1. Obstructive Sleep Apnea and Heart Disease
Cardiology Cath Conference
3/31/11
Andrew Binder

2. Overview Prevalence and Definition General hemodynamic effects
OSA and specific cardiovascular effects
HTN
Heart Failure
Atherosclerosis and Inflammation
Arrhythmias
Pulmonary Hypertension
Treatment of OSA

3. Obstructive Sleep Apnea
Affects 15 million adult Americans
Repetitive collapse of the pharynx that triggers apneas during sleep
Intermittent hypoxia
Exaggerated negative intrathoracic pressures
Surges in sympathetic nervous system activity
Increased blood pressure
Frequent awakenings
Cardiovascular system is exposed to all these things which may have adverse consequences.
Kasai et al. JACC 2011

4. Pathogenesis of OSA OSA patients usually have a narrow pharynx
At sleep onset there is loss of pharyngeal dilator muscle tone which causes complete or partial pharyngeal collapse causing obstructive apneas and hypopneas.
Pharyngeal collapse occurs posterior to the tongue, uvula, and soft palate or some combination of these structures. This area is dependent on muscle activity to maintain patency. The primary abnormality in patients with OSA is a small pharyngeal airway resulting from obesity, bone and soft tissue structures. During sleep the reflex pharyngeal muscle activity is reduced or lost, leading to narrowing and complete collapse of the pharynx.
Kasai et al. JACC 2011

5. Spaak J et al. Hypertension 2005
Screening for OSA
Epworth Sleepiness Scale
Berlin questionnaire
Overnight oximetry – most often used in clinical practice
A definitive diagnosis often requires spending a night in a sleep lab.
Spaak J et al. Hypertension 2005

6. Definition
Apnea - > 90% reduction in tidal volume lasted > 10 seconds
Hypopnea – reduction in tidal volume of 50 – 90%, lasted > 10 seconds accompanied by > 3% decrease in oxygen saturation or terminated by arousal from sleep
AHI – apnea-hypopnea index > 5 = OSA disorder
An obstructive apnea is a >10 second pause in respiration associated with ongoing ventilatory effort
AHI of > 5 episodes (meaning 5 episodes of apnea or hypopnea per hour of sleep) is defined as a OSA disorder
Kasai et al. JACC 2011

7. Diagnosis of OSA OSA syndrome
> 5 episodes of apnea or hypopnea per hour of sleep
Hypersomnolence
Episodes of choking or gasping during sleep
Recurrent awakenings
Unrefreshing sleep
Daytime fatigue
Impaired concentration or memory
OSA syndrome has accompanied symptoms
This is usually confirmed by overnight polysomnography in a sleep laboratory during which sleep architecture, cardiac rhythm, sats, airflow, and thoracoabdominal movements are recorded.
Kasai et al. JACC 2011

8. OSA

9. Sleep Disordered Breathing- “The basic definition”
Obstructive Sleep Apnea
Central Sleep Apnea
Cheyne-Stokes Respiration
Idiopathic Central Sleep Apnea Syndrome
Central Sleep apnea – apnea or hypopnea resulting from complete or partial withdrawal of central respiratory drive to the muscles of respiration during sleep. So there is no associated ventilatory effort as there is with OSA.
CSA and OSA can-coexist.

10. Spaak J et al. Hypertension 2005
Mechanisms of Disease
Multiple mechanisms including ((middle panel)) causing badness in cardiovascular system, which I will go through.
Spaak J et al. Hypertension 2005

11. Prevalence of OSA in Stable Outpatients with Heart Failure
Although beta-blockers and CRT therapy have both been shown to improve CSA, even with modern therapy and high beta-blocker use, CSA continues to have a high prevalence.

12. Prevalence of OSA in HF
The prevalence of OSA reported in 4 studies involving unselected patients with HF who underwent overnight polysomnography. Ferrier et al. (73) used an apnea-hypopnea index cutoff of 10 whereas the others used 15.
Kasai et al. JACC 2011

13. Risk Factors for OSA Age: females after menopause
Obesity: particularly males and middle aged women
Neck circumference
Craniofacial predisposition and family history
Certain racial groups
Cardiovascular disease and heart failure

14. Symptoms of OSA Snoring Excessive daytime sleepiness Witnessed apneas
Poor memory and concentration, irritability or personality changes
Other: Dry throat, morning headache, and nocturia

15. Physical Examination in OSA
Malampati Class
Obesity and thick neck
> 17 inch males
> 16 inch females
Craniofacial anatomy
Inferiorly positioned hyoid bone
Mandibular insufficiency
Increased mid-facial height
Nasal obstruction

16. Upper Airway in OSA
Normal
Patient

17. Normal Individual
Obese Patient

18. Sleep – Cardiovascular Quiescence
Normally, during non-REM sleep:
Decrease in metabolic rate, sympathetic nervous system activity (SNA), blood pressure (BP), and heart rate (HR)
Increase in cardiac vagal activity
Disrupted by OSA
HF patients sleep approximately 1.3 hours less than subjects without HF
HF patients may not enjoy the fully restorative effects of sleep

19. C
During obstructive apneas, negative inspiratory intrathoracic pressure generated against the occluded pharynx increases LV transmural pressure, and hence afterload. It also increases venous return, augmenting RV pre-load, whereas OSA-induced hypoxic pulmonary vasoconstriction increases RV afterload. Consequent RV distention and leftward septal displacement during diastole impairs LV filling. This combination of increased LV afterload and diminished preload reduces stroke volume and cardiac output more in HF patients than in healthy subjects. Whereas stroke volume recovers abruptly to baseline in healthy subjects at apnea termination, recovery is delayed in patients with HF.
Increased LV transmural pressure also increases myocardial oxygen demand while simultaneously reducing coronary blood flow during which apnea-related hypoxia reduces oxygen delivery. This can precipitate myocardial ischemia and impair cardiac contractility and diastolic relaxation. Over time, such stress may contribute to development of progression of cardiac remodeling, hypertrophy, and failure.
Kasai et al. JACC 2011

20. Spaak J et al. Hypertension 2005
Effects of OSA
OSA augments sympathetic and diminishes parasympathetic activity.
These adverse autonomic effects of OSA may persist into wakefulness.
Spaak J et al. Hypertension 2005

21. Selim et al. Clim Chest Med 2010
OSA
OSA has been independently linked to multiple cardiovascular outcomes
HTN
CVA
Myocardial Ischemia
Arrhythmias
Fatal and nonfatal cardiovascular events
All cause mortality
Treatment of OSA may represent a novel target to reduce cardiovascular health outcomes.
Selim et al. Clim Chest Med 2010

22. Logan et al. J Hypertension 2001
50% of OSA patients are hypertensive
30% of hypertensive patients also have OSA, often undiagnosed
Non-dippers
Logan et al found the prevalence of OSA in resistant hypertension to be 83%
OSA patients are more likely to be nocturnal non-dippers.
Logan et al. J Hypertension 2001

23. Hypertension
The Wisconsin Sleep Cohort Study – describe table then read next line.
We found a dose–response association between sleep-disordered breathing at base line and the presence of hypertension four years later that was independent of known confounding factors. The findings suggest that sleep-disordered breathing is likely to be a risk factor for hypertension and consequent cardiovascular morbidity in the general population.
Peppard PE et al. NEJM 2000

24. Hypertension
Multiple studies with conflicting results of effect of treatment of OSA on hypertension
3 recent meta-analyses shown significant but modest reduction in BP (~ 2 mm Hg).
Patient with more severe OSA, difficult to control hypertension, and better CPAP compliance had more substantial BP reduction with CPAP.
Haentjens P et al. Arch Intern Med 2007
Bazzano et al Hypertension 2007
Alajmi et al Lung 2007

25. Spaak J et al. Hypertension 2005
Heart Failure
11% - 37% of patients with systolic dysfunction had OSA detected on polysomnography
Very few complained of excessive daytime sleepiness
Men > Women (38% vs. 31%)
Major risk factor in men: obesity
Major risk factor in women: older age
Prospective study where polysomnography was performed on all consenting patients newly referred to a tertiary hospital heart failure clinic
26% had OSA with an AHI > 15
OSA noted in > 50% of HFPEF
1- In the Sleep Heart Health Study (6424 men and women), the presence of OSA (defined as an AHI 11/h) conferred a 2.38 relative increase in the likelihood of having HF, independent of other known risk factors.
Spaak J et al. Hypertension 2005

26. Spaak J et al. Hypertension 2005
OSA and Heart Failure
Most direct mechanism in which OSA can induced LV dysfunction is by raising BP.
Also:
Increased sympathetic outflow
Increased LV afterload acutely and chronically
Hypoxia induced increase of RV afterload
Increased risk of myocardial infarction
OSA patients have higher production of cytokines, catecholamines, endothelin, and other growth factors == contribute to ventricular hypertrophy independent of hypertension.
Spaak J et al. Hypertension 2005

27. Yumino et al. Circulation 2010
OSA and Heart Failure
OSA Heart Failure
OSA probably contributes to the development or progression of heart failure, and HF might also contribute to causation of OSA.
Fluid accumulation in the legs while upright during the day could shift into the neck when recumbent during sleep, this fluid displacement might cause distention of the neck veins and/or edema of pharyngeal soft tissue predisposing to pharyngeal obstruction.
There have been a few studies which showed with lower body positive pressure and displacement of approx cc fluid from both legs, the neck circumference increases and there is increased resistance to airflow and collapsibility of the neck.
Yumino took 57 patients with heart failure (ejection fraction < 45%) and measured change in leg fluid volume and neck circumference before and after polysomnography and found
a progressively greater reduction in LFV (leg fluid volume) from patients with mild to no sleep apnea (M-NSA) (AHI 15; n19) to OSA (AHI 15; n21) to CSA (AHI 15; n17).
These observations strongly suggest that in HF, overnight rostral fluid displacement from the legs contributes to the severity of OSA by causing fluid accumulation in the neck that narrows that pharynx and increases it collapsibility during sleep.
Yumino et al. Circulation 2010

28. Spaak J et al. Hypertension 2005, Usui K et al. JACC 2005
Heart Failure
Left side – Patient with HF (60 patients with EF < 45%), the presence of OSA is associated with higher muscle SNA than in those without OSA.
Right side – Treating OSA with CPAP in HF patients reduces muscle SNA in association with BP lowering (SBP from 135 to 120).
Elevated SNA is associated with increased mortality risk in patients with HF. Probably by causing cardiac beta-receptors desensitization, myocyte injury and necrosis, and hypertension.
OSA may contributes to worse prognosis in HF at least partly through autonomic dysregulation.
Spaak J et al. Hypertension 2005, Usui K et al. JACC 2005

29. Kaplan–Meier survival curves of death from any cause in patients with (A) ischemic heart failure (HF) and (B) non-ischemic HF.
Kaplan–Meier survival curves of death from any cause in patients with (A) ischemic heart failure (HF) and (B) non-ischemic HF. In the ischemic group, mortality was significantly higher in patients with sleep apnea (SA; p = 0.006). After adjusting for confounding factors, SA remained a significant independent risk factor for death (HR = 3.03, p = 0.043) (A). In contrast, in the non-ischemic group, there was no difference in mortality between the two groups (unadjusted p = 0.987) (B). HR, hazard ratio; M-NSA, mild or no sleep apnoea; SA, sleep apnoea.
Yumino D et al. Heart 2009;95:
©2009 by BMJ Publishing Group Ltd and British Cardiovascular Society

30. Serizawa N et al. Am J Cardiol 2008
ICD therapy and SDB
This study looked at sleep-disordered breathing and life-threatening ventricular arrhythmias in patients with heart failure with an ICD. 71 patients with HF and an ICD were followed for 180 days after a sleep study. All patients had EF < 35%. SDB was diagnosed in 47 of 71 patients (66%). There were no statistical differences between patients with and without SDB in baseline cardiac function.
This figure shows appropriate ICD therapies occurred more frequently in patients with (43%) than without SDB (17%; p ).
Serizawa N et al. Am J Cardiol 2008

31. Day-Night pattern of ICD therapy
Day-night pattern of ICD therapy in patients with HF with and without SDB. The frequency distribution of ICD therapy for the four 6-hour intervals was compared between patients with and without SDB.
The rate of total ICD therapy from midnight to 6 A.M. was significantly higher in patients with (34%) than without SDB (13%; p ).
In conclusion, in patients with HF with an ICD, the presence of SDB was common and an independent predictor of life-threatening ventricular arrhythmias that were more likely to occur during sleep.
Serizawa N et al. Am J Cardiol 2008

32. Effect of OSA treatment on HF
1st one – 1 month randomized trial in HF patients with severe OSA, but normal Epworth Sleepiness scores (<10), CPAP increased LVEF by 9% in association with reduced systolic BP and HR.
2nd one – 3 month randomized trail involving 40 patient with less severe HF and OSA but an elevated Epworth score > 10, CPAP improved LVEF and QOL but not BP.
3rd one – no change in LVEF
4th one – 50 HF patients with normal Epworth , CPAP improved LVEF after 3 months, but no change in NYHA or 6 min walking test.
So, CPAP increased LVEF. There were larger CPAP related increases in EF and reductions in BP in trials with patients with lower EF and more severe OSA (higher AHIs). CPAP improved epworth scores and QOL in patients with scores > 10 but failed to do so in patients with scores < 10.
Spaak J et al. Hypertension 2005

33. Savransky et al. Am J Respir Crit Care Med 2007
Atherosclerosis
Forty male C57BL/6J mice, 8 weeks of age, were fed either a high-cholesterol diet or a regular chow diet and subjected either to CIH or intermittent air (control conditions) for 12 weeks.
Cross-sections of the ascending aorta (sinus of Valsalva) in C57BL/6J mice exposed to
Intermittent air (IA) control conditions and regular diet
chronic intermittent hypoxia (CIH) and regular diet
IA and a high cholesterol diet
CIH and a high cholesterol diet.
The thick arrow points at the atherosclerotic plaque with a necrotic core. The thin arrow points at the fatty streak.
9 of the 10 mice simultaneously exposed to CIH (chronic intermittent hypoxia) and high cholesterol diet developed atherosclerotic lesions, none of the other mice did.
Savransky et al. Am J Respir Crit Care Med 2007

34. Minoguchi et al. Am J Respir Crit Care Med 2005
Endothelial Effects
Oxidative stress  reactive oxygen species  inflammation
Intermittent hypoxia and post-apneic reoxygenation induce oxidative stress, generate reactive oxygen species, and provoke inflammation and inflammatory mediators such as TNF alpha, IL 6, IL 8, and CRP.
Study looked at 36 patients with OSA and 16 obese control subjects and evaluated whether carotid IMT is associated with inflammatory markers in OSA.
This figure shows that as OSA is gets worse, CIMT is increased (a marker for early atherosclerosis)
Minoguchi et al. Am J Respir Crit Care Med 2005

35. Drager et al. Am J Respir Crit Care Med 2005
CIMT and OSA
This study had 12 healthy volunteers, 15 patients with mild to moderate OSA, and 15 with severe OSA, looked at CIMT. All participants were free of hypertension, diabetes, and smoking, and were not on any medications.
Figure shows CIMT worsens as OSA worsens.
Drager et al. Am J Respir Crit Care Med 2005

36. Treatment of OSA and CIMT
2 years later, same group looked at effect of treatment with CPAP on CIMT.
They randomly assigned 24 patients with severe OSA who were free of comorbidities to receive no treatment or CPAP for 4months, found a significant difference in CIMT.
Drager et al. Am J Respir Crit Care Med 2007

37. Yokoe et al. Circulation 2003
CPAP and inflammation
Study looked at 30 patients with OSA and 14 obese control subjects and looked at effect of nasal CPAP on levels of CRP and IL-6. Patients received 1 month of nasal CPAP and had significant decrease in levels of CRP.
Yokoe et al. Circulation 2003

38. Spaak J et al. Hypertension 2005
Myocardial Ischemia
Prevalence of SDB in CAD patients is up to 2-fold greater than in non-CAD subjects.
Spaak J et al. Hypertension 2005

39. Myocardial Ischemia and Infarction
Severe intermittent hypoxemia
Acidosis
Increased BP
Sympathetic vasoconstriction
Changes in intra thoracic and cardiac trans mural pressures
CAD
Endothelial dysfunction
Systemic inflammation
Spaak J et al. Hypertension 2005

40. Multivariate analysis for the association between OSA severity measured by AHI quartile and CAC.
202 consecutive patients with no history of coronary disease underwent electron-beam CT within 3 years of polysomnography.
Median CAC scores (Agatston units) were 9 in OSA patients and 0 in non-OSA patients (p < 0.001).
Median CAC score was higher as OSA severity increased (p for trend by AHI quartile < 0.001). With multivariate adjustment, the odds ratio for CAC increased with OSA severity.
In patients without clinical coronary disease, the presence and severity of OSA is independently associated with the presence and extent of CAC.
Multivariate analysis for the association between OSA severity measured by AHI quartile and CAC.
Sorajja D et al. Chest 2008;133:
©2008 by American College of Chest Physicians

41. Sudden Cardiac Death in OSA
People proven to be free of OSA have the greatest likelihood of death between 6 and 11 am, the traditional window of cardiovascular vulnerability. In striking contrast, more than half of sudden cardiac deaths in patients with proven OSA occur during the sleeping hours, between 10 pm and 6 am. OSA appears to affect the timing of sudden cardiac death: however it is not yet known whether OSA increases the overall risk of SCD.
N Engl J Med 2005;352:

42. Arrhythmias
Nocturnal arrhythmias have been shown to occur in up to 50% of OSA patients.
Nonsustainted ventricular tachycardia
Sinus arrest
Second degree AV block
Frequent PVC’s
Controversy remains as to whether OSA is a primary etiologic factor for tachyarrhythmia's because of the high incidence of cardiovascular comorbidities in persons diagnosed with OSA.
Franz et al. Circulation 1992
Aviles et al. Circulation 2003

43. Mehra R et al. Am J Respir Crit Care Med 2006
Arrhythmias and OSA
The sleep heart health study looked at 338 subjects without sleep disordered breathing and 228 with SDB
This graph shows arrhythmia prevalence (%) according to sleep-disordered breathing (SDB) status. Shaded bars, SDB; open bars, non-SDB. AF, atrial fibrillation; CVE, complex ventricular ectopy; NSVT, nonsustained ventricular tachycardia. n 228 with SDB and n 338 without SDB.
Conclusion of study was individuals with severe sleep-disordered breathing have two- to fourfold higher odds of complex arrhythmias than those without sleep-disordered breathing even after adjustment for potential confounders.
Mehra R et al. Am J Respir Crit Care Med 2006

44. Garrigue et al. Circulation 2007
Brady arrhythmias
Apnea and hypoxemia in OSA can elicit the diving reflex resulting in cardiac vagal activation
AV blocks or asystole may develop, even in the absence of cardiac conduction disease.
59% of patients with pacemakers have sleep apnea
The European Multi-Center Polysomnographic Study showed a remarkable high prevalence of sleep apnea in patients with pacemakers. ? If primary treatment of sleep apnea would have reduced the number of people getting pacemakers.
Garrigue et al. Circulation 2007

45. Pulmonary Hypertension
16% - 42% of patients with OSA have PH
PH in OSA patients is associated with:
Obesity
Poor lung function
Degree and duration of hypoxemia
Hypercapnea
Not associated with age, gender or OSA severity
Typically mean PAP is only mildly elevated unless there is underlying lung or heart disease.
Chaouat A et al. Chest 1996
Selim et al. Clin Chest Med 2010

46. Pulmonary Hypertension
Hypoxemia-induced pulmonary vasoconstriction leads to vascular remodeling
Large negative intrathoracic pressures generated during obstructive apneas
increase LV transmural pressure causing greater myocardial oxygen demand, reduced CO, and increased wedge pressure.
Increase wall stiffness of large vessels and increase impedance
………vascular remodeling contributes to the development of chronic pulmonary hypertension in some OSA patients.
…..increase impedance results in increased RV load and the pulmonary vessels are unable to store and deliver the entire stroke volume of the RV, which results in loss of pulmonary flow during diastole. Pulsatile flow is requires by distal pulmonary artery endothelial cells for optimal Nitric oxide production for normal pulmonary vasodilation. Also get elevated levels of endothelin 1, a vasoconstictor. The end result of this imbalance in vasodilator and vasoconstriction factors is an increase in resting vascular tone.
Spaak J et al. Hypertension 2005

47. Pulmonary Hypertension
Randomized, cross-over trial
23 middle-aged OSA and otherwise healthy patients
10 control subjects
Measured PA pressure by TTE
In this randomized and cross-over trial, 23 middle-aged OSA (apnea–hypopnea index, 44.1±29.3 h−1) and otherwise healthy patients and 10 control subjects were included. OSA patients randomly received either sham or effective CPAP for 12 weeks. Echocardiographic parameters, blood pressure recordings, and urinary catecholamine levels were obtained at baseline and after both treatment modalities. Two patients were removed from the study because of inadequate CPAP compliance.
Arias et al. Eur Heart Journal 2006

48. Individual values for the PASP in OSA patients and control subjects.
At baseline, OSA patients had higher pulmonary artery systolic pressure than control subjects (29.8±8.8 vs. 23.4±4.1 mmHg, respectively, P=0.036). Ten out of 23 patients [43%, (95% CI: 23–64%)] and none of the control subjects had PH at baseline (P=0.012).
Arias M A et al. Eur Heart J 2006;27:
© The European Society of Cardiology All rights reserved. For Permissions, please

49. Individual values for the PASP after both sham and effective CPAP treatment in OSA patients.
Effective CPAP induced a significant reduction in the values for pulmonary systolic pressure (from 28.9±8.6 to 24.0±5.8 mmHg, P<0.0001). The reduction was greatest in patients with either PH or left ventricular diastolic dysfunction at baseline.
Arias M A et al. Eur Heart J 2006;27:
© The European Society of Cardiology All rights reserved. For Permissions, please

50. Treatment of OSA Obesity is single most important cause of OSA
Weight loss leads to
Decrease in AHI
Improved sleep efficiency
Decreased snoring
Improved oxygenation
Positional apnea
Apnea often is worse in the supine posture, for these patients with positional apnea, behavioral techniques aimed at keeping the patient in the lateral posture during sleep may offer benefit. (Like putting an uncomfortably object sewn in to the back of the nightshirt or positional alarms.

51. Treatment of OSA CPAP Oral appliances Surgery
Proper introduction and education
Proper humidification
Careful selection of appropriate mask
Pressure ramp
Bilevel or autotitrating device
Oral appliances
Surgery
Adherence to therapy is an issue due to the mask.
If CPAP is intolerable than try oral appliances, they lead to anterior mandibular repositioning, pulls the lower jaw and tongue forward and enlarges the pharyngeal airway. Recent analysis showed oral appliances are preferred over CPAP and were successful in improving snoring, but only 52% were successful at relieving OSA (AHI < 10).
Surgery to enlarge the pharyngeal airway or bypass the obstruction.
Tracheostomy is curative but not done frequently.
Uvulopalatopharyngoplasty, but efficacy has been somewhat limited.

52. Conclusion OSA is prevalent
Multiple adverse cardiovascular consequences
Resistant Hypertension and heart failure should probably be the focus for screening