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
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%
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