Hypertension and sleep apnea in black South Africans a case control study

AJH 1995; 8:1200-1205

Hypertension and Sleep Apnea in Black South Africans A Case Control Study Peter R. Bartel, Magriet Loock, Cornelis van der Meyden, Elna Robinson, and Pieter Becker

Despite relatively consistent findings that patients with hypertension have higher than anticipated prevalences of sleep apnu/hypopnea (SAH), inadequately controlled factors such as age and obesity have been implicated as possibly accounting for these f i n d i n p . All-nisht polysomno~rams were performed on 20 hypertensive black South Africans, a Stoup with increased risk for this disease. They were matched with a control group of black subjects in respect of age, 8~nder, body mass index (BMI), neck circumference and scores on a sleep questionnaire. While the groups failed to differ sisnificantly in terms of demo~aphic variables, nor in regard to 8/9 a n t h r o ~ c measures, the hypertensive group had a sitp~ficantly hisher apnea/hypopnea index (AHI) (P = .01), lonser duration of AH (P = .01) and lower mean minimum arterial oxygen saturation levels (P = .OOS). Of the anthropometric measures, only age and neck cir-

cumference were found to be cofactors for AHI and were accounted for in the analysis. Five of the hypertensive patients and two of t h e controls had an AHI >10, giving a prevalence odds ratio of 3 (95% confidence interval: 0.66-14.50). The present study appears to be the first in black African subjects and with prevalence findings largely comparable to those obtained in other ethnic groups. There was a trend for more severe SAH to occur in this subgroup of five hypertensives (AHI = 14--30) than in controls (maximum AHI = 12). While data are lacking to link antihypertensive medication to SAH in humans, further study is necessary before discarding this factor. Am J Hypertens 1995;8:12001205

here is considerable agreement that a relatively high percentage of patients with obstructive sleep apnea (OSA) have systemic arterial hypertension1 and that patients with hypertension have a higher prevalence of sleep apnea/hypopnea (SAH) than would be predicted in the normal population. 2 The proposal that there might be

a causal link between these two diseases has resulted in controversy.3 Regarded as supportive of a causal link are a number of polysomnographic studies reportin~ a n elevated prevalence of SAH in hypertension. ~-° These findings have been strengthened by recent reports that the effective treatment of OSA by tracheostomy9 or by continuous positive airway pressure (CPAP) therapy9-11 reduces daytime blood pressure. A causal link between hypertension and SAH is disputed on the basis of a minority of polysomnographic studies which failed to find increased SAH in hypertensive patients as compared to control groups 12 and particularly by relatively extensive studies which failed to find more nocturnal oxygen desat-

T

Received February 2, 1995. Accepted June 12, 1995. From the Department of Neurology,University of Pretoria and I-IF Verwoerd Hospital, Pretoria (PRB, CvdM, ER); Department of Internal Medicine, University of Pretoria and Kalafong Hospital, Pretoria (ML); Centre for Epidemiological Research in Southern Africa, Medical Research Council, Pretoria (PB); South Africa. Address correspondence and reprint requests to Dr P. Bartel, Department of Neurology, Private Bag X169, 0001 Pretoria, South

Africa. © 1995 by the American Journal of Hypertension, Ltd.

K~¥ WORDS: Sleep apnea, hypertension, anthropometry, demography.

0895-7061/95/$9.50 0895-7061 (95)00387-8

HYPERTENSIONAND SLEEP APNEA 1201

AJH-DECEMBER 1995-VOL. 8, NO. 12, PART 1

aminase and alanine transaminase not more than 50% of the normal values, gamma glutamyl transferase (GGT) not more than twice the normal values and serum creatine not exceeding 180 mmol/L. The first phase of the study included an interview incorporating a questionnaire with items regarding subjective sleep characteristics possibly associated with SAH. Items included excessive daytime sleepiness, loud nocturnal snoring, multiple awakenings from sleep, feeling tired and unrefreshed upon awakening or during the course of the day, excessive motility during sleep and frequent morning headaches. The maximum possible score was 7. In addition, relevant demographic details were recorded and the fols e x . 17 lowing measurements of body habitus were made: This study involved a group of patients (black weight, height, body mass index (BMI), neck circumSouth Africans) with an anticipated higher preva- ference, percentage predicted neck circumference lence of hypertension 2° and which is also possibly (PPNC), ~ waist circumference, hip circumference, more severe 21 than in white South Africans. The hy- waist-hip ratio (WHR) and subscapular skinfold. In the second phase, 20 of the initial 61 subjects pertensives were matched to a group of black controls in terms of age, gender and a number of measures of were selected for all-night polysomnography on the basis of either positive responses in respect of hyperadiposity. somnolence and snoring, or alternatively, a total questionnaire score of three or more. There were four METHODS m e n and 16 women with a mean age of 50.5 years Subjects Following approval by an ethics commit(range 34 to 63 years). All subjects were receiving tee of the University of Pretoria, 61 hypertensive paa n t i h y p e r t e n s i v e medication u p o n e n t e r i n g the tients gave informed consent to participate in this study. Medication was distributed as follows: low study. There were 26 m e n and 35 w o m e n with a doses (6.25 mg/day) of hydrochlorothiazide (HCTZ) mean age of 51 years (range was 34 to 70 years). (n = 5); doxazosin 2 mg/day (n = 3); low doses (5 Hypertension was defined by WHO criteria as sitrag/day) of the calcium-channel blocker amlodipine ting systolic blood pressure between 141 and 180 m m (n = 4); low doses of HCTZ plus doxazosin (n = 5); Hg (phase I, Riva-Rocci) and diastolic blood t,~ressure HCTZ plus a-methyldopa and hydralazine (n = 2); between 95 and 115 m m Hg (Korotkoff V).~ Blood HCTZ and angiotensin converting enzyme (ACE) inpressure was measured using a standard mercury hibitors (n = 1). sphygmomanometer as well as a Trinity (model 601; A large group of mainly hospital workers were iniRandburg, South Africa) automatic sphygmomanometially seen before identifying 61 normotensive subter. All measuremnts were recorded by the same objects matched to the hypertensive group for age, genserver (ML) and represent the average of three meader, BMI, and neck circumference. These subjects surements (Table 1). Further inclusion criteria were: no were apparently healthy, were normotensive, and clinical evidence of secondary hypertension, no recent had not received previous treatment for major medmyocardial infarction or stroke, no evidence of neuroical disorders. The 20 matched controls who underactive disease, no signs of hepatic or renal failure, the w e n t p o l y s o m n o g r a p h i c r e c o r d i n g s w e r e also absence of malignant or accelerated hypertension (retmatched for scores on the sleep questionnaire. inopathy grade III or IV), no serious concordant disease, no treatment with other investigational drugs, P o l y w m m o s r a p h y The polysomnographic recordcompliance >95%, complete urinalysis, aspartate trans- ings included four channels of EEG: a central to con-

urafions in patients with hypertension compared to normal subjects. 3"13 Furthermore the prevalence of hypertension in snorers with SAH appears to be no different to snorers without SAH.14 A possible explanation for these discordant findings is that the same confounders predisposing a patient to become hypertensive also predisposes the patient to experience OSA. 2"15'16 Some of the polysomnographic studies have been criticized for failing to take these factors into account. 2 More recently a community-based study 17 and cross-sectional studies of patients referred to sleep laboratories 18"19reported an association between hypertension and SAH independent of obesity and age 17-19 and also independent of

TABLE 1. BLOOD PRESSURE MEASUREMENTS FOR THE HYPERTENSIVE AND THE CONTROL GROUP Systolic (nun I-I8)

Hypertensives: basal Hypertensives: on therapy Controls: basal

Diastolic (ram Hg)

Mean (SD)

Range

Mean (SD)

Ranse

159.6 (9.2) 143.6 (9.1) 133.9 (9.4)

146-177 129-160 114-155

106.7 (4.7) 94.4 (5.0) 87.4 (3.6)

99--115 88--108 79--93

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A J H - D E C E M B E R 1995--VOL. 8, N O . 12, P A R T 1

tralateral mastoid derivation, 24 two transverse central channels centering on Cz for vertex events and a parieto-occipital channel for the optimal recording of the a-rhythm. Eye movements and the submental electromyogram (EMG) were recorded in the standard manner. 24 The EKG was recorded from an electrode on the wrist referred to the left mastoid. Anterior tibialis EMGs were recorded separately from the right and left legs. Nasal-oral airflow was detected by thermocouple thermistors (Pro-Tech Servkms Inc., WoodinviUe, WA). Respiratory movements of the rib cage and abdomen were recorded by two Crystal Trace piezo respiratory effort sensors (Pro-Tech Services Inc.) or by N i h o n - K o h d e n TR-651T strain gauges (Nihon-Kohden Corporation, Tokyo). Oxyhemoglobin saturation was recorded by a Nil~nKohden pulse oximeter (Model OLV-1100K) using a finger probe. A Nihon-Kohden polygraph (model 4421) was used for all recordings. Sleep stages were determined in the standard manner. 24 Sleep almea was defined as a lO-sec or longer period during which airflow declined by 90% or more relative to baseline values. Sleep hypopnea involved a 10-sec or longer period during which airflow declined by 50% to 90% and was associated with either a 4% or greater SaO2 desaturation cr an arousal from sleep. The classification of the type of SAH used the following criteria: 1) obstructive SAH was characterized by absent airflow past nasa] and buccal thermistors despite persistent respiratory ~fort recorded by thoracic and abdominal strain gauges; 2) central SAH showed a cessation of airflow accomFmnied by cessation of respiratory movements; and 3) mixed SAH consisted of the cessation of airflow and of respiratory effort early in the episode, followed by the resumption of unsuccesshtl respiratory effort in the latter part of the episode. 25A All respiratory events were checked by two p o l y s o m n ~ . An AHI >10 was regarded as indicative of SAH. Statistical Analyses With respect to the categorical parameters, intergroup comparisons were made with the ×2 test, while for continuous parameters Student's unpaired t test was used. All the latter results were also confirmed with the Mann-Whitney test. As some of the anthropometric measm~s were considered to be potential cofactors for AHL this was tested for and then AHI was assessed in an analysis of covariance. All statistical testing was done at the .05 level of significance. RESULTS

Demographic and anthropometric results are shown in Table 2. Only the waist-hip ratio revealed a significantly higher value for the hypertensive group. However, the magnitude of the difference of 0.04 be-

TABLE 2. D E M O G ~ C , ANTHROPOMETRIC A N D SLEEP QUF.STIONNAIRE FINDINGS FOR THE HYPEI~TENSIVE A N D NORMOTENSIVE CONTROL GROUPS Hypem.nsives

Controls

(SD}

Mean (SD)

P

50.6 (8.0) 29.5 (6.0)

49.6 (8.7) 28.6 (5.4)

NS* NS

27.0 (14.2) 25.7 (13.8)

23.2 (9.8) 28.2 (14.1)

NS NS

34.4 (5.8)

32.5 (4.9)

NS

35.8 (3.2)

34.8 (3.0)

NS

89.5 (7.8)

86.9 (7.0)

NS

95.2 (11.9)

90.5 (13.0)

NS

107.8 (12.6)

108.2 (12.0)

NS

0.88 (0.07) 4.25 (1.4)

0.84 (0.07) 4.10 (1.5)

0.01 NS

Mean

Age Ors) Body mass index (kg/m2) Triceps skinfoid (ram) Subscapularskinfold

(mm) Arm circumference

(cm) Neck drcumference

(cm) % predicted neck drcumference Waist circumference

(cm) Hip circumference

(an) Waist--hip ratio Sleep questionnaire score *NS = not significantly different.

tween the group means was slight, in fact <1 standard deviation (Table 2). There were no further significant intergroup differences. Group findings regarding sleep questionnaire scores are shown in Table 2. There were no significant intergroup differences. Polysomnographic results are summarized in Table 3. For a number of important variables the group differences were statistically significant and indicative of impaired sleep in the hypertensive group. In the case

TABLE 3. POLYSOMNOGRAPHIC RESULTS FOR THE HYI~RTENSIVE A N D NORMOTENSIVE GROUPS Hypertensives (SD)

Mean (SD)

P**

321.5 (54.7)

348.4 (53.6)

NS*

77.4 (13.4) 12.9 (11.0) 8.1 (9.0)

83.0 (12.3) 10.2 (4.9) 2.7 (3.4)

his NS .01

17.1 (5.8)

12.9 (4.8)

.01

5.9 (2.3)

4.7 (1.9)

NS

80.8 (8.7)

87.2 (3.5)

.005

Man

Total sleep time

Controls

(mm) Sleep efficiency (%) Arousal index Apneathypopnea (AH) index Mean duration of AH

(s,c) Mean desaturation during AH (%) Mean minimum SaO2

(%)

*NS = not sign~icantly different **P values asaocmted with Student's t-test except in the case of AHI where an ANCOVA was emldoyed after arcreaing for age and neck circumference.

HYPERTENSION AND SLEEP APNEA 1203

AJH-DECEMBER 1995-VOL. 8, NO. 12, PART 1

of AHI, age and neck circumference were found to be significant cofactors. After correcting for these factors in an analysis of covariance, the groups were still significantly different with respect to their mean AHI values. However, the proportion of subjects with and without SAH based on an AHI criterion of > 10 was not significantly different between the two groups (Fisher's Exact Test, two-tail; P = .41). The distribution of subjects over AHI intervals is shown in Table 4. Periodic leg movements occurred in two subjects with movement arousal indices of 19 and 26 per hour of sleep, one subject from each group. Sleep was substantiaUy disrupted by these movements but neither of these subjects had SAH. DISCUSSION

The main finding of this study was that even when potentially confounding factors such as age, gender and, of particular importance, obesity were taken into account, there were significant intergroup differences indicative of more marked disordered breathing in the hypertensive group. This was reflected by a higher mean AHI, a longer mean duration of SAH and lower mean minimum oxygen saturation levels. These findings are thus contrary to the suggestions that SAH in hypertensive patients may largely be explained by the confounding factors already mentioned. 3'13 Furthermore, our inclusion criteria regarding G G T would have precluded subjects with significant alcohol abuse. In our study, two factors, increasing age and greater neck circumference, were significantly associated with SAH. As regards age, Lavie et al4 also reported a preponderance of SAH among older hypertensive patients. Neck circumference was the only measure of body habitus to reveal a significant interaction with AHI. The importance of this factor has been emphasized previously. 26 Increased waist-hip ratios (WHR) are regarded as indicative of upper body obesity and have been re-

TABLE 4. THE DISTRIBUTION OF SUBJECTS (AND PERCENTAGE OF GROUP) IN THE HYPERTENSIVE AND CONTROL GROUPS ACROSS POUR INTERVALS OF THE APNEA/HYPOPNEA INDEX (AHI) AHI

0-4.9 5-9.9 10-19.9 >20

Hypertensives

Controls

10 (50%) 5 (25%) 2 (10%) 3 (15%)

15 (75%) 3 (15%) 2 (10%) 0 (0%)

lated to an increased incidence of SAH TM and may be a risk factor for the development of hypertension. 27 Although the mean WHR was significantly higher in the hypertensive group compared to the control group in the present study, the m e a n difference was <5% and is probably unlikely to be of clinical relevance. An unresolved issue is the relationship between the degree of hypertension and the severity of SAH. Although a significant association has b e e n reported, "° a later study failed to confirm this. 19 Despite largely negative preliminary findings, 8 the possible role of antihypertensive medication in causing or exacerbating SAH has clearly not been resolved. 3 It has been suggested that a sedating antihypertensive medication (ot-methyldopa) may decrease activity in upper airway muscles 29 and may worsen SAH, but is probably not a major factor. 2 Some recent studies have demonstrated significant improvements in SAH following administration of an ACE inhibitor 3°'31 or metoprolol. 3° In contrast, metoprolol has also been reported to exacerbate sleep disordered breathing. 32 The possibility that some antihypertensive medications may exacerbate SAH, and particularly central SAH, requires further study. The hypertensive patients with SAH in the present study used various types of medication, without a distinct tendency for any particular medication regime to predominate. These findings are compatible with previous studies. 6-a The prevalence of SAH in the hypertensive group was 25% versus 10% in the control group, the latter not surprising w h e n considering recent data. 3a The prevalence odds ratio for the hypertensive group was 3, which falls within the range of previous studies 2 despite important methodological and perhaps patient differences. The present study appears to be the first in black African subjects with results largely comparable to those obtained in other ethnic groups. In several respects our study design closely approximates that of Lavie et al4 in Israel who detected SAH in 69% of hypertensive subjects (12/16 of their subjects were men), using the same AHI criterion, but apparently not evaluating hypopneas. Our substantiaUy lower value of 25% is potentially biased in at least two ways. Firstly, our subjects consisted largely of w o m e n (16/20) who have lower prevalences of SAH than men. 33 However, a recent study has revealed a much higher prevalence of SAH in w o m e n than previously suspected 33 and, furthermore, it has been suggested that SAH is relatively common in postmenopausal w o m e n and is strongly related to hypertension. 34 On the other hand, our prevalence value could be an over-estimation because all subjects had scores suggestive of sleep disturbances. However, as in the case of previous reports, 6'7 we found

1204 BARRELET AL

no association between sleep questionnaire scores and AHI. We concur with the recommendation of Hoffstein et al2 that the routine clinical evaluation of hypertensive patients should include questions regarding snoring, hypersomnolence and morning tiredness. In cases of suspected SAH, polysomnography should be considered, especially in older patients. However, it seems likely that the avadlability of valid, but simpler and less expensive screening devices for SAH will be necessary before this potentially important assessment becomes more accessible to hypertensive patients in our situation, due to the very small and scarce sleep laboratory fa"cllities.

AJH-DECEMBER 1995-VOL. 8, NO. 12, PART 1

12.

13.

14.

15.

16.

ACKNOWLEDGMENT The authors thank Dr R. du Pont for assisting with subject recruitment and Dr P. Rheeder for assisting with subject interviews. Anthropological measurements were conducted by the Department of Dietetics, Ka~fong Hospital and the University of Pret(a-ia. P ~ recordings and partial analyses were conducted by R. Hawthipersadh, A. Barnard, G. Heystek, J. Verster, I. Nepaul, and P. Vermaak.

17.

18.

19.

REFERENCES 1. Guilleminault C, Tilkian A, Dement WC: The sleep apnea syndromes. Annu Rev Med 1976;27:465-484. 2. Hoffstein V, Chan CK, Slutsky AS: Sleep apnea and systemic hypertension: a causal association review. Am J Med 1991;91:190-196. 3. Wafley ARH, Mitchell JH, Stxadling JR: Prevalence of nocturnal hypoxaemia amongst men with mild to moderate hypertension. Q J Med 1988;68:637-644. 4. Lavie P, Ben-Yosef R, Rubin AE: Prevalence of sleep apnea syndrome among patients with essential hypertension. Am Heart J 1984;108:373-376. 5. Kales A, Bixler EO, Cadieux RJ, et al: Sleep apnea in a hypertensive population. Lanoet 1984;ii:1005-1008. 6. Williams AJ, Houston D, Finberg S, et al: Sleep apnea syndrome and essential hypertension. Am J Cardiol 1985;55:1019-1022. 7. Fletcher EC, DeBehnke RD, Lovoi MS, et al: Undiagnosed sleep apnea in patients with essential hypertension. Ann Intern IVied 1985;103:190-195. 8. Hirshkowitz M, Karacan I, Gurakar A, et al: Hypertension, erectile dysfunction, and occult sleep apnea. Sleep 1989;12:223-232. 9. Guilleminault C, Suzuki M: Sleep-related hemodynamics and hypertension with partial or complete upper airway obstruction during sleep. Sleep 1992;15: $20-24. 10. Wilcox I, Grunstein RR, Hedner JA, et al: Effect of nasal continuous positive airway pressure during sleep on 24-hour blood pressure in obstructive sleep apnea. Sleep 1993;16:539-544. 11. Suzuki M, Otsuka K, Guilleminault C: Long-term nasal continuous positive airway pressure administra-

20.

21. 22.

23.

24.

25.

26.

27.

28.

29.

tion can normalize hypertension in obstructive sleep apnea patients. Sleep 1993;16:545-549. McGinty D, Beahm E, Stern N, et al: Nocturnal hypotension in older men with sleep-related breathing disorders. Chest 1988;94:305-311. Stradling JR, Crosby JH: Relation between systemic hypertension and sleep hypoxaemia or snoring: analysis in 748 men drawn from general practice. Br Med J 1990;300:75-78. Rauscher H, Popp W, Zwick H: Systemic hypertension in snorers with and without sleep apnea. Chest 1992;102:367-371. Hoffstein V, Mateika S, Rubinstein I, et al: Determinants of blood pressure in snorers. Lancet 1988;2:992994. Millman RP, Redline S, Carlisle CC, et al: Daytime hypertension in obstructive sleep apnea. Prevalence and contributing risk factors. Chest 1991;99:861-866. Hla KM, Young TB, Bidwell T, et al: Sleep apnea and hypertension. A population-based study. Ann Intern Med 1994;120:382-388. Grunstein R, Wilcox I, Yang T-S, et al: Snoring and sleep apnea in men: association with central obesity and hypertension. Int J Obes 1993;17:533-540. Carlson JT, Hedner JA, Ejnell H, et al: High prevalence of hypertension in sleep apnea patients independent of obesity. Am J Respir Crit Care Med 1994; 150:72-77. Seftel HC, Johnson S, Muller EA: Distribution and biosocial correlations of blood pressure levels in Johannesburg blacks. S Afr Med J 1980;57:313-320. Seftel HC: Diseases in urban and rural black populations. S Afr Med J 1977;51:121-123. Rose GA, Blackburn H, Gillum RF, et al: Cardiovascular Survey Methods, Geneva, World Health Organization, 1982. Davies RJO, Stradling JR: The relationship between neck circumference, radiographic pharyngeal anatomy, and the obstructive sleep apnea syndrome. Eur Respir J 1990;3:509-514. Rechtschaffen A, Kales A (eds): A Manual of Standardized Terminology, Techniques and Scoring System for Sleep Stages of Human Subjects. Los Angeles, Brain Information Service, University of California, 1968. Radtke RA: Sleep disorders, in Daly DD, Pedley TA (eds): Current Practice of Clinical Electroencephalography, 2nd ed. Raven Press, New York, 1990, p 576. Katz I, Stradling J, Slutsky AS, et al: Do patients with obstructive sleep apnea have thick necks? Am Rev Respir Dis 1990;141:1228--1231. Levinson PD, McGarvey ST, Carlisle CC, et al: Adiposity and cardiovascular risk factors in men with obstructive sleep apnea. Chest 1993;103:1336-1342. Kiselak J, Clark M, Pera V, et al: The association between hypertension and sleep apnea in obese patients. Chest 1993;104:775-780. Lahive KC, Weiss JW, Weinberger SE: (x-Methyldopa selectively reduces alae nasi activity. Clin Sci 1988;74: 547-551.

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30. Weichler U, Herres-Mayer B, Mayer J, et al: Influence of antihypertensive drug therapy on sleep pattern and sleep apnea activity. Cardiology 1991;78:124130. 31. Mayer J, Peter JH" First experience with Cilazapril in the treatment of sleep apnea-related hypertension. Drugs 1991;41(suppl 1):37-47. 32. Kantola I, Rauhala E, Erkinjuntti M, et al: Sleep disturbances in hypertension: a double-blind study be-

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tween isradipine and metoprolol. J Cardiovasc pharmacol 1991;18(Suppl 3):$41-$45. 33. Young T, Palta M, Dempsey J, et al: The occurrence of sleep-disordered breathing among middle-aged adults. N Engl J Med 1993;328:1230-1235. 34. Gislason T, Benediktsd6ttir B, BjOrnsson JK, et al: Snoring, hypertension, and the sleep apnea syndrome. An epidemiologic survey of middle-aged women. Chest 1993;103:1147-1151.