A Hypertensive Response to Exercise Is Prominent in Patients With Obstructive Sleep Apnea and Hypertension: A Controlled Study

Abstract

Blood pressure (BP) behavior during exercise is not clear in hypertensive patients with obstructive sleep apnea (OSA). The authors studied 57 men with newly diagnosed essential hypertension and untreated OSA (apnea‐hypopnea index [AHI] ≥5) but without daytime sleepiness (Epworth Sleepiness Scale score ≤10), and an equal number of hypertensive controls without OSA matched for age, body mass index, and office systolic BP. All patients underwent ambulatory BP measurements, transthoracic echocardiography, and exercise treadmill testing according to the Bruce protocol. A hypertensive response to exercise (HRE) was defined as peak systolic BP ≥210 mm Hg. Patients with OSA and control patients had similar ambulatory and resting BP, ejection fraction, and left ventricular mass. Peak systolic BP was significantly higher in patients with OSA (197.6±25.6 mm Hg vs 187.8±23.6 mm Hg; P=.03), while peak diastolic BP and heart rate did not differ between groups. Furthermore, an HRE was more prevalent in patients with OSA (44% vs 19%; P=.009). Multiple logistic regression revealed that an HRE is independently predicted by both the logAHI and minimum oxygen saturation during sleep (odds ratio, 3.94; confidence interval, 1.69–9.18; P=.001 and odds ratio, 0.94; confidence interval, 0.89–0.99; P=.02, respectively). Exaggerated BP response is more prevalent in nonsleepy hypertensives with OSA compared with their nonapneic counterparts. This finding may have distinct diagnostic and prognostic implications.

Obstructive sleep apnea (OSA) is a composite entity that variably encompasses genetic susceptibility, lifestyle missteps, metabolic disorientation, and a cluster of neural, hormonal, chemical, and endothelial sequelae triggered by the bursts of hypoxias, müller maneuvers, and arousals.1 Accordingly, epidemiologic data have associated untreated OSA with an increased risk of hypertension as well as all‐cause and cardiovascular mortality.2 Although a direct causality between OSA and hypertension is still unclear,3 a usual clinical phenotype of the OSA patient is a middle‐aged man with a sedentary lifestyle, increased body weight, and high blood pressure (BP). However, OSA often escapes diagnosis because of its low medical suspicion or misconception by the patient of the relevant symptoms as normal.4

The exercise treadmill test, apart from being a simple screening tool for coronary artery disease, may provide additional information of diagnostic and prognostic significance. For example, a hypertensive response to exercise (HRE), although variably defined, may confer an increased risk for cardiovascular events or target organ damage.5 Even though numerous studies have examined the association of resting BP levels with OSA as well as the relevant effect of continuous positive airway pressure (CPAP),6 the BP response to exercise in hypertensives with OSA is unknown. Pathophysiologic mechanisms that have been associated with an HRE have been reported in the setting of OSA, including increased sympathetic activity, impaired endothelial function, higher angiotensin II levels, and increased arterial stiffness.7, 8, 9, 10 We hypothesized that nonsleepy hypertensive patients with OSA would exhibit higher peak exercise BP and more often an HRE. Therefore, we studied the behavior of BP and accompanying hemodynamic changes at peak exercise and recovery in this group of patients.

Methods

Study Population

We studied 57 men, aged 35 years and older, with newly diagnosed stage I or II hypertension and OSA confirmed by polysomnography, but without daytime sleepiness (Epworth Sleepiness Scale [ESS] score ≤10). An equal number of untreated hypertensive patients with a low clinical suspicion of OSA and subsequently a negative sleep test, who were matched for male sex, age, body mass index (BMI), and office systolic BP, served as a control group. Patients were excluded if they presented with a history of atherosclerotic cardiovascular disease, severe valvular heart disease, systolic dysfunction or heart failure, significant chronic renal or pulmonary disease, any other systemic illness, or orthopedic problems that would not allow maximal effort on the treadmill, or if they were undergoing treatment with cardiovascular or respiratory drugs. Other exclusion criteria were bundle branch block, preexcitation syndromes, pacing rhythm, atrial fibrillation, signs of left ventricular hypertrophy, or ischemic disease on a resting electrocardiogram. Finally, patients were not receiving treatment with CPAP or other form of ventilator support. The trial protocol complies with the Declaration of Helsinki, was approved by the local ethics committee of the hospital, and written informed consent was obtained from all participants.

Study Protocol and Measurements

Demographic and anthropometric data were collected from all patients. Office BP was recorded as the average of the second and third of 3 consecutive BP measurements with 2‐minute intervals. Hypertension was defined as average office BP >140/90 mm Hg in 3 separate visits.11 Ambulatory BP monitoring was also performed during a working day with a validated device (SpaceLabs 90207, SpaceLabs Healthcare, Redmond, WA) as previously described.12 Patients underwent standard transthoracic echocardiographic examination with a Vivid 3 PRO ultrasound imager (General Electric, Milwaukee, WI) according to current guidelines.13 Left ventricular ejection fraction was obtained by the Simpson method and left ventricular mass was calculated with the method of Devereux and colleagues and normalized for height^2.7 (left ventricular mass index [LVMI]).

Screening for OSA and Polysomnography

Patient screening for OSA was based on evaluation of associated symptoms including excessive snoring, choking, or gasping during sleep; observed apneas; and recurrent awakenings. Subjective daytime sleepiness was assessed with the ESS questionnaire, which has been validated in various languages.14 All participants underwent conventional overnight, technician‐attended, diagnostic polysomnography at the sleep laboratory, as described previously.10 The obstructive apnea/hypopnea index (AHI) was defined according to American Academy of Sleep Medicine Task Force clinical research criteria as the number of apnea plus hypopnea episodes per hour of sleep.15 OSA was diagnosed as an AHI of ≥5 episodes per hour of sleep, while 15 to 29 episodes per hour and >30 episodes per hour identified moderate and severe OSA, respectively. The lowest arterial oxygen saturation value during sleep was also recorded.

Exercise Test

All participants underwent maximal exercise testing in the morning hours, using the multistage Bruce protocol on a Quinton 5000 treadmill system (Quinton Instruments, Seattle, WA). Patients were verbally encouraged to exercise until exhaustion. The test was terminated on patients' request or volitional fatigue, at the achievement of the age‐predicted maximal heart rate (220 beats per minute minus age in years), when systolic BP increased >250 mm Hg or decreased by 10 mm Hg; at the presentation of chest pain, syncope, or near‐syncope; and as select ECG changes such as an ischemic ST‐segment response, complex ventricular arrhythmia, sustained atrial arrhythmia, or a second‐ or third‐degree atrioventricular block were experienced. After peak workload, patients spent at least 3 minutes in a cool‐down period during treadmill testing at a low workload. This period was considered the recovery period.

Resting heart rate and BP were recorded as the average of 3 measurements in the seated position after a 5‐minute rest. Subsequently, BP and heart rate were measured during the last minute of each 3‐minute stage, at peak effort, and every minute during the first 3 minutes of recovery with a mercury sphygmomanometer and with the arm relaxed at the side without holding on to the side bar of the treadmill according to current guidelines.16

Peak heart rate and systolic and diastolic BP were defined as the highest values recorded during the test. An HRE was defined as a peak exercise systolic BP ≥210 mm Hg, in line with the Framingham criteria.17 Exercise capacity was expressed as metabolic equivalents (METs), which were estimated based on maximal speed and grade of the treadmill according to standard tables. Chronotropic incompetence was defined as failure to achieve 85% of the age‐predicted maximal heart rate. Heart rate recovery was set as the difference between peak heart rate and after 1, 2, and 3 minutes of recovery.18 BP recovery was set as the ratio of BP at each minute of recovery over peak BP.19

Statistics

Continuous variables are expressed as the mean value and standard deviation and categorical variables as numbers and percentages. Due to its skewed distribution, the AHI is presented as median value (interquartile range). To compare continuous data between groups with and without OSA, the independent samples t test was used. Categoric data were compared using the chi‐square test. Simple Pearson correlations were performed to identify associations among variables of interest. The AHI was logarithmically transformed to enter the correlation analysis. Binary logistic regression analysis was used to identify independent predictors of an HRE. Statistical significance was set to a P value of <.05. All analyses were performed with the Statistical Package for Social Sciences version 15.0 (SPSS Statistical Software, Chicago, IL).

Results

Clinical, laboratory, and polysomnographic characteristics of the study groups are presented in Table 1. Patients were middle‐aged and obese and did not differ in their smoking habits. The two groups exhibited similar ambulatory BP levels as well as left ventricular ejection fraction and LVMI. Fifty‐one percent of the OSA group was diagnosed with severe disease.

Table 1.

Demographic, Clinical, and Laboratory Characteristics of Hypertensive Patients With and Without OSA

Parameter	Hypertensives With OSA (n=57)	Hypertensives Without OSA (n=57)	P Value
Age, y	51.6±8.7	51.7±8.4	.93
Body mass index, kg/m2	31.7±4.5	31.4±2.9	.60
Waist circumference, cm	109.0±14	108.1±10	.71
Neck circumference, cm	42.1±3.4	39.9±2.3	<.001
Current smokers, No. (%)	20 (35)	16 (28)	.54
24‐h SBP, mm Hg	136.8±11.8	134.9±12.7	.42
24‐h DBP, mm Hg	85.9±8.2	85.7±9.1	.88
24‐h PP, mm Hg	50.9±8.1	49.3±8.4	.29
24‐h heart rate, bpm	74.3±8.2	73.2±9.7	.50
ESS score, points	4.7±2.56	3.9±1.98	.08
AHI, events per h	30 (20–50)	2 (2–3)	<.001
LogAHI, events per h	1.50±0.23	0.39±0.11	<.001
Minimum oxygen saturation,%	80.4±10.7	92.6±1.7	<.001
Ejection fraction,%	63±4.9	63±4.6	.97
LVMIheight 2.7, g/m2.7	43±9.7	43±10.5	.99
RWT	0.45±0.05	0.43±0.07	.15

Abbreviations: AHI, apnea‐hypopnea index; bpm, beats per minute; DBP, diastolic blood pressure; ESS, Epworth Sleepiness Scale; LVMI, left ventricular mass index; OSA, obstructive sleep apnea; PP, pulse pressure; RWT, relative wall thickness; SBP, systolic blood pressure.

Exercise test data are presented in Table 2. While resting systolic and diastolic BPs were similar between the two groups, peak systolic BP was significantly higher in the OSA group (by 9.8 mm Hg, P=.03). An HRE was more often experienced among OSA patients (by 25%, P=.009). Exercise duration and capacity, as well as peak heart rate and frequency of chronotropic incompetence, did not differ between the two groups. During the recovery period, there was a similar evolution of both systolic and diastolic BP as well as heart rate between groups (Table 3, Figure 1 and Figure 2). By using the cutoff value of a 12‐beats‐per‐minute decrease in the first minute of recovery, 6 of 7 patients (86%) who presented an abnormal value for heart rate recovery belonged to the OSA group.18

Table 2.

Exercise Characteristics of Hypertensive Patients With and Without OSA

	Hypertensives With OSA (n=57)	Hypertensives Without OSA (n=57)	P Value
Total exercise time, min	8.9±1.5	9.1±1.9	.59
METs, mL/kg/min	10.6±1.8	10.9±2.1	.43
Resting systolic BP, mm Hg	146.1±13.4	145.4±17.2	.82
Resting diastolic BP, mm Hg	97.1±9.5	96.9±11.6	.92
Resting PP, mm Hg	48.9±11.7	48.5±11.1	.84
Resting heart rate, bpm	75.3±8.8	76.4±10.2	.55
Peak exercise systolic BP, mm Hg	197.6±25.6	187.8±23.6	.03
Peak exercise diastolic BP, mm Hg	92.3±10.9	90.3±10.4	.31
Peak exercise Pulse Pressure, mm Hg	105.3±21.6	97.5±20.1	.048
HRE, n (%)	25 (44%)	11 (19%)	.009
Peak exercise heart rate, bpm	158.9±16.2	159.3±13.7	.92
Percent predicted peak heart rate,%	93.5±10	94.6±7	.49
Chronotropic incompetence (n,%)	7 (12.3)	6 (10.5)	1.00

Abbreviations: BP, blood pressure; bpm, beats per minute; HRE, hypertensive response to exercise; METs, metabolic equivalents; OSA, obstructive sleep apnea; PP, pulse pressure.

Table 3.

Recovery Data of Hypertensive Patients With and Without OSA

	Hypertensives With OSA (n=57)	Hypertensives Without OSA (n=57)	P Value
SBP recovery – 1 min	0.94±0.04	0.93±0.06	.23
DBP recovery – 1 min	0.96±0.5	0.96±0.06	.63
HR recovery – 1 min, bpm	25±10	26±9	.52
SBP recovery – 2 min	0.88±0.06	0.88±0.08	.52
DBP recovery – 2 min	0.94±0.06	0.95±0.06	.27
HR recovery – 2 min, bpm	44±10	46±11	.37
SBP recovery – 3 min	0.80±0.06	0.81±0.08	.19
DBP recovery – 3 min	0.90±0.07	0.92±0.05	.09
HR recovery – 3 min, bpm	56±10	54±10	.28

Abbreviations: bpm, beats per minute; DBP, diastolic blood pressure; HR, heart rate; OSA, obstructive sleep apnea; SBP, systolic blood pressure. Blood pressure recovery is defined as recovery value divided by peak value. HR recovery is defined as peak value minus recovery value.

Figure 1.

Systolic blood pressure (SBP) and diastolic blood pressure (DBP) at exercise peak and recovery (mm Hg). OSA indicates obstructive sleep apnea.

Figure 2.

Heart rate (HR) response at exercise peak and recovery (beats per minute). OSA indicates obstructive sleep apnea.

In the entire population, peak diastolic BP was correlated with age (r=–0.42, P<.001), smoking (r=0.24, P=.009), resting diastolic BP (r=0.23, P=.015), 24‐hour diastolic BP (r=0.33, P<.001), and peak heart rate (r=0.21, P=.028), while there was a trend for an inverse association with minimum oxygen saturation (r=–0.17, P=.072). Peak systolic BP was significantly correlated with resting systolic BP (r=0.19, P=.047), 24‐hour systolic BP (r=0.22, P=.019), exercise duration (r=–0.29, P=.002), METs (r=–0.26, P=.005), logAHI (r=0.25, P<.007), and minimum oxygen saturation (r=–0.20, P=.032). The AHI and minimum oxygen saturation were also associated with the HRE (r=0.34, P<.001 and r=–0.26, P=.004). Binary logistic regression analysis revealed that every unit increase of logAHI and minimum oxygen saturation was associated with an odds ratio (OR) of 3.94 (confidence interval [CI], 1.69–9.18), P=.001) and 0.94 (CI, 0.89–0.99, P=.020) for an HRE, respectively, after controlling for BMI, smoking status, LVMI, resting systolic BP and heart rate, and METs (Table 4).

Table 4.

Independent Predictors of a Hypertensive Response to Exercise in the Entire Population

Parameters	B	P Value	OR (95% CI)
Model 1 LogAHI as a covariate
LogAHI, events per h	1.372	.001	3.943 (1.693–9.185)
Resting SBP, mm Hg	0.034	.035	1.035 (1.002–1.068)
METs, mL/kg/min	−0.303	.024	0.738 (0.568–0.960)
Model 2 Minimum oxygen saturation as a covariate
Minimum oxygen saturation,%	−0.061	.020	0.941 (0.893–0.990)
Resting SBP, mm Hg	0.032	.046	1.032 (1.001–1.065)
METs, mL/kg/min	−0.291	.022	0.747 (0.583–0.959)

Abbreviations: AHI, apnea‐hypopnea index; CI, confidence interval; METs, metabolic equivalents; OR, odds ratio; SBP, systolic blood pressure.

Discussion

This is the first study to our knowledge that investigates BP behavior and rates of a HRE in the setting of newly diagnosed hypertension and OSA. The main finding is that untreated hypertensive patients with OSA and no daytime sleepiness have higher peak exercise systolic BP and more often exhibit an HRE compared with their non‐OSA counterparts. Furthermore, two widely used indices of OSA severity, namely the AHI and minimum oxygen saturation, were significantly associated with both peak systolic BP and HRE.

Data reporting exercise BP in OSA are limited and should be contrasted with caution to our results because of diverse sample sizes, exercise protocols, and study populations with respect to sex, obesity, and hypertension history.20, 21, 22, 23, 24, 25 In the study by Kaleth and colleagues,21 exercise testing with a cycle ergometer revealed only a delay in the decline of systolic BP at early recovery in patients with OSA compared with controls. The study population differed from ours as patients were younger and normotensive and had less severe disease. In a group of morbidly obese, middle‐aged, partly hypertensive and predominantly female patients, Vanhecke and associates22 reported a similar rise in systolic BP as well as higher peak levels and a faster recovery of diastolic BP in OSA patients compared with controls. A study by Rizzi and coworkers23 on lean, mostly normotensive patients, did not report differences in peak BP between OSA patients and controls. In an uncontrolled study by Maeder and colleagues24 of OSA patients without any negative inotropic treatment, systolic BP rose from 139 mm Hg to 199 mm Hg at peak exercise, while diastolic BP remained unchanged, values resembling our results. Our results also agree with the study by Przybylowski and coworkers25 on newly diagnosed OSA patients of a similar age and BMI to ours. Thirty percent were hypertensive, in whom peak BP was 198/89 mm Hg, while 35% of the patients presented with an HRE.

OSA marks a series of alterations in the vascular control matrix that support our finding. The sympathetic nervous system seems to be pivotal in the regulation of BP during exercise through its effect on systemic vasoconstriction and peripheral resistance.26 The repetitive obstructive episodes in OSA are accompanied by surges in sympathetic activity, which eventually remains elevated beyond sleep time and is accompanied by impaired baroreflex, chemoreflex, and vasomotor function.7 Higher levels of angiotensin II, potentially implicated in the mechanism of an HRE, have been reported in OSA.8 Impaired endothelial function marking blunted vasodilation has also been a consistent finding.9, 27 Finally, decreased aortic distensibility may further contribute to an enhanced BP response during exercise,28 and we have previously shown that arterial stiffness is higher in hypertensives with OSA compared with hypertensive controls.10

In our study, the only exercise parameter clearly affected in patients with OSA was peak systolic BP. With respect to exercise heart rate, reduced chronotropic competence has been reported in some21, 22 but not all studies,20, 29 and the suggested mechanism is downregulation of beta receptors due to sympathetic activation. A delayed heart rate recovery has been documented in a controlled study, however, which included only young otherwise healthy adults.29 Accordingly, the AHI has been associated with heart rate recovery in younger but not older adults.30 Compared with studies of middle‐aged OSA patients, the percentage of predicted peak heart rate in our population was similar.23, 24, 25 Nevertheless, most patients who had a heart rate recovery below the proposed 12 beats per minute for an abnormal value belonged to the OSA group.18 Heart rate recovery is driven primarily by parasympathetic reactivation early on and its balance with sympathetic outflow later in the post‐exercise course, two factors that may be altered by OSA. On the other hand, the BP increase during exercise is under the influence of diverse mechanisms that may variably but more evidently be affected early with the development of OSA and further enhanced on the grounds of hypertension. There is evidence that the coexistence of the two conditions may exhibit an additive effect on arterial stiffness, heart structure, and carotid atherosclerosis independent of BP values.31, 32 Because these were patients newly diagnosed with OSA, it is possible that long‐running and untreated disease may present with a more adverse effect on heart rate during and after exercise.

In our population, there was a significant association of the AHI and minimum oxygen saturation with levels of peak systolic BP, as well as with an HRE. A number of studies have identified associations of OSA severity with measures of intermediate pathways linking OSA to cardiovascular sequelae including inflammatory markers, antioxidant levels, left ventricular dysfunction, and albumin excretion.1, 12 Our study suggests that frequency of apneas and apnea‐induced oxygen dipping sufficiently reflect the net effect of OSA‐related pathophysiology leading to an augmented rise in exercise BP. Furthermore, as this association is independent of BMI, our finding is in concordance with studies reporting that OSA rather than obesity is the main determinant of increased sympathetic nerve activity documented with microneurography,33 as well as endothelial dysfunction,34 in obese individuals. Most importantly, the similar levels of both office and 24‐hour BP between groups further supports an effect of OSA on peak exercise BP that stretches beyond the hemodynamic load.

Placing our results into the clinical setting, it may be proposed that, when available, an HRE in newly diagnosed hypertensives could qualify as an additional sign for a more thorough evaluation for OSA, even in the absence of relevant daytime symptoms. Although an HRE has been associated with increased left ventricular mass and diastolic dysfunction in hypertensive patients,17 ejection fraction and left ventricular mass did not differ between groups in our population, possibly because of the similar BP levels and the early stages of both diseases. Similarly, left ventricular geometry as expressed by relative wall thickness did not significantly differ between the two groups. Nevertheless, an HRE could mark ongoing OSA‐triggered subclinical left ventricular adaptations that may thus signify the need for more prompt treatment with CPAP.35 The latter has failed to present with remarkable results with respect to BP lowering even in hypertensive populations,6 but sufficient data regarding its effect on exercise BP are lacking.

Study Limitations

Group matching for age, BMI, and BP and the fact that patients were all newly diagnosed hypertensives free of any treatment that could distort their response during exercise, are important advantages of our study, but certain limitations should be addressed. Exercise BP was measured with a mercury sphygmomanometer, and the accuracy of measurements may be affected by background noise and motion. We did not evaluate possible pathophysiologic mechanisms such as arterial stiffness that may have helped explain our findings. We also did not assess habitual physical activity of the patients, since it may affect exercise test measures; however, this is hard to quantify securely as it is also related to other parameters including social status, occupation, and education level.

Conclusions

In the present study, we identified higher peak systolic BP and increased prevalence of an HRE in patients with newly diagnosed hypertension and OSA without daytime sleepiness who were treatment naive for both conditions. An association with disease severity was documented as well, while other exercise characteristics did not seem to be affected by OSA. These observations may reflect specific attributes of OSA in the setting of hypertension compared with OSA populations who are otherwise healthy. Such a finding may be helpful in patient screening for OSA, while it may reflect early vascular and cardiac adaptations to the disease in hypertensive patients.

J Clin Hypertens (Greenwich). 2013;15:497–502. ©2013 Wiley Periodicals, Inc.23815538