the mammillary bodies. When UCLA neuroscientists* scanned the brains of 43 sleep apnea patients & 66 healthy volunteers using magnetic MRI, they discovered that the OSA patients’ mammillary bodies were nearly 20% smaller than those of the untroubled sleepers. OSA & Memory Affection: *Newswise: Study Links Common Sleep Disorder to Memory Loss Retrieved on June 11, 2008
  • Page  Stroke has been linked to OSA & sleep apnea is highly prevalent in patients with stroke. Mechanisms that have been implicated in any increased risk of stroke in OSA include BP swings, reduction in cerebral blood flow, altered cerebral autoregulation, impaired endothelial function, accelerated atherogenesis, & prothrombotic & proinflammatory states. OSA & Stroke: Somers et al., JACC 2008;52:686–717
  • Page  OSA & Stroke: Bassetti & Aldrich, Sleep 22:217, 1999 0 5 10 15 20 25 30 35 Stroke (n=48) TIA (n=32) Controls (n=25) AverageAHI(Episodes/hour)
  • Page  The prevalence of OSA in ESRD ranged from 40% - 60%. Long-standing OSA contributes to the origin of ESRD by inducing chronic elevations in BP & increasing sympathetic nerve discharge directed at the kidney & other vascular beds. OSA & End-Stage Renal Disease: Hanly, Semin Dial. 2004;17:109 –14
  • Page  Conclusion
  • Page  Zamarron, Eur J Int Med 2008; 19: 390-98
  • Page  The Association of OSAS with Endocrine-Metabolic & Cardiovascular Alternations indicates that, More than a Local Abnormality, OSAS should be considered a Systemic Disease.
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  • Page  23#, Verse30#Room, Chapter-Ar
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