1. OBSTRUCTIVE SLEEP
APNEA IS A SYSTEMIC
DISEASE
Iman Galal, MD
Assistant Professor Pulmonary Medicine
Ain Shams University

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47#, Verse25#Furqan, Chapter-Al

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Obstructive Sleep Apnea Syndrome & Metabolic
Syndrome.
Obstructive Sleep Apnea Syndrome & Cardiovascular
Diseases.
Effect of Continuous Positive Airway Pressure treatment.
Content:

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Obstructive Sleep Apnea:

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Obstructive
Sleep
Apnea
Memory
Problems
Increased
Insulin
Resistance
Stroke
Increased
Traffic
Accidents
Cardiac
Problems
Hypertension

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Introduction:
Obstructive sleep apnea, a
highly prevalent
disease, affecting 4% of men
& 2% of women, is a disorder
characterized by recurrent
episodes of upper airway
obstruction, & is associated
with reductions in
ventilation, resulting in
recurrent arousals & episodic
oxyhemoglobin desaturations
during sleep.

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A variety of phenomena are implicated in OSAS such as
modifications in the autonomic nervous
system, hypoxemia–reoxygenation cycles, inflammation, &
coagulation–fibrinolysis imbalance.
OSAS patients also present increased levels of certain
biomarkers linked to endocrine-metabolic & cardiovascular
alterations among other systemic consequences.
Introduction:

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Metabolic Syndrome:
The National Cholesterol Education Program (NCEP) Adult Treatment
Panel III (ATP III) report recommended the use of 5 variables:
1) Abdominal Obesity: waist circumference (≥102 cm in , ≥88 cm in
)
2) ↑ TG (≥150 mg/dL or drug treatment)
3) ↓ HDL (<40 mg/dL in , <50 mg/dL in , or drug treatment)
4) Hypertension: BP (systolic BP ≥130 mmHg, or diastolic BP ≥ 85
mmHg, or drug treatment for hypertension)
5) Glucose Intolerance: fasting glucose (≥100 mg/dL or drug treatment)
Subjects meeting 3 of these 5 criteria are classified as having
Metabolic Syndrome.
Grundy et al. Circulation 2005; 112: 285-90

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Metabolic Syndrome:
International Diabetes Federation (IDF) Consensus Definition
2005 Criteria for Identification of the MS:
Alberti, Lancet 2005
Abdominal Obesity: (waist circumference)
 ethnicity specific
 for Europids: Men >94 cm
Women >80 cm
Plus any Two of the following
Triglycerides ≥150 mg/dL
HDL cholesterol
Men <40 mg/dL
Women <50 mg/dL
Blood Pressure ≥130 / ≥85mmHg
Fasting Glucose ≥100mg/dL or Type II Diabetes

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The metabolic disturbances in patients with obstructive
sleep apnea syndrome (OSAS) include insulin resistance &
elevated levels of pro-inflammatory cytokines & vascular
adhesion molecules, as well as an elevation of hormones
derived from the adipose tissue as leptin.
OSA & Metabolic Syndrome
“Syndrome Z”

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OSA & MS in Adults
Reference Design Results
Coughlin et al.,2004
Case controlled (matched for BMI)
OSA: AHI > 15
Control subjects: AHI < 5
MS: NCEP (ATP III) criteria
Independent* associations between:
1. OSA & MS
2. OSA& systolic and diastolic blood pressure, fasting
insulin, triglyceride, HDL, total/HDL cholesterol
Gruber et al., 2006
Case controlled
OSA: AHI criteria not given
MS: International Diabetes
Federation criteria
Independent* association between:
1. OSA & MS
2. No independent association between OSA & insulin
resistance (assessed by HOMA)
Lam et al., 2006
Community based
OSA: AHI > 5
MS: NCEP (ATP III) criteria
OSA and MS
Independent association between OSA & waist, diastolic
blood pressure*, fasting glucose*, MS*
Independent determinants of OSA: age, gender, BMI, MS
Sasanabe et al.,2006
OSA: AHI > 15
Control subjects: AHI < 5
MS: criteria for Japanese population
Independent* association between OSA & MS in not in
Parish et al., 2007 Retrospective PSG & chart review Higher prevalence of MS in patients with OSA (60 vs.40%)
Coughlin et al., 2007
Randomized, controlled study
MS: NCEP (ATP III) criteria
No change in proportion of subjects with MS with CPAP
Significant ↓ in blood pressure

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OSA & Obesity:
OSAS often coexists with obesity.
OSAS is present in approximately
40% of obese individuals, & about
70% of OSAS patients are obese.
In recent years, much attention has
been focused on the interaction
between OSAS & products released by
adipose tissue such as Leptin,
Adiponectin, Resistin & Ghrelin.

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OSA & Obesity:
Gate et al., J Nutr 2004

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Leptin is an adipocyte-derived hormone that suppresses
appetite & promotes satiety.
Several studies have shown increased levels of Leptin in
OSAS, suggesting resistance to the metabolic effects of leptin
(Leptin Resistance).
Obesity is a major confounding factor in the association
between Leptin & OSA.
Treatment with CPAP reduces leptin levels & also may be
associated with decreased visceral fat accumulation.
OSA & Obesity:

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Sleep Apnea & Visceral Fat
AHI
Visceral Fat (cm2)
SaO2nadir%
0
20
40
60
80
100
50 150 250 350 450
r = .70
p = .00
0
20
40
60
80
100
50 150 250 350 450
r = -.61
p = .001
0
100
200
300
400
OSA Obese
Controls
*
AbdominalFat
Distribution(cm2)
Subcutaneous Fat
Visceral Fat
Vgontzas et al. J Clin Endocrin Metab 2000; 85: 1151-8

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Effect of CPAP on Visceral Fat
Fataccumulation(cm2)
BW= BW
0
BW= BW
100
200
300
* *
*
Visceral Subcutaneous
Chin et al., Circulation 1999; 100: 706-12

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OSA & Obesity:
Increased Leptin:
Chin et al., Circulation 1999; 100: 706-12.
Ip et al., Chest 2000; 118: 580-6.
Schafer et al., Chest 2002; 122: 829-39 (Obesity+)
Shimizu et al., Thorax 2002; 57: 429-34.
Ozturk et al., Arch Otolaryngol Head Neck Surg 2003; 129: 538-40.
Sanner et al., Eur Respir J 2004; 23: 601-4.
Shimura et al., Chest 2005; 127: 543-9 (Hypercapnia+)
Barcelo et al., Am J Respir Crit Care Med 2005; 171: 183-7 (Obesity+)
Tatsumi et al., Chest 2005; 127: 716-21.
Ulukavak Ciftci et al., Respiration 2005; 72: 395-401.

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Adiponectin is an adipocyte-derived cytokine with
regulatory functions in both glucose & lipid metabolism.
In addition, Adiponectin has profound anti-inflammatory
& antiatherogenic effects.
Plasma levels of Adiponectin decreases in obesity &
metabolic syndromes e.g., OSAS.
CPAP treatment of OSAS does not effectively normalize
Adiponectin levels.
OSA & Obesity:
Harsch et al, Respiration 2004; 10: 710-580-6
Zhang et al, Chin Med J 2004; 117: 1603-1606

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Resistin is a white adipose tissue hormone whose
physiological function has not yet been established.
In a study of 20 obese OSA patients, there was a weak link
between Resistin & Insulin Sensitivity.
CPAP treatment of OSA had no significant influence on
Resistin levels.
OSA & Obesity:
Harsch et al, Med Sci Monit 2004; 10: 510-5

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OSA & Obesity:
Adiponectin: variable results
Zhang et al., Chin Med J 2004; 117: 1603-1606
Harsch et al., Respiration 2004; 71: 580-586 (obesity+)
Wolk et al., Obes Res 2005; 13: 186-190
Zhang et al., Respiration 2006; 73: 73-77
Makino et al., Clin Endocrinol 2006; 64:12-19
Resistin:
Harsch et al., Med Sci Monit 2004; 10: 510-5 (insulin sensitivity , inflammation+)
Ghrelin: variable results
Harsch et al., Eur Respir J 2003; 22:251-257
Ulukavak et al., Respiration 2005; 72: 395-401 =

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OSA & Obesity:
OSA is less prevalent in than , yet this difference diminishes
after menopause 2ry to the decline in estrogen & progesterone.
Accordingly, estrogen replacement therapy in menopausal
lessens the prevalence of OSAS.
OSAS in causes reduced pituitary-gonadal function
(possibly 2ry to obesity) → decline in morning serum
testosterone levels, reduced androgen secretion & libido. In
addition, ↑ leptin → impaired testicular Leyding cell function.
Anttalainen et al., Acta Obstet Gynecol Scand 2006; 85: 1381-8
Wesstrom et al., Acta Obstet Gynecol Scand 2005; 84: 54-7
Teloken et al., Urology2006; 76:1033-7
Luboshitzky et al., Obes Res2005;13:780-6
Ishikawa et al., Andrologia2007;39:22-7

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Insulin Resistance
Kasuga, J Clin Invest 2006
Normal
Normal
Increased
Normal or IGT Diabetes mellitus
Decreased
Pancreatic
Islets
cell compensation cell failure
Insulin
secretion
by cells
Blood
glucose

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Insulin Signaling in Cells
Kasuga, J Clin Invest 2006

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Relation between OSA, MS & Type II DM
Tasali & Ip, he Proceedings of the American Thoracic Society 2008;5:207-17

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OSA & Diabetes Mellitus:
In 2001, El Masry & co-workers proved that the prevalence
of severe OSA was significantly higher in diabetic patients
than in normoglycaemic subject independent of BMI.
Although obesity is the main risk factor for diabetes, yet
coexistent severe OSA may add to this risk .
El Masry et al., J Intern Med. 2001; 249: 153-61

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Reference
TTT
Period
Study Population Measures of Glucose Main Results
Brooks et al.,1994 4 ms
10 severely obese pts
with DM with OSA
Hyperinsulinemic
euglycemic clamp
Improvement in
insulin sensitivity
Harsh et al.2004 3 ms
40 Pts without DM
with OSA
Hyperinsulinemic
euglycemic clamp
Improvement in
insulin sensitivity
Harsh et al.2004 3 ms
9 Pts with DM with
OSA
Hyperinsulinemic
euglycemic clamp
Improvement in
insulin sensitivity
Babu et al.,2005 3 ms
25 Pts with DM with
OSA
72-h interstitial
glucoseHemoglobin A1c
Improvement in 1h
postprandial glucose
& decrease in
hemoglobin A1c
Hassaballa et al.,2005 3-4 ms
38 Pts with DM with
OSA
Hemoglobin A1c
Slight decrease in
hemoglobin A1c
Lindberg et al.,2006 3 wks
28 with OSA
28 Matched control
Fasting insulin &
HOMA
Reductions in fasting
insulin levels & IR
Effect of CPAP on Glucose Metabolism:

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Reference
TTT
Period
Study
Population
Measures of Glucose Main Results
Saini et al.,1993 1 Night 8 pts with OSA
Profiles of glucose &
insulin at night
No change in nocturnal glucose & insulin
profiles
Cooper et al.1995 1 Night
6 Obese Pts
without DM
with OSA
Profiles of glucose &
insulin at night
No change in nocturnal glucose & insulin
profiles
Stoohs et al.2004 2 ms 5 Pts with OSA
Fasting glucose & insulin
Profiles of glucose &
insulin at night
↑ in fasting & nocturnal glucose levels
No change in fasting or nocturnal insulin
levels
Saarlainen et al.,1997 3 ms 7 Pts with OSA
Hyperinsulinemic
euglycemic clamp
No improvement in insulin sensitivity
Ip et al.,2000 6 ms 9 Pts with OSA Fasting glucose & insulin No change in fasting glucose & insulin levels
Sumurra et al.,2006 2 ms
16 pts with
OSA
Hyperinsulinemic
euglycemic clamp
OGTT
No change in insulin sensitivity & glucose
tolerance
Czupryniak et al.,2005 1 Night
9 pts without
DM with OSA
Nocturnal Intestinal
glucose
Fasting insulin & HOMA
↑ in nocturnal glucose
No difference in fasting insulin levels & IR
Coughlin et al.,2007 6 wks
34 Obese pts
with OSA
HOMA
No change in insulin sensitivity with
therapeutic CPAP vs. with placebo CPAP
Effect of CPAP on Glucose Metabolism:

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OSA & Cardiovascular System:
The association of OSAS & cardiovascular consequences can
be addressed by 3 key questions:
First: Is OSA an independent cardiovascular risk factor?
Second: If so, does treatment of OSA reduce
cardiovascular risk, morbidity & mortality?
Third: Is screening for OSAS indicated for patients at risk
for cardiovascular disease?

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Cardiovascular Events In OSA:
Abu et al, JAMA. 2003;290:1906-1914

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OSA & Cardiovascular System:
Somers et al, N Engl J Med. 1993;328:303-307
In healthy individuals, physiologic normal sleep is
associated with distinct sleep stage–related changes in
cardiovascular regulation.
Sympathetic nerve traffic to muscles, as well as HR, BP, SV,
COP, & SVR, all decrease progressively during deeper stages
of NREM sleep.
However, REM sleep is accompanied by striking increases
in sympathetic drive.

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OSA & Cardiovascular System:
Narkiewicz et al, Circulation 1998;97:943–945
The mechanism for increased sympathetic activation is not
known.
One possibility is that increased chemoreflex gain in OSA
results in tonic chemoreflex activation even during
normoxia, with consequent increased sympathetic activity.
Administration of 100% oxygen (to eliminate tonic
chemoreflex drive) significantly lowers sympathetic activity,
HR, & BP in OSA patients during daytime wakefulness.

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Neural & Circulatory Changes in OSA:
Somers et al, J Clin Invest. 1995;96:1897-1904

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Somers et al, J Clin Invest 1995
Neural & Circulatory Changes in OSA:

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Impaired Cardiovascular Variability:
Narkiewicz et al, Circulation 1998;98:1071–77
Singh et al, Hypertension 1998;32:293–97
Fratolla et al, J Hypertens 1993;11:1133–37
Compared with similarly obese control subjects, resting
awake OSA patients have diminished heart rate variability &
increased BP variability.
The Framingham Heart Study has implicated lower HR
variability as a precursor to the development of future
hypertension, & increased BP variability has been
implicated in increased risk of end-organ damage in
patients with hypertension.

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Heart Rate Variability in OSA:
Thurnbeer, Swiss Med Wkly 2007; 137: 217-22
Var: HR variability, variability of > 6 bpm

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In OSA, the combination of repetitive hypoxemia & sleep
deprivation may be associated with increased levels of plasma
cytokines e.g., IL-6, α-TNF, CAMs, serum amyloid A, & CRP.
CRP contribute to vascular disease & dysfunction by
inhibiting nitric oxide synthase & increasing expression of cell
adhesion molecules.
Adhesion of circulating leukocytes to the endothelial cells is
considered one of the initial steps in the pathogenesis of
atherosclerosis.
OSA & Inflammation:
Vgontzas et al, J Clin Endocrinol Metab. 1997;82:1313-16
Shamsuzzaman et al, Circulation. 2002;105:2462-64
Venugopa et al, Circulation. 2002;106:1439-41
Ross et al, Nature;1993;362:801-809

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0
0.5
1
1.5
2
2.5
3
pg/mL
Normal OSA Narcolepsy Idiopathic
Hypersomnia
TNF
IL-6
**
Normal OSA Narcolepsy Idiopathic
Hypersomnia
Cytokines & Disorders of EDS:
Vgontzas et.al., 1997

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OSA & Adhesion Molecules:
Galal IH (2007)
0
100
200
300
400
500
600
700
0 1 2 3 4
sICAM-1
ng/mL
0
500
1000
1500
2000
2500
3000
3500
0 1 2 3 4
sVCAM-1
ng/mL

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In OSA, the hypoxia/reoxygenation phenomenon that
occurs in response to apneas followed by hyperventilation,
may elicit increased vascular oxidative stress.
Low oxygen tension is a trigger for activation of
polymorphonuclear neutrophils, which adhere to the
endothelium & release free oxygen radicals.
Prevention of OSA by CPAP reduces production of
superoxide.
OSA & Oxidative Stress:
Schulz et al, Am J Respir Crit Care Med. 2000;162:566-70
Prabhakar et al, Am J Respir Crit Care Med. 2002;165:859-60

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Hypercoagulability in OSAS results from the imbalance
between coagulation & fibrinolysis.
Increases in hematocrit, nocturnal & daytime levels of
fibrinogen, platelet aggregation, blood
viscosity, FVIIa, FXIIa, VWF, D-dimer & fibrinolysis-
inhibiting enzyme plasminogen inhibitor (PAI-1) in
OSA, likely contribute to predisposition to clot formation &
atherosclerosis.
CPAP therapy can alleviate some of these abnormalities &
can reduce factor VII clotting activity.
OSA & Hpercoagulability:
Hoffstein al, Chest. 1994;106:787-91
Chin et al, Am J Resp Crit Care Med. 1996;153:1972-76
Nobil et al, Clin Hemorheol Microcirc. 2000;22:21-27
Wessendorf et al, Am J Resp Crit Care Med. 2000;162:2039-42

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OSA & Endothelial Dysfunction:
The hypoxia, hypercapnia, & pressor surges accompanying obstructive
apneic events serve as potent stimuli for ↑ in the release of endothelin &
↓ in NO → endothelial dysfunction.
Endothelial dysfunction is often seen with OSA comorbidites
e.g., HTN, hyperlipidemia, DM, or smoking → ↑ risk of cardiovascular
events.
In addition, OSA itself may be an independent risk factor for the
development of endothelial dysfunction.
CPAP treatment plays an important role in the improvement &
protection of vascular endothelial dysfunction.
Zhang et al, Chin Med J. 200;116:844-7
Zamarron et al., Eur J Inten Med.2008;19:390-8

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Cardiovascular Events In OSA:
Abu et al, JAMA. 2003;290:1906-14

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It is estimated that 50% of OSA
patients are hypertensive, &
30% of hypertensive patients
also have OSA, often
undiagnosed.
OSA & Hypertension:
Silverberg et al, Curr Opin Nephrol Hypertens. 1998;7:353–7
Fletcher et al., Ann Intern Med. 1985;103:190 –5

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OSAS is identified as an independent risk factor for the
onset of arterial hypertension.
A clear dose-effect is evident: the more apneas/ hr of sleep,
the higher the chance for becoming hypertensive.
In 2003, the “Joint National Council on High Blood
Pressure” listed OSA as the first identifiable cause of arterial
hypertension.
Harsch et al, Med Sci Monit 2004; 10: 510-5
OSA & Hypertension:

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Potential mechanisms linking OSA with HTN:
Hoffmann et al, Minerva Med. 2004;95:281-90
Obstructive Sleep Apnea
HYPERTENSION
Chemoreflex activation
Baroreflex dysfunction
Arousals
Intrathoracic pressure changes
Sympathetic activation
Leptin R
Insulin R
Inflammation
Oxidative
stress
Obesity
RAS
activation
Endothelial
dysfunction

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Drug-Resistant Hypertension: (clinical blood pressure
of >140/90mmHg while taking a sensible combination of ≥
antihypertensive drugs) a high prevalence of OSAS has been
reported.
(Fletcher EC 1985, Isaksson H, 1991)
In a group of 41 patients taking a mean of 3.6 different
antihypertensive medications daily:
96% of the men & 65% of the women had OSAS, with men
suffering from more severe OSAS (AHI 32 vs. 14).
(Logan AG, 2001)
OSA & Hypertension:

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60
80
100
120
140
MAP(mmHg)
baseline
effective nCPAP
715
pm 1115
pm 315
am 715
am315
pm 1115
am
Becker, Circulation 2003
Effect of nCPAP on Blood Pressure in OSA:
-25
-20
-15
-10
-5
0
5
10
15
mmHg
* * *
MAP systolic diastolic

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OSA & Heart Failure:
Marin et al., Lancet. 2005; 365:1 046 –53
OSA contribute to the progression of heart failure
through several pathological mechanisms:
1) by eliciting greater sympathetic outflow to the heart, kidney, &
resistance vessels during wakefulness & sleep.
2) by increasing left ventricular afterload both acutely & chronically.
3) by inducing hypoxia & 2ry increases in right ventricular afterload.
4) by increasing the risk of myocardial infarction.
However, yet to be established is whether OSA can cause
heart failure. In addition, whether the presence of OSA in
Heart failure accelerates mortality remains unclear.

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Heart failure patients with CPAP-treated OSA have low
mortality rate compared with untreated OSA.
Effect of treatment on OSA on HF:
Wang et al., J Am Coll Cardiol. 2007;49:1625-31

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Epidemiological data suggest that OSA is overrepresented
in patients with CAD.
Conversely, the clinical course of CAD is initiated (or)
accelerated by the presence of OSA.
More than half of sudden cardiac deaths in patients with
proven OSA occur during the sleeping hours (between 10
PM & 6 AM). Thus, OSA appears to affect the timing of
sudden cardiac death.
OSA & CAD:
Hedner et al., 2005
Somers et al., JACC 2008;52:686–717

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In patients with combined OSA & CAD, treatment of OSA
was associated with a decrease in the occurrence of new
cardiovascular events.
Repots from patients’ spouses describe marked changes in
sleep patterns, snoring severity, & witnessed apneas after
bypass surgery and sometimes even after angioplasty.
Effect of treatment on OSA & CAD:
Milleron et al., Eur Heart J. 2004;25:728 –34
Somers et al., JACC 2008;52:686–717

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OSA & Arrhythmia:
Zwillich et al, J Clin Invest. 1982;69:1286-92
Somers et al., JACC 2008;52:686–717
Nocturnal arrhythmias have been
reported in up to 50% of patients with
OSA even in absence of pre-existing
cardiac disease.
The most common arrhythmias include
2nd degree heart block, AF,
ventricular extrasystole & sinus
bradycardia, representing in part the
diving reflex response to apnea &
hypoxia

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Recurrence of AF After Cardioversion:
0
10
20
30
40
50
60
70
80
90
100
Controls (n=79) Treated OSA
(n=12)
Untreated Osa
(n=27)
% Recurrence
at 12 Months
**
Kanagola et al, Circ 107:2589, 2003

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In small series of patients with OSA (without clinical
history of chronic obstructive pulmonary disorder) the
reported daytime pulmonary arterial hypertension was
found in 20- 42% of cases
The most likely primary mechanism OSA-related PAH is
hypoxemia, which is known to reflexively induce an acute
increase in PAP.
OSA & PAH:
Yamakawa et al, Psychiatry Clin Neurosci.,2002;56:311–12
Voelkel, Am Rev Respir Dis. 1986;133:1186 –95

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Buchner et al. AJRCCM 2007
CPAP Treatment & Cardiovascular Risk:

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*
Cardiovascular Disease & Mortality in OSAS:
Doherty et al. Chest 2005; 127: 2076-84

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Memories are formed in the mammillary bodies.
When UCLA neuroscientists* scanned the brains of 43 sleep apnea
patients & 66 healthy volunteers using magnetic MRI, they discovered
that the OSA patients’ mammillary bodies were nearly 20% smaller than
those of the untroubled sleepers.
OSA & Memory Affection:
*Newswise: Study Links Common Sleep Disorder to Memory Loss Retrieved on June 11, 2008

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Stroke has been linked to OSA & sleep apnea is highly
prevalent in patients with stroke.
Mechanisms that have been implicated in any increased risk
of stroke in OSA include BP swings, reduction in cerebral
blood flow, altered cerebral autoregulation, impaired
endothelial function, accelerated atherogenesis, &
prothrombotic & proinflammatory states.
OSA & Stroke:
Somers et al., JACC 2008;52:686–717

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OSA & Stroke:
Bassetti & Aldrich, Sleep 22:217, 1999
0
5
10
15
20
25
30
35
Stroke (n=48) TIA (n=32) Controls (n=25)
AverageAHI(Episodes/hour)

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The prevalence of OSA in ESRD ranged from 40% - 60%.
Long-standing OSA contributes to the origin of ESRD by
inducing chronic elevations in BP & increasing sympathetic
nerve discharge directed at the kidney & other vascular
beds.
OSA & End-Stage Renal Disease:
Hanly, Semin Dial. 2004;17:109 –14

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Conclusion

63. Page 
Zamarron, Eur J Int Med 2008; 19: 390-98

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The Association of OSAS with
Endocrine-Metabolic &
Cardiovascular Alternations
indicates that, More than a Local
Abnormality, OSAS should be
considered a Systemic Disease.

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23#, Verse30#Room, Chapter-Ar

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