Syndrome Z: Apnea’s Metabolic Syndrome Expert Interview With Virend K. Somers, MD, Mayo Clinic

Mark Swanson, ND

The best prescription for prevention is often a simple one: for the conditions described herein, it would be getting a good night’s sleep. But for many, that 8 hours of uninterrupted z’s has become a wishful event. By far, the most common sleep disturbance is obstructive sleep apnea (OSA). Daytime sleepiness resulting from unresolved chronic OSA is known as obstructive sleep apnea–hypopnea syndrome. It affects upward of 18 million individuals in the United States, and millions remain undiagnosed. It is characterized by upper airway collapse and obstruction during sleep, sleep interruptions and fragmentation, recurrent sleep hypoxia (with partial or complete breathing cessation during sleep), and daytime sleepiness.1

Obstructive sleep apnea–hypopnea syndrome is independently associated with the 4 primary components (or factors) of the metabolic syndrome (syndrome X), with this first-order cluster being insulin resistance, obesity, hypertension, and dyslipidemia. Collectively, the components present with a complex pathogenesis that accelerates the development of multiple organ system diseases, especially obesity, type 2 diabetes mellitus, and a more aggressive type of cardiovascular disease. Other presentations include stroke, erectile and sexual dysfunction, cognitive decline, and gray matter insult.

The co-occurrence of OSA with the metabolic syndrome has increasingly been referred to as “syndrome Z.” The concept was first described in 1998 by Wilcox et al.2 This eventually brought a needed critical awareness that OSA affects much more than a good night’s sleep and daytime tiredness. Recently, the first empirical evidence for the concept of syndrome Z was proposed using a hierarchical 5-factor model unifying 5 traits (the 4 first-order factors aforelisted plus sleep disturbance).3 In this model, obesity was the most important determining causality loading factor, followed closely by sleep disturbance, with the apnea-hypopnea index being the strongest measure of sleep disturbance. The remaining factors in order of causality effect were insulin resistance, hypertension, and dyslipidemia. In prior 4-factor models of syndrome X, insulin resistance is the most important causality factor, followed by obesity. How syndrome Z might differ from syndrome X In the incidence of cardiovascular disease and type 2 diabetes remains an active part of ongoing research.

Men and women can differ in their OSA symptoms. Men are more likely to display typical symptoms of OSA, such as loud snoring with a more noticeable “silence between the snores.” Men often display more obvious daytime sleepiness and general tiredness. Women are more likely to report atypical symptoms of insomnia, restlessness, palpitations at night, mood changes, and nightmares. A woman’s apnea breathing episodes may be milder and less noticeable by her partner. Women who report daytime sleepiness more often have this attributed to other non-OSA causes. Insulin resistance is also more than twice as prevalent among persons with than without OSA. Men may have a greater health decline toward more aggressive heart disease, stroke, and end-organ damage. Men younger than 45 years having OSA may have the lowest levels of saturated oxygen compared with older men having OSA and often have higher incidences of aggressive congestive heart disease. Among women with OSA, the actual prevalence may not be as obvious because physician awareness is more oriented to the diagnosis among men. This is beginning to change, and the true prevalence may turn out to be divided more evenly between the sexes.

My distinguished guest for this segment of the “Expert Report” is Virend K. Somers, MD, who has 124 literature citations in PubMed, with 12 publications about sleep apnea and the metabolic syndrome.4-15 Much of his research has been on the interactions among OSA, obesity, and the metabolic syndrome, as well as the subsequent comorbidity of cardiovascular disease and hypertension. Thank you for briefly sharing some of this valuable expertise.

What is your educational background and current position?

I received my medical degree in South Africa and doctor of philosophy at Oxford University in the UK. I completed my internal medicine residency and cardiology fellowship training at the University of Iowa. I am presently a Mayo Foundation Clinical Investigator and professor of medicine in cardiovascular disease at the Mayo Clinic. I also direct the Cardiovascular Research Laboratory and Sleep Research Laboratory in the Mayo Clinical Research Unit. In addition, I serve as international director of the International Clinical Research Center in Brno in the Czech Republic.

What led to your special expertise and focus on the interplay between sleep apnea and metabolic syndrome?

I have had a long-standing interest in sleep and sleep apnea from my studies at Oxford and eventually went on to do detailed clinical research studies in patients with sleep apnea. Over this time, I developed a very strong interest in obesity and its interactions with sleep apnea, which led to trying to explain why there appears to be a high prevalence of metabolic syndrome in sleep apnea patients.

Can you explain the difference between obstructive sleep apnea and central sleep apnea in relation to metabolic syndrome?

Obstructive sleep apnea is often but not always linked to obesity and to the metabolic syndrome. Central sleep apnea occurs primarily in patients with heart failure, where the metabolic syndrome is less of an issue.

Comment: The first prospective study16 to examine whether OSA is associated with heart failure has found that there is a link, particularly in men.

The term syndrome Z was first used by Wilcox et al2 in 1998 to describe the coexistence of metabolic syndrome (syndrome X) with obstructive sleep apnea. Has it become an accepted term to use when referring to this co-occurrence, thus indicating it is a distinct pathology?

Syndrome Z is an appropriate term since we very frequently see the comorbidity of metabolic syndrome and sleep apnea. This may be purely an association, or alternatively it may be because there are features of sleep apnea and/or metabolic syndrome that lead to an increased predisposition to the other.

Can you briefly review the clustering of clinical markers and their similarities between the metabolic syndrome and OSA?

The key markers that are common to both sleep apnea and metabolic syndrome are the presence of glucose intolerance, high blood pressure, and abdominal obesity. The issue is whether it is obesity that contributes to metabolic syndrome and OSA without any interaction between the metabolic syndrome and OSA. However, given the effects of repetitive severe hypoxemia, it is my suspicion that the pathophysiology of OSA may in the longer term predispose to some of the features of the metabolic syndrome. This is likely to be true for hypertension and may be true for insulin resistance and increased abdominal obesity.

Are there health consequences of the co-occurrence of OSA with metabolic syndrome that may be different than either alone?

It is my suspicion that the OSA–metabolic syndrome comorbidity may have synergistic effects on cardiovascular and metabolic pathology that is more than one would have expected from each of the individual conditions alone, although we need longitudinal randomized control studies to provide a definitive answer.

Who should be screened for syndrome Z?

I think it would be appropriate to evaluate OSA patients for the metabolic syndrome since the major features are obtained anyway on routine evaluation. Screening for OSA in metabolic syndrome patients is more difficult because of the significant associated costs and the fact there is the absence of randomized trials showing that any specific patient population with cardiovascular disease benefits from treatment of sleep apnea in terms of decreased mortality or decreased heart attacks or strokes.

Comment: Obstructive sleep apnea should be suspected following recent weight gain.10 In men, elevated serum glucose level was most associated with higher probability of OSA vs blood pressure, waist circumference, and triglycerides or high-density lipoprotein cholesterol levels.17 Obstructive sleep apnea is also associated with elevated markers of inflammation (eg, C-reactive protein and interleukin 6).18 Apolipoprotein B level and the ratio of apolipoprotein B to apolipoprotein A-1 are also associated with the metabolic syndrome and insulin resistance in nondiabetic individuals. Apolipoprotein B level alone may better predict congestive heart disease death than any routine lipoprotein measurement.11-13

What is the difference between visceral vs subcutaneous adiposity in terms of cardiovascular implications?

Generally, visceral fat seems to carry greater negative prognostic implications. Recently, we completed a study of overfeeding healthy lean subjects so as to increase their body weight by 8 to 10 lb. We found that, although all subjects increased body weight and body fat, it was only in those with a predominant increase in visceral fat in whom endothelial dysfunction (dysfunction of the single layer of cells which play an important role in blood pressure control and prevention of intravascular clot) was evident. So generally, we think that visceral adiposity is more strongly tied to inflammation and cardiovascular risk than is subcutaneous fat.

Comment: “Cardiac obesity” (epicardial and pericardial fat) also predicts coronary heart disease.14,19 Its accumulation is strongly associated with visceral obesity and appears to be independent of body mass index (BMI) and can occur in normal weight obesity (NWO). Both cardiac and visceral fat can be reduced with exercise and calorie restriction. Natural agents such as polyphenols (eg, olive phenols, taurine, and inositol) can also be useful.

Can you comment on sleep duration, inadequate sleep, and shift working in relation to metabolic syndrome?

With regard to sleep duration, we are getting increasing evidence that people who sleep less tend to be at higher risk for hypertension, diabetes, and perhaps even heart attacks. This may be developing into even more of a problem given the close tie-in between our lives and electronic communications which tend to keep us up late at night. Inadequate sleep is also a problem for kids in school and may be linked to the increasing prevalence of obesity both in children and in adults. In fact, we are studying the link between sleep duration and cardiac and metabolic abnormalities by admitting people to our research unit for about 2 weeks and depriving them of between 1 and 2 hours of sleep per night. With regard to shift work, this is a difficult area because it is very hard to have controlled randomized studies to provide definitive answers. Nevertheless, there is a general perception that people who do shift work, especially those staying awake throughout the night, tend to have a higher likelihood of obesity and perhaps even cardiovascular risk.

Your recent work highlights a high prevalence of cardiometabolic dysregulation in normal weight obesity.15 How does BMI relate to NWO?

Normal weight obesity describes patients who have a normal body mass index but on more detailed evaluation have a high level of body fat. This approach is intended to get away from thinking of BMI as a sine qua non of obesity. There are people who have high BMIs with very little body fat and people with seemingly normal BMIs who have high levels of body fat. It is in these normal weight people with high body fat (normal weight obese) in whom there is an increased likelihood of metabolic disturbances. We at this time do not have any solid information on the link between OSA and normal weight obesity, but it is an area that we are studying.

Naturopathic physicians are ideally qualified to provide many therapeutic intervention opportunities that address syndrome Z challenges. What is the role of a multidisciplinary approach in treating sleep apnea and metabolic syndrome?

Sleep apnea is a multidisciplinary disease because it affects so many organ systems, including blood pressure, the heart, mental alertness, erectile function, and metabolism, among others. Metabolic syndrome also comprises a number of specialties, including hypertension, endocrinology, and cardiology, because of the associated cardiovascular risk. Our plan is to continue to explore how normal and disordered sleep, especially inadequate sleep, links to metabolic changes so that we can better understand the etiologic interaction between disordered sleep and cardiometabolic abnormalities.

Dr Swanson’s Concluding Remarks

I want to thank Dr Somers for his participation in this issue of NDNR. His continued work in the area of sleep apnea, obesity, and the metabolic syndrome has undoubtedly led to a greater awareness and understanding of the nature of syndrome Z. For the OSA component, apnea management includes weight loss, fitness improvement, and mechanical continuous positive airway pressure as the current hallmark for successful treatment. Naturopathic physicians have the unique opportunity to provide much-needed complementary psychotherapy to assist, repair, and normalize the various pathophysiological disturbances resulting from syndrome Z.


Mark_Swanson_Headshot_2.jpgMark Swanson, ND is a 1984 “pioneer” graduate of Bastyr University, and is in private practice in Sequim, Wash. He has been the senior medical advisor at a leading professional-label supplement company for 18 years; is a former editor of the Journal of Naturopathic Medicine; and has years of experience as a national product director, consultant, and representative to supplement manufacturers and functional medicine laboratories. Dr Swanson’s clinical and research interests range from osteoporosis to metabolic syndrome/diabetes, cardiovascular disease, asthma and complex illness. Enjoying life on the Olympic Peninsula is a mandatory prescription for good health.

References

  1. Rowley JA. Obstructive sleep apnea–hypopnea syndrome. http://emedicine.medscape.com/article/302773-overview. Accessed February 22, 2011.
  2. Wilcox I, McNamara SG, Collins FL, Grunstein RR, Sullivan CE. “Syndrome Z”: the interaction of sleep apnoea, vascular risk factors and heart disease. Thorax. 1998;53(suppl 3):S25-S28.
  3. Nock NL, Li L, Larkin EK, Patel SR, Redline S. Empirical evidence for “syndrome Z”: a hierarchical 5-factor model of the metabolic syndrome incorporating sleep disturbance measures. Sleep. 2009;32(5):615-622.
  4. Wolk R, Somers VK. Sleep and the metabolic syndrome. Exp Physiol. 2007;92(1):67-78.
  5. Gami AS, Somers VK. Obstructive sleep apnoea, metabolic syndrome and cardiovascular outcomes [editorial]. Eur Heart J. 2004;25(9):709-711.
  6. Romero-Corral A, Caples SM, Lopez-Jimenez F, Somers VK. Interactions between obesity and obstructive sleep apnea: implications for treatment. Chest. 2010;137(3):711-719.
  7. Wolk R, Shamsuzzaman AS, Somers VK. Obesity, sleep apnea, and hypertension. Hypertension. 2003;42(6):1067-1074.
  8. Gami AS, Witt BJ, Howard DE, et al. Metabolic syndrome and risk of incident cardiovascular events and death: a systematic review and meta-analysis of longitudinal studies. J Am Coll Cardiol. 2007;49(4):403-414.
  9. Trombetta IC, Somers VK. Consequences of comorbid sleep apnea in the metabolic syndrome: implications for cardiovascular disease risk. Sleep. 2010;33(9):1193-1199.
  10. Phillips BG, Hisel TM, Kato M, et al. Recent weight gain in patients with newly diagnosed obstructive sleep apnea. J Hypertens. 1999;17(9):1297-1300.
  11. Sierra-Johnson J, Fisher RM, Romero-Corral A, et al. Concentration of apolipoprotein B is comparable with the apolipoprotein B/apolipoprotein A-I ratio and better than routine clinical lipid measurements in predicting coronary heart disease mortality: findings from a multi-ethnic population. Eur Heart J. 2009;30(6):710-717.
  12. Sierra-Johnson J, Romero-Corral A, Somers VK, Lopez-Jimenez F. The apolipoprotein B/apolipoprotein AI ratio in the metabolic syndrome: should we start using it? J Cardiometab Syndr. 2008;3(1):53-54.
  13. Sierra-Johnson J, Romero-Corral A, Somers VK. ApoB/apoA-1 ratio: an independent predictor of insulin resistance in US non-diabetic subjects. Eur Heart J. 2007;28(21):2637-2643.
  14. Chaowalit N, Somers VK, Pellikka PA, Rihal CS, Lopez-Jimenez F. Adipose tissue of atrial septum as a marker of coronary artery disease. Chest. 2007;132(3):817-822.
  15. Romero-Corral, Somers VK, Sierra-Johnson J, et al. Normal weight obesity: a risk factor for cardiometabolic dysregulation and cardiovascular mortality. Eur Heart J. 2010;31(6):737-746.
  16. Gottlieb D, Yenokyan G, Newman AB, et al. Prospective study of obstructive sleep apnea and incident coronary heart disease and heart failure: the Sleep Heart Health Study. Circulation. 2010;122(4):352-360.
  17. Papanas N, Steiropoulos P, Nena E, et al. Predictors of obstructive sleep apnea in males with metabolic syndrome. Vasc Health Risk Manag. 2010;6:281-286.
  18. Han F. Obstructive sleep apnea hypopnea syndrome: a proinflammatory disorder. Chin Med J (Engl). 2007;120(17):1475-1476.
  19. Chaowalit N, Lopez-Jimenez. Epicardial adipose tissue: friendly companion or hazardous neighbor for adjacent coronary arteries [editorial]? Eur Heart J. 2008;29:695-697.
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