Patent foramen ovale: assessment, clinical significance and therapeutic options.

Abstract: Foramen ovale plays an important function in the fetus but is of no physiologic significance after birth and closes in most individuals. In about one fourth of the population, however, foramen ovale remains open for life and has been associated with cerebrovascular accidents, especially in younger patients, presumably through paradoxical embolism. Patent foramen ovale (PFO) has also been associated with hypoxia, migraine headaches and neurologic findings of decompression illness in scuba divers. Availability of transesophageal echocardiography and its frequent use in the management of patients with stroke has lead to frequent detection of PFO. In addition, the recent development of devices and techniques for percutaneous closure of PFO has resulted in widespread enthusiasm for such interventions, even when a clear etiologic role for PFO may not be established. In the United States, the Federal Drug Administration (FDA) has approved two such devices through compassionate investigational device exemption without adequate data from large randomized clinical studies. Other such devices are undergoing evaluation in clinical trials. Expert opinions have been helpful for clinical decision making in management of patients with PFO associated with stroke, hypoxia, decompression sickness and migraine headaches.

Key Words: patent foramen ovale, atrial septal defect, percutaneous closure, cerebrovascular accident, paradoxical embolism

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In humans, birth is primarily a cardiorespiratory event. The fetus has outgrown its insufficient circulatory dependence on the mother and needs an effective oxygen delivery system; the umbilical cord clamps off, the lungs aerate, the ductus arteriosus involutes, and the foramen ovale seals shut. In as many as a fourth of the population, however, the foramen ovale fails to close. Such a patent foramen ovale (PFO) was first described in 1564 by Leonardi Botali and in 1877, Cohnheim described paradoxical embolism due to PFO. (1) An autopsy study has indicated that the size of the PFO increases from a mean of 3.4 mm in the first decade to 5.8 mm in the 10th decade of life due to the stretching effect of aging on the valve of fossa ovalis. (2) The prevalence of PFO detected by echocardiographic contrast studies has ranged from 10 to 15%, whereas autopsy studies have identified PFO in about one fourth of adults, likely due to direct visualization of the defect rather than relying on pressure differences between the two atria. (2)

Embryologically, fossa ovalis membrane is the only remnant of septum primum, the membrane that first forms to divide the left and right atria. The remaining portion of this membrane is resorbed as septum secundum forms the actual atrial septum, to the right of septum primum, with an opening in its mid-posterior section corresponding to the foramen ovale. Fossa ovalis membrane remains partly open during intrauterine life, in a valve-like manner, to allow highly oxygenated blood to reach the left atrium from the inferior vena cava. High right atrial pressure in the fetus keeps the valve of foramen ovale open. As the surface area of the fossa ovalis membrane is larger than that of the foramen ovale, shortly after birth, the left atrial pressure rises and the flap of the fossa ovalis membrane is lightly pushed against the septum secundum and closes the foramen ovale functionally. Hoffman and Kaplan (3) also suggested that an atrial left-to-right shunt resulting from an incompetent foramen ovale might exist in children without heart disease for more than a year, with eventual closure later in life. Anatomic patency may occur for several months and 50% of all infants have a probe-patent PFO at the end of the first year of life. (4) In 25% of the population, anatomic closure never occurs. Formerly regarded as an anatomic variant, often found at autopsy and of little or no consequence, PFO is now implicated in the etiology of cryptogenic stroke secondary to paradoxical embolism, platypnea-orthodeoxia syndrome, neurologic decompression illness in scuba divers, and migraine headaches, especially when accompanied with aura. The advent of transesophageal echocardiography with agitated saline contrast has lead to increased premortem diagnosis of PFO. In addition, the availability of devices for percutaneous closure of PFO has revolutionized treatment of these defects without a need for open heart surgery in the majority of patients.

Clinical Significance

Even though the foramen ovale may remain open in some individuals, shunting through this potential opening is prevented by higher than normal pressure in the left compared with the right atrium and by gravitational forces as the left atrium is situated cephalad to the right atrium. The combination of these two factors keeps the valve of foramen ovale closed. However, it is likely that transient reversal of gradient occurs in early systole as the mitral annulus begins its descent toward the left ventricular apex shortly before the tricuspid annulus descent, thus creating a vacuum effect. This reversal of gradient is thought to be responsible for paradoxical embolism in some patients with PFO and normal intracardiac pressures. Alternatively, a transient (eg, Valsalva maneuver) or persistent (eg, pulmonary embolism, cor pulmonale, right ventricular infarction) elevation of right atrial pressure may favor right-to-left shunt. (5) In addition, left atrial enlargement as frequently seen in hypertensive, ischemic and valvular heart disease may stretch the flap valve of the foramen ovale and create a "valvular incompetent" PFO that remains open in all phases of the cardiac cycle. In otherwise healthy individuals, there are generally no signs or symptoms from PFO. Rarely, intermittent cyanosis is present on crying or straining at stools in infants; otherwise PFO is associated with normal health.

Association with Congenital Heart Disease 

Many patients with Ebstein anomaly have a PFO. (6,7) This may be due to right atrial distention caused by tricuspid regurgitation, which prevents complete closure of the valve of foramen ovale. In severe pulmonic stenosis, shunting through a PFO may result in central cyanosis. (8-10) In tricuspid atresia, venous return often finds access to systemic circulation through a restrictive PFO. (11) Other forms of congenital heart disease are also associated with a PFO. These include pulmonary atresia with an intact ventricular septum, a large patent ductus arteriosus, congenital mitral stenosis, mitral regurgitation, or ventricular septal defect, tricuspid valve stenosis, right ventricular hypoplasia and pulmonary hypertension. PFO can act as an obligatory shunt in mitral atresia in the left-to-right direction, while acting as a right-to-left shunt in tricuspid atresia and anomalous pulmonary venous connections. Left-to-right shunting through a PFO generally causes no signs or symptoms until later in life, while right-to-left shunt can cause cyanosis, especially with Valsalva maneuver. Persistent cyanosis may be present during the neonatal period until pulmonary vascular resistance falls. In older patients with PFO, systemic oxygen desaturation may occur in conditions that transiently or persistently elevate right atrial pressure. The extent of hypoxemia in such cases is dependent on the size of the PFO, pressure gradient between the atria, as well as the direction of the inferior vena cava blood flow. The presence of a eustachian valve often favors direct streaming of inferior vena cava blood toward foramen ovale.

PFO and Neurologic Problems. As mentioned earlier, PFO is a common finding in the healthy population (2) and the most common cardiac finding in young patients (<55 years of age) with cryptogenic stroke, presumably through paradoxical embolism. (12) A recent meta-analysis of case-control studies has confirmed the increased prevalence of PFO in young patients with cryptogenic stroke (odds ratio, 5.01; 95% confidence interval, 3.24-7.75) compared with persons 55 years of age or older (odds ratio, 1.20; 95% confidence interval, 0.56-2.56). (13) A significant association between PFO and cryptogenic stroke has also been shown in a prospective study in which the diagnosis of PFO was made without knowledge of the clinical history. Despite this association, the etiologic role of patent foramen ovale in cryptogenic stroke has been questioned. (14,15) Also, in support of the "paradoxical embolism" theory, various studies have demonstrated thrombus straddling the foramen in rare patients with deep vein thrombosis and systemic embolism. (16) In most patients, however, determining whether paradoxical embolism has occurred through a PFO requires the presence of the triad of elevated right atrial pressure, a venous source of thrombosis, and a PFO. (17) Conditions that promote right-to-left shunting, such as pulmonary hypertension or Valsalva-inducing activities, are occasionally documented in patients with PFO and stroke. (18) Also, deep vein thrombosis, especially in the frequently disregarded calf and pelvic area has been found in some patients. (19,20) The incidence of stroke in association with a PFO is higher in those with larger defects, (21) with increased right-to-left shunting, (22) shunting at rest or increased septal mobility, (23) as well as the presence of an atrial septal aneurysm. (24) In situ thrombus formation, within a redundant fossa ovalis membrane has also been suggested as a mechanism for paradoxical embolism. (25) Several studies have also shown an association between PFO and prothrombotic states such as factor V Leiden and prothrombin A (G 202010) gene mutation.

Migraine Headaches. In some cases of migraine headache with aura, patients have been found to have a PFO and their headaches improved with medical treatment in the form of antiplatelet and anticoagulant drugs or upon closure of the PFO. (26,27) The question whether or not true migraine or migraine-like symptoms are due to transient ischemic attacks or paradoxical embolism is not yet resolved.

Neurologic Decompression Sickness. PFO is associated with neurologic decompression sickness. (28,29) In scuba divers there is an increased risk of nitrogen gas embolism across PFO. As only a small percentage of scuba divers with PFO develop decompression sickness, screening of all scuba divers is controversial. PFO can worsen hypoxemia in scuba divers at great depths and can lead to death, especially in inadequately trained divers. (30)

Obstructive Sleep Apnea 

PFO increases the risk of hypoxemia during sleep in obstructive sleep apnea as there is transient elevation of right atrial pressure with augmentation of right to left shunt leading to systemic arterial desaturation. (31,32)

Cardiac Surgery

PFO is associated with increased risk of postoperative atrial fibrillation and may worsen hypoxemia, especially in off-pump coronary artery bypass surgery. (33,34)

Diagnosis of Patent Foramen Ovale

Transesophageal echocardiography (TEE) is superior to transthoracic echocardiography (TTE) and is considered the imaging procedure of choice for detection of PFO. (35-37) During TEE, agitated normal saline contrast is typically injected into a peripheral vein during the strain phase and the atrial septum is imaged during the release phase of a Valsalva maneuver. Care needs to be taken to perform the contrast study at a time when the patient is relatively awake and can perform an adequate Valsalva maneuver. Currently, no standard definition for PFO identification and quantification exists, although large trials have proposed some guidelines (French PFO-ASA Study 2001, Patent Foramen Ovale in Cryptogenic Stroke Study (PICSS) 2002). The amount of right-to-left contrast shunting is dependent on the expiratory pressure during the Valsalva maneuver and the magnitude of contrast shunting does not necessarily correlate with the true anatomic size of the PFO. (38-40) Some have advocated the use of a foot vein for administration of saline bubbles because of the difference in blood flow orientation between the superior and inferior vena cava. (41,42) Although the timing of the appearance of saline microbubbles in the left atrium after a complete right atrial opacification (within 3 cardiac cycles), has been used to distinguish PFO from pulmonary arteriovenous malformations, this may not always be reliable. (43-45) Transcranial Doppler is an alternative method for detecting a PFO and is considered by some to be superior to the use of two-dimensional echocardiographic imaging of the atrial septum after IV injection of saline contrast medium. (46)

New Trends in PFO Management

Paradoxical embolism via a PFO has been implicated as the most likely mechanism of stroke in cryptogenic stroke/TIA, and therefore, therapeutic measures for secondary prevention are intended to eliminate thrombus formation, paradoxical embolization, or both. Different treatments have been used to prevent thromboembolic events in patients with cryptogenic stroke or TIA due to PFO.

Medical Therapy

Pending randomized controlled trials, aspirin has been recommended for treatment of patients with only a PFO and no other risk factors for stroke, as the annual risk of stroke is less than 1%. If the PFO is associated with an atrial septal aneurysm, hypercoagulable state, cryptogenic stroke or deep vein thrombosis, data is insufficient to make firm recommendations. The options for management of such patients include long-term antiplatelet treatment (including combination of aspirin and clopidogrel), long-term anticoagulation with warfarin (with an annual major bleeding risk of 2%), or percutaneous/surgical closure of the PFO. Mas and Zuber (47) retrospectively evaluated 132 patients younger than 60 years, treated using either aspirin (250-500 mg) or oral anticoagulants (target INR 2-3) during a follow-up period of 23 months. The average annual rate of recurrence was 1.2% for stroke and 3.4% for the combined endpoint of TIA and stroke. In the Lausanne Stroke Registry, (48) 92 patients were treated with aspirin (250-500 mg/d) and 37 with oral anticoagulants (target INR 2-3). The average annual recurrence rate during a 3-year follow up was 1.9% for stroke and 3.8% for the combined endpoint of TIA and stroke.

Closure of PFO

A review of the available data, including the one presented by Windecker et al, (49) would seem to support the following recommendation: embolic stroke patients who are younger, have large PFOs, and who either fail anticoagulant therapy or can not take anticoagulants may be considered candidates for anatomic closure of PFO.

Percutaneous Device Closure

Because of the unacceptable risk of complications from long-term anticoagulation therapy in younger patients, percutaneous closure of PFO is favored by many pending appropriate clinical trials. The general recommendations for percutaneous PFO closure in younger patients with cryptogenic stroke are the presence of an associated atrial septal aneurysm (annual risk of recurrent stroke 4% on aspirin), clinical or imaging evidence of unexplained stroke, recurrent stroke or transient ischemic attack on antithrombotic therapy, or deep vein thrombosis before the stroke. The general indications for percutaneous device closure of PFO are listed in Table 1. Following percutaneous PFO closure, antiplatelet and warfarin anticoagulation is recommended for six months. The Federal Drug Administration has approved two percutaneous devices for PFO closure:

(1) CardioSEAL Septal Occlusion System (NMT Medical Inc., Boston, MA) is a double umbrella-shaped permanent implant, which is made of a metal (MP35N) framework to which polyester fabric is attached. The CardioSEAL implant is available in sizes 17 mm, 23 mm, 28 mm and 33 mm. It requires a 24 to 48 hour hospitalization after placement.

(2) Amplatzer PFO Occluder (AGA Medical Corp, Golden Valley, Minn) is an occluder made of self-expanding wire mesh with double discs. It contains inner polyester fabric patches that, along with the wire mesh, cause the formation and accumulation of a blood clot which actually seals the opening. After the device is in place, tissue will grow over it, and the device then becomes part of the atrial septum. It also requires a 24 to 48 hour hospitalization.

A third device, the PFO STAR (Cardia, Burnsville MN) closure device is now being investigated in clinical trials. A complete list of percutaneous PFO closure devices can be found in Table 2.

These septal occluder devices are inserted through the femoral vein and deployed under transesophageal echo (TEE) or intracardiac echo guidance into the PFO. Later, clot formation at the device implantation site and subsequent fibrosis leads to permanent PFO closure.

Percutaneous PFO closure was initially reported by Bridges et al, (50) who treated 36 patients (mean age 39 years) with a clamshell device. Eight patients had a residual shunt after the procedure. During a mean follow up of 8 months, 4 patients experienced a TIA.

Windecker et al (51) studied 80 patients (mean age 52 years) with PFO and at least one paradoxical event. Five different devices were used. During 5 years of follow up (mean 1.6 year) the actuarial annual risk of a recurrent thromboembolic event was 2.5% for TIA, 0% for stroke, 0.9% for peripheral emboli, and 3.4% for the combined endpoint of stroke and transient ischemic attack. Presence of a postprocedural shunt was predictive of recurrent paradoxical embolism (relative risk 4.2, 9.5% confidence interval, 1.1-17.8).

A comprehensive literature review identified 10 studies involving 1355 stroke patients treated with transcatheter PFO closure and 6 studies involving 895 medically treated patients. (49,52) The one year rate of recurrent neurologic events ranged from 0 to 4.9% with the percutaneous closure group and 3.8 to 12% with the medical therapy group. In none of these studies were patients randomized nor was clinical endpoint assessment blinded.

To our knowledge, no randomized controlled trial of a PFO closure device has been completed, although at least 4 randomized trials are being conducted to study the safety and effectiveness of specific devices in preventing recurrent strokes in patients with a PFO and first cryptogenic stroke. (53,54) Although the acute success rate of PFO closure device placement exceeds 95%, incomplete closure may occur in 20% of the patients. (55) Complications of device implantation occur in 6 to 10% of patients and include device embolization or fracture, air embolism, pulmonary embolism, bleeding requiring transfusion, infection, perforation of atrial wall, cardiac tamponade and death. (49,52) The incidence of long-term complications such as atrial fibrillation and recurrent neurologic events is poorly defined. Contraindications to device placement include active infection at the site of catheter insertion, systemic infection and blood clots in the vein or a very narrow vein causing difficulty in implanting the device. MRI or metal detectors do not affect these implants, as they are not metallic in nature.

Surgical Closure

Surgical closure is recommended when the PFO is more than 25 mm in size, when there is an inadequate rim of tissue around the defect, or in cases of percutaneous device failure. The main advantage of surgical closure is that it provides a permanent closure of the defect, thereby preventing future paradoxical emboli without the risks associated with long-term anticoagulation. The major disadvantage is that surgical closure requires general anesthesia, open-heart surgery and a hospital stay of several days. Furthermore, it can be associated with complications such as pericardial effusion or tamponade, postpericardiotomy syndrome, atrial arrhythmia and surgical wound infection. (56-59) Surgically, the PFO is closed either by double continuous suture or by Dacron or pericardial patches. This is done through a median sternotomy, a limited right thoracotomy or mini-sternotomy. Homma et al (56) studied 28 patients (mean age 41 years) who underwent surgical PFO closure by open thoracotomy. In his study group the recurrent stroke /TIA rate was 20% at 13 months. Guffi et al (57) had 11 patients (mean age 39.4 years) with surgical PFO closure. None experienced recurrence of thromboembolic events during a median follow up of 12.2 months. Similar results were obtained by Ruchat et al, (58) who surgically treated 59 patients with a mean age of 42 years. Dearani et al (59) retrospectively studied 91 patients (mean age 42 years) who underwent surgical PFO closure (also see Table 1 (60-62)). The median follow up was 2 years. No transient ischemic attack or stroke was observed at 1 and 4 years of follow up in 92% and 83% of patients respectively.

Prognosis

The patient's prognosis depends upon underlying cardiac defects, but is good in isolated PFO. Associated congenital heart disease such as Ebstein anomaly result in an increase in the size of the PFO with the growth of the child that increases the right-to left shunt, especially with exercise.

Conclusions

As PFO is present in one-fourth of the population, awareness of this defect is of importance to all physicians. Usually a part of other congenital heart malformations, it may cause neurologic disorders including cryptogenic stroke and may even be responsible for migraine headaches in some patients. New devices have been introduced which can effectively seal this hole in the heart, thus preventing its potential complications in high-risk patients.

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Farhan Aslam, MD, Jamshid Shirani, MD, and Attiya Anwar Haque, MD

From the Departments of Internal Medicine and Cardiology, Geisinger Medical Center, Danville, PA.

Reprint requests to Farhan Aslam, MD, Department of Internal Medicine, Geisinger Medical Center, 100 North Academy Avenue, Danville, PA 17822. Email: [e-mail]

Accepted March 15, 2006.

RELATED ARTICLE: Key Points

** Interatrial communication through a patent foramen ovale (PFO) is reported in about one fourth of the adult population.

** PFO is a common finding in the healthy population and the most common cardiac finding in young patients (<55 years of age) with cryptogenic stroke, presumably through paradoxical embolism.

** In situ thrombus formation, within a redundant fossa ovalis membrane has also been suggested as a mechanism for paradoxical embolism.

** In some cases of migraine headache with aura, patients have been found to have a PFO and their headaches improved with medical treatment in the form of anti-platelet and anticoagulant drugs or upon closure of PFO.

** Transesophageal echocardiography (TEE) is superior to transthoracic echocardiography (TTE) and is considered the imaging procedure of choice for detection of PFO.

Table 1. Indications for PFO closure

** Current approved recommendation: Closure of PFO in patients who have
   recurrent cryptogenic stroke due to presumed paradoxical embolism
   through a PFO and who have failed conventional drug therapy
** Other PFO closure "off-label" uses or indications that are under
   investigation:
   - Cryptogenic stroke due to presumed paradoxical embolism through a
     PFO
** After the first clinical event
** Patients who have contraindications to anticoagulant treatment
** As an alternative to medical therapy or surgical closure
   - Cryptogenic TIA due to presumed paradoxical embolism through a PFO
** Presumed paradoxical peripheral or coronary arterial embolism through
   a PFO
** Cryptogenic stroke, TIA, or peripheral or coronary embolism due to
   presumed paradoxical embolism through a PFO that is associated with a
   hypercoagulability state
   - Divers with a PFO who are at risk of clinical events that are
     related to paradoxical embolism through a PFO during decompression
     (*Knauth et al, 1997)
   - Systemic deoxygenation due to right-to-left shunting through a PFO
     in the absence of severe pulmonary hypertension (eg, platypnea
     orthodeoxia, right ventricular infarction) (*Begin et al, 1981)
   - Migraine headaches accompanied by aura (*Azarbal et al, 2005)
   - Posttraumatic fat embolism syndrome with cerebral embolism by way
     of PFO

PFO, Patent foramen ovale; TIA, Transient ischemic attack.
*Knauth et al, (60) Begin et al, (61) Azarbal et al. (62)

Table 2. Percutaneous devices used for closure of PFO

1)  CardioSEAL* (Nitinol Medical Technologies, Boston, MA)
2)  STARFlex (Nitinol Medical Technologies, Boston, Massachusetts, USA)
3)  Angel Wings (Guardian Angel) device (Microvena Corp, Whitebear Lake,
      Minnesota, USA)
4)  Sideris buttoned device (Custom Medical Devices, Amarillo, Texas,
      USA)
5)  Amplatzer PFO occluder* (AGA Medical Corp., Goldenvalley, Minnesota)
6)  PFO STAR (Cardia, Burnsville, Minnesota, USA)
7)  Helex septal occluder (WL Gore and Associates, Flagstaff, Arizona,
      USA)

PFO, patent foramen ovale.