Victoria Cooper
Institute for Cardiovascular Research, University of Leeds, Leeds, UK

https://doi.org/10.36866/pn.62.29

Obstructive sleep apnoea (OSA) is a common, and yet often under­diagnosed and under-recognised, clinical disorder. It is more common in men aged 30-65 years, but can occur in all age groups, and is estimated to affect approximately 4% of middle­aged men and 2% of middle-aged women in the UK. OSA is defined as a cessation in airflow for at least 10 seconds during sleep despite continuing respiratory effort. It occurs as the result of obstruction to the upper airways, most commonly caused by excess fat due to obesity. During sleep, upper airway muscles relax and their tone is reduced. Inspiration also helps to favour airway collapse due to negative pressure within the airway. These factors combined, together with excess parapharyngeal fat or some other obstructive factor, result in closure of the airways. As a result hypoxia and hypercapnia develop, with oxygen saturation levels falling below 50% in severe cases. Fortunately, this leads to an arousal which acts to increase muscle tone and open up the airways so breathing can resume. Sleep then ensues and the cycle starts over. This cycle can occur from five times (the clinical definition of OSA) to more than 100 times per hour of sleep. Clearly this leads to severe sleep fragmentation, which is more deleterious than sleep deprivation. The most common symptom of this condition is excessive daytime sleepiness (Fig. 1).

Aside from the impact sleepiness has in social functioning, work performance and driving ability, there are more sinister consequences to OSA. There is increasing evidence that OSA has direct and deleterious effects on cardiac and vascular structure and function, with OSA patients at increased risk of arterial hypertension, heart failure, cardiac ischemia, arrhythmias and stroke. The prevalence of hypertension in patients with severe untreated OSA may be greater than 50%, and the incidence of OSA in hypertensive patients is greater than 25%. The incidence of OSA in resistant hypertension is even greater, with one study reporting that 87% of hypertensive patients refractory to maximal medical therapy had undiagnosed OSA (Logan et al. 2001).

The mechanisms by which OSA leads to hypertension and other cardiovascular disorders have undergone much research in recent years. Although there is no apparent consensus, the mechanisms are clearly multi-factorial. Episodes of OSA result in large swings in intrathoracic pressure, arterial oxygen desaturation, hypercapnia and acidosis. Events terminate in arousal and are accompanied by marked surges in arterial pressure, preceded by an increase in sympathetic vasoconstrictor tone. All these factors probably have some role to play in the development of cardiovascular complications.

One of the first mechanisms to be considered in the link between OSA and hypertension was that both are manifestations of a common cause, e.g. obesity. This is an attractive hypothesis since there is a known association between obesity and both hypertension and OSA. However, numerous studies have shown that even after adjustment for body mass index, although the strength of the association is predictably reduced, there is still an independent link between OSA and hypertension. Also against this hypothesis is the finding that successful treatment of OSA, particularly using nasal continuous positive airway pressure (nCPAP), reduces blood pressure despite no alteration in weight.

Frequent arousals result in abnormal electrophysiological sleep structure, in particular a reduction in the deep sleep stages 3 and 4. Arousal also results in transient increases in heart rate, blood pressure, ventilation and surges in sympathetic output. It has been suggested that movement arousals also influence daytime sympathetic tone independently of respiratory disturbance index (the number of >3% desaturations per hour of sleep) and night-time saturation (Loredo et al. 1999). However, animal models have not shown arousal in itself to lead sustained hypertension (Brooks et al. 1997).

Probably of more importance than arousal is the effect of repetitive hypoxia and hypercapnia. Animal models have suggested that intact carotid chemoreceptors, sympathetic nervous system, renal nerves and activation of the renin-angiotensin system are all critical to the rise in blood pressure in sleep apnoea-induced hypertension. We have recently shown that brief periods of asphyxia or hypercapnia result in resetting of the carotid baroreflex to maintain arterial pressure at a higher level, and that this is sustained after the removal of the stimulus (Cooper et al. 2004a, 2005). This is also true for sympathetic activation (Morgan et al. 1995). Indeed, augmented resting (waking) sympathetic activity and a potentiated chemoreflex response to hypoxia have been found in patients with OSA (Narkiewicz et al. 1999). Renal handling of sodium and water is also impaired in OSA. Hypoxia leads to a deficit in renal sodium excretion and this may lead to volume expansion and hypertension. Hypoxia also has cellular effects, particularly on vascular endothelial cells. This may directly affect vascular remodelling, reactivity and resistance vessel tone, all factors which may promote hypertension.

Another point to consider is the effect of night-time surges in blood pressure on arterial baroreceptors. Baroreflexes act to maintain blood pressure at a given level, but may reset when pressure is altered for a prolonged period, so that pressure is maintained at the new prevailing pressure. A canine model of sleep apnnoea suggested that the baroreflex curve is shifted to the right without a change in slope (Brooks et al. 1999). We have also recently found something similar in patients with OSA. The baroreflex ‘set point’ (the pressure corresponding to maximal slope) is shifted to the right first thing in the morning in OSA patients, whereas the reverse is true in healthy control subjects who have a reduced blood pressure during sleep (Cooper et al. 2004b). We propose that night-time reductions in blood pressure during normal sleep act to reset baroreceptors towards lower levels, and that this may be a protective mechanism. This mechanism is absent in OSA and is actually reversed, which would therefore promote hypertension.

Other possible factors to be considered are changes in endothelial cell function and also insulin resistance, which is a known risk factor for atherosclerosis and thus cardiovascular and cerebrovascular disease.

In summary, OSA causes alterations in chemoreflex and baroreflex function, sympathetic tone, insulin resistance and endothelial cell function. These alterations, through a number of mechanisms, will promote hypertension and cardiovascular disease. Whatever the underlying mechanism, the increased risk of cardiovascular morbidity and mortality in patients with OSA is real. Therefore early diagnosis and treatment is essential in reducing this risk.

References

Brooks D, Horner RL, Kozar LF, Render-Teixeira CL & Phillipson EA (1997). Obstructive sleep apnea as a cause of systemic hypertension. Evidence from a canine model. J Clin Invest 99, 106­109.

Brooks D, Horner RL, Floras JS et al. (1999). Baroreflex control of heart rate in a canine model of obstructive sleep apnea. Am J Respir Crit Care Med 159, 1293-1297.

Cooper VL, Bowker CM, Pearson SB, Elliott, MW & Hainsworth R (2004a). Effects of simulated obstructive sleep apnoea on the human carotid baroreceptor-vascular resistance reflex. J Physiol 557, 1055­1065.

Cooper V, Bowker C, Elliott M, Pearson S & Hainsworth R (2004b). Baroreflex resetting in obstructive sleep apnoea – a mechanism for promoting hypertension. Clin Auton Res 337.

Cooper VL, Pearson SB, Bowker CM, Elliott MW & Hainsworth R (2005). Interaction of chemoreceptor and baroreceptor reflexes by hypoxia and hypercapnia – a mechanisms for promoting hypertension in obstructive sleep apnoea. J Physiol 568, 677-687.

Logan AG, Perlikowski SM, Mente A, Tisler A, Tkacova R, Niroumand M, Leung RS & Bradley TD (2001). High prevalence of unrecognized sleep apnoea in drug-resistant hypertension. J Hypertens 19, 2271-2277.

Loredo JS, Ziegler MG, Ancoli-Israel S, Clausen JL & Dimsdale JE (1999). Relationship of arousals from sleep to sympathetic nervous system activity in obstructive sleep apnoea. Chest 116, 655-659.

Morgan BJ, Crabtree DC, Palta M & Skatrud JB (1995). Combined hypoxia and hypercapnia evokes long-lasting sympathetic activation in humans. J Appl Physiol 79(1), 205-13.

Narkiewicz K, van de Borne PJH, Pesek CA, Dyken ME, Montano N & Somers VK (1999). Selective potentiation of peripheral chemoreflex sensitivity in obstructive sleep apnea. Circulation 99, 1183-1189.