Obstructive Sleep Apnoea and the Metabolic Syndrome

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Obstructive Sleep Apnea and the Metabolic Syndrome

Obstructive Sleep Apnoea and the Metabolic SyndromeDr Muhammed AslamDepartment of Pulmonary MedicineDM WIMS Meppadi

Is there any association between OSA and Metabolic syndrome??

Is there a causality between these two factors ??

OutlineIntroductionOSA and the Metabolic SyndromeOSA and ObesityOSA and HypertensionOSA and Insulin ResistanceOSA and DyslipidemiaPathogenesis Effect of TreatmentConclusion

IntroductionThe Metabolic Syndrome- Visceral obesity, Insulin resistance, Hypertension and Dyslipidemia

Increased cardiovascular morbidity and mortality in OSA, independent of obesity

IntroductionNational Cholesterol Education Program Adult Treatment Panel III - 3 out of 5 clinically identifiable variables : hypertension, glucose intolerance, low serum HDL ,elevated serum triglyceride and abdominal obesity.

The WHO and the European Group for the Study of Insulin Resistance recommends insulin resistance or glucose intolerance to be an essential criterion

Prevalence of Metabolic Syndrome

8% (India) to 44% (native Americans in the USA) in men

7% (France) to 57% (native Americans in the USA) in women

Cameron AJ, Shaw JE, Zimmet PZ. The metabolic syndrome prevalence in worldwide populations. Endocrinol. Metab. Clin. North Am.33,351-375 (2004).

Association Between OSA and the Metabolic Syndrome

Association Between OSA and the Metabolic Syndrome

Two case controlled studies on Caucasian men - ninefold and sixfold risk

Association Between OSA and the Metabolic Syndrome

Community based Chinese study- fivefold risk A positive correlation between AHI and the number of metabolic components present

Association Between OSA and the Metabolic Syndrome

OSA and ObesityPositive correlation between the severity of OSA and the degree of obesitySleep apnea patients have a greater amount of visceral fat compared with obese controls matched for BMISuggesting that central or abdominal obesity are more closely associated with OSA than general obesity.

Vgontzas AN et al. Sleep apnea and daytime sleepiness and fatigue: relation to visceral obesity, insulin resistance, and hypercytokinemia. J. Clin. Endocrinol. Metab.85(3),1151-1158 (2000).

OSA and metabolic dysfunction is a vicious cycle

Pillar G, Shehadeh N. Abdominal fat and sleep apnea: the chicken or the egg? Diabetes Care. 2008;31(Suppl 2):S3039

OSA and HypertensionStudies shown that blood pressure level and the risk of hypertension increased with increasing AHI levels after correction for confounders such as obesity, age and gender.AHI of greater than 15 was associated with elevation of 3.6 mmHg and 1.8 mmHg for systolic and diastolic blood pressure, respectively

Young T, Peppard P, Palta M et al. Population-based study of sleep-disordered breathing as a risk factor for hypertension. Arch. Intern. Med.157(15),1746-1752 (1997).

OSA and HypertensionA study showed that each additional apneic event per hour of sleep was associated with increases of 0.1 and 0.04 mmHg in systolic and diastolic blood pressure, respectively .

(Lavie P, Herer P, Hoffstein V. Obstructive sleep apnea syndrome as a risk factor for hypertension: population study. BMJ320,479-482 (2000).)

Prospective longitudinal follow up over 4 years confirmed increased risks of developing hypertension that were dependent on the degree of elevation of AHI at baseline (Peppard etal, NEJM)

OSA and Hypertension

Nasal CPAP treatment in OSA have demonstrated reductions in both systolic and diastolic blood pressure and of decrease in mean arterial blood pressure ranged from 2.5 to 10 mmHg.

OSA and Hypertension

Greater treatment related reductions in ambulatory mean blood pressure among patients with more severe OSA and better effective nocturnal use of CPAP device

OSA and HypertensionSubjects who do not suffer from sleepiness may also behave differently

2 randomized interventional trials did not reveal any decrease in blood pressure, despite treatment of severe OSA although another study of mildly sleepy subjects did show a positive effect

Robinson GV, Smith DM, Langford BA et al. Continuous positive airway pressure does not reduce blood pressure in nonsleepy hypertensive OSA patients. Eur. Resp. J.27,1229-1235 (2006)

OSA and Insulin ResistanceSubjects with OSA may have multiple factors like obesity that promote insulin resistance and glucose intolerance

Positive and independent association between OSA and insulin resistance/glucose intolerance/diabetes

The increase in insulin resistance attributable to OSA was observed not only in the overweight or obese, but also in the non obese

Obstructive sleep apnea is independently associated with insulin resistance. Am. J. Respir. Crit. Care Med.165,670-676 (2002).

Nevertheless, it should be acknowledged that adiposity is an important factor towards adverse glucose metabolism in OSA,[70] probably more so than sleepdisordered breathing alone. In contrast to the positive association on crosssectional analysis, a longitudinal study of 1300 subjects in the Wisconsin Sleep Cohort did not find any independent relationship between OSA and incident diabetes at 4year followup,despite a higher prevalence of diabetes in OSA subjects independent of other risk factors at baseline20

OSA and Insulin Resistance

3 months of CPAP treatment reduced insulin resistance in sleepy but not in non sleepy OSA subjects with similar AHI levels

OSA and Insulin Resistance

CPAP was found to improve insulin sensitivity after 2 days as well as 3 months of treatment and the improvement was greater in non obese patients with a BMI of less than 30.

OSA and Insulin Resistance

Using the intravenous glucose tolerance test, non diabetic OSA men were shown to have impaired insulin sensitivity as well as impaired insulin secretion.

OSA and Dyslipidemia

HDL cholesterol levels were inversely related to AHI levels, independent of obesity, in younger men and women, but not in older men

Triglycerides levels were positively associated with AHI also in younger men and women only

OSA and Dyslipidemia

Sleep clinic subjects with OSA demonstrated a higher prevalence of dyslipidemia compared with those without OSA, after adjustment for BMI

Few observational studies reported that nasal CPAP treatment improved lipid parameters

No consistent data from randomized, controlled studies to support that

OSA and Dyslipidemia

2 randomized, controlled trials demonstrated that the group receiving CPAP treatment had a 15% reduction in total cholesterol level, but the between group difference failed to achieve statistical significance.

Robinson GV, Pepperrell JC, Segal HC, Davies RJ, Stradling JR. Circulating cardiovascular risk factors in obstructive sleep data from randomized controlled trials. Thorax59(9),777-782 (2004).

[84] Another randomized, crossoverstudy was also negative, but the treatment period of 6 weeks was probably insufficient for changes in circulating lipid levels tooccur27

PATHOGENESIS OF CARDIOMETABOLIC DYSFUNCTION IN OBSTRUCTIVE SLEEP APNEA

Sympathetic Activation and Other Neurohumoral ChangesOSA is postulated to be a chronic stress state with activation of neurohumoral pathways that participate in metabolic regulation.

Studies of OSA subjects demonstrated elevation of sympathetic activity beyond that attributed to obesity.

Sympathetic overactivity accompany transient increases in systemic blood pressure in phase with sleep apneic episodes, and sympathoadrenal activation persists in the day

Sympathetic Activation and Other Neurohumoral ChangesSympathetic activation leads to vasoconstriction, modulate angiotensin renin system, insulin and adiponectin

A study in mice found that intermittent hypoxia resulted in insulin resistance, despite abolition of autonomic nervous system activity

Iiyori N, Alonso LC, Li J et al. Intermittent hypoxia causes insulin resistance in lean mice independent of autonomic activity. Am. J. Respir. Crit. Care Med.175,851-857 (2007).

Sympathetic Activation and Other Neurohumoral ChangesHealthy subjects subjected to sleep restriction in the laboratory setting showed upregulation of the hypo thalamic pituitary adrenal axis and somatotrophic axis

In a population based study, those reporting short sleep duration were found to have higher ghrelin and lower leptin levels, in keeping with promotion of weight gain.

Taheri S, Lin L, Austin D, Young T, Mignot E. Short sleep duration is associated with reduced leptin, elevated ghrelin, and increased body mass index. PLoS Med.1(3),e62 (2004).

OSA subjects have been reported to have altered pattern of cortisol secretion, although there is significantdisagreement about this among studies.[

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Intermittent Hypoxia and Oxidative StressRecurrent intermittent hypoxia with reoxygenation may result in generation of oxidative stress leading to cardiometabolic dysfunction

OSA subjects have been reported to have increased levels of various oxidative stress markers, such as nitric oxide, 8 isoprostane, reactive oygen species and lipid peroxidation

InflammationEvidence for increased inflammation is observed in OSA, independent of obesity

Inflammation plays a key role in the pathogenesis of endothelial dysfunction, insulin resistance and lipid peroxidation

This includes activation of neutrophils, lymphocytes, monocytes and platelets activation of NFB, increased circulating levels of proinflammatory or p