Resistant hypertension, obesity, sleep apnea, and aldosterone: theory and therapy

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.     

Obesity, obstructive sleep apnoea and metabolic syndrome

OSA is increasingly recognized as a major health problem in developed countries. Obesity is the most common risk factor in OSA and hence, the prevalence of OSA is undoubtedly rising given the epidemic of obesity. Recent data also suggest that OSA is highly associated with the metabolic syndrome, and it is postulated that OSA contributes to cardiometabolic dysfunction, and subsequently vasculopathy. Current evidence regarding the magnitude of impact on ultimate cardiovascular morbidity or mortality attributable to OSA-induced metabolic dysregulation is scarce. Given the known pathophysiological triggers of intermittent hypoxia and sleep fragmentation in OSA, the potential mechanisms of OSA-obesity-metabolic syndrome interaction involve sympathetic activation, oxidative stress, inflammation and neurohumoral changes. There is accumulating evidence from human and animal/cell models of intermittent hypoxia to map out these mechanistic pathways. In spite of support for an independent role of OSA in the contribution towards metabolic dysfunction, a healthy diet and appropriate lifestyle modifications towards better control of metabolic function are equally important as CPAP treatment in the holistic management of OSA.     

Obesity, sleep apnea, aldosterone, and hypertension

The pathogenesis of hypertension associated with obesity is unclear. This review provides evidence supporting excess visceral fat as an early aspect, and obstructive sleep apnea and elevated levels of aldosterone as factors closer to hypertension in the mechanistic chain. Features of visceral obesity and obstructive sleep apnea that may stimulate aldosterone secretion are described here. Possible therapeutic interventions addressing the hypertension associated with obesity are briefly mentioned.     

Left ventricular hypertrophy independent of hypertension in patients with obstructive sleep apnoea

To evaluate cardiac structure and function as well as blood pressure in the obstructive sleep apnoea syndrome (OSAS), we investigated 61 male patients and 61 male controls with M-mode and two-dimensional echocardiography. All patients had a history of habitual snoring and a diagnosed light to severe OSAS by previous investigations of nocturnal oxygen saturation status. No subject in the control group had a history of OSAS or hypertension. Body weight was higher in the OSAS patients than in the controls (P less than 0.001). Fifty per cent (31 out of 61) of the OSAS patients had systemic hypertension; 17 of these 31 were on pharmacological antihypertensive treatment. Neither the systolic nor the diastolic blood pressures were found to correlate to the severity of the OSAS (desaturation index). The heart rate was higher at rest in the OSAS patients with or without systemic hypertension compared to the controls with or without a blood pressure level above 165/95 mmHg (P less than 0.05 and P less than 0.01, respectively). Left ventricular (LV) internal dimensions as assessed by echocardiography did not differ between the two groups, while the interventricular septum and the LV posterior wall were thicker in the OSAS group. Thus, the LV mass and the LV mass index were significantly higher among the OSAS patients (P less than 0.001 and P less than 0.001). The LV mass index was approximately 15% higher among the 30 normotensive OSAS patients with no history of cardiac disease compared with the normotensive controls (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

QT interval dispersion in obstructive sleep apnoea syndrome patients without hypertension.

QT interval dispersion (QT(d)) reflects inhomogeneity of repolarisation. Delayed cardiac repolarisation leading to the prolongation of the QT interval is a well-characterised precursor of arrhythmias. Obstructive sleep apnoea syndrome (OSAS) can cause cardiovascular complications, such as arrhythmias, myocardial infarction, and systemic and pulmonary hypertension. The aim of this study was to assess QT(d) in OSAS patients without hypertension. A total of 49 subjects without hypertension, diabetes mellitus, any cardiac or pulmonary diseases, or any hormonal, hepatic, renal or electrolyte disorders were referred for evaluation of OSAS. An overnight polysomnography and a standard 12-lead ECG were performed in each subject. According to the apnoea-hypopnoea index (AHI), subjects were divided into control subjects (AHI <5, n = 20) and moderate-severe OSAS patients (AHI > or =15, n = 29). QT(d) (defined as the difference between the maximum and minimum QT interval) and QT-corrected interval dispersion (QT(cd)) were calculated using Bazzet's formula. In conclusion, the QT(cd) was significantly higher in OSAS patients (56.1+/-9.3 ms) than in controls (36.3+/-4.5 ms). A strong positive correlation was shown between QT(cd) and AHI. In addition, a significantly positive correlation was shown between QT(cd) and the desaturation index (DI). The AHI and DI were significantly related to QT(cd) as an independent variable using stepwise regression analysis. The QT-corrected interval dispersion is increased in obstructive sleep apnoea syndrome patients without hypertension, and it may reflect obstructive sleep apnoea syndrome severity.     

Maxillo-mandibular surgery for obstructive sleep apnoea

Many therapeutic approaches, including mandibular surgery, have been proposed for the treatment of obstructive sleep apnoea syndrome. In the largest study of its type yet reported, 54 patients (population A) underwent mandibular surgery: 36 had palato-pharyngoplasty and inferior sagittal osteotomy of the mandible with hyoid myotomy and resuspension, and 18 (population B) had maxillo-mandibular hyoid advancement, a procedure consisting of palato-pharyngoplasty, inferior sagittal osteotomy of the mandible with hyoid myotomy and, several months later, a maxillo-mandibular osteotomy. Criteria for procedure selection and for evaluation of results were pre-set, and clinical and polygraphic follow-up occurred 6-8 months after final surgery. In population A, 32 of the 36 patients had improved; but only 20 were evaluated as "satisfactory". In contrast, all of the population B patients were judged satisfactory. Four of the population B patients received nasal continuous positive airway pressure (CPAP) before any surgery, and both approaches gave similar good polygraphic results. The degree of skeletal cranio-facial deficiencies, particularly retrognathia, is crucial for procedure selection. We describe potential procedural risks and problems.     

Overview and implications of obstructive sleep apnoea

Obstructive sleep apnoea (OSA) is a leading public health problem both in the developed and developing nations. However, awareness regarding diagnostic options, management and consequences of untreated OSA remains inadequate. In developing nations, the resources for adequate sleep medicine facilities are scarce. Therefore, there is a need for low cost, simple and accurate diagnostic and therapeutic modalities exists. Untreated OSA leads to excessive daytime sleepiness, diminished performance and an overall poor quality of life. The role of OSA in promoting insulin resistance, atherosclerosis, hypertension and a procoagulant state has now been established. Newer insights into the biochemical and genetic mediators of OSA have raised hopes regarding the development of a "cure". However, as of now, continuous positive airway pressure (CPAP) therapy remains the first-line treatment. Though its use improves the quality of life as well as metabolic derangements observed in OSA, patients' acceptance remains low. Its high cost and long-term use are also cumbersome. Newer modes of delivering CPAP, oral appliances and upper airway surgery are the other options available. It is hoped that their appropriate use to increase patients' compliance may improve the quality of life as well as provide a survival benefit.     

The genetics of obstructive sleep apnoea

Obstructive sleep apnoea (OSA) is a common chronic disease and is associated with high social and economic costs. OSA is heritable, and there is evidence of both direct genetic contributions to OSA susceptibility and indirect contributions via ‘intermediate’ phenotypes such as obesity, craniofacial structure, neurological control of upper airway muscles and of sleep and circadian rhythm. Investigation of the genetics of OSA is an important research area and may lead to improved understanding of disease aetiology, pathogenesis, adverse health consequences and new preventive strategies and treatments. Genetic studies of OSA have lagged behind other chronic diseases; however recent gene discovery efforts have been successful in finding genetic loci contributing to OSA‐associated intermediate phenotypes. Nevertheless, many of the seminal questions relating to the genetic epidemiology of OSA and associated factors remain unanswered. This paper reviews the current state of knowledge of the genetics of OSA, with a focus on genomic approaches to understanding sleep apnoea.     

Update on paediatric obstructive sleep apnoea

Obstructive sleep apnoea (OSA) is one of the most common causes of sleep-disordered breathing (SDB) in children. It is associated with significant morbidity, potentially impacting on long-term neurocognitive and behavioural development, as well as cardiovascular outcomes and metabolic homeostasis. The low grade systemic inflammation and increased oxidative stress seen in this condition are believed to underpin the development of these OSA-related morbidities. The significant variance in degree of end organ morbidity in patients with the same severity of OSA highlights the importance of the interplay of genetic and environmental factors in determining the overall OSA phenotype. This review seeks to summarize the current understanding of the aetiology and mechanisms underlying OSA, its risk factors, diagnosis and treatment.     

Hypercapnia in obstructive sleep apnoea syndrome

BACKGROUND: The reports on the prevalence of hypercapnia in Obstructive Sleep Apnoea Syndrome (OSAS) are conflicting. We studied the prevalence of hypercapnia in a population of OSAS patients referred to a Department of Respiratory Medicine and the mechanism of the respiratory failure in OSAS associated with Obesity Hypoventilation Syndrome (OHS) or with Chronic Obstructive Pulmonary Disease (COPD) (Overlap syndrome). METHODS: We studied 219 consecutive OSAS patients during a period of 3 years. We recorded age and anthropomorphic data and performed polysomnography and pulmonary function tests. In relation to the value of PaCO(2), the patients were divided in hypercapnic (PaCO(2)>45 mmHg) patients and normocapnic patients. They were also divided into three groups in relation to the presence of "simple" or "pure" OSAS, to the presence of OSAS associated with COPD, to the presence of OSAS associated with OHS. RESULTS: Seventeen per cent of the patients were hypercapnic. They were significantly heavier, had more severe lung function test abnormalities and more severe nocturnal oxyhemoglobin desaturations than the normocapnic ones, while Forced Expiratory Volume in one second as a percentage of Forced Vital Capacity (FEV1/FVC %) and Apnoea/Hypopnoea Index (AHI) were similar. OHS patients (13%) were significantly younger and heavier, had lower PaO(2) and higher PaCO(2) than "simple" OSAS patients (77%) and Overlap patients (10%) and had more severe restrictive defect. There was no difference in terms of AHI among the three groups, but nocturnal oxyhemoglobin desaturations were more severe in OHS group. In OHS group hypercapnia was correlated to FVC% of predicted and FEV1% of predicted and to the mean nocturnal oxyhemoglobin saturation; in Overlap patients PaCO(2) was correlated to Forced Expiratory Flow rate at low Vital Capacity. CONCLUSION: Seventeen per cent of OSAS patients referred to a Department of Respiratory Medicine were hypercapnic. Hypercapnia in OHS patients correlates to the restrictive ventilatory defect whereas in Overlap patients it seems to correlate to peripheral airways obstruction. The distinction between patients with "simple" or "pure" OSAS and patients affected by OSAS associated with OHS or COPD could be important not only for clinical and prognostic implications, but also for the consequences in terms of ventilatory treatment.     

Resistant hypertension and aldosterone: an update

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.     

Frequency and mechanism of daytime pulmonary hypertension in patients with obstructive sleep apnoea syndrome

In order to study the frequency and the mechanisms of daytime pulmonary hypertension (PH) in obstructive sleep apnoea syndrome (OSAS) lung function tests, blood gas analysis and right-heart catheterization were performed in 46 consecutive patients. OSAS was assessed by polysomnography. 9 patients only (20%) had PH (mean pulmonary artery pressure (Ppa) greater than or equal to 20 mmHg). Patients with PH had lower daytime PaO2 (60.8 +/- 7.6 vs. 76.2 +/- 9.4 mmHg; p less than 0.001), higher daytime PaCO2 (44.8 +/- 4.2 vs. 38.0 +/- 4.0 mmHg; p less than 0.001), lower forced vital capacity (FVC) and forced expiratory volume (FEV1) (p less than 0.001), but the severity of OSAS was not different whether PH was present or not (apnoea index: 62 +/- 34 hour in the PH group vs. 65 +/- 40 hour, apnoea + hypopnoea index 102 +/- 33 hour in the PH group vs. 86 +/- 36 hour, lowest sleep SaO2: 59 +/- 21% in the PH group vs. 66 +/- 18%). There were significant correlations between Ppa and: daytime PaO2 (r = -0.61; p less than 0.001), PaCO2 (r = 0.55; p less than 0.001), FEV1 (r = -0.52; p less than 0.001) but not between Ppa and apnoea index, apnoea + hypopnoea index, lowest sleep SaO2. PH and daytime hypoxaemia were associated either with chronic airway obstruction or with severe obesity.     

阻塞性睡眠呼吸暂停与糖尿病专家共识

一、前言 阻塞性睡眠呼吸暂停(obstructive sleep apnea,OSA)在2型糖尿病患者中很常见~([1]),两者在临床、流行病学和发病机制方面具有相关性,且独立于肥胖之外.目前2型糖尿病对健康的危害已为人们所认识,而OSA对健康的危害及其带来的医疗负担还远没有被人们所认识.因此需要通过各学科的努力使人们认识到OSA与2型糖尿病之间的关系,并着手采取实际行动.     

Adipose tissue in obesity and obstructive sleep apnoea

A European Respiratory Society research seminar on "Metabolic alterations in obstructive sleep apnoea (OSA)" was jointly organised in October 2009 together with two EU COST actions (Cardiovascular risk in the obstructive sleep apnoea syndrome, action B26, and Adipose tissue and the metabolic syndrome, action BM0602) in order to discuss the interactions between obesity and OSA. Such interactions can be particularly significant in the pathogenesis of metabolic abnormalities and in increased cardiovascular risk in OSA patients. However, studying the respective role of OSA and obesity is difficult in patients, making it necessary to refer to animal models or in vitro systems. Since most OSA patients are obese, their management requires a multidisciplinary approach. This review summarises some aspects of the pathophysiology and treatment of obesity, and the possible effects of sleep loss on metabolism. OSA-associated metabolic dysfunction (insulin resistance, liver dysfunction and atherogenic dyslipidaemia) is discussed from the perspective of both obesity and OSA in adults and children. Finally, the effects of treatment for obesity or OSA, or both, on cardio-metabolic variables are summarised. Further interdisciplinary research is needed in order to develop new comprehensive treatment approaches aimed at reducing sleep disordered breathing, obesity and cardiovascular risk.