Markers of adipose tissue hypoxia are elevated in subcutaneous adipose tissue of severely obese patients with obesity hypoventilation syndrome but not in the moderately obese.

It has been suggested that metabolic dysfunction in obesity is at least in part driven by adipose tissue (AT) hypoxia. However, studies on AT hypoxia in humans have shown conflicting data. Therefore we aimed to investigate if markers of AT hypoxia were present in the subcutaneous AT of severly obese individuals (class III obesity) with and without hypoventilation syndrome (OHS) in comparison to moderately obese (class I obesity) and lean controls. To provide a proof-of-concept study, we quantified AT hypoxia by hypoxia inducible factor 1 A (HIF1A) protein abundance in human participants ranging from lean to severly obese (class III obesity). On top of that nightly arterial O2 saturation in individuals with obesity OHS was assessed. Subjects with class III obesity (BMI > 40 kg/m2) and OHS exhibited significantly higher adipose HIF1A protein levels versus those with class I obesity (BMI 30-34.9 kg/m2) and lean controls whereas those with class III obesity without OHS showed an intermediate response. HIF1A gene expression was not well correlated with protein abundance. Although these data demonstrate genuine AT hypoxia in the expected pathophysiological context of OHS, we did not observe a hypoxia signal in lesser degrees of obesity suggesting that adipose dysfunction may not be driven by hypoxia in moderate obesity.

Does either obesity or OSA severity influence the response of autotitrating CPAP machines in very obese subjects?

PURPOSE: The pressures delivered by autotitrating continuous positive airways pressure (CPAP) devices not only treat obstructive sleep apnoea (OSA) effectively but also give potentially interesting physiological information about the forces impinging on the pharynx. In earlier work from this unit, we used correlations between autoCPAP pressure and both OSA severity and obesity, to construct an algorithm to estimate the fixed CPAP pressure a patient required for subsequent clinical use. We wished to discover if these relationships could be reliably extended to a much more obese group. METHODS: We performed a prospective cohort study in an obese population. Measurements of obesity were made, OSA severity was recorded, and the 95th centile autoCPAP pressure was recorded during 1 week of autoCPAP. Spearman's rank correlation was performed between measurements of obesity and autoCPAP pressure, and between OSA severity and autoCPAP pressure. RESULTS: Fifty-four obese individuals (median body mass index (BMI) 43.0 kg/m(2)), 52 % of whom had OSA (apnoea-hypopnoea index (AHI) ≥ 15), had a median 95th centile autoCPAP pressure of 11.8 cmH2O. We found no significant correlation between autoCPAP pressure and neck circumference, waist circumference or BMI. There was a moderate correlation between autoCPAP pressure and OSA severity (AHI r = 0.34, p = 0.02; oxygen desaturation index (ODI) r = 0.48, p < 0.001). CONCLUSIONS: In this population, neither BMI nor neck circumference nor waist circumference is predictive of autoCPAP pressure. Therefore, the previously derived algorithm does not adequately predict the fixed CPAP pressure for subsequent clinical use in these obese individuals. In addition, some subjects without OSA generated high autoCPAP pressures, and thus, the correlation between OSA severity and autoCPAP pressure was only moderate.

Biomarkers of oxidative stress following continuous positive airway pressure withdrawal: data from two randomised trials.

There is conflicting evidence whether intermittent hypoxia in obstructive sleep apnoea (OSA) influences oxidative stress. We hypothesised that withdrawal of continuous positive airway pressure (CPAP) from patients with OSA would raise markers of oxidative stress.59 patients with CPAP-treated moderate-to-severe OSA (oxygen desaturation index (ODI) >20 events·h(-1)) were randomised 1:1 to either stay on CPAP (n=30) or change to sham CPAP (n=29) for 2 weeks. Using samples from two similar studies at two sites, we measured early morning blood malondialdehyde (MDA, a primary outcome in one study and a secondary outcome in the other), lipid hydroperoxides, total antioxidant capacity, superoxide generation from mononuclear cells and urinary F2-isoprostane. We also measured superoxide dismutase as a marker of hypoxic preconditioning. "Treatment" effects (sham CPAP versus CPAP) were calculated via linear regression.Sham CPAP provoked moderate-to-severe OSA (mean ODI 46 events·h(-1)), but blood markers of oxidative stress did not change significantly (MDA "treatment" effect (95% CI) -0.02 (-0.23 to +0.19) µmol·L(-1)). Urinary F2-isoprostane fell significantly by ~30% (-0.26 (-0.42 to -0.10) ng·mL(-1)) and superoxide dismutase increased similarly (+0.17 (+0.02 to +0.30) ng·mL(-1)).We found no direct evidence of increased oxidative stress in patients experiencing a return of their moderate-to-severe OSA. The fall in urinary F2-isoprostane and rise in superoxide dismutase implies that hypoxic preconditioning may have reduced oxidative stress.

Correlates of obesity-related chronic ventilatory failure.

INTRODUCTION: Only a third of obese patients develop chronic ventilatory failure. This cross-sectional study assessed multiple factors potentially associated with chronic ventilatory failure. MATERIALS/PATIENTS AND METHODS: Participants had a body mass index (BMI) >30 kg/m(2), with or without chronic ventilatory failure (awake arterial partial pressure of carbon dioxide >6 kPa or base excess (BE) ≥2 mmols/L). Factors investigated were grouped into domains: (1) obesity measures, (2) pulmonary function, (3) respiratory and non-respiratory muscle strength, (4) sleep study derivatives, (5) hypoxic and hypercapnic responses, and (6) some hormonal, nutritional and inflammatory measures. RESULTS: 71 obese participants (52% male) were studied over 27 months, 52 (SD 9) years and BMI 47 (range 32-74) kg/m(2). The best univariate correlates of BE from each domain were: (1) dual-energy X-ray absorptiometry measurement of visceral fat (r=+0.50, p=0.001); (2) supine forced expiratory volume in 1 s (r=-0.40, p=0.001); (3) sniff maximum pressure (r=-0.28, p=0.02); (4) mean overnight arterial oxygen saturation (r=-0.50, p<0.001); (5) ventilatory response to 15% O2 breathing (r=-0.28, p=0.02); and (6) vitamin D (r=-0.30, p=0.01). In multivariate analysis, only visceral fat and ventilatory response to hypoxia remained significant. CONCLUSIONS: We have confirmed that in the obese, BMI is a poor correlate of chronic ventilatory failure, and the best independent correlates are visceral fat and hypoxic ventilatory response. TRIAL REGISTRATION NUMBER: NCT01380418.

Is a raised bicarbonate, without hypercapnia, part of the physiologic spectrum of obesity-related hypoventilation?

BACKGROUND: Obesity hypoventilation syndrome (OHS) conventionally includes awake hypercapnia, but an isolated raised bicarbonate, even in the absence of awake hypercapnia, may represent evidence of "early" OHS. We investigated whether such individuals exhibit certain features characteristic of established OHS. METHODS: Obese subjects (BMI > 30 kg/m(2)) were identified from a variety of sources and divided into those with (1) normal blood gas measurements and normal acid-base balance, (2) an isolated raised base excess (BE) (≥ 2 mmol/L), and (3) awake hypercapnia (> 6 kPa; ie, established OHS). Two-point ventilatory responses to hypoxia and hypercapnia were performed. Polygraphic sleep studies were done to identify intermittent and prolonged hypoxia. RESULTS: Seventy-one subjects (BMI, 47.2; SD, 9.8; age, 52.1 years; SD, 8.8 years) were recruited into three groups (33, 22, and 16 respectively). The Paco2 and BE values were 5.15, 5.42, 6.62 kPa, and +0.12, +3.01, +4.78 mmol/L, respectively. For nearly all the ventilatory response and sleep study measures, group 2 (with only an isolated raised BE) represented an intermediate group, and for some of the measures they were more similar to the third group with established OHS. CONCLUSIONS: These data suggest that obese individuals with a raised BE, despite normocapnia while awake, should probably be regarded as having early obesity-related hypoventilation. This has important implications for clinical management as well as randomized controlled treatment trials, as they may represent a group with a more reversible disease process. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01380418; URL: www.clinicaltrials.gov.

The role of cardiac biomarkers for predicting left ventricular dysfunction and cardiovascular mortality in acute exacerbations of COPD.

The presence of cardiovascular comorbidities is frequently associated with poor outcomes in chronic obstructive pulmonary disease (COPD). No clear role has been defined for cardiac biomarkers in acute exacerbations of COPD (AECOPD). The aim of this systematic review was to examine the prognostic value of brain natriuretic peptide (BNP) and troponins in patients with AECOPD. Two independent authors searched the PubMed and Cochrane Library to collect clinical trials, observational studies and meta-analyses studying the prognostic value of cardiac biomarkers in AECOPD. The reference lists of all the included studies were also reviewed. A total of 14 studies were included in the review, of which 10 measured troponins, 7 measured BNP or NT-proBNP, and 3 measured both. Of the studies that used mortality in AECOPD as an end point, some but not all found that elevated BNP and/or troponins were associated with increased mortality. Of the studies that used left ventricular (LV) dysfunction in AECOPD as an end point, all found a significant association between elevated BNP and troponins in the diagnosis of LV dysfunction. In summary, it appears that there may be a link between an elevated level of BNP or NT-proBNP and increased cardiovascular mortality in AECOPD, although the data currently available are not conclusive. The inconsistencies in biomarkers measured, time points of measurements and the variability in outcome measured preclude more robust analysis.