Apnoea-hypopnoea index (AHI), the universal clinical metric of sleep apnoea severity, poorly predicts the adverse outcomes of sleep apnoea, potentially because the AHI, a frequency measure, does not adequately capture disease burden. Therefore, we sought to evaluate whether quantifying the severity of sleep apnoea by the 'hypoxic burden' would predict mortality among adults aged 40 and older.

Elevated loop gain, consequent to hypersensitive ventilatory control, is a primary nonanatomical cause of obstructive sleep apnoea (OSA) but it is not possible to quantify this in the clinic. Here we provide a novel method to estimate loop gain in OSA patients using routine clinical polysomnography alone. We use the concept that spontaneous ventilatory fluctuations due to apnoeas/hypopnoeas (disturbance) result in opposing changes in ventilatory drive (response) as determined by loop gain (response/disturbance). Fitting a simple ventilatory control model (including chemical and arousal contributions to ventilatory drive) to the ventilatory pattern of OSA reveals the underlying loop gain. Following mathematical-model validation, we critically tested our method in patients with OSA by comparison with a standard (continuous positive airway pressure (CPAP) drop method), and by assessing its ability to detect the known reduction in loop gain with oxygen and acetazolamide. Our method quantified loop gain from baseline polysomnography (correlation versus CPAP-estimated loop gain: n=28; r=0.63, p<0.001), detected the known reduction in loop gain with oxygen (n=11; mean±SEM change in loop gain (ΔLG) −0.23±0.08, p=0.02) and acetazolamide (n=11; ΔLG −0.20±0.06, p=0.005), and predicted the OSA response to loop gain-lowering therapy. We validated a means to quantify the ventilatory control contribution to OSA pathogenesis using clinical polysomnography, enabling identification of likely responders to therapies targeting ventilatory control.

Key points• Obstructive sleep apnoea (OSA) probably results from the interaction of key pathophysiological traits including compromised pharyngeal anatomy, inadequate upper-airway muscle function, high ventilatory response to a change in ventilation (high loop gain), and a low arousal threshold.• Because the standard therapy with positive airway pressure is often poorly tolerated, alternative options have long been sought which have included various pharmacological interventions.• Acetazolamide may be a useful therapeutic tool, yet there have been few studies examining how it affects the traits causing OSA.• Our study demonstrates that acetazolamide reduces loop gain by approximately 40% in individuals with OSA, but has little impact on the remaining OSA traits.• The marked reduction in loop gain with acetazolamide suggests that acetazolamide may be of therapeutic benefit when used alone or in combination with other therapies to treat individuals whose loop gain is known to contribute to OSA.Abstract There is some evidence to suggest that acetazolamide may improve obstructive sleep apnoea (OSA). However, how acetazolamide affects the key traits causing OSA remains uncertain. We aimed to investigate the effect of acetazolamide on the traits contributing to OSA and its severity. Acetazolamide (500 mg twice daily) was administered for 1 week to 13 OSA subjects. Pharyngeal anatomy/collapsibility, loop gain (LG), upper-airway muscle responsiveness (gain) and the arousal threshold were determined using multiple 3 min 'CPAP pressure drops': pharyngeal anatomy/collapsibility was quantified as the ventilation at CPAP = 0.LG was defined as the ratio of the ventilatory overshoot to the preceding reduction in ventilation. Upper-airway gain was taken as the ratio of the increase in ventilation to the increase in ventilatory drive across the drop. Arousal threshold was quantified as the level of ventilatory drive associated with arousal. The apnoea-hypopnoea index (AHI) was assessed on separate nights using standard poly- (50 [36-57] versus 24 [13-42] events h −1 ; P < 0.05), but did not significantly alter pharyngeal anatomy/collapsibility, upper-airway gain, or arousal threshold. There was a modest correlation between the percentage reduction in LG and the percentage reduction in AHI (r = 0.660, P = 0.05). Our findings suggest that acetazolamide can improve OSA, probably due to reductions in the sensitivity of the ventilatory control system. Identification of patients who may benefit from reductions in LG alone or in combination with other therapies to alter the remaining traits may facilitate pharmacological resolution of OSA in the future.

Rationale: A low respiratory arousal threshold (ArTH) is one of several traits involved in obstructive sleep apnea pathogenesis and may be a therapeutic target; however, there is no simple way to identify patients without invasive measurements.Objectives: To determine the physiologic determinates of the ArTH and develop a clinical tool that can identify patients with low ArTH.Methods: Anthropometric data were collected in 146 participants who underwent overnight polysomnography with an epiglottic catheter to measure the ArTH (nadir epiglottic pressure before arousal). The ArTH was measured from up to 20 non-REM and REM respiratory events selected randomly. Multiple linear regression was used to determine the independent predictors of the ArTH. Logistic regression was used to develop a clinical scoring system.Measurements and Main Results: Nadir oxygen saturation as measured by pulse oximetry, apnea-hypopnea index, and the fraction of events that were hypopneas (F hypopneas ) were independent predictors of the ArTH (r 2 = 0.59; P , 0.001). Using this information, we used receiver operating characteristic analysis and logistic regression to develop a clinical score to predict a low ArTH, which allocated a score of 1 to each criterion that was satisfied: (apnea-hypopnea index, ,30 events per hour) 1 (nadir oxygen saturation as measured by pulse oximetry .82.5%) 1 (F hypopneas .58.3%). A score of 2 or above correctly predicted a low arousal threshold in 84.1% of participants with a sensitivity of 80.4% and a specificity of 88.0%, a finding that was confirmed using leaveone-out cross-validation analysis.Conclusions: Our results demonstrate that individuals with a low ArTH can be identified from standard, clinically available variables. This finding could facilitate larger interventional studies targeting the ArTH.Keywords: sleep apnea; respiratory-induced arousals; arousal threshold; phenotype traits; lung Obstructive sleep apnea (OSA) is a common disease with major neurocognitive and cardiovascular sequelae (1-3). Despite its high prevalence and well-recognized consequences, treatment of OSA remains unsatisfactory because of poor adherence (e.g., continuous positive airway pressure) and variable efficacy of existing therapies (e.g., surgery, oral appliances) (4), creating a need for further research into underlying mechanisms to identify new therapeutic targets.

n-3 FA are beneficial for cardiovascular health, reducing platelet aggregation, TG levels, and the risk of sudden death from myocardial infarction. The percentage of EPA + DHA in red blood cells (RBC), also known as the Omega-3 Index, has recently been proposed as a risk marker for death from coronary heart disease (CHD). The purpose of this study was to begin to explore the factors that can influence RBC EPA + DHA. We collected information on the number of servings of tuna or nonfried fish consumed per month, as well as on age, gender, ethnicity, smoking status, the presence of diabetes, and body mass index (BMI) in 163 adults in Kansas City who were not taking fish oil supplements. The average RBC EPA + DHA in this population was 4.9 +/- 2.1%. On a multivariate analysis, four factors significantly and independently influenced the Omega-3 Index: fish servings, age, BMI, and diabetes. The Index increased by 0.24 units with each additional monthly serving of tuna or nonfried fish (P < 0.0001), and by 0.5 units for each additional decade in age (P < 0.0001). The Index was 1.13% units lower in subjects with diabetes (P = 0.015) and decreased by 0.3% units with each 3-unit increase in BMI (P = 0.001). Gender or smoking status had no effect, and the univariate relationship with ethnicity vanished after controlling for fish intake. Given the importance of n-3 FA in influencing risk for death from CHD, further studies are warranted to delineate the nondietary factors that influence RBC EPA + DHA content.

Background-Omega-3 fatty acids (FAs) appear to reduce the risk of sudden death from myocardial infarction. This reduction is believed to occur via the incorporation of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) into the myocardium itself, altering the dynamics of sodium and calcium channel function. The extent of incorporation has not been determined in humans. Methods and Results-We first determined the correlation between red blood cell (RBC) and cardiac omega-3 FA levels in 20 heart transplant recipients. We then examined the effects of 6 months of omega-3 FA supplementation (1 g responses among tissues were not significantly different). Conclusions-Although any of the tissues examined could serve as a surrogate for cardiac omega-3 FA content, RBC EPAϩDHA was highly correlated with cardiac EPAϩDHA; the RBC omega-3 response to supplementation was similar to that of the heart; RBCs are easily collected and analyzed; and they have a less variable FA composition than plasma. Therefore, RBC EPAϩDHA (also called the Omega-3 Index) may be the preferred surrogate for cardiac omega-3 FA status.

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A, White DP. A simplified method for determining phenotypic traits in patients with obstructive sleep apnea. J Appl Physiol 114: 911-922, 2013. First published January 24, 2013 doi:10.1152/japplphysiol.00747.2012.-We previously published a method for measuring several physiological traits causing obstructive sleep apnea (OSA). The method, however, had a relatively low success rate (76%) and required mathematical modeling, potentially limiting its application. This paper presents a substantial revision of that technique. To make the measurements, continuous positive airway pressure (CPAP) was manipulated during sleep to quantify 1) eupneic ventilatory demand, 2) the level of ventilation at which arousals begin to occur, 3) ventilation off CPAP (nasal pressure ϭ 0 cmH 2O) when the pharyngeal muscles are activated during sleep, and 4) ventilation off CPAP when the pharyngeal muscles are relatively passive. These traits could be determined in all 13 participants (100% success rate). There was substantial intersubject variability in the reduction in ventilation that individuals could tolerate before having arousals (difference between ventilations #1 and #2 ranged from 0.7 to 2.9 liters/min) and in the amount of ventilatory compensation that individuals could generate (difference between ventilations #3 and #4 ranged from Ϫ0.5 to 5.5 liters/min). Importantly, the measurements accurately reflected clinical metrics; the difference between ventilations #2 and #3, a measure of the gap that must be overcome to achieve stable breathing during sleep, correlated with the apneahypopnea index (r ϭ 0.9, P Ͻ 0.001). An additional procedure was added to the technique to measure loop gain (sensitivity of the ventilatory control system), which allowed arousal threshold and upper airway gain (response of the upper airway to increasing ventilatory drive) to be quantified as well. Of note, the traits were generally repeatable when measured on a second night in 5 individuals. This technique is a relatively simple way of defining mechanisms underlying OSA and could potentially be used in a clinical setting to individualize therapy. pathophysiology of sleep apnea; loop gain; pharyngeal critical closing pressure; upper airway; arousal threshold RECENT EVIDENCE SUGGESTS that obstructive sleep apnea (OSA) is a multifactorial disorder. Contributing factors include a small or collapsible pharyngeal airway (9, 12, 23), a high loop gain (large ventilatory response to a ventilatory disturbance) (2,11,21,25,26,31), poor pharyngeal muscle responsiveness during sleep (5, 14 -16, 20, 27, 29), and a low respiratory arousal threshold (13, 28). The relative contribution of these traits varies substantially between individuals (24, 30).Despite the multifactorial nature of OSA, common therapies [continuous positive airway pressure (CPAP), upper airway surgery, dental appliances] are directed at only one trait: the abnormal airway anatomy. Moreover, the most effective treatment, CPAP, has an acceptance rate of only ϳ50% (8, 17). We believe that if the tr...