This is the largest community-based study of the prevalence and characteristics of CSA to date and demonstrates a prevalence of CSA that is intermediate to those previously noted. Contrary to prior data from clinic based samples, individuals with heart failure were much more likely to have OSA than CSA.

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Study Objectives: Evaluate consequences of intermediate to high risk of undiagnosed obstructive sleep apnea (OSA) among individuals with chronic obstructive pulmonary disease (COPD). Methods: Using data from the Long Term Oxygen Treatment Trial (LOTT), we assessed OSA risk at study entry among patients with COPD. We compared outcomes among those at intermediate to high risk (modified STOP-BANG score ≥ 3) relative to low risk (score < 3) for OSA. We compared risk of mortality or first hospitalization with proportional hazard models, and incidence of COPD exacerbations using negative binomial regression. We adjusted analyses for demographics, body mass index, and comorbidities. Last, we compared St. George Respiratory Questionnaire and Quality of Well-Being Scale results between OSA risk groups. Results: Of the 222 participants studied, 164 (74%) were at intermediate to high risk for OSA based on the modified STOP-BANG score. Relative to the 58 low-risk individuals, the adjusted hazard ratio of mortality or first hospitalization was 1.61 (95% confidence interval 1.01-2.58) for those at intermediate to high risk of OSA. Risk for OSA was also associated with increased frequency of COPD exacerbations (adjusted incidence rate ratio: 1.78, 95% confidence interval 1.10-2.89). Respiratory symptoms by St. George Respiratory Questionnaire were 5.5 points greater (P = .05), and Quality of Well-Being Scale scores were .05 points lower (P < .01) among those at intermediate to high risk for OSA, indicating more severe respiratory symptoms and lower quality of life. Conclusions: Among individuals with COPD, greater risk for undiagnosed OSA is associated with poor outcomes. Increased recognition and management of OSA in this group could improve outcomes.

Comorbidity was associated with 30-day readmission and mortality, and with delivery of fewer treatments known to be beneficial among patients with COPD exacerbation.

Cells sense oxygen availability using not only the absolute value for cellular oxygen in regard to its energetic and metabolic functions, but also the gradient from the cell surface to the lowest levels in the mitochondria. Signals are used for regulatory purposes locally as well as in the generation of cellular, tissue, and humoral remodeling. Lowered oxygen availability (hypoxia) is theoretically important in the consideration of pharmacology because (1) hypoxia can alter cellular function and thereby the therapeutic effectiveness of the agent, (2) therapeutic agents may potentiate or protect against hypoxia-induced pathology, (3) hypoxic conditions may potentiate or mitigate drug-induced toxicity, (4) hypoxia may alter drug metabolism and thereby therapeutic effectiveness, and (5) therapeutic agents might alter the relative coupling of blood flow and energy metabolism in an organ. The prototypic biochemical effect of hypoxia is related to its known role as a cofactor in a number of enzymatic reactions, e.g., oxidases and oxygenases, which are affected independently from the bioenergetic effect of low oxygen on energetic functions. The cytochrome P-450 family of enzymes is another example. Here, there is a direct effect of oxygen availability on the conformation of the enzyme, thereby altering the metabolism of drug substrates. Indirectly, the NADH/NAD+ ratio is increased with 10% inspired oxygen, leading not only to reduced oxidation of ethanol but also to reduction of azo- and nitro-compounds to amines and disulfides to sulfhydryls. With chronic hypoxia, many of these processes are reversed, suggesting that hypoxia induces the drug-metabolizing systems. Support for this comes from observations that hypoxia can induce the hypoxic inducible factors which in turn alters transcription and function of some but not all cytochrome P-450 isoforms. Hypoxia is identified as a cofactor in cancer expression and metastatic potential. Thus, the effects of hypoxia play an important role in pharmacology, and the signaling pathways that are affected by hypoxia could become new targets for novel therapy or avenues for prevention.

Although central to the susceptibility of adult diseases characterized by abnormal rhythmogenesis, characterizing the genes involved is a challenge. We took advantage of the C57BL/6J (B6) trait of hypoxia-induced periodic breathing and its absence in the C57BL/6J-Chr 1(A/J)/NaJ chromosome substitution strain to test the feasibility of gene discovery for this abnormality. Beginning with a genetic and phenotypic analysis of an intercross study between these strains, we discovered three quantitative trait loci (QTLs) on mouse chromosome 1, with phenotypic effects. Fine-mapping reduced the genomic intervals and gene content, and the introgression of one QTL region back onto the C57BL/6J-Chr 1(A/J)/NaJ restored the trait. mRNA expression of non-synonymous genes in the introgressed region in the medulla and pons found evidence for differential expression of three genes, the highest of which was apolipoprotein A2, a lipase regulator; the apo a2 peptide fragment (THEQLTPLVR), highly expressed in the liver, was expressed in low amounts in the medulla but did not correlate with trait expression. This work directly demonstrates the impact of elements on mouse chromosome 1 in respiratory rhythmogenesis.

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The C57/BL6 (B6) mouse strain exhibits post-hypoxic frequency decline and periodic breathing, as well as greater amount of irregular breathing during rest in comparison to the A/J and to the B6a1, a chromosomal substitution strain whereby the A/J chromosome 1 is bred onto the B6 background (Han et al., 2002; Yamauchi et al., 2008a,b). The hypothesis was that morphological differences in the carotid body would associate with such trait variations. After confirming strain differences in post-hypoxic ventilatory behavior, histological examination (n = 8 in each group) using hematoxylin and eosin (H&E) staining revealed equivalent, well-defined tissue structure at the bifurcation of the carotid arteries, an active secretory parenchyma (type I cells) from the supportive stromal tissue, and clustering of type I cells in all three strains. Tyrosine hydroxylase (TH) immunohistochemical staining revealed a typical organization of type I cells and neurovascular components into glomeruli in all three strains. Image analysis from 5 μm sections from each strain generated a series of cytological metrics. The percent carotid body composition of TH+ type I cells in the A/J, B6 and B6a1 was 20 ± 4%, 39 ± 3%, and 44 ± 3%, respectively (p = 0.00004). However, cellular organization in terms of density and ultrastructure in the B6a1 is more similar to the B6 than to the A/J. These findings indicate that genetic mechanisms that produce strain differences in ventilatory function do not associate with carotid body structure or tyrosine hydroxylase morphology, and that A/J chromosome 1 does not contribute much to B6 carotid body morphology.