John F. Garvey

Cardiovascular disease in obstructive sleep apnoea syndrome: the role of intermittent hypoxia and inflammation.

There is increasing evidence that intermittent hypoxia plays a role in the development of cardiovascular risk in obstructive sleep apnoea syndrome (OSAS) through the activation of inflammatory pathways. The development of translational models of intermittent hypoxia has allowed investigation of its role in the activation of inflammatory mechanisms and promotion of cardiovascular disease in OSAS. There are noticeable differences in the response to intermittent hypoxia between body tissues but the hypoxia-sensitive transcription factors hypoxia-inducible factor-1 and nuclear factor-κB appear to play a key role in mediating the inflammatory and cardiovascular consequences of OSAS. Expanding our understanding of these pathways, the cross-talk between them and the activation of inflammatory mechanisms by intermittent hypoxia in OSAS will provide new avenues of therapeutic opportunity for the disease.

A mitochondria-targeted S-nitrosothiol modulates respiration, nitrosates thiols, and protects against ischemia-reperfusion injury

Nitric oxide (NO•) competitively inhibits oxygen consumption by mitochondria at cytochrome c oxidase and S-nitrosates thiol proteins. We developed mitochondria-targeted S-nitrosothiols (MitoSNOs) that selectively modulate and protect mitochondrial function. The exemplar MitoSNO1, produced by covalently linking an S-nitrosothiol to the lipophilic triphenylphosphonium cation, was rapidly and extensively accumulated within mitochondria, driven by the membrane potential, where it generated NO• and S-nitrosated thiol proteins. MitoSNO1-induced NO• production reversibly inhibited respiration at cytochrome c oxidase and increased extracellular oxygen concentration under hypoxic conditions. MitoSNO1 also caused vasorelaxation due to its NO• generation. Infusion of MitoSNO1 during reperfusion was protective against heart ischemia-reperfusion injury, consistent with a functional modification of mitochondrial proteins, such as complex I, following S-nitrosation. These results support the idea that selectively targeting NO• donors to mitochondria is an effective strategy to reversibly modulate respiration and to protect mitochondria against ischemia-reperfusion injury.

PGC-1α is coupled to HIF-1α-dependent gene expression by increasing mitochondrial oxygen consumption in skeletal muscle cells

Mitochondrial biogenesis occurs in response to increased cellular ATP demand. The mitochondrial electron transport chain requires molecular oxygen to produce ATP. Thus, increased ATP generation after mitochondrial biogenesis results in increased oxygen demand that must be matched by a corresponding increase in oxygen supply. We found that overexpression of peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α), which increases mitochondrial biogenesis in primary skeletal muscle cells, leads to increased expression of a cohort of genes known to be regulated by the dimeric hypoxia-inducible factor (HIF), a master regulator of the adaptive response to hypoxia. PGC-1α-dependent induction of HIF target genes under physiologic oxygen concentrations is not through transcriptional coactivation of HIF or up-regulation of HIF-1α mRNA but through HIF-1α protein stabilization. It occurs because of intracellular hypoxia as a result of increased oxygen consumption after mitochondrial biogenesis. Thus, we propose that at physiologic oxygen concentrations, PGC-1α is coupled to HIF signaling through the regulation of intracellular oxygen availability, allowing cells and tissues to match increased oxygen demand after mitochondrial biogenesis with increased oxygen supply.

An intact canonical NF-κB pathway is required for inflammatory gene expression in response to hypoxia.

Hypoxia is a feature of the microenvironment in a number of chronic inflammatory conditions due to increased metabolic activity and disrupted perfusion at the inflamed site. Hypoxia contributes to inflammation through the regulation of gene expression via key oxygen-sensitive transcriptional regulators including the hypoxia-inducible factor (HIF) and NF-κB. Recent studies have revealed a high degree of interdependence between HIF and NF-κB signaling; however, the relative contribution of each to hypoxia-induced inflammatory gene expression remains unclear. In this study, we use transgenic mice expressing luciferase under the control of NF-κB to demonstrate that hypoxia activates NF-κB in the heart and lungs of mice in vivo. Using small interfering RNA targeted to the p65 subunit of NF-κB, we confirm a unidirectional dependence of hypoxic HIF-1α accumulation upon an intact canonical NF-κB pathway in cultured cells. Cyclooxygenase-2 and other key proinflammatory genes are transcriptionally induced by hypoxia in a manner that is both HIF-1 and NF-κB dependent, and in mouse embryonic fibroblasts lacking an intact canonical NF-κB pathway, there is a loss of hypoxia-induced inflammatory gene expression. Finally, under conditions of hypoxia, HIF-1α and the p65 subunit of NF-κB directly bind to the cyclooxygenase-2 promoter. These results implicate an essential role for NF-κB signaling in inflammatory gene expression in response to hypoxia both through the regulation of HIF-1 and through direct effects upon target gene expression.

Nasal pillows as an alternative interface in patients with obstructive sleep apnoea syndrome initiating continuous positive airway pressure therapy

Side‐effects directly due to the nasal mask are common in patients with obstructive sleep apnoea syndrome (OSAS) commencing continuous positive airway pressure (CPAP). Recently, nasal pillows have been designed to overcome these issues. Limited evidence exists of the benefits and effectiveness of these devices. Twenty‐one patients (19 male, 49 ± 10 years) with the established diagnosis of OSAS [apnoea/hypopnoea index (AHI): 52 ± 22] and who had a successful CPAP titration were commenced on CPAP therapy (10 ± 2 cmH2O), and randomized to 4 weeks of a nasal pillow (P) and a standard nasal mask (M) in a crossover design. Outcome measures were objective compliance, AHI, quality of life, Epworth Sleepiness Score (ESS) and CPAP side‐effects. There was no difference in compliance (M versus P: 5.1 ± 1.9 h versus 5.0 ± 1.7 h; P = 0.701) and AHI (2.6 ± 2.7 versus 3.0 ± 2.9; P = 0.509). Quality of life and ESS improved with CPAP, but there was no difference in the extent of improvement between both devices. Usage of nasal pillows resulted in less reported pressure on the face and more subjects found the nasal pillow the more comfortable device. However, there was no clear overall preference for either device at the end of the study (mask = 57%, pillow = 43%; P = 0.513). The applied CPAP pressure did not correlate with compliance, AHI and ESS. Furthermore, no differences in outcome parameters were noted comparing groups with CPAP pressure <10 and ≥10 cm H2O. Nasal pillows are equally effective in CPAP therapy, but do not generally lead to improved compliance.

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

Towards Automated Sleep State Estimation using a Holter-Oximeter

Single-channel ECG and linger photoplethysmogram were used to estimate sleep states in obstructive sleep apnea patients. Overnight Holter-oximeter recordings from 14 subjects with suspected sleep apnea were analysed. Parameters including the RR interval, photoplethysmogram amplitude and rise time, and pulse arrival time were characterised and a hidden Markov model classifier used to identify wake, REM and sleep states. An overall accuracy of 77% and Cohens kappa of 0.54 was achieved, establishing a baseline level of usefulness for sleep state estimation using a Holter-oximeter. Autonomic arousals detected using pulse arrival time also appeared to be strongly correlated with Epworth Sleepiness Scale scores.

Pleural effusion arising from a rare pancreatic neoplasm

To the Editors: Pleural effusions are common entities and may complicate a number of disease processes. We present the case of a large pleural effusion associated with a rare pancreatic neoplasm. The patient, a 67-yr-old female, was referred for respiratory opinion by the Breast Cancer Service at St Vincent’s University Hospital (Dublin, Ireland). She had a background of invasive ductal carcinoma of the right breast 4 yrs previously for which she had undergone a wide local excision and was taking hormonal therapy. Other past medical history included a diagnosis of seropositive rheumatoid arthritis requiring only analgesic therapy. She had known tuberculosis (TB) exposure in childhood and was a nonsmoker. She drank alcohol only on occasion. She had initially noticed that she was sinking to the left side while swimming over the previous month. This was followed by progressive dyspnoea on exertion, left-sided chest pain and nocturnal non-productive cough. She denied haemoptysis or weight loss and was systemically well. Physical examination identified stony-dull percussion and reduced breath sounds over the mid-lower left lung. She was comfortable at rest with oxygen saturations of 96% on room air. There was no clubbing or lymphadenopathy. A chest radiograph confirmed a large left-sided pleural effusion (fig. 1a). Pleural …