Obstructive Sleep Apnea reduced by Omega-3 – June 2016

Focusing on Omega-3 Fatty Acids for Treatment of Obstructive Sleep Apnea and its Cardiovascular Complications

Journal of Respiratory Research
Christopher Papandreou, Susheel Patil, Devon A. Dobrosielski

• Christopher Papandreou, Human Nutrition Unit, Department of Biochemistry & Biotechnology, School of Medicine, Rovira i Virgili University, Reus, Spain; Department of Clinical Sciences and Nutrition, University of Chester, Chester, United Kingdom, papchris10@gmail.com
• Susheel Patil, Division of Pulmonary and Critical Care Medicine, Johns Hopkins Sleep Disorders Center, Johns Hopkins University School of Medicine, Baltimore, USA
• Devon A. Dobrosielski, Department of Kinesiology, Towson University, Towson, MD, USA

ABSTRACT
The aim of this review is to focus on the role of omega-3 fatty acids on OSA and associated CVD risk, as well as provide novel hypotheses on their functional impact. Obstructive sleep apnea (OSA) is associated with increased cardiovascular disease (CVD) morbidity and mortality and is highly prevalent in obesity. The American Academy of Sleep Medicine recommends dietary induced weight-loss as a behavioral treatment option for OSA. Since a complex, rather than linear, relationship exists between weight loss and OSA improvement, dietary intervention studies must focus not only on the direct effects of weight loss, but whether dietary-quality may also affect OSA severity, through potential improvements in neuromuscular function of the upper airway.

OBSTRUCTIVE SLEEP APNEA

Obstructive sleep apnea (OSA) is characterized by recurrent episodes of partial (hypopnea) or complete (apnea) collapse of the upper airway during sleep [1], which result in oxygen desaturation and arousals despite ongoing inspiratory efforts. These symptoms have dire consequences on cardiovascular health. Indeed, OSA persists in a large proportion of patients with hypertension and other cardiovascular disorders; including coronary artery disease, stroke, and atrial fibrillation [2]. The prevalence of OSA among the general population is approximately 2 to 7%, and has increased with the obesity epidemic [3]. Although the precise mechanisms by which obesity increases the risk for OSA are not entirely understood, it is generally believed that increases in central adiposity impose mechanical loads on both the upper airway and respiratory system, predisposing the airway to collapse during sleep [4]. Thus, weight loss is likely to improve sleep apnea severity through reductions in upper airway mechanical loads.

Weight loss for OSA treatment

The American Academy of Sleep Medicine [5] recommends behaviorally induced weight loss as a viable treatment option for OSA. This recommendation has been bolstered by findings from large-scale clinical trials that have demonstrated improvement of OSA with interventions that incorporate calorie restricted [6-7], or very low calorie diets [8]. Furthermore, others have reported that the magnitude of reduction in apnea-hypopnea index (AHI), a measure of OSA severity, is associated with the degree of weight loss [9-10]. On the contrary, a recent study found no difference in the change in AHI among OSA patients randomized to surgically induced weight loss or weight loss achieved through very low-energy diet, despite the greater weight loss being achieved in the surgically treated group [11]. These findings suggest a complex, rather than simple weight load pathogenesis of OSA. Indeed, central obesity is a source of pro-inflammatory cytokines (IL-6, TNF-a) [12], known for their somnogenic central nervous system activity that may lead to pharyngeal neuromuscular dysfunction [13]. Morever, these cytokines have been found to induce the production of reactive-oxygen species, thereby promoting oxidative stress [14] that has the ability to impair skeletal muscle force-generating capacity, and adversely affect upper-airway function through myopathic and neuropathic changes [15]. In this context, it is interesting to consider how altering dietary quality might affect OSA severity beyond simply facilitating weight and fat loss. For example, omega-3 fatty acids are known for their anti-inflammatory and anti-oxidative properties, and therefore may have potential for treatment of OSA and related cardiovascular disease (CVD) complications.

OMEGA-3 FATTY ACIDS AND OSA

Omega-3 fatty acids are classified as polyunsaturated fatty acids; also known as essential fatty acids since they cannot be synthesized in the human body and must be obtained from the diet [16]. The omega-3 family includes alpha-linolenic acid (ALA), eicosapentaenoic (EPA), and docosahexaenoic acids (DHA). ALA can be found in plant based foods (flaxseeds, canola, soy, perilla, and walnut oils), while EPA and DHA are found in marine foods (seafood and in greatest amounts in ‘fatty’ fish like sardines, herrings, scomber fishes as various mackerel species, salmon) [16].

A previous cross-sectional study found an independent, inverse relation between red blood cell DHA-levels and OSA severity in 350 consecutive patients undergoing sleep studies, independent of age, body mass index, fish intake and fish oil supplements, alcohol consumption and smoking [17]. Others have found that increasing the levels of marine omega-3 fatty acids in neuronal tissues can stabilize the upper airway innervations, musculature, and feedback control systems [18]. Since severe OSA is associated with increased expression of several pro-inflammatory cytokines (especially increased levels of IL-6, TNF-a) and oxidative stress within the muscular compartments of upper airway tissue [19], the tissue concentration of the anti-inflammatory and anti-oxidative n-3 PUFAs may increase upper-airway muscle-contractile function via an improved upper airway muscle force-generating capacity of dilator muscles (Figure 1).

OMEGA-3 FATTY ACIDS AND OSA RELATED CVD COMPLICATIONS

Marine omega-3 fatty acids may also be able to reduce cardiac dysfunction and even the occurrence of premature death in patients with OSA. Higher blood levels of EPA plus DHA are associated with reduced fatal cardiac events. Both EPA and DHA [20] have been associated with improving vascular and cardiac hemodynamics, endothelial function, controlled blood pressure, reduced hypertriglyceridemia, and reduced insulin-insensitivity [21-23]. To what extent marine omega-3 fatty acids improve the OSA-associated cardiovascular-risks, requires further investigation.

CONCLUSION

The 2015 U.S. Dietary Guidelines for Americans [24] recommends that the general population without established CVD morbidity should consume at least 250 mg/day of EPA+DHA in order to reduce the risk of CVD [25]. In spite of these recommendations, the intake of marine omega-3 fatty acids is low among the average U.S. adult population (41 mg/day and 72 mg/day of EPA and DHA from foods and supplements, respectively) [26]. Whether the aforementioned dietary recommendation or other doses of marine omega-3 fatty acids are suitable for OSA patients at high risk of CVD and with suboptimal marine omega-3 intake remains to be established. Future research is needed to examine the effect of marine omega-3 fatty acids on OSA severity and associated cardiovascular risk. Potential improvements in OSA severity may, in turn, lead to improvements in cardiovascular risk.

CONFLICT OF INTERESTS: The author declare that they do not have conflict of interests.

REFERENCES

• 1American Academy of Sleep Medicine Task Force. Sleep-related breathing disorders in adults: recommendations for syndrome definition and measurement techniques in clinical research. Sleep 1999; 22: 667-689.
• 2Somers VK, White DP, Amin R, Abraham W, Costa F, Culebras A, Daniels S, Floras J, Hunt C, Olson L, Pickering T. Sleep apnea and cardiovascular disease. Circulation 2008; 118: 1080-1111.
• 3Peppard PE, Young T,Barnet JH, Palta M, Hagen EW, Hla KM. Increased prevalence of sleep-disordered breathing in adults. Am J Epidemiol 2013; 177: 1006-1014.
• 4Schwartz AR, Patil SP, Laffan AM, Polotsky V, Schneider H, Smith PL. Obesity and obstructive sleep apnea: pathogenic mechanisms and therapeutic approaches. Proc Am Thorac Soc 2008; 5: 185-192.
• 5Epstein LJ, Kristo D, Strollo PJ, Friedman N, Malhotra A, Patil SP, Ramar K, Rogers R, Schwab RJ, Weaver EM, Weinstein MD. Clinical guideline for the evaluation, management and long-term care of obstructive sleep apnea in adults. J Clin Sleep Med 2009; 5: 263-276.
• 6St-Onge M-P, Shechter A. Sleep disturbances, body fat distribution, food intake and/or energy expenditure: pathophysiological aspects. Horm Mol Biol Clin Investig 2014; 17: 29-37.
• 7Araghi MH, Chen YF, Jagielski A, Choudhury S, Banerjee D, Hussain S, Thomas GN, Taheri S. Effectiveness of lifestyle interventions on obstructive sleep apnea (OSA): systematic review and meta-analysis. Sleep 2013; 36: 1553-1562.
• 8Johansson K, Neovius M, Lagerros YT, Harlid R, Rössner S, Granath F, Hemmingsson E. Effect of a very low energy diet on moderate and severe obstructive sleep apnoea in obese men: a randomised controlled trial. BMJ 2009; 339: b4609.
• 9Johansson K, Hemmingsson E, Harlid R, Lagerros YT, Granath F, Rössner S, Neovius M. Longer term effects of very low energy diet on obstructive sleep apnoea in cohort derived from randomised controlled trial: prospective observational follow-up study. BMJ 2011; 342: d3017
• 10Kuna ST, Reboussin DM, Borradaile KE, Sanders MH, Millman R.P, Zammit G, Newman AB, Wadden TA, Jakicic JM, Wing RR, Pi-Sunyer FX, Foster GD, Sleep AHEAD Research Group. Long-term effect of weight loss on obstructive sleep apnea severity in obese patients with type 2 diabetes. Sleep 2013; 36: 641-649.
• 11Tuomilehto H, Gylling H, Peltonen M, Martikainen T, Sahlman J, Kokkarinen J, Randell J, Tukiainen H, Vanninen E, Partinen M, Tuomilehto J, Uusitupa M, Seppä J; Kuopio Sleep Apnea Group. Sustained improvement in mild obstructive sleep apnea after a diet- and physical activity-based lifestyle intervention: post-interventional follow-up. Am J Clin Nutr 2010; 92: 688-696.
• 12Cancello R, Clément K. Is obesity an inflammatory illness? Role of low-grade inflammation and macrophage infiltration in human white adipose tissue. BJOG 2006; 113: 1141-1147.
• 13Schwartz AR, Patil SP, Squier S, Schneider H, Kirkness JP, Smith PL. Obesity and upper airway control during sleep. J Appl Physiol 2010; 108: 430-435.
• 14Fernández-Sánchez A, Madrigal-Santillán E, Bautista M, Esquivel-Soto J, Morales-González A, Esquivel-Chirino C, Durante-Montiel I, Sánchez-Rivera G, Valadez-Vega C, Morales-González JA. Inflammation, oxidative stress, and obesity. Int J Mol Sci 2011; 12: 3117-3132.
• 15Kimoff RJ, Hamid Q, Divangahi M, Hussain S, Bao W, Naor N, Payne RJ, Ariyarajah A, Mulrain K, Petrof BJ. Increased upper airway cytokines and oxidative stress in severe obstructive sleep apnoea. Eur Respir J 2011; 38: 89-97.
• 16Nakamura MT, Nara TY. Essential fatty acid synthesis and its regulation in mammals. Prostaglandins Leukot Essent Fatty Acids 2003; 68: 145-150.
• 17Ladesich JB, Pottala JV, Romaker A, Harris WS. Membrane level of omega-3 docosahexaenoic acid is associated with severity of obstructive sleep apnea. J Clin Sleep Med 2011; 7: 391-396.
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  " For every 1-SD increase in RBC DHA, there was an approximately 50% reduction in the likelihood of having severe OSA."
• 18Dyall SC. Long-chain omega-3 fatty acids and the brain: a review of the independent and shared effects of EPA, DPA and DHA. Front Aging Neurosci 2015; 7: 52
• 19Kimoff RJ, Hamid Q, Divangahi M, Hussain S, Bao W, Naor N, Payne RJ, Ariyarajah A, Mulrain K, Petrof BJ. Increased upper airway cytokines and oxidative stress in severe obstructive sleep apnoea. Eur Respir J 2011; 38: 89-97.
• 20Mozaffarian D, Wu JH. (N-3) fatty acids and cardiovascular health: are effects of EPA and DHA shared or complementary? J Nutr 2012; 142: 614S-625S.
• 21Saravanan P, Davidson NC, Schmidt EB, Calder PC. Cardiovascular effects of marine omega-3 fatty acids. Lancet 2010; 376: 540-550.
• 22Dasilva G, Pazos M, García-Egido E, Gallardo JM, Rodríguez I, Cela R, Medina I. Healthy effect of different proportions of marine ?-3 PUFAs EPA and DHA supplementation in Wistar rats: Lipidomic biomarkers of oxidative stress and inflammation. J Nutr Biochem 2015; 26: 1385-1392.
• 23 Mozaffarian D, Wu JH. Omega-3 fatty acids and cardiovascular disease: effects on risk factors, molecular pathways, and clinical events. J Am Coll Cardiol 2011; 58: 2047-6710.
• 24 U.S. Department of Health and Human Services and U.S. Department of Agriculture. 2015 – 2020 Dietary Guidelines for Americans. 8th Edition.
• 25Harris WS, Mozaffarian D, Lefevre M, Toner CD, Colombo J, Cunnane SC, Holden JM, Klurfeld DM, Morris MC, Whelan J. Towards establishing dietary reference intakes for eicosapentaenoic and docosahexaenoic acids. J Nutr 2009; 139: 804S-819S.
• 26Papanikolaou Y, Brooks J, Reider C, Fulgoni VL. 3rd. U.S. adults are not meeting recommended levels for fish and omega-3 fatty acid intake: results of an analysis using observational data from NHANES 2003-2008. Nutr J 2014; 13: 31.

Peer reviewers: Satoshi Hamada, Department of Respiratory, Medicine, Graduate School of Medicine, Kyoto University, 54 Shogoin Kawaharacho, Sakyo-ku, Kyoto, 606-8507, Japan; Kagan Ucok, MD, PhD, Departments of Physiology and Sports Physiology, Faculty of Medicine, Afyon Kocatepe University, Afyonkarahisar, 03080, Turkey.