Maria Rosaria Bonsignore

Sleep, sleep-disordered breathing and metabolic consequences

Sleep profoundly affects metabolic pathways. In healthy subjects, experimental sleep restriction caused insulin resistance (IR) and increased evening cortisol and sympathetic activation. Increased obesity in subjects reporting short sleep duration leads to speculation that, during recent decades, decreased sleeping time in the general population may have contributed to the increasing prevalence of obesity. Causal inference is difficult due to lack of control for confounders and inconsistent evidence of temporal sequence. In the general population, obstructive sleep apnoea (OSA) is associated with glucose intolerance. OSA severity is also associated with the degree of IR. However, OSA at baseline does not seem to significantly predict the development of diabetes. Prevalence of the metabolic syndrome is higher in patients with OSA than in obese subjects without OSA. Treatment with continuous positive airway pressure seems to improve glucose metabolism both in diabetic and nondiabetic OSA but mainly in nonobese subjects. The relative role of obesity and OSA in the pathogenesis of metabolic alterations is still unclear and is intensively studied in clinical and experimental models. In the intermittent hypoxia model in rodents, strong interactions are likely to occur between haemodynamic alterations, systemic inflammation and metabolic changes, modulated by genetic background. Molecular and cellular mechanisms are currently being investigated.

Autonomic cardiac regulation in obstructive sleep apnea syndrome : evidence from spontaneous baroreflex analysis during sleep

Objective To assess spontaneous baroreceptor-heart rate reflex sensitivity during sleep in patients with obstructive sleep apnea syndrome, a condition associated with increased cardiovascular morbidity and mortality and characterized by marked sympathetic activation, which is believed to originate from hypoxic chemoreceptor stimulation, although little is known of other possible mechanisms such as baroreflex impairment. Design and methods In 11 patients with severe obstructive sleep apnea syndrome (mean ± SD age 46.8 ± 8.1 years, apnea/hypopnea index 67.9 ± 19.1 h), who were normotensive or borderline hypertensive during wakefulness by clinic blood pressure measurements, finger blood pressure was monitored beat-by-beat non-invasively (Finapres) at night during polysomnography. Periods of wakefulness and sleep were identified based on electroencephalographic recordings. Baroreflex sensitivity was assessed by the sequence technique, as the slope of the regression line between spontaneous increases or reductions in systolic blood pressure (SBP) and the related lengthening or shortening in the RR interval, occurring over spontaneous sequences of four or more consecutive beats. The number of these sequences was also computed, as an additional index of baroreflex engagement by the spontaneous blood pressure fluctuations. The controls were age-related normotensive or borderline hypertensive subjects without sleep apnea who had been investigated in previous studies; in these subjects blood pressure was recorded intra-arterially over 24 h in ambulatory conditions and spontaneous baroreflex sensitivity was assessed by the sequence technique. Results In our patients the lowest nocturnal arterial oxygen saturation was 78.6 ± 12.1% (mean ± SD). During sleep, the number of pooled +RR/+SBP and −RR/−SBP sequences per hour was 20.3 ± 2.7 per h in patients with sleep apnea and 27.1 ± 2.1/h in controls (means ± SEM). The average baroreflex sensitivity during sleep periods was 7.04 ± 0.8 ms/mmHg in sleep apnea patients and 10.05 ± 2.1 ms/mmHg in controls. Both the pooled number of sequences and baroreflex sensitivity values of the sleep apnea patients were significantly (P <0.01) less than the corresponding night values of control subjects. In the sleep apnea patients, at variance from controls, baroreflex sensitivity did not show any increase during sleep compared with its values during wakefulness (6.9 ± 1.0 ms/mmHg). Conclusions Our data provide evidence that spontaneous baroceptor reflex sensitivity is depressed in severe obstructive sleep apnea syndrome. This suggests that in such patients baroreflex dysfunction and not only chemoreceptor stimulation by hypoxia may be involved in the sympathetic activation which occurs during sleep. Such dysfunction may contribute to the higher rate of cardiovascular morbidity and mortality reported in these patients.

Circulating haemopoietic and endothelial progenitor cells are decreased in COPD

Circulating CD34+ cells are haemopoietic progenitors that may play a role in tissue repair. No data are available on circulating progenitors in chronic obstructive pulmonary disease (COPD). Circulating CD34+ cells were studied in 18 patients with moderate-to-severe COPD (age: mean±sd 68±8 yrs; forced expiratory volume in one second: 48±12% predicted) and 12 controls, at rest and after endurance exercise. Plasma concentrations of haematopoietic growth factors (FMS-like tyrosine kinase 3 (Flt3) ligand, kit ligand), markers of hypoxia (vascular endothelial growth factor (VEGF)) and stimulators of angiogenesis (VEGF, hepatocyte growth factor (HGF)) and markers of systemic inflammation (tumour necrosis factor (TNF)-α, interleukin (IL)-6, IL-8) were measured. Compared with the controls, the COPD patients showed a three-fold reduction in CD34+ cell counts (3.3±2.5 versus 10.3±4.2 cells·µL−1), and a 50% decrease in AC133+ cells. In the COPD patients, progenitor-derived haemopoietic and endothelial cell colonies were reduced by 30–50%. However, four COPD patients showed progenitor counts in the normal range associated with lower TNF-α levels. In the entire sample, CD34+ cell counts correlated with exercise capacity and severity of airflow obstruction. After endurance exercise, progenitor counts were unchanged, while plasma Flt3 ligand and VEGF only increased in the COPD patients. Plasma HGF levels were higher in the COPD patients compared with the controls and correlated inversely with the number of progenitor-derived colonies. In conclusion, circulating CD34+ cells and endothelial progenitors were decreased in chronic obstructive pulmonary disease patients and could be correlated with disease severity.

Cigarette smoke increases Toll-like receptor 4 and modifies lipopolysaccharide-mediated responses in airway epithelial cells.

Airway epithelium is emerging as a regulator of innate immune responses to a variety of insults including cigarette smoke. The main goal of this study was to explore the effects of cigarette smoke extracts (CSE) on Toll‐like receptor (TLR) expression and activation in a human bronchial epithelial cell line (16‐HBE). The CSE increased the expression of TLR4 and the lipopolysaccharide (LPS) binding, the nuclear factor‐κB (NF‐κB) activation, the release of interleukin‐8 (IL‐8) and the chemotactic activity toward neutrophils. It did not induce TLR2 expression or extracellular signal‐regulated signal kinase 1/2 (ERK1/2) activation. The LPS increased the expression of TLR4 and induced both NF‐κB and ERK1/2 activation. The combined exposure of 16‐HBE to CSE and LPS was associated with ERK activation rather than NF‐κB activation and with a further increase of IL‐8 release and of chemotactic activity toward neutrophils. Furthermore, CSE decreased the constitutive interferon‐inducible protein‐10 (IP‐10) release and counteracted the effect of LPS in inducing both the IP‐10 release and the chemotactic activity toward lymphocytes. In conclusion, cigarette smoke, by altering the expression and the activation of TLR4 via the preferential release of IL‐8, may contribute to the accumulation of neutrophils within the airways of smokers.

Recommendations for the management of patients with obstructive sleep apnoea and hypertension

This article is aimed at addressing the current state-of-the-art in epidemiology, pathophysiology, diagnostic procedures and treatment options for appropriate management of obstructive sleep apnoea (OSA) in cardiovascular (in particular hypertensive) patients, as well as for the management of cardiovascular diseases (in particular arterial hypertension) in OSA patients. The present document is the result of work performed by a panel of experts participating in the European Union COST (Cooperation in Scientific and Technological research) Action B26 on OSA, with the endorsement of the European Respiratory Society and the European Society of Hypertension. In particular, these recommendations are aimed at reminding cardiovascular experts to consider the occurrence of sleep-related breathing disorders in patients with high blood pressure. They are also aimed at reminding respiration experts to consider the occurrence of hypertension in patients with respiratory problems at night.

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.

Increased airway inflammatory cells in endurance athletes: what do they mean?

Background Inflammatory cells are increased in the airways of endurance athletes, but their role in causing exercise‐induced respiratory symptoms and bronchoconstriction, or their possible long‐term consequences, are uncertain.

Metabolic syndrome, insulin resistance and sleepiness in real-life obstructive sleep apnoea

The metabolic syndrome shows a variable prevalence in obstructive sleep apnoea (OSA), and its association with insulin resistance or excessive daytime sleepiness in OSA is unclear. This study assessed the following in consecutive patients with newly diagnosed OSA: 1) the prevalence of metabolic syndrome; and 2) its association with insulin resistance and daytime sleepiness. Metabolic syndrome (National Cholesterol Education Program Adult Treatment Panel (NCEP-ATP) III criteria), insulin resistance (Homeostatic Model Assessment (HOMA) index, n=288) and daytime sleepiness (Epworth Sleepiness Scale) were assessed in 529 OSA patients. The prevalence of metabolic syndrome was 51.2%, which increased with OSA severity. Each metabolic syndrome component correlated with apnoea/hypopnoea index, but only blood pressure retained significance after correction for confounders. Both obesity and OSA contributed to metabolic abnormalities, with different sex-related patterns, since diagnosis of metabolic syndrome was significantly associated with neck circumference, age, body mass index and lowest arterial oxygen saturation in males, and with age and arousal index in females. The number of metabolic syndrome components increased with HOMA index (p<0.001). Prevalence of sleepiness was the same in patients with and without metabolic syndrome. The metabolic syndrome occurs in about half of “real-life” OSA patients, irrespective of daytime sleepiness, and is a reliable marker of insulin resistance.

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.

Ventilation and entrainment of breathing during cycling and running in triathletes.

PURPOSE To assess whether entrainment of breathing (E) during exercise: 1) differed according to the test protocol in well-trained triathletes, and 2) improved ventilatory efficiency during exercise. METHODS Eight triathletes performed three incremental tests until exhaustion: while cycling (CE), while running at increasing grade and constant speed (increasing GRADE) and while running at increasing speed and constant grade (increasing SPEED), respectively. E was evaluated as the percentage of breaths occurring at respiratory rates (F) corresponding to integer ratios of the exercise cycle rate. To assess whether E improved ventilatory efficiency, deltaVE/VO2 between nonentrained and entrained breaths was measured at each load. RESULTS Mean E was higher in CE (57.2+/-21.9%) than in increasing GRADE (46.9+/-18.7%) and increasing SPEED (41.4+/-17.2%). E decreased at high loads in CE and increasing SPEED but not in increasing GRADE. In the group of subjects, E correlated with the degree of fitness (evaluated as VO2Tvent/VO2peak%) only during increasing GRADE. By multiple regression analysis on all data, minute ventilation correlated with CO2 production but not with the exercise cycle rate; however, either F or tidal volume correlated significantly with both these variables. VE/VO2 was lower in entrained than nonentrained breaths at each load in CE and increasing GRADE experiments, but the difference was small. CONCLUSIONS In spite of some differences among protocols, triathletes showed significant E during incremental exercise tests. Spontaneous E appeared to slightly improve ventilatory efficiency during CE and increasing GRADE protocols.