Menopause and Sleep Apnea.
Perger Elisa,Mattaliano Paola,Lombardi Carolina
Obstructive sleep apnea (OSA) is a chronic and common adult disorder characterized by recurrent episodes of upper-airway obstruction and reopening during sleep. OSA is associated with intermittent hypoxia, sympathetic overactivity, oxidative stress and high cardiovascular mortality and morbidity. It is known to be more common in men than women, partly due to differences in anatomy and functional respiratory components. There are also gender differences in reported symptoms, leading to potential under-diagnosis in females. This gender difference tends to decrease after menopause, demonstrating a role of menopausal status itself in OSA phenotypes. Aging, fat mass distribution, sex hormones and upper-airway collapsibility are postulated to play a major role in these findings. This review focuses on the most recent studies exploring gender differences in the prevalence, pathogenesis and clinical features of OSA. It discusses the role of menopause in this, and explore the underlying pathophysiological mechanisms.
Adropin and Inflammation Biomarker Levels in Male Patients With Obstructive Sleep Apnea: A Link With Glucose Metabolism and Sleep Parameters.
Bozic Josko,Borovac Josip A,Galic Tea,Kurir Tina Ticinovic,Supe-Domic Daniela,Dogas Zoran
Journal of clinical sleep medicine : JCSM : official publication of the American Academy of Sleep Medicine
STUDY OBJECTIVES:The main objectives of the study were to determine plasma adropin, systemic inflammation biomarker levels, and glucose metabolism parameters in patients with moderate and severe obstructive sleep apnea (OSA) compared to healthy controls. METHODS:In this study, we included 50 male patients with OSA (25 moderate and 25 severe) and 25 age- and sex-matched control subjects. All subjects underwent fasting sampling of peripheral blood for laboratory analyses. RESULTS:Adropin plasma levels were significantly lower in the severe OSA group in comparison with the moderate and control groups (4.50 ± 1.45 versus 6.55 ± 1.68 versus 8.15 ± 1.79 ng/mL, < .001). Plasma biomarkers of systemic inflammation were significantly increased in patients with moderate OSA (interleukin [IL]-6 and tumor necrosis factor alpha [TNF-α]) and severe OSA (IL-6, TNF-α, high-sensitivity C-reactive protein) when compared with controls ( < .001). Adropin levels showed a significant negative correlation with IL-6 ( = -.419, < .001), TNF-α ( = -.540, < .001), fasting glucose ( = -.331, = .004), hemoglobin A1c ( = -.438, < .001), homeostatic model assessment insulin resistance index ( = -.213, = .046), and polysomnographic parameters including apnea-hypopnea index ( = -.615, < .001) and oxygen desaturation index ( = -.573, < .001). A multivariate regression analysis showed that plasma adropin remained as a significant negative predictor of severe OSA status, when adjusted for age and body mass index and computed along with other inflammatory biomarkers in the regression model (odds ratio 0.069, 95% confidence interval 0.009-0.517, = .009). CONCLUSIONS:Plasma adropin concentrations significantly correlate with indices of disease severity in patients with OSA, suggesting that adropin potentially plays an important role in the complex pathophysiology of the disease.
Obstructive sleep apnea and CPAP therapy alter distinct transcriptional programs in subcutaneous fat tissue.
Gharib Sina A,Hurley Amanda L,Rosen Michael J,Spilsbury James C,Schell Amy E,Mehra Reena,Patel Sanjay R
Obstructive sleep apnea (OSA) has been linked to dysregulated metabolic states, and treatment of sleep apnea may improve these conditions. Subcutaneous adipose tissue is a readily samplable fat depot that plays an important role in regulating metabolism. However, neither the pathophysiologic consequences of OSA nor the effects of continuous positive airway pressure (CPAP) in altering this compartment's molecular pathways are understood. This study aimed to systematically identify subcutaneous adipose tissue transcriptional programs modulated in OSA and in response to its effective treatment with CPAP. Two subject groups were investigated: Study Group 1 was comprised of 10 OSA and 8 controls; Study Group 2 included 24 individuals with OSA studied at baseline and following CPAP. For each subject, genome-wide gene expression measurement of subcutaneous fat was performed. Differentially activated pathways elicited by OSA (Group 1) and in response to its treatment (Group 2) were determined using network and Gene Set Enrichment Analysis (GSEA). In Group 2, treatment of OSA with CPAP improved apnea-hypopnea index, daytime sleepiness, and blood pressure, but not anthropometric measures. In Group 1, GSEA revealed many up-regulated gene sets in OSA subjects, most of which were involved in immuno-inflammatory (e.g. interferon-γ signaling), transcription, and metabolic processes such as adipogenesis. Unexpectedly, CPAP therapy in Group 2 subjects was also associated with up-regulation of several immune pathways as well as cholesterol biosynthesis. Collectively, our findings demonstrate that OSA alters distinct inflammatory and metabolic programs in subcutaneous fat, but these transcriptional signatures are not reversed with short-term effective therapy.
Acetazolamide Reduces Blood Pressure and Sleep-Disordered Breathing in Patients With Hypertension and Obstructive Sleep Apnea: A Randomized Controlled Trial.
Eskandari Davoud,Zou Ding,Grote Ludger,Hoff Erik,Hedner Jan
Journal of clinical sleep medicine : JCSM : official publication of the American Academy of Sleep Medicine
STUDY OBJECTIVES:The carbonic anhydrase inhibitor acetazolamide (AZT) modulates blood pressure at high altitude and reduces sleep-disordered breathing in patients with obstructive sleep apnea (OSA). We aimed to investigate the treatment effect of AZT and in combination with continuous positive airway pressure (CPAP) on blood pressure in patients with hypertension and OSA. METHODS:In a prospective, randomized, three-way crossover study, 13 male patients with hypertension and moderate to severe OSA (age 64 ± 7 years, body mass index 29 ± 4 kg/m, and mean apnea-hypopnea index 37 ± 23 events/h) received AZT, CPAP, or AZT plus CPAP for 2-week periods. Antihypertensive medication was washed out. Office and 24-hour blood pressure, arterial stiffness, polygraphic sleep study data, and blood chemistry were compared. RESULTS:AZT alone and AZT plus CPAP, but not CPAP alone, reduced office mean arterial pressure compared to baseline (-7 [95% CI -11 to -4], -7 [95% CI -11 to -4] and -1 [95% CI -5 to 4] mmHg, respectively; repeated- measures analysis of variance (RM-ANOVA; = .015). Aortic systolic pressure and augmentation index, assessed by radial artery oscillatory tonometry, were unaffected by CPAP but decreased after AZT and AZT plus CPAP (RM-ANOVA = .030 and .031, respectively). The apnea-hypopnea index was significantly reduced in all three treatment arms, most prominently by AZT plus CPAP (RM-ANOVA = .003). The reduction of venous bicarbonate concentration following AZT was correlated with the change of apnea-hypopnea index ( = 0.66, = .013). CONCLUSIONS:AZT reduced blood pressure, vascular stiffness, and sleep-disordered breathing in patients with OSA and comorbid hypertension. Carbonic anhydrase inhibition may constitute a potential target for drug therapy in patients with sleep apnea and comorbid hypertension. CLINICAL TRIAL REGISTRATION:Registry: ClinicalTrials.gov; Identifier: NCT02220803; Title: A Short Term Open, Randomized Cross-over Trial Exploring the Effect of Carbonic Anhydrase Inhibition by Acetazolamide on Sleep Apnea Associated Hypertension and Vascular Dysfunction; URL: https://clinicaltrials.gov/ct2/show/NCT02220803 and Registry: EU Clinical Trials Register; EudraCT Number: 2013-004866-33; Title: A short term open, randomized cross over trial exploring the effect of carbonic anhydrase inhibition by acetazolamide on sleep apnea associated hypertension; URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=2013-004866-33.
Role of nocturnal rostral fluid shift in the pathogenesis of obstructive and central sleep apnoea.
White Laura H,Bradley T Douglas
The Journal of physiology
Obstructive sleep apnoea (OSA) is common in the general population and increases the risk of motor vehicle accidents due to hypersomnolence from sleep disruption, and risk of cardiovascular diseases owing to repetitive hypoxia, sympathetic nervous system activation, and systemic inflammation. In contrast, central sleep apnoea (CSA) is rare in the general population. Although their pathogenesis is multifactorial, the prevalence of both OSA and CSA is increased in patients with fluid retaining states, especially heart failure, where they are associated with increased mortality risk. This observation suggests that fluid retention may contribute to the pathogenesis of both OSA and CSA. According to this hypothesis, during the day fluid accumulates in the intravascular and interstitial spaces of the legs due to gravity, and upon lying down at night redistributes rostrally, again owing to gravity. Some of this fluid may accumulate in the neck, increasing tissue pressure and causing the upper airway to narrow, thereby increasing its collapsibility and predisposing to OSA. In heart failure patients, with increased rostral fluid shift, fluid may additionally accumulate in the lungs, provoking hyperventilation and hypocapnia, driving below the apnoea threshold, leading to CSA. This review article will explore mechanisms by which overnight rostral fluid shift, and its prevention, can contribute to the pathogenesis and therapy of sleep apnoea.
A prospective study of the prevalence of primary aldosteronism in 1,125 hypertensive patients.
Rossi Gian Paolo,Bernini Giampaolo,Caliumi Chiara,Desideri Giovambattista,Fabris Bruno,Ferri Claudio,Ganzaroli Chiara,Giacchetti Gilberta,Letizia Claudio,Maccario Mauro,Mallamaci Francesca,Mannelli Massimo,Mattarello Mee-Jung,Moretti Angelica,Palumbo Gaetana,Parenti Gabriele,Porteri Enzo,Semplicini Andrea,Rizzoni Damiano,Rossi Ermanno,Boscaro Marco,Pessina Achille Cesare,Mantero Franco,
Journal of the American College of Cardiology
OBJECTIVES:We prospectively investigated the prevalence of curable forms of primary aldosteronism (PA) in newly diagnosed hypertensive patients. BACKGROUND:The prevalence of curable forms of PA is currently unknown, although retrospective data suggest that it is not as low as commonly perceived. METHODS:Consecutive hypertensive patients referred to 14 hypertension centers underwent a diagnostic protocol composed of measurement of Na+ and K+ in serum and 24-h urine, sitting plasma renin activity, and aldosterone at baseline and after 50 mg captopril. The patients with an aldosterone/renin ratio >40 at baseline, and/or >30 after captopril, and/or a probability of PA (by a logistic discriminant function) > or =50% underwent imaging tests and adrenal vein sampling (AVS) or adrenocortical scintigraphy to identify the underlying adrenal pathology. An aldosterone-producing adenoma (APA) was diagnosed in patients who in addition to excess autonomous aldosterone secretion showed: 1) lateralized aldosterone secretion at AVS or adrenocortical scintigraphy, 2) adenoma at surgery and pathology, and 3) a blood pressure decrease after adrenalectomy. Evidence of excess autonomous aldosterone secretion without such criteria led to a diagnosis of idiopathic hyperaldosteronism (IHA). RESULTS:A total of 1,180 patients (age 46 +/- 12 years) were enrolled; a conclusive diagnosis was attained in 1,125 (95.3%). Of these, 54 (4.8%) had an APA and 72 (6.4%) had an IHA. There were more APA (62.5%) and fewer IHA cases (37.5%) at centers where AVS was available (p = 0.002); the opposite occurred where AVS was unavailable. CONCLUSIONS:In newly diagnosed hypertensive patients referred to hypertension centers, the prevalence of APA is high (4.8%). The availability of AVS is essential for an accurate identification of the adrenocortical pathologies underlying PA.
Prevalence and Clinical Manifestations of Primary Aldosteronism Encountered in Primary Care Practice.
Monticone Silvia,Burrello Jacopo,Tizzani Davide,Bertello Chiara,Viola Andrea,Buffolo Fabrizio,Gabetti Luisa,Mengozzi Giulio,Williams Tracy A,Rabbia Franco,Veglio Franco,Mulatero Paolo
Journal of the American College of Cardiology
BACKGROUND:Despite being widely recognized as the most common form of secondary hypertension, among the general hypertensive population the true prevalence of primary aldosteronism (PA) and its main subtypes, aldosterone-producing adenoma (APA) and bilateral adrenal hyperplasia (BAH), remains a matter of debate. OBJECTIVES:This study sought to determine the prevalence and clinical phenotype of PA in a large cohort of unselected patients with hypertension, consecutively referred to our hypertension unit, by 19 general practitioners from Torino, Italy. METHODS:Following withdrawal from all interfering medications, patients were screened for PA using the ratio of serum aldosterone to plasma renin activity. PA was diagnosed according to Endocrine Society guidelines. The diagnosis was confirmed or excluded by an intravenous saline infusion test or captopril challenge test and subtype differentiation was performed by adrenal computed tomography scanning and adrenal vein sampling, using strict criteria to define successful cannulation and lateralization of aldosterone production. RESULTS:A total of 1,672 primary care patients with hypertension (569 newly diagnosed and 1,103 patients already diagnosed with arterial hypertension) were included in the study. A total of 99 patients (5.9%) were diagnosed with PA and conclusive subtype differentiation by adrenal vein sampling was made in 91 patients (27 patients with an APA and 64 patients with BAH). The overall prevalence of PA increased with the severity of hypertension, from 3.9% in stage 1 hypertension to 11.8% in stage 3 hypertension. Patients with PA more frequently displayed target organ damage and cardiovascular events compared with those without PA, independent of confounding variables. CONCLUSIONS:Our results demonstrated that PA is a frequent cause of secondary hypertension, even in the general population of patients with hypertension, and indicates that most of these patients should be screened for PA.
The Management of Primary Aldosteronism: Case Detection, Diagnosis, and Treatment: An Endocrine Society Clinical Practice Guideline.
Funder John W,Carey Robert M,Mantero Franco,Murad M Hassan,Reincke Martin,Shibata Hirotaka,Stowasser Michael,Young William F
The Journal of clinical endocrinology and metabolism
OBJECTIVE:To develop clinical practice guidelines for the management of patients with primary aldosteronism. PARTICIPANTS:The Task Force included a chair, selected by the Clinical Guidelines Subcommittee of the Endocrine Society, six additional experts, a methodologist, and a medical writer. The guideline was cosponsored by American Heart Association, American Association of Endocrine Surgeons, European Society of Endocrinology, European Society of Hypertension, International Association of Endocrine Surgeons, International Society of Endocrinology, International Society of Hypertension, Japan Endocrine Society, and The Japanese Society of Hypertension. The Task Force received no corporate funding or remuneration. EVIDENCE:We searched for systematic reviews and primary studies to formulate the key treatment and prevention recommendations. We used the Grading of Recommendations, Assessment, Development, and Evaluation group criteria to describe both the quality of evidence and the strength of recommendations. We used "recommend" for strong recommendations and "suggest" for weak recommendations. CONSENSUS PROCESS:We achieved consensus by collecting the best available evidence and conducting one group meeting, several conference calls, and multiple e-mail communications. With the help of a medical writer, the Endocrine Society's Clinical Guidelines Subcommittee, Clinical Affairs Core Committee, and Council successfully reviewed the drafts prepared by the Task Force. We placed the version approved by the Clinical Guidelines Subcommittee and Clinical Affairs Core Committee on the Endocrine Society's website for comments by members. At each stage of review, the Task Force received written comments and incorporated necessary changes. CONCLUSIONS:For high-risk groups of hypertensive patients and those with hypokalemia, we recommend case detection of primary aldosteronism by determining the aldosterone-renin ratio under standard conditions and recommend that a commonly used confirmatory test should confirm/exclude the condition. We recommend that all patients with primary aldosteronism undergo adrenal computed tomography as the initial study in subtype testing and to exclude adrenocortical carcinoma. We recommend that an experienced radiologist should establish/exclude unilateral primary aldosteronism using bilateral adrenal venous sampling, and if confirmed, this should optimally be treated by laparoscopic adrenalectomy. We recommend that patients with bilateral adrenal hyperplasia or those unsuitable for surgery should be treated primarily with a mineralocorticoid receptor antagonist.
Resistant Hypertension Management: Comparison of the 2017 American and 2018 European High Blood Pressure Guidelines.
Grassi Guido,Calhoun David A,Mancia Giuseppe,Carey Robert M
Current hypertension reports
PURPOSE OF REVIEW:To compare European and American guidelines for the diagnosis, evaluation, and management of resistant hypertension. RECENT FINDINGS:Resistant hypertension is defined as high blood pressure that remains above goal with the use of 3 or more antihypertensive agents, commonly a renin-angiotensin blocker (either an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker), a long-acting calcium channel blocker, and thiazide or thiazide-like diuretic. Resistant hypertension is common, with a recent analysis indicating that it affects approximately 17-19% of adult Americans with hypertension. Pseudocauses of apparent resistant hypertension, including inaccurate blood pressure measurement, white coat effect, undertreatment, and poor medication adherence, must be excluded in order to confirm true resistant hypertension. Evaluation of resistant hypertension requires identifying and treating secondary causes of hypertension, including obstructive sleep apnea, primary aldosteronism, and renal artery stenosis. Treatment of resistant hypertension includes a combined use of lifestyle modification and prescription of effective multiple-drug combinations. Preferential use of a long-acting thiazide-like diuretic, either chlorthalidone or indapamide, and a mineralocorticoid receptor blocker, most commonly spironolactone, is recommended if needed to achieve blood pressure control. Aside for small exceptions, European and American guidelines agree in terms of recommendations for diagnosing, evaluating, and treating resistant hypertension.
What Is the Most Common Cause of Secondary Hypertension?: An Interdisciplinary Discussion.
Almeida Madson Q,Silva Giovanio V,Drager Luciano F
Current hypertension reports
PURPOSE OF REVIEW:Traditional statements in medical textbooks pointed that 90 to 95% of cases of hypertension is essential or primary. However, secondary hypertension seems to be common in those patients with resistant forms of hypertension. Appropriate investigation and treatment may have prognostic impact but frequently hypertension remission did not occur raising concerns about the real meaning of secondary hypertension. Here, we provided an interdisciplinary and critical discussion comprising an endocrinologist, a nephrologist, and a cardiologist with expertise in resistant hypertension. We reviewed the literature approaching each one of the recognizable cause of hypertension. RECENT FINDINGS:Recent studies pointed that the most common causes of secondary hypertension are those who overall responses to their treatments do not promote hypertension remission including obstructive sleep apnea (OSA), chronic kidney disease, renovascular hypertension and primary aldosteronism. The authors raised concerns regarding the lack of inclusion of obesity by several societies as a formal cause of hypertension considering not only the biologic plausibility but also the huge impact of weight loss therapies such as bariatric surgery on hypertension remission. In contrast, there is no discussion that a very rare condition-namely pheochromocytoma-is the most "typical" cause of hypertension by promoting hypertension remission in the majority of patients after surgical procedure. Hypertension is a complex condition with multiple environmental and genetics interactions. In clinical practice, it is challenging to prove causality in hypertension. Common conditions largely acceptable as causes of hypertension (OSA, chronic kidney disease, renovascular hypertension, and primary aldosteronism) frequently occur in a setting of an established hypertension background and therefore do not promote hypertension remission in a significant proportion of patients. If obesity becomes largely accepted by several societies as a secondary form of hypertension, this pandemic condition will be certainly the most common cause of hypertension.
Effects of chronically high levels of aldosterone on different cognitive dimensions: an investigation in patients with primary aldosteronism.
Engler Lukas,Adolf Christian,Heinrich Daniel A,Brem Anna-Katharine,Riester Anna,Franke Anna,Beuschlein Felix,Reincke Martin,Steiger Axel,Künzel Heike
Primary aldosteronism is a natural model for chronic aldosterone excess in humans and associated with symptoms of anxiety and depression. Cognitive deficits are inherent to the symptomatology of depression and anxiety disorders. Mineralocorticoid receptors and aldosterone appear to play a role in memory. Aldosterone was additionally supposed to be a risk factor for cognitive decline in patients with essential hypertension. The objective of this study was to investigate possible effects of chronically high aldosterone concentrations on cognitive function. A range of cognitive dimensions were assessed in 19 patients (9 males, 10 females); mean age 47.1 (12.5) under standardized treatment and several rating scales for anxiety, depression, quality of life and sleep were administered. Cognitive parameters were compared to standard norms from a large, healthy standardization sample. Patients showed increased levels of anxiety and depression without meeting diagnostic criteria for a disorder. Besides a numerically lower attention score, patients did not show any significant differences in the cognitive dimensions. Anxiety and depression were negatively correlated with quantitative performance in males. In females, a negative correlation between sleep disturbances and abstract reasoning and a positive correlation with quantitative performance were found. Our data showed no specific effect of chronic aldosterone in the tested cognitive parameters overall at least in younger patients, but they indicate sexually dimorphic regulation processes.
Resistant Hypertension: Diagnosis and Management.
Nagarajan Nagalakshmi,Jalal Diana
Advances in chronic kidney disease
Resistant hypertension is defined as high blood pressure requiring 3 or more medications for adequate control or controlled blood pressure requiring 4 or more medications. Considering the growing prevalence of hypertension and the strong link with cardiovascular disease, it is vital to understand the causes and treatment of resistant hypertension. This review article starts with an overview of the prevalence and little-known pathophysiology of resistant hypertension. Afterward, we discuss the evaluation and management of suspected secondary resistant hypertension in 2 broad categories: pseudoresistant hypertension and true resistant hypertension. Strategies for the identification and management of pseudoresistant hypertension are addressed. In addition, causes of true resistant hypertension, such as obstructive sleep apnea, primary aldosteronism, and renal artery stenosis, are examined along with their respective treatments. Finally, treatment of resistant hypertension is reviewed including pharmacologic treatments and novel procedural interventions for resistant hypertension. Overall, the review hopes to provide practitioners with a cohesive approach for the diagnosis and treatment of resistant hypertension.
Resistant hypertension and aldosterone: an update.
Clark Donald,Ahmed Mustafa I,Calhoun David A
The Canadian journal of cardiology
Resistant hypertension (RHTN) is defined as a blood pressure remaining above goal despite the concurrent use of 3 antihypertensive medications of different classes, including, ideally a diuretic. RHTN is an important health problem with a prevalence rate expected to increase as populations become older, more obese, and at higher risk of having diabetes and chronic kidney disease, all of which are important risk factors for development of RHTN. The role of aldosterone has gained increasing recognition as a significant contributor to antihypertensive treatment resistance. In prospective studies, the prevalence of primary aldosteronism (PA) has ranged from 14%-21% in patients with RHTN, which is considerably higher than in the general hypertensive population. Furthermore, marked antihypertensive effects are seen when mineralocorticoid antagonists are added to the treatment regimen of patients with RHTN, further supporting aldosterone excess as an important cause of RHTN. A close association exists between hyperaldosteronism, RHTN, and obstructive sleep apnea (OSA) based upon recent studies which indicate that OSA is worsened by aldosterone-mediated fluid retention. This interaction is supported by preliminary data which demonstrates improvement in OSA severity after treatment with spironolactone.
Positive relationship of sleep apnea to hyperaldosteronism in an ethnically diverse population.
Sim John J,Yan Eric H,Liu In Lu A,Rasgon Scott A,Kalantar-Zadeh Kamyar,Calhoun David A,Derose Stephen F
Journal of hypertension
OBJECTIVE:Approximately, 50-60% of patients with sleep apnea have hypertension. To explore a mechanism of this relationship, we compared its prevalence in a hypertensive population with and without hyperaldosteronism. METHODS:Using the Kaiser Permanente Southern California database, hypertensive individuals who had plasma aldosterone and plasma renin activity measured between 1 January 2006 and 31 December 2007 were evaluated. Hyperaldosteronism was defined as an aldosterone : renin ratio more than 30 and plasma aldosterone more than 20 ng/dl or an aldosterone : renin ratio more than 50 (ng/dl : ng/ml per h). Hypertension was identified by International Classification of Disease, Ninth Revision (ICD-9) coding and sleep apnea was defined by ICD-9 coding or procedural coding for dispensation of positive airway devices. RESULTS:Of 3428 hypertensive patients, 575 (17%) had hyperaldosteronism. Sleep apnea was present in 18% (105) with hyperaldosteronism vs. 9% (251) without hyperaldosteronism (P < 0.001). Odds ratio for sleep apnea in patients with hyperaldosteronism was 1.8 (95% confidence interval 1.3-2.6) after controlling for other sleep apnea risk factors. No ethnic group was at greater risk for sleep apnea. CONCLUSION:The prevalence of sleep apnea in a diverse hypertensive population is increased in patients with hyperaldosteronism, even when controlling for other sleep apnea risk factors.
Obstructive sleep apnea: the most common secondary cause of hypertension associated with resistant hypertension.
Pedrosa Rodrigo P,Drager Luciano F,Gonzaga Carolina C,Sousa Marcio G,de Paula Lílian K G,Amaro Aline C S,Amodeo Celso,Bortolotto Luiz A,Krieger Eduardo M,Bradley T Douglas,Lorenzi-Filho Geraldo
Hypertension (Dallas, Tex. : 1979)
Recognition and treatment of secondary causes of hypertension among patients with resistant hypertension may help to control blood pressure and reduce cardiovascular risk. However, there are no studies systematically evaluating secondary causes of hypertension according to the Seventh Joint National Committee. Consecutive patients with resistant hypertension were investigated for known causes of hypertension irrespective of symptoms and signs, including aortic coarctation, Cushing syndrome, obstructive sleep apnea, drugs, pheochromocytoma, primary aldosteronism, renal parenchymal disease, renovascular hypertension, and thyroid disorders. Among 125 patients (age: 52±1 years, 43% males, systolic and diastolic blood pressure: 176±31 and 107±19 mm Hg, respectively), obstructive sleep apnea (apnea-hypopnea index: >15 events per hour) was the most common condition associated with resistant hypertension (64.0%), followed by primary aldosteronism (5.6%), renal artery stenosis (2.4%), renal parenchymal disease (1.6%), oral contraceptives (1.6%), and thyroid disorders (0.8%). In 34.4%, no secondary cause of hypertension was identified (primary hypertension). Two concomitant secondary causes of hypertension were found in 6.4% of patients. Age >50 years (odds ratio: 5.2 [95% CI: 1.9-14.2]; P<0.01), neck circumference ≥41 cm for women and ≥43 cm for men (odds ratio: 4.7 [95% CI: 1.3-16.9]; P=0.02), and presence of snoring (odds ratio: 3.7 [95% CI: 1.3-11]; P=0.02) were predictors of obstructive sleep apnea. In conclusion, obstructive sleep apnea appears to be the most common condition associated with resistant hypertension. Age >50 years, large neck circumference measurement, and snoring are good predictors of obstructive sleep apnea in this population.
Mechanisms and treatment of resistant hypertension.
Pimenta Eduardo,Gaddam Krishna K,Oparil Suzanne
Journal of clinical hypertension (Greenwich, Conn.)
Resistant hypertension is defined as blood pressure (BP) that remains uncontrolled in spite of the use of >/=3 antihypertensive medications. Stricter BP goals, higher obesity rates, older age, and increased use of exogenous BP-elevating substances are related to an increasing prevalence of resistant hypertension. The evaluation of patients with resistant hypertension is focused on identifying contributing and secondary causes of hypertension, including hyperaldosteronism, obstructive sleep apnea, chronic kidney disease, renal artery stenosis, and pheochromocytoma. Hyperaldosteronism is now recognized as the most common cause of resistant hypertension, and all patients with resistant hypertension should be screened with a plasma aldosterone/renin ratio even if the serum potassium level is normal. Treatment includes removal of contributing factors, appropriate management of secondary causes, and use of effective multidrug regimens. Recent studies indicate that the addition of spironolactone to standard treatment induces significant BP reduction in most patients with resistant hypertension.
Resistant hypertension and hyperaldosteronism.
Gonzaga Carolina C,Calhoun David A
Current hypertension reports
Resistant hypertension is defined as blood pressure that remains uncontrolled in spite of >or= 3 antihypertensive medications at effective doses, ideally including a diuretic. Although exact prevalence is unknown, clinical trials suggest that 20% to 30% of study participants are resistant. Hyperaldosteronism, obesity, refractory volume expansion, and obstructive sleep apnea are common findings in resistant hypertension patients. Multiple studies indicate that primary aldosteronism (PA) is common (approximately 20%) in patients with resistant hypertension. Screening for PA is recommended for most patients with resistant hypertension, ideally by measurement of 24-hour urinary aldosterone excretion, or by the plasma aldosterone/plasma renin activity ratio. Successful treatment of resistant hypertension is predicated on improvement of lifestyle factors; accurate diagnosis and treatment of secondary causes of hypertension; and use of effective multidrug regimens. A long-acting diuretic, specifically chlorthalidone, is recommended as part of the treatment regimen. Recent studies demonstrate that mineralocorticoid receptor antagonists provide substantial antihypertensive benefit when added to multidrug regimens, even in patients without demonstrable aldosterone excess.
Resistant hypertension: who and how to evaluate.
Acelajado Maria Czarina,Calhoun David A
Current opinion in cardiology
PURPOSE OF REVIEW:Resistant hypertension is found in an important and rapidly growing subset of the hypertensive population, and data characterizing this group of patients are limited. The purpose of this review is to present the latest evidence on resistant hypertension, its risk factors, patient characteristics, and approach to diagnosis. We focus on important associations between resistant hypertension and primary aldosteronism and with obstructive sleep apnea. RECENT FINDINGS:Resistant hypertension comprises 20-35% of the general hypertensive population. It is important to ascertain that a patient has true resistant hypertension and not merely uncontrolled hypertension. Twenty-four-hour ambulatory blood pressure monitoring can reliably rule out a white-coat effect and may have prognostic significance in patients with resistant hypertension. Patients should be screened for secondary causes of hypertension. Primary aldosteronism is common among patients with resistant hypertension, as is obstructive sleep apnea. A plasma aldosterone to renin ratio is a useful screening tool for primary aldosteronism. Aldosterone has been found to accelerate the increase in left ventricular mass in patients with hypertension. SUMMARY:Patients with resistant hypertension comprise a unique subset, with risk factors and associations that are distinct or pronounced compared with the general hypertensive population. It is important to bear these associations in mind when dealing with patients with true resistant hypertension.
The role of aldosterone antagonists in the management of resistant hypertension.
Nishizaka Mari K,Calhoun David A
Current hypertension reports
Resistant hypertension is an increasingly common problem faced by primary care physicians and specialists and will undoubtedly become even more common as the adult population ages and gains weight. In the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), at least 8% of subjects were resistant to treatment based on the need for three or more antihypertensive agents. Characteristics of patients with resistant hypertension include being older, black, obese, and diabetic, and having chronic kidney disease as well as untreated sleep apnea. Hyperaldosteronism is common in patients with resistant hypertension, with a prevalence of approximately 20%. This, however, is likely an underestimation of the role aldosterone excess plays in causing drug resistance. In subjects with resistant hypertension, suppressed renin levels are common, exceeding 75% in our studies, suggesting aldosterone excess effects beyond cases of true primary hyperaldosteronism. Recent studies indicate that aldosterone antagonists provide significant blood pressure reduction when added to antihypertensive regimens of patients with resistant hypertension. Interestingly, the blood pressure reduction with use of spironolactone is not limited to patients with hyperaldosteronism, consistent with the concept of aldosterone excess as a continuum from low-renin hypertension with normal aldosterone levels to true primary hyperaldosteronism.
Resistant or difficult-to-treat hypertension.
Calhoun David A
Journal of clinical hypertension (Greenwich, Conn.)
Resistant hypertension, defined as uncontrolled hypertension on three medications, is becoming an increasingly common problem. In most cases, blood pressure remains elevated because of persistently high systolic blood pressure levels. Common characteristics of patients with resistant hypertension include older age, obesity, excessive dietary salt ingestion, and presence of sleep apnea. The evaluation of patients with resistant hypertension is focused on identifying contributing and secondary causes of hypertension. Treatment should include both lifestyle changes (weight loss, exercise, dietary salt restriction) and the use of effective multidrug regimens, including a diuretic. Recent data indicate that aldosterone antagonists may be effective when added to existing antihypertensive regimens even in the absence of primary aldosteronism.
Use of aldosterone antagonists in resistant hypertension.
Calhoun David A
Progress in cardiovascular diseases
Resistant hypertension is defined as an elevated blood pressure in spite of treatment with 3 different antihypertensive agents. The prevalence of resistant hypertension is unknown, but recent cross-sectional analyses and hypertension outcome studies suggest it is a common clinical problem and will become even more so with an aging and increasingly heavy population. Secondary causes of hypertension are common in patients with resistant hypertension, in particular, obstructive sleep apnea and hyperaldosteronism. Treatment of resistant hypertension is predicated upon identification and reversal of secondary causes of hypertension, as possible, and effective use of multidrug regimens. Recent clinical studies indicate that aldosterone antagonists, spironolactone and amiloride, provide significant additional blood pressure reduction when added to treatment regimens of patients with resistant hypertension. Both agents are generally well tolerated. Hyperkalemia is an uncommon complication of aldosterone antagonists, but it can occur; therefore, biochemical monitoring is necessary, particularly in high-risk patients.
Obstructive Sleep Apnea-Induced Neurogenic Nocturnal Hypertension: A Potential Role of Renal Denervation?
Kario Kazuomi,Hettrick Douglas A,Prejbisz Aleksander,Januszewicz Andrzej
Hypertension (Dallas, Tex. : 1979)
There is a bidirectional, causal relationship between obstructive sleep apnea (OSA) and hypertension. OSA-related hypertension is characterized by high rates of masked hypertension, elevated nighttime blood pressure, a nondipper pattern of nocturnal hypertension, and abnormal blood pressure variability. Hypoxia/hypercapnia-related sympathetic activation is a key pathophysiological mechanism linking the 2 conditions. Intermittent hypoxia also stimulates the renin-angiotensin-aldosterone system to promote hypertension development. The negative and additive cardiovascular effects of OSA and hypertension highlight the importance of effectively managing these conditions, especially when they coexist in the same patient. Continuous positive airway pressure is the gold standard therapy for OSA but its effects on blood pressure are relatively modest. Furthermore, this treatment did not reduce the cardiovascular event rate in nonsleepy patients with OSA in randomized controlled trials. Antihypertensive agents targeting sympathetic pathways or the renin-angiotensin-aldosterone system have theoretical potential in comorbid hypertension and OSA, but current evidence is limited and combination strategies are often required in drug resistant or refractory patients. The key role of sympathetic nervous system activation in the development of hypertension in OSA suggests potential for catheter-based renal sympathetic denervation. Although long-term, randomized controlled trials are needed, available data indicate sustained and relevant reductions in blood pressure in patients with hypertension and OSA after renal denervation, with the potential to also improve respiratory parameters. The combination of lifestyle interventions, optimal pharmacological therapy, continuous positive airway pressure therapy, and perhaps also renal denervation might improve cardiovascular risk in patients with OSA.
Resistant hypertension and obstructive sleep apnea.
Khan Akram,Patel Nimesh K,O'Hearn Daniel J,Khan Supriya
International journal of hypertension
Hypertension (HTN) is a modifiable, highly prevalent risk factor for cardiovascular morbidity and renal dysfunction worldwide. In the United States, HTN affects one in three adults, contributes to one out of every seven deaths and to nearly half of all cardiovascular disease-related deaths. HTN is considered resistant when the blood pressure remains above goal despite lifestyle modification and administration of three antihypertensive agents of different classes including a diuretic. Large population-based studies have suggested that obstructive sleep apnea (OSA) is a risk factor for resistant HTN. The mechanism proposed is a pattern of intermittent hypoxia associated with hyperaldosteronism, increased sympathetic tone, endothelial dysfunction, and inflammation. In this review we discuss the association between OSA and resistant HTN, the physiologic mechanisms linking OSA with resistant HTN, and the effect of continuous positive airway pressure therapy (CPAP) on blood pressure in patients with resistant HTN. While the reduction in blood pressure with CPAP is usually modest in patients with OSA, a decrease of only a few mmHg in blood pressure can significantly reduce cardiovascular risk. Patients presenting to a center specializing in management of hypertension should be screened and treated for OSA as a potentially modifiable risk factor.
Trends in cause-related comorbidities in hospitalized patients with secondary hypertension in China from 2013 to 2016: a retrospective analysis of hospital quality monitoring system data.
Zhang Long,Li Jianping,Li Nanfang,Sun Ningling,Xie Liangdi,Han Qinghua,Li Yong,Lu Xin Zheng,Sun Pengfei,Li Yuxi,Shi Ying,Wang Haibo,Zhang Yan,Chen Hu,Huo Yong
Journal of hypertension
BACKGROUND:Secondary hypertension has emerged as a major public health problem in China. Early diagnosis and treatment can significantly improve the clinical outcomes. However, data on the current cause composition in China are seldom reported. OBJECTIVE:To describe the trends in cause-related comorbidities in hospitalized patients with secondary hypertension in China from 2013 to 2016. METHODS:This was a retrospective analysis based on the national Hospital Quality Monitoring System (HQMS) database, which collects information from the front pages of in-hospital medical records. Hospitalized patients with secondary hypertension from 746 tertiary hospitals that consistently uploaded data to the HQMS from 2013 to 2016 were enrolled. All diagnoses were identified using International Classification of Diseases version 10 (ICD-10) diagnostic codes. Descriptive analyses were used to determine the proportions of secondary hypertension causes and changing trends over 4 years. RESULT:The study collected data on 402 371 hospitalized patients with secondary hypertension from the HQMS during 2013-2016. Secondary hypertension caused by renal parenchymal disease ranked first and accounted for more than 50%. Obstructive sleep apnea syndrome (OSAS) followed closely with a rate of approximately 25%. Primary aldosteronism presented the highest proportion among all causes of endocrine hypertension. Regarding longitudinal changes over time, the rates of renal hypertension showed a significant downward trend from 2013 to 2016 (P < 0.001). In contrast, OSAS, endocrine hypertension, renal vascular disease, and aorta diseases maintained a significant upward trend from 2013 to 2016 (P < 0.001). The rates of these diseases in women with common secondary hypertension was higher than that of men, except in patients with OSAS (P < 0.001). In addition, renal parenchymal diseases and renal vascular diseases gradually decreased with age, whereas OSAS and aortic diseases gradually increased with age. The proportion of endocrine hypertension in the middle-aged group was higher than the other two age groups. CONCLUSION:The study provides important information on the changing trends of cause rate of secondary hypertension modified by age and sex in China during 2013-2016. Renal parenchymal disease is still the most common cause of secondary hypertension with a decreasing trend, followed by OSAS with an increasing trend.
Intermittent hypoxia increases arterial blood pressure in humans through a Renin-Angiotensin system-dependent mechanism.
Foster Glen E,Hanly Patrick J,Ahmed Sofia B,Beaudin Andrew E,Pialoux Vincent,Poulin Marc J
Hypertension (Dallas, Tex. : 1979)
Intermittent hypoxia (IH) is believed to contribute to the pathogenesis of hypertension in obstructive sleep apnea through mechanisms that include activation of the renin-angiotensin system. The objective of this study was to assess the role of the type I angiotensin II receptor in mediating an increase in arterial pressure associated with a single 6-hour IH exposure. Using a double-blind, placebo-controlled, randomized, crossover study design, we exposed 9 healthy male subjects to sham IH, IH with placebo medication, and IH with the type I angiotensin II receptor antagonist losartan. We measured blood pressure, cerebral blood flow, and ventilation at baseline and after exposure to 6 hours of IH. An acute isocapnic hypoxia experimental protocol was conducted immediately before and after exposure to IH. IH with placebo increased resting mean arterial pressure by 7.9+/-1.6 mm Hg, but mean arterial pressure did not increase with sham IH (1.9+/-1.5 mm Hg) or with losartan IH (-0.2+/-2.4 mm Hg; P<0.05). Exposure to IH prevented the diurnal decrease in the cerebral blood flow response to hypoxia, independently of the renin-angiotensin system. Finally, in contrast to other models of IH, the acute hypoxic ventilatory response did not change throughout the protocol. IH increases arterial blood pressure through activation of the type I angiotensin II receptor, without a demonstrable impact on the cerebrovascular or ventilatory response to acute hypoxia.
Relationship between primary aldosteronism and obstructive sleep apnoea, metabolic abnormalities and cardiac structure in patients with resistant hypertension.
Prejbisz Aleksander,Florczak Elżbieta,Klisiewicz Anna,Dobrowolski Piotr,Janaszek-Sitkowska Hanna,Bieleń Przemysław,Szwench-Pietrasz Elżbieta,Warchoł-Celińska Ewa,Kołodziejczyk-Kruk Sylwia,Janas Jadwiga,Kabat Marek,Imiela Jacek,Sliwiński Paweł,Januszewicz Andrzej
INTRODUCTION:The aim of this study was to evaluate in patients with resistant hypertension (RHTN) enrolled in the RESIST-POL study the relationship between primary aldosteronism (PA) and obstructive sleep apnoea (OSA) and their effect on metabolic abnormalities and cardiac structure. MATERIAL AND METHODS:We included 204 patients (123 M, 81 F, mean age 48.4 yrs) with true RHTN, eGFR > 60 mL/min/1,73 m(2) and no known diabetes. OSA was defined as an apnoea/hypopnoea index of 15/h or more. Metabolic syndrome components were assessed. On echocardiography, left ventricular hypertrophy (LVH), concentric remodelling (RWT > 0.45), E' velocity, E/E' index and global strain (GLS) were evaluated. RESULTS:PA was diagnosed in 32 patients (15.7%). OSA occurred more frequently in patients with PA (59.4 v. 42.4%; p = 0.058). Patients were divided into four groups: PA+ OSA+ , PA+ OSA-, PA-OSA+ and PA-OSA-. Newly diagnosed diabetes, impaired glucose tolerance and increased fasting glucose were most frequent in the PA+ OSA+ group compared to other groups. The presence of OSA was associated with concentric remodelling, and the presence of PA was associated with higher left ventricular mass and higher frequency of left ventricular hypertrophy. In the PA+ OSA+ and PA+ OSA- groups, the most frequent geometry patterns were concentric hypertrophy (68.4%) and eccentric hypertrophy (54.5%) respectively. E' velocity was lowest and E/E' was highest in PA+ OSA+ compared to other groups. GLS was lower in patients with OSA compared to those without OSA. CONCLUSIONS:Both metabolic abnormalities and target organ damage are more pronounced in patients with RHTN, PA and OSA. OSA and PA influence differently left ventricular geometry.
Obstructive sleep apnea and hypertension.
Calhoun David A
Current hypertension reports
Obstructive sleep apnea (OSA) and hypertension commonly coexist. Observational studies indicate that untreated OSA is associated with an increased risk of prevalent hypertension, whereas prospective studies of normotensive cohorts suggest that OSA may increase the risk of incident hypertension. Randomized evaluations of continuous positive airway pressure (CPAP) indicate an overall modest effect on blood pressure. However, these studies do indicate a wide variation in the blood pressure effects of CPAP, with some patients, on an individual basis, manifesting a large antihypertensive benefit. OSA is particularly common in patients with resistant hypertension. The reason for this high prevalence of OSA is not fully explained, but data from our laboratory suggest that it may be related to the high occurrence of hyperaldosteronism in patients with resistant hypertension. We hypothesize that aldosterone excess worsens OSA by promoting accumulation of fluid in the neck, which then contributes to increased upper airway resistance.
Increased dietary sodium is related to severity of obstructive sleep apnea in patients with resistant hypertension and hyperaldosteronism.
Pimenta Eduardo,Stowasser Michael,Gordon Richard D,Harding Susan M,Batlouni Michel,Zhang Bin,Oparil Suzanne,Calhoun David A
BACKGROUND:Obstructive sleep apnea (OSA) is a strong and independent risk factor for the development of hypertension, particularly resistant hypertension, and cardiovascular diseases. Patients with resistant hypertension have a high prevalence of OSA in association with elevated aldosterone levels, high salt intake, and salt-sensitive BP. The objective of this study was to determine whether dietary salt and aldosterone are associated with severity of OSA in patients with resistant hypertension. METHODS:Ninety-seven patients with resistant hypertension were prospectively evaluated by overnight polysomnography and 24-h urinary sodium and aldosterone levels while maintaining their usual diet. Hyperaldosteronism was defined as a plasma renin activity of < 1 ng/mL/h and urinary aldosterone level of ≥ 12 μg/24 h. RESULTS:Overall, patients' mean clinic BP was 156.3 ± 22.4/88.9 ± 13.3 mm Hg while taking an average of 4.3 ± 1.1 antihypertensive medications. Prevalence of OSA was 77.3%. Twenty-eight (28.9%) patients had hyperaldosteronism. Urinary sodium level was an independent predictor of severity of OSA only in patients with hyperaldosteronism. CONCLUSIONS:The findings suggest that dietary salt is related to the severity of OSA in patients with resistant hypertension and hyperaldosteronism. The results support dietary salt restriction as a treatment strategy for reduction of OSA severity in these patients.
Aldosteronism and resistant hypertension.
Acelajado Maria Czarina,Calhoun David A
International journal of hypertension
Resistant hypertension (RHTN) is defined as blood pressure (BP) that remains uncontrolled in spite of intake of ≥3 antihypertensive medications, ideally prescribed at optimal doses and one of which is a diuretic. The incidence of primary aldosteronism (PA) in patients with RHTN is estimated in prospective studies to be 14 to 23%, which is higher than in the general hypertensive population. Patients with PA are at an increased cardiovascular risk, as shown by higher rates of stroke, myocardial infarction, and arrhythmias compared to hypertensive individuals without PA. Likewise, RHTN is associated with adverse cardiovascular outcomes, and the contribution of PA to this increased risk is undetermined. Similar to PA, obstructive sleep apnea (OSA) is closely associated with RHTN, and a causal link between PA, OSA, and RHTN remains to be elucidated. The addition of MR antagonists to the antihypertensive regimen in patients with RHTN produces a profound BP-lowering effect, and this effect is seen in patients with or without biochemical evidence of PA, highlighting the role of relative aldosterone excess in driving treatment resistance in this group of patients.
Characterization of resistant hypertension: association between resistant hypertension, aldosterone, and persistent intravascular volume expansion.
Gaddam Krishna K,Nishizaka Mari K,Pratt-Ubunama Monique N,Pimenta Eduardo,Aban Inmaculada,Oparil Suzanne,Calhoun David A
Archives of internal medicine
BACKGROUND:Resistant hypertension is a common clinical problem and greatly increases the risk of target organ damage. METHODS:We evaluated the characteristics of 279 consecutive patients with resistant hypertension (uncontrolled despite the use of 3 antihypertensive agents) and 53 control subjects (with normotension or hypertension controlled by using <or=2 antihypertensive medications). Participants were prospectively examined for plasma aldosterone concentration, plasma renin activity, aldosterone to renin ratio, brain-type natriuretic peptide, atrial natriuretic peptide, and 24-hour urinary aldosterone (UAldo), cortisol, sodium, and potassium values while adhering to a routine diet. RESULTS:Plasma aldosterone (P < .001), aldosterone to renin ratio (P < .001), 24-hour UAldo (P = .02), brain-type natriuretic peptide (P = .007), and atrial natriuretic peptide (P = .001) values were higher and plasma renin activity (P = .02) and serum potassium (P < .001) values were lower in patients with resistant hypertension vs controls. Of patients with resistant hypertension, men had significantly higher plasma aldosterone (P = .003), aldosterone to renin ratio (P = .02), 24-hour UAldo (P < .001), and urinary cortisol (P < .001) values than women. In univariate linear regression analysis, body mass index (P = .01), serum potassium (P < .001), urinary cortisol (P < .001), urinary sodium (P = .02), and urinary potassium (P < .001) values were correlated with 24-hour UAldo levels. Serum potassium (P = .001), urinary potassium (P < .001), and urinary sodium (P = .03) levels were predictors of 24-hour UAldo levels in multivariate modeling. CONCLUSIONS:Aldosterone levels are higher and there is evidence of intravascular volume expansion (higher brain-type and atrial natriuretic peptide levels) in patients with resistant hypertension vs controls. These differences are most pronounced in men. A significant correlation between 24-hour urinary aldosterone levels and cortisol excretion suggests that a common stimulus, such as corticotropin, may underlie the aldosterone excess in patients with resistant hypertension.
Prevalence, Characteristics, and Association of Obstructive Sleep Apnea with Blood Pressure Control in Patients with Resistant Hypertension.
Sapiña-Beltrán Esther,Torres Gerard,Benitez Ivan,Fortuna-Gutiérrez Ana Maria,Márquez Paola Ponte,Masa Juan Fernando,Corral-Peñafiel Jaime,Drager Luciano F,Cabrini Mayara,Félez Miguel,Vázquez Susana,Abad Jorge,Lee Chi-Hang,Aung Aye Thandar,García-Río Francisco,Casitas Raquel,Sanchez-de-la-Torre Manuel,Gaeta Anna Michela,Barbé Ferran,Dalmases Mireia
Annals of the American Thoracic Society
Obstructive sleep apnea (OSA) is associated with poor blood pressure (BP) control and resistant hypertension (RH). Nevertheless, studies assessing its prevalence, characteristics, and association with BP control in patients with RH are limited. The aim of this multicenter study was to assess the prevalence of OSA in a large cohort of subjects with RH and to evaluate the association of OSA with BP control. We recruited consecutive subjects with RH from three countries. A formal sleep test and blood pressure measurements, including 24-hour ambulatory blood pressure monitoring, were performed in all participants. In total, 284 subjects with RH were included in the final analysis. Of these, 83.5% (95% confidence interval [CI], 78.7-87.3%) had OSA (apnea-hypopnea index ≥ 5 events/h); 31.7% (95% CI, 26.5-37.3%) had mild OSA, 25.7% (95% CI, 21-31.1%) had moderate OSA, and 26.1% (95% CI, 21.3-31.5%) had severe OSA. Patients with severe OSA had higher BP values than subjects with mild to moderate or no OSA. A greater effect was observed on the average nighttime BP, with an adjusted effect of 5.72 mm Hg (95% CI, 1.08-10.35 mm Hg) in severe OSA compared with participants without OSA. A dose-response association between the severity of OSA and BP values was observed. The prevalence of severe OSA was slightly higher in uncontrolled participants (adjusted odds ratio, 1.69; 95% CI, 0.97-2.99) but was not statistically significant. The present study confirms the high prevalence of OSA in participants with RH. Furthermore, it shows a dose-response association between OSA severity and BP measurements, especially in the nighttime.Clinical trial registered with www.clinicaltrials.gov (NCT03002558).
Cardiovascular complications of patients with aldosteronism associated with autonomous cortisol secretion.
Nakajima Yasuyo,Yamada Masanobu,Taguchi Ryo,Satoh Tetsurou,Hashimoto Koshi,Ozawa Atsushi,Shibusawa Nobuyuki,Okada Shuichi,Monden Tsuyoshi,Mori Masatomo
The Journal of clinical endocrinology and metabolism
CONTEXT:Primary aldosteronism (PA) is sometimes associated with the autonomous secretion of cortisol. OBJECTIVE:Our objective was to investigate the effect of autonomous cortisol secretion on the prevalence of cardiovascular events (CVE) in patients with PA. DESIGN:This was a retrospective cross-sectional study of cases collected from Gunma University Hospital between 2002 and 2010. PATIENTS:Seventy-six consecutive patients hospitalized for an evaluation of PA were analyzed. MAIN OUTCOME MEASURES:Rates of CVE dependent on autonomous cortisol secretion were examined. RESULTS:Of the 76 patients with PA, 21 (28%) had a history of CVE, including 14 with stroke, one with myocardial infarction, and six with atrial fibrillation. The multivariate logistic-regression and receiver operating characteristic analyses revealed that PA patients with CVE had significantly higher midnight cortisol levels than those without CVE; the adjusted odds ratio with a cutoff value of 7.4 μg/dl was 7.0 (95% confidence interval, 1.8-30.6; P = 0.006). In addition, results of the 1-mg dexamethasone suppression test with a cutoff value of 3.0 μg/dl differed significantly (odds ratio, 5.0; 95% confidence interval, 1.4-20.7; P = 0.018). Conversely, 67 and 50% of the PA patients with a midnight cortisol level of at least 7.4 μg/dl and 1-mg dexamethasone suppression test of at least 3.0 μg/dl had a history of CVE. Other factors such as age, expected glomerular filtration rate, blood pressure, glucose intolerance, the serum aldosterone concentration, plasma renin activity, and the duration of hypertension had no effect. CONCLUSION:The patients with PA associated with autonomous cortisol secretion had high incidence of CVE, and this association may further increase the risk of CVE in patients with PA.
Steroid metabolome analysis reveals prevalent glucocorticoid excess in primary aldosteronism.
Arlt Wiebke,Lang Katharina,Sitch Alice J,Dietz Anna S,Rhayem Yara,Bancos Irina,Feuchtinger Annette,Chortis Vasileios,Gilligan Lorna C,Ludwig Philippe,Riester Anna,Asbach Evelyn,Hughes Beverly A,O'Neil Donna M,Bidlingmaier Martin,Tomlinson Jeremy W,Hassan-Smith Zaki K,Rees D Aled,Adolf Christian,Hahner Stefanie,Quinkler Marcus,Dekkers Tanja,Deinum Jaap,Biehl Michael,Keevil Brian G,Shackleton Cedric Hl,Deeks Jonathan J,Walch Axel K,Beuschlein Felix,Reincke Martin
BACKGROUND:Adrenal aldosterone excess is the most common cause of secondary hypertension and is associated with increased cardiovascular morbidity. However, adverse metabolic risk in primary aldosteronism extends beyond hypertension, with increased rates of insulin resistance, type 2 diabetes, and osteoporosis, which cannot be easily explained by aldosterone excess. METHODS:We performed mass spectrometry-based analysis of a 24-hour urine steroid metabolome in 174 newly diagnosed patients with primary aldosteronism (103 unilateral adenomas, 71 bilateral adrenal hyperplasias) in comparison to 162 healthy controls, 56 patients with endocrine inactive adrenal adenoma, 104 patients with mild subclinical, and 47 with clinically overt adrenal cortisol excess. We also analyzed the expression of cortisol-producing CYP11B1 and aldosterone-producing CYP11B2 enzymes in adenoma tissue from 57 patients with aldosterone-producing adenoma, employing immunohistochemistry with digital image analysis. RESULTS:Primary aldosteronism patients had significantly increased cortisol and total glucocorticoid metabolite excretion (all P < 0.001), only exceeded by glucocorticoid output in patients with clinically overt adrenal Cushing syndrome. Several surrogate parameters of metabolic risk correlated significantly with glucocorticoid but not mineralocorticoid output. Intratumoral CYP11B1 expression was significantly associated with the corresponding in vivo glucocorticoid excretion. Unilateral adrenalectomy resolved both mineralocorticoid and glucocorticoid excess. Postoperative evidence of adrenal insufficiency was found in 13 (29%) of 45 consecutively tested patients. CONCLUSION:Our data indicate that glucocorticoid cosecretion is frequently found in primary aldosteronism and contributes to associated metabolic risk. Mineralocorticoid receptor antagonist therapy alone may not be sufficient to counteract adverse metabolic risk in medically treated patients with primary aldosteronism. FUNDING:Medical Research Council UK, Wellcome Trust, European Commission.
Sympathetic nervous system in obesity-related hypertension: mechanisms and clinical implications.
Kalil Graziela Z,Haynes William G
Hypertension research : official journal of the Japanese Society of Hypertension
Obesity markedly increases the risk of hypertension and cardiovascular disease, which may be related to activation of the sympathetic nervous system (SNS). Sympathetic overactivity directly and indirectly contributes to blood pressure (BP) elevation in obesity, including stimulation of the renin-angiotensin-aldosterone system (RAAS). The adipocyte-derived peptide leptin suppresses appetite, increases thermogenesis, but also raises SNS activity and BP. Obese individuals exhibit hyperleptinemia but are resistant to its appetite-suppressing actions. Interestingly, animal models of obesity exhibit preserved sympathoexcitatory and pressor actions of leptin, despite resistance to its anorexic and metabolic actions, suggesting selective leptin resistance. Disturbance of intracellular signaling at specific hypothalamic neural networks appears to underlie selective leptin resistance. Delineation of these pathways should lead to novel approaches to treatment. In the meantime, treatment of obesity-hypertension has relied on antihypertensive drugs. Although sympathetic blockade is mechanistically attractive in obesity-hypertension, in practice its effects are disappointing because of adverse metabolic effects and inferior outcomes. On the basis of subgroup analyses of obese patients in large randomized clinical trials, drugs such as diuretics and RAAS blockers appear superior in preventing cardiovascular events in obesity--hypertension. An underused alternative approach to obesity-hypertension is induction of weight loss, which reduces circulating leptin and insulin, partially reverses resistance to these hormones, decreases sympathetic activation and improves BP and other risk factors. Though weight loss induced by lifestyle is often modest and transient, carefully selected pharmacological weight loss therapies can produce substantial and sustained antihypertensive effects additive to lifestyle interventions.
Adipose angiotensinogen is involved in adipose tissue growth and blood pressure regulation.
Massiéra F,Bloch-Faure M,Ceiler D,Murakami K,Fukamizu A,Gasc J M,Quignard-Boulange A,Negrel R,Ailhaud G,Seydoux J,Meneton P,Teboul M
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
White adipose tissue and liver are important angiotensinogen (AGT) production sites. Until now, plasma AGT was considered to be a reflection of hepatic production. Because plasma AGT concentration has been reported to correlate with blood pressure, and to be associated with body mass index, we investigated whether adipose AGT is released locally and into the blood stream. For this purpose, we have generated transgenic mice either in which adipose AGT is overexpressed or in which AGT expression is restricted to adipose tissue. This was achieved by the use of the aP2 adipocyte-specific promoter driving the expression of rat agt cDNA in both wild-type and hypotensive AGT-deficient mice. Our results show that in both genotypes, targeted expression of AGT in adipose tissue increases fat mass. Mice whose AGT expression is restricted to adipose tissue have AGT circulating in the blood stream, are normotensive, and exhibit restored renal function compared with AGT-deficient mice. Moreover, mice that overexpress adipose AGT have increased levels of circulating AGT, compared with wild-type mice, and are hypertensive. These animal models demonstrate that AGT produced by adipose tissue plays a role in both local adipose tissue development and in the endocrine system, which supports a role of adipose AGT in hypertensive obese patients.
Role for aldosterone in blood pressure regulation of obese adolescents.
Rocchini A P,Katch V L,Grekin R,Moorehead C,Anderson J
The American journal of cardiology
To determine the role of aldosterone in the regulation of blood pressure (BP) in obese adolescents, supine and 2-hour upright plasma renin activity (PRA), and aldosterone and cortisol were measured in 10 nonobese and 30 obese adolescents before and after a 20-week weight loss program. The obese adolescents had significantly higher supine and 2-hour upright plasma aldosterone concentrations (17 +/- 8 vs 6 +/- 2 ng/dl [p less than 0.01 supine obese vs nonobese] and 30 +/- 11 vs 14 +/- 8 ng/dl [p less than 0.01 2-hour upright]). Although PRA was not significantly different between the 2 groups of children, a given increment in PRA produced a greater increment in aldosterone in the obese adolescents. In addition, obese subjects had a significantly increased mean BP (93 +/- 12 vs 74 +/- 8, p less than 0.005) and a weak correlation between BP and plasma aldosterone concentration. Compared with an obese control group, weight loss resulted in a significant decrease in plasma aldosterone (p less than 0.01) without an associated decrease in PRA. After weight loss there was also a significant decrease in the slope of the posture-induced relation between PRA and aldosterone. In addition to weight loss being associated with a significant decrease in BP (p less than 0.01), there was a significant correlation between the change in plasma aldosterone and the change in mean BP (r = 0.538; p less than 0.002 change in upright aldosterone vs change in mean BP). Obese adolescents have an increased plasma aldosterone concentration that may be important in the regulation of their BP.
Mechanisms of obesity-related hypertension.
Lamounier-Zepter V,Bornstein S R,Ehrhart-Bornstein M
Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme
Obesity has become an epidemic problem in western societies, contributing to metabolic diseases, hypertension and cardiovascular disease. Although the importance of obesity as a cause of hypertension is well established, the molecular basis of the relationship between obesity and increased blood pressure remains poorly understood. This brief review examines the association between obesity and hypertension along with the mechanisms proposed to explain this association, while presenting evidence of a direct causal effect of adipose tissue in the development of hypertension through the involvement of the adrenal cortex.
Obstructive Sleep Apnea and Diabetes: A State of the Art Review.
Reutrakul Sirimon,Mokhlesi Babak
OSA is a chronic treatable sleep disorder and a frequent comorbidity in patients with type 2 diabetes. Cardinal features of OSA, including intermittent hypoxemia and sleep fragmentation, have been linked to abnormal glucose metabolism in laboratory-based experiments. OSA has also been linked to the development of incident type 2 diabetes. The relationship between OSA and type 2 diabetes may be bidirectional in nature given that diabetic neuropathy can affect central control of respiration and upper airway neural reflexes, promoting sleep-disordered breathing. Despite the strong association between OSA and type 2 diabetes, the effect of treatment with CPAP on markers of glucose metabolism has been conflicting. Variability with CPAP adherence may be one of the key factors behind these conflicting results. Finally, accumulating data suggest an association between OSA and type 1 diabetes as well as gestational diabetes. This review explores the role of OSA in the pathogenesis of type 2 diabetes, glucose metabolism dysregulation, and the impact of OSA treatment on glucose metabolism. The association between OSA and diabetic complications as well as gestational diabetes is also reviewed.
Obstructive sleep apnea and abnormal glucose metabolism.
Kim Nan Hee
Diabetes & metabolism journal
Obstructive sleep apnea (OSA) is a chronic disorder that is prevalent, especially in subjects with obesity or diabetes. OSA is related to several metabolic abnormalities, including diabetes, insulin resistance, hypertension, and cardiovascular diseases. Although Koreans are less obese than Caucasians, the prevalence of OSA is comparable in both groups. Thus, the impact of OSA on metabolism may be similar. Many epidemiologic and experimental studies have demonstrated that OSA is associated with glucose intolerance and insulin resistance via intermittent hypoxia, sleep fragmentation, and sleep deprivation. The effect of continuous positive airway pressure treatment on glucose metabolism is still controversial. Randomized controlled trials are needed to evaluate the ability of OSA treatment to reduce the risk of diabetes and insulin resistance in subjects without diabetes and to ameliorate glucose control in patients with diabetes.
Obstructive sleep apnea is independently associated with insulin resistance.
Ip Mary S M,Lam Bing,Ng Matthew M T,Lam Wah Kit,Tsang Kenneth W T,Lam Karen S L
American journal of respiratory and critical care medicine
Epidemiological studies have implicated obstructive sleep apnea (OSA) as an independent comorbid factor in cardiovascular and cerebrovascular diseases. It is postulated that recurrent episodes of occlusion of upper airways during sleep result in pathophysiological changes that may predispose to vascular diseases. Insulin resistance is a known risk factor for atherosclerosis, and we postulate that OSA represents a stress that promotes insulin resistance, hence atherogenesis. This study investigated the relationship between sleep-disordered breathing and insulin resistance, indicated by fasting serum insulin level and insulin resistance index based on the homeostasis model assessment method (HOMA-IR). A total of 270 consecutive subjects (197 male) who were referred for polysomnography and who did not have known diabetes mellitus were included, and 185 were documented to have OSA defined as an apnea-hypopnea index (AHI) > or =5. OSA subjects were more insulin resistant, as indicated by higher levels of fasting serum insulin (p = 0.001) and HOMA-IR (p < 0.001); they were also older and more obese. Stepwise multiple linear regression analysis showed that obesity was the major determinant of insulin resistance but sleep-disordered breathing parameters (AHI and minimum oxygen saturation) were also independent determinants of insulin resistance (fasting insulin: AHI, p = 0.02, minimum O(2), p = 0.041; HOMA-IR: AHI, p = 0.044, minimum O(2), p = 0.022); this association between OSA and insulin resistance was seen in both obese and nonobese subjects. Each additional apnea or hypopnea per sleep hour increased the fasting insulin level and HOMA-IR by about 0.5%. Further analysis of the relationship of insulin resistance and hypertension confirmed that insulin resistance was a significant factor for hypertension in this cohort. Our findings suggest that OSA is independently associated with insulin resistance, and its role in the atherogenic potential of sleep disordered breathing is worthy of further exploration.
Obstructive sleep apnea: a cardiometabolic risk in obesity and the metabolic syndrome.
Drager Luciano F,Togeiro Sônia M,Polotsky Vsevolod Y,Lorenzi-Filho Geraldo
Journal of the American College of Cardiology
Obstructive sleep apnea (OSA) is an underdiagnosed condition characterized by recurrent episodes of obstruction of the upper airway leading to sleep fragmentation and intermittent hypoxia during sleep. Obesity predisposes to OSA, and the prevalence of OSA is increasing worldwide because of the ongoing epidemic of obesity. Recent evidence has shown that surrogate markers of cardiovascular risk, including sympathetic activation, systemic inflammation, and endothelial dysfunction, are significantly increased in obese patients with OSA versus those without OSA, suggesting that OSA is not simply an epiphenomenon of obesity. Moreover, findings from animal models and patients with OSA show that intermittent hypoxia exacerbates the metabolic dysfunction of obesity, augmenting insulin resistance and nonalcoholic fatty liver disease. In patients with the metabolic syndrome, the prevalence of moderate to severe OSA is very high (∼60%). In this population, OSA is independently associated with increased glucose and triglyceride levels as well as markers of inflammation, arterial stiffness, and atherosclerosis. A recent randomized, controlled, crossover study showed that effective treatment of OSA with continuous positive airway pressure for 3 months significantly reduced several components of the metabolic syndrome, including blood pressure, triglyceride levels, and visceral fat. Finally, several cohort studies have consistently shown that OSA is associated with increased cardiovascular mortality, independent of obesity. Taken together, these results support the concept that OSA exacerbates the cardiometabolic risk attributed to obesity and the metabolic syndrome. Recognition and treatment of OSA may decrease the cardiovascular risk in obese patients.
Primary aldosteronism: who should be screened?
Monticone S,Viola A,Tizzani D,Crudo V,Burrello J,Galmozzi M,Veglio F,Mulatero P
Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme
Primary aldosteronism (PA) has a prevalence in the general hypertensive population from 5 to 10%, and is widely recognized as the most frequent form of secondary hypertension. The 2 main PA subtypes are aldosterone producing adenoma (APA) and bilateral adrenal hyperplasia (BAH) that account for 95% of all PA cases. The diagnosis of PA is a 3-step process that comprises screening, confirmatory testing, and subtype differentiation. The different categories of patients at an increased risk of PA who should thus undergo a screening test were described in the first Endocrine Society (ES) Practice Guidelines for diagnosis and treatment of PA published in 2008. These categories include patients with Joint National Committee Stage 2, Stage 3, or drug-resistant hypertension; hypertension, and spontaneous or diuretic-induced hypokalemia; hypertension with adrenal incidentaloma; hypertension and a family history of early-onset hypertension or cerebrovascular accident at a young age and all hypertensive first degree relatives of patients with PA. Recently, a growing number of studies have linked PA with the metabolic syndrome, diabetes, and obstructive sleep apnea that may be partly responsible for the higher rate of cardio and cerobrovascular accidents in PA patients. The aim of this review is to discuss, which patients should be screened for PA, focusing not only on the well-established categories of the ES Guidelines, but also on additional other group of patients with a potentially high prevalence of PA that has emerged from recent research.
Effect of eplerenone on the severity of obstructive sleep apnea and arterial stiffness in patients with resistant arterial hypertension.
Krasińska Beata,Miazga Angelika,Cofta Szczepan,Szczepaniak-Chicheł Ludwina,Trafas Tomasz,Krasiński Zbigniew,Pawlaczyk-Gabriel Katarzyna,Tykarski Andrzej
Polskie Archiwum Medycyny Wewnetrznej
INTRODUCTION Obstructive sleep apnea (OSA) is considered to be one of the major causes of resistant arterial hypertension (RAH). Apnea episodes cause hypoxia, which triggers the activation of the renin-angiotensin-aldosterone system. This leads to water retention and swelling in the neck region, exacerbating OSA symptoms. It is assumed that the use of eplerenone may reduce the swelling and thus alleviate the severity of OSA. OBJECTIVES We aimed to prospectively assess the impact of eplerenone on the severity of OSA and arterial stiffness in patients with RAH. PATIENTS AND METHODS The study included 31 patients with RAH and OSA. The exclusion criteria were as follows: secondary hypertension, myocardial infarction, stroke 6 months prior to the study, congestive heart failure, chronic kidney failure, alcohol or drug addiction, and active cancer. In all patients, the following tests were performed: blood pressure (BP) measurement (traditionally and using ambulatory BP measuring [ABPM]), applanation tonometry, polysomnography, and the apnea-hypopnea index (AHI) calculation. The tests were done before and after 3 months of eplerenone therapy. Patients received 50 mg of oral eplerenone daily, along with other hypertensive drugs. RESULTS The mean age of participants was 57.76 ±6.16 years. After 3 months of eplerenone therapy, we observed a significant reduction in the AHI, neck circumference, BP, aortic pulse wave, and arterial wall stiffness. There were significant correlations between the AHI and mean BP measured by ABPM and between the AHI and arterial stiffness parameters. CONCLUSIONS Our results provide evidence for the clinical significance of eplerenone, not only as an antihypertensive medication but also as a drug that may reduce the severity of OSA and arterial stiffness in patients with RAH and OSA.
Spironolactone reduces severity of obstructive sleep apnoea in patients with resistant hypertension: a preliminary report.
Gaddam K,Pimenta E,Thomas S J,Cofield S S,Oparil S,Harding S M,Calhoun D A
Journal of human hypertension
Obstructive sleep apnoea (OSA) and hyperaldosteronism are very common in subjects with resistant hypertension. We hypothesized that aldosterone-mediated chronic fluid retention may influence OSA severity in patients with resistant hypertension. We tested this in an open-label evaluation by assessing the changes in the severity of OSA in patients with resistant hypertension after treatment with spironolactone. Subjects with resistant hypertension (clinical blood pressure (BP) >or=140/90 mm Hg on >or=3 antihypertensive medications, including a thiazide diuretic and OSA (defined as an apnoea-hypopnoea index (AHI) >or=15) had full diagnostic, polysomnography before and 8 weeks after spironolactone (25-50 mg a day) was added to their ongoing antihypertensive therapy. In all, 12 patients (mean age 56 years and body mass index 36.8 kg m(-2)) were evaluated. After treatment with spironolactone, the AHI (39.8+/-19.5 vs 22.0+/-6.8 events/h; P<0.05) and hypoxic index (13.6+/-10.8 vs 6.7+/-6.6 events/h; P<0.05), weight and clinic and ambulatory BP were significantly reduced. Plasma renin activity (PRA) and serum creatinine were significantly higher. This study provides preliminary evidence that treatment with a mineralocorticoid receptor antagonist substantially reduces the severity of OSA. If confirmed in a randomized assessment, it will support aldosterone-mediated chronic fluid retention as an important mediator of OSA severity in patients with resistant hypertension.
Prevalence and associated factors of obstructive sleep apnea in patients with resistant hypertension.
Muxfeldt Elizabeth S,Margallo Victor S,Guimarães Gleison M,Salles Gil F
American journal of hypertension
BACKGROUND:Obstructive sleep apnea (OSA) syndromes are strongly associated with resistant hypertension, although this has not been systematically examined. The aim of our study was to investigate the prevalence of OSA and its associated factors in a large cohort of resistant hypertensive patients. METHODS:A cross-sectional analysis with 422 resistant hypertensive patients (31.3% men; mean age = 62.4±9.9 years) submitted to a full-night polysomnography. The presence of OSA was defined by an apnea-hypopnea index (AHI) >5 per hour and moderate/severe OSA was defined by an AHI >15. Statistical analysis included bivariable comparisons between patients with and without moderate/severe OSA and logistic regressions to assess the independent correlates of OSA severity. RESULTS:Three-hundred forty-seven patients (82.2%) had OSA, and 234 patients (55.5%) had moderate/severe OSA. Patients with moderate/severe OSA were more frequently elderly and obese men with larger waist and neck circumferences, had higher prevalences of diabetes and left ventricular hypertrophy, and had higher proteinuria than patients with no/mild OSA. No difference was found in plasma aldosterone and renin activity. Nighttime systolic blood pressures and pulse pressures were higher in moderate/severe OSA, with lower nocturnal blood pressure fall. In multivariable logistic regression, male sex, older age, diabetes, obesity, increased waist and neck circumferences, and nighttime systolic blood pressure were the independent correlates of moderate/severe OSA. CONCLUSIONS:Resistant hypertensive patients had a very high prevalence of OSA, and patients with moderate/severe OSA had an adverse ambulatory BP profile, with higher nighttime systolic blood pressures and pulse pressures and higher prevalence of nondipping patterns. Other correlates of OSA severity were mainly demographic-anthropometric variables.
Effect of intensified diuretic therapy on overnight rostral fluid shift and obstructive sleep apnoea in patients with uncontrolled hypertension.
Kasai Takatoshi,Bradley T Douglas,Friedman Oded,Logan Alexander G
Journal of hypertension
OBJECTIVES:Fluid displacement from the lower extremities to the upper body during sleep is strongly associated with obstructive sleep apnoea in hypertensive patients. The present pathophysiological study tests the hypothesis that intensified diuretic therapy will reduce the apnoea-hypopnoea index and blood pressure of uncontrolled hypertensive patients with obstructive sleep apnoea in proportion to the reduction in overnight change in leg fluid volume. METHODS:Uncontrolled treated hypertensive patients underwent overnight polysomnography and measurement of overnight changes in leg fluid volume and neck circumference. Those with an apnoea-hypopnoea index at least 20 events per hour (n=16) received metolazone 2.5 mg and spironolactone 25 mg daily for 7 days after which the daily dose was doubled for 7 additional days. Baseline testing was again repeated. RESULTS:Intensified diuretic therapy reduced the apnoea-hypopnoea index from 57.7 ± 33.0 to 48.5 ± 28.2 events per hour (P=0.005), overnight change in leg fluid volume from -418.1 ± 177.5 to -307.5 ± 161.9 ml (P<0.001) and overnight change in neck circumference from 1.2 ± 0.6 to 0.7 ± 0.4 cm (P<0.001). There was an inverse correlation between the reduction in overnight change in leg fluid volume and decrease in apnoea-hypopnoea index (r=-0.734, P=0.001). The reduction in overnight change in leg fluid volume was also significantly correlated with the change in morning blood pressure (r=0.708, P=0.002 for SBP; r=0.512, P=0.043 for DBP). CONCLUSION:The findings provide further evidence that fluid redistribution from the legs to the neck during sleep contributes to the severity of obstructive sleep apnoea in hypertension and may be an important link between these two conditions.
Targeting volume overload and overnight rostral fluid shift: A new perspective to treat sleep apnea.
Perger Elisa,Jutant Etienne-Marie,Redolfi Stefania
Sleep medicine reviews
Sleep apnea is a common condition associated with increased morbidity and mortality. Continuous positive airway pressure and oral appliances are efficient for treating sleep apnea; however, they are often poorly tolerated. Therefore, alternative therapies are needed. Overnight rostral fluid shift has been implicated in the pathogenesis of sleep apnea, particularly in conditions associated with fluid overload. Fluid shift predisposes to both obstructive and central sleep apnea, with the type of sleep apnea being related to whether the fluid shifts from the legs into the neck or chest, respectively. The amount of fluid that shifts from the legs to the upper part of the body at night is correlated with the severity of sleep apnea. As a result of this observation, it has been suggested that the prevention of overnight fluid shift may reduce sleep apnea severity. It has recently been shown that interventions targeting fluid overload and daytime fluid accumulation in the legs consistently attenuate nocturnal fluid shift and sleep apnea, as greater reductions in fluid shift are correlated with greater reductions in sleep apnea severity. This review will focus on interventions that counteract fluid shift, such as diuretics, ultrafiltration/dialysis, physical activity, compression stockings and salt/fluid restriction, which have been shown to have efficacy in reducing sleep apnea severity.
Sleep apnea, aldosterone, and resistant hypertension.
Pimenta Eduardo,Calhoun David A,Oparil Suzanne
Progress in cardiovascular diseases
Obstructive sleep apnea, aldosterone excess, and resistant hypertension are common comorbidities in obese patients. The mechanisms that link these conditions are not fully elucidated, but sympathetic nervous system activation, sodium retention, renin-angiotensin-aldosterone system stimulation, endothelial dysfunction, and increased production of reactive oxidative species may be contributing factors. Patients diagnosed with this triad should be treated with low-salt diet, weight-loss counseling, and continuous positive airway pressure, as well as aggressive antihypertensive therapy, usually with multiple agents, including a mineralocorticoid receptor antagonist. Patients with aldosterone-producing adenoma may require adrenalectomy.
Abnormal vasoactive hormones and 24-hour blood pressure in obstructive sleep apnea.
Møller Dorthe S,Lind Pernille,Strunge Benedicte,Pedersen Erling B
American journal of hypertension
BACKGROUND:Patients with obstructive sleep apnea (OSA) are at increased risk for hypertension. The mechanisms responsible for the development of hypertension are controversial. We hypothesized that patients with OSA had an abnormal 24-h blood pressure (BP) and an abnormal activity in vasoactive hormones, and that both BP and hormones were normalized during treatment with long-term nasal continuous positive airway pressure (CPAP). METHODS:The 24-h BP and plasma levels of the vasoactive hormones (renin, angiotensin II, aldosterone, atrial natriuretic peptide, brain natriuretic peptide, vasopressin, and endothelin-1) were measured in 24 patients with OSA and in 18 control subjects. Thirteen patients with OSA were reexamined after 14 months of CPAP therapy. RESULTS:Patients with OSA had significantly increased BP and heart rate and a reduced nocturnal BP drop. Both angiotensin II (13.3 +/- 1.6 v 7.8 +/- 1.0 pmol/L) and aldosterone (94.0 +/- 9.4 v 62.2 +/- 4.5 pmol/L) were significantly higher in OSA than in control subjects. Positive correlations were found between angiotensin II and daytime BP (systolic: r = 0.49, P <.01; diastolic: r = 0.52, P <.01). The CPAP therapy resulted in a decrease in BP, and this CPAP-induced reduction in BP was correlated with a decrease in both plasma renin (r = 0.76 to 0.92, all P <.01) and plasma angiotensin II concentration (r = 0.58 to 0.81, all P <.05). CONCLUSIONS:Plasma angiotensin II and aldosterone were elevated in OSA, and plasma angiotensin II was correlated with BP. Long-term CPAP reduced BP, and this decrease in BP was correlated with the reductions in plasma renin and angiotensin II levels. We suggest that OSA mediates hypertension, at least in part, via a stimulation of angiotensin II production.
Obstructive sleep apnea, hypertension and cardiovascular diseases.
Gonzaga C,Bertolami A,Bertolami M,Amodeo C,Calhoun D
Journal of human hypertension
Obstructive sleep apnea (OSA) is characterized by recurrent episodes of partial (hypopnea) or complete interruption (apnea) in breathing during sleep due to airway collapse in the pharyngeal region. OSA and its cardiovascular consequences have been widely explored in observational and prospective studies. Most evidence verifies the positive relationship between OSA and hypertension, coronary artery disease, atrial fibrillation, stroke and heart failure. However, more studies are needed to better assess the impact of OSA, and possible benefit of treatment with continuous positive airway pressure (CPAP) on dyslipidemia, type 2 diabetes, insulin resistance and cardiovascular mortality. The leading pathophysiological mechanisms involved in the changes triggered by OSA, include intermittent hypoxemia and re-oxygenation, arousals and changes in intrathoracic pressure. Hypertension is strongly related with activation of the sympathetic nervous system, stimulation of the renin-angiotensin-aldosterone system and impairment of endothelial function. The high prevalence of OSA in the general population, hypertensive patients and especially obese individuals and patients resistant to antihypertensive therapy, highlights the need for effective screening, diagnosis and treatment of OSA to decrease cardiovascular risk.
Association Between Sleep Apnea and Blood Pressure Control Among Blacks.
Johnson Dayna A,Thomas S Justin,Abdalla Marwah,Guo Na,Yano Yuichiro,Rueschman Michael,Tanner Rikki M,Mittleman Murray A,Calhoun David A,Wilson James G,Muntner Paul,Redline Susan
BACKGROUND:Blacks have a high prevalence of hypertension and uncontrolled blood pressure (BP), each of which may be partially explained by untreated sleep apnea. We investigated the association of sleep apnea with uncontrolled BP and resistant hypertension in blacks. METHODS:Between 2012 and 2016, Jackson Heart Sleep Study participants (N=913) underwent an in-home Type 3 sleep apnea study, clinic BP measurements, and anthropometry. Moderate or severe obstructive sleep apnea (OSA) was defined as a respiratory event index ≥15, and nocturnal hypoxemia was quantified as percent sleep time with <90% oxyhemoglobin saturation. Prevalent hypertension was defined as either a systolic BP ≥130 mm Hg or diastolic BP >80mm Hg, use of antihypertensive medication, or self-report of a diagnosis of hypertension. Controlled BP was defined as systolic BP <130 mm Hg and diastolic BP <80 mm Hg; uncontrolled BP as systolic BP ≥130 mm Hg or diastolic BP ≥80 mm Hg with use of 1 to 2 classes of antihypertensive medication; and resistant BP as systolic BP ≥130 mm Hg or diastolic BP ≥80 mm Hg with the use of ≥3 classes of antihypertensive medication (including a diuretic) or use of ≥4 classes of antihypertensive medication regardless of BP level. Multinomial logistic regression models were fit to determine the association between OSA severity and uncontrolled BP or resistant hypertension (versus controlled BP) after multivariable adjustment. RESULTS:The analytic sample with hypertension (N=664) had a mean age of 64.0 (SD,10.6) years, and were predominately female (69.1%), obese (58.6%), and college educated (51.3%). Among the sample, 25.7% had OSA, which was untreated in 94% of participants. Overall, 48% of participants had uncontrolled hypertension and 14% had resistant hypertension. After adjustment for confounders, participants with moderate or severe OSA had a 2.0 times higher odds of resistant hypertension (95% confidence interval [CI], 1.14-3.67). Each standard deviation higher than <90% oxyhemoglobin saturation was associated with an adjusted odds ratio for resistant hypertension of 1.25 (95% CI 1.01-1.55). OSA and <90% oxyhemoglobin saturation were not associated with uncontrolled BP. CONCLUSION:Untreated moderate or severe OSA is associated with increased odds of resistant hypertension. These results suggest that untreated OSA may contribute to inadequate BP control in blacks.
Validity of plasma aldosterone-to-renin activity ratio in African American and white subjects with resistant hypertension.
Nishizaka Mari K,Pratt-Ubunama Monique,Zaman Mohammad A,Cofield Stacey,Calhoun David A
American journal of hypertension
BACKGROUND:Recent reports suggesting that primary aldosteronism (PA) is more common than historically thought have often relied on use of the plasma aldosterone concentration (PAC) to plasma renin activity (PRA) ratio (ARR) to identify patients with PA. Prior determinations of the validity of the ARR had been generally limited to subjects that could be withdrawn from antihypertensive therapy and to non-African American subjects. METHODS AND RESULTS:The current study was designed to evaluate prospectively the diagnostic value of the ARR in treated African American and white subjects with resistant hypertension. Consecutive subjects referred to a university hypertension clinic for resistant hypertension were evaluated with an early morning ARR and a 24-h urinary aldosterone and sodium. The presence of PA was defined as a suppressed PRA (<1.0 ng/mL/h) and elevated urinary aldosterone excretion (>12 microg/24 h) during high dietary sodium ingestion (>200 mEq/24 h). In 58 subjects, PA was confirmed. The ARR was elevated (>20) in 45 of 58 subjects with PA and in 35 of the 207 patients without PA, resulting in a sensitivity of 78% and specificity of 83% with a corresponding positive predictive value of 56% and a negative predictive value of 93%. Among African American subjects, the ARR was less sensitive than in white subjects (75% v 80%), but it still had a high negative predictive value (92% v 94%). CONCLUSIONS:These data indicate that the ARR is valid as a screening test for PA in African American and white patients on stable antihypertensive treatments, but a high percentage of false-positive results precludes using it for accurate diagnosis of PA.
Plasma levels of prorenin and renin in blacks and whites: their relative abundance and associations with plasma aldosterone concentration.
Tu Wanzhu,Eckert George J,Pratt J Howard,Jan Danser A H
American journal of hypertension
BACKGROUND:All renin arises from prorenin. The proportion of renin relative to prorenin could influence overall renin-angiotensin-aldosterone activity. We sought to determine whether prorenin levels were related to extracellular volume, as reflected by the levels of plasma renin activity (PRA), and to aldosterone. METHODS:We analyzed plasma levels of prorenin, renin, and aldosterone, as well as their interactions, in 129 young blacks and whites. RESULTS:Blacks had lower plasma renin concentration (PRC) and PRA, but had prorenin levels similar to whites (69 pg/ml in blacks vs. 62 pg/ml in whites, P = 0.41). As a result, the renin-to-total renin ratio was significantly lower in blacks (11.5% in blacks as compared to 19.8% in whites; P = 0.0001). Because prorenin also resides in tissues including the adrenal where it can bind to a specific receptor to generate angiotensin II, we examined the relationship of prorenin levels to plasma aldosterone concentrations (PAC). While a positive association between PRC and PAC was found in both blacks and whites, PAC was positively related to prorenin in whites (P = 0.04) but negatively in blacks, an observation that we hypothesize was due to reduced prorenin-to-renin conversion in blacks. CONCLUSIONS:We observed a disproportionately high level of prorenin in blacks. These high circulating prorenin levels however do not result in greater adrenal angiotensin II and aldosterone production in healthy young blacks.
Racial differences in sleep-disordered breathing in African-Americans and Caucasians.
Redline S,Tishler P V,Hans M G,Tosteson T D,Strohl K P,Spry K
American journal of respiratory and critical care medicine
In this case-control family study of sleep-disordered breathing (SDB), we describe the distributions of SDB and SDB risk factors in African-Americans and Caucasians. A total of 225 African-Americans and 622 Caucasians, ages 2 to 86 yr, recruited as members of families with an individual with known sleep apnea (85 index families) or as members of neighborhood control families (63 families) were studied with an overnight home sleep-study, questionnaires, and physical measurements. A subsample underwent cephalometry. Outcome measures were the respiratory disturbance index (RDI) and a binary variable indicating the presence of increased apneic activity (IAA). In both races, a strong relationship was demonstrated between the (log transformed) RDI and age and age2. African-Americans with SDB were younger than Caucasians with SDB (37.2 +/- 19.5 versus 45.6 +/- 18.7 yr, p < 0.01). In subjects < or = 25 yr, RDI level and IAA prevalence were higher in African-Americans (odds ratio, adjusted for obesity, sex, proband sampling, and familial clustering, 1.88, 1.03 to 3.52, 95% CI). In this age group, racial differences also were observed in the relationship between RDI and age (p < 0.001 for the RDI-age interaction). This suggests that young African-Americans may be at increased risk for sleep apnea.
Sleep-disordered breathing symptoms among African-Americans in the Jackson Heart Study.
Fülöp Tibor,Hickson DeMarc A,Wyatt Sharon B,Bhagat Rajesh,Rack Michael,Gowdy Otis,Flessner Michael F,Taylor Herman A
BACKGROUND:Sleep-disordered breathing (SDB) is an increasingly recognized risk factor for cardiovascular disease (CVD). Limited data are available from large African American cohorts. METHODS:We examined the prevalence, burden, and correlates of sleep symptoms suggestive of SDB and risk for obstructive sleep apnea (OSA) in the Jackson Heart Study (JHS), an all-African-American cohort of 5301 adults. Data on selected daytime and nighttime sleep symptoms were collected using a modified Berlin questionnaire during the baseline examination. Risk of OSA was calculated according to published prediction model. Age and multivariable-adjusted logistic regression models were used to examine the associations between potential risk factors and measures of sleep. RESULTS:Sleep symptoms, burden, and risk of OSA were high among men and women in the JHS and increased with age and obesity. Being married was positively associated with sleep symptoms among women. In men, poor to fair perceived health and increased levels of stress were associated with higher odds of sleep burden, whereas prevalent hypertension and CVD were associated with higher odds of OSA risk. Similar associations were observed among women with slight variations. Sleep duration <7h was associated with increased odds of sleep symptoms among women and increased sleep burden among men. Moderate to severe restless sleep was consistently and positively associated with odds of adverse sleep symptoms, sleep burden, and high risk OSA. CONCLUSIONS:Sleep symptoms in JHS had a strong positive association with features of visceral obesity, stress, and poor perceived health. With increasing obesity among younger African Americans, these findings are likely to have broad public health implications.
Epidemiological characteristics and gender-specific differences of obstructive sleep apnea in a Chinese hypertensive population: a cross-sectional study.
Cai Anping,Zhou Yingling,Zhang Jiawei,Zhong Qi,Wang Rui,Wang Ling
BMC cardiovascular disorders
BACKGROUND:Obstructive sleep apnea (OSA) is associated with an increase in the prevalence and incidence of hypertension and cardiovascular diseases. Data about epidemiological characteristics of OSA in Chinese hypertensive populations is limited. METHODS:Hypertensive subjects without a prior diagnosis of OSA were recruited, and the apnea-hyponea index (AHI) was assessed by polysomnography. Comparisons were performed between subjects without OSA and with different degrees of OSA. Gender-specific differences in epidemiological characteristics of OSA were also analyzed. Univariate and multivariate regression analyses were conducted to evaluate the associations between OSA and other variables. RESULTS:A total of 971 hypertensive subjects were enrolled and 685 (70.5%) were diagnosed with OSA. Compared to those without OSA, subjects with OSA were more likely male (78.4% versus 71.7%, P = 0.016) and at higher cardiovascular risk in subjects with moderate-severe OSA. Among the 685 OSA subjects, 79.4% (537 cases) were males. Gender-specific differences in epidemiological characteristics of OSA were observed. Multivariate regression analyses revealed that after adjusting for covariates, only body mass index positively correlated with OSA in males (odds ratio (OR): 1.064, 95% confidence interval (CI): 1.008-1.123, P = 0.024). In female subjects, after adjusting for covariates, only age positively correlated with OSA (OR: 1.071, 95% CI: 1.029-1.116, P = 0.001). CONCLUSION:In summary, in a Chinese hypertensive population, OSA prevalence is strikingly high. Hypertensive subjects with the most severe OSA are at greater cardiovascular risk. There are significant differences in epidemiological characteristics of OSA between male and female.
A community study of sleep-disordered breathing in middle-aged Chinese men in Hong Kong.
Ip M S,Lam B,Lauder I J,Tsang K W,Chung K F,Mok Y W,Lam W K
BACKGROUND:Sleep-disordered breathing (SDB) in Asian populations is being increasingly recognized. This study investigated the prevalence of SDB in Chinese middle-aged office-based male workers in Hong Kong. METHODS:Sleep questionnaires were distributed to 1,542 men (age range, 30 to 60 years), and 784 questionnaires were returned. Subsequently, full polysomnographic (PSG) examinations were conducted in 153 questionnaire respondents. Subjects with an apnea-hypopnea index (AHI) > or =5 were recalled for clinical assessment. RESULTS:Questionnaire respondents were similar in age and body mass index (BMI) to the general community in the target age range and gender. Habitual snoring was reported by 23% of this cohort and was associated with excessive daytime sleepiness (EDS), hypertension, witnessed abnormal breathing pattern, BMI, and leg movements during sleep. Allowing for subject bias in undergoing PSG, the estimated prevalence of SDB and obstructive sleep apnea syndrome (OSAS) (defined as SDB in the presence of EDS) at various AHI cutoff threshold values was 8.8% and 4.1% (AHI > or =5), 6.3% and 3.2% (AHI > or =10), and 5.3% and 3.1% (AHI > or =15). Multiple stepwise logistic regression analysis identified BMI, habitual snoring, time taken to fall asleep, and age as predictors of SDB at AHI > or =5. Analysis of anthropometric parameters indicated that the relative risk of OSAS attributable to obesity was less than in white subjects. CONCLUSION:This community-based study of sleep apnea among middle-aged men in Hong Kong using full PSG demonstrated an estimated prevalence of OSAS (AHI > or =5 and EDS) at 4.1%. Increasing BMI and age were associated with SDB, although factors other than adiposity may also have an important pathogenic role in OSA in Chinese subjects.
A community study of sleep-disordered breathing in middle-aged Chinese women in Hong Kong: prevalence and gender differences.
Ip Mary S M,Lam Bing,Tang Lawrence C H,Lauder Ian J,Ip Toi Yan,Lam Wah Kit
STUDY OBJECTIVES:To investigate the prevalence of sleep-disordered breathing (SDB) and obstructive sleep apnea syndrome (OSAS) in community-based, middle-aged Chinese women, and to compare the differences between gender with a similar study in men. DESIGN:A cross-sectional study conducted in Hong Kong from 1998 to 2000. SETTING:Sleep questionnaires were distributed to women (30 to 60 years old) in three offices and two community centers. All were invited to undergo full polysomnography in a sleep laboratory. PARTICIPANTS:Questionnaires were distributed to 1,532 women, and 854 questionnaires were returned. Polysomnography was conducted in 106 respondents. MEASUREMENTS AND RESULTS:Conservative estimated prevalence of SDB (apnea-hypopnea index [AHI] > = 5) and OSAS (AHI > or = 5 plus excessive daytime sleepiness [EDS]) were 3.7% and 2.1%, respectively. Age-specific prevalence of OSAS was 0.5%, 2.2%, and 6.1% in the 30- to 39-year-old, 40- to 49-year-old, and 50- to 60-year-old age groups, respectively. Stepwise multiple logistic regression analysis identified body mass index (BMI) and age as predictors of SDB. Compared to Chinese men, the prevalence of SDB and OSAS in women was lower, but the gender difference decreased with age. The AHI of affected women was also significantly lower despite comparable BMI. Compared to men, women with SDB had same degree of self-reported snoring and a similar degree of EDS despite the lower AHI. CONCLUSIONS:This study demonstrated an estimated prevalence of OSAS at 2.1% among middle-aged Chinese women in Hong Kong, with a 12-fold rise from the fourth to the sixth decade of life. BMI and age were significant independent predictors of SDB. Compared to men, women with SDB had lower AHIs, despite similar BMIs.
Racial/Ethnic Differences in Sleep Disturbances: The Multi-Ethnic Study of Atherosclerosis (MESA).
Chen Xiaoli,Wang Rui,Zee Phyllis,Lutsey Pamela L,Javaheri Sogol,Alcántara Carmela,Jackson Chandra L,Williams Michelle A,Redline Susan
OBJECTIVES:There is limited research on racial/ethnic variation in sleep disturbances. This study aimed to quantify the distributions of objectively measured sleep disordered breathing (SDB), short sleep duration, poor sleep quality, and self-reported sleep disturbances (e.g., insomnia) across racial/ethnic groups. DESIGN:Cross-sectional study. SETTING:Six US communities. PARTICIPANTS:Racially/ethnically diverse men and women aged 54-93 y in the Multi-Ethnic Study of Atherosclerosis Sleep Cohort (n = 2,230). INTERVENTIONS:N/A. MEASUREMENTS AND RESULTS:Information from polysomnography-measured SDB, actigraphy-measured sleep duration and quality, and self-reported daytime sleepiness were obtained between 2010 and 2013. Overall, 15.0% of individuals had severe SDB (apnea-hypopnea index [AHI] ≥ 30); 30.9% short sleep duration (< 6 h); 6.5% poor sleep quality (sleep efficiency < 85%); and 13.9% had daytime sleepiness. Compared with Whites, Blacks had higher odds of sleep apnea syndrome (AHI ≥ 5 plus sleepiness) (sex-, age-, and study site-adjusted odds ratio [OR] = 1.78, 95% confidence interval [CI]: 1.20, 2.63), short sleep (OR = 4.95, 95% CI: 3.56, 6.90), poor sleep quality (OR = 1.57, 95% CI: 1.00, 2.48), and daytime sleepiness (OR = 1.89, 95% CI: 1.38, 2.60). Hispanics and Chinese had higher odds of SDB and short sleep than Whites. Among non-obese individuals, Chinese had the highest odds of SDB compared to Whites. Only 7.4% to 16.2% of individuals with an AHI ≥ 15 reported a prior diagnosis of sleep apnea. CONCLUSIONS:Sleep disturbances are prevalent among middle-aged and older adults, and vary by race/ethnicity, sex, and obesity status. The high prevalence of sleep disturbances and undiagnosed sleep apnea among racial/ethnic minorities may contribute to health disparities.
Prevalence of sleep-disordered breathing in the general population: the HypnoLaus study.
Heinzer R,Vat S,Marques-Vidal P,Marti-Soler H,Andries D,Tobback N,Mooser V,Preisig M,Malhotra A,Waeber G,Vollenweider P,Tafti M,Haba-Rubio J
The Lancet. Respiratory medicine
BACKGROUND:Sleep-disordered breathing is associated with major morbidity and mortality. However, its prevalence has mainly been selectively studied in populations at risk for sleep-disordered breathing or cardiovascular diseases. Taking into account improvements in recording techniques and new criteria used to define respiratory events, we aimed to assess the prevalence of sleep-disordered breathing and associated clinical features in a large population-based sample. METHODS:Between Sept 1, 2009, and June 30, 2013, we did a population-based study (HypnoLaus) in Lausanne, Switzerland. We invited a cohort of 3043 consecutive participants of the CoLaus/PsyCoLaus study to take part. Polysomnography data from 2121 people were included in the final analysis. 1024 (48%) participants were men, with a median age of 57 years (IQR 49-68, range 40-85) and mean body-mass index (BMI) of 25·6 kg/m(2) (SD 4·1). Participants underwent complete polysomnographic recordings at home and had extensive phenotyping for diabetes, hypertension, metabolic syndrome, and depression. The primary outcome was prevalence of sleep-disordered breathing, assessed by the apnoea-hypopnoea index. FINDINGS:The median apnoea-hypopnoea index was 6·9 events per h (IQR 2·7-14·1) in women and 14·9 per h (7·2-27·1) in men. The prevalence of moderate-to-severe sleep-disordered breathing (≥15 events per h) was 23·4% (95% CI 20·9-26·0) in women and 49·7% (46·6-52·8) in men. After multivariable adjustment, the upper quartile for the apnoea-hypopnoea index (>20·6 events per h) was associated independently with the presence of hypertension (odds ratio 1·60, 95% CI 1·14-2·26; p=0·0292 for trend across severity quartiles), diabetes (2·00, 1·05-3·99; p=0·0467), metabolic syndrome (2·80, 1·86-4·29; p<0·0001), and depression (1·92, 1·01-3·64; p=0·0292). INTERPRETATION:The high prevalence of sleep-disordered breathing recorded in our population-based sample might be attributable to the increased sensitivity of current recording techniques and scoring criteria. These results suggest that sleep-disordered breathing is highly prevalent, with important public health outcomes, and that the definition of the disorder should be revised. FUNDING:Faculty of Biology and Medicine of Lausanne, Lausanne University Hospital, Swiss National Science Foundation, Leenaards Foundation, GlaxoSmithKline, Ligue Pulmonaire Vaudoise.
Clinical characteristics of patients with resistant hypertension: the RESIST-POL study.
Florczak E,Prejbisz A,Szwench-Pietrasz E,Sliwiński P,Bieleń P,Klisiewicz A,Michałowska I,Warchoł E,Januszewicz M,Kała M,Witkowski A,Więcek A,Narkiewicz K,Somers V K,Januszewicz A
Journal of human hypertension
Recent studies indicate that resistant hypertension (RHTN) is present in about 12% of the treated hypertensive population. However, patients with true RHTN (confirmed out of the office) have not been widely studied. We prospectively studied 204 patients (123 male, 81 female, mean age 48.4 years, range 19-65 years) with truly RHTN (ambulatory daytime mean blood pressure >135/85 mm Hg). We evaluated the frequency of obstructive sleep apnea (OSA), renal artery stenosis (RAS), primary aldosteronism (PA) and other secondary forms of hypertension (HTN) and conditions. Mild, moderate and severe OSA were present in 55 (27.0%), 38 (18.6%) and 54 (26.5%) patients, respectively. Secondary forms of HTN were diagnosed in 49 patients (24.0%), the most frequent being PA (15.7%) and RAS (5.4%). Metabolic syndrome (MS) was present in 65.7% of patients. Excessive sodium excretion was evident in 33.3% of patients and depression in 36.8% patients. In patients with RHTN, OSA and MS were the most frequent conditions, frequently overlapping with each other and also with PA. Our data indicate that in the vast majority of patients with truly RHTN, at least one of three co-morbidities-OSA, MS and PA-is present. Other conditions, even though less frequent, should also be taken into the consideration.
Prevalence of obstructive sleep apnea in the general population: A systematic review.
Senaratna Chamara V,Perret Jennifer L,Lodge Caroline J,Lowe Adrian J,Campbell Brittany E,Matheson Melanie C,Hamilton Garun S,Dharmage Shyamali C
Sleep medicine reviews
With this systematic review we aimed to determine the prevalence of obstructive sleep apnea (OSA) in adults in the general population and how it varied between population sub-groups. Twenty-four studies out of 3807 found by systematically searching PubMed and Embase databases were included in this review. Substantial methodological heterogeneity in population prevalence studies has caused a wide variation in the reported prevalence, which, in general, is high. At ≥5 events/h apnea-hypopnea index (AHI), the overall population prevalence ranged from 9% to 38% and was higher in men. It increased with increasing age and, in some elderly groups, was as high as 90% in men and 78% in women. At ≥15 events/h AHI, the prevalence in the general adult population ranged from 6% to 17%, being as high as 49% in the advanced ages. OSA prevalence was also greater in obese men and women. This systematic review of the overall body of evidence confirms that advancing age, male sex, and higher body-mass index increase OSA prevalence. The need to a) consider OSA as having a continuum in the general population and b) generate consensus on methodology and diagnostic threshold to define OSA so that the prevalence of OSA can be validly compared across regions and countries, and within age-/sex-specific subgroups, is highlighted.
Resistant hypertension, obstructive sleep apnoea and aldosterone.
Dudenbostel T,Calhoun D A
Journal of human hypertension
Obstructive sleep apnoea (OSA) and hypertension commonly coexist. Observational studies indicate that untreated OSA is strongly associated with an increased risk of prevalent hypertension, whereas prospective studies of normotensive cohorts suggest that OSA may increase the risk of incident hypertension. Randomized evaluations of continuous positive airway pressure (CPAP) indicate an overall modest effect on blood pressure (BP). Determining why OSA is so strongly linked to having hypertension in cross-sectional studies, but yet CPAP therapy has limited BP benefit needs further exploration. The CPAP studies do, however, indicate a wide variation in the BP effects of CPAP, with some patients manifesting a large antihypertensive benefit such that a meaningful BP effect can be anticipated in some individuals. OSA is particularly common in patients with resistant hypertension (RHTN). The reason for this high prevalence of OSA is not fully explained, but data suggest that it may be related to the high occurrence of hyperaldosteronism in patients with RHTN. In patients with RHTN, it has been shown that aldosterone levels correlate with severity of OSA and that blockade of aldosterone reduces the severity of OSA. Overall, these findings are consistent with aldosterone excess contributing to worsening of underlying OSA. We hypothesize that aldosterone excess worsens OSA by promoting accumulation of fluid within the neck, which then contributes to increased upper airway resistance.
Aldosterone excretion among subjects with resistant hypertension and symptoms of sleep apnea.
Calhoun David A,Nishizaka Mari K,Zaman Mohammad A,Harding Susan M
OBJECTIVE:The severity of obstructive sleep apnea (OSA) correlates with the difficulty of controlling BP. The mechanism, however, by which sleep apnea contributes to the development of resistant hypertension remains obscure. Having observed a high prevalence of OSA among hypertensive subjects with primary hyperaldosteronism, we hypothesized a possible association between sleep apnea and aldosterone excretion. DESIGN:In consecutive subjects referred to a university clinic for resistant hypertension, we prospectively determined plasma renin activity (PRA), plasma aldosterone concentration (PAC), and 24-h urinary aldosterone excretion during high dietary salt ingestion. In addition, all subjects completed the Berlin Questionnaire, a survey designed to identify subjects at risk of having sleep apnea. Primary hyperaldosteronism (PA) was defined as a PRA < 1.0 ng/mL/h and 24-h urinary aldosterone excretion > 12 micro g during high urinary sodium excretion (> 200 mEq/24 h). RESULTS:Of the 114 subjects evaluated, 72 subjects had a high probability and 42 subjects had a low probability of having sleep apnea based on their responses to the Berlin Questionnaire. Subjects at high risk for sleep apnea were almost two times more likely to have PA diagnosed (36 vs 19%, p < 0.05), tended to have lower PRA (1.2 +/- 1.8 ng/mL/h vs 1.9 +/- 4.1 ng/mL/h), and had significantly greater 24-h urinary aldosterone excretion (13.6 +/- 9.6 micro g vs 9.8 +/- 7.6 micro g, p < 0.05) compared to subjects at low risk of sleep apnea. CONCLUSION:These data provide evidence of increased aldosterone excretion in subjects with resistant hypertension and symptoms of sleep apnea. While the causality of this association is unknown, it is hypothesized that sleep apnea contributes to the development of resistant hypertension by stimulating aldosterone excretion.
Resistant hypertension, obesity, sleep apnea, and aldosterone: theory and therapy.
Goodfriend Theodore L,Calhoun David A
Hypertension (Dallas, Tex. : 1979)
Hypertension resistant to 2 antihypertensive drugs is more common among obese patients than among lean patients. The case we describe and the observations we report suggest that refractoriness among obese hypertensives is frequently caused by obstructive sleep apnea and/or inappropriately high plasma aldosterone levels. In other words, obese hypertensives may have sleep apnea, obese hypertensives without sleep apnea may have inappropriately elevated levels of plasma aldosterone, and a surprising number of obese patients with sleep apnea also have elevated levels of aldosterone. The mechanisms by which obesity and obstructive sleep apnea increase aldosterone levels and raise blood pressure are not understood, but sympathetic nervous system activation and production of nonclassical adrenal stimuli are two possibilities. Obstructive sleep apnea can be detected with a careful history and various sleep studies. Inappropriately elevated aldosterone levels can be detected by measuring the ratio of plasma aldosterone concentration to plasma renin activity. Successful treatment of these resistant hypertensives often can be achieved by devices that provide positive pressure to the upper airway to correct obstructive sleep apnea and by incorporating an aldosterone antagonist in the therapeutic regimen.
Renin-angiotensin-aldosterone system in patients with sleep apnoea: prevalence of primary aldosteronism.
Di Murro A,Petramala L,Cotesta D,Zinnamosca L,Crescenzi E,Marinelli C,Saponara M,Letizia C
Journal of the renin-angiotensin-aldosterone system : JRAAS
Obstructive sleep apnoea (OSA) is a sleep disorder characterized by recurrent episodes of oxygen desaturation during sleep, representing an independent risk factor for cardiovascular disease, such as myocardial infarction, stroke, congestive heart failure and resistant hypertension. Several neurohormonal mechanisms have been suggested to account for blood pressure increases, such as sympathetic nervous system hyperactivity, oxidative stress, renin-angiotensin-aldosterone system (RAAS) activation, endothelin system activation, and endothelial dysfunction. The aim of this study was to evaluate the behaviour of RAAS and the presence of primary aldosteronism (PA) in these patients and possible correlations between RAAS and the severity of OSA. From October 2007 to November 2008 we studied 325 consecutive newly diagnosed hypertensive patients; 71 patients (21.8%) presented with clinical signs of sleep disorders, evaluated also through a specific questionnaire (Epworth Sleepiness Scale). In hypertensive patients with sleep disorders, 53 patients were affected by OSA; in this group 18 patients were affected by PA (five with aldosterone-producing adenoma (APA) and 13 with bilateral hyperplasia (IHA)); obesity was also demonstrated (BMI > 30 kg/m(2)). Overall, in patients with OSA PRA levels correlated positively with apnoea/hypopnoea index (AHI; r = 0.35; p<0.01), and in all groups the waist circumference and the neck circumference were correlated positively with AHI (r = 0.3 p<0.02 and r = 0.3 p<0.03, respectively). We revealed a high prevalence of PA in patients with OSA, and we can conclude that patients with hypertension and OSA, especially those who are newly diagnosed, must be evaluated for PA.
Obstructive sleep apnea syndrome as a cause of resistant hypertension.
Parati Gianfranco,Ochoa Juan Eugenio,Bilo Grzegorz,Mattaliano Paola,Salvi Paolo,Kario Kazuomi,Lombardi Carolina
Hypertension research : official journal of the Japanese Society of Hypertension
Evidence has consistently supported the association of obstructive sleep apnea syndrome (OSAS) with an increased prevalence of hypertension. It has also been shown that the severity of OSAS is directly correlated with the degree of blood pressure (BP) elevation and that hypertension occurring in subjects with OSAS is more likely to be severe, resistant to antihypertensive treatment and associated with alterations in day-to-night BP changes. Proposed mechanisms for the pathogenesis of OSAS-related hypertension include the activation of the sympathetic nervous system, alterations in autonomic cardiovascular (CV) modulation, the activation of the renin-angiotensin-aldosterone system, endothelial dysfunction, systemic and vascular inflammation, oxidative stress, metabolic abnormalities, arterial stiffness and alterations in cardiac function and structure. Given the adverse prognostic implications of OSAS-related hypertension for CV morbidity and mortality, the confirmation of resistant hypertension by using ambulatory BP monitoring (ABPM) and the identification of alterations in day-to-night BP changes is of the utmost importance to implement more aggressive strategies for achieving BP control. In turn, the proper identification and implementation of specific treatment strategies for OSAS (that is, continuous positive airway pressure) in subjects with resistant hypertension may promote BP control and optimize CV protection. The present paper will review the evidence supporting the association of OSAS with resistant hypertension and the proposed mechanisms for this association. It will also address the role of ABPM in the confirmation of resistant hypertension in subjects with OSAS and whether the proper identification and management of OSAS in subjects with resistant hypertension will improve BP control.
Endocrine responses during CPAP withdrawal in obstructive sleep apnoea: data from two randomised controlled trials.
Thiel Sira,Haile Sarah R,Peitzsch Mirko,Schwarz Esther I,Sievi Noriane A,Kurth Salome,Beuschlein Felix,Kohler Malcolm,Gaisl Thomas
The aim of this investigation was to elucidate the effect of CPAP withdrawal on neurometabolic and cardiometabolic markers in patients with obstructive sleep apnoea. We evaluated 70 patients (mean age 61±10 years, 82% men) treated with CPAP in two 2-week, parallel, randomised controlled trials. CPAP withdrawal resulted in elevated 3,4-dihydroxyphenylglycol, norepinephrine and cortisol after 2 weeks of CPAP withdrawal; however, no statistically significant changes of the renin-angiotensin-aldosterone system (RAAS) determinants were documented. In summary, CPAP withdrawal may be more prominently linked to short-term increases in sympathetic activation than hypothalamic-pituitary-adrenal axis or RAAS activation. ClinicalTrials.gov Identifier: NCT02493673 and NCT02050425.
Evaluation of continuous positive airway pressure therapy on renin-angiotensin system activity in obstructive sleep apnea.
Nicholl David D M,Hanly Patrick J,Poulin Marc J,Handley George B,Hemmelgarn Brenda R,Sola Darlene Y,Ahmed Sofia B
American journal of respiratory and critical care medicine
RATIONALE:Obstructive sleep apnea (OSA) has been associated with kidney function loss, which may be related to changes in the renin-angiotensin system (RAS). OBJECTIVES:We sought to determine the effect of continuous positive airway pressure (CPAP) of patients with OSA on renal hemodynamics at baseline and in response to angiotensin II (AngII), which reflects RAS activity. METHODS:Twenty normotensive, nondiabetic, newly diagnosed OSA subjects (15 men, 5 women, 50 ± 2 yr, respiratory disturbance index [RDI] > 15 h(-1)) with nocturnal hypoxemia (SaO2 < 90% for >12% of the night) were studied in high-salt balance pre- and post-CPAP therapy (>4 h CPAP use/night for 1 mo). Glomerular filtration rate (GFR), renal plasma flow (RPF), and filtration fraction (FF) (a surrogate marker for intraglomerular pressure) were measured pre- and post-CPAP using inulin and para-aminohippurate clearance techniques at baseline and in response to graded AngII infusion (3 ng/kg/min × 30 min and 6 ng/kg/min × 30 min, respectively). MEASUREMENTS AND MAIN RESULTS:CPAP corrected OSA and hypoxemia (RDI: 42 ± 4 vs. 4 ± 1 h(-1), P < 0.001; duration SaO2 < 90%: 36% ± 5% vs. 6 ± 2%, P < 0.001). CPAP reduced GFR (124 ± 8 ml/min vs. 110 ± 6 ml/min, P = 0.014), increased RPF (692 ± 36 ml/min vs. 749 ± 40 ml/min, P = 0.059), and reduced baseline FF (18.9 ± 1.6% vs. 15.3 ± 1.0%, P = 0.004). Post-CPAP demonstrated a blunted GFR response (-9 ± 3 ml/min vs. -2 ± 2 ml/min, P = 0.033) and augmented RPF response (-182 ± 22 ml/min vs. -219 ± 25 ml/min, P = 0.024) to AngII. FF response was maintained (P = 0.4). CPAP reduced baseline mean arterial pressure (94 ± 2 vs. 89 ± 2 mm Hg, P = 0.002), plasma aldosterone (149 ± 18 vs. 109 ± 10 pmol/L, P = 0.003), and urinary protein excretion (61 [39-341] mg/day vs. 56 [22-204] mg/d, P = 0.003). CONCLUSIONS:CPAP therapy was associated with improved renal hemodynamics and down-regulation of renal RAS activity, suggesting a potential therapeutic benefit for kidney function.
Relationship between aldosterone and the metabolic syndrome in patients with obstructive sleep apnea hypopnea syndrome: effect of continuous positive airway pressure treatment.
Barceló Antonia,Piérola Javier,Esquinas Cristina,de la Peña Mónica,Arqué Meritxell,Alonso-Fernández Alberto,Bauçà Josep Miquel,Robles Juan,Barceló Bernardino,Barbé Ferran
BACKGROUND:Metabolic syndrome (MS) occurs frequently in patients with obstructive sleep apnea-hypopnea syndrome (OSAHS). We hypothesized that aldosterone levels are elevated in OSAHS and associated with the presence of MS. METHODS:We studied 66 patients with OSAHS (33 with MS and 33 without MS) and 35 controls. The occurrence of the MS was analyzed according to the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) clinical criteria. Measurements of plasma renin activity (PRA), aldosterone, aldosterone:PRA ratio, creatinine, glucose, triglycerides, cholesterol and HDL cholesterol were obtained at baseline and after CPAP treatment. RESULTS:Aldosterone levels were associated with the severity of OSAHS and higher than controls (p = 0.046). Significant differences in aldosterone levels were detected between OSAHS patients with and without MS (p = 0.041). A significant reduction was observed in the aldosterone levels in patients under CPAP treatment (p = 0.012). CONCLUSION:This study shows that aldosterone levels are elevated in OSAHS in comparison to controls, and that CPAP therapy reduces aldosterone levels. It also shows that aldosterone levels are associated with the presence of metabolic syndrome, suggesting that aldosterone excess might predispose or aggravate the metabolic and cardiovascular complications of OSAHS. TRIAL REGISTRATION:The study is not a randomized controlled trial and was not registered.
A randomized controlled study of CPAP effect on plasma aldosterone concentration in patients with resistant hypertension and obstructive sleep apnea.
Lloberes Patricia,Sampol Gabriel,Espinel Eugenia,Segarra Alfons,Ramon Maria-Antònia,Romero Odile,Ferrer Roser,Martínez-Garcia Miguel-Angel,Tovar José-Luis
Journal of hypertension
OBJECTIVE:The high prevalence of obstructive sleep apnea in patients with resistant hypertension could be mediated by an activation of the renin-angiotensin-aldosterone system. This study assessed the impact of continuous positive airway pressure (CPAP) treatment on plasma aldosterone concentration (PAC). METHODS:One hundred and twenty-four patients with resistant hypertension were assessed, and those who fulfilled inclusion criteria (n = 116) underwent full night polysomnography, 24-h ambulatory blood pressure monitoring, and PAC measurement. Patients with an apnea-hypopnea index above 15 (n = 102) were randomized to CPAP (n = 50) or to conventional treatment (n = 52) for 3 months. RESULTS:Seventy-eight patients completed the follow-up (36 CPAP, 42 conventional treatment); 58 had true resistant hypertension (74.3%), whereas 20 had white-coat resistant hypertension (25.6%). Most patients were men (70.7%), age 58.3 ± 9.4 years, and the mean apnea-hypopnea index was 50.1 ± 21.6. In patients with true resistant hypertension, CPAP achieved a significant decrease in most 24-h BP measurements and a nonsignificant decrease in PAC (25 ± 8.7 vs. 22.7 ± 9 ng/dl; P < 0.182). In patients with white-coat resistant hypertension, CPAP achieved a significant decrease in PAC (26.1 ± 11.2 vs. 18.9 ± 10.1 ng/dl; P < 0.041) and in night-time DBP. After adjustment, a weak but significant association was found between cumulative time spent with SaO2 below 90% (CT90%) and baseline PAC (P < 0.047, R 0.019), and between changes in PAC and changes in office DBP (P < 0.020, R 0.083) CONCLUSIONS:: Night-time hypoxemia and changes in DBP showed an association with baseline and changes in PAC, respectively. CPAP achieved a significant reduction in PAC only in patients with white-coat resistant hypertension, although the CPAP effect on BP was highest in patients with true resistant hypertension.
Meta-analysis of effects of obstructive sleep apnea on the renin-angiotensin-aldosterone system.
Jin Ze-Ning,Wei Yong-Xiang
Journal of geriatric cardiology : JGC
BACKGROUND:Obstructive sleep apnea (OSA) is the most common cause of resistant hypertension, which has been proposed to result from activation of the renin-angiotensin-aldosterone system (RAAS). We meta-analyzed the effects of OSA on plasma levels of RAAS components. METHODS:Full-text studies published on MEDLINE and EMBASE analyzing fasting plasma levels of at least one RAAS component in adults with OSA with or without hypertension. OSA was diagnosed as an apnea-hypopnea index or respiratory disturbance index ≥ 5. Study quality was evaluated using the Newcastle-Ottawa Scale, and heterogeneity was assessed using the I (2) statistic. Results from individual studies were synthesized using inverse variance and pooled using a random-effects model. Subgroup analysis, sensitivity analysis, and meta-regression were performed, and risk of publication bias was assessed. RESULTS:The meta-analysis included 13 studies, of which 10 reported results on renin (n = 470 cases and controls), 7 on angiotensin II (AngII, n = 384), and 9 on aldosterone (n = 439). AngII levels were significantly higher in OSA than in controls [mean differences = 3.39 ng/L, 95% CI: 2.00-4.79, P < 0.00001], while aldosterone levels were significantly higher in OSA with hypertension than OSA but not with hypertension (mean differences = 1.32 ng/dL, 95% CI: 0.58-2.07, P = 0.0005). Meta-analysis of all studies suggested no significant differences in aldosterone between OSA and controls, but a significant pooled mean difference of 1.35 ng/mL (95% CI: 0.88-1.82, P < 0.00001) emerged after excluding one small-sample study. No significant risk of publication bias was detected among all included studies. CONCLUSIONS:OSA is associated with higher AngII and aldosterone levels, especially in hypertensive patients. OSA may cause hypertension, at least in part, by stimulating RAAS activity.
Bidirectional relationship of hypertension with obstructive sleep apnea.
Jhamb Manisha,Unruh Mark
Current opinion in pulmonary medicine
PURPOSE OF REVIEW:Hypertension (HTN) and obstructive sleep apnea (OSA) are coexistent in millions of people, and both have been associated with heart disease, stroke, and premature death. OSA is an important risk factor for HTN. However, the relationship between OSA and HTN may be bidirectional, with high blood pressure (BP) contributing to an increased risk and severity of OSA. The aim of this review is to summarize the current literature supporting a bidirectional relationship of sleep apnea and HTN. RECENT FINDINGS:The treatment of HTN to a lower BP target may improve sleep apnea by improving upper airway tone, by targeting hormone pathways (aldosterone, renin-angiotensin system) that may exacerbate OSA, and by reducing the nocturnal rostral fluid shifts through the use of a low-sodium diet, diuretics, and dialysis. SUMMARY:Intensive BP and volume overload control may be a promising approach to treat OSA. Future studies examining the hormonal mechanisms and comparing the effect of different antihypertensive medications on OSA are needed.
Effect of spironolactone on patients with resistant hypertension and obstructive sleep apnea.
Yang Lirui,Zhang Huimin,Cai Menggengtuya,Zou Yubao,Jiang Xiongjing,Song Lei,Liang Erpeng,Bian Jin,Wu Haiying,Hui Rutai
Clinical and experimental hypertension (New York, N.Y. : 1993)
OBJECTIVE:To examine whether spironolactone could reduce the severity of obstructive sleep apnea (OSA) and lower blood pressure in patients with resistant hypertension. METHODS:This was a blank-controlled, single-center study. Patients with resistant hypertension and moderate-to-severe OSA (apnea-hypopnea index >15 events/h) were enrolled and randomly assigned to the therapy or control group. Patients in the therapy group were administered spironolactone 20 mg once daily (up to 40 mg once daily for 4 weeks, if required) in addition to original antihypertensive medication. Follow-up was 12 weeks. RESULTS:Thirty patients were enrolled (n = 15 per group). After 12 weeks of follow-up, apnea-hypopnea index (21.8 ± 15.7 vs. 1.8 ± 12.8, p < 0.05), hypopnea index (9.8 ± 11.1 vs. -2.7 ± 16.8, p < 0.05), oxygen desaturation index (20.8 ± 15.0 vs. 0.3 ± 16.1, p < 0.05), clinical blood pressure, ambulatory blood pressure, and plasma aldosterone level (9.8 ± 6.3 vs. 2.9 ± 6.7, p < 0.05) were reduced significantly in the therapy group compared with the control group. No side effects were reported. CONCLUSIONS:Spironolactone reduced the severity of OSA and reduced blood pressure in resistant hypertension patients with moderate-to-severe OSA. These findings may assist in the treatment of OSA in patients with resistant hypertension.
Effects of continuous positive airway pressure treatment on aldosterone excretion in patients with obstructive sleep apnoea and resistant hypertension: a randomized controlled trial.
de Souza Fabio,Muxfeldt Elizabeth S,Margallo Victor,Cortez Arthur F,Cavalcanti Aline H,Salles Gil F
Journal of hypertension
OBJECTIVE:Aldosterone excess has been equally associated with resistant hypertension (RHT) and obstructive sleep apnoea (OSA). We conducted a randomized controlled study to assess the effect of continuous positive airway pressure (CPAP) treatment on 24-h urinary aldosterone excretion in patients with RHT and moderate/severe OSA. METHODS:A total of 117 patients were randomized (57 CPAP and 60 control groups). Aldosterone excretion was determined by 24 h urine (24h-UAldo) collected at randomization and after 6 months of follow-up. Twenty-four hour UAldo differences were assessed by general linear model with the allocation group (CPAP or control) as a fixed factor adjusted for their respective baseline values. Both intention-to-treat and per-protocol (45 patients with optimal adherence to CPAP) analyses were performed. RESULTS:Baseline 24h-UAldo was higher in severe OSA than in moderate OSA patients. After CPAP treatment, there was a borderline significant reduction in 24h-UAldo [mean difference: -2.5 μg/24 h; 95% confidence interval (95% CI): -5.3 to +0.3 μg/24 h; P = 0.07] in intention-to-treat analysis, whereas in the per-protocol analysis, the CPAP group had a greater reduction in 24h-UAldo than the control group (mean difference: -3.3 μg/24 h; 95% CI: -6.1 to -0.4 μg/24 h; P = 0.027). This effect occurred solely in patients with uncontrolled ambulatory BPs, and was more pronounced in those with the nondipping pattern, not using spironolactone, less obese, and with lowest sleep SaO2 levels. CONCLUSION:Only optimal CPAP treatment reduced aldosterone excretion in patients with uncontrolled RHT, while on intention-to-treat the effect was borderline. Although nondefinitive, our results suggest that CPAP treatment might improve cardiovascular outcomes by reducing aldosterone excess in resistant hypertensive individuals with OSA. CLINICAL TRIAL REGISTRATION:ClinicalTrials.gov Identifier: NCT01508754.
The impact of obstructive sleep apnea syndrome on renin and aldosterone.
Lykouras D,Theodoropoulos K,Sampsonas F,Lagiou O,Lykouras M,Spiropoulou A,Flordellis C,Alexandrides T,Karkoulias K,Spiropoulos K
European review for medical and pharmacological sciences
OBJECTIVE:Obstructive Sleep Apnoea Syndrome (OSAS) is a respiratory disorder characterized by recurrent airflow obstruction caused by total or partial collapse of the upper airway. OSAS is an established independent factor of cardiovascular risk together with other risk factors such as smoking and increased lipids. The aim of our study was to measure serum levels of aldosterone and renin in OSAS patients that did not suffer from arterial hypertension and compare them to matched healthy subjects in order to reveal the impact of chronic intermittent hypoxia on the renin-angiotensin-aldosterone system. PATIENTS AND METHODS:The patients that enrolled in this study were 19 OSAS patients who had undergone overnight polysomnography and had an Apnoea Hypopnoea Index (AHI) greater than 10 events/hour. They were compared to 20 healthy non-OSAS closely matched controls. Serum aldosterone and direct renin concentration were measured by radioimmunoassay. RESULTS:Aldosterone concentration follows a diurnal variation; therefore, all blood samples were obtained at the same time (6 AM). There were no significant differences in serum aldosterone levels between the two studied groups of OSAS patients and the healthy subjects group (140.6 pg/ml ± 25.2 vs. 133.2 pg/ml ± 18.5 with p = 0.223). Similar were the results for the renin levels (25.0 ± 6.9 vs. 24.9 ± 4.4 with p = 0.360). CONCLUSIONS:Our study suggests that patients with OSAS, but without existing hypertension have aldosterone and renin levels similar to healthy subjects. According to our findings a direct connection between OSAS and the development of arterial hypertension may not be established via sympathetic system activation.
Does continuous positive airway pressure reduce aldosterone levels in patients with obstructive sleep apnea?
Yang Si-Jiu,Jiang Xing-Tang,Zhang Xiao-Bin,Yin Xiao-Wen,Deng Wei-Xian
Sleep & breathing = Schlaf & Atmung
PURPOSE:Aldosterone is associated with the development of obstructive sleep apnea (OSA) and cardiovascular diseases. Continuous positive airway pressure (CPAP) is an effective treatment for OSA, but the impact of CPAP therapy on aldosterone levels in patients with OSA remains unclear. To address this issue, a meta-analysis was conducted to evaluate the effects of CPAP therapy on serum aldosterone levels in OSA. METHODS:Two reviewers independently searched PubMed, Cochrane library, Embase, and Web of Science before March 2015. Information on characteristics of subjects, study design, and pre- and post-CPAP treatment of serum aldosterone was extracted for analysis. Standardized mean difference (SMD) was calculated to estimate the treatment effects of CPAP therapy. RESULTS:A total of 5 studies involving 329 patients were pooled into this meta-analysis, including 3 observational studies and 2 randomized controlled studies. Results indicated significantly decreased aldosterone levels after CPAP therapy (SMD = -0.236, 95 % confidence interval (CI) = -0.45 to -0.02, z = 2.12, p = 0.034). CONCLUSIONS:This meta-analysis suggested that CPAP therapy was associated with a decrease in serum aldosterone in patients with OSA. Further large-scale, well-designed interventional investigations are needed to clarify this issue.
Role of aldosterone blockade in resistant hypertension.
Egan Brent M,Li Jiexiang
Seminars in nephrology
Apparent treatment-resistant hypertension (aTRH), defined as uncontrolled blood pressure using 3 or more antihypertensive medications or controlled using 4 or more antihypertensive medications, affects approximately 30% of uncontrolled and 12% of controlled blood pressure (BP) patients. aTRH is used when pseudoresistance cannot be excluded (eg, BP measurement artifacts, mainly office resistance, suboptimal adherence, suboptimal treatment regimens, and true TRH). True TRH comprises approximately 30% to 50% of TRH. Patients with TRH have a high prevalence of obesity, insulin resistance, sleep apnea, and volume expansion. Aldosterone, a mineralocorticoid, is an important contributor to TRH, with primary aldosteronism present in approximately 20% of patients. Spironolactone, a mineralocorticoid-receptor antagonist, as a fourth-line agent, decreases BP 20 to 25/10 to 12 mm Hg in TRH patients with and without primary aldosteronism. The BP response to spironolactone is roughly double that of other classes of antihypertensive medications in TRH. Although approximately 70% of patients with uncontrolled TRH have estimated glomerular filtration rate of 50 or greater and a serum potassium level of 4.5 or less, which are associated with a low risk for hyperkalemia, only a small percentage receive a mineralocorticoid-receptor antagonist. This review examines the clinical epidemiology and pharmacotherapy of controlled and uncontrolled hypertension with an emphasis on aTRH, the role of aldosterone in blood pressure regulation, and the potential benefits of mineralocorticoid-receptor antagonist in uncontrolled TRH.
Secondary Hypertension: Discovering the Underlying Cause.
Charles Lesley,Triscott Jean,Dobbs Bonnie
American family physician
Most patients with hypertension have no clear etiology and are classified as having primary hypertension. However, 5% to 10% of these patients may have secondary hypertension, which indicates an underlying and potentially reversible cause. The prevalence and potential etiologies of secondary hypertension vary by age. The most common causes in children are renal parenchymal disease and coarctation of the aorta. In adults 65 years and older, atherosclerotic renal artery stenosis, renal failure, and hypothyroidism are common causes. Secondary hypertension should be considered in the presence of suggestive symptoms and signs, such as severe or resistant hypertension, age of onset younger than 30 years (especially before puberty), malignant or accelerated hypertension, and an acute rise in blood pressure from previously stable readings. Additionally, renovascular hypertension should be considered in patients with an increase in serum creatinine of at least 50% occurring within one week of initiating angiotensin-converting enzyme inhibitor or angiotensin receptor blocker therapy; severe hypertension and a unilateral smaller kidney or difference in kidney size greater than 1.5 cm; or recurrent flash pulmonary edema. Other underlying causes of secondary hypertension include hyperaldosteronism, obstructive sleep apnea, pheochromocytoma, Cushing syndrome, thyroid disease, coarctation of the aorta, and use of certain medications.
Neuroglobin correlates with cryptochrome-1 in obstructive sleep apnea with primary aldosteronism.
Tedjasukmana Rimawati,Purba Jan Sudir,Wanandi Septelia Inawati,Suyatna Franciscus D
BACKGROUND:Neuroglobin (Ngb) is highly expressed in the suprachiasmatic nucleus, and can regulate Per1 gene expression. It is still not known whether Ngb also influences Cryptochrome (Cry). Cry is implicated in hypertension and primary aldosteronism (PA) in mice. There is a strong correlation between Obstructive Sleep Apnea (OSA) and PA. We propose to prove that Ngb and Cry play a role in OSA with PA. METHODS:Subjects were recruited consecutively from residents of Jakarta, Indonesia; subjects aged 30-65 years with moderate to severe OSA and hypertension were included in the study. OSA was diagnosed using an unattended type 2 portable monitor (Alice Pdx), hypertension was diagnosed when morning blood pressure exceeded 140/90 mmHg or when taking anti-hypertensive drugs. Serum concentration of aldosterone, renin, Cry1, Cry2 and Ngb protein were determined using ELISA method. Primary aldosteronism (PA) was defined as ARR ≥20. RESULTS:Forty subjects were recruited, 26 male and 14 female, median age 52.5 years, BMI 27.46 kg/m2, and AHI 34.8 times/hour. We found 16 subjects with PA and 24 non PA. Cry1 and Cry2 did not correlate with ARR in PA and non PA groups. Ngb correlated positively with Cry1 (Spearman's rho = 0.455, p = 0.038) but not Cry2 in PA patients. Cry1 concentration decreased in severe hypoxia. CONCLUSIONS:Ngb correlates with Cry1 in OSA with PA. There is no correlation between Cry1 or Cry2 with PA.
Clinical characteristics of snoring patients with primary aldosteronism and obstructive sleep apnea-hypopnea syndrome.
Li Mingyan,Ge Qian,Sheng Chang-Sheng,Zhang Jin,Li Hua,Niu Wenquan,Tang Xiaofeng,Xu Jianzhong,Gao Ping-Jin,Wang Ji-Guang,Zhu Limin
Journal of human hypertension
The 2016 guideline on the work-up of primary aldosteronism recommended that patients with obstructive sleep apnea-hypopnea syndrome (OSAS) be screened. This study aimed to identify the clinical characteristics of snoring patients with primary aldosteronism (PA) complicated by OSAS. Sixty-eight self-reported or witnessed snoring patients and 609 non-snoring patients diagnosed with PA between 2010 and 2015 were recruited in this retrospective study. Compared to non-snoring patients, snoring patients had significantly (P < 0.05) higher body mass index (BMI), diastolic blood pressure (DBP), and serum and urinary sodium, as well as lower estimated glomerular filtration rate (eGFR). Moreover, snoring patients exhibited significantly (P < 0.01) higher plasma renin activity levels and lower plasma aldosterone levels and aldosterone-to-renin activity ratios (ARRs) than patients with PA alone. When age, sex, duration of hypertension, and BMI were matched between groups, snoring patients still showed significantly (P < 0.05) higher plasma renin activity, serum and urinary sodium, and lower ARR and eGFR than those in the PA-only group. All 68 snoring patients underwent polysomnography, with 7 having mild (apnea-hypopnea index (AHI) ≥ 5 and <15), 21 moderate (AHI ≥ 15 and <30), and 40 severe (AHI ≥ 30) OSAS. The BMI of patients with OSAS was negatively correlated with the lowest SaO (r = -0.318, P = 0.018) but not with the AHI. In conclusion, snoring patients with PA tend to have increased BMI and DBP, as well as decreased eGFR and ARR. Snoring patients with PA had higher prevalence of moderate-to-severe OSAS.
Hyperaldosteronism as a common cause of resistant hypertension.
Calhoun David A
Annual review of medicine
Resistant hypertension affects an estimated 10-15 million American adults and is increasing in prevalence. The etiology of resistant hypertension is almost always multifactorial, including obesity, older age, high dietary salt, chronic kidney disease, and aldosterone excess. Classical primary aldosteronism and lesser degrees of aldosterone excess, possibly originating from visceral adipocytes, contribute broadly to antihypertensive treatment resistance. Treatment of resistant hypertension is predicated on appropriate lifestyle changes and use of effective combinations of antihypertensive agents from different classes. Blockade of aldosterone with spironolactone has been shown to be particularly effective for treatment of resistant hypertension. The antihypertensive benefit of spironolactone is not limited to patients with demonstrable hyperaldosteronism but instead can be effective in resistant hypertensive patients regardless of aldosterone levels. Chlorthalidone is a potent, long-acting thiazide-like diuretic and should be used preferentially to treat resistant hypertension as it is superior to normally used doses of hydrochlorothiazide.
Plasma aldosterone is related to severity of obstructive sleep apnea in subjects with resistant hypertension.
Pratt-Ubunama Monique N,Nishizaka Mari K,Boedefeld Robyn L,Cofield Stacey S,Harding Susan M,Calhoun David A
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] > or = 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.
Primary Aldosteronism and Obstructive Sleep Apnea: Casual Association or Pathophysiological Link?
Pecori Alessio,Buffolo Fabrizio,Pieroni Jacopo,Forestiero Vittorio,Sconfienza Elisa,Veglio Franco,Mulatero Paolo,Monticone Silvia
Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme
The coexistence of aldosterone oversecretion and obstructive sleep apnea is frequently observed, especially in patients with resistant hypertension, obesity, and metabolic syndrome. Since aldosterone excess and sleep apnea are both independently associated with an increased risk of cardiovascular disease, to investigate whether their coexistence might be attributed to common predisposing conditions, such as metabolic disorders, or to an actual pathophysiological interconnection appears of great importance. Fluid overload and metabolic abnormalities relating to aldosterone oversecretion may be implicated in obstructive sleep apnea development. Nocturnal intermittent hypoxia may in turn exacerbate renin-angiotensin-aldosterone system activity, thus leading to hyperaldosteronism. Furthermore, fat tissue excess and adipocyte secretory products might predispose to both sleep apnea and aldosterone oversecretion in subjects with obesity. Consistent with these evidences, obstructive sleep apnea frequently affects patients with primary aldosteronism. Conversely, whether primary aldosteronism is more prevalent in individuals affected by obstructive sleep apnea compared to the general population remains controversial.
Secondary arterial hypertension: when, who, and how to screen?
Rimoldi Stefano F,Scherrer Urs,Messerli Franz H
European heart journal
Secondary hypertension refers to arterial hypertension due to an identifiable cause and affects ∼5-10% of the general hypertensive population. Because secondary forms are rare and work up is time-consuming and expensive, only patients with clinical suspicion should be screened. In recent years, some new aspects gained importance regarding this screening. In particular, increasing evidence suggests that 24 h ambulatory blood pressure (BP) monitoring plays a central role in the work up of patients with suspected secondary hypertension. Moreover, obstructive sleep apnoea has been identified as one of the most frequent causes. Finally, the introduction of catheter-based renal denervation for the treatment of patients with resistant hypertension has dramatically increased the interest and the number of patients evaluated for renal artery stenosis. We review the clinical clues of the most common causes of secondary hypertension. Specific recommendations are given as to evaluation and treatment of various forms of secondary hypertension. Despite appropriate therapy or even removal of the secondary cause, BP rarely ever returns to normal with long-term follow-up. Such residue hypertension indicates either that some patients with secondary hypertension also have concomitant essential hypertension or that irreversible vascular remodelling has taken place. Thus, in patients with potentially reversible causes of hypertension, early detection and treatment are important to minimize/prevent irreversible changes in the vasculature and target organs.
Drug therapy of apparent treatment-resistant hypertension: focus on mineralocorticoid receptor antagonists.
Glicklich Daniel,Frishman William H
Apparent treatment-resistant hypertension (aTRH) is defined as blood pressure (BP) >140/90 mmHg despite three different antihypertensive drugs including a diuretic. aTRH is associated with an increased risk of cardiovascular events, including stroke, chronic renal failure, myocardial infarction, congestive heart failure, aortic aneurysm, atrial fibrillation, and sudden death. Preliminary studies of renal nerve ablation as a therapy to control aTRH were encouraging. However, these results were not confirmed by the Symplicity 3 trial. Therefore, attention has refocused on drug therapy. Secondary forms of hypertension and associated conditions such as obesity, sleep apnea, and primary aldosteronism are common in patients with aTRH. The pivotal role of aldosterone in the pathogenesis of aTRH in many cases is well recognized. For patients with aTRH, the Joint National Committee-8, the European Society of Hypertension, and a recent consensus conference recommend that a diuretic, ACE inhibitor, or angiotensin receptor blocker and calcium channel blocker combination be used to maximally tolerated doses before starting a 'fourth-line' drug such as a mineralocorticoid receptor (MR) antagonist. Although the best fourth-line drug for aTRH has not been extensively investigated, a number of studies summarized here show that an MR antagonist is effective in reducing BP when added to the standard multi-drug regimen.
The Triad of Sleep Apnea, Hypertension, and Chronic Kidney Disease: A Spectrum of Common Pathology.
Aziz Fahad,Chaudhary Kunal
Obstructive sleep apnea (OSA), hypertension, and chronic kidney disease (CKD) are different entities and are generally managed individually most of the time. However, CKD, OSA, and hypertension share many common risk factors and it is not uncommon to see this complex triad together. In fact, they share similar pathophysiology and have been interlinked with each other. The common pathophysiology includes chronic volume overload, hyperaldosteronism, increased sympathetic activity, endothelial dysfunction, and increased inflammatory markers. The combination of this triad has significant negative impact on the cardiovascular health, and increases the mortality and morbidity in this complicated group of patients. On one hand, progression of CKD can lead to the worsening of OSA and hypertension; similarly, worsening sleep apnea can make the hypertension difficult to treat and enhance the progression of CKD. This review article highlights the bidirectional interlink among these apparently different disease processes which share common pathophysiological mechanisms and emphasizes the importance of treating them collectively to improve outcomes.
Prevalence of potential modifiable factors of hypertension in patients with difficult-to-control hypertension.
Van Der Sande Nicolette G C,Blankestijn Peter J,Visseren Frank L J,Beeftink Martine M,Voskuil Michiel,Westerink Jan,Bots Michiel L,Spiering Wilko
Journal of hypertension
BACKGROUND:A comprehensive diagnostic evaluation of potential modifiable factors of difficult-to-control hypertension would enable clinicians to target-specific amendable causes. Therefore, we assessed the prevalence of underlying medical conditions, lifestyle factors, and concomitant medication use in an integrated diagnostic evaluation in patients with difficult-to-control hypertension, referred to a tertiary center. METHODS:The study population consisted of 653 patients referred between 2006 and 2016 for difficult-to-control hypertension to the University Medical Center Utrecht. Difficult-to-control hypertension was defined by not reaching blood pressure (BP) goals despite BP-lowering drug use, or high office BP (>160/100 mmHg) without BP-lowering drug use. Patients were evaluated according to a highly standardized protocol including 24-h ambulatory blood measurements after cessation of BP-lowering drugs, 24-h urine sample, and a isotonic (0.9%) saline infusion test. RESULTS:In 621 patients (95%) one or more modifiable factors related to hypertension were identified (mean 2.1, SD 1.1). Obesity-related insulin resistance was the most common underlying medical condition which was diagnosed in 130 patients (20%). Primary aldosteronism was diagnosed in 40 patients (6%) and obstructive sleep apnea in 17 patients (3%). Sodium intake was deemed to high (urinary excretion of >6 g/day) in 433 patients (66%). In total, 283 patients (43%) were physical inactive (<30 min/day, during 5 days/week). Oral contraceptive-related hypertension was diagnosed in 10 women (3% of women). CONCLUSION:In patients with difficult-to-control hypertension there is a high prevalence of potential modifiable factors related to hypertension, highlighting the importance for an integrated diagnostic evaluation.
Detection of Secondary Causes and Coexisting Diseases in Hypertensive Patients: OSA and PA Are the Common Causes Associated with Hypertension.
Wang Lei,Li Nanfang,Yao Xiaoguang,Chang Guijuan,Zhang Delian,Heizhati Mulalibieke,Wang Menghui,Luo Qin,Kong Jianqiong
BioMed research international
BACKGROUND:Since the control rate of blood pressure is lower in mainland China, the aim of this study is to investigate the proportion of secondary causes and coexisting diseases of hypertension in hypertensive patients. METHODS:Data on consecutive patients with hypertension who visited the Hypertension Center. Diseases were detected using an established strict screening protocol. RESULTS:Detection rate of secondary causes and coexisting diseases of hypertension was 39.5% among 3003 hypertensive patients. Obstructive sleep apnea (OSA) was the most common, accounting for 24.7% of patients, followed by primary aldosteronism (PA) (5.8%) and PA + OSA (4.9%). Endocrine hypertension accounted for 12.1% of patients, including 10.7% of patients with PA, 1.1% with hypothyroidism, 0.1% with pheochromocytoma, 0.1% with Cushing's syndrome, and 0.1% with hyperthyroidism, respectively. Those who smoke, those who are obese, and those who have diabetes accounted for 31.3%, 27.5%, and 16.6% of total patients, respectively. There were overlapping conditions in secondary causes and coexisting diseases of hypertension. OSA was the most common in each age- and BMI-stratified group. CONCLUSION:Findings from the current study suggest an increasing frequency of secondary forms of hypertension, highlighting the burden of OSA and PA in hypertensive patients.
Role of Mineralocorticoid Receptors in Obstructive Sleep Apnea and Metabolic Syndrome.
Valaiyapathi Badhma,Calhoun David A
Current hypertension reports
PURPOSE OF REVIEW:This review will summarize recent developments in the research on the mineralocorticoid receptor and its impact on obstructive sleep apnea and metabolic syndrome. RECENT FINDINGS:Aldosterone excess plays an important role in the association between resistant hypertension and obstructive sleep apnea. The prevalence of obesity is increasing rapidly worldwide and is especially common among patients with obstructive sleep apnea, resistant hypertension, and metabolic syndrome, suggesting probable mechanistic links between these three conditions. Mineralocorticoid receptor expression is increased in obese individuals, which may contribute to the common association between obesity and hyperaldosteronism. Mineralocorticoid receptor blockers reduce the severity of obstructive sleep apnea among resistant hypertension patients. A large body of literature demonstrates a strong association between obesity, hyperaldosteronism, resistant hypertension, and sleep apnea, including specific benefit of treatment with mineralocorticoid receptor blockers for these separate disorders.
Associations between primary aldosteronism and diabetes, poor bone health, and sleep apnea-what do we know so far?
Loh Huai Heng,Sukor Norlela
Journal of human hypertension
Primary aldosteronism (PA), the most common cause of secondary hypertension, is a well-recognized condition that can lead to cardiovascular and renal complications. PA is frequently left undiagnosed and untreated, leading to aldosterone-specific morbidity and mortality. In this review we highlight the evidence linking PA with other conditions such as (i) diabetes mellitus, (ii) obstructive sleep apnea, and (iii) bone health, along with clinical implications and proposed underlying mechanisms.
Sleep quality in patients with primary aldosteronism.
Hanusch Franziska M,Fischer Evelyn,Lang Katharina,Diederich Sven,Endres Stephan,Allolio Bruno,Beuschlein Felix,Reincke Martin,Quinkler Marcus
Hormones (Athens, Greece)
OBJECTIVE:In subjects at high risk for sleep apnea (SA), aldosterone concentrations correlate with severity of SA and primary aldosteronism (PA) is very often diagnosed. Patients with PA show a high prevalence of SA. Treatment of PA either by adrenalectomy (ADX) or mineralocorticoid receptor (MR) blockade is thought to abolish the increased comorbidities. However, no data are available regarding effectiveness of different PA treatments on quality of sleep. DESIGN:This prospective multi-center study included 15 patients with newly diagnosed PA evaluated before and 0.7 ± 0.2 years after treatment initiation, and a second cohort including 81 patients who were evaluated 5.3 and 6.8 years after treatment initiation. Biochemical parameters, 24h blood pressure and three validated self-assessment questionnaires (Giessen Complaint List (GBB-24), Epworth Sleepiness Scale (ESS) and Pittsburgh Sleep Quality-Index (PSQI)) were analyzed. RESULTS:Z-scores of exhaustion tendency of GBB significantly improved in newly diagnosed PA patients after treatment initiation (1.8 ± 1.4 vs. 1.0 ± 1.2, p=0.034). In the second cohort no differences were found in GBB-24, ESS and PSQI. No differences were found in all three questionnaires independently of type of PA therapy. However, female patients scored significantly higher than males in the PSQI (8.7 ± 3.6 vs 5.7 ± 4.2, p<0.005), indicating lower sleep quality, independently of the type of therapy. CONCLUSIONS:For the first time, we analyzed quality of sleep in patients with PA, demonstrating that therapy initiation improves exhaustion tendency. Surprisingly, female PA patients showed significantly more sleep disturbances than male PA patients several years after treatment initiation.
Treatment of Primary Aldosteronism Reduces the Probability of Obstructive Sleep Apnea.
Wang Elizabeth,Chomsky-Higgins Kathryn,Chen Yufei,Nwaogu Iheoma,Seib Carolyn D,Shen Wen T,Duh Quan-Yang,Suh Insoo
The Journal of surgical research
BACKGROUND:Aldosterone excess is hypothesized to worsen obstructive sleep apnea (OSA) symptoms by promoting peripharyngeal edema. However, the extent to which primary aldosteronism (PA), hypertension, and body mass index (BMI) influence OSA pathogenesis remains unclear. METHODS:We conducted a cross-sectional study of PA patients from our endocrine database to retrospectively evaluate OSA probability before and after adrenalectomy or medical management of PA. A control group of patients undergoing adrenalectomy for nonfunctioning benign adrenal masses was also evaluated. We categorized patients as high or low OSA probability after evaluation with the Berlin Questionnaire, a validated 10-question survey that explores sleep, fatigue, hypertension, and BMI. RESULTS:We interviewed 91 patients (83 PA patients and eight control patients). Median follow-up time was 2.6 y. The proportion of high OSA probability in all PA patients decreased from 64% to 35% after treatment for PA (mean Berlin score 1.64 versus 1.35, P < 0.001). This decline correlated with improvements in hypertension (P < 0.001) and fatigue symptoms (P = 0.03). Both surgical (n = 48; 1.69 versus 1.33, P < 0.001) and medical (n = 35; 1.57 versus 1.37, P = 0.03) treatment groups demonstrated reduced OSA probability. BMI remained unchanged after PA treatment (29.1 versus 28.6, P = nonsignificant), and the impact of treatment on OSA probability was independent of BMI. The control surgical group showed no change in OSA probability after adrenalectomy (1.25 versus 1.25, P = nonsignificant). CONCLUSIONS:Both surgical and medical treatments of PA reduce sleep apnea probability independent of BMI and are associated with improvements in hypertension and fatigue. Improved screening for PA could reduce OSA burden.
Primary Aldosteronism and Obstructive Sleep Apnea: Is This A Bidirectional Relationship?
Prejbisz Aleksander,Kołodziejczyk-Kruk Sylwia,Lenders Jacques W M,Januszewicz Andrzej
Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme
It has been suggested that the high prevalence of obstructive sleep apnea (OSA) in resistant hypertension (RHT) may be related to the high prevalence of primary aldosteronism (PA) in patients with RHT. It has been also hypothesized that the relationship between aldosterone and OSA might be bidirectional. In patients with RHT, it has been shown that aldosterone levels correlate with severity of OSA and that blockade of aldosterone reduces the severity of OSA. It has been postulated that aldosterone worsens OSA by promoting accumulation of fluid, which shifted in the supine position to the neck, contributes to increased upper airway resistance. Also there is growing data that PA is more frequent in patients with OSA and that the treatment of PA positively influences OSA course. Also in some studies it has been shown that patients with OSA are characterized by higher aldosterone levels and higher prevalence of PA than patients without OSA and that causal treatment of OSA might decrease aldosterone levels. Moreover, the recent guideline of the Endocrine Society on management of PA recommends to screen hypertensive patients with OSA for PA.
Treatment of primary aldosteronism is associated with a reduction in the severity of obstructive sleep apnoea.
Wolley M J,Pimenta E,Calhoun D,Gordon R D,Cowley D,Stowasser M
Journal of human hypertension
Obstructive sleep apnoea (OSA) is known to commonly co-exist with primary aldosteronism (PA), but it is unknown if treatment of PA improves sleep apnoea parameters in these patients. We therefore aimed to determine whether specific medical or surgical treatment of PA improves OSA, as measured by the apnoea-hypopnoea index (AHI). We recruited patients undergoing diagnostic workup for PA if they had symptoms suggestive of OSA. Patients with confirmed PA underwent polysomnography (PSG) at baseline and again at least 3 months after specific treatment for PA. Of 34 patients with PA, 7 (21%) had no evidence of OSA (AHI <5), 9 (26%) had mild (AHI ⩾5 and <15), 8 (24%) moderate (AHI ⩾15 and <30) and 10 (29%) severe OSA (AHI ⩾30). Body mass index tertile, neck circumference and 24 h urinary sodium correlated with the AHI. Twenty patients had repeat PSG performed after treatment for PA (mineralocorticoid receptor antagonists in 13 with bilateral PA and adrenalectomy in 7 with unilateral PA). In this group the median (s.d.) AHI reduced from 22.5 (14.7) to 12.3 (12.1) (P=0.02). Neck circumference reduced with PA treatment (41.6 vs 41.2 cm, P=0.012). OSA is common in patients with primary aldosteronism and may improve with specific therapy for this disease. Aldosterone and sodium-mediated fluid retention in the upper airways and neck region may be a potential mechanism for this relationship.