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1 Cardiovascular Consequences of
Obstructive Sleep Apnea

2 Ronald J. Green, MD, FCCP, FAASM Diplomate, American Board of Sleep Medicine Sleep Medicine, Pulmonary Disease & Smoking Cessation, The Everett Clinic Associate Medical Director North Puget Sound Center for Sleep Disorders Everett, WA ;

3 Cardiovascular disease is
Common Dangerous Easily recognized Treatable

4 Obstructive Sleep Apnea Syndrome (OSAS) is
Common Dangerous Easily recognized Treatable The important message to take home from this talk is that sleep apnea is a common disorder; it is dangerous for the patient and others; and it is easily recognizable and is treatable. We will first define what sleep apnea is, then describe the physiological consequences of the disorder and how these lead to the presenting features. This will be followed by a discussion of clinical features and risk factors suggestive of the presence of sleep apnea and methods for making the diagnosis. Finally, we will discuss the treatment options available for patients with sleep apnea.

5 I hope to demonstrate to you today that OSAS is associated with the development of cardiovascular disease

6 OUTLINE Overview of obstructive sleep apnea syndrome (OSAS)
OSAS & the cardiovascular system: pathophysiology OSAS and Hypertension Myocardial ischemia and infarction Congestive heart failure Stroke Cardiac dysrhythmias, particularly Atrial fibrillation Effects of OSAS treatment on cardiovascular disease Conclusions The important message to take home from this talk is that sleep apnea is a common disorder; it is dangerous for the patient and others; and it is easily recognizable and is treatable. We will first define what sleep apnea is, then describe the physiological consequences of the disorder and how these lead to the presenting features. This will be followed by a discussion of clinical features and risk factors suggestive of the presence of sleep apnea and methods for making the diagnosis. Finally, we will discuss the treatment options available for patients with sleep apnea.

7 Overview of The obstructive sleep apnea syndrome

8 What is the “apnea” in sleep apnea?
Cessation of airflow > 10 seconds Hypopnea Decreased airflow > 10 seconds associated with: Arousal from sleep Oxyhemoglobin desaturation When abnormal breathing patterns disrupt sleep, this is called sleep-disordered breathing. There are different types which can occur in one of several patterns. An apnea is defined as the cessation of airflow for 10 or more seconds.1 Controversy exists about the definition of hypopnea. Because of the relationship of sleep fragmentation and daytime sleepiness, many investigators consider a decrease in airflow for > 10 seconds accompanied by an arousal as a significant disordered breathing (hypopnea) event without requiring a specific level of desaturation.2 Recently, the presence of apneas and hypopneas has been associated with an increased prevalence of cardiovascular disease.3 In this study, hypopnea was defined as an event lasting at least 10 seconds with a greater than 30% reduction in thorocoabdominal movement or airflow, and with at least a 4% oxygen desaturation. When a 4% desaturation criteria is applied to the definition of hypopnea significant cardiovascular co-morbidity has been detected at an AHI => 5 per hour. For this talk, hypopnea will be broadly defined as those obstructive events, lasting > 10 seconds, accompanied by either oxyhemoglobin desaturation or an arousal. 1. American Thoracic Society. Indications and standards for the use of nasal continuous positive airway pressure (CPAP) in sleep apnea syndromes. Am J Respir Crit Care Med 1994;150(6 Pt 1): 2. American Academy of Sleep Medicine Task Force. Sleep-related breathing disorders in adults: recommendations for syndrome definition and measurement techniques in clinical research. SLEEP 1999;22(5): 3. Shahar E, Whitney CW, Redline S, Lee ET, Newman AB, Javier Nieto F, O’Connor GT, Boland LL, Schwartz JE, Samet JM. Sleep-disordered breathing and cardiovascular disease: cross-sectional results of the Sleep Heart Health Study. Am J Respir Crit Care Med 2001;163(1):19-25.

9 Measures of Sleep Apnea Frequency
Apnea Index # apneas per hour of sleep Apnea / Hypopnea Index (AHI) # apneas + hypopneas per hour of sleep > 5 considered abnormal in adults These are the terms most commonly used to describe the frequency of sleep apnea. The Apnea Index is defined as the number of apneas per hour of sleep. The Apnea/Hypopnea Index, or AHI, represents the total number of apneas and hypopneas per hour of sleep. This has also been called the Respiratory Disturbance Index or RDI. An AHI < 5 is considered normal.5 What frequency above this level requires therapy or leads to adverse clinical consequences is controversial. The sleep apnea syndrome, or clinical sleep apnea, is defined as recurrent apneas or hypopneas that are associated with clinical impairment, such as daytime sleepiness, motor vehicle accidents or cardiovascular disease.1 5. National Center on Sleep Disorders Research. Sleep apnea: is your patient at risk? Department of Health and Human Services, National Institutes of Health, National Heart, Lung, and Blood Institute, NIH Publication No , September 1995. 1. American Thoracic Society. Indications and standards for the use of nasal continuous positive airway pressure (CPAP) in sleep apnea syndromes. Am J Respir Crit Care Med 1994;150:

10 Pathophysiology of an obstructive apnea
This slide shows the effect of sleep on the upper airway in a sleep apnea patient. In the figure on the left, the patient is awake and the airway is narrowed but patent. The upper airway dilator muscles are responsible for maintaining the patency of the airway despite the reduced size of the airway, which may be due to fat deposition from obesity or structural abnormalities such as retrognathia. Note that collapse, shown on the right, may occur anywhere along the upper airway, from the retropalatal space to the hypopharynx, and often occurs in multiple places.

11 Pathophysiology of Obstructive Sleep Apnea
Awake: Small airway + neuromuscular compensation Loss of neuromuscular compensation Sleep Onset Hyperventilate: connect hypoxia & hypercapnia Decreased pharyngeal muscle activity Airway opens Airway collapses Pharyngeal muscle activity restored Apnea Arousal from sleep Hypoxia & Hypercapnia Increased ventilatory effort + This figure depicts the repetitive pathophysiologic events which occur during sleep apnea. The primary problem in the sleep apnea patient is the presence of an anatomically small pharyngeal airway. To prevent airway collapse during wakefulness, the action of the airway dilator muscles is augmented – a neuromuscular compensation for the small airway. With sleep onset, there is a loss of the upper airway reflex which drives this neuromuscular compensation. As a result, dilator muscle activity falls, the pharynx closes and the apnea begins. During the apnea, hypoxia and hypercapnia develop, leading to increasing ventilatory effort. Once this effort reaches a threshold level, the patient arouses. Pharyngeal muscle activity is restored, and the airway opens. The patient then hyperventilates to correct the blood gas derangements, returns to sleep, and the cycle begins again. As a result, sleep can be severely disrupted by the repetitive arousals needed to end the apneas, and episodes of cyclic hypoxia and hypercapnia occur. These events lead to the observed clinical consequences.

12 Clinical Consequences
Obstructive Sleep Apnea Sleep fragmentation, Hypoxia / Hypercapnia excessive daytime sleepiness cardiovascular & metabolic complications As we proceed to detail the many clinical consequences of sleep apnea, it will be helpful to recall that all these adverse effects are the result of the two fundamental abnormalities which characterize sleep apnea. First, the patient cycles from apnea to arousal many times each night which leads to severe sleep fragmentation. Second, most apneic episodes are accompanied by hypoxemia and hypercapnia, which repeatedly stress the patient’s cardiovascular system. The many ill-effects which result from these two abnormalities can be broadly grouped into two categories: excessive daytime sleepiness and cardiovascular dysfunction. The end result of all these adverse effects is a substantial increase in both morbidity and mortality among sleep apnea patients. Morbidity Mortality

13 Obstructive Sleep Apnea: Most common risk factors
Obesity Increasing age Male gender Anatomic abnormalities of upper airway Family history of OSAS Alcohol or sedative use A number of factors which put people at higher risk for developing sleep apnea are listed on this slide. The most common risk factor is the presence of obesity, specifically measures of central obesity. Upper body fat distribution is one of the major contributing factors to the development of sleep apnea. In both sexes the syndrome is more prevalent with increasing age,6 reaching very high rates in patients over 65 years.24 Males appear to have a higher rate of sleep apnea than women, with a ratio of 2:1 to 10:1, depending on the study.11 Any condition resulting in an anatomic abnormality which narrows the posterior airspace can predispose to the development of sleep apnea. This includes nasal obstruction, retro- or micrognathia, tonsillar hypertrophy and macroglossia. Several studies have demonstrated a higher risk for development of sleep apnea if there is a family history of the disorder, with increasing risk with increasing number of affected relatives.25 Use of alcohol or sedative medication can contribute to the development of sleep apnea through their relaxant effect on the upper airway muscles.26 A longitudinal epidemiological study showed that smokers are at an increased risk for developing sleep apnea, with current smokers at greater risk than nonsmokers, and heavy smokers having the greatest risk.27 Cessation of smoking resulted in the elimination of the increased risk. Associated conditions: Hypothyroidism can contribute to the development of sleep apnea through the development of macroglossia or obesity, and through its effect on upper airway muscle function. Other conditions in which sleep apnea has been reported – due to their effects on upper airway anatomy or muscle function – include acromegaly, amyloidosis, vocal cord paralysis, post-polio syndrome, neuromuscular disorders, Marfan syndrome and Down syndrome.11 6. Young T, Palta M, Dempsey J, Skatrud J, Weber S, Badr S. The occurrence of sleep-disordered breathing among middle-aged adults. N Engl J Med 1993;328(17): 24. Ancoli-Israel S, Klauber MR, Kripke DF, Parker L, Cobarrubias M. Sleep apnea in female patients in a nursing home. Increased risk of mortality. Chest 1989;96(5): 11. Strohl KP, Redline S. Recognition of obstructive sleep apnea. Am J Respir Crit Care Med 1996;154(2 Pt 1): 25. Redline S, Tishler PV, Tosteson TD, et al. The familial aggregation of obstructive sleep apnea. Am J Respir Crit Care Med 1995:151(3 Pt 1): 26. Issa FG, Sullivan CD. Alcohol, snoring and sleep apnea. J Neurol Neruosurg Psychiatry 1982;45(4): 27. Wetter DW, Young BT, Bidwell TR, Badr MS, Palta M. Smoking as a risk factor for sleep-disordered breathing. Arch Intern Med 1994;154(19):

14 Diagnosis: History Loud snoring (not all snore)
Nocturnal gasping and choking Ask bed partner (witnessed apneas) Automobile or work related accidents Personality changes or cognitive problems Risk factors Excessive daytime sleepiness (often not recognized by patient) Frequent nocturia The first step in making a diagnosis of sleep apnea is taking a thorough history of the patient’s sleep schedule and sleep apnea symptoms. The responses shown on this slide indicate an increased probability of obstructive sleep apnea.5 Patients with loud, long-standing snoring are at an increased risk of having sleep apnea,41 especially if paired with gasping or choking episodes during sleep. These episodes may represent apneic events. It is very important that an attempt be made to elicit information from the patient’s bed partner. The patient is often unaware of what occurs during sleep and may not be aware of symptoms such as snoring. A bed partner’s description of witnessed apneas is highly suggestive of the presence of sleep apnea.42 A history of multiple automobile or work-related accidents, especially when associated with tiredness or fatigue, should prompt an investigation for sleep apnea.43 Information concerning risk factors – such as family history, alcohol or sedative use, predisposing medical conditions or cigarette smoking – should be elicited from anyone suspected of having sleep apnea. Most patients with sleep apnea are objectively sleepy, although daytime sleepiness is frequently underreported. As a result, it is important to know how to assess daytime sleepiness. Sleep Apnea: Is Your Patient at Risk? NIH Publication, No 5. National Center on Sleep Disorders Research. Sleep apnea: Is your patient at risk? Department of Health and Human Services, National Institutes of Health, National Heart, Lung, and Blood Institute, NIH Publication No , September 1995. 41. Stradling JR, Crosby JH. Predictors and prevalence of obstructive sleep apnoea and snoring in 1001 middle aged men. Thorax 1991;46(2):85-90. 42. Kump K, Whalen C, Tishler PV, Browner I, Ferrette V, Strohl KP, Rosenberg C, Redline S. Assessment of the validity and utility of a sleep-symptom questionnaire. Am J Respir Crit Care Med 1994;150(3): 43. American Thoracic Society. Sleep apnea, sleepiness, and driving risk. Am J Respir Crit Care Med 1994;150(5 Pt 1):

15 Diagnosis: Physical Examination
Upper body obesity / thick neck > 17” males > 16” females Hypertension Obvious airway abnormality The presence of these physical characteristics on physical examination should raise the physicians’ suspicion about the presence of sleep apnea. Obesity, particularly upper body obesity, is associated with the presence and severity of sleep apnea.29 In general, men with a neck circumference of 17 inches or greater and women with a neck circumference of 16 inches or greater are at a higher risk for sleep apnea.28 Systemic hypertension is common in sleep apnea patients.44 The presence of any obvious airway abnormality – such as a crowded oropharynx, tonsillar hypertrophy, retrognathia or nasal obstruction – puts the patient at risk for the development of sleep apnea.45 29. Millman RP, Carlisle CC, McGarvey ST, Eveloff SE, Levinson PD. Body fat distribution and sleep apnea severity in women. Chest 1995;107(2): 28. Davies RJ, Stradling JE. The relationship between neck circumference, radiographic pharyngeal anatomy, and the obstructive sleep apnoea syndrome. Eur Respir J (Denmark) 1990;3(5): 44. Hla KM, Young TB, Bidwell T, Palta M, Skatrud JB, Dempsey J. Sleep apnea and hypertension. A population-based study. Ann Intern Med 1994;120(5): 45. Shepard JW Jr., Gefter WB, Guilleminault C, et al. Evaluation of the upper airway in patients with obstructive sleep apnea. SLEEP 1991;14(4):

16 Exam: Oropharynx Slide 16 Level 2
This picture demonstrates a common finding in sleep apnea patients, the crowded oropharynx. The soft palate hangs low, the uvula is slightly enlarged and there is crowding by the lateral tonsillar pillars. The palatine tonsils are not visualized. Slide 16 Level 2 46. Shepard JW Jr, Olsen KD. Uvulopalatopharygoplasty for treatment of obstructive sleep apnea. Mayo Clin Proc 1990;65(9):

17 Physical Examination This patient demonstrates structural abnormalities which can lead to airway narrowing and sleep apnea. Note the presence of a thick neck and retrognathia.47 Guilleminault C et al. Sleep Apnea Syndromes. New York: Alan R. Liss, 1978. 47. Coccagna G, et al. The bird-like face syndrome (acquired micrognathia, hypersomnia, and sleep apnea). In: Guilleminault C, Dement WC, eds. Sleep apnea syndromes. New York: Alan R Liss, 1978:

18 Why Get a Sleep Study? Signs and symptoms poorly predict disease severity Appropriate therapy dependent on severity Failure to treat leads to: Increased morbidity Motor vehicle crashes Mortality Help diagnose other causes of daytime sleepiness A sleep study is performed to confirm the presence of sleep apnea and to assess the level of severity of the disorder. Although identification of patients at risk for sleep apnea can be made through the history and physical, the signs and symptoms in any particular patient are poor indicators of the level of disease severity.51 The severity of illness determines the type and urgency of treatment. Delay in confirming the diagnosis and determining the severity of sleep apnea can lead to delay in initiating treatment. This can lead to increased morbidity from the cardiovascular consequences, increased risk of motor vehicle accidents and, as a result, increased mortality. Before initiating treatment, it is also important to confirm the diagnosis and rule out other possible causes of excessive daytime sleepiness such as periodic limb movements of sleep, narcolepsy or insufficient amounts of sleep. Because sleepiness is a nonspecific symptom that can be caused by other disorders, and snoring is common even in people without sleep apnea, it is necessary to confirm the presence of sleep apnea. A sleep study will provide this information. 51. Viner S, Szalai JP, Hoffstein V. Are history and physical examination a good screening test for sleep apnea? Ann Intern Med 1991;115(5):

19 Polysomnography This slide shows the setup of equipment on a patient undergoing overnight polysomnography. Note the multiple EEG, EOG, EMG and respiratory electrodes required for full physiologic monitoring.

20 Treatment of Obstructive Sleep Apnea Syndrome

21 Treatment Objectives Reduce mortality and morbidity
Decrease cardiovascular complications Reduce sleepiness Improve metabolic derangements, including type 2 diabetes mellitus Improve quality of life The goal of treatment for patients with sleep apnea should be the reduction of morbidity and mortality and improvement of their quality of life. This can be accomplished by preventing the cardiovascular consequences of sleep apnea and reducing the complications of daytime sleepiness.

22 Therapeutic Approach Risk counseling Apnea treatment
Motor vehicle crashes Job-related hazards Judgment impairment Apnea treatment Weight loss; avoidance of alcohol & sedatives CPAP Oral appliance Surgery (UPPP) As part of the therapeutic approach to sleep apnea, all patients should be counseled regarding their increased risk of motor vehicle crashes, job related injuries and impairment of judgement.43 The treatment of sleep apnea and existing or consequent comorbidities can include behavioral, medical or surgical interventions.57 43. American Thoracic Society. Sleep apnea, sleepiness, and driving risk. Am J Respir Crit Care Med 1994;150(5 Pt 1): 57. Strollo PJ Jr., Rogers RM. Obstructive sleep apnea. N Engl J Med 1996;334(2):

23 Positive Airway Pressure
This slide depicts the therapeutic effect of continuous positive airway pressure (CPAP). In the panel on the left, you can see upper airway closure in an untreated sleep apnea patient. Note that the airway closure is diffuse, involving both the palate and the base of the tongue. In the second panel, CPAP is applied and the airway is splinted open by the positive pressure. 69. Sullivan CE, Issa FG, Berthon-Jones M, Eves L. Reversal of obstructive sleep apnoea by continuous positive airway pressure applied through the nares. Lancet 1981;1(8225):

24 Positive Airway Pressure
This slide depicts a patient sleeping while using a positive airway pressure system. These devices are highly portable, fit on a nightstand, and can easily be transported outside of the home.

25 Oral Appliance: Mechanics
There are several types of oral appliances available for the treatment of sleep apnea. This slide depicts a mandibular repositioning device. The oral appliance causes the mandible to move forward and the bite to open slightly. The effect of this mandibular repositioning is to enlarge the airway, reduce airway collapsibility and decrease airway resistance.82 The device also anchors the mandible so that contraction of the genioglossus muscle moves the hyoid bone forward rather than just opening the mouth. Another proposed mechanism is the activation of upper airway muscles, although this has not been proven conclusively. In some patients, oral appliances are an effective treatment for sleep apnea. 82. Schmidt-Nowara W, Lowe A, Wiegand L, Cartwright R, Perez-Guerra F, Menn S. Oral appliances for the treatment of snoring and obstructive sleep apnea: a review. SLEEP 1995;18(6):

26 Uvulopalatopharyngoplasty (UPPP)
This slide depicts the uvulopalatopharyngoplasty (UPPP) surgical technique. The panel on the left depicts the preoperative upper airway, demonstrating a long soft palate and the presence of palatine tonsils. The incision site is marked with the dotted line. The panel on the right depicts the postoperative oropharynx, with amputation of the uvula, bilateral palatine tonsillectomy, and trimming and suturing together of the anterior and posterior tonsillar pillars. 89. Fujita S, Conway W, Zorick F, Roth T. Surgical correction of anatomic abnormalities in obstructive sleep apnea syndrome: uvulopalatopharyngoplasty. Otolaryngol Head Neck Surg 1981;89(6):

27 Primary Care Management
Risk counseling Behavior modification (weight loss, etc) Monitor symptoms and compliance Monitor weight and blood pressure Ask about recurrence of symptoms Evaluate CPAP use and side effects A variety of issues should be addressed by the primary care clinician5: 1. Risk counseling should be provided for all patients with sleep apnea. 2. Initiation of appropriate behavioral modification treatments such as weight loss and smoking cessation. 3. Patients undergoing treatment require monitoring for efficacy of and compliance with treatment and resolution of symptoms. Weight loss and changes in blood pressure should be monitored. Patients should be periodically re-evaluated for recurrence of symptoms after successful treatment. CPAP equipment should be checked periodically for proper functioning. Finally, objective compliance with CPAP should be documented, using hour meters currently available on most machines, and side effects or troubles with use detected and resolved. Sleep Apnea: Is Your Patient at Risk? NIH Publication No 5. National Center on Sleep Disorders Research. Sleep Apnea: Is Your Patient at Risk? U.S. Department of Health and Human Services, National Institutes of Health, National Heart, Lung and Blood Institute, NIH Publication No , September 1995.

28 Cardiovascular Consequences of Obstructive Sleep Apnea

29 Effects of normal sleep on the cardiovascular system (vs wake)
Decreased metabolic rate Decreased sympathetic nervous activity Decreased blood pressure Decreased heart rate Increased cardiac vagal tone Bradley & Floras, The Lancet, :

30 Effects of obstructive sleep apnea on the cardiovascular system (vs wake)
Interruption of cardiovascular quiescence: Increased sympathetic nervous activity Increased blood pressure Increased heart rate Decreased parasympathetic nervous activity Bradley & Floras, The Lancet, :

31 OSA triggers a cascade of events effecting the cardiovascular system
Bradley & Floras, The Lancet, :

32 OSA Impact on Cardiovascular System
Sonia Ancoli-Israel, Ph.D. OSA Impact on Cardiovascular System Hypoxia Increases metabolic demands on heart Impairs cardiac contractility Increases pulmonary artery pressures NOCTURNAL ISCHEMIA Leung AJRCCM 2001 Naughton Circulation 1995

33 OSA Impact on Cardiovascular System
Sonia Ancoli-Israel, Ph.D. OSA Impact on Cardiovascular System Arousals from sleep Surges in heart rate and blood pressure Increases in sympathetic nervous activity REPETITIVE STRAIN Leung AJRCCM 2001 Naughton Circulation 1995

34 Effects of OSAS on sympathetic nerve activity and BP in OSA pt without HTN
Somers, et al, J Clin Invest, :

35 Effects of OSAS on sympathetic nerve activity and BP in OSA pt without HTN
Somers, et al, J Clin Invest, :

36 Effects of OSAS on sympathetic nerve activity and BP in OSA pt without HTN
Somers, et al, J Clin Invest, :

37 Repetitive apnea-induced hypoxia and CO2 retention cause
Ineffective inspiratory effort increased negative intra-thoracic pressure  increased LV transmural pressure (increased afterload) which causes LV hypertrophy Increased negative intra-thoracic pressure increased RV preload (pulls blood into RV) Hypoxia causes pulmonary vasoconstriction leading to pulmonary HTN Bradley & Floras, The Lancet, :

38 Repetitive apnea-induced hypoxia and CO2 retention cause
Pulmonary vasoconstrictionincreased RV afterload  RV distention impaired LV diastolic filling  decreased LV stroke volume Apnea cycles cause oscillations in sympathetically-mediated peripheral vasoconstriction which raises systemic BP Arousal from sleep which terminates the apnea results in increased sympathetic tone and decreased vagal tone  surge in heart rate and blood pressure Bradley & Floras, The Lancet, :

39 Repetitive apnea-induced hypoxia and CO2 retention
Effects on blood pressure and heart rate can be sustained into wakefulness resulting in systemic HTN These changes are rapidly relieved with treatment of OSAS by CPAP Bradley & Floras, The Lancet, :

40 Vascular effects of OSAS
Intermittent hypoxia  O2 free radicals  activation of inflammatory pathways  impaired vascular endothelial function & increased BP independent of sympathetic activation. Hypercoagulability from increased expression of adhesion molecules & vascular smooth muscle proliferation This could predispose to HTN & atherosclerosis Bradley & Floras, The Lancet, :

41 Vascular effects of OSAS
Increased risk of thrombosis in OSAS increased platelet activation & aggregability Elevated morning fibrinogen levels Decreased plasminogen activator inhibitor type-1 activity Bradley & Floras, The Lancet, :

42 Given the pathophysiology just discussed, if you think there is
an increased incidence of OSAS in pts with cardiovascular disease, you are right!

43 Higher prevalence of OSAS in patients with cardiovascular disease
Prevalence of OSAS in general population: 7-10% Hypertension: 30-83% Congestive heart failure: 12-53% Ischemic heart disease: 30-58% Stroke: 43-91% Note that confounding variables including obesity need to be taken into account so correlation does not prove causality You need to have HIGH index of suspicion for OSAS in these patient populations Bradley & Floras, The Lancet, : Young, et al, N Engl J Med, :

44 OSAS and hypertension OSA is one known cause of HTN
Patients with OSA more likely to develop HTN OSA listed by Joint National Committee on the Detection & Management of HTN as important identifiable cause of HTN Possible mechanisms: Intermittent hypoxemia Chemoreceptor stimulation Sympathetic activation Renin-angiotensin system Chobanian JAMA 2003; Lesske J Hypertens 1997 Fletcher Hypertension 1992; Brooks J Clin Invest 1997

45 Adjusted Odds Ratio of developing HTN
Dose response effect of OSA severity and risk of HTN (adjusted for confounders) Adjusted Odds Ratio of developing HTN >15.0 Baseline AHI Peppard NEJM 2000

46 Experimental evidence: OSAS can raise blood pressure
Dogs exposed to OSA developed HTN during sleep and wake which resolved on reversal of the OSA Rats exposed to intermittent hypoxia (mimicking OSA) developed HTN. This was prevented by sympathectomy or peripheral chemoreceptor denervation. Bradley & Floras, The Lancet, :

47 OSAS and medication-resistant hypertension
OSAS is VERY common in medication-resistant HTN 3 observational studies: >70% of patients with difficult-to-treat or resistant HTN have sleep disordered breathing (versus its presence in <40% of patients with controlled HTN) Logan Eur Respir J 2003 Goncalves Chest 2007 Logan J Hypertens 2001

48 OSAS and medication-resistant hypertension
HTN in OSAS often associated with biochemical features of primary aldosteronism which in turn can lead to oxidative stressinflammation LV fibrosis and hypertrophy Bradley & Floras, The Lancet, : Logan, J Hypertension, : Marney & Brown, Clin Sci (Lond), :

49 OSAS and medication-resistant hypertension
If your patient is on 3 or more anti-hypertensive medications, think OSAS Bradley & Floras, The Lancet, : Logan, J Hypertension, : Marney & Brown, Clin Sci (Lond), :

50 Risk of myocardial ischemia and infarction in OSAS
Marin, et al: prospective study showed more fatal and non-fatal MI in severe, untreated OSAS vs control. No difference in rates in OSAS treated w/ CPAP vs control. In CAD patients, OSAS associated with higher mortality, more major cardiac events and higher restenosis rate after PTCA vs controls without OSAS. Case-control study: graded increase in odds of acute MI with increased sleep apnea severity. People with OSA more likely than those without to have family hx of premature death from CAD Somers, et al, Circ, : Marin, et al, The Lancet, : Yumino, et al, Am J Cardiol, :

51 Sonia Ancoli-Israel, Ph.D.
OSAS and CHF CHF patients with sleep apnea have worse prognosis than CHF patients without sleep apnea Ancoli-Israel Chest 2003

52 Sonia Ancoli-Israel, Ph.D.
OSAS and CHF prognosis Years of Survival Cumulative Survival 2 4 6 8 10 12 Ancoli-Israel Chest 2003

53 Sonia Ancoli-Israel, Ph.D.
OSAS and CHF mortality 164 patients with LVEF < 45% OSA = AHI > 15 At 3 year follow-up: Patients with OSA had higher cardiac mortality than patients without OSA 8.7 vs 4.2 deaths/100 patient-years Wang JACC 2007

54 Sonia Ancoli-Israel, Ph.D.
OSAS and CHF mortality Hazard ratio = 2.81 M-NSA: mild to no sleep apnea * Adjusted for LVEF, NYHA class, age Wang JACC 2007

55 Cerebrovascular effects of OSAS
Decrease in cerebral blood flow due to decreased cardiac output If flow-limiting carotid atherosclerosis present, could predispose to ischemic events OSAS patients vs controls: greater carotid intima-media thickness, decreased arterial compliance and higher incidence of silent brain infarcts Bradley & Floras, The Lancet, :

56 Stroke and OSAS Mod-severe OSA (AHI > 20) vs no OSA: 4.33 greater odds of stroke Sleep Heart Health Study, in OSAS: 1.58 times higher stroke risk in highest vs lowest AHI quartiles Study of pts > age 70, severe OSA (AHI > 30) vs OSA with AHI < 30, 2.52-times increased risk of stroke at 5 year follow up. Bradley & Floras, The Lancet, : Artz, et al, Am J Respir Crit Care Med, : Shahar, et al. Am J Respir Crit Care Med, : Munoz, et al. Stroke, :

57 Stroke and OSAS Several studies suggest post-stroke pts with OSAS (vs those without OSAS) have decreased motivation and cognitive capacity; Post-stroke pts with OSAS may have increased risk of recurrent stroke and death. In rehab unit, post-stroke pts with OSAS had worse functional impairment and spent longer time in hospital and rehab. Somers, et al, Circ, : Hsu, et al, J Neurol Neurosurg Pshychiatry, : Palombini, et al, Eur J Neurol, : Kaneko, et al, Sleep, :

58 Cardiac dysrhythmias and OSAS
More frequent in people with OSAS Increase with number of apneic episodes Increase with severity of oxygen desaturations Occur in up to 50% of OSAS patients Most common: NSVT, sinus arrest, frequent PVCs Somers, et al, Circ, :

59 Atrial fibrillation and OSAS
Increased likelihood of Afib vs controls (odd ratio 4.02) Potential mechanisms: Hypoxemia, sympathetic activation, pressor surges, transmural pressure changes, systemic inflammation in OSAS Afib OSAS is associated with left atrial enlargement Somers, et al, Circ, : Mehra, et al, Am J Respir Crit Care Med, : Otto, et al, Am J Cariol, : Romero-Corral, et al, Chest., :

60 Atrial fibrillation and OSAS
In OSAS, persistent atrial tachyarrhythmias more likely to occur at night. 50% of OSAS pts with Afib are likely to have Afib recurrence after cardioversion vs 30% likelihood in general cardiology clinic population without OSAS. Somers, et al, Circ, : Mitchell, et al, Am Heart J, : Gami, et al, Circulation, :

61 OSAS treatment with CPAP decreases cardiovascular consequences

62 Physiologic effects of CPAP
Immediate reversal of nocturnal hypoxemia and hypercapnia Resolution of nocturnal apnea-induced arousals Rapid reversal of intrathoracic pressure abnormalities and cardiac distention Decreased inflammatory marker levels (TNF alpha, interleukin 8, C-reactive protein, interleukin 6) Drop in morning fibrinogen levels Bradley & Floras, The Lancet, :

63 CPAP therapy: Effects on HTN
Acute and significant decrease in BP and sympathetic activity. 3 studies showed drop in BP with therapeutic vs sham (control) CPAP use. In patients intolerant of CPAP, oral appliance therapy may also lower BP. Somers, et al, J Clin Invest, : Pepperell, et al, Lancet, : Dimsdale, et al, Hypertension, : Becker, et al, Circulation, :

64 CPAP therapy: Effects on HTN
Most robust BP response to CPAP most likely in patients with: More severe OSA Difficult-to-control HTN Better CPAP compliance Somers, et al, J Clin Invest, : Pepperell, et al, Lancet, : Dimsdale, et al, Hypertension, : Becker, et al, Circulation, :

65 CPAP therapy: Effects on HTN
Chronic effects on blood pressure are less clear due to lack of longitudinal, controlled studies. Somers, et al, Circ, :

66 CPAP therapy: Effects on myocardial ischemia and infarction
Treated OSAS pts had fewer cardiac events than untreated OSAS pts. Treated OSAS pts had decreased cardiac mortality than untreated OSAS pts. Nocturnal angina and ST depressions are improved with CPAP therapy. Somers, et al, Circ, : Milleron, et al, Eur Heart J, : Doherty, et al, Chest, :

67 CPAP therapy: Effects on CHF
CPAP can eliminate recurring nocturnal hypoxia and reduce nocturnal BP & heart rate. After one month on CPAP, LVEF increased from 37% to 49% and returned to baseline one week after CPAP stopped. Tkacova, et al, Circulation, : Malone, et al, Lancet, : Somers, et al, Circ, :

68 CPAP therapy: Effects on CHF
CPAP vs no CPAP: after one month in pts on optimum CHF med therapy, LVEF increased from 25% to 34% AND morning SBP dropped from 126 to 116 mm Hg. CPAP induced a lowering of sympathetic vasoconstrictor nerve discharge in CHF. CPAP treated pts had increase of LVEF from 38 to 43% and decrease in nocturnal urinary norepinephrine. Kaneko, et al , N Engl J Med, : Usui, et al, J Am Coll Cardiol , : Mansfield, et al. Am J Respir Crit Care Med, : Bradley & Floras, The Lancet, :

69 CPAP therapy: Effects on stroke
CPAP compliance and tolerance are poor in stroke pts and beneficial effects have not been confirmed. These pts should still be treated. Somers, et al, Circ, :

70 CPAP therapy: Effects on cardiac dysrhythmias
82% risk of Afib recurrence after cardioversion in untreated OSAS pts (which is double the risk of pts treated for OSAS). Randomized, controlled trial: 58% reduction in frequency of PVCs after one month on CPAP in pts with OSAS and systolic dysfunction and reduction in urinary norepinephrine concentrations. Somers, et al, Circ, : Kanagala, et al, Circulation, : Ryan, et al, Thorax, :

71 Unanswered questions Does OSAS contribute or independently lead to the development of CAD, CHF, Afib and stroke? Is HTN an intermediate step between OSAS and development of cardiovascular disease? Does treatment of OSAS actually decrease risk of developing HTN and cardiovascular disease? In established cardiovascular disease, does treatment of OSAS decrease CV morbidity and mortality? Is there a long term mortality benefit of treating CHF patients with CPAP? Somers, et al, Circ, : Bradley & Floras, The Lancet, :

72 IN CONCLUSION

73 Cardiovascular disease and OSAS are
Dangerous Common Easily recognized Treatable Inter-related

74 Think about diagnosing and treating OSAS in your patients with
Hypertension, especially those on 3 or more anti-hypertensives Coronary artery disease CHF Atrial fibrillation Stroke/TIA

75 The ultimate goal:


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