Obstructive Sleep Apnea

[Guest guest]

I read this article this morning decided that it might

be of interest to many in this group. OSA is often a

cause of many of the problems patients when it comes

to various disease states. We often find a strong

association between various factors and sometimes we

attribute inappropriately cause and effect. Does OSA

contribute to obesity or is it caused by obesity or

does each worsen the other? Early detection of OSA is

often very difficult until the damage is done and may

be difficult to reverse.

Ralph Giarnella MD

Southington Ct USA

************************************

An Update on Obstructive Sleep Apnea and the Metabolic

Syndrome

Lam; Ip

Curr Opin Pulm Med. 2007;13(6):484-489. ©2007

Lippincott & Wilkins

Posted 11/02/2007

Abstract and Introduction

Abstract

Purpose of Review: Patients with obstructive sleep

apnea are often overweight or obese, and they

frequently exhibit metabolic aberrations, collectively

known as the metabolic syndrome, an established

cardiovascular risk factor. We review recent data on

the relationship between obstructive sleep apnea and

metabolic syndrome or its components, including

abdominal obesity, insulin resistance, hypertension,

and dyslipidemia.

Recent Findings: There is accumulating evidence for an

independent association between obstructive sleep

apnea and metabolic syndrome or its components. Recent

epidemiologic and clinical data suggest a causal role

of severe obstructive sleep apnea in development of

hypertension, but findings for insulin resistance and

dyslipidemia are controversial. Visceral obesity

remains a confounding issue in analyses. Animal models

and translational studies indicate that obstructive

sleep apnea may promote metabolic dysfunction through

cycles of intermittent hypoxia; proposed underlying

pathophysiologic mechanisms include oxidative stress,

sympathetic activation, and inflammation.

Summary: There is suggestive evidence, but independent

associations between obstructive sleep apnea and

metabolic syndrome or its components are not fully

established because of the confounding effect of

obesity. Large randomized interventional trials are

needed to identify any cause-effect relationship.

Long-term follow-up studies would help to clarify the

role of treatment of sleep apnea in reducing

cardio-metabolic morbidity.

Introduction

Obstructive sleep apnea (OSA) is a prevalent condition

worldwide, affecting at least 1-5% of middle-aged

individuals in various ethnic populations, and obesity

has been demonstrated to be a major risk factor.[1-4]

There is growing concern regarding the potential

adverse health outcomes attributable to OSA, in

particular its impact on cardiovascular disease.[5**]

It is now recognized that there is a marked

association between OSA and the metabolic

syndrome,[6,7,8*,9,10*] a cluster of obesity-related

cardio-metabolic factors that are known to increase

cardiovascular risk.[11,12] Mechanistically, there is

accumulating evidence demonstrating that OSA results

in many systemic effects that may contribute,

independent of obesity, to the generation of various

metabolic aberrations or cardiovascular

pathology.[5**,13] This review presents recently

reported data on the link between OSA and metabolic

syndrome, with a focus on the evidence for an

independent causal role of OSA in exacerbating

cardio-metabolic risk factors.

Metabolic Syndrome

The metabolic syndrome represents a constellation of

metabolic derangements, including central obesity,

hypertension, glucose intolerance, and dyslipidemia.

It is a well recognized risk factor for cardiovascular

disease.[11] The National Cholesterol Education

Program Adult Treatment Panel III report[12]

recommended the use of five variables, with

established diagnostic cut-offs, to define metabolic

syndrome: hypertension, insulin resistance or glucose

intolerance, low serum high-density lipoprotein

(HDL)-cholesterol, elevated serum triglyceride, and

abdominal obesity. Any individuals satisfying three of

these five criteria would be classified as having the

metabolic syndrome. These criteria are clinically

identifiable, thus making it easy to recognize the

metabolic syndrome in practice.

Using the Adult Treatment Panel III definitions, the

Third National Health and Nutritional Examination

Survey[14] reported that the age-adjusted prevalence

of metabolic syndrome in the USA was 23.7%, with the

highest prevalence found among Mexican Americans. With

the trend toward increasing body weight in many

populations in developed and developing countries,[15]

the prevalence of metabolic syndrome and its

health-related consequences will certainly increase.

Obstructive Sleep Apnea and the Metabolic Syndrome

Over the years, many studies have investigated the

relationship between OSA and various cardio-metabolic

parameters. More recently, studies have emerged

regarding the relationship between OSA and metabolic

syndrome.[6,7,8*,9,10*,16] Compared with non-OSA

control individuals, OSA was found to be independently

associated with individual metabolic parameters in the

metabolic syndrome as well as with an increased

prevalence of metabolic syndrome, with an odds ratio

of 9.1.[6] A study of similar design found OSA to be

independently associated with metabolic syndrome but

not with insulin resistance.[9] A community-based

study conducted in Chinese adults in Hong Kong[7]

identified a fivefold increased risk for having

metabolic syndrome in individuals with OSA, and the

severity of OSA correlated with number of components

of the metabolic syndrome. A marked association of

sleep disordered breathing (SDB) and metabolic

syndrome was also identified in adolescents.[10*] In a

study that included a group of control individuals who

were matched for obesity,[17*] however, those with OSA

exhibited no increase in the proportion having

metabolic syndrome, though they had a comparatively

worse metabolic profile. These studies recruited

mostly obese individuals, whereas a case controlled

study of nonobese Japanese men matched for visceral

fat[18*] found OSA to be associated with hypertension,

dyslipidemia, and hyperglycemia, suggesting that even

nonobese persons with OSA may also be prone to

development of metabolic syndrome.

Studies on the effect of treatment for OSA have

largely dealt with individual metabolic variables

rather than the metabolic syndrome entity. In a

randomized placebo-controlled crossover trial

conducted in obese patients with severe OSA,[19*] 6

weeks of treatment with continuous positive airway

pressure (CPAP) reduced waking blood pressure but did

not produce any improvement in the other components of

the metabolic syndrome, or in the proportion of

patients with metabolic syndrome. The presence of

metabolic syndrome in patients with OSA treated with

CPAP did not appear to confer additional

cardiovascular risk compared with those who did not

have metabolic syndrome.[16]

Mechanistically, recurrent obstructive events with

cyclic intermittent hypoxia and sleep fragmentation

are believed to be the key triggers of various

pathogenetic mechanisms in OSA, including sympathetic

activation, cellular oxidative stress, and systemic

inflammation,[5**,13,20,21] leading to characteristic

features of the metabolic syndrome. Intermittent

hypoxia followed by reoxygenation may result in

increased oxidative stress, which is a fundamental

cellular pathogenic process in metabolic and

cardiovascular function.[20,21,22*,23] A number of

observational studies have demonstrated that OSA is

independently associated with increased markers of

oxidative stress.[20,21,22*,23,24] Intermittent

hypoxia may selectively upregulate inflammatory

pathways over adaptive pathways,[25] and generate

cytokines and other mediators that modulate metabolic

and vascular functions.[26] OSA is associated with

heightened sympathetic activation both at night and in

the day,[27] and this is believed to be an important

mechanism in the pathogenesis of hypertension in

OSA.[28] Sympathoadrenal and other neurohumoral

activations are also putative mediators of insulin

resistance.[29**] The above mechanisms have intricate

interactions, with multidirectional positive or

negative feedback among them.[13].

Obstructive Sleep Apnea and Obesity/Visceral Obesity

Obesity and visceral obesity are associated with an

array of health risks, the most notable of which are

type II diabetes and cardiovascular disease, and OSA

has recently joined the list. Although OSA also occurs

in lean individuals, adiposity is still a major risk

factor in various ethnic populations.[2-4] A 10%

weight gain was associated with a sixfold increase in

the odds of developing sleep apnea, a 10% weight loss

predicted a 26% decrease in the apnea-hyponea index

(AHI),[30] and every 6 kg/m2 increment in BMI

increased the risk for developing OSA by more than

fourfold.[31] OSA has also been shown to be closely

related to visceral obesity, even more so than

BMI.[32] There are ethnic differences in attributable

health risks, and therefore the threshold criteria for

abdominal obesity recommended by the World Health

Organization for Asians are lower than for

Caucasians.[33] In the elderly OSA is not as closely

associated with obesity.[31] In young children

adenotonsillar hypertrophy is a major risk factor,

although this has been overtaken by obesity in

prepubertal children and adolescents in recent

years.[34*]

Visceral fat is now known to be a metabolically active

tissue, which produces large amounts of

proinflammatory or vasoactive substances,[35] giving

rise to metabolic dysregulation and atherogenesis.

Hence, the study of the cardio-metabolic consequences

attributed to OSA per se is notoriously confounded by

coexistent adiposity. On the other hand, OSA may well

modulate the expression of adipokines, cytokines, or

hormones in adipose tissues, which may contribute

systemically to the development of various features of

metabolic syndrome and cardiovascular disease.[35,36]

The role in OSA of leptin, one of the known

adipocytokines, has been explored, but the data are

conflicting because of the significant confounding

effect of obesity.[5**] In a study including a group

of control individuals matched for obesity, serum

leptin was significantly higher in those with OSA,

suggesting that OSA may indeed be a leptin-resistant

state.[17*]

Although obesity is believed to be an etiologic risk

factor for OSA, SDB may also feedback to obesity.

Sleep disturbance and sleep loss, through as yet ill

defined mechanisms, may both adversely affect insulin

and glucose homeostasis and predispose to weight

gain.[37] Furthermore, OSA may promote weight gain

through increased insulin resistance or leptin

resistance.[38] Thus, there is potentially a vicious

cycle between OSA and metabolic dysfunction.[13]

Obstructive Sleep Apnea and Insulin Resistance/Glucose

Intolerance/Diabetes Mellitus

Insulin resistance and visceral obesity are considered

to be at the core of the constellation of risk factors

that define the metabolic syndrome.[11] Insulin

resistance is strongly associated with visceral

obesity. OSA exhibits pathophysiologic mechanisms that

may potentially contribute to the development of

insulin resistance, including autonomic activation,

alterations in neuroendocrine function, direct effects

of hypoxemia on glucose regulation, and release of

proinflammatory cytokines such as interleukin-6 and

tumor necrosis factor-?.[29**,39,40]

A number of studies have looked at the association

between OSA and insulin resistance/glucose

intolerance.[29**,39] Epidemiologic data from the

Sleep Heart Health Study[41] suggested that patients

with mild or moderate to severe OSA have increased

risks for fasting glucose intolerance after adjustment

for confounding factors. Previous clinical studies

including smaller samples of patients have yielded

conflicting results, whereas recent studies have more

consistently demonstrated an independent association

between OSA and insulin resistance in

adults,[29**,39-42] although this is by no means a

universal finding.[43] In pediatric age groups, the

results have also been conflicting.[10*,34*]

Insulin resistance is the hallmark of type II

diabetes. A study of 1682 diabetic men in the UK[44*]

estimated OSA prevalence at 23%, and OSA was

significantly associated with diabetes, independent of

age, BMI, and neck size. The Wisconsin Cohort

Study[45] reported that 3% of individuals with an AHI

below 5 had a diagnosis of type II diabetes, whereas

15% of those with an AHI of 15 or greater had

diabetes, at a twofold relative risk after adjustment

for age, sex, and body habitus. A 4-year follow up,

however, did not confirm an increased incidence of

diabetes after controlling for confounding factors,

and thus a causal role for SDB in the development of

diabetes cannot be established.

Interventional data on OSA and insulin resistance have

mostly been observational, involving small samples of

individuals. The effect of CPAP treatment on insulin

resistance in nondiabetic OSA patients has been

conflicting, and most studies failed to demonstrate

any significant effect,[40] whereas one study showed

improvement mainly in nonobese individuals.[46]

Recently, a randomized controlled cross-over study of

obese OSA men[19*] did not demonstrate any effect of

CPAP treatment for 6 weeks on insulin resistance.

Observational studies in OSA patients with

diabetes[47,48] suggested that CPAP treatment may

result in better glycemic control. These findings must

be corroborated by randomized controlled trials before

any conclusions can be drawn.

The effect of OSA on glucose homeostasis has been

investigated in animal experiments. Exposure to

chronic intermittent hypoxia led to an increase in

insulin resistance in leptin-deficient obese mice.[49]

Sympathetic activation is a putative mechanism in the

development of insulin resistance in OSA, but a study

of acute intermittent hypoxia in lean mice showed that

insulin resistance occurred independent of autonomic

activation.[50]

In summary, although there is growing evidence for an

independent contribution of OSA to insulin resistance,

the picture is far from complete.

Obstructuve Sleep Apnea and Hypertension

OSA is frequently associated with hypertension. The

etiology of hypertension in OSA patients is probably

multifactorial, with environmental, dietary, and

genetic inputs involved.

Several potential mechanisms may mediate the

association of OSA with hypertension, including

sympathetic activation, resetting of arterial

chemoreceptor response, decreased baroreceptor

sensitivity, and release of vasoactive mediators with

altered endothelial and vascular function, and

abnormal salt and water metabolism.[5**,23,27,51,52]

Epidemiologic and large cross-sectional studies have

consistently demonstrated an association between OSA

and hypertension, independent of obesity.[52] The

association was found even in mild OSA,[53] whereas

those with moderate OSA had almost three times greater

risk for developing hypertension than did control

individuals with no documented SDB events.[53] There

was also a dose-response association between SDB at

baseline and the presence of hypertension at 4 years

of follow up, independent of age, sex, BMI, and neck

circumference. The findings suggest that SDB is likely

to be a risk factor for hypertension and consequent

cardiovascular morbidity in the general population.

The evidence for a causal role of OSA in the

development of hypertension was consolidated by data

from randomized trials comparing therapeutic CPAP with

sham or subtherapeutic CPAP,[19*,54-57] which showed a

blood pressure lowering effect in the group receiving

active treatment. Although association studies have

demonstrated a relationship between hypertension and

even mild to moderate sleep apnea,[53,58,59]

interventional studies have only been able to

demonstrate an effect in severe OSA,[54] but not in

mild or moderate OSA.[60] Given the high prevalence of

mild to moderate OSA in the general population,

determining whether treatment of OSA in this group

will confer a beneficial effect on blood pressure is

important. Evidence for a pre-emptive effect of

treatment of OSA on development of hypertension, which

will confirm a causal role for OSA, must await the

completion of long-term randomized controlled trials.

Furthermore, CPAP therapy appeared to produce no

effect on blood pressure in OSA patients who were not

sleepy[61,62*] Thus, current practice guidelines

consider treatment of OSA for its blood pressure

lowering effect as 'optional due to inconsistent and

variably conclusive evidence.'[63**] In the clinical

scenario, the decision is likely to be guided by the

severity of OSA and hypertension, and the presence of

sleepiness and other cardiovascular comorbidities.

Obstructive Sleep Apnea and Dyslipidemia

Abnormal lipid profiles have frequently been reported

in patients with OSA. In the Sleep Heart Health Study

of over 6000 men and women,[64] there was an inverse

relationship between AHI and HDL-cholesterol levels

and a positive association between AHI and

triglycerides, especially in younger individuals, on

adjustment for confounding factors. Case controlled

studies also demonstrated that OSA patients had more

adverse lipid profiles than did BMI-matched

individuals without OSA,[5**,6,43] although the

affected lipid parameters were different.

There are limited interventional data on OSA and

dyslipidemia. Pooled data from two randomized

controlled trials demonstrated that the group treated

with therapeutic CPAP for 1 month experienced a

significant decrease in serum total cholesterol, but

the difference between changes in the therapeutic CPAP

and sham CPAP groups failed to reach statistical

significance.[65] An observational study[66] found a

small but significant improvement in HDL-cholesterol

after 6 months of CPAP therapy, which was most evident

in those with abnormal baseline values. The previously

cited randomized study[19*] found no changes in lipid

profiles between therapeutic and sham CPAP treatment

for 6 weeks, however. Studies with larger sample size

and longer follow-up periods would be useful in

further delineating treatment responses.

Other than affecting the circulating levels, sleep

apnea may modulate the functions of lipids.

Low-density lipoprotein (LDL)-cholesterol is much more

atherogenic in an oxidized form, and individuals with

OSA have been reported to exhibit lipid peroxidation,

with higher levels of oxidized LDL-cholesterol

compared with non-OSA individuals.[67] Furthermore, a

lower capacity for HDL-cholesterol to protect

LDL-cholesterol from oxidation was found in OSA, and

the degree of HDL dysfunction correlated with the

severity of OSA and oxidative stress.[68*]

Corroborative evidence is emerging from animal

studies. Exposure to intermittent hypoxia caused an

upregulation of lipid biosynthesis and

dyslipidemia[69,70] and led to lipid peroxidation in

the liver in a dose-dependent manner.[71]

Conclusion

With the sweeping obesity epidemic, the prevalence of

both OSA and the metabolic syndrome are expected to

increase significantly. New insights into the

metabolic and cardiovascular risks in OSA are

emerging. Because of the common feature of visceral

obesity, the association between OSA and metabolic

syndrome is not unexpected, but the key issue remains

whether OSA itself contributes to the initiation or

aggravation of these cardio-metabolic aberrations. A

causal role played by SDB in hypertension among those

with severe symptomatic OSA is supported by good

evidence, but independent associations and

cause-effect relationships with insulin resistance and

dyslipidemia are controversial. Data on the entire

spectrum of SDB, especially in the mild and moderate

categories, as well as information on the relationship

of OSA and metabolic syndrome in females, are scant.

Further interactions with environmental factors and

personal susceptibility may contribute to final health

outcomes in the individual.[22*] Large randomized

trials of longer follow-up duration are required to

clarify causal relationships and explore the potential

for treatment of OSA to mitigate against

cardiovascular morbidity and mortality. Clinically, a

high index of awareness and early identification of

metabolic risk factors in OSA subjects, and vice

versa, would be of benefit in terms of patient care.

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