Brian D. Kent

Hypoxemia in patients with COPD: cause, effects, and disease progression

Chronic obstructive pulmonary disease (COPD) is a leading cause of death and disability internationally. Alveolar hypoxia and consequent hypoxemia increase in prevalence as disease severity increases. Ventilation/perfusion mismatch resulting from progressive airflow limitation and emphysema is the key driver of this hypoxia, which may be exacerbated by sleep and exercise. Uncorrected chronic hypoxemia is associated with the development of adverse sequelae of COPD, including pulmonary hypertension, secondary polycythemia, systemic inflammation, and skeletal muscle dysfunction. A combination of these factors leads to diminished quality of life, reduced exercise tolerance, increased risk of cardiovascular morbidity, and greater risk of death. Concomitant sleep-disordered breathing may place a small but significant subset of COPD patients at increased risk of these complications. Long-term oxygen therapy has been shown to improve pulmonary hemodynamics, reduce erythrocytosis, and improve survival in selected patients with severe hypoxemic respiratory failure. However, the optimal treatment for patients with exertional oxyhemoglobin desaturation, isolated nocturnal hypoxemia, or mild-to-moderate resting daytime hypoxemia remains uncertain.

Diabetes Mellitus Prevalence and Control in Sleep-Disordered Breathing: The European Sleep Apnea Cohort (ESADA) Study

BACKGROUND OSA is associated with an increased risk of cardiovascular morbidity. A driver of this is metabolic dysfunction and in particular type 2 diabetes mellitus (T2DM). Prior studies identifying a link between OSA and T2DM have excluded subjects with undiagnosed T2DM, and there is a lack of population-level data on the interaction between OSA and glycemic control among patients with diabetes. We assessed the relationship between OSA severity and T2DM prevalence and control in a large multinational population. METHODS We performed a cross-sectional analysis of 6,616 participants in the European Sleep Apnea Cohort (ESADA) study, using multivariate regression analysis to assess T2DM prevalence according to OSA severity, as measured by the oxyhemoglobin desaturation index. Patients with diabetes were identified by previous history and medication prescription, and by screening for undiagnosed diabetes with glycosylated hemoglobin (HbA1c) measurement. The relationship of OSA severity with glycemic control was assessed in diabetic subjects. RESULTS T2DM prevalence increased with OSA severity, from 6.6% in subjects without OSA to 28.9% in those with severe OSA. Despite adjustment for obesity and other confounding factors, in comparison with subjects free of OSA, patients with mild, moderate, or severe disease had an OR (95% CI) of 1.33 (1.04-1.72), 1.73 (1.33-2.25), and 1.87 (1.45-2.42) (P < .001), respectively, for prevalent T2DM. Diabetic subjects with more severe OSA had worse glycemic control, with adjusted mean HbA1c levels 0.72% higher in patients with severe OSA than in those without sleep-disordered breathing (analysis of covariance, P < .001). CONCLUSIONS Increasing OSA severity is associated with increased likelihood of concomitant T2DM and worse diabetic control in patients with T2DM.

Obstructive sleep apnea and inflammation: relationship to cardiovascular co-morbidity.

Obstructive sleep apnoea syndrome (OSAS) is a highly prevalent disease and associated with cardiovascular morbidity and mortality. The pathogenesis of cardiovascular complications in OSAS is incompletely understood but a multifactorial etiology is likely. There is emerging evidence that inflammatory processes leading to endothelial dysfunction play a pivotal role. Various studies have demonstrated elevated inflammatory markers in OSAS patients in comparison to matched control subjects with a significant fall after effective treatment with continuous positive airway pressure. Cell culture and animal studies have significantly enhanced our understanding of the mechanisms of inflammation in OSAS. Intermittent hypoxia, the hallmark feature of OSAS, leads to a preferential activation of inflammatory pathways with the downstream consequence of expression of pro-inflammatory cytokines, chemokines and adhesion molecules that may contribute to endothelial dysfunction. Further studies are required to determine the precise role of inflammation in the cardiovascular pathogenesis of OSAS, particularly its interaction with oxidative stress, obesity and metabolic dysfunction.

Epidemiological aspects of obstructive sleep apnea

Obstructive sleep apnea (OSA) is probably the most common respiratory disorder, with recent data from the United States and Europe suggesting that between 14% and 49% of middle-aged men have clinically significant OSA. The intimate relationship between OSA and obesity means that its prevalence will only increase as the global obesity epidemic evolves. At an individual level, OSA leads to a significant decrease in quality of life (QOL) and functional capacity, alongside a markedly increased risk of cardiovascular disease and death. Emerging data also suggest that the presence and severity of OSA and associated nocturnal hypoxemia are associated with an increased risk of diabetes and cancer. At a societal level, OSA not only leads to reduced economic productivity, but also constitutes a major treatable risk factor for hypertension, coronary artery disease (CAD) and stroke. This article addresses OSA from an epidemiological perspective, from prevalence studies to economic aspects to co-morbidity.

Acute Pulmonary Admissions Following Implementation of a National Workplace Smoking Ban

BACKGROUND The implementation of workplace smoking bans has contributed to a significant reduction in the incidence of acute coronary syndrome admissions, but their influence on adult acute pulmonary disease admissions is unclear. We sought to assess the impact of a national smoking ban on nationwide admissions of individuals of working age with acute pulmonary illness. METHODS Data relating to emergency hospital admissions of subjects aged 20 to 70 years preceding and succeeding the implementation of the Irish smoking ban were obtained from a central registry. Population, weather, pollution, and influenza data were obtained from the relevant authorities. Poisson regression analysis was used to assess adjusted risk of emergency hospital admission following implementation of the smoking ban. RESULTS Overall admissions with pulmonary illness decreased from 439 per 100,000 population per annum to 396 per 100,000 population per annum following the ban (unadjusted relative risk [RR], 0.91; 95% CI, 0.83-0.99; P = .048). This persisted following adjustment for confounding factors (adjusted RR, 0.85; 95% CI, 0.72-0.99; P = .04) and was most marked among younger age groups and in admissions due to asthma (adjusted RR, 0.60; 95% CI, 0.39-0.91; P = .016). Admissions with acute coronary syndromes (adjusted RR, 0.82; 95% CI, 0.70-0.97; P = .02), but not stroke (adjusted RR, 0.93; 95% CI, 0.73-1.20; P = .60), were also reduced. CONCLUSIONS The implementation of a nationwide workplace smoking ban is associated with a decline in admissions with acute pulmonary disease among specific age groups and an overall reduction in asthma admissions. This may result from reduced exposure of vulnerable individuals to environmental tobacco smoke, emphasizing the potential benefit of legislation reducing second-hand smoke exposure.

The genetics of obstructive sleep apnoea.

Purpose of review Obstructive sleep apnoea syndrome (OSAS) is a highly prevalent disorder associated with reduced quality of life and adverse cardiovascular and metabolic sequelae. Recent years have seen an intensification of the research effort to establish the genetic contribution to the development of OSAS and its sequelae. This review explores emerging evidence in this field. Recent findings A genetic basis for sleep-disordered breathing has been demonstrated for discrete disorders such as Treacher–Collins and Down syndromes, but the picture is less clear in so-called idiopathic OSAS. A degree of heritability appears likely in some of the intermediate phenotypes that lead to OSAS, particularly craniofacial morphology. However, only sparse and often contradictory evidence exists regarding the role of specific polymorphisms in causing OSAS in the general population. Similarly, investigations of the cardiovascular sequelae of OSAS have in general failed to consistently find single causative genetic mutations. Nonetheless, evidence suggests a role for tumour necrosis factor-α polymorphisms in particular, and large-scale family studies have suggested shared pathogenetic pathways for the development of obesity and OSAS. Summary As with other common disorders, OSAS is likely to result from multiple gene–gene interactions occurring in a suitable environment. The application of modern genetic investigative techniques, such as genome-wide association studies, may facilitate new discoveries in this field.

Human adipocytes are highly sensitive to intermittent hypoxia induced NF-kappaB activity and subsequent inflammatory gene expression

INTRODUCTION Intermittent hypoxia (IH)-induced activation of pro-inflammatory pathways is a major contributing factor to the cardiovascular pathophysiology associated with obstructive sleep apnea (OSA). Obesity is commonly associated with OSA although it remains unknown whether adipose tissue is a major source of inflammatory mediators in response to IH. The aim of this study was to test the hypothesis that IH leads to augmented inflammatory responses in human adipocytes when compared to cells of non-adipocyte lineages. METHODS AND RESULTS Human primary subcutaneous and visceral adipocytes, human primary microvascular pulmonary endothelial cells (HUMEC-L) and human primary small airway epithelial cells (SAEC) were exposed to 0, 6 or 12 cycles of IH or stimulated with tumor necrosis factor (TNF)-α. IH led to a robust increase in NF-κB DNA-binding activity in adipocytes compared with normoxic controls regardless of whether the source of adipocytes was visceral or subcutaneous. Notably, the NF-κB response of adipocytes to both IH and TNF-α was significantly greater than that in HUMEC-L and SAEC. Western blotting confirmed enhanced nuclear translocation of p65 in adipocytes in response to IH, accompanied by phosphorylation of I-κB. Parallel to p65 activation, we observed a significant increase in secretion of the adipokines interleukin (IL)-8, IL-6 and TNF-α with IH in adipocytes accompanied by significant upregulation of mRNA expression. PCR-array suggested profound influence of IH on pro-inflammatory gene expression in adipocytes. CONCLUSION Human adipocytes demonstrate strong sensitivity to inflammatory gene expression in response to acute IH and hence, adipose tissue may be a key source of inflammatory mediators in OSA.

Insulin resistance, glucose intolerance and diabetes mellitus in obstructive sleep apnoea

Obstructive sleep apnoea (OSA) is a highly prevalent disorder, which conveys an increased risk of cardiovascular disease and death. Type 2 diabetes mellitus (T2DM), glucose intolerance and insulin resistance (IR) are common in subjects with OSA, but a shared intimate relationship with obesity makes discerning an independent link challenging. Nonetheless, mechanistic studies suggest that OSA could contribute to impaired glucose metabolism via the effects of sleep fragmentation, sympathetic excitation and intermittent hypoxia (IH) on pancreatic B-cell function, insulin sensitivity, and systemic inflammation. In particular, emerging data suggest that IH may have an important detrimental effect on adipose tissue function and inflammation. Similarly, data from population-and clinic-level studies suggest that OSA is independently related with the prevalence and incidence of T2DM and IR, and may also lead to worse glycaemic control in diabetics. However, the ability of continuous positive airway pressure (CPAP) therapy to make a meaningful impact on T2DM or IR remains uncertain. In this review we explore the available evidence linking OSA with IR, glucose intolerance and T2DM, and discuss potential pathobiological mechanisms by which sleep disordered breathing can affect metabolic health.

Severity of obstructive sleep apnoea predicts coronary artery plaque burden: a coronary computed tomographic angiography study

Obstructive sleep apnoea (OSA) is associated with significantly increased risk of cardiovascular disease. Carotid ultrasonography and retrospective, uncontrolled, coronary imaging studies have suggested an association of OSA with subclinical atherosclerosis, but there is a lack of prospective, controlled studies directly evaluating the relationship of OSA with occult coronary artery disease. We performed coronary computed tomographic angiography and inpatient-attended sleep studies on a cohort of otherwise healthy males attending our sleep laboratory, and compared coronary artery plaque volume between subjects with low and high apnoea/hypopnoea index (AHI) scores. 29 subjects participated. The median AHI was 15.5 events·h−1, with subjects who scored above this classified as high AHI. No significant differences were observed in demographic, anthropometric and clinical variables between the high- and low-AHI groups. Coronary plaque volume was significantly greater in the high-AHI group (mean plaque volume 2.6±0.7 mm2 versus 0.8±0.2 mm2; p=0.017) and, furthermore, correlated significantly with AHI (Spearman’s r=0.433; p=0.019). Following adjustment for dyslipidaemia and fasting plasma glucose levels, AHI remained a significant predictor of plaque volume (standardised &bgr;=0.424; p=0.027). In this prospective case–control study, we found that severity of OSA may predict occult coronary atherosclerosis in otherwise healthy overweight or obese male subjects. Increasing OSA severity predicts a greater burden of occult coronary artery disease in healthy overweight or obese males http://ow.ly/nSXEU

Sleep apnoea severity independently predicts glycaemic health in nondiabetic subjects: the ESADA study

Obstructive sleep apnoea (OSA) is associated with increased risk of dysglycaemia but the intimate link of these conditions with obesity makes discerning an independent relationship between them challenging. Glycosylated haemoglobin (HbA1c) levels predict adverse cardiovascular outcomes in nondiabetics but there is a lack of population-level data exploring the relationship of HbA1c with OSA. A cross-sectional analysis of 5294 participants in the multinational European Sleep Apnoea Cohort (European Sleep Apnoea Database) study was performed, assessing the relationship of OSA severity with HbA1c levels in nondiabetic subjects, with adjustment for confounding factors. HbA1c levels correlated significantly with OSA severity in univariate analysis. Following adjustment for confounding factors, apnoea–hypopnoea index (AHI) (standardised &bgr; 0.158; p<0.001), along with nocturnal hypoxaemia, predicted HbA1c. Adjusted mean HbA1c levels were lower in the lowest AHI quartile (5.24%, 95% CI 5.21–5.27%) than in the second (5.37%, 95% CI 5.34–5.40%), third (5.44%, 95% CI 5.41–5.47%) or highest (5.50%, 95% CI 5.46–5.53%) quartiles. Subjects in the higher quartiles had significantly greater adjusted odds ratios of HbA1c level ≥6.0% than those in the first quartile. In stratified analyses, OSA severity predicted glycaemic health irrespective of sleep study modality, sex, obesity or daytime sleepiness. OSA severity independently predicts glycaemic health in nondiabetic subjects. Further studies should assess the impact of OSA treatment on glycaemic health and elucidate underlying mechanisms. Increasing sleep apnoea severity was associated with elevated HbA1c levels in a nondiabetic multinational cohort http://ow.ly/u1RLR