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Sleep Apnea: Types, Mechanisms and
Clinical Cardiovascular Consequences
A Frequent Condition, but Easily Missed
Shahrokh Javaheri, MD
Sleep Physician, Bethesda North Hospital
Professor Emeritus, University of Cincinnati, Cincinnati, Ohio
New York Cardiovascular Symposium
December 11-13, 2015
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Definitions
Apnea Cessation of airflow ≥10 seconds
(missing 2 breaths)
Hypopnea Decrease in airflow
≥10 seconds
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Definitions
Apnea: Cessation of airflow ≥10 seconds
2 phenotypes:
OSA and CSA
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Sleep and Genioglossus MuscleOA, Hypopnea and Snoring
Normal Airway Obstructed Airway
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AHI is the metric to define the presence and
the severity of sleep apnea as a disorder
• AHI: number of events per hour of sleep
• Nl : less than 5
• Mild sleep apnea : 5, <15
• Moderate sleep apnea :15, < 30
• Severe sleep apnea : ≥30
( HSAT)
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Risk Factors for OSA
1. Obesity : Most important risk factor for OSA
Neck fat ( within the throat)
Neck size 17 in males16 in females
35% of US population are obese
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Current Prevalence of OSA in USA population
(Age, years)2007-2010
Peppard/Young
Am J Epidemiol, 20132015
Men (%)
AHI > 5/hr (30-70) 34 ?
AHI > 15/hr (30-70) 13
Women (%)
AHI > 5/hr (30-70) 17 ?
AHI > 15/hr (30-70) 6
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OSA a Major Public Health Issue
34% in males and 17% in females
34% + 17% = 51/ 2 = 25%
25% of 300,000000 = 75000000
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diagnosed sleep apnea
“undiagnosed” sleep
apnea in general
population
…..Only the “tip” has received medical attention
Few millions
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OSA a Major Public Health Issue
Cardio-metabolic consequences of OSAHTN
Resistant HTNPulmonary HTN CADCHF, HFrEF and HFpEFA. Fib TIA StrokeSudden deathMetabolic dysregulation-Insulin Resist/DMHuge Health Cost
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Wisconsin Sleep Study
2013
22-30%
64-70%
40-65%
12-38%
Drager, L. Am J Cardiol. 2010
Pedrosa, RP. Hypertension. 2011
Zhao LP. J Clin Sleep Med. 2014
Gami AS. Circulation. 2004
Bitter, T. . Dtsch Arztebl Int. 2009
Javaheri, S.. Int J Cardiol. 2006
Oldenburg, O. Eur J Heart Fail. 2007
13% 6%
General population
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Overnight pathophysiological consequences
of OSA Arousal:
↑HR/BP
Hypoxia-reoxygenation
Negative swings in juxta-cardiac Pressure
Apnea
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OSA
↑HR/BP
Hypoxia-reoxygenation
Negative swings in juxta-cardiac Pressure
PCO2
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Polysomnography - 5 minutes page
Recurrent episodes OSA( AHI=80/hr)
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Biological pathways mediating CV complications of sleep apnea
Javaheri, Principles and Practice of Sleep Medicine, 2016
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CVD Comorbidities with OSA and Impact of
Therapy with CPAP
•
• Resistant HTN
• A. Fib
• HF •
• Mortality and SCD
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Mean change in 24-h BP from 4 RCTs in
Resistant HTN
• The pooled estimate shows a favorable reduction of BP with CPAP treatment in patients with
resistant hypertension and OSA.
• The effect sizes are larger than those previously reported in patients with OSA without
resistant hypertension J Hypertens 2014 32:2341–2350
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Prevalence of secondary causes associated with resistant hypertension.
Pedrosa et al. Hypertension. 2011
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OSA as a cause and recurrence of A Fib
Negative swings in intrathoracic/juxtacardiac pressure
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100 140 100
100 140 100
Ppl Ppl Ppl
0.0 0.0 -40
100 - (0.0) = 100 140 - (0.0) = 140 100 - (-40) = 140
Normal Hypertension UAO
PrLVTm
UAO ↑ transmural Pr
of all cardiac chambers
Implications for A. fib and increased ventricular afterload
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OSA is arrhythmogenic
1. Hypoxia
2. Acidosis
3. Increased sympathetic activity
4. Increased negative intrathoracic pressure resulting in activation of mechano receptors
and ion channels
5. Upregulation of oxidative stress and inflammatory cascades
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(n=118)
Follow-pup 12 m
P=0.013
P=0.034
P=NS
P=NS
P=NS P=NS
P<0.001
(n=3,000)
Follow-up 32 m
(n=720)
Follow-up 42 m
P=0.01
(n=426)
Follow-up 12 m
(n=153)
Follow-up 18 m
P=0.01
P=NS
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0
20
40
60
80
100
Controls UntreatedOSA
TreatedOSA
(%)(%)
*
OSA and Recurrent Atrial Fibrillation
Kanagala et al., Circulation, 2003
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CPAP decreases recurrence of post-ablation A Fib in OSA
(Qureshi et al, Am J Cardiol, 2015)
N= 1247 OSACPAP=698
No CPAP= 549CPAP decreased recurrence rate by
44%, RR=.56CI= .47, .68
p<.001
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Obesity begets A FibThe link between OSA and AF
Obesity begets A FibThe link between OSA and AF
Obesity Atrial
fibrillation
OSAHypoxia
Acidosis
ANS dysregulation
Atrial mechanorecptor
stimulation
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Study Cohort
N=30,719
SA tested
N=572 (2%)Not SA tested
N=30,147 (98%)
SA Dx: N=553 (97%) No SA Dx N=19 (3%)
tested, diagnosed,
not treated
N=295
tested, diagnosed,
treated
N=258
Heart failure comorbid with OSA
Javaheri et al. Am J Respir Crit Care Med 2011
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Study Cohort
N=30,719
SA tested
N=572 (2%)Not SA tested
N=30,147 (98%)
SA Dx: N=553 (97%) No SA Dx N=19 (3%)
tested, diagnosed,
not treated
N=295
tested, diagnosed,
treated
N=258
Heart failure comorbid with OSA
Javaheri et al. Am J Respir Crit Care Med 2011
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Kaplan-Meier Survival Curves, Adjusted by Age, Gender,
and Charlson Comorbidity Index, 2004-2005
60
70
80
90
100
Baseline 1 2 3 4 5 6 7 8
Quarters after HF diagnosis
Hazard ratio = .33 (95% CI = .21-.51), P <.0001
Percent of Cohort Alive
258 HF patients Tested, diagnosed with sleep apnea, and treated
30,065 HF patients Not tested and not treated for sleep apnea
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2 y hospitalizations, all cause mortality and mortality
Patients, No (%)
Mortality, No (%)
Patients hospitalized, No (%)
Medicare payment per patient
Difference per patient
Clinicallysuspected
tested, diagnosedtreated
258 (100)
20 (7.8)
192 (74)
42859 $
Clinically suspectednot testednot treated
630 (100)
185 (29.4)
570 (91)
63747 $
21000 $
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Medicare savings
If 630 patients were all tested, diagnosed
and treated with CPAP :
Cost of 2 sleep studies 1300 $
Cost of CPAP device 1200 $
Cost per patient 2500 $
Cost for 630 patients 1,6 million $
Actual cost difference for 630 patients 13,200000 $
2 y Medicare savings for 630 patients 12 million $
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50%
60%
70%
80%
90%
100%
0 5 10 15 20
Years of follow-up
% S
urv
ivin
g
AHI < 5
AHI 5-15
AHI 15-30
AHI >30
All-cause mortality with untreated SDB, (sample excludes 126 CPAP users )(Young,Sleep,2008)
Probability of survival over 18 year f/u period (n=1522)
HR for all-cause mortality: 3.8 (95% CI = 1.6-9.0)
HR for CV mortality: 5.2 (CI = 1.4-19.2)
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0
10
20
30
40
50
Gami, Howard, Olson, Somers NEJM 2005
Day-Night Pattern of SCDDay-Night Pattern of SCDP
rop
ort
ion
of
tota
l s
ud
de
n
ca
rdia
c d
ea
ths
(%
)
0:00-5:59
Time of day
6:00-11:59 12:00-17:59 18:00-23:59
21%
41%
26%
12%
No OSA (n=34)General population
46%
20%
9%
24%
OSA (n=78)
16%
25%24%
35%
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HCSB breathing and CSA in HF
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Cardiac Transplantation
Medications
TheophyllineNasal Oxygen
Acetazolamide CPAP ASVBilevel
Positive Airway Pressure Devices
Phrenic Nerve Stimulation
Treatment of CSA
Optimization of cardiac dysfunction
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Transplant-free survival in SHF patients
according to effect of CPAP on CSA (Artz, Circ, 2007)
CPAP responders, AHI = 6.5
n = 57, ß blocker, 81%
CPAP non-responders
(AHI at 3 months ≥≥≥≥ 15/hr, n = 43)
0 6 12 18 24 30 36 42 48 54 60
Time from enrollment (months)
Control, AHI = 36
n=130
ß blocker, 78%
0
20
40
60
80
100
Tra
nsp
lan
t-fr
ee s
urv
iva
l (%
)
* vs. control: HR=0.36, p=0.040
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Transplant-free survival
in the control group and according to effect of CPAP on CSA
CPAP responders, n = 57
AHI at 3 months < 15/hr, mean=6.5
CPAP non-responders, n = 43AHI at 3 months ≥≥≥≥ 15/hr, mean=35
0 6 12 18 24 30 36 42 48 54 60
Time from enrollment (months)
0
20
40
60
80
100T
ran
sp
lan
t-fr
ee
su
rviv
al
(%)
*versus control: HR=0.36, p=0.040
Control, n = 110AHI at 3 months ≥≥≥≥ 15/hr, mean=36
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3 RCT in Sleep Apnea Comorbid with HFrEFStudy
Name
Sleep
Apnea
Sites NO Intervention Primary
Endpoints
SERVE-HF CSA Europe 1325 ASV vs
conservative
treatment
Morbidity and
Mortality
ADVENT-
HF
CSA
OSA
Multi-
national860 ASV
vs conservative
treatment
Morbidity and
Mortality
Remede
system
CSA multinat
ional173 PNS vs. optimal
therapy
AHI reduction of
50% with PNS40
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Stimulation LocationRight Phrenic Nerve
Stimulation Site
Left Pericardiophrenic or
Left Brachiocephalic Vein
Left Phrenic Nerve
Stimulation Site
Right Brachiocephalic Vein
Diaphragm↑
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Cardima Catheter in Left Pericardiophrenic Vein
Augostini et al. Heart Rhythm Society 2011
Left Pericardiophrenic Vein
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Therapy Terminates CSA
Ponikowski et al. 2011 Eur Heart J doi:10.1093/eurheartj/ehr298
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“Don’t ever go to sleep. Too many people die there.”
Mark Twain