Abstract
Patent foramen ovale (PFO) has a prevalence of 25%–27% in the general population and it has been suggested to be the mediator for a wide variety of syndromes based on the paradoxical embolism. The obstructive sleep apnea syndrome (OSAS) is a common disorder in the middle-aged population. An echocardiographically visible PFO was detected in 27%–69% of patients with documented OSAS suggesting a relationship between PFO and OSAS, but the pathophysiology of this potential relationship is still unclear. It has been shown that obstructive apnea can induce right-to-left shunting (RLS) through PFO with two proposed mechanisms including a large swing in pleural pressure and pulmonary hypertension. Pulmonary artery hypertension and oxygen desaturation have been suggested to be caused by the concurrence of OSAS and PFO. Arguments against and in favour of this potential relationship are discussed in this brief review.
1
Introduction
Patent foramen ovale (PFO) has a prevalence of 25%–27% in the general population and it has been suggested to be the mediator for a wide variety of syndromes based on the paradoxical embolism. PFO-related paradoxical embolism involves a number of potential consequences including cerebral ischemia, migraine, peripheral, coronary and splanchnic organs, and left atrial functional dysfunction . Unfortunately, although PFO plays an important role in many syndromes, major key points in understanding its pathophysiology, clinical syndromes and correct treatment are still debated . The obstructive sleep apnea syndrome (OSAS) is a common disorder in the middle-aged population . An echocardiographically visible PFO was detected in 27%–69% of patients with documented OSAS , a clearly higher incidence than in non-OSAS patients, suggesting a relationship between PFO and OSAS, but the pathophysiology of this potential relationship is still unclear. The authors in this brief review attempted to clarify this controversy.
2
OSAS: epidemiology and features
Epidemiological studies demonstrated that OSAS or better OSASH (obstructive sleep apnea/hypopnea syndrome) is common in adults and even in children affecting 2%–5% of middle aged population and is defined on the basis of symptoms of daytime sleepiness and objective measures of disordered breathing during sleep. OSASH is typically characterized by obstruction of the upper airway during sleep, resulting in repetitive breathing pauses accompanied by oxygen desaturation and arousal from sleep: this results in diurnal sleepiness leading to cognitive impairment. Obstructive sleep apnea, as defined by apnea hypopnea index of 5 or more per hour is a common disorder and affects up to 9%–26% of middle aged people. OSASH is an independent risk factor for hypertension and cardiovascular and cerebrovascular morbidity . Continuous positive air pressure (CPAP) has been described as a beneficial and effective treatment for this syndrome .
2
OSAS: epidemiology and features
Epidemiological studies demonstrated that OSAS or better OSASH (obstructive sleep apnea/hypopnea syndrome) is common in adults and even in children affecting 2%–5% of middle aged population and is defined on the basis of symptoms of daytime sleepiness and objective measures of disordered breathing during sleep. OSASH is typically characterized by obstruction of the upper airway during sleep, resulting in repetitive breathing pauses accompanied by oxygen desaturation and arousal from sleep: this results in diurnal sleepiness leading to cognitive impairment. Obstructive sleep apnea, as defined by apnea hypopnea index of 5 or more per hour is a common disorder and affects up to 9%–26% of middle aged people. OSASH is an independent risk factor for hypertension and cardiovascular and cerebrovascular morbidity . Continuous positive air pressure (CPAP) has been described as a beneficial and effective treatment for this syndrome .
3
PFO-OSASH: pro
3.1
Pathophysiology
It has been shown that obstructive apnea can induce right-to-left shunting (RLS) through PFO , but the point is the mechanism of RLS in an awake patient. Two hypotheses have been suggested to explain this cause–effect mechanism in awake patients including a large swing in pleural pressure and pulmonary hypertension.
3.2
Swing in pleural pressure
Usually two manoeuvres are responsible for revealing a silent PFO: the well-known Valsalva manoeuvre and the Mueller manoeuvre. The first one induces a large positive pleural pressure , the second one, by inducing a large negative pleural pressure, increases venous flow to the heart, facilitating RLS through PFO . Obstructive apnea may be considered as a succession of Valsalva and Mueller manoeuvres as the patient expires and inspires against an occluded airway.
Indeed many patients with OSASH have also increased upper airway resistance because of different reasons including interstitial oedema with a mild inflammatory reaction and diminution of pharyngeal diameter . The role of increased airway resistance in generating RLS through PFO is also supported by the increased prevalence of PFO in patients with chronic obstructive pulmonary disease .
3.3
Pulmonary hypertension
Pulmonary hypertension is quite common in OSAS accounting for 15%–20% of all patients . Inversion of the right-to-left pressure gradient may cause reopening of a PFO and may explain, at least in part, the high prevalence of RLS in chronic obstructive pulmonary disease patients.
It is noticeable that CPAP my reverse both upper airway resistance and also pulmonary hypertension, diminishing or abolishing RLS.
3.4
Oxygen desaturation
Shanoudy et al and more recently Lau et al demonstrated that significant hypoxemia, particularly during the Valsalva manoeuvre can be present in one third of patients with OSASH and PFO; Johansson et al suggested that nocturnal oxygen desaturation occurs more often in OSASH subjects with PFO than in patients without . The cause–effect relationship has not been fully clarified yet because the degree of desaturation is dependent from the size of PFO and interatrial pressure relation and size of PFO during Valsalva can be made only in awake patients. The size and interatrial pressure relation during sleep periods are unknown. To overcome this weakness, Johanson et al , rather than measuring the maximum desaturation, measured the frequency of moderate desaturation (difference of > 4%) founding a substantial increase of number of desaturation in patients with OSAS and PFO compared to patients with OSAS only. Such patients had also significantly more hypopneas than patients without PFO probably because of a reduced hypoxic ventilator drive.
3.5
Effects of transcatheter closure on OSAS
There are some anecdotal evidences that transcatheter closure of PFO in OSASH patients may mitigate OSASH symptoms including improvement in polysomnographic testing, daytime sleepiness, use of CPAP, and increase in oxygen saturation .The exact mechanism of such improvements is not known in detail. The hypothesis is that closing a significant PFO may reduce the desaturation number also decreasing the risk of stroke correlated with OSAHS.
An indirect proof of such concept may be found in the positive effect of transcatheter closure in patients with platypnea–orthodeoxia syndrome , in whom mechanical closure has been suggested to abolish oxygen desaturation. Obviously it is likely that the same anatomic–functional features suggested as risk indicators for PFO patients, such as presence of atrial septal aneurysm , Eustachian valve , permanent shunt , could identify the patients with OSAHS with the worse clinical features, such as an increase of desaturation number and the need for CPAP treatment.
4
PFO-OSAS: cons
4.1
Pathophysiology
Theoretically, along with some preliminary clinical data, the above argument appears fascinating. The euphoria, however quickly wanes as we scratch below the surface.
While overlap between two common disorders is not unusual, it does not imply a causal relationship between the two. The two studies which looked at the prevalence of PFO in obstructive sleep apnea were relatively small and did not exclude OSA with “gold standard” polysomnography in controls. The study by Shanoudy showed very high prevalence of PFO in OSA population but was found to have methodological limitations . There was also large variation in effect size which suggests selection bias. Only one study recently published had performed polysomnography on all patients and excluded conditions known to be associated with PFO. This study however did not find any significant oxygen desaturation due to the shunting, thereby questioning the clinical relevance for RLS.
4.2
Swing in pleural pressure
The discrepancy in findings on oxygen desaturations may be explained by the hemodynamic alterations caused by obstructive sleep apnea. Studies have revealed that apneic events during obstruction sleep apnea are related to acute rise in blood pressure due to sympathetic stimulation caused by apnea related arousals. . Acute elevation of blood pressure is known to increase left ventricular end diastolic pressure . During diastole the left atrium is directly exposed to pressures from the left ventricle, resulting in raised left atrial pressure. This transient elevation of blood pressure may raise left ventricular end diastolic pressure and left atrial pressure, thus reducing the gradient between the two sides. So while the swings in the pleural pressures may transiently raise the right side pressures it most likely is counteracted by the raised left sided pressure, thus making it clinically insignificant.
4.3
Oxygen desaturation
The Johansson et al study used ratio of oxygen desaturation index (ODI) to apnea hypopnea index (AHI) to calculate the proportion of oxygen desaturation. However ODI gives more information on frequency of desaturations rather than the severity of oxygen desaturation which is more important in evaluation of clinical impact of RLS. Subsequent study by Lau et al however did not find any oxygen desaturations .
While chronic obstructive pulmonary disease has been associated with increased risk for stroke and other cardiovascular diseases it is much more likely due to shared strong risk factors like smoking. Another potential mechanism touted is the increased systemic inflammation present in chronic obstructive pulmonary disease . Studies have shown that medications for COPD have a potential to stimulate the heart thus increasing the heart rate and blood pressure and thereby increasing the risk of cardiovascular events . There is no evidence that RLS in COPD independently increases the risk for stroke.
4.4
Pulmonary hypertension
While the prevalence of pulmonary hypertension is around 15% in patient with obstructive sleep apnea, stroke is not necessarily noted to be a common complication of pulmonary hypertension. In fact a recent study by French researchers found that the RLS related to PAH is not related to reopening of PFO .
Another weakness in these studies is that most studies evaluated shunt by performing Valsalva manoeuvre during wake period. Obstructive sleep apnea is a condition which afflicts patients during sleep and the physiology of events mirrors Mueller manoeuvre more than Valsalva.
4.5
Effects of transcatheter closure on OSAS
Lastly improvement in OSA after PFO repair defies current understanding of OSA. While PFO repair may theoretically prevent oxygen desaturation by terminating shunt physiology it would be a leap of faith to suggest that it would have any impact on the upper airway collapsibility, responsible for the obstructive events .
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