Defining Phenotypic Causes of Obstructive Sleep Apnea. Identification of Novel Therapeutic Targets

Eckert, Danny J.; White, David P.; Jordan, Amy S.; Malhotra, Atul; Wellman, Andrew

doi:10.1164/rccm.201303-0448oc

Cited by 893 publications

(818 citation statements)

References 53 publications

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“…Wellman and colleagues have proposed that four physiologic traits affect OSA susceptibility, including the respiratory arousal threshold, defined as the intensity of respiratory stimuli (e.g., negative pharyngeal pressure and increase of carbon dioxide concentration) required to invoke awakening (10,48). As a surrogate for respiratory arousability, we analyzed average apnea and hypopnea event duration length, with shorter duration events indicating greater arousability (49).…”

mentioning

confidence: 99%

Genetic Associations with Obstructive Sleep Apnea Traits in Hispanic/Latino Americans

Cade

Chen

Stilp

et al. 2016

Am J Respir Crit Care Med

120

102

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Rationale: Obstructive sleep apnea is a common disorder associated with increased risk for cardiovascular disease, diabetes, and premature mortality. Although there is strong clinical and epidemiologic evidence supporting the importance of genetic factors in influencing obstructive sleep apnea, its genetic basis is still largely unknown. Prior genetic studies focused on traits defined using the apnea-hypopnea index, which contains limited information on potentially important genetically determined physiologic factors, such as propensity for hypoxemia and respiratory arousability.Objectives: To define novel obstructive sleep apnea genetic risk loci for obstructive sleep apnea, we conducted genome-wide association studies of quantitative traits in Hispanic/Latino Americans from three cohorts.Methods: Genome-wide data from as many as 12,558 participants in the Hispanic Community Health Study/Study of Latinos, MultiEthnic Study of Atherosclerosis, and Starr County Health Studies population-based cohorts were metaanalyzed for association with the apnea-hypopnea index, average oxygen saturation during sleep, and average respiratory event duration.Measurements and Main Results: Two novel loci were identified at genome-level significance (rs11691765, GPR83, P = 1.90 3 10 28 for the apnea-hypopnea index, and rs35424364; C6ORF183/CCDC162P, P = 4.88 3 10 28 for respiratory event duration) and seven additional loci were identified with suggestive significance (P , 5 3 10 27 ). Secondary sex-stratified analyses also identified one significant and several suggestive associations. Multiple loci overlapped genes with biologic plausibility.Conclusions: These are the first genome-level significant findings reported for obstructive sleep apnea-related physiologic traits in any population. These findings identify novel associations in inflammatory, hypoxia signaling, and sleep pathways.

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mentioning

confidence: 99%

Genetic Associations with Obstructive Sleep Apnea Traits in Hispanic/Latino Americans

Cade

Chen

Stilp

et al. 2016

Am J Respir Crit Care Med

120

102

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“…Importantly, however, the choice of personalized treatment other than nCPAP for Patient A would be different than for Patient B. Patient A would likely benefit most from oral appliance therapy whereas Patient B may be better served by a pharmacologic intervention to lower loop gain and arousal threshold 10, 16, 17 . Also importantly, swapping therapy between patients would be particularly ineffective (e.g., Patient A instead receiving a pharmacologic intervention to lower loop gain and arousal threshold, and Patient B receiving oral appliance therapy), as the interventions would not target the primary causative factor in those individuals.…”

Section: Phenotyping Osa Patients Is Critical To Targeted Therapymentioning

confidence: 99%

A resource of potential drug targets and strategic decision‐making for obstructive sleep apnoea pharmacotherapy

2017

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There is currently no pharmacotherapy for OSA, but there is no principled a-priori reason why there shouldn’t be one. This review identifies a rational decision-making strategy with the necessary logical underpinnings that any reasonable approach would be expected to navigate to develop a viable pharmacotherapy for OSA. The process first involves phenotyping an individual to quantify and characterize the critical predisposing factor(s) to their OSA pathogenesis and identify, a-priori, if the patient is likely to benefit from a pharmacotherapy that targets those factors. We then identify rational strategies to manipulate those critical predisposing factor(s), and the barriers that have to be overcome for success of any OSA pharmacotherapy. A new analysis then identifies candidate drug targets to manipulate the upper airway motor circuitry for OSA pharmacotherapy. The first conclusion is that there are two general pharmacological approaches for OSA treatment that are of most potential benefit and are practically realistic, one being fairly intuitive but the second perhaps less so. The second conclusion is that after identifying the critical physiological obstacles to OSA pharmacotherapy, there are current therapeutic targets of high interest for future development. The final analysis provides a tabulated resource of “druggable” targets that are relatively restricted to the circuitry controlling the upper airway musculature, with these candidate targets being of high priority for screening and further study. We also emphasize that a pharmacotherapy may not cure OSA per se, but may still be a useful adjunct to improve the effectiveness of, and adherence to, other treatment mainstays.

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“…Although the majority of cases will be due to poor airway anatomy, other factors such as ventilatory control, arousal threshold, and upper airway muscle responsiveness might be important in some. 1 We recently described a method to determine these traits, but we hypothesize that much of the same information could also be determined from a careful study of the PSG. 2 Similarly, careful study of inspiratory fl ow patterns (not just peak amplitude of fl ow, as respiratory events are currently scored) might tell us about timing (inspiratory vs. expiratory) or location (e.g., palate, tongue base, lateral walls) of upper airway collapse.…”

Section: E D I T O R I a Lmentioning

confidence: 99%

PSGs: More Than Just the AHI

Edwards

Wellman

Owens

2013

Journal of Clinical Sleep Medicine

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e d i t o R i a lT he in-laboratory attended polysomnogram (PSG) has been the driver of the growth in Sleep Medicine for the last 25 years. Reimbursements drove construction of more laboratory space and the training of more technicians. However, within the last two years, the in-lab PSG has been increasingly replaced by home sleep testing (HST). This rapid shift has had a disastrous impact on practices built around an in-laboratory model. Reasons behind the shift have been discussed both in the lay press and in academic journals. First, HST devices are marvels of biomedical engineering, which offer patients the option of accurate testing in the comfort of their own home. Second, home studies are much cheaper than in-lab studies and thus offer value to both patients and their insurers. Implicit in these arguments is the idea that all we need from a sleep study of any type is the apnea-hypopnea index (AHI), and that continuous positive airway pressure (CPAP) is the only viable treatment for obstructive sleep apnea (OSA). We believe that this singular focus on the AHI and CPAP is detrimental to both patients and to the fi eld. We argue here that physiology is the key to revitalizing Sleep Medicine. That is, the PSG can re-vitalize Sleep Medicine if we are able to use the valuable information that each study contains.Using a PSG for nothing more than the AHI is as absurd as using an electrocardiogram (ECG) for nothing more than the heart rate. Instead, the ECG is interpreted to provide anatomic (e.g., ventricular hypertrophy) or functional information (localizing coronary ischemia), as well as to diagnose other conditions (e.g., pericarditis, atrial fi brillation). From this simple test, there is a wealth of information gained. In contrast, an in-laboratory PSG requires more than 20 electrodes and other sensors, approximately 45 minutes of setup time, hours of sleep time, a specialized laboratory, and the continuous presence of a trained and certifi ed technician. At the end of the study, however, for the overwhelming majority of studies, the only "take-home" value is the AHI, or perhaps also the oxygen saturation nadir. Certainly the PSG has a role in a subset of patients, but in the vast majority of cases-that is, patients with OSA-it is clear that most of the recorded data are never used. We should be able to do better.So what could a PSG tell us (that HST cannot)? First, we and others believe that careful study of the PSG might reveal the underlying cause of OSA in individual patients. That is, two OSA patients might have the same AHI for very different reasons. Although the majority of cases will be due to poor airway anatomy, other factors such as ventilatory control, arousal threshold, and upper airway muscle responsiveness might be important in some. 1 We recently described a method to determine these traits, but we hypothesize that much of the same information could also be determined from a careful study of the PSG. 2 Similarly, careful study of inspiratory fl ow patterns (not just peak amplitude of fl ow,...

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Defining Phenotypic Causes of Obstructive Sleep Apnea. Identification of Novel Therapeutic Targets

Cited by 893 publications

References 53 publications

Genetic Associations with Obstructive Sleep Apnea Traits in Hispanic/Latino Americans

Genetic Associations with Obstructive Sleep Apnea Traits in Hispanic/Latino Americans

A resource of potential drug targets and strategic decision‐making for obstructive sleep apnoea pharmacotherapy

PSGs: More Than Just the AHI

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