David A. Calhoun , MD
Associate Professor of Medicine
Department of Medicine, Division of Cardiovascular Disease

Susan M. Harding , MD
Professor of Medicine
Department of Medicine, Division of Pulmonary/Allergy/Critical Care

The University of Alabama at Birmingham
Birmingham, Alabama

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UAB investigators have unveiled a direct relationship among aldosterone elevation, the severity of obstructive sleep apnea (OSA), and hypertension-associated cardiovascular changes, particularly left ventricular remodeling, a known risk factor for heart failure. Their findings may improve evidence-based management of treatment-resistant hypertension and its often undiagnosed counterpart, OSA.

“Researchers have repeatedly found 50% of patients with hypertension have obstructive sleep apnea, and half of those with obstructive sleep apnea have hypertension. Newer studies at UAB’s hypertension clinics are more alarming — 85% of patients with treatment-resistant hypertension also have obstructive sleep apnea,” says UAB hypertension specialist David A. Calhoun, MD, who has published numerous studies on aldosterone elevation and its role in hypertension and in obstructive sleep apnea. “Incorporating overnight sleep studies and aldosterone elevation screening may help clinicians evaluate hypertension that remains refractory to medical management by diagnosing underlying factors and opening the door to other treatment regimens,” he says.

Both elevated urinary aldosterone levels and a high incidence of severe OSA were found in treatment-resistant hypertensive participants in a recent UAB study funded by the National Heart, Lung, and Blood Institute (Chest. 2007;131[2]:453-459). Investigators evaluated more than 70 treatment-resistant hypertension participants with overnight polysomnography to evaluate for OSA and measured vascular endothelial changes with ultrasound. They were surprised to learn that both the frequency of obstructive sleep apnea and the degree of endothelial impairment was much higher than reported in previous studies (Circulation. 2004;109:2857-2861).

“We theorize that aldosterone becomes elevated during hypoxic events in people with obstructive sleep apnea. Decreased oxygen stimulates aldosterone release, which then produces endothelial dysfunction and contributes to left ventricular remodeling,” Calhoun explains. Prevention or reversal of left ventricular remodeling through lifestyle modifications, drug therapy, and noninvasive sleep apnea treatments, including continuous positive airway pressure (CPAP), can potentially reduce the risk of cardiovascular events and stroke.

Findings from the National Heart, Lung, and Blood Institute’s Sleep Heart Health Study show a relationship between severe OSA and an increased risk of coronary artery disease, congestive heart failure, and stroke. The study is the largest cross-sectional study to date to suggest sleep-disordered breathing and obstructive sleep apnea are associated with systemic hypertension in a middle-aged and older population (JAMA. 2000;283[4]:1829-1836).

OSA is potentially lethal in patients with treatment-resistant hypertension (blood pressure >140/90 mm Hg refractory to ≥2 medications) who frequently have additional cardiovascular risk factors, including diabetes and obesity. However, an observational cohort study of nearly 700 people with OSA found the condition increases the risk of stroke or death from any cause, and this rise may be independent of other risk factors, including hypertension (N Engl J Med. 2005;353:2034-2041).

“Clinically, all resistant hypertensive patients should be questioned about their sleep habits and considered for evaluation for aldosterone excess and obstructive sleep apnea,” he says. “Aldosterone excess frequently underlies resistant hypertension, so we advise systematic screening.” Recent studies suggest 50% of patients with primary aldosteronism have an adrenal adenoma, which requires surgical treatment. Although the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) guidelines advise thiazide-type diuretics for first-line hypertension treatment, patients with elevated aldosterone levels may benefit more from mineralocorticoid receptor antagonists, such as the potassium-sparing diuretics amiloride or spironolactone, which address aldosterone excess specifically. Spironolactone may be associated with breast tenderness with or without gynecomastia, sexual dysfunction, and menstrual irregularities. “However, both drugs are generally well-tolerated,” Calhoun says. Patients must be carefully monitored for hyperkalemia, an uncommon but potential occurrence that is more frequent when angiotensin-converting enzyme inhibitors or angiotensin receptor blockers are used, or when patients have chronic kidney disease.”

A comprehensive sleep study by sleep medicine specialists can confirm suspected OSA. Using infrared cameras and nocturnal polysomnography, specialists at UAB’s Sleep/Wake Disorders Center monitor sleep staging, airflow and ventilatory effort, body position, eye movement, cardiac function, arterial oxygen saturation, and periodic limb movement.

“CPAP is the gold standard therapy for obstructive sleep apnea, and we often begin treatment within hours of diagnosis. Many patients observe a marked improvement in their symptoms after using CPAP for one night in the unit,” says UAB’s Sleep/Wake Disorders Center Medical Director Susan M. Harding, MD.

Calhoun, Harding, and UAB hypertension fellows Mari K. Nishizaka, MD, and Mohammad A. Zaman, MD, studied patients with resistant hypertension and primary hyperaldosteronism and found that resistance to antihypertensive therapy was associated with a higher apnea-hypopnea index, and consequently, more severe sleep apnea (Chest. 2004;125:112-117).

CPAP provides sufficient pressure to maintain an open airway and improve oxygenation during sleep and can potentially improve blood pressure, Calhoun explains. “Although patients may be reluctant to embrace CPAP, those who use the device typically report rapidly improved sleep and quality of life,” he says. “Explaining the benefits of CPAP on overall sleep health and on blood pressure may help reluctant patients with uncontrolled hypertension incorporate it into their treatment plan.”

“Sleep disturbances can negatively impact cardiovascular disease and stroke risk,” Harding adds. “The Sleep Heart Health Study investigated more than 6000 patients and found hypertension prevalence increased proportionately with the number of apneas and hypopneas noted per hour of sleep. The Nurses’ Health Study noted an age-adjusted relative risk of cardiovascular events of 1.46 for occasional snorers and 2.02 for regular snorers, and a risk of stroke of 1.60 for occasional snorers and 1.88 for regular snorers,” she says.

“Sleep apnea also is associated with pulmonary hypertension, neurocognitive effects, depressed quality of life, motor vehicle accidents, awakening headache, childhood growth interruption, pregnancy-induced hypertension, fetal growth retardation, and disruption of the bed partners’ sleep quality,” she says. “Future UAB studies will examine the possibility of causality, pathophysiologic mechanisms, and outcomes of therapeutic interventions for OSA and its many consequences.”

Hypertensive patients whose blood pressure is severe and uncontrolled despite medical management may benefit from evaluation through UAB’s Hypertension Program. Calhoun suggests patients with hypertension warrant a low threshold for polysomnography. “Hypertension and OSA are strongly associated, and both are independent risk factors for stroke,” he says. “Resistant hypertensives who complain of excessive daytime sleepiness despite adequate self-reported sleep, whose partners have witnessed apneic events, or whose aldosterone levels are elevated should undergo a comprehensive sleep study. If OSA underlies resistant hypertension, the patient also is at risk of hyperaldosteronism, and may benefit from spironolactone.

“Now that we have established a link among aldosterone elevation, obstructive sleep apnea, and resistant hypertension, our researchers are recruiting patients for a study to define the triad’s cause and effect. We plan to explore the benefits of OSA treatment and mineralocorticoid receptor antagonists on cardiovascular health, and eventually, clinicians can begin to diagnose and treat underlying issues to improve resistant hypertension as well as quality of life.”

For more information:

Dr. David A. Calhoun
Dr. Susan M. Harding
1-800-UAB-MIST
mist@uabmc.edu

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