Cardiovascular Disease and Sleep Apnea. Elizabeth Lynch, MD Sleep Institute of New England

Transcription

1 Cardiovascular Disease and Sleep Apnea Elizabeth Lynch, MD Sleep Institute of New England

2 Purpose Describe the types and prevalence of sleep apnea and its meaning in patients at risk for or who already have cardiovascular disease

3 Emphasis Recognizing patients with cardiovascular disease who have coexisting sleep apnea Understanding the mechanisms by which sleep apnea may contribute to the progression of the cardiovascular condition Review positive airway pressure treatment strategies

4 Main Questions Does sleep apnea initiate the development of cardiovascular disease? Does sleep apnea accelerate heart disease progression? Does treatment of sleep apnea cause fewer cardiovascular events and reduce mortality?

5 The Letter Conundrum SDB sleep disordered breathing OSA obstructive sleep apnea CSA - central sleep apnea CSR Cheyne Stokes respiration AHI apnea hypopnea index CAI central apnea index PAP positive airway pressure CPAP continuous positive airway pressure

6 Sleep disordered breathing and cardiovascular disease Highly prevalent in patients with CV disease OSA affects at least 15 million adult Americans CAD, stroke, atrial fibrillation CSA occurs mainly in patients with heart failure

7 Evidence-based Research Limitations Close association between obesity and OSA obscures the differentiation Multiple comorbidities (CV disease, metabolic syndrome and diabetes) Randomization of sleep apnea patients to treatment or no treatment; need to treat patients with severe daytime somnolence

8 Topics of Interest Definitions obstructive, central, mixed, complex Diagnosis Pathophysiology Hypertension Heart Failure Stroke Arrhythmias Myocardial Ischemia and Infarction Pulmonary Arterial Hypertension (PAH) End Stage Renal Disease (ESRD) CPAP Treatment

9 Definitions Obstructive Apnea repetitive cessations of ventilation during sleep caused by collapse of the pharyngeal airway

10 Definitions Obstructive Hypopnea repetitive interruptions of ventilation during sleep caused by incomplete collapse of the pharyngeal airway

11 Definitions Central Sleep Apnea repetitive cessation of ventilation during sleep resulting from loss of ventilatory drive

12 Normal Breathing Definitions

13 Definitions

14 Definition OSA syndrome Apnea or hypopnea 10 seconds in length Hypopneas - majority Sleep Heart Health Study > 6000 adults with hypopneas associated with > 4% decrease in O2 saturation were independently associated with CV disease 1 1 Punjabi NM et al. Sleep disordered breathing and cardiovascular disease: an outcome-based definition of hypopneas. Am J Respir Crit Care Med 2008.

15 Definition & Prevalence OSA syndrome AHI > 5 with symptoms of excessive daytime sleepiness AHI = number of apneas and hypopneas per hour of sleep 1 in 5 adults - mild OSA (AHI > 5) 1 in 15 adults - moderate to severe OSA (AHI > 15) Significant progression of OSA over time 1,2 (Wisconsin Sleep Cohort study and Cleveland Family Study) 1 Young T et al. Epidemiology of obstructive sleep apnea: a population health perspective. Am J Respir Crit Care Med Tishler PV et al. Incidence of sleep disordered breathing in an urban adult population: the relative importance of risk factors in the development of sleep disordered breathing. JAMA

16 Prevalence of CSA CAI > 2.5-0% (20-44), 1.7% (45-64) and 12% (>65) 1,2 CAI > 1-9% (40 to 97) in men in SHHS 3 Higher in those with diabetes, HF, LV dysfunction and stroke Fewer women with heart failure have CSA CAI > 15-40% of men with heart failure 4 1 Bixler EO et al. Prevalence of sleep disordered breathing in women: effects of gender. Am J Respir Crit Care Med Bixler EO et al. Effects of age on sleep apnea in men: I: prevalence and severity. Am J Respir Crit Care Med Young T et al. Sleep Heart Health Study Research Group. Predictors of sleep-disordered breathing in community dwelling Adults: the Sleep Heart Health Study. Arch Intern Med Javaheri S et al. Sleep apnea in 81 ambulatory male patients with stable heart failure. Types and their prevalences, consequences and presentations. Circulation 1998.

17 Pathophysiology of OSA Small pharyngeal airway Airflow resistance during wake Intrapharyngeal negative pressure during inspiration when awake via mechanoreceptors in larynx Activity of number of pharyngeal dilator muscles Maintain airway patency

18 Pathophysiology of OSA Small pharyngeal airway Airflow resistance during wake Intrapharyngeal negative pressure during inspiration when awake via mechanoreceptors in larynx Activity of number of pharyngeal dilator muscles Maintain airway patency

19 Pathophysiology of OSA Small pharyngeal airway Airflow resistance during wake Intrapharyngeal negative pressure during inspiration when awake via mechanoreceptors in larynx Activity of number of pharyngeal dilator muscles Maintain airway patency

20 Pathophysiology of OSA Small pharyngeal airway Airflow resistance during wake Intrapharyngeal negative pressure during inspiration when awake via mechanoreceptors in larynx Activity of number of pharyngeal dilator muscles Maintain airway patency

21 Pathophysiology of OSA Small pharyngeal airway Airflow resistance during wake Intrapharyngeal negative pressure during inspiration when awake via mechanoreceptors in larynx Activity of number of pharyngeal dilator muscles Maintain airway patency Pharyngeal narrowing & intermittent collapse O 2 and CO 2 Sleep deprivation Stimulate ventilatory effort Arousals

22 Pathophysiology of OSA Deficient pharyngeal anatomy

23 Pathophysiology of OSA Deficient pharyngeal anatomy Ventilatory control system instability Cycling respiratory output to ventilatory pump muscles & upper airway dilatation muscles Apneas and hypopneas

24 Pathophysiology of OSA Deficient pharyngeal anatomy Ventilatory control system instability Cycling respiratory output to ventilatory pump muscles & upper airway dilatation muscles Apneas and hypopneas Variable surface tension of pharyngeal airway

25 Pathophysiology of OSA Deficient pharyngeal anatomy Ventilatory control system instability Cycling respiratory output to ventilatory pump muscles & upper airway dilatation muscles Apneas and hypopneas Variable surface tension of pharyngeal airway Asynchronous timing of activation of upper airway versus pump muscles

26 Pathophysiology of OSA Deficient pharyngeal anatomy Ventilatory control system instability Cycling respiratory output to ventilatory pump muscles & upper airway dilatation muscles Apneas and hypopneas Variable surface tension of pharyngeal airway Arousal threshold Asynchronous timing of activation of upper airway versus pump muscles

27 Pathophysiology of OSA Deficient pharyngeal anatomy Ventilatory control system instability Cycling respiratory output to ventilatory pump muscles & upper airway dilatation muscles Apneas and hypopneas Variable upper airway dilator muscle control Variable surface tension of pharyngeal airway Arousal threshold Asynchronous timing of activation of upper airway versus pump muscles

28 Pathophysiology of OSA Loss of lung volume Longitudinal traction More collapsible Deficient pharyngeal anatomy Ventilatory control system instability Cycling respiratory output to ventilatory pump muscles & upper airway dilatation muscles Apneas and hypopneas Variable upper airway dilator muscle control Variable surface tension of pharyngeal airway Arousal threshold Asynchronous timing of activation of upper airway versus pump muscles

29 Mechanism of disease and CV Risk Cardiovascular variability HR and BP variability during wake Cardiovascular Disease Risk

30 Mechanism of disease and CV Risk Cardiovascular variability HR and BP variability during wake Endothelial dysfunction (Systemic inflammation, sympathetic activation, pressor surges, oxidative stress) Cardiovascular Disease Risk

31 Mechanism of disease and CV Risk Cardiovascular variability HR and BP variability during wake Cardiovascular Disease Risk Endothelial dysfunction (Systemic inflammation, sympathetic activation, pressor surges, oxidative stress) Insulin resistance/ metabolic dysregulation Glucose intolerance Leptin

32 Mechanism of disease and CV Risk Cardiovascular variability HR and BP variability during wake Cardiovascular Disease Risk Endothelial dysfunction (Systemic inflammation, sympathetic activation, pressor surges, oxidative stress) Insulin resistance/ metabolic dysregulation Glucose intolerance Leptin Thrombosis Platelet activation fibrinogen

33 Mechanism of disease and CV Risk Cardiovascular variability HR and BP variability during wake Cardiovascular Disease Risk Endothelial dysfunction (Systemic inflammation, sympathetic activation, pressor surges, oxidative stress) Insulin resistance/ metabolic dysregulation Glucose intolerance Leptin Intrathoracic pressure changes Mueller maneuver Thrombosis Platelet activation fibrinogen

34 Mechanism of disease and CV Risk Cardiovascular variability HR and BP variability during wake Cardiovascular Disease Risk Endothelial dysfunction (Systemic inflammation, sympathetic activation, pressor surges, oxidative stress) Insulin resistance/ metabolic dysregulation Glucose intolerance Leptin Oxidative Stress (thiobarbituric acid reactive substances, isopropanes, oxidized LDL) Intrathoracic pressure changes Mueller maneuver Thrombosis Platelet activation fibrinogen

35 Mechanism of disease and CV Risk Cardiovascular variability HR and BP variability during wake Endothelial dysfunction (Systemic inflammation, sympathetic activation, pressor surges, oxidative stress) Inflammation / Hypoxemia (Pentraxin3, IL-6, CRP, NO NFkB, TNFa, adhesion molecules, serum amyloid A, leukocyte activation) Cardiovascular Disease Risk Oxidative Stress (thiobarbituric acid reactive substances, isopropanes, oxidized LDL) Intrathoracic pressure changes Mueller maneuver Insulin resistance/ metabolic dysregulation Glucose intolerance Leptin Thrombosis Platelet activation fibrinogen

36 Mechanism of disease and CV Risk Vasoactive substances recurrent hypoxemic stress endothelin Inflammation / Hypoxemia (Pentraxin3, IL-6, CRP, NO NFkB, TNFa, adhesion molecules, serum amyloid A, leukocyte activation) Cardiovascular variability HR and BP variability during wake Cardiovascular Disease Risk Oxidative Stress (thiobarbituric acid reactive substances, isopropanes, oxidized LDL) Intrathoracic pressure changes Mueller maneuver Endothelial dysfunction (Systemic inflammation, sympathetic activation, pressor surges, oxidative stress) Insulin resistance/ metabolic dysregulation Glucose intolerance Leptin Thrombosis Platelet activation fibrinogen

37 Mechanism of disease and CV Risk Sympathetic Activation HR during wake Vasoactive substances recurrent hypoxemic stress endothelin Inflammation / Hypoxemia (Pentraxin3, IL-6, CRP, NO NFkB, TNFa, adhesion molecules, serum amyloid A, leukocyte activation) Cardiovascular variability HR and BP variability during wake Cardiovascular Disease Risk Oxidative Stress (thiobarbituric acid reactive substances, isopropanes, oxidized LDL) Intrathoracic pressure changes Mueller maneuver Endothelial dysfunction (Systemic inflammation, sympathetic activation, pressor surges, oxidative stress) Insulin resistance/ metabolic dysregulation Glucose intolerance Leptin Thrombosis Platelet activation fibrinogen

38 Mechanism of disease and CV Risk Occluded pharynx (Mueller Maneuver)

39 Mechanism of disease and CV Risk Occluded pharynx (Mueller Maneuver) Negative intrathoracic pressure

40 Mechanism of disease and CV Risk Occluded pharynx (Mueller Maneuver) Negative intrathoracic pressure Transmural gradients across atria, ventricles & aorta

41 Mechanism of disease and CV Risk Occluded pharynx (Mueller Maneuver) Negative intrathoracic pressure Transmural gradients across atria, ventricles & aorta Ventricular function Autonomic & hemodynamic instability Myocardial oxygen demand

42 Mechanism of disease and CV Risk Occluded pharynx (Mueller Maneuver) Negative intrathoracic pressure Transmural gradients across atria, ventricles & aorta Ventricular function Autonomic & hemodynamic instability Myocardial oxygen demand Preload Afterload Atrial size Wall stress Stroke volume Impaired diastolic function Thoracic aortic dilation / dissection Ventricular hypertrophy / remodeling

43 Mechanism of disease and CV Risk From the Journal of the American College of Cardiology

44 Hypertension 50% of OSA patients are hypertensive 30% of hypertensive patients have OSA OSA may predominantly raise systolic BP 1 Linear/causal relationship between 24- hour BP and AHI 2,3 1 Haas DC et al. Age-dependent association between sleep disordered breathing and hypertension: importance in discriminating between systolic/diastolic hypertension and isolated systolic hypertension in the Sleep Heart Health Study. Circulation Young T et al. Population based study of sleep disordered breathing as a risk factor for hypertension. Arch Intern Med Chobanian AV et al. The 7 th Annual Report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure. JAMA 2003.

45 Hypertension Wisconsin Sleep Cohort study 1, Sleep Heart Health Study 2, Nurses Health Study 3, Outcomes of Sleep Disorders in Older Men Study 4 OSA is an independent risk factor for essential HTN Nocturnal BP nondipping is associated with coexisting OSA 5, cerebral white matter disease 6 and all-cause mortality 7 1 Peppard PE et al. Prospective study of the association between SDB and HTN. N Engl J Med Nieto FJ et al. Association of SDB, sleep apnea, and HTN in a large community-based study. JAMA Hu FB et al. Prospective study of snoring and risk of hypertension in women. Am J Epidemiol Mehra R et al. Prevalence and correlates of SDB in older men: osteoporotic fractures in men sleep study. Am J Geriatr Soc Portaluppi F et al. Undiagnosed SDB among male nondippers with essential hypertension. J Hypertens Schwartz GL et al. Association with ambulatory blood pressure with ischemic brain injury. Hypertension Ben-Dov IZ et al. Predictors of all-cause mortality in clinical ambulatory monitoring: unique aspects of blood pressure during sleep. Hypertension 2007.

46 Hypertension CPAP therapy decreases Mean Arterial Pressure (MAP) by 2-5 mmhg 1 Better antihypertensive response if daytime sleepiness 2,3,4 and more severe disease 5 CPAP markedly reduced BP and sympathetic production in sleep 6 CPAP reduces arterial stiffness 7 Larger prospective studies needed 1 Giles TL et al. CPAP for obstructive sleep apnoea in adults. Cochrane Database Syst Rev Robinson GV et al. CPAP does not reduce blood pressure in nonsleepy hypertensive OSA patients. Eur Respir J Faccenda JF et al. Randomized placebo-controlled trial of CPAP on BP in the sleep apnea-hypopnea syndrome. Am J Respir Crit Care Med Pepperell JC et al. Ambulatory BP after therapeutic & subtherapeutic nasal CPAP for OSA: a randomised parallel trial. Lancet Dernaika TA et al. Effects of nocturnal CPAP therapy in patients with resistant HTN and OSA. J Clin Sleep Med Somers VK et al. Sympathetic neural mechanisms in obstructive sleep apnea. J Clin Invest Buchner NJ et al. Treatment of OSA reduces arterial stiffness. Sleep Breath 2011.

47 Progression of HTN in OSA Intermittent Hypoxia Chemoreceptor Stimulation (6-OH dopamine) Sympathetic Activation Renin-angiotensionaldosterone System (RAAS) (aldosteronism)

48 Heart Failure SDB is present in 75% of patients with symptomatic or decompensated HF 1, % prevalence of all HF patients 3,4 Prevalence of 69% in HFNEF (40%/29%) 5 Men (obesity) > women (older age) HF patients with SBD are older and have higher BMI, BNP, PCWP and lower PaCO2 1 Khayat RN et al. In-hospital testing for SDB in hospitalized patients with decompensated heart failure: report of prevalence and patient characteristics. J Card Fail Oldenburg O et al. SDB in patients with symptomatic heart failure: a contemporary study of prevalence in and characteristics of 700 patients. Eur J Heart Fail Paulino A et al. Prevalence of SDB in a 316-patient French cohort of stable congestive heart failure. Arch Cardiovasc Dis Arias MA et al. OSA syndrome affects left ventricular diastolic function: effects of nasal PAP in men. Circulation Bitter T et al. SDB in heart failure with normal left ventricular ejection fraction. Eur J Heart Fail 2009.

49 Heart Failure OSA and CSA are prevalent OSA may not manifest with sleepiness CSA/CSR independent predictor of mortality HTN - most common risk factor for ventricular hypertrophy and failure 1 Nocturnal O2 desaturation predicts impaired ventricular relaxation during diastole 2 LVH may be more closely linked to HTN during sleep 3 1 Levy D et al. The progression from hypertension to congestive heart failure. JAMA Fung JW et al. Severe OSA is associated with left ventricular diastolic dysfunction. Chest Verdecchia P et al. Circadian blood pressure changes and left ventricular hypertrophy in essential hypertension. Circulation 1990.

50 Progression of HF in OSA Increased sympathetic outflow Increasing risk off MI increase myocardial demand in recurrent hypoxia Cytokines, catecholamines, endothelin - Ventricular hypertrophy Negative intrathoracic pressure - increases preload and afterload Inducing hypoxia and increases in RV afterload

51 Progression of HF in CSA Higher resting sympathetic drive Increased cardiac filling pressures with LV dysfunction Greater cardiac electrical instability Pulmonary congestion Increased chemoreflexes Prolonged circulation time

52 Heart Failure OSA is associated with altered cardiac structure and function 1,2,3,4 and they may be reversible with CPAP 3 months of CPAP improved abnormal diastolic filling and function 2 CPAP improved LVEF and quality of life 5,6 CPAP - decreases myocardial irritability and risk of arrhythmia 7 1 Otto ME et al. Comparison of structural & functional changes in obese otherwise healthy adults w/ vs w/o OSA. Am J Cardiol Arias MA et al. OSA syndrome affects LV diastolic function: effects of nasal PAP in men. Circulation Shivalkar B et al. OSA syndrome: more insights on structural and functional cardiac alterations, and the effects of treatment with CPAP. J Am Coll Cardiol Marin JM et al. Long-term cardiovascular outcomes in men with obstructive sleep apnea-hypopnoea with or without treatment with CPAP: an observational study. Lancet Kaneko Y et al. Cardiovascular effect of CPAP in patient with heart failure and OSA. N Engl J Med Mansfield DR et al. Controlled trial of CPAP in OSA and heart failure. Am J Respir Crit Care Med Javaheri S et al. Effects of CPAP on sleep apnea and ventricular irritability in patients with heart failure. Circulation 2000.

53 Heart Failure Effect of CPAP on CSA in patients with HF is not well understood CANPAP study did not improve survival 1 Cardiac resynchronization CSA/CSR patients 2,3,4 Not clear if treatment of OSA or CSA with CPAP will reduce incidence of HF or improve survival 1 Bradley TD et al. CPAP for central sleep apnea and heart failure. N Engl J Med Melzer C et al. Nocturnal overdrive pacing for the treatment of sleep apnea syndrome. Sleep Gabor JY et al. Improvement in Cheyne-Stokes Respiration following cardiac resynchronization therapy. Eur Respir J Luthje L et al. Cardiac resynchronization therapy and atrial overdrive pacing for the treatment of central sleep apnea. Eur J Heart Fail 2009.

54 Stroke High prevalence 40-70% (OSA and CSA) 1 Biased and study only stroke survivors and rehab patients SDB is a risk factor for stroke 2 and stroke is a risk factor for SDB 3 Severe SDB is an independent risk factor for stroke in men 4 1 Chan W et al. Sleep apnea in patients with TIA and minor stroke: opportunity for risk reduction of recurrent stroke. Stroke Capampangan DJ et al. Is OSA an independent risk factor for stroke? A critically appraised topic. Neurologist Dyken ME. Obstructive sleep apnea and stroke. Chest Redline S et al. Obstructive sleep apnea hypopnea and incident stroke: The Sleep Heart Health Study. Am J Respir Crit Care Med 2010.

55 Stroke Increased rate of stroke or death in patients with OSA over 4 years 1 10 year f/u data of patients with stroke increased risk of death with OSA (HR 1.76; 95% CI: 1.05 to 2.95; P=0.03) but not with CSA (HR 1.07; 95% CI:0.65 to 1.76; P=0.80) 2 1 Yaggi HK. Obstructive sleep apnea is a risk factor for stroke and death. N Engl J Med Sahlin C et al. Obstructive sleep apnea is a risk factor for death in patients with stroke. Arch Intern Med 2008

56 Stroke in OSA Impaired endothelial function BP fluctuations Accelerated atherogenesis Stroke Prothrombotic and Proinflammatory states Reductions in cerebral blood flow / hypoxia Altered cerebral autoregulation

57 Stroke CPAP normalizes cerebral blood flow after 4 to 6 weeks 1 Hypoxic events - poor post stroke recovery Improved long-term survival in CPAP compliant post stroke patients 2 Low compliance Unclear if treatment of SDB reduces risk of stroke 1 Foster GE. Effects of CPAP on cerebral vascular response to hypoxia in patients with OSA. Am J Respir Crit Care Med Martinez-Garcia MA et al. CPAP treatment reduces mortality in patients with ischemic stroke and OSA: a 5 year follow-up study. Am J Respir Crit Care Med 2009.

58 Arrhythmia Noc arrhythmias - 50% of SDB patients 1 Increase with AHI and hypoxia Most common Afib, nonsustained VT, sinus arrest, 2 nd degree AVB, PVC s (66%) 17 fold increased odds of an arrhythmia (Afib and nonsustained VT) after SDB 2 Afib - CSA 3 Complex ventricular ectopy OSA 3 1 Mehra R et al. Association of nocturnal arrhythmias with SDB: The Sleep Heart Health Study. Am J Respir Crit Care Med Monahan k et al. Triggering of nocturnal arrhythmias by SDB events (SHHS). J Am Coll Cardiol Mehra R et al. Nocturnal arrhythmia across a spectrum of obstructive and central SDB in older men. Arch Int Med 2009.

59 Arrhythmia Prevalence of undiagnosed OSA in patients with pacemakers is 59% and SDB present in 68% with AVB 1 Postop Afib more likely in OSA patients 2 50% Afib patients at cardioversion likely to have OSA 3 1 Garrigue S et al. High prevalence of sleep apnea syndrome in patients with long-term pacing: the European Multicenter Polysomnographic Study. Circulation Mooe T et al. SDB a novel predictor of atrial fibrillation after coronary artery bypass surgery. Coron Artery Dis Gami AS et al. Association of atrial fibrillation and obstructive sleep apnea. Circulation 2004.

60 Arrhythmia in OSA Cardiac vagal activation Hypoxemia Arrhythmia Transmural pressure changes Pressor surges Sympathetic activation to the periphery Systemic inflammation

61 Arrhythmia Risk of arrhythmia in OSA decreases with CPAP therapy 1 Lower recurrence of Afib after elective cardioversion in OSA patients treated with CPAP (82% vs 42%) after 1 year 2 58% decrease in PVC s with CPAP in patients with OSA & systolic dysfunction 3 1 Simantirakis EN et al. Severe bradyarrhythmias in patients with sleep apnoea: the effect of CPAP treatment: a long-term evaluation using an insertable loop recorder. Eur Heart J Kanagala R et al. Obstructive sleep apnea and the recurrent of atrial fibrillation. Circulation Ryan CM et al. The effects of CPAP on ventricular ectopy in heart failure patients with OSA syndrome. Thorax 2005.

62 Atrial overdrive pacing for OSA Initial report showed 50% reduction of OSA 1 No effect on OSA severity or nocturnal oxygen desaturation 2,3,4 1 Garrigue S et al. Benefit of atrial pacing in sleep apnea syndrome. N Engl J Med Simantirakis EN et al. Atrial overdrive pacing for the obstructive sleep apnea-hypopnea syndrome. N Engl J Med Krahn AD et al. Physiologic pacing in patients with OSA: a prospective, randomized crossover trial. J Am Coll Cardiol Sharafkhaneh et al. Effects of atrial overdrive pacing on OSA in patients with systolic heart failure. Sleep Med 2007.

63 Cardiovascular Disease and SDB Prevalence of SDB in CAD 2x increase 1,2 Risk of CAD primarily in men < 70 3 OSA patients have subclinical CAD (coronary artery calcification) 4 OSA with no CVD have microcirculation oxidant production and endothelial dysfunction 5 Untreated severe OSA (men) at 10 yrs - increased fatal and nonfatal CV events 6 1 Sanner BM et al. SDB in patients referred for angina evaluation-association with LV dysfunction. Clin Cardiol Shafer H et al. Obstructive sleep apnea as a risk marker in CAD. Cardiology Gottlieb DJ et al. Prospective study of OSA and incident CHD and heart failure: the SHHS. Circulation Sorajja D et al. Independent association between OSA and subclinical CAD. Chest Patt BT et al. Endothelial dysfunction in the microcirculation of patients with OSA. Am J Respir Crit Care Med Peker Y et al. Respiratory disturbance index: an independent predictor of mortality in CAD. Am J Respir Crit Care Med 2000.

64 Cardiovascular Disease and SDB ST depressions occur in 1/3 of patients with severe OSA 1 Nocturnal angina and ST depressions are diminished with CPAP 2,3 Patients with SDB and CAD 5 yr f/u composite endpoint (death, MI, CVA) - men 28 vs 16%, women 20 vs 14% 4 1 Hanly P et al. ST - segment depression during sleep in OSA. Am J Cardiol Franklin KA et al. Sleep apnoea and nocturnal angina. Lancet Peled N et al. Nocturnal ischemic events in patients with OSA syndrome and ischemic heart disease: effects of CPAP treatment. Am J Coll Cardiol Mooe T et al. Sleep disordered breathing and coronary artery disease: long-term prognosis. Am J Respir Crit Care Med 2001.

65 Cardiovascular Disease and SDB Sudden cardiac death no OSA (6 to 11am), OSA (10pm to 6am) 1 Decreased occurrence of CV death, ACS, HF, revascularization if treat OSA 2 Men with severe OSA marked increase in fatal and nonfatal CV events (much less if treated with CPAP) 3 1 Gami AS et al. Day-night pattern of sudden death in OSA. N Engl J Med Milleron O et al. Benefits of obstructive sleep apnea treatment in CAD: a long-term follow up study. Eur Heart J Marin JM et al. Long-term cardiovascular outcomes in men with obstructive sleep apnea-hypopnoea with or without treatment with CPAP: an observational study. Lancet 2005.

66 CAD and OSA after PCI OSA associated with restenosis and remodeling 1 Increase incidence of revascularizations and cardiac mortality 2 Less increase in LVEF and wall motion 3 Treatment of OSA after PCI reduced cardiac deaths 4 1 Steiner S et al. Impact of OSA on the occurrence of restenosis after elective PCI in ischemic heart disease. Respir Res Yumino D et al. Impact of OSA on clinical and angiographic outcomes following PCI in patients a with ACS. Am J Cardiol Nakashima H et al. OSA inhibits the recovery of LV function in patients with acute myocardial infarction. Eur Heart J Cassar A et al. Treatment of OSA is associated with decreased cardiac death after PCI. J Am Coll Cardiol 2007.

67 Cardiovascular Disease in OSA Increased BP Hypoxemia and acidosis Endothelial dysfunction and vascular remodeling Intrathoracic and cardiac transmural pressure changes Sympathetic vasoconstriction Systemic inflammation

68 Cardiovascular Disease and SDB CPAP improves early atheroslcerosis 1 and microvascular disease and endothelial dysfunction 2 No randomized control trials for treatment of OSA and risk of CAD, MI or sudden death RICCADSA study CPAP on composite endpoint in CAD & OSA patients over 3 years HeartBEAT study CPAP or low flow O2 will change cardiac biomarkers SAVE study CPAP to treat OSA to prevent CVD 1 Drager LF et al. Effects of CPAP on early signs of atherosclerosis in OSA. Am J Respir Crit Care Med Nguyen PK et al. Nasal CPAP improves myocardial perfusion reserve and endothelial-dependent vasodilatation in patients with OSA. J Cardiovasc Magn Reson 2010.

69 Pulmonary Arterial Hypertension (PAH) Prevalence of PAH in OSA 17 to 42% Pulmonary hypertensive OSA patients - increased pulmonary vascular reactivity to hypoxia 1? OSA causes sustained daytime PAH Pulmonary artery pressures decrease after treatment with CPAP 2,3 1 Sajkov D et al. Daytime pulmonary hemodynamics in patients with OSA without lung disease. Am J Respir Crit Care Med Sajkov D et al. CPAP improves pulmonary hemodynamics in patients with OSA. Am J Respir Crit Care Med Arias MA e al. Pulmonary hypertension in obstructive sleep apnoea: effects of CPAP: a randomized, controlled cross-over study. Eur Heart J 2006.

70 End Stage Renal Disease (ESRD) Prevalence of OSA in ESRD is 40 to 60% (often mixed sleep apnea) OSA - contribute to ESRD by chronic HTN OSA may increase risk of CV complications Prevalence of OSA in ESRD is the same before and after HD 1 Nocturnal peritoneal dialysis attenuate sleep apnea 2 1 Wadhwa NK et al. Sleep related respiratory disorders in end-stage renal disease patients on peritoneal dialysis. Perit Dial Int Tang SC et al. Alleviation of sleep apnea in patients with chronic renal failure by nocturnal cycler-assisted peritoneal dialysis compared with conventional continuous ambulatory peritoneal dialysis. J Am Soc Nephrol 2006.

71 ESRD in OSA Uremia destabilized ventilatory control & upper airway edema Glomerular hyperfiltration Chronic Hypertension Hypoxemia Systemic Inflammation Cystatin C Sympathetic nerve discharge at kidney

72 Treatment of SDB OSA Weight loss Positional sleep Oral appliance Surgery tracheostomy, UPPP Positive airway pressure CSA Optimize HF treatment (ACE-I, diuresis, b blocker) Cardiac resynchronization therapy (CRT) CPAP, BiPAP, Adaptive pressure support servoventilation Supplemental O2 Acetazolamide

73 Summary A persuasive body of data supporting a causal association between SDB and cardiovascular disease Randomized control trials are underway to investigate whether SDB accelerates heart disease progression treatment results in fewer cardiovascular events treatment reduces mortality

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75 Contact Information Elizabeth A. Lynch, MD Sleep Institute of New England Ph Fax