Sleep Apnea and Cardiovascular Health Reena Mehra MD, MS, FCCP, FAASM Director, Sleep Disorders Research Associate Professor of Medicine Wake Up to Sleep Disorders Cleveland Clinic Sleep Symposium April 10, 2015
Overview • Definitions and Prevalence • Biological Plausibility and Physiology • Potential Causative or Contributory Role of Sleep Apnea to Cardiac Disease • Ongoing Clinical Research - Opportunities to Address Knowledge Gaps
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Obstructive Sleep Apnea
A Highly Prevalent and Under-Recognized Physiologic Stressor • 17% of the general adult population, increasing with obesity epidemic - Nearly 1 in 15 affected by at least moderate sleep apnea -
Young et al NEJM 1993, Peppard et al. Am J Epi 2013
- 85% of cases estimated to be undiagnosed! -
Kapur VK et al Sleep and Breath 2002
• 30-40% of patients with CAD -
Mooe T et al Chest 1996; Schaker et al H Cardiol 1999; Leung RS et al AJRCCM 2001
• > 50% of patients with diabetes or hypertension
Prevalence of Sleep Disordered Breathing in Cardiovascular Disease Disorder
Prevalence of OSA
Prevalence of CSA
Hypertension Drug Resistant Hypertension Heart Failure Atrial Fibrillation Stroke Coronary Artery Disease
35% 65-80%
-
12-53% 49% 60% 30%
21-37% 12% -
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Sleep Disordered Breathing Physiologic Consequences
POTENTIALLY MODIFIABLE RISK FACTORS: Obesity Craniofacial Abnormalities AdenotonsillarHypertrophy Endocrine Disorders Neurologic Disorders
Sleep Apnea
NON-MODIFIABLE RISK FACTORS: Male Sex Race/Ethnicity Genetics Age Congential Syndromes (i.e. Down’s syndrome)
PHYSIOLOGIC PERTURBATIONS
Chronic Intermittent Hypoxia Ventilatory Overshoot Hyperoxia Increased Sympathetic Nervous System Activity
INTERMEDIATE MARKERS
Increased Inflammation Increased Oxidative Stress Metabolic Dysfunction/
Intrathoracic Pressure Swings
Insulin Resistance
Hypercapnia
Hypercoaguability
Sleep Fragmentation/ Increased Arousals Reduced Sleep Duration REM Sleep Fragmentation
Endothelial Dysfunction Autonomic Dysfunction
CLINICAL OUTCOMES
Systemic Hypertension Ischemic Heart Disease/Atherosclerosis Diastolic Dysfunction Congestive Heart Failure Cardiac Arrhythmias Stroke Increased Mortality and Sudden Death
Mehra R Curr Resp Med Rev 2007
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Pathophysiological Effects
Sympathetic Nervous System Activity in Obstructive Sleep Apnea During Wakefulness Normal controls: 34±3bursts/min p=0.003
Sleep Apnea: 59±14 bursts/min,
Somers et al. J Clin Invest. 1995;96:1897.
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Sympathetic Nervous System Activity in Sleep Apnea
Decrease CPAP pressure from 8 to 6
Somers et al. J Clin Invest. 1995;96:1897.
BP = blood pressure; CPAP = continuous positive airway pressure; REM = rapid eye movement; RESP = respiration; SNA = sympathetic nerve activity
Upper Airway Occlusion Leads to Negative Intrathoracic Pressure Swings •Increased preload •Increased LV afterload (increased transmural pressure) •Impaired diastolic function •Atrial and aortic enlargement
Tracheal Pressure (mmHg)
LV Pressure (mmHg)
LV Transmural Pressure (mmHg)
LV End Systolic Volume (mL)
Parker Am J Respir Crit Care Med 1999; 160: 1888-96
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Obstructive Sleep Apnea and Pulmonary Hypertension
Pro-Inflammatory and Atherogenic Effects • Upregulation of inflammatory mediators • IL6*, sIL6R*, IL-8, TNFα, CRP, (NF-Kappa B) • Enhanced thrombotic potential - PAI-1*, fibrinogen*, P-selectin - VEGF • Oxidation of serum proteins and lipids* • Endothelial dysfunction*
Hansson NEJM 352: 2005
• Insulin Resistance and Dyslipidemia Mehra R et al AJRCCM 2010, Mehra R et al Arch of Int Med 2006, Mehra R et al. AJRCCM, 2010; 181: A2474
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Sleep Disordered Breathing and Hypertension
Obstructive Sleep Apnea and Incident Hypertension
ADJUSTED ODDS RATIO (95% CI)
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Association of Treated and Untreated Obstructive Sleep Apnea and Risk of Hypertension n=1889, Spanish study
Declined CPAP: ~2-fold increased risk of incident hypertension CPAP Non-adherent: ~80% increased risk of incident hypertension Treated: ~30% reduction in risk of incident hypertension Marin JAMA. 2012; 307 (20): 2169
4.62
4.62
3.49
3.49
2.72
2.72
2.12
2.12
PAT ratio
PAT ratio
Sleep Apnea, Endothelial Dysfunction and Non-Dipping Blood Pressure
1.65 1.28
1.65 1.28
1
1
0.78
0.78
0.57
Increasing AHI and ODI associated with reduction in PAT ratio, p=0.04 and 0.05 respectively
0.57 13.9
20
30
40
50
60
65.6
14.6
20
30
1.0
A
0.8 0.6 0.4 0.2 0.0 14.6
20
25
30 AHI
35
40
49.3
Seif F, J Sleep Res 2013
AHI Probability of non−dipping systolic blood pressure
Probability of non−dipping systolic blood pressure
ODI
40
45
49.3
1.0
4% increased odds of non-dipping blood pressure per unit increase of AHI or ODI, p=0.012 and 0.009 respectively
B
0.8 0.6 0.4 0.2 0.0 13.9 20
30
40 ODI
50
60
69.7
Seif F, J Hypertension 2013
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Randomized Controlled Trial Effect of CPAP on Intermediate Cardiovascular Measures % Change
Sham (n=71)
CPAP (n=72)
p-value
Systemic Inflammation IL-6
19.941 ± 8.571
8.837 ± 8.245
0.35
Soluble IL-6R
2.789 ± 1.833
-2.872 ± 1.764
0.028
Blood Pressure (morning) SBP
0.338 ± 0.986
-2.516 ± 0.979
0.042
DBP
1.884 ± 1.347
-2.156 ± 1.338
0.035
-0.2 ± 1.3
6.5 ± 1.4
0.009
Vascular Measures (morning) *difference Augmentation Index
Ashraf F et al SLEEP meeting 2014, oral presentation Paz Y Mar et al SLEEP meeting 2014, oral presentation
CPAP versus Oxygen in Obstructive Sleep Apnea N Eng J Med. 2014 Jun 12: 370(24): 2276-85 Gottlieb DJ, Punjabi NM, Mehra R, etal.
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Higher Resistant Blood Pressure in Severe OSA on Intensive Anti-hypertensive Regimen
BP≥130/80 mm Hg
Intensive anti-hypertensive medication regimen Walia et al SLEEP meeting 2013, oral presentation
Effect of CPAP in Obstructive Sleep Apnea and Resistant Hypertension: HIPARCO trial • Improvement in 24-hour BP measures driven by reduction in nocturnal BP • ~2-4 mmHg reduction in nocturnal BP measures
JAMA 2013; 310(22): 2407-2415
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Meta-Analysis Change in Blood Pressure with CPAP • 16 RCTs with n=1166 participants • Modest but significant reductions in: - Office SBP (-3.2mmHg), DBP (-2.9mmHg) - 24-hour DBP (-3.5mmHg) - 24-hour mean arterial BP (-3.6mmHg) - Night-time SBP (-4.9mmHg) - Mean night-time BP (-2.7mmHg) Schein J of Hypertension; Sept 2014; 1762
Sleep Apnea and Hypertension • OSA is an independent risk factor for hypertension • Sustained effect of OSA on BP even during the daytime • OSA is associated with endothelial dysfunction and non-dipping blood pressure profiles • Treatment of OSA in patients with hypertension reduces blood pressure • Patients with OSA and resistant hypertension represent a particularly responsive group to CPAP
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Sleep Disordered Breathing and Heart Failure
CSA Predictor of 6-month cardiac readmission Adjusted rate ratio 1.53, p=0.03 Khayat R et al. J Card Fail 2012
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Worsening Survival of Patients With Heart Failure and OSA AHI30) 25
23.9
Adjusted OR 95% CI 20 14.7
15 13
SDB Non-SDB
11.3
10
5
8.9
7.8 5.5
4.9 3.1
Atrial Fibrillation
4.5
1.2, 17
CVE or NSVT
1.8
1.2, 2.8
AF or NSVT
3.7
1.7, 8.0
CVE Odds > 7.0, 50-60 years old
0.8
0
Mehra R AJRCCM 2006 AF (p=.002)*
CVE (p=.03)*
NSVT (p=.003)*
BigeminyQuadrigeminy (p=.03)* (p=.009)*
Mehra R AJRCCM 2006
Case-Cross-Over Study: Relative Risk of a Paroxysmal Arrhythmia Occurring After an Apnea/Hyponea: 17 Monahan JACC 2008
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Incidence of AF by Obstructive Sleep Apnea Severity n=3053 =23.9
Mehra R et al Arch Int Med 2009
Sleep Disordered Breathing and Stroke
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Obstructive Sleep Apnea and Incident Stroke in Men Unadjusted
Age-Adjusted
FullyAdjusted*
IV: 19.13 – 164.5
3.91 (1.55 – 9.86)
3.05 (1.21 – 7.72)
2.86 (1.10 – 7.39)
III: 9.50 – 19.12
2.35 (0.89 – 6.20)
1.97 (0.74 – 5.21)
1.86 (0.70 – 4.95)
II: 4.05 – 9.49
1.96 (0.71 – 5.40)
1.86 (0.68 – 5.13)
1.86 (0.67 – 5.12)
I: 0.00 – 4.04)
1.00
1.00
1.00
Covariate Quartile of AHI
*Adjusted for age, BMI, smoking status, SBP, blood pressure medications, diabetes, and race Redline et al. Am J Respir Crit Care Med Vol 182. pp 269–277, 2010
Nocturnal Hypoxia as a Predictor of Stroke Outcomes of Sleep Disorders in Older Men Study, n=3028 Percent of sleep time with SaO2 70 years
Punjabi NM et al, PLOS One 2010
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“Don’t ever go to sleep. Too many people die there.” Mark Twain
Sleep is Cardio-Protective, but….
Lown et al. Circulation 1973
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Nocturnal Predilection for Sudden Cardiac Death in OSA
Gami AS NEJM 2005:352
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Sleep Research NHLBI-funded Sleep Related Respiratory and Electrophysiological Atrial Fibrillation Predictors
Transvenous Phrenic Nerve Stimulation Device for CSA Treatment
Predictors of AF in a longitudinal study of ~3000 participants of the MrOS Sleep Study NHLBI-funded RCT to
examine effect of sleep apnea treatment on intermediate CV measures
NHLBI-funded Sleep apnea and Atrial Fibrillation Electrophysiology: Biomarkers and Evaluating Atrial Triggers
NHLBI ARRA funded trial, Multi-center trial to examine utility of nocturnal supplemental oxygen in treating patients at high CV risk with sleep apnea
Sleep Apnea:
A Novel Modifiable Cardiac Risk Factor • A substantial proportion of cardiovascular disease is preventable • Standard Risk Factors -
Overweight and obesity Physical inactivity Diabetes Cigarette smoking High blood pressure Dyslipidemia
• Target Sleep Apnea as a Novel Risk Factor Estimated that 5 to 20% of Cardiovascular Disease may be preventable by treating/preventing Sleep Apnea
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