OBSTRUCTIVE SLEEP APNEA AS A CAUSE OF HYPERTENSION

Yksel Peker MD, PhD, Associate Professor

Sleep Medicine Unit, Skaraborg Hospital, Skvde & University of Gothenburg, Sweden

ASSOCIATIONS

OSAHypertension

Hypertension OSAOSAS

Obesity OSAHypertension

Hypertension OSAObesityGender Aging

OSA

Immediate changes

Long-term effects

Modified from Grote L, Schneider H, 1997

Acute Blood Pressure Changes in OSA - Mechanisms -

Part

SaO2

EMG

EEG

EOG

Flow

Effort

30 sec

Grote L. et al., J. Cardiovasc. Pharmacol. 1994

Cardiovascular mechanisms (I)

Repeated nocturnal hypoxemiaCoccogna G et al, 1972; Podszus T et al, 1986

Sympathetic nervous activity Fletcher EC et al, 1987; Hedner J et al, 1988; Narkiewicz K & Somers VK 2003

Vascular endothelial dysfunction Carlson J et al, 1996; Remsburg S et al, 1999; Kraiczi H et al, 2000

Cardiovascular mechanisms (II)

Enhanced release of superoxide from polymorphonuclear neutrophils in OSA. Impact of CPAP. Schulz R et al, AJRCCM 2000

Plasma vascular endothelial growth factor in OSAS: Effects of CPAP. Lavie L et al, AJRCCM 2002

Elevated levels of C-reactive protein and interleukin-6 in patients with OSAS are decreased by CPAP. Yokoe T et al, Circulation 2003

OSA & Hypertension

Sleep clinic population

Hypertensive population

General population

OSAS as an independent risk factor for hypertension (sleep-clinic population, n=599)

Grote et al., AJRCCM, 1999

Chart1

11.522.072.154.15

BMI (kg/m2)123.24.96

Age (years)11.831.982.98

GenderGender11.1Gender

= 40Systolic and diastolic hypertension72.654.833.919.44.8

% hypertensive patients41.660.369.170.386.2

% controlled hypertensives28.814.724.613.9811.96

< 55 -< 1010 - < 2020 - < 40> = 40

% hypertensive patients20.533.738.53553.4

< 55 -< 1010 - < 2020 - < 40> = 40

% controlled hypertensives28.814.724.613.9811.96

5 = 405 = 40

% hypertensive patients on treatment25.545.654.470.4% hypertensive patients (total 798)41.666.770.386.2

% controlled hypertension on treatment28.820.913.9811.96% hypertensive patients on treatment (total 599)25.545.654.470.4

% controlled hypertension on treatment (total 100 out of 599)33.825.82117.7

Sheet3

Control of Hypertension in OSA

Grote et al., J. Hypertension, 2000

Chart3

130.1

132.9

137.3

146.2

Systolic Blood Pressure

Age

mmHg

Systolic Blood Pressure and age in patients referred to the Marburg Sleep Disorders Centre (n=591 patients, no antihypertensive medication)

Chart4

83.6

86.2

88

85.1

Diastolic Blood Pressure

Age

mmHg

Diastolic Blood Pressure and age in patients referred to the Marburg Sleep Disorders Centre (n=591, no antihypertensive medication)

Chart5

69.8

71.2

72.6

72.5

Heart Rate

Age

bpmin-1

Heart Rate and age in patients referred to the Marburg Sleep Disorders Centre (n=591, no antihypertensive medication)

Chart6

46.5

46.8

49.4

57.1

Pulse Pressure

age

mmHg

Pulse Pressure and age in patients referred to the Marburg Sleep Disorders Centre (n=591, no antihypertensive medication)

Chart7

13.9

19.5

20.7

22.1

RDI

age

events/hour of sleep

OSA activity (RDI) and age in patients referred to the Marburg Sleep Disorders Centre (n=591, no antihypertensive mediaction)

Chart8

130.183.669.8

132.986.271.2

137.38872.6

146.285.172.5

&A

Page &P

Systolic Blood Pressure

Diastolic Blood Pressure

Heart Rate

Age

mmHg/bpmin-1

Blood Pressure and Heart Rate in patients referred to the Marburg Sleep Disorders Centre (n=591, no antihypertensive medication)

Chart9

21.527.715.410.824.6

20.611.82517.625

25.417.516.717.522.8

14.719.619.621.724.5

1114.416.724.933

RDI-Classes

sys bp = 170

% patients

Control of systolic blood pressure in prediagnosed hypertensive patients in relation to OSA activity (n=599)

Chart10

15.423.19.227.724.6

10.313.210.329.436.8

14.921.99.627.226.3

718.913.329.431.5

7.714.81024.443.1

dia bp < 90

dia bp 90-94

dia bp 95-99

dia bp 100-104

dia bp >= 105

RDI-Classes

% patients

Control of diastolic blood pressure in prediagnosed hypertensive patients in relation to OSA activity (n=599)

Chart11

10.833.8

5.920.6

9.628.9

4.221

4.817.7

controlled hypertension < 140/90

controlled hypertension < 160/95

RDI Classes

% patients

Control of hypertension in relation to OSA activity (n=599)

Chart1

51.212.70.613.921.7

37.613.9216.829.7

32.814.70.921.630.2

30.8102.521.735

34.16.83.411.444.3

normotension

borderline isolated systolic hpt

isolated systolic hpt

diastolic hpt

systolic and diastolic hpt

RDI-Classes

% patients

Type of Hypertension and OSA Activity Patients referred to the Marburg Sleep Disorders Centrewith no previous history of hypertension (n=591)

Chart2

51.24161.8

37.643.616.82

32.853.410.32.6

30.850.815.82.5

34.134.1255.7

normotension

stage 1 hypertension

stage 2 hypertension

stage 3 hypertension

RDI Classes

% patients

Stage of Hypertension and OSA Activity Patients referred to the Marburg Sleep Disorders Centre with no previous history of hypertension (n=591)

Chart18

21.527.715.410.824.6

23.615.419.817.623.6

14.719.619.621.724.5

1114.416.724.933

sys bp = 170

RDI-Classes

% Patients

Chart23

15.423.19.227.724.6

13.218.79.92830.2

718.913.329.431.5

7.714.81024.443.1

dia bp < 90

dia bp 90-94

dia bp 95-99

dia bp 100-104

dia bp >= 105

RDI-Classes

% patients

Chart24

10.833.8

8.225.8

4.221

4.817.7

controlled hypertension < 140/90

controlled hypertension < 160/95

RDI-Classes

% patients

Chart25

51.212.70.613.921.7

32.814.70.921.630.2

30.8102.521.735

34.16.83.411.444.3

normotension

borderline isolated systolic hpt

isolated systolic hpt

diastolic hpt

systolic and diastolic hpt

DI-Classes

% patients

Type of Hypertension and OSA ActivityPatients referred to the Marburg Sleep Disorders Centre with no previous history of hypertension (n=591)

Chart26

51.24161.8

3548.813.42.3

30.850.815.82.5

34.134.1255.7

normotension

stage 1 hypertension

stage 2 hypertension

stage 3 hypertension

RDI-Classes

% patients

Stage of Hyperetnsion and OSA Activity Patients from the Marurg Sleep Disorders Clinic with no previous history of hypertension (n=591)

Chart28

12.70.613.921.7

14.70.921.630.2

102.521.735

6.83.411.444.3

borderline isolated systolic hpt

isolated systolic hpt

diastolic hpt

systolic and diastolic hpt

RDI Classes

% patients

Type of Hypertension and OSA Activity Newly diagnosed hypertensive Patients referred to the Marburg Sleep Disorders Centre (n=363)

Chart29

4161.8

48.813.42.3

50.815.82.5

34.1255.7

stage 1 hypertension

stage 2 hypertension

stage 3 hypertension

RDI-Classes

% patients

Stage of Hypertension and OSA Activity Newly diagnosed hypertensive patients referred to the Marburg Sleep Disorders Centre (n=363)

Sheet1

Stage of Hypertension and OSA

Grote et al., J Hypertens. 2001

Chart3

130.1

132.9

137.3

146.2

Systolic Blood Pressure

Age

mmHg

Systolic Blood Pressure and age in patients referred to the Marburg Sleep Disorders Centre (n=591 patients, no antihypertensive medication)

Chart4

83.6

86.2

88

85.1

Diastolic Blood Pressure

Age

mmHg

Diastolic Blood Pressure and age in patients referred to the Marburg Sleep Disorders Centre (n=591, no antihypertensive medication)

Chart5

69.8

71.2

72.6

72.5

Heart Rate

Age

bpmin-1

Heart Rate and age in patients referred to the Marburg Sleep Disorders Centre (n=591, no antihypertensive medication)

Chart6

46.5

46.8

49.4

57.1

Pulse Pressure

age

mmHg

Pulse Pressure and age in patients referred to the Marburg Sleep Disorders Centre (n=591, no antihypertensive medication)

Chart7

13.9

19.5

20.7

22.1

RDI

age

events/hour of sleep

OSA activity (RDI) and age in patients referred to the Marburg Sleep Disorders Centre (n=591, no antihypertensive mediaction)

Chart8

130.183.669.8

132.986.271.2

137.38872.6

146.285.172.5

&A

Page &P

Systolic Blood Pressure

Diastolic Blood Pressure

Heart Rate

Age

mmHg/bpmin-1

Blood Pressure and Heart Rate in patients referred to the Marburg Sleep Disorders Centre (n=591, no antihypertensive medication)

Chart9

21.527.715.410.824.6

20.611.82517.625

25.417.516.717.522.8

14.719.619.621.724.5

1114.416.724.933

RDI-Classes

sys bp = 170

% patients

Control of systolic blood pressure in prediagnosed hypertensive patients in relation to OSA activity (n=599)

Chart10

15.423.19.227.724.6

10.313.210.329.436.8

14.921.99.627.226.3

718.913.329.431.5

7.714.81024.443.1

dia bp < 90

dia bp 90-94

dia bp 95-99

dia bp 100-104

dia bp >= 105

RDI-Classes

% patients

Control of diastolic blood pressure in prediagnosed hypertensive patients in relation to OSA activity (n=599)

Chart11

10.833.8

5.920.6

9.628.9

4.221

4.817.7

controlled hypertension < 140/90

controlled hypertension < 160/95

RDI Classes

% patients

Control of hypertension in relation to OSA activity (n=599)

Chart1

51.212.70.613.921.7

37.613.9216.829.7

32.814.70.921.630.2

30.8102.521.735

34.16.83.411.444.3

normotension

borderline isolated systolic hpt

isolated systolic hpt

diastolic hpt

systolic and diastolic hpt

RDI-Classes

% patients

Type of Hypertension and OSA Activity Patients referred to the Marburg Sleep Disorders Centrewith no previous history of hypertension (n=591)

Chart2

51.24161.8

37.643.616.82

32.853.410.32.6

30.850.815.82.5

34.134.1255.7

normotension

stage 1 hypertension

stage 2 hypertension

stage 3 hypertension

RDI Classes

% patients

Stage of Hypertension and OSA Activity Patients referred to the Marburg Sleep Disorders Centre with no previous history of hypertension (n=591)

Chart18

21.527.715.410.824.6

23.615.419.817.623.6

14.719.619.621.724.5

1114.416.724.933

sys bp = 170

RDI-Classes

% Patients

Chart23

15.423.19.227.724.6

13.218.79.92830.2

718.913.329.431.5

7.714.81024.443.1

dia bp < 90

dia bp 90-94

dia bp 95-99

dia bp 100-104

dia bp >= 105

RDI-Classes

% Patients

Chart24

10.833.8

8.225.8

4.221

4.817.7

controlled hypertension < 140/90

controlled hypertension < 160/95

RDI-Classes

% patients

Chart25

51.212.70.613.921.7

32.814.70.921.630.2

30.8102.521.735

34.16.83.411.444.3

normotension

borderline isolated systolic hpt

isolated systolic hpt

diastolic hpt

systolic and diastolic hpt

DI-Classes

% patients

Type of Hypertension and OSA ActivityPatients referred to the Marburg Sleep Disorders Centre with no previous history of hypertension (n=591)

Chart26

51.24161.8

3548.813.42.3

30.850.815.82.5

34.134.1255.7

normotension

stage 1 hypertension

stage 2 hypertension

stage 3 hypertension

RDI-Classes

% patients

Stage of Hyperetnsion and OSA Activity Patients from the Marurg Sleep Disorders Clinic with no previous history of hypertension (n=591)

Chart28

12.70.613.921.7

14.70.921.630.2

102.521.735

6.83.411.444.3

borderline isolated systolic hpt

isolated systolic hpt

diastolic hpt

combined systolic and diastolic hpt

RDI-Classes

% patients

Chart29

4161.8

48.813.42.3

50.815.82.5

34.1255.7

grade 1 hypertension

grade 2 hypertension

grade 3 hypertension

RDI-Classes

% patients

Sheet1

Lavie P et al; BMJ 2000;320:479-482OSAS as a risk factor for hypertension (sleep-clinic population, n=2677)

OR FOR HYPERTENSION

Odds ratio

Wald 95% CI

3.5

3.0

2.5

2.0

1.5

1.0

5

10

15

20

30

40

50

60

70

APN-HYPOPNINDEX (per hour)

Samband mellan hypertoni och apn-hypopn index hos 2452 oselekterade patienter remitterade till ett smnlaboratorium under en 10-rs period. Odds ratio och Wald 95% KI fr hypertension associerad med AHI niver av 5,15,30,40,50,60,och 70predikterade genom bst anpassad multipel logistisk modell: T=e.012apn-hypopn index+.081lder+.161manligt kn+.067BMI . Omarbetad frn Lavie et al. BMJ 2000; 320:479-82.

Poor control of hypertension in OSAS

Grote et al., J. Hypertension, 2000

Chart3

130.1

132.9

137.3

146.2

Systolic Blood Pressure

Age

mmHg

Systolic Blood Pressure and age in patients referred to the Marburg Sleep Disorders Centre (n=591 patients, no antihypertensive medication)

Chart4

83.6

86.2

88

85.1

Diastolic Blood Pressure

Age

mmHg

Diastolic Blood Pressure and age in patients referred to the Marburg Sleep Disorders Centre (n=591, no antihypertensive medication)

Chart5

69.8

71.2

72.6

72.5

Heart Rate

Age

bpmin-1

Heart Rate and age in patients referred to the Marburg Sleep Disorders Centre (n=591, no antihypertensive medication)

Chart6

46.5

46.8

49.4

57.1

Pulse Pressure

age

mmHg

Pulse Pressure and age in patients referred to the Marburg Sleep Disorders Centre (n=591, no antihypertensive medication)

Chart7

13.9

19.5

20.7

22.1

RDI

age

events/hour of sleep

OSA activity (RDI) and age in patients referred to the Marburg Sleep Disorders Centre (n=591, no antihypertensive mediaction)

Chart8

130.183.669.8

132.986.271.2

137.38872.6

146.285.172.5

&A

Page &P

Systolic Blood Pressure

Diastolic Blood Pressure

Heart Rate

Age

mmHg/bpmin-1

Blood Pressure and Heart Rate in patients referred to the Marburg Sleep Disorders Centre (n=591, no antihypertensive medication)

Chart9

21.527.715.410.824.6

20.611.82517.625

25.417.516.717.522.8

14.719.619.621.724.5

1114.416.724.933

RDI-Classes

sys bp = 170

% patients

Control of systolic blood pressure in prediagnosed hypertensive patients in relation to OSA activity (n=599)

Chart10

15.423.19.227.724.6

10.313.210.329.436.8

14.921.99.627.226.3

718.913.329.431.5

7.714.81024.443.1

dia bp < 90

dia bp 90-94

dia bp 95-99

dia bp 100-104

dia bp >= 105

RDI-Classes

% patients

Control of diastolic blood pressure in prediagnosed hypertensive patients in relation to OSA activity (n=599)

Chart11

10.833.8

5.920.6

9.628.9

4.221

4.817.7

controlled hypertension < 140/90

controlled hypertension < 160/95

RDI Classes

% patients

Control of hypertension in relation to OSA activity (n=599)

Chart1

51.212.70.613.921.7

37.613.9216.829.7

32.814.70.921.630.2

30.8102.521.735

34.16.83.411.444.3

normotension

borderline isolated systolic hpt

isolated systolic hpt

diastolic hpt

systolic and diastolic hpt

RDI-Classes

% patients

Type of Hypertension and OSA Activity Patients referred to the Marburg Sleep Disorders Centrewith no previous history of hypertension (n=591)

Chart2

51.24161.8

37.643.616.82

32.853.410.32.6

30.850.815.82.5

34.134.1255.7

normotension

stage 1 hypertension

stage 2 hypertension

stage 3 hypertension

RDI Classes

% patients

Stage of Hypertension and OSA Activity Patients referred to the Marburg Sleep Disorders Centre with no previous history of hypertension (n=591)

Chart18

21.527.715.410.824.6

23.615.419.817.623.6

14.719.619.621.724.5

1114.416.724.933

sys bp = 170

RDI-Classes

% Patients

Chart23

15.423.19.227.724.6

13.218.79.92830.2

718.913.329.431.5

7.714.81024.443.1

dia bp < 90

dia bp 90-94

dia bp 95-99

dia bp 100-104

dia bp >= 105

RDI-Classes

% patients

Chart24

10.833.8

8.225.8

4.221

4.817.7

controlled hypertension < 140/90

controlled hypertension < 160/95

RDI-Classes

% patients

Chart25

51.212.70.613.921.7

32.814.70.921.630.2

30.8102.521.735

34.16.83.411.444.3

normotension

borderline isolated systolic hpt

isolated systolic hpt

diastolic hpt

systolic and diastolic hpt

DI-Classes

% patients

Type of Hypertension and OSA ActivityPatients referred to the Marburg Sleep Disorders Centre with no previous history of hypertension (n=591)

Chart26

51.24161.8

3548.813.42.3

30.850.815.82.5

34.134.1255.7

normotension

stage 1 hypertension

stage 2 hypertension

stage 3 hypertension

RDI-Classes

% patients

Stage of Hyperetnsion and OSA Activity Patients from the Marurg Sleep Disorders Clinic with no previous history of hypertension (n=591)

Chart28

12.70.613.921.7

14.70.921.630.2

102.521.735

6.83.411.444.3

borderline isolated systolic hpt

isolated systolic hpt

diastolic hpt

systolic and diastolic hpt

RDI Classes

% patients

Type of Hypertension and OSA Activity Newly diagnosed hypertensive Patients referred to the Marburg Sleep Disorders Centre (n=363)

Chart29

4161.8

48.813.42.3

50.815.82.5

34.1255.7

stage 1 hypertension

stage 2 hypertension

stage 3 hypertension

RDI-Classes

% patients

Stage of Hypertension and OSA Activity Newly diagnosed hypertensive patients referred to the Marburg Sleep Disorders Centre (n=363)

Sheet1

OSA & Hypertension

Sleep clinic population

Hypertensive population

General population

Prevalence of OSA in hypertension-clinicpopulations

OSA 30% in unselected patients with hypertensionKales et al, 1984; Fletcher et al, 1985

OSA 56% in non-responding HT, 19% in responding HT Isaksson & Svanborg, 1991

All non-dippers (n=10) but none in dippers had OSAPortaluppi F et al, J Hypertension 1997

OSA & Hypertension

Sleep clinic population

Hypertensive population

General population

OSA & Hypertension (cross-sectional data)Adjusted OR for HT1.37 (95% CI 1.03-1.83)(comparing AHI>30 vs AHI

CAUSAL RELATIONSHIP

Causal relation

OSA causes hypertension?

Hypertension causes OSA?

50-60 apneas / h of sleep

AJRCCM 2002All normotensive at baseline

FOURVARIABLES

6.56.756.8

4.16.727

3.3021.6

1.6016.2

Non OSA (n=122)

Efficiently treated OSA (n=15)

Incompletely treated OSA (n=37)

%

Blad1

OSA (ineffectively treated)OSA (effectively treated)Non OSA

Coronary Artery Disease804

Hypertension1015

Cardiovascular Disease2118

Non OSA (n=122)Efficiently treated OSA (n=15)Incompletely treated OSA (n=37)

Cardiovascular disease6.56.756.8

Hypertension4.16.727.0

Coronary artery disease3.3021.6

Cardiovascular event1.6016.2

Pepperell J et al, LANCET 2001; 359: 204-210Ambulatory BP after therapeutic and subtherapeutic CPAP for OSA: a randomised parallel trial

Normotensive & HypertensiveOSAS (n=118)More BP-reduction in hypertensivesMore BP-reduction in severe OSAS

Becker HF et al, Circulation 2003;107:68-73Effect of CPAP treatment on BP in patients with OSAS

Moderate to severe OSAS with HT (n=60)Randomized to therapeutic vs subtherapeutic CPAP; follow-up 9 w32 subjects completed (16 in each group)

AHI reduction 95% versus 50%BP reduction 10 mmHg versus no change (p=0.01)Reduction in both systolic & diastolic BP, both daytime & at night

The drop in mean BP by 10mmHg would be predicted to reduce CAD-event risk by 37% and stroke risk by 56%

OSA & Hypertension (cross-sectional data)Adjusted OR for HT1.37 (95% CI 1.03-1.83)(comparing AHI>30 vs AHI

Nieto FJ et al, JAMA 2000; 283:1829-36n.s.?Gender differences?

n=344 patients183 HT, 161 normotensivesMatched for age and gender

Ambulatory home PSG

Independent association between OSA and hypertension in men

Not identifiable in these essentially postmenopausal females

The contribution of OSA to hypertension risk may be sex-dependent and higher in males than in females

OSA & Hypertension (cross-sectional data)Gender differences in a population-based cohort

adapted from Hashimoto M et al, Circulation 1995; 92:3431-5S-Estradiol: M phase: 122 pmol/L; F phase: 632 pmol/L; L phase: 534 pmol/LEndothelial function during menstrual, follicular and luteal phase

GENDER AND HYPERTENSIONEndothelial dysfunction

Endothelial dysfunction starts in men a decade earlier than in womenCelermajer DS et al, J Am Coll Cardiol 1994; 24:71-6

Age related impairment of endothelium-dependent vasodilatation is only observed after menopauseTaddei S et al, Hypertension 1996; 28:576-82

Influence of menopause on blood pressureStaessen JA et al, J Hum Hypertens 1998; 12:587-92

Hormone Replacement Therapy and Longitudinal Changes in BP in Postmenopausal Women After 10 YearsScuteri A et al, Ann Intern Med 2001;135:229-38n=226Normotensive at baseline

Obesity causes hypertension?

OSA causes hypertension?

CONCLUSIONS (I)

Recurrent obstructive events during sleep, independently or in concert with other recognized risk factors, seem to have harmful effects on vascular structure and function

Development of hypertension in OSA is likely to depend on genotypic and phenotypic factors

Not only may OSA induce hypertension but also the events in themselves may worsen the response to antihypertensive medication

CONCLUSIONS (II)

OSA should be considered among factors regarding the primary and secondary prevention models of hypertension

OSA should be treated not only to eliminate daytime sleepiness. Treatment may also have a beneficial prognostic impact by reducing blood pressure levels in hypertensive patients.

However, more RCT are necessary to address this impact in non-sleepy OSA subjects with hypertension