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doi:10.1378/chest.06-1442
(Chest. 2007; 131:453-459)
© 2007 American College of Chest Physicians
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Plasma Aldosterone Is Related to Severity of Obstructive Sleep Apnea in Subjects With Resistant Hypertension*

Monique N. Pratt-Ubunama, MD; Mari K. Nishizaka, MD; Robyn L. Boedefeld, MD; Stacey S. Cofield, PhD; Susan M. Harding, MD, FCCP and David A. Calhoun, MD

* From the Vascular Biology and Hypertension Program, Division of Cardiovascular Disease (Drs. Pratt-Ubunama, Nishizaka, and Calhoun), Division of Pulmonary, Allergy and Critical Care Medicine and Sleep/Wake Disorders Center (Drs. Boedefeld and Harding), and Department of Biostatistics (Dr. Cofield), University of Alabama at Birmingham, Birmingham, AL.

Correspondence to: David A. Calhoun, MD, 933 Nineteenth St S, Room 115, Birmingham, AL 35294; email: dcalhoun{at}uab.edu

Abstract

Objective: Obstructive sleep apnea (OSA) and primary aldosteronism are common in subjects with resistant hypertension; it is unknown, however, if the two disorders are causally related. This study relates plasma aldosterone and renin levels to OSA severity in subjects with resistant hypertension, and in those with equally severe OSA but without resistant hypertension serving as control subjects.

Methods: Seventy-one consecutive subjects referred to the University of Alabama at Birmingham (UAB) for resistant hypertension (BP uncontrolled on three medications) and 29 control subjects referred to UAB Sleep Disorders Center for suspected OSA were prospectively evaluated by an early morning plasma aldosterone concentration (PAC) and renin level, and by overnight, attended polysomnography.

Results: OSA (apnea-hypopnea index [AHI] ≥ 5/h) was present in 85% of subjects with resistant hypertension. In these subjects, PAC correlated with AHI ({rho} = 0.44, p = 0.0002) but not renin concentration. Median PAC was significantly lower in control subjects compared to subjects with resistant hypertension (5.5 ng/dL vs 11.0 ng/dL, p < 0.05) and not related to AHI. In male subjects compared to female subjects with resistant hypertension, OSA was more common (90% vs 77%) and more severe (median AHI, 20.8/h vs 10.8/h; p = 0.01), and median PAC was significantly higher (12.0 ng/dL vs 8.8 ng/dL, p = 0.006).

Conclusion: OSA is extremely common in subjects with resistant hypertension. A significant correlation between PAC and OSA severity is observed in subjects with resistant hypertension but not in control subjects. While cause and effect cannot be inferred, the data suggest that aldosterone excess may contribute to OSA severity.

Key Words: aldosterone • obstructive sleep apnea • resistant hypertension

Untreated obstructive sleep apnea (OSA) is associated with an increased risk of hypertension and, in normotensive subjects, predicts the future development of hypertension.12 OSA risk is particularly high in subjects with resistant hypertension. In 42 subjects with resistant hypertension referred to a university center, Logan et al3 found that 83% of subjects had unsuspected OSA (apnea-hypopnea index [AHI] ≥ 10/h).

Primary aldosteronism (PA) is common in subjects with resistant hypertension. In our laboratory, PA was diagnosed in 18 of 88 consecutive subjects (20%) referred for resistant hypertension.4 In studies56 conducted in Seattle, WA, and Oslo, Norway, the prevalence of PA in subjects with difficult-to-treat hypertension was 17% and 23%, respectively. Thus, approximately 20% of subjects referred to tertiary care centers for resistant hypertension have hyperaldosteronism. The cause of this aldosterone excess is unknown.

Recognizing that OSA and hyperaldosteronism are both common in subjects with resistant hypertension, we hypothesize that the two conditions may be causally related and interact on a pathophysiologic basis. To begin testing this hypothesis, we prospectively screened subjects with resistant hypertension for OSA risk utilizing the Berlin questionnaire.78 Subjects with a high risk of having OSA were more than twice as likely to have PA diagnosed compared to subjects with a low Berlin score, providing preliminary evidence for a possible interaction between OSA and hyperaldosteronism. The current study investigates whether OSA severity, assessed by overnight, attended polysomnography, is related to plasma aldosterone levels in subjects with resistant hypertension. Subjects with equally severe OSA but without resistant hypertension served as control subjects.

Materials and Methods

Subjects
Consecutive subjects referred to the University of Alabama at Birmingham (UAB) Hypertension Clinic for resistant hypertension were enrolled. Resistant hypertension was defined as uncontrolled BP (> 140/90 mm Hg) in spite of use of three or more antihypertensive agents of different classes.9 Consecutive subjects referred to the UAB Sleep/Wake Disorders Center for suspicion of OSA and without resistant hypertension (normotensive or BP controlled on two or fewer antihypertensive medications) were recruited as control subjects. All subjects were enrolled over a 16-month period (July 2004 to October 2005). This study was approved by the UAB Institutional Review Board, and all subjects provided written consent prior to study enrollment.

All hypertensive subjects were receiving a stable antihypertensive regimen for at least 4 weeks prior to study entry. All antihypertensive medications were continued, except for spironolactone, amiloride, or triamterene, for which a non-potassium-sparing diuretic was substituted for at least 6 weeks prior to evaluation. Serum potassium levels were corrected as necessary with oral supplementation to maintain a serum level > 3.5 mEq/L prior to biochemical evaluation. Exclusion criteria included a prior diagnosis of OSA, recent myocardial infarction (within 6 months prior to study), congestive heart failure, chronic kidney disease (serum creatinine ≥ 1.8 mg/dL), and current use of systemic glucocorticoids.

BP Measurement
A standardized history and physical examination was performed prior to biochemical analysis. Clinic BP was measured in all subjects according to American Heart Association guidelines.10

Biochemical Evaluation
Outpatient biochemical assessment included an early morning, ambulatory plasma aldosterone concentration (PAC) and plasma direct renin level (PDR). Blood samples were collected in fasted subjects between 7 AM and 9 AM in seated position during their normal diet.

OSA Evaluation
All subjects with resistant hypertension underwent full-night, attended, diagnostic polysomnography, and control subjects underwent split-night, attended polysomnography. During a split-night evaluation, continuous positive airway pressure (CPAP) treatment is initiated if the diagnosis of OSA is confirmed with a minimum of 2 h of sleep time. Polysomnographic evaluation included airflow monitoring with thermocouple and/or nasal pressure, respiratory effort using piezo belts at the chest and abdominal positions, oxygen saturation using pulse oximetry, heart rate using a single-lead ECG, EEG (C4-A1, C3-A2, O2-A1,O1-A2), submental and tibial electromyograms, and bilateral electro-oculograms. Apnea was defined as a cessation in airflow ≥ 10 s. Hypopnea was defined as a reduction in the amplitude of airflow of at least 30% ≥ 10 s, followed by either a decrease in oxygen saturation of 4%, or signs of physiologic arousal (at least 3 s of {alpha} activity). The AHI was calculated as the total number of apneas plus hypopneas divided by the hours of sleep. Sleep was staged according to criteria of Rechtschaffen and Kales.11 The percentage of sleep time spent with an oxygen saturation < 90%, the hypoxic index (HI), was also determined. Sleep stage and nocturnal events were continuously supervised by a registered polysomnographic technologist. The scoring of all studies was confirmed by an American Board of Sleep Medicine Diplomat blinded to the biochemical assessment. OSA was defined as an AHI ≥ 5/h.11

Laboratory Methods
PAC and PDR were measured using standardized techniques. PAC was measured by radioimmunoassay (Mayo Medical Laboratories; Rochester, MN), as was PDR (Quest Diagnostics; Atlanta, GA). The reference range for PAC is 1.0 to 21.0 ng/dL, and for an ambulatory PDR is 5.0 to 13.0 µU/mL.

Statistical Analysis
Differences in baseline demographics, clinic BP during the physical examination, and biochemical data between hypertensive and control subjects were compared using a Wilcoxon signed-rank test. Correlations between aldosterone and renin levels and severity of OSA (AHI, HI) were assessed using Spearman {rho}. Covariate adjusted-rank linear mixed models were used to assess the impact of covariates (age, gender, body mass index [BMI], PDR) on the relationship of aldosterone and AHI or HI. Results are expressed as median, median with range, and mean ± SD. Statistical significance was defined as p < 0.05. All analyses were performed using statistical software (JMP v5.1 or SAS v9.1; SAS Institute; Cary, NC).

Results

Resistant Hypertension Subjects
Biochemical assessment and overnight polysomnography were completed in 71 subjects with resistant hypertension. The demographic, biochemical, and polysomnographic values are listed in Table 1 . Forty-five percent of subjects were African American. The majority of subjects were receiving a thiazide diuretic (83%), an angiotensin-converting enzyme inhibitor (67%), a calcium-channel antagonist (72%), and a ß-adrenergic antagonist (68%). Subjects with resistant hypertension had a higher prevalence of known coronary disease (1.4% vs 0%) and diabetes (23.9% vs 6.9%) compared to control subjects. Median PAC was significantly higher (11.0 ng/dL vs 5.5 ng/dL, p = 0.002) and renin levels were significantly lower (8.0 µU/mL vs 19.0 µU/mL, p = 0.0005) in subjects with resistant hypertension compared to control subjects.


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  		Table 1.. Demographic, Biochemical, and Polysomnographic Findings of Subjects With and Without Resistant Hypertension

 
PAC was positively and significantly correlated with AHI ({rho} = 0.44, p = 0.0002) [Fig 1 , left panel]. Similarly, PAC was positively and significantly correlated with HI ({rho} = 0.38, p = 0.001) [Fig 1, right panel], but no correlation was noted between PDR and AHI or HI. There were no covariate-adjusted models (age, gender, BMI, PDR) that significantly improved the relationship between PAC and AHI or HI. There were no significant gender differences in age, BMI, or systolic BP. The number and types of prescribed antihypertensive medications were not different in male and female subjects. Median diastolic BP (90 mm Hg vs 81 mm Hg, p = 0.01) and median PAC were significantly greater in male subjects compared to female subjects (12.0 ng/dL vs 8.8 ng/dL, p = 0.005). There was no gender difference in median PDR. OSA was more severe (median AHI, 20.8/h vs 10.8/h, p = 0.01; median HI, 5.5% vs 1.3%, p = 0.005) and more common (90% vs 77%) in male subjects compared to female subjects with resistant hypertension.


Figure 1
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  		Figure 1.. AHI ({rho} = 0.44, p = 0.0002) [left panel] and HI ({rho} = 0.38, p = 0.001) [right panel] correlate with PAC in subjects with resistant hypertension (n = 71).

 
Control Subjects
Biochemical assessment and overnight polysomnography were completed in 29 control subjects (Table 1). Thirty-three percent of control subjects were African American. All subjects were normotensive and receiving no antihypertensive medications, except for three individuals whose BP was controlled with one or two antihypertensive medications. There were no significant differences between the control and hypertensive groups in terms of gender or race.

In contrast to subjects with resistant hypertension, PAC was not related to AHI ({rho} = 0.12, p = 0.52) or HI ({rho} = 0.002, p = 0.99) in control subjects (Fig 2 ). Likewise, PDR did not correlate with OSA severity. In male subjects compared to female control subjects, OSA was more common (87% vs 79%) and more severe (median AHI, 31.1/h vs 10.3/h, p = 0.01). There were no gender differences in PAC, PDR, or HI.


Figure 2
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  		Figure 2.. AHI ({rho} = 0.12, p = 0.52) [left panel] and HI ({rho} = 0.002, p = 0.99) [right panel] do not correlate with PAC in control subjects (n = 29).

 
Discussion

This study is novel in demonstrating a strong positive correlation between plasma aldosterone and OSA severity in subjects with resistant hypertension. In contrast, there was no correlation noted between OSA and aldosterone levels in control subjects with equally severe OSA as defined by AHI. These results do not prove causality but are consistent with the hypothesis that hyperaldosteronism induces and/or exacerbates OSA. Less likely, although not excluded, is the possibility that aldosterone release is stimulated by OSA. If the former hypothesis is true, the effects would be from peripheral and/or central effects of aldosterone and/or sodium and fluid retention contributing to the development of upper airway obstruction.

Our results confirm a high prevalence of OSA (85%) in subjects with resistant hypertension. Our data are in agreement with Logan et al,3 who reported an 83% prevalence of OSA (AHI ≥ 10/h) in subjects with resistant hypertension. In this earlier study,3 men were much more likely to have OSA compared to women (93% vs 65%, respectively). We observed a similar gender difference, with OSA being severe and more prevalent in male subjects (90%) compared to female subjects (77%). Applying the stricter criteria used by Logan et al3 (AHI ≥ 10/h), we found an overall prevalence of OSA of 65% with a higher prevalence in male subjects compared to female subjects (73% vs 53%). Given the increased cardiovascular risk associated with untreated OSA,1213 as well as the potential antihypertensive benefit of CPAP treatment,141516 the results of these two studies support aggressive screening for OSA in all patients with resistant hypertension.

The relationship between OSA and the renin-angiotensin-aldosterone system is complex, and data are inconsistent. In a study17 of seven normotensive subjects with mild-to-severe OSA, nighttime plasma aldosterone levels were lower compared to non-OSA control subjects. In a study18 of subjects with severe OSA, a single overnight CPAP session increased both plasma aldosterone and plasma renin activity; while in another study19 evaluating the chronic effects of CPAP on renin-aldosterone, long-term CPAP therapy (3 months) significantly reduced plasma aldosterone levels in 11 obese subjects with untreated hypertension. Lastly, data have shown that plasma angiotensin II and aldosterone levels are higher in hypertensive subjects with untreated OSA compared to healthy control subjects; CPAP use for an average of 14 months was associated with lower angiotensin II but not aldosterone levels.20 In a separate study,21 1 month of CPAP treatment did not change renin or aldosterone levels in male subjects. None of these studies evaluated subjects with resistant hypertension.

In the current study, male subjects with resistant hypertension had significantly higher plasma aldosterone levels compared to female subjects. This is an unexpected finding, as prior evaluations2223 of normotensive and mildly hypertensive subjects have generally noted higher PAC levels in female subjects. Renin levels were not different between male subjects and female subjects with resistant hypertension, suggesting that higher aldosterone levels observed in male subjects were not secondary to greater renin-angiotensin II stimulation. Confirmation of a true gender difference in aldosterone levels in subjects with resistant hypertension vs other explanations such as a possible referral bias will require further evaluation.

Hyperaldosteronism, specifically, and resistant hypertension in general are characterized by inappropriate sodium and fluid retention.242526 One explanation of the current results is that hyperaldosteronism and the consequential sodium and fluid retention also contributes to worsening OSA. OSA in general is associated with increased sodium and water excretion as reflected by nocturnal polyuria and the release of atrial natriuretic peptide.272829 It is suggested that increased urine and salt excretion and increased vascular membrane permeability leads to a fluid shift from the plasma to the extracellular space.30 Although speculative, in patients with resistant hypertension in whom there is increased sodium and fluid retention, this shift of fluid from the intravascular space into the surrounding tissue, particularly within the neck, may be accentuated, resulting in increased airway resistance and/or an increased propensity for airway collapse resulting in respiratory events. Such an aldosterone-induced effect may not have been seen in the control subjects because of the overall lower aldosterone levels. That is, inappropriate fluid retention may not have manifest except in the setting of aldosterone excess. Such a threshold effect is consistent with recent studies3132 demonstrating that aldosterone-induced target organ damage is limited to subjects with high aldosterone levels.

The current study is strengthened by its prospective design, inclusion of a large number of consecutive subjects referred for evaluation of resistant hypertension, quantification of OSA severity in the subjects with resistant hypertension by attended, fully diagnostic polysomnography, and by comparison to control subjects similar in BMI and OSA severity. Study limitations include doing biochemical assessments in the setting of ongoing antihypertensive treatment, quantifying OSA severity in the control subjects by split-night polysomnography, and use of an observational design that relates OSA to aldosterone secretion but does not attribute cause and effect.

Ideally, aldosterone and renin levels are best measured in the absence of medications; however, in the current study this was not possible for safety reasons, as withdrawal of mediations would have likely resulted in severe BP elevations. The effects of the medications would have been divergent on renin levels; ß-blockers would have tended to suppress, while diuretics, angiotensin-converting enzyme inhibitors, and angiotensin-receptor blockers would have tended to increase renin. In addition to the higher aldosterone levels, the lower renin levels observed in subjects with resistant hypertension compared to control subjects may have been related to greater ß-blocker use, a slightly higher percentage of African-American subjects, and/or greater fluid retention secondary to subtle kidney disease. Plasma aldosterone levels were significantly higher in the resistant hypertensive subjects in spite of use of antihypertensive medications that tend to suppress aldosterone release.3334

All subjects with resistant hypertension underwent a full-night, diagnostic polysomnography, while the control subjects were evaluated by a split-night polysomnography with a minimum of 2 h of sleep time to diagnose OSA. The diagnostic accuracy of split-night evaluations, including quantifying severity of sleep apnea, has been compared favorably to full-night evaluations.35 In the absence of rapid eye movement sleep during the diagnostic portion of the study, OSA severity can be underestimated by a split-night evaluation,36 such that the severity of OSA in our control subjects may have been even worse if they had received full-night as opposed to split-night evaluations.

In summary, we confirm a high prevalence of unsuspected OSA in subjects with resistant hypertension. We further demonstrate a positive correlation between plasma aldosterone and OSA severity in subjects with resistant hypertension but not in control subjects. While causation cannot be inferred, these results seem most consistent with the hypothesis that aldosterone excess worsens OSA severity. If so, it would suggest that OSA risk is increased in patients with resistant hypertension because of the underlying hyperaldosteronism that is common in these patients. The current results, however, do not exclude the opposite possibility that untreated OSA stimulates aldosterone release.

Clinical Implications
The results of the current study confirm that patients with resistant hypertension are at extremely high risk of having OSA. These results and those of Logan et al3 support aggressively screening all patients with resistant hypertension for OSA. The current results further indicate that patients with resistant hypertension and OSA have elevated aldosterone levels consistent with an increased likelihood of having PA. Whether treatment of OSA will reduce aldosterone levels or whether preferential use of a mineralocorticoid receptor antagonist will lessen severity OSA in patients with resistant hypertension needs to be explored.

Acknowledgements

We thank David Moore, RPSGT, and S. Justin Thomas, BS, RPSGT, for assistance in conducting and scoring the overnight sleep studies.

Footnotes

Abbreviations: AHI = apnea-hypopnea index; BMI = body mass index; CPAP = continuous positive airway pressure; HI = hypoxic index; OSA = obstructive sleep apnea; PA = primary aldosteronism; PAC = plasma aldosterone concentration; PDR = plasma direct renin level; UAB = University of Alabama at Birmingham

This work was supported by American Heart Association Grant-in-Aid 0355302B received by Dr. Calhoun, and National Heart, Lung, and Blood Institute grants HL075614 and SCCOR P50HL077100 received by Dr. Calhoun, HL007457 received by Dr. Pratt-Ubunama, and National Institutes of Health grant M01-RR00032 received by the General Clinical Research Center.

Drs. Pratt-Ubunama, Nishizaka, Boedefeld, and Cofield have no conflicts of interest to disclose. Dr. Calhoun has received research support from Novartis and AstraZeneca LLP and has participated in an advisory board for AstraZeneca LLP. Dr. Harding has received research support, honoraria, and consultant payments from AstraZeneca LLP. There was no off-label or investigational drug use.

Received for publication June 7, 2006. Accepted for publication September 28, 2006.

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