OSA is a systemic disease

OBSTRUCTIVE SLEEP OBSTRUCTIVE SLEEP APNEA IS A SYSTEMIC APNEA IS A SYSTEMIC

DISEASEDISEASE

Iman Galal, MDIman Galal, MDAssistant Professor Pulmonary MedicineAssistant Professor Pulmonary Medicine

Ain Shams UniversityAin Shams University

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Al-Furqan, Chapter #25, Verse #47Al-Furqan, Chapter #25, Verse #47

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Obstructive Sleep Apnea Syndrome & Metabolic Obstructive Sleep Apnea Syndrome & Metabolic

Syndrome.Syndrome.

Obstructive Sleep Apnea Syndrome & Obstructive Sleep Apnea Syndrome &

Cardiovascular Diseases. Cardiovascular Diseases.

Effect of Continuous Positive Airway Pressure Effect of Continuous Positive Airway Pressure

treatment.treatment.

Content:Content:

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Obstructive Sleep Obstructive Sleep Apnea:Apnea:

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ObstructivObstructive Sleep e Sleep ApneaApnea

Memory Memory ProblemsProblems

IncreasedIncreased

Insulin Insulin

ResistanceResistance

StrokeStrokeIncreased Increased

Traffic Traffic AccidentsAccidents

Cardiac Cardiac ProblemsProblems

HypertensioHypertensionn

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Introduction:Introduction:Obstructive sleep apnea, Obstructive sleep apnea,

a highly prevalent a highly prevalent

disease, affecting 4% of disease, affecting 4% of

men & 2% of women, is a men & 2% of women, is a

disorder characterized by disorder characterized by

recurrent episodes of recurrent episodes of

upper airway obstruction, upper airway obstruction,

& is associated with & is associated with

reductions in ventilation, reductions in ventilation,

resulting in recurrent resulting in recurrent

arousals & episodic arousals & episodic

oxyhemoglobin oxyhemoglobin

desaturations during desaturations during

sleep.sleep.

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A variety of phenomena are implicated in OSAS A variety of phenomena are implicated in OSAS

such as modifications in the autonomic nervous such as modifications in the autonomic nervous

system, hypoxemia–reoxygenation cycles, system, hypoxemia–reoxygenation cycles,

inflammation, & coagulation–fibrinolysis imbalance.inflammation, & coagulation–fibrinolysis imbalance.

OSAS patients also present increased levels of OSAS patients also present increased levels of

certain biomarkers linked to endocrine-metabolic & certain biomarkers linked to endocrine-metabolic &

cardiovascular alterations among other systemic cardiovascular alterations among other systemic

consequences. consequences.

Introduction:Introduction:

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Metabolic Syndrome:Metabolic Syndrome:The National Cholesterol Education Program (NCEP) Adult The National Cholesterol Education Program (NCEP) Adult

Treatment Treatment

Panel III (ATP III) report recommended the use of 5 variables:Panel III (ATP III) report recommended the use of 5 variables:

1)1) Abdominal Obesity: Abdominal Obesity: waist circumference (≥102 cm in waist circumference (≥102 cm in ♂♂, ,

≥88 cm in ≥88 cm in ♀♀))

2)2) ↑ ↑ TG (≥150 mg/dL or drug treatment)TG (≥150 mg/dL or drug treatment)

3)3) ↓ ↓ HDL (<40 mg/dL in ♂, <50 mg/dL in ♀, or drug treatment)HDL (<40 mg/dL in ♂, <50 mg/dL in ♀, or drug treatment)

4)4) Hypertension: Hypertension: BP (systolic BP ≥130 mmHg, or diastolic BP BP (systolic BP ≥130 mmHg, or diastolic BP

≥ 85 mmHg, or drug treatment for hypertension)≥ 85 mmHg, or drug treatment for hypertension)

5)5) Glucose Intolerance: Glucose Intolerance: fasting glucose (≥100 mg/dL or drug fasting glucose (≥100 mg/dL or drug

treatment)treatment)

Subjects meeting 3 of these 5 criteria are classified as Subjects meeting 3 of these 5 criteria are classified as

having Metabolic Syndrome.having Metabolic Syndrome. Grundy et al. Circulation 2005; 112: 285-90Grundy et al. Circulation 2005; 112: 285-90

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Metabolic Syndrome:Metabolic Syndrome:

International Diabetes Federation (IDF) Consensus International Diabetes Federation (IDF) Consensus

Definition 2005 Criteria for Identification of the MS:Definition 2005 Criteria for Identification of the MS:

Alberti, Lancet 2005Alberti, Lancet 2005

Abdominal ObesityAbdominal Obesity: : (waist circumference) (waist circumference)

ethnicity specificethnicity specific

for Europids: Men >94 cmfor Europids: Men >94 cm

WomenWomen >80 cm>80 cm

Plus anyPlus any Two Two of the followingof the following

TriglyceridesTriglycerides ≥≥150 mg/dL150 mg/dL

HDL cholesterolHDL cholesterol

MenMen <40 mg/dL<40 mg/dL

WomenWomen <50 mg/dL<50 mg/dL

Blood PressureBlood Pressure ≥≥130 / ≥85mmHg130 / ≥85mmHg

Fasting GlucoseFasting Glucose ≥≥100mg/dL or Type II Diabetes100mg/dL or Type II Diabetes

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The metabolic disturbances in patients with The metabolic disturbances in patients with

obstructive sleep apnea syndrome (OSAS) include obstructive sleep apnea syndrome (OSAS) include

insulin resistance & elevated levels of pro-insulin resistance & elevated levels of pro-

inflammatory cytokines & vascular adhesion inflammatory cytokines & vascular adhesion

molecules, as well as an elevation of hormones molecules, as well as an elevation of hormones

derived from the adipose tissue as leptin. derived from the adipose tissue as leptin.

OSA & Metabolic SyndromeOSA & Metabolic Syndrome“Syndrome Z”“Syndrome Z”

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OSA & MS in AdultsOSA & MS in Adults

ReferenceReference DesignDesign ResultsResults

Coughlin et Coughlin et al.,2004al.,2004

Case controlled (matched for Case controlled (matched for BMI) BMI)

OSA: AHI > 15 OSA: AHI > 15

Control subjects: AHI < 5 Control subjects: AHI < 5

MS: NCEP (ATP III) criteria MS: NCEP (ATP III) criteria

Independent* associations between: Independent* associations between:

1.1. OSA & MSOSA & MS

2.2. OSA& systolic and diastolic blood pressure, OSA& systolic and diastolic blood pressure, fasting insulin, triglyceride, HDL, total/HDL fasting insulin, triglyceride, HDL, total/HDL cholesterol cholesterol

Gruber et al., 2006 Gruber et al., 2006

Case controlled Case controlled

OSA: AHI criteria not given OSA: AHI criteria not given

MS: International Diabetes MS: International Diabetes Federation criteria Federation criteria

Independent* association between: Independent* association between:

1.1. OSA & MSOSA & MS

2.2. No independent association between OSA & No independent association between OSA & insulin resistance (assessed by HOMA) insulin resistance (assessed by HOMA)

Lam et al., 2006Lam et al., 2006

Community based Community based

OSA: AHI > 5OSA: AHI > 5


OSA and MS OSA and MS

Independent association between OSA & waist, Independent association between OSA & waist, diastolic blood pressure*, fasting glucose*, MS* diastolic blood pressure*, fasting glucose*, MS*

Independent determinants of OSA: age, gender, Independent determinants of OSA: age, gender, BMI, MS BMI, MS

Sasanabe et Sasanabe et al.,2006al.,2006

OSA: AHI > 15 OSA: AHI > 15

Control subjects: AHI < 5Control subjects: AHI < 5

MS: criteria for Japanese MS: criteria for Japanese populationpopulation

Independent* association between OSA & MS in Independent* association between OSA & MS in ♂♂ not in not in ♀♀

Parish et al., 2007Parish et al., 2007 Retrospective PSG & chart Retrospective PSG & chart review review

Higher prevalence of MS in patients with OSA (60 Higher prevalence of MS in patients with OSA (60 vs.40%) vs.40%)

Coughlin et al., Coughlin et al., 20072007

Randomized, controlled study Randomized, controlled study


No change in proportion of subjects with MS with No change in proportion of subjects with MS with CPAPCPAP

Significant Significant ↓ ↓ in blood pressure in blood pressure

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OSA & Obesity:OSA & Obesity:OSAS often coexists with obesity.OSAS often coexists with obesity.

OSAS is present in approximately OSAS is present in approximately

40%40% of obese individuals, & of obese individuals, &

about about 70%70% of OSAS patients are of OSAS patients are

obese.obese.

In recent years, much attention In recent years, much attention

has been focused on the has been focused on the

interaction between OSAS & interaction between OSAS &

products released by adipose products released by adipose

tissue such as tissue such as Leptin, Leptin,

Adiponectin, Resistin & Adiponectin, Resistin &

Ghrelin.Ghrelin.

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OSA & Obesity:OSA & Obesity:

Gate et al., J Nutr Gate et al., J Nutr 20042004

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Leptin Leptin is an adipocyte-derived hormone thatis an adipocyte-derived hormone that

suppresses appetite & promotes satiety..

Several studies have shown increased levels of Several studies have shown increased levels of

LeptinLeptin in OSAS, suggesting resistance to the in OSAS, suggesting resistance to the

metabolic effects of leptin metabolic effects of leptin (Leptin Resistance).(Leptin Resistance).

Obesity is a major confounding factor in the Obesity is a major confounding factor in the

association between association between LeptinLeptin && OSA.OSA.

Treatment with CPAP reduces leptin levels & also Treatment with CPAP reduces leptin levels & also

may be associated with decreased visceral fat may be associated with decreased visceral fat

accumulation.accumulation.


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Sleep Apnea & Visceral FatSleep Apnea & Visceral Fat

AH

IA

HI

Visceral Fat (cmVisceral Fat (cm22))

SaO

SaO

22 n

ad

ir n

ad

ir %

%

0

20

40

60

80

100

50 150 250 350 450

r = .70p = .00

0

20

40

60

80

100

50 150 250 350 450

r = -.61p = .001

0

100

200

300

400

OSAOSA Obese Obese ControlsControls

*

Ab

dom

inal

Fat

Ab

dom

inal

Fat

Dis

trib

uti

on

(c

mD

istr

ibu

tion

(c

m22))

Subcutaneous FatSubcutaneous Fat

Visceral FatVisceral Fat

Vgontzas et al. J Clin Endocrin Metab 2000; 85: 1151-8Vgontzas et al. J Clin Endocrin Metab 2000; 85: 1151-8

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Effect of CPAP on Visceral FatEffect of CPAP on Visceral Fat

Fat

accu

mu

lati

on

(cm

Fat

accu

mu

lati

on

(cm

22))

BW=BW= BW BW

0

BW=BW= BW BW

100

200

300

* **

VisceralVisceral SubcutaneousSubcutaneous

Chin et al., Circulation 1999; 100: 706-12Chin et al., Circulation 1999; 100: 706-12

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Increased LeptinIncreased Leptin::

Chin Chin et al., Circulationet al., Circulation 1999; 100: 706-12. 1999; 100: 706-12.

Ip Ip et al., Chestet al., Chest 2000; 118: 580-6. 2000; 118: 580-6.

Schafer Schafer et al., Chestet al., Chest 2002; 122: 829-39 2002; 122: 829-39 (Obesity+)(Obesity+)

Shimizu Shimizu et al., Thoraxet al., Thorax 2002; 57: 429-34. 2002; 57: 429-34.

Ozturk Ozturk et al., Arch Otolaryngol Head Neck Surget al., Arch Otolaryngol Head Neck Surg 2003; 129: 538- 2003; 129: 538-

40.40.

Sanner Sanner et al., Eur Respir Jet al., Eur Respir J 2004; 23: 601-4. 2004; 23: 601-4.

Shimura Shimura et al., Chestet al., Chest 2005; 127: 543-9 2005; 127: 543-9 (Hypercapnia+)(Hypercapnia+)

Barcelo Barcelo et al., Am J Respir Crit Care Medet al., Am J Respir Crit Care Med 2005; 171: 183-7 2005; 171: 183-7

(Obesity+)(Obesity+)

Tatsumi Tatsumi et al., Chestet al., Chest 2005; 127: 716-21. 2005; 127: 716-21.

Ulukavak Ciftci Ulukavak Ciftci et al., Respirationet al., Respiration 2005; 72: 395-401. 2005; 72: 395-401.

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AdiponectinAdiponectin is an adipocyte-derived cytokine with is an adipocyte-derived cytokine with

regulatory functions in both glucose & lipid regulatory functions in both glucose & lipid

metabolism.metabolism.

In addition,In addition, Adiponectin Adiponectin has profound anti-has profound anti-

inflammatory & antiatherogenic effects.inflammatory & antiatherogenic effects.

Plasma levels ofPlasma levels of AdiponectinAdiponectin decreases in obesity decreases in obesity

& metabolic syndromes e.g., OSAS.& metabolic syndromes e.g., OSAS.

CPAP treatment of OSAS does not effectively CPAP treatment of OSAS does not effectively

normalize normalize AdiponectinAdiponectin levels. levels.


Harsch et al, Respiration 2004; 10: 710-580-6Harsch et al, Respiration 2004; 10: 710-580-6Zhang et al, Chin Med J 2004; 117: 1603-1606Zhang et al, Chin Med J 2004; 117: 1603-1606

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ResistinResistin is a white adipose tissue hormone whose is a white adipose tissue hormone whose

physiological function has not yet been established.physiological function has not yet been established.

In a study of 20 obese OSA patients, there was a In a study of 20 obese OSA patients, there was a

weak link between weak link between ResistinResistin & & Insulin Sensitivity.Insulin Sensitivity.

CPAP treatment of OSA had no significant influence CPAP treatment of OSA had no significant influence

on on ResistinResistin levels.levels.


Harsch et al, Med Sci Monit 2004; 10: 510-5Harsch et al, Med Sci Monit 2004; 10: 510-5

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AdiponectinAdiponectin:: variable results variable results

Zhang Zhang et al.,et al., Chin Med JChin Med J 2004; 117: 1603-1606 2004; 117: 1603-1606

Harsch Harsch et al., Respirationet al., Respiration 2004; 71: 580-586 (obesity+) 2004; 71: 580-586 (obesity+)

Wolk Wolk et al., Obes Reset al., Obes Res 2005; 13: 186-190 2005; 13: 186-190

Zhang Zhang et al.,et al., RespirationRespiration 2006; 73: 73-77 2006; 73: 73-77

Makino Makino et al., Clin Endocrinolet al., Clin Endocrinol 2006; 64:12-19 2006; 64:12-19

Resistin:Resistin:

Harsch Harsch et al., Med Sci Monitet al., Med Sci Monit 2004; 10: 510-5 2004; 10: 510-5 (insulin sensitivity ±, (insulin sensitivity ±,

inflammation+)inflammation+)

Ghrelin:Ghrelin: variable resultsvariable results

Harsch Harsch et al., Eur Respir Jet al., Eur Respir J 2003; 22:251-257 2003; 22:251-257

Ulukavak Ulukavak et al.,et al., RespirationRespiration 2005; 72: 395-401 = 2005; 72: 395-401 =

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OSA is less prevalent in OSA is less prevalent in ♀ than ♂, yet this difference ♀ than ♂, yet this difference

diminishes after menopause 2ry to the decline in estrogen & diminishes after menopause 2ry to the decline in estrogen &

progesteroneprogesterone..

Accordingly, estrogen replacement therapy in Accordingly, estrogen replacement therapy in

menopausal ♀menopausal ♀ lessens the prevalence of OSAS.lessens the prevalence of OSAS.

OSAS in ♂ causes reduced pituitary-gonadal OSAS in ♂ causes reduced pituitary-gonadal

function (possibly 2ry to obesity) function (possibly 2ry to obesity) → → decline in decline in

morning serum testosterone levels, reduced morning serum testosterone levels, reduced

androgen secretion & libido. In addition, androgen secretion & libido. In addition, ↑ ↑ leptin leptin → →

impaired testicular Leyding cell function.impaired testicular Leyding cell function.Anttalainen et al., Acta Obstet Gynecol Scand 2006; 85: 1381-8Anttalainen et al., Acta Obstet Gynecol Scand 2006; 85: 1381-8Wesstrom et al., Acta Obstet Gynecol Scand 2005; 84: 54-7Wesstrom et al., Acta Obstet Gynecol Scand 2005; 84: 54-7Teloken et al., Urology2006; 76:1033-7Teloken et al., Urology2006; 76:1033-7Luboshitzky et al., Obes Res2005;13:780-6Luboshitzky et al., Obes Res2005;13:780-6Ishikawa et al., Andrologia2007;39:22-7Ishikawa et al., Andrologia2007;39:22-7

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Insulin ResistanceInsulin Resistance

Kasuga, J Clin Invest 2006Kasuga, J Clin Invest 2006

NormalNormal

NormalNormal

IncreasedIncreased

Normal or IGT Normal or IGT Diabetes mellitus Diabetes mellitus

DecreasedDecreased

PancreaticPancreatic IsletsIslets

cell compensationcell compensation cell failurecell failure

InsulinInsulinsecretion secretion by by cells cells

Blood Blood glucoseglucose

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Insulin Signaling in CellsInsulin Signaling in Cells

Kasuga, J Clin Invest 2006Kasuga, J Clin Invest 2006

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Relation between OSA, MS & Type II DMRelation between OSA, MS & Type II DM

Tasali & Ip, Tasali & Ip, he Proceedings of the American Thoracic Society 2008;5:207-17he Proceedings of the American Thoracic Society 2008;5:207-17

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OSA & Diabetes Mellitus:OSA & Diabetes Mellitus:

In 2001, El Masry & co-workers proved that the In 2001, El Masry & co-workers proved that the

prevalence of severe OSA was significantly higher in prevalence of severe OSA was significantly higher in

diabetic patients than in normoglycaemic subject diabetic patients than in normoglycaemic subject

independent of BMI.independent of BMI.

Although obesity is the main risk factor for Although obesity is the main risk factor for

diabetes, yet coexistent severe OSA may add to this diabetes, yet coexistent severe OSA may add to this

risk .risk .

El Masry et al., J Intern Med. 2001; 249: 153-61El Masry et al., J Intern Med. 2001; 249: 153-61

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ReferenceReferenceTTT TTT

PeriodPeriodStudy PopulationStudy Population Measures of Measures of

GlucoseGlucose Main ResultsMain Results

Brooks et al.,1994Brooks et al.,1994 4 ms4 ms10 severely obese 10 severely obese pts with DM with pts with DM with

OSA OSA

Hyperinsulinemic Hyperinsulinemic euglycemic clamp euglycemic clamp

Improvement in Improvement in insulin sensitivity insulin sensitivity

Harsh et al.2004 Harsh et al.2004 3 ms3 ms 40 Pts without DM 40 Pts without DM with OSA with OSA



Harsh et al.2004 Harsh et al.2004 3 ms3 ms 9 Pts with DM with 9 Pts with DM with OSA OSA



Babu et al.,2005Babu et al.,2005 3 ms3 ms 25 Pts with DM 25 Pts with DM with OSA with OSA

72-h interstitial 72-h interstitial glucoseHemoglobin glucoseHemoglobin

A1c A1c

Improvement in Improvement in 1h postprandial 1h postprandial

glucose & glucose & decrease in decrease in

hemoglobin A1c hemoglobin A1c

Hassaballa et Hassaballa et al.,2005al.,2005 3-4 ms3-4 ms 38 Pts with DM 38 Pts with DM

with OSA with OSA Hemoglobin A1c Hemoglobin A1c Slight decrease in Slight decrease in hemoglobin A1c hemoglobin A1c

Lindberg et Lindberg et al.,2006 al.,2006 3 wks3 wks

28 28 ♂♂ with OSA with OSA

28 Matched 28 Matched control control ♂♂

Fasting insulin & Fasting insulin & HOMA HOMA

Reductions in Reductions in fasting insulin fasting insulin

levels & IR levels & IR

Effect of CPAP on Glucose Metabolism:Effect of CPAP on Glucose Metabolism:

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ReferenceReferenceTTT TTT

PerioPeriodd

Study Study PopulationPopulation

Measures of Measures of GlucoseGlucose

Main ResultsMain Results

Saini et al.,1993Saini et al.,1993 1 1 NightNight

8 pts with 8 pts with OSA OSA

Profiles of glucose & Profiles of glucose & insulin at nightinsulin at night

No change in nocturnal glucose & No change in nocturnal glucose & insulin profiles insulin profiles

Cooper et al.1995Cooper et al.1995 1 1 NightNight

6 Obese ♂ 6 Obese ♂ Pts Pts

without without DM with DM with

OSA OSA


No change in nocturnal glucose & No change in nocturnal glucose & insulin profiles insulin profiles

Stoohs et al.2004 Stoohs et al.2004 2 ms2 ms 5 Pts with 5 Pts with OSA OSA

Fasting glucose & Fasting glucose & insulininsulin


↑↑ in fasting & nocturnal glucose levelsin fasting & nocturnal glucose levels

No change in fasting or nocturnal No change in fasting or nocturnal insulin levels insulin levels

Saarlainen et Saarlainen et al.,1997al.,1997 3 ms3 ms 7 Pts with 7 Pts with

OSA OSA Hyperinsulinemic Hyperinsulinemic euglycemic clampeuglycemic clamp No improvement in insulin sensitivity No improvement in insulin sensitivity

Ip et al.,2000Ip et al.,2000 6 ms6 ms 9 Pts with 9 Pts with OSA OSA

Fasting glucose & Fasting glucose & insulininsulin

No change in fasting glucose & insulin No change in fasting glucose & insulin levels levels

Sumurra et al.,2006 Sumurra et al.,2006 2 ms2 ms 16 pts with 16 pts with OSAOSA

Hyperinsulinemic Hyperinsulinemic euglycemic clampeuglycemic clamp

OGTTOGTT

No change in insulin sensitivity & No change in insulin sensitivity & glucose tolerance glucose tolerance

Czupryniak et Czupryniak et al.,2005al.,2005

1 1 NightNight

9 pts without 9 pts without DM with DM with

OSAOSA

Nocturnal Intestinal Nocturnal Intestinal glucoseglucose

Fasting insulin & Fasting insulin & HOMAHOMA

↑↑ in nocturnal glucose in nocturnal glucose

No difference in fasting insulin levels No difference in fasting insulin levels & IR& IR

Coughlin et al.,2007 Coughlin et al.,2007 6 wks6 wks 34 Obese pts 34 Obese pts with OSAwith OSA HOMAHOMA

No change in insulin sensitivity with No change in insulin sensitivity with therapeutic CPAP vs. with placebo therapeutic CPAP vs. with placebo

CPAP CPAP

Effect of CPAP on Glucose Metabolism:Effect of CPAP on Glucose Metabolism:

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OSA & Cardiovascular System:OSA & Cardiovascular System:The association of OSAS & cardiovascular The association of OSAS & cardiovascular

consequences can consequences can

be addressed by 3 key questions:be addressed by 3 key questions:

FirstFirst:: Is OSA an independent cardiovascular risk Is OSA an independent cardiovascular risk

factor? factor?

Second:Second: If so, does treatment of OSA reduce If so, does treatment of OSA reduce

cardiovascular risk, morbidity & cardiovascular risk, morbidity &

mortality?mortality?

ThirdThird:: Is screening for OSAS indicated for Is screening for OSAS indicated for

patients at risk patients at risk

for cardiovascular disease?for cardiovascular disease?

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Cardiovascular Events In OSA:Cardiovascular Events In OSA:

Abu et al, JAMA. 2003;290:1906-1914 Abu et al, JAMA. 2003;290:1906-1914

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OSA & Cardiovascular System:OSA & Cardiovascular System:

Somers et al, N Engl J Med. 1993;328:303-307 Somers et al, N Engl J Med. 1993;328:303-307

In healthy individuals, physiologic normal sleep is In healthy individuals, physiologic normal sleep is

associated with distinct sleep stage–related associated with distinct sleep stage–related

changes in cardiovascular regulation.changes in cardiovascular regulation.

Sympathetic nerve traffic to muscles, as well as HR, Sympathetic nerve traffic to muscles, as well as HR,

BP, SV, COP, & SVR, all decrease progressively BP, SV, COP, & SVR, all decrease progressively

during deeper stages of NREM sleep.during deeper stages of NREM sleep.

However, REM sleep is accompanied by striking However, REM sleep is accompanied by striking

increases in sympathetic drive. increases in sympathetic drive.

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OSA & Cardiovascular System:OSA & Cardiovascular System:

Narkiewicz et al, Circulation 1998;97:943–945Narkiewicz et al, Circulation 1998;97:943–945

The mechanism for increased sympathetic The mechanism for increased sympathetic

activation is not known.activation is not known.

One possibility is that increased chemoreflex gain One possibility is that increased chemoreflex gain

in OSA results in tonic chemoreflex activation even in OSA results in tonic chemoreflex activation even

during normoxia, with consequent increased during normoxia, with consequent increased

sympathetic activity. sympathetic activity.

Administration of 100% oxygen Administration of 100% oxygen (to eliminate tonic (to eliminate tonic

chemoreflex drive)chemoreflex drive) significantly lowers sympathetic significantly lowers sympathetic

activity, HR, & BP in OSA patients during daytime activity, HR, & BP in OSA patients during daytime

wakefulness.wakefulness.

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Neural & Circulatory Changes in OSA:Neural & Circulatory Changes in OSA:

Somers et al, J Clin Invest. 1995;96:1897-1904 Somers et al, J Clin Invest. 1995;96:1897-1904

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Somers et al, J Clin Invest 1995Somers et al, J Clin Invest 1995

Neural & Circulatory Changes in OSA:Neural & Circulatory Changes in OSA:

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Impaired Cardiovascular Variability:Impaired Cardiovascular Variability:

Narkiewicz et al, Circulation 1998;98:1071–77Narkiewicz et al, Circulation 1998;98:1071–77Singh et al, Hypertension 1998;32:293–97 Singh et al, Hypertension 1998;32:293–97 Fratolla et al, J Hypertens 1993;11:1133–37Fratolla et al, J Hypertens 1993;11:1133–37

Compared with similarly obese control subjects, Compared with similarly obese control subjects,

resting awake OSA patients have diminished heart resting awake OSA patients have diminished heart

rate variability & increased BP variability. rate variability & increased BP variability.

The Framingham Heart Study has implicated lower The Framingham Heart Study has implicated lower

HR variability as a precursor to the development of HR variability as a precursor to the development of

future hypertension, & increased BP variability has future hypertension, & increased BP variability has

been implicated in increased risk of end-organ been implicated in increased risk of end-organ

damage in patients with hypertension.damage in patients with hypertension.

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Heart Rate Variability in OSA:Heart Rate Variability in OSA:

Thurnbeer, Swiss Med Wkly 2007; 137: 217-22Thurnbeer, Swiss Med Wkly 2007; 137: 217-22Var: HR variability, variability of > 6 bpm

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In OSA, the combination of repetitive hypoxemia & In OSA, the combination of repetitive hypoxemia &

sleep deprivation may be associated with increased sleep deprivation may be associated with increased

levels of plasma cytokines e.g., IL-6, levels of plasma cytokines e.g., IL-6, αα-TNF, CAMs, -TNF, CAMs,

serum amyloid A, & CRP.serum amyloid A, & CRP.

CRP contribute to vascular disease & dysfunction by CRP contribute to vascular disease & dysfunction by

inhibiting nitric oxide synthase & increasing inhibiting nitric oxide synthase & increasing

expression of cell adhesion molecules.expression of cell adhesion molecules.

Adhesion of circulating leukocytes to the endothelial Adhesion of circulating leukocytes to the endothelial

cells is considered one of the initial steps in the cells is considered one of the initial steps in the

pathogenesis of atherosclerosis.pathogenesis of atherosclerosis.

OSA & OSA & Inflammation:Inflammation:

Vgontzas et al, J Clin Endocrinol Metab. Vgontzas et al, J Clin Endocrinol Metab. 1997;82:1313-161997;82:1313-16Shamsuzzaman et al, Circulation. 2002;105:2462-Shamsuzzaman et al, Circulation. 2002;105:2462-6464Venugopa et al, Circulation. 2002;106:1439-41Venugopa et al, Circulation. 2002;106:1439-41Ross et al, Nature;1993;362:801-809Ross et al, Nature;1993;362:801-809

Page 38

0

0.5

1

1.5

2

2.5

3

0

1

2

3

4

pg/mL

Normal OSA Narcolepsy Idiopathic Hypersomnia

TN

F

IL-6

**

Normal OSAOSA NarcolepsyNarcolepsy Idiopathic Idiopathic HypersomniaHypersomnia

Cytokines & Disorders of EDS:Cytokines & Disorders of EDS:

Vgontzas et.al., 1997Vgontzas et.al., 1997

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OSA & Adhesion OSA & Adhesion Molecules:Molecules:

Galal IH (2007)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

Page 40

In OSA, the hypoxia/reoxygenation phenomenon In OSA, the hypoxia/reoxygenation phenomenon

that occurs in response to apneas followed by that occurs in response to apneas followed by

hyperventilation, may elicit increased vascular hyperventilation, may elicit increased vascular

oxidative stress.oxidative stress.

Low oxygen tension is a trigger for activation of Low oxygen tension is a trigger for activation of

polymorphonuclear neutrophils, which adhere to polymorphonuclear neutrophils, which adhere to

the endothelium & release free oxygen radicals.the endothelium & release free oxygen radicals.

Prevention of OSA by CPAP reduces production of Prevention of OSA by CPAP reduces production of

superoxide.superoxide.

OSA & Oxidative OSA & Oxidative Stress:Stress:

Schulz et al, Am J Respir Crit Care Med. 2000;162:566-Schulz et al, Am J Respir Crit Care Med. 2000;162:566-7070Prabhakar et al, Am J Respir Crit Care Med. Prabhakar et al, Am J Respir Crit Care Med. 2002;165:859-602002;165:859-60

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Hypercoagulability in OSAS results from the Hypercoagulability in OSAS results from the

imbalance between coagulation & fibrinolysis.imbalance between coagulation & fibrinolysis.

Increases in hematocrit, nocturnal & daytime levels Increases in hematocrit, nocturnal & daytime levels

of fibrinogen, platelet aggregation, blood viscosity, of fibrinogen, platelet aggregation, blood viscosity,

FVIIa, FXIIa, VWF, D-dimer & fibrinolysis-inhibiting FVIIa, FXIIa, VWF, D-dimer & fibrinolysis-inhibiting

enzyme plasminogen inhibitor (PAI-1) in OSA, likely enzyme plasminogen inhibitor (PAI-1) in OSA, likely

contribute to predisposition to clot formation & contribute to predisposition to clot formation &

atherosclerosis.atherosclerosis.

CPAP therapy can alleviate some of these CPAP therapy can alleviate some of these

abnormalities & can reduce factor VII clotting abnormalities & can reduce factor VII clotting

activity.activity.

OSA & OSA & Hpercoagulability:Hpercoagulability:

Hoffstein al, Chest. 1994;106:787-91Hoffstein al, Chest. 1994;106:787-91Chin et al, Am J Resp Crit Care Med. 1996;153:1972-76Chin et al, Am J Resp Crit Care Med. 1996;153:1972-76Nobil et al, Clin Hemorheol Microcirc. 2000;22:21-27Nobil et al, Clin Hemorheol Microcirc. 2000;22:21-27Wessendorf et al, Am J Resp Crit Care Med. Wessendorf et al, Am J Resp Crit Care Med. 2000;162:2039-422000;162:2039-42

Page 42

OSA & Endothelial Dysfunction:OSA & Endothelial Dysfunction:

The hypoxia, hypercapnia, & pressor surges accompanying The hypoxia, hypercapnia, & pressor surges accompanying

obstructive apneic events serve as potent stimuli for obstructive apneic events serve as potent stimuli for ↑ ↑ inin the the

release of endothelin & release of endothelin & ↓↓ in NO in NO → → endothelial dysfunction.endothelial dysfunction.

Endothelial dysfunction is often seen with OSA comorbidites Endothelial dysfunction is often seen with OSA comorbidites

e.g., HTN, hyperlipidemia, DM, or smoking → e.g., HTN, hyperlipidemia, DM, or smoking → ↑↑ risk of risk of

cardiovascular events.cardiovascular events.

In addition, OSA itself may be an independent risk factor for In addition, OSA itself may be an independent risk factor for

the development of endothelial dysfunction.the development of endothelial dysfunction.

CPAP treatment plays an important role in the improvement CPAP treatment plays an important role in the improvement

& protection of vascular endothelial dysfunction.& protection of vascular endothelial dysfunction.Zhang et al, Chin Med J. 200;116:844-7Zhang et al, Chin Med J. 200;116:844-7Zamarron et al., Eur J Inten Med.2008;19:390-8 Zamarron et al., Eur J Inten Med.2008;19:390-8

Page 43

Cardiovascular Events In OSA:Cardiovascular Events In OSA:

Abu et al, JAMA. 2003;290:1906-14 Abu et al, JAMA. 2003;290:1906-14

Page 44

It is estimated that 50% of It is estimated that 50% of

OSA patients are OSA patients are

hypertensive, & 30% of hypertensive, & 30% of

hypertensive patients also hypertensive patients also

have OSA, often have OSA, often

undiagnosed.undiagnosed.

OSA & Hypertension:OSA & Hypertension:

Silverberg et al, Curr Opin Nephrol Hypertens. Silverberg et al, Curr Opin Nephrol Hypertens. 1998;7:353–71998;7:353–7Fletcher et al., Ann Intern Med. 1985;103:190 –5Fletcher et al., Ann Intern Med. 1985;103:190 –5

Page 45

OSAS is identified as an independent risk factor for OSAS is identified as an independent risk factor for

the onset of arterial hypertension.the onset of arterial hypertension.

A clear dose-effect is evident: the more apneas/ hr A clear dose-effect is evident: the more apneas/ hr

of sleep, the higher the chance for becoming of sleep, the higher the chance for becoming

hypertensive.hypertensive.

In 2003, theIn 2003, the “Joint National Council on High Blood “Joint National Council on High Blood

Pressure” listed OSA as the first identifiable cause Pressure” listed OSA as the first identifiable cause

of arterial hypertension.of arterial hypertension.Harsch et al, Med Sci Monit 2004; 10: 510-5Harsch et al, Med Sci Monit 2004; 10: 510-5


Page 46

Potential mechanisms linking OSA with Potential mechanisms linking OSA with HTN:HTN:

Hoffmann et al, Minerva Med. 2004;95:281-90Hoffmann et al, Minerva Med. 2004;95:281-90

Obstructive Sleep ApneaObstructive Sleep Apnea

HYPERTENSIONHYPERTENSION

Chemoreflex activationChemoreflex activationBaroreflex dysfunctionBaroreflex dysfunction

ArousalsArousalsIntrathoracic pressure Intrathoracic pressure

changeschanges

Sympathetic activationSympathetic activation Leptin RLeptin RInsulin RInsulin R

InflammationInflammation

Oxidative Oxidative stressstress

ObesityObesity

RAS RAS activatioactivatio

nn

EndothelialEndothelialdysfunctiondysfunction

Page 47

Drug-Resistant HypertensionDrug-Resistant Hypertension:: (clinical blood (clinical blood

pressure of >140/90mmHg while taking a sensible pressure of >140/90mmHg while taking a sensible

combination of ≥ antihypertensive drugs) a high combination of ≥ antihypertensive drugs) a high

prevalence of OSAS has been reported.prevalence of OSAS has been reported.

(Fletcher EC 1985, Isaksson (Fletcher EC 1985, Isaksson

H, 1991)H, 1991)

In a group of 41 patients taking a mean of 3.6 In a group of 41 patients taking a mean of 3.6

different antihypertensive medications daily:different antihypertensive medications daily:

96%96% of the men & of the men & 65%65% of the women had OSAS, of the women had OSAS,

with men suffering from more severe OSAS (AHI with men suffering from more severe OSAS (AHI

32 vs. 14). 32 vs. 14).

(Logan AG, (Logan AG,

2001)2001)


Page 48

60

80

100

120

140

MAP

(mmH

g)

baseline

effective nCPAP

715 pm 1115 pm 315 am 715 am315 pm 1115 am

Becker, Circulation 2003Becker, Circulation 2003

Effect of nCPAP on Blood Pressure in Effect of nCPAP on Blood Pressure in OSA:OSA:

-25

-20

-15

-10

-5

0

5

10

15

mmHg

* * *

MAP systolic diastolic

Page 49

OSA & Heart Failure:OSA & Heart Failure:

Marin et al., Lancet. 2005; 365:1 046 –Marin et al., Lancet. 2005; 365:1 046 –5353

OSA contribute to the progression of heart OSA contribute to the progression of heart

failurefailure

through several pathological mechanisms:through several pathological mechanisms:

1)1) by eliciting greater sympathetic outflow to the heart, kidney, by eliciting greater sympathetic outflow to the heart, kidney,

& resistance vessels during wakefulness & sleep. & resistance vessels during wakefulness & sleep.

2)2) by increasing left ventricular afterload both acutely & by increasing left ventricular afterload both acutely &

chronically. chronically.

3)3) by inducing hypoxia & 2ry increases in right ventricular by inducing hypoxia & 2ry increases in right ventricular

afterload. afterload.

4)4) by increasing the risk of myocardial infarction.by increasing the risk of myocardial infarction.

However, yet to be established is whether OSA can However, yet to be established is whether OSA can

causecause

heart failure. In addition, whether the presence of heart failure. In addition, whether the presence of

OSA inOSA in

Heart failure accelerates mortality remains unclear.Heart failure accelerates mortality remains unclear.

Page 50

Heart failure patients with CPAP-treated OSA have Heart failure patients with CPAP-treated OSA have

low mortality rate compared with untreated OSA.low mortality rate compared with untreated OSA.

Effect of treatment on OSA on HF:Effect of treatment on OSA on HF:

Wang et al., J Am Coll CardiolWang et al., J Am Coll Cardiol. . 2007;49:1625-312007;49:1625-31

Page 51

Epidemiological data suggest that OSA is Epidemiological data suggest that OSA is

overrepresented in patients with CAD.overrepresented in patients with CAD.

Conversely, the clinical course of CAD is initiated Conversely, the clinical course of CAD is initiated

(or) accelerated by the presence of OSA.(or) accelerated by the presence of OSA.

More than half of sudden cardiac deaths in patients More than half of sudden cardiac deaths in patients

with proven OSA occur during the sleeping hours with proven OSA occur during the sleeping hours

(between 10 PM & 6 AM). Thus, OSA appears to (between 10 PM & 6 AM). Thus, OSA appears to

affect the timing of sudden cardiac death.affect the timing of sudden cardiac death.

OSA & CAD:OSA & CAD:

Hedner et al., 2005Hedner et al., 2005Somers et al., JACC 2008;52:686–Somers et al., JACC 2008;52:686–717717

Page 52

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:Effect of treatment on OSA & CAD:

Milleron et al., Eur Heart J. 2004;25:728 Milleron et al., Eur Heart J. 2004;25:728 –34–34Somers et al., JACC 2008;52:686–717Somers et al., JACC 2008;52:686–717

Page 53

OSA & Arrhythmia:OSA & Arrhythmia:

Zwillich et al, J Clin Invest. Zwillich et al, J Clin Invest. 1982;69:1286-921982;69:1286-92Somers et al., JACC 2008;52:686–717Somers et al., JACC 2008;52:686–717

Nocturnal arrhythmias have been Nocturnal arrhythmias have been

reported in reported in up to 50% of patients patients

with OSA even in absence of pre-with OSA even in absence of pre-

existing cardiac disease.existing cardiac disease.

The most common arrhythmias The most common arrhythmias

include include 22ndnd degree heart block degree heart block, ,

AFAF, , ventricular extrasystoleventricular extrasystole & &

sinus bradycardiasinus bradycardia, representing , representing

in part the diving reflex response in part the diving reflex response

to apnea & hypoxiato apnea & hypoxia

Page 54

Recurrence of AF After Cardioversion:Recurrence of AF After Cardioversion:

0102030405060708090

100

Controls (n=79) Treated OSA(n=12)

Untreated Osa(n=27)

% Recurrence at 12 Months

**

Kanagola et al, Circ 107:2589, 2003Kanagola et al, Circ 107:2589, 2003

Page 55

In small series of patients with OSA In small series of patients with OSA (without (without

clinical history of chronic obstructive pulmonary clinical history of chronic obstructive pulmonary

disorder)disorder) the reported daytime pulmonary arterial the reported daytime pulmonary arterial

hypertension was found in 20- 42% of caseshypertension was found in 20- 42% of cases

The most likely primary mechanism OSA-related The most likely primary mechanism OSA-related

PAH is hypoxemia, which is known to reflexively PAH is hypoxemia, which is known to reflexively

induce an acute increase in PAP.induce an acute increase in PAP.

OSA & PAH:OSA & PAH:

Yamakawa et al, Psychiatry Clin Yamakawa et al, Psychiatry Clin Neurosci.,2002;56:311–12Neurosci.,2002;56:311–12Voelkel, Am Rev Respir Dis. 1986;133:1186 –95Voelkel, Am Rev Respir Dis. 1986;133:1186 –95

Page 56Buchner et al. AJRCCM 2007Buchner et al. AJRCCM 2007

CPAP Treatment & Cardiovascular Risk:CPAP Treatment & Cardiovascular Risk:

Page 57

*

Cardiovascular Disease & Mortality in Cardiovascular Disease & Mortality in OSAS:OSAS:

Doherty et al. Chest 2005; 127: 2076-84Doherty et al. Chest 2005; 127: 2076-84

Page 58

Memories are formed in the mammillary bodies.Memories are formed in the mammillary bodies.

When UCLA neuroscientists* scanned the brains of 43 sleep When UCLA neuroscientists* scanned the brains of 43 sleep

apnea patients & 66 healthy volunteers using magnetic MRI, apnea patients & 66 healthy volunteers using magnetic MRI,

they discovered that the OSA patients’ mammillary bodies they discovered that the OSA patients’ mammillary bodies

were nearly 20% smaller than those of the untroubled were nearly 20% smaller than those of the untroubled

sleepers. sleepers.

OSA & Memory Affection:OSA & Memory Affection:

*Newswise: Study Links Common Sleep Disorder to Memory Loss Retrieved on June 11, 2008*Newswise: Study Links Common Sleep Disorder to Memory Loss Retrieved on June 11, 2008

Page 59

Stroke has been linked to OSA & sleep apnea is Stroke has been linked to OSA & sleep apnea is

highly prevalent in patients with stroke.highly prevalent in patients with stroke.

Mechanisms that have been implicated in any Mechanisms that have been implicated in any

increased risk of stroke in OSA include BP swings, increased risk of stroke in OSA include BP swings,

reduction in cerebral blood flow, altered cerebral reduction in cerebral blood flow, altered cerebral

autoregulation, impaired endothelial function, autoregulation, impaired endothelial function,

accelerated atherogenesis, & prothrombotic & accelerated atherogenesis, & prothrombotic &

proinflammatory states.proinflammatory states.

OSA & Stroke:OSA & Stroke:

Somers et al., JACC 2008;52:686–717Somers et al., JACC 2008;52:686–717

Page 60

OSA & Stroke:OSA & Stroke:

Bassetti & Aldrich, Sleep 22:217, 1999Bassetti & Aldrich, Sleep 22:217, 1999

0

5

10

15

20

25

30

35

Stroke (n=48) TIA (n=32) Controls (n=25)

Ave

rage

AH

I (E

piso

des/

hour

)

Page 61

The prevalence of OSA in ESRD ranged from 40% - The prevalence of OSA in ESRD ranged from 40% -

60%.60%.

Long-standing OSA contributes to the origin of Long-standing OSA contributes to the origin of

ESRD by inducing chronic elevations in BP & ESRD by inducing chronic elevations in BP &

increasing sympathetic nerve discharge directed at increasing sympathetic nerve discharge directed at

the kidney & other vascular beds.the kidney & other vascular beds.

OSA & End-Stage Renal Disease:OSA & End-Stage Renal Disease:

Hanly, Semin Dial. 2004;17:109 –14Hanly, Semin Dial. 2004;17:109 –14

Page 62

ConclusionConclusion

Page 63

Zamarron, Eur J Int Med Zamarron, Eur J Int Med 2008; 19: 390-982008; 19: 390-98

Page 64

The Association of OSAS with The Association of OSAS with

Endocrine-Metabolic & Endocrine-Metabolic &

Cardiovascular Alternations Cardiovascular Alternations

indicates that, More than a indicates that, More than a

Local Abnormality, OSAS should Local Abnormality, OSAS should

be considered a Systemic be considered a Systemic

Disease. Disease.

Page 65

Page 66

Ar-Room, Chapter #30, Verse #23Ar-Room, Chapter #30, Verse #23

Page 67

Science

OSA is a systemic disease