Introduction

Obstructive sleep apnea (OSA) may occur in 5-15 % of the middle-aged population and is associated with significant proven cardiovascular consequences.¹ It is characterized by intermittent hypoxia occurring during sleep, which induces hypoxic pulmonary vasoconstriction resulting in increased right atrial pressure. OSA also confers an increased incidence of hypertension, nocturnal arrhythmias and hematological disturbances, thus increasing the risk of stroke and cardiovascular morbidity. Patent foramen ovale (PFO) is a congenital cardiac defect present in approximately 25% of healthy adults.² In patients with PFO, it can lead to a right-to-left shunt, which may also provide the nidus for systemic embolization.³ PFO is usually asymptomatic and OSA also remains frequently undiagnosed. This explains the fact that the association of both of these pathologies is poorly known and little studied.

In this review we will try to seek answer to the following questions,

1. Do patients with severe OSA have a higher prevalence of PFO compared to healthy individuals?
2. Does PFO combined with OSA result in higher risk of stroke?
3. Does PFO closure result in improvement of OSA symptoms?

First, we will summarize the studies addressing each of the above questions, followed by a short discussion.

1. Do patients with severe OSA have a higher prevalence of PFO compared to healthy individuals?

Few studies have evaluated the relationship between PFOs and OSA.

A case control study by Shanoudy et al. compared 48 males with OSA with 24 control male patients.⁴ The study found the following:

• Prevalence of PFOs in patients with OSA was greater compared with controls with no OSA (65% vs. 17%, p + 0.0001).
• Patients with OSA in the presence of PFOs had significant hypoxia compared to controls (69% vs. 17%, p = 0.007).
• With Valsalva maneuver , OSA patients with PFO had increased desaturations (-2.0 ± 1.3 vs. -0.9 =/- 0.7, p + 0.0002)
• Pulmonary arterial systolic pressure was significantly increased in the OSA group (32.0 =/- 10.3 mm Hg vs. 22.0 ± 6.3 mm hg, p = 0.003).

A case controlled study by Johansson et al. evaluated the severity of oxygen saturation in patients with OSA (n = 209) in the presence and absence of PFOs.¹ The study found the following:

• Patients with large PFOs had higher oxygen desaturation (9/15, 60%, p = 0.002) compared with the low desaturation group (2/15, 13%).
• Study concluded that oxygen desaturation occurred to a higher degree in OSA patients with PFOs who developed frequent respiratory disturbances compared with OSA patients without PFOs.

However, in contrast to the above studies, Lau et al. showed that degree of right-to-left shunting from a PFO did not significantly impact oxygen desaturation even though an increased prevalence of PFO was found in OSA patients.⁵

2. Does PFO combined with OSA result in higher risk of stroke?

Case reports of two patients by Ozdemir et al. describe cryptogenic strokes in two patients. Both of them were later found to have PFOs.⁶

A Cohort study by Guchlerner et al. reports a greater incidence of right-to-left shunting in the presence of a PFOs with concomitant OSA.⁷ They concluded that such an association may possibly enhance the probability of stroke.

3. Does PFO closure result in improvement of OSA symptoms?

A case report by Silver et al. showed improvement of sleep apnea symptoms and a major reduction in apnea and disappearance of hypopnea episodes, after PFO closure.⁸

Another similar case by Agnoletti et al. showed disappearance of OSA symptoms and exercise related dyspnea after PFO closure.⁹

A recent prospective study by Shaikh et al. evaluated the effects of percutaneous PFO closure via transthoracic echocardiogram (TTE) and transcranial Doppler in patients with large shunts who also had severe OSA.¹⁰ A total of 150 patients were followed over the period of 12 months, 100 had severe OSA (apnea-hypopnea index [AHI] 54 ± 18 events/hour) and 50 controls (AHI = 2 ± 2 events/hour). A subgroup of patients with OSA with large shunts underwent percutaneous PFO closure with the following results:

• PFO prevalence was 43% in patients with OSA and 30% in control subjects (p = 0.16).
• Large shunts were detected in 18% of patients with OSA and 6% in control subjects (p = 0.049).
• Patients with OSA with clinically significant shunts had higher oxygen-desaturation index (ODI)/AHI ratios than patients without (ratio, 1.05 [0.27] vs. 0.86 [0.26], P = 0.004).
• Six patients with OSA underwent PFO closure, which was not associated with a reduction in ODI (baseline, 48 [18]; 12 months, 51 [19] events/h; P = 0.92) or percentage of the night with arterial oxygen desaturation, 90% (baseline, 23% [16%]; 12 months, 20% [22%]; P = 0.35).

Discussion/Conclusion

The epidemiologic studies thus far do point to the fact that PFO prevalence is likely to be higher in OSA patients. These patients may also be susceptible to greater nocturnal oxygen desaturation during sleep. It is also to some extent evident that if OSA is diagnosed and patient has a history of cryptogenic stroke, evaluation of PFO should be considered. If OSA and PFO co-exist, OSA can hypothetically provoke the hemodynamic conditions necessary to induce right-to-left shunting via a PFO. Only case reports show that PFO closure may be beneficial in OSA patients and a prospective study refutes these findings. However, it consisted of only six patients, so there is no conclusive evidence proving or disproving a benefit of PFO closure in OSA patients. We also have trials such as CLOSURE I and RESPECT not showing the benefit of PFO closure over medical therapy, for stroke prophylaxis.^11,12 Therefore, PFO closure for stroke prophylaxis in general, is not recommended.

Further research in the cerebrovascular effects of the concomitant presence of a PFO with OSA and the benefit of PFO closure in OSA patients is required.

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References

1. Johansson MC, Eriksson P, Peker Y, et al. The influence of patent foramen ovale on oxygen desaturation in obstructive sleep apnoea. Eur Respir J 2007;29:149-55.
2. Fisher DC, Fisher EA, Budd JH, et al. The incidence of patent foramen ovale in 1,000 consecutive patients. A contrast transesophageal echocardiography study. Chest 1995;107:1504-9.
3. Lau EM, Yee BJ, Grunstein RR, Celermajer DS. Patent foramen ovale and obstructive sleep apnea: a new association? Sleep Med Rev 2010;14:391-5.
4. Shanoudy H, Soliman A, Raggi P, et al. Prevalence of patent foramen ovale and its contribution to hypoxemia in patients with obstructive sleep apnea. Chest 1998;113:91-6.
5. Lau EM, Jaijee SK, Melehan KL, et al. Prevalence of patent foramen ovale and its impact on oxygen desaturation in obstructive sleep apnea. Int J Cardiol 2013;165:35-40.
6. Ozdemir O, Beletsky V, Hachinski V, Spence JD. Cerebrovascular events on awakening, patent foramen ovale and obstructive sleep apnea syndrome. J Neurol Sci 2008;268:193-4.
7. Guchlerner M, Kardos P, Liss-Koch E, Frankie J, Wunderlich N, Bertog S, et al. PFO and right-to-left shunting in patients with obstructive sleep apnea. J Clin Sleep Med 2012;8:375-80.
8. Silver B, Greenbaum A, McCarthy S. Improvement in sleep apnea associated with closure of a patent foramen ovale. J Clin Sleep Med 2007;3:295-6.
9. Agnoletti G, Iserin L, Lafont A, et al. Obstructive sleep apnoea and patent foramen ovale: successful treatment of symptoms by percutaneous foramen ovale closure. J Interv Cardiol 2005;18:292-5.
10. Shaikh ZF, Jaye J, Ward N, et al. Patent foramen ovale in severe obstruction sleep apnea: clinical features and effects of closure. Chest 2013 143:56-63.
11. Furlan Aj, Reisman M, Massaro J, et al. Closure or medical therapy for cryptogenic stroke with patent foramen ovale. N Engl J Med 2012;366:991-9.
12. Carroll JD, Saver JL, Thaier DE, et al., on behalf of the RESPECT Investigator Closure of patent foramen ovale versus medical therapy after cryptogenic stroke. N Engl JMed 2013;368:1092-100.

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