June 16, 2007 – Milan, Italy – Obstructive sleep apnea (OSA) is a risk factor for cardiovascular (CV) events. An observational case control study of about 1400 men followed prospectively for 10 years, showed the odds ratio for a fatal CV event was 2.87 and for a nonfatal CV event was 3.17 in the presence of untreated OSA. About 15-35% had hypertension. These and other data were reviewed in a lecture by Prof. T. Hedner, Goteborg, Sweden.

Prevalence data from Young and colleagues published in 1993 show that 24% of men and 9% of women have an apnea hypoxia index (AHI)  >/=5 and that 0.3-2.7% of men and 1.1-2.5% of women have obstructive sleep apnea (OSA). Snoring was found in 9-50% of men and 4-17% of women. A substantial proportion of persons with OSA are asymptomatic and undiagnosed. Only 1 of 10 persons with OSA have daytime sleepiness and “non-sleepy sleep apneics are considered asymptomatic and require laboratory diagnosis of OSA.

The prevalence of sleep-disordered breathing (SDB) was shown by Young and colleagues to be closely linked with obesity, with a prevalence of about 30%-50% in men. A clear relation between weight and severity of OSA was shown by Peppard and colleagues, with increases in weight associated with worsening of disease and decreases in weight associated with improvement in disease.

A study of 87 men (BMI 34.2 kg/m2, age 46 years) showed that sibutramine-assisted weight loss along with changes in diet and exercise resulted in a decrease in weight and a concomitant decrease in the severity of OSA.

Regarding the metabolic syndrome (MetSyn), Coughlin and colleagues showed in a consecutive population presenting at a sleep laboratory that compared to controls, about 50% of persons with OSA had traditional risk factors for MetSyn. Many of the metabolic and CV risk factors are independently associated with OSA.

New data link OSA and NFκB, a key aspect of the inflammatory pathway for traditional CV risk factors. Yamauchi and colleague showed that healthy non-smoking OSA persons had higher NFκB activation and that treatment of OSA “tunes down” this activation. Minoguchi and colleagues have shown elevated production of TNF-alpha by monocytes in the setting of OSA. Other data implicate IL-6 and Il-8, although these are more debated pathways, while other data show adhesion molecule activation. Ip and colleagues have reported that CPAP (continuous positive airway pressure) treatment of OSA reversed endothelial dysfunction in 28 persons with OSA compared to controls.

In sum, the data show that OSA is associated with marked inflammatory activation, thereby linking it to risk factors for CV disease and MetSyn.  

OSAS and cardiovascular complications: phenotypes and genotypes

A 3-fold increased risk for CV disease in persons with untreated, severe OSA was shown in a study of the natural history of OSA and CV disease by Marin and colleagues. Small reductions in mean arterial pressure have been shown with CPAP therapy. Current evidence shows that a 3.3 mmHg reduction in blood pressure (BP) is associated with a 20% reduction in stroke and a 15% reduction in coronary risk, and a 6.6 mmHg reduction is associated with a 40% reduction in stroke and a 30% reduction in CHD.

Phenotype refers to the total physical appearance and constitution of the gene or person in the context of disease. Phenotype plasticity is the ability of an organism with a given genotype to change its phenotype in response to changes in the environment, that is, the impact of the environment in changes in the phenotype.

OSA has a 40% heritability. Diagnosis of OSA requires physiologic data and objective and subjective evaluation. Although the American Academy of Sleep Medicine Task Force (1999) is the most widely accepted definition of OSA, it does not account for age and some other factors and it is technology dependent.

Hypertension has a 30-40% heritability, and a large number of environmental factors affect its development, including dietary sodium and alcohol.

OSA can be considered as an isolated and independent risk factor for hypertension. To date, there is limited data on candidate genes for the development of hypertension in OSA; the most studied candidate gene is angiotensin converting enzyme (ACE), but the data are inconsistent and controversial.

Both OSA and essential hypertension are complex polygenic diseases. Intermediate phenotypes interact to produce a single phenotype that is seen in the clinic. The degree of environmental influence must be considered, but currently this is difficult to factor into genetic studies.

In the future, longitudinal population studies are needed to understand the relation between OSA and hypertension and to study the variables to best define the phenotype. It may be necessary to not view this in a linear model, but rather more broadly in a matrix.

OSAS and secondary hypertension

OSA is widely prevalent in hypertensive patients, yet it remains underdiagnosed and undertreated. OSA should be strongly suspected in persons with resistant hypertension. Effective treatment of OSA may attenuate neurohumoral and metabolic abnormalities, lower BP, and reduce CV risk

A gradual relation between OSA and the development of hypertension was shown in the Wisconsin Sleep Study, where an AHI >/=15 was associated with a 3-fold increased risk for hypertension and an AHI 0.1-4.9 associated with a 1.5-fold increased risk. OSA was an independent predictor of hypertension.

Lavie and colleagues showed in a Swedish study of 2677 patients with suspected OSA found that that 20% of the patients with an AHI < 10 and 50% of those with an AHI > 50 had hypertension. Further, an increase by one respiratory event (apnea, hypopnea) per hour of sleep was associated with a 1% increased relative risk of hypertension, independent of age, sex, and BMI.

Ambulatory blood pressure (ABP) monitoring showed a reduction in the fall in nighttime BP in 45 subjects with moderate to severe OSA compared to 45 controls and also diastolic differences during the daytime.

Resistant hypertension (>160/95 mmHg) has been shown in 80% of persons with OSA. Further, a study by Garcia-Rio in 2004 showed the prevalence of non-dipping to be 66% of persons with OSA and hypertension, 73% of persons with OSA and white-coat hypertension, 62% in OSA and normal blood pressure, and 20% in controls. Basquet and colleagues have shown that increased nocturnal DBP is most prevalent in OSA, especially in younger patients.

Studies using microneurography have shown that a consequence of obesity may be OSA and increases muscle sympathetic nerve activity (MSNA). A study by Peled and colleagues showed alternating bradycardia-tachycardia and ST segment depression during sleep in OSA.

OSA is considered an associated condition for resistant hypertension, including the new 2007 ESH-ESC Guidelines for the Treatment of Arterial Hypertension.  Logan and colleagues in Canada showed that 65% of obese women and 97% of obese men with different forms of OSA have drug-resistant hypertension (≥ 3 antihypertensive drugs at maximal dose).

Treatment of OSA has been shown to decrease fluctuations in BP during sleep. One-year of CPAP treatment was shown to improve baroreflex control of heart rate in OSA. A 59% increase in nighttime wakefulness and 68% increase in non-REM stage 2 sleep.

The effect of CPAP on BP is relatively modest in the relatively few well-designed, randomized trials that have been conducted. CPAP seems to have the greatest effect in persons with OSA and hypertension. In 180 patients with OSA, 32% had hypertension and 1-year of CPAP treatment significantly reduced BP. A recently published meta-analysis (Hypertension 2007;50:1-7) of 16 studies showed a modest 2.5 mmHg reduction in SBP and a significant 1.8 mmHg reduction in DBP.

Age appears to be a strong component in the relation between OSA and hypertension, with the relation much stronger in younger and middle-aged persons, compared to elderly persons who have vascular structural changes.