This article reviews the main clinical aspects of patent foramen ovale (PFO), such as its prevalence in the population, the diagnostic techniques to detect its presence, its role as a risk factor for ischemic stroke of otherwise unexplained origin, and its controversial association with migraine. Some cofactors possibly involved in the association between PFO and stroke are discussed, along with the various therapeutic options to prevent recurrent cerebral ischemic events in stroke patients with a PFO.
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Target Audience
This activity is designed for all cardiovascular physicians and cardiac sonographers with a primary interest and knowledge base in the field of echocardiography; in addition, residents, researchers, clinicians, intensivists, and other medical professionals with a specific interest in cardiac ultrasound will find this activity beneficial.
Target Audience
This activity is designed for all cardiovascular physicians and cardiac sonographers with a primary interest and knowledge base in the field of echocardiography; in addition, residents, researchers, clinicians, intensivists, and other medical professionals with a specific interest in cardiac ultrasound will find this activity beneficial.
Objectives
Upon completing the reading of this article, participants will better be able to:
- 1.
Describe the anatomy of a patent foramen ovale (PFO) and how this abnormality may be the source of a cryptogenic stroke.
- 2.
Identify the diagnostic techniques utilized in assessing a PFO, and understand the strengths, weaknesses, and technical considerations for each technique, especially saline contrast injections.
- 3.
Characterize associated findings that can increase the risk for paradoxical embolization in patients diagnosed with PFO.
- 4.
Define current treatment options and associated risks and benefits of each.
Frequency of Patent Foramen Ovale in the General Population
The foramen ovale is a normal and quite important component of the fetal circulation, allowing oxygenated blood to cross from the right atrium into the left atrium, because blood flow through the fetal lungs is absent. The two components of the interatrial septum, the septum primum and secundum, fuse after birth in most individuals. However, in some individuals, a small communication may persist in the fossa ovalis region, giving origin to a PFO. The frequency of PFOs in the general population has been estimated at 15% to 35% in autopsy studies. The prevalence of PFOs appears to decrease with age, whereas the average size of PFOs appears to increase, both circumstances that suggest that some small PFOs may spontaneously close during life. The size of a PFO, expressed as the maximum opening of the interatrial communication, may vary from 1 mm to >1 cm in diameter; its surface area has been reported to range from 0.2 to 1.5 cm 2 . A condition often associated with a PFO is an atrial septal aneurysm (ASA), a localized outpouching of a redundant atrial septum with phasic septal excursion into either atrial chamber during the cardiac cycle. Although prevalence is influenced by both diagnostic criteria (10 vs 15 mm of excursion; see criteria later in this review) and diagnostic technique (transthoracic echocardiography [TTE] vs transesophageal echocardiography [TEE]), ASA is infrequently observed in the general population (approximately 1%-4% of subjects). However, when present, ASA is associated with PFOs in >60% of patients.
Detection of Patent Foramen Ovale
Unlike an atrial septal defect, which is a fixed opening in the atrial septum that allows the bidirectional passage of blood between the atria, flow across a PFO is more typically functional and therefore dependent on relative pressures in the two atria. With the occasional exception of patients in which PFOs are “stretched” and may allow bidirectional shunts to occur, the two components of the atrial septum overlap, and right-to-left interatrial shunting may occur only when the pressure in the right atrium exceeds the pressure in the left atrium ( Figure 1 , Video 1 ; view video clip online.). Therefore, the methods used to detect a PFO in vivo are based on the detection of a right-to-left shunt, at rest or with the aid of maneuvers that increase right atrial pressure, such as the Valsalva maneuver or coughing.
The diagnostic techniques most commonly used for PFO detection are TTE, TEE, and transcranial Doppler (TCD), all performed with saline solution as a contrast agent. Agitated saline is usually prepared by mixing 0.5 to 1 mL of air with 9 mL of normal saline using two syringes connected by a 3-way stopcock. A small amount of the patient’s blood can be added to the mix to increase the contrast effect. Polygelatine agents have been substituted for saline solution in some studies, with a possible but not well-established improvement in sensitivity for PFO detection. The contrast agent is rapidly injected into an antecubital vein, and a right-to-left shunt is sought (see below for details). Because the blood flows more directly toward the atrial septum, injection in a femoral vein is associated with a greater frequency of PFO detection than injection in an arm vein but it is rarely used in clinical practice and was not used in the case-control studies on which the assessment of the PFO-related stroke risk was based.
A contrast study is considered positive for right-to-left shunting when any microbubble is seen in the left-sided chamber after the contrast material fills the right-sided chambers. To make the diagnosis more specific, some authors have used the presence of ≥3 microbubbles in the left-sided chambers as a criterion to diagnose a shunt. However, there is no evidence that this definition works better than the presence of any microbubble for the prediction of future embolic events than the presence of any microbubble. At my institution, we prefer to use “any microbubble” for the diagnosis, because other definitions tend to emphasize the concept of amount rather than the presence of a shunt, whereas a shunt is an “all-or-nothing” event that can be heralded by the demonstration of even a single shunting microbubble.
An adequate Valsalva maneuver should be obtained from the patient, because the transient increase in right atrial pressure that occurs during the maneuver may unmask the presence of a PFO not detected at rest. Particular attention should be paid to the bowing of the septum toward the left side, because this represents a proof of an actual increase of right atrial pressure compared with the resting condition. Several contrast injections should be performed at rest and during Valsalva maneuver or coughing, because the PFO detection rate may increase with repeated injections; 5 injections under different conditions (rest, Valsalva maneuver, and coughing) have been recommended.
TEE is considered the gold standard for the diagnosis of PFO, with up to 100% sensitivity and specificity when both color Doppler and contrast evaluation are performed. In fact, the prevalence of PFO in a transesophageal echocardiographic study on a sample of the general population was found to be 24.3%, very similar to that reported in autopsy studies. TEE also affords the direct visualization and measurement of PFO openings in most patients ( Figure 2 A, Video 2 ; view video clip online.), the semiquantitative assessment of the shunt (by count of the shunting microbubbles; Figure 2 B, Video 2 ;
view video clip online.), and the differentiation from a shunt caused by transpulmonary recirculation, a source of PFO misdiagnosis that can be avoided by TEE through the direct visualization of the PFO and pulmonary veins.
TEE can also identify the presence of an ASA very accurately ( Figure 3 , Video 3 ; view video clip online.). A protrusion of the septum of ≥10 mm is generally considered diagnostic of ASA, although other studies have suggested excursions of 11 mm and 15 mm as cutoffs, as well as a base width of the aneurysm of ≥15 mm instead of 10 mm. Because no definition has been shown to be more accurate in the prediction of embolic risk, the 10-mm cutoff for both base width and excursion (resulting in a slightly higher prevalence of ASA than the larger cutoffs) appears to be a reasonable choice. In any case, the excursion should be measured by adding the maximum excursions of the septum from the midline into either atrial chamber.
Although major complications arising from the performance of TEE are infrequent (0.2% of patients in a large series ), the test is semi-invasive and requires conscious sedation, characteristics that make it unsuitable for PFO screening and more appropriate in cases that are diagnostically equivocal, or when the morphologic characterization of the PFO is necessary (for example, when PFO closure is entertained). In addition, when excessive sedation is administered, the patient may be less able to perform an effective Valsalva maneuver, thus potentially lowering the sensitivity of the test for PFO detection. For screening purposes, TTE or TCD with contrast is used. TTE during contrast injection ( Figure 4 ) has lower sensitivity for PFO detection compared with TEE (50%-60%), but this is due largely to inadequate imaging windows (a possible indication to proceed to TEE) or to the presence of small PFOs with small associated shunts, which may be less important from a clinical standpoint. Probably because of the lower sensitivity of TTE for detecting small shunts, the prevalence of PFOs in a sample of the general population was reported to be 14.9%, lower than in TEE-based studies. Because the direct visualization of the PFO opening is not obtained by TTE, the distinction between a PFO and an intrapulmonary shunt is made empirically on the basis of the timing of microbubbles appearance in the left-sided chambers (within 3 cardiac cycles from complete opacification of the right atrium for PFO; delayed appearance in the case of an intrapulmonary shunt). Saline contrast using transmitral pulsed-wave Doppler has been used to quantify PFO functional size. An ASA can also be visualized by TTE ( Figure 4 ), although with less sensitivity than by TEE, especially for small aneurysms.
TCD with contrast injection can also detect the presence of a PFO. On TCD, shunting microbubbles appear as spikes superimposed to the normal blood flow pattern in the middle cerebral artery ( Figure 5 ). The sensitivity of TCD for PFO detection has been shown to be intermediate between those of TEE and TTE, or just inferior to TEE, in some studies but essentially equivalent to TEE in others. Because the heart is not visualized by TCD, and the distance and time from the shunt to the point of detection (middle cerebral artery) is longer, the separation between the PFO and the intrapulmonary shunt may be difficult. Obviously, a potentially important disadvantage of TCD is that the coexistence of an ASA cannot be diagnosed. The performance of TEE should therefore be considered in patients with positive results on TCD when the location of the site of shunt is crucial, especially when a potential PFO closure is contemplated.
Patent Foramen Ovale, Atrial Septal Aneurysm, and Risk for Ischemic Stroke
The causes of ischemic stroke remain unknown in up to 40% of patients. These strokes, often termed “cryptogenic,” have been linked to the presence of PFOs, as mentioned above. The purported stroke mechanism is that the PFO would act as a conduit for paradoxical embolization, which is the embolization to the systemic arterial circulation (to the brain in the case of stroke) of a thrombus originating in the venous circulation. The existence of this mechanism is documented by the occasional detection of thrombus lodged in the PFO in patients with embolic events ( Figure 6 , Video 4 ; view video clip online.). However, the diagnosis remains presumptive in the vast majority of patients and based on the exclusion of other potential causes of cerebral embolism in the setting of an embolic-appearing stroke rather than on the actual demonstration of paradoxical embolization. The same association between PFO and stroke appears to differ depending on the source of the information, whether it is a sample of the general population or studies examining patients who already had first strokes.
General Population
The PFO-related risk for ischemic stroke in the general population (ie, in individuals tested for PFOs as part of population studies, as opposed to subjects tested because of recent embolic events) has been investigated in two community-based studies. In the Stroke Prevention: Assessment of Risk in a Community (SPARC) study, 577 volunteers underwent TEE to assess for cardiac embolic sources. The prevalence of PFOs was 24.3%. Over a median follow-up of 61 months, PFOs were found not to be independently associated with increased risk for cerebrovascular events after adjustment for other stroke risk factors (hazard ratio, 1.46; 95% confidence interval, 0.74-2.88).
In the population-based Northern Manhattan Study (NOMAS), 1100 stroke-free subjects underwent contrast TTE for PFO detection. PFO prevalence was 14.9%, reflecting the lower sensitivity of TTE compared with TEE. Over a mean follow-up period of approximately 80 months, PFOs were not found to be independently associated with ischemic stroke (hazard ratio, 1.64; 95% confidence interval, 0.87-3.09).
Although different in the cohort characteristics and in the methods used to detect PFOs, the two studies obtained remarkably similar results. Although slightly higher than in patients without PFOs, the risk for stroke in subjects with PFOs was not significantly different. These combined results suggest that the PFO-related stroke risk in the general population is low. Explanations for this observation could be that (1) PFO is truly not associated with stroke (a conclusion that clashes with results presented later in this review); (2) the sample sizes and/or follow-up durations of the two studies were not sufficient to detect a significant effect; or (3) the slight, nonsignificant risk excess seen in the PFO cohorts may have been driven by a minority of subjects at high risk, whose effect on the stroke risk of the overall PFO cohort was diluted, making the comparison in the overall study groups not significant. Whatever the explanation, and in the absence of reliable ways to predict which individuals with PFOs have high risk for strokes, any form of preventive treatment in asymptomatic subjects with PFOs detected incidentally appears unjustified given the present state of knowledge.
Case-Control Studies
The relationship between PFO and cryptogenic stroke was first described in patients aged <55 years or <40 years. Over the years, several studies using contrast TTE or TEE have confirmed the association between PFO and cryptogenic stroke in younger patients. Overall, the prevalence of PFOs in younger patients with strokes has been found to be increased by 4-fold in comparison with control subjects of the same sex and age ( Table 1A ).
| Study | N (patients) | Age | PFO (Cryptogenic) | PFO (Control) | P Value |
|---|---|---|---|---|---|
| Lechat | 26 | <55 | 54% (14/26) | 10% (10/100) | <.001 |
| Webster | 34 | <40 | 56% (19/34) | 15% (6/40) | <.001 |
| Cabanes | 64 | <55 | 56% (36/64) | 18% (9/50) | <.001 |
| De Belder ∗ | 39 | <55 | 13% (5/39) | 3% (1/39) | – |
| Di Tullio | 21 | <55 | 47% (10/21) | 4% (1/24) ∗∗ | <.001 |
| Hausmann | 18 | <40 | 50% (9/18) | 11% (2/18) | <.05 |
| Handke | 82 | <55 | 44% (36/82) | 14% (7/49) ∗∗ | <.001 |
| TOTAL | 45% (129/284) | 11% (36/320) | <.001 |
∗ Includes different stroke subtypes.
In older patients, the association of PFO with ischemic stroke risk has been more controversial. Early studies either supported or negated the existence of a significant association. A meta-analysis of case-control studies published until 2000 supported the association with stroke of PFO, ASA, and their combination in patients aged <55 years; in older patients, however, the association was still significant for ASA and the combination of PFO plus ASA, but not for PFO alone. Finally, a recent transesophageal echocardiographic study on a large number of patients supported the existence of an association between PFO and stroke in the older age group. After adjustment for age, aortic plaque thickness, hypertension, and coronary artery disease, PFO was strongly associated with cryptogenic stroke in both the younger (odds ratio, 3.70; 95% confidence interval, 1.42-9.65; P = .008) and the older (odds ratio, 3.00; 95% confidence interval, 1.73-5.23; P < .001) groups.
The combined data from all these studies suggest that an association between PFO and stroke risk is present in older patients but is not as strong as in younger ones ( Table 1B ). The prevalence of PFO in older patients is lower than in younger patients and increased by nearly 2-fold in comparison with age-matched controls (compared with a 4-fold increase in younger patients). However, stroke incidence increases significantly with age, and the attributable risk of PFO in the elderly may therefore be as big or bigger than in the younger.
| Study | N (patients) | Age | PFO (Cryptogenic) | PFO (Control) | P Value |
|---|---|---|---|---|---|
| De Belder ∗ | 64 | >55 | 20% (13/64) | 5% (3/56) | <.001 |
| Di Tullio | 24 | >55 | 38% (9/24) | 8% (6/77) ∗∗ | <.001 |
| Hausmann | 20 | >40 | 15% (3/20) | 23% (23/98) | NS |
| Jones | 57 | >50 | 18% (10/57) | 16% (29/183) | NS |
| Handke | 145 | >55 | 28% (41/145) | 12% (28/232) ∗∗ | <.001 |
| TOTAL | 25% (76/310) | 14% (89/646) | <.001 |
∗ Includes different stroke subtypes.
Associated Factors
Because PFOs are present in approximately one quarter of the general population, but only a small fraction of individuals with PFOs will have strokes, it is reasonable to believe that conditions may exist that increase the risk for paradoxical embolization through a PFO. Moreover, a recent meta-analysis of published studies using a Bayesian approach suggested that the presence of a PFO may be an incidental rather than causative finding in one third of patients with cryptogenic strokes and PFOs, again underscoring the possibility that associated factors may be important in increasing the risk for paradoxical embolization through a PFO. The identification of these cofactors might help identify a subgroup of individuals at high risk in whom preventive interventions might be addressed.
Certain anatomic characteristics of the atrial septum and of the right atrium have been suggested among potential cofactors. The size of the septal separation seen on TEE, although a rough representation of the PFO size, has been associated with increased stroke risk. Patients with presumed paradoxical embolization have been shown to have larger PFOs compared with controls, as assessed by contrast TTE, TEE, TCD, or cardiac catheterization. Additionally, large PFO size, defined as ≥2 mm in septal separation, has been shown to be more frequent in patients with strokes considered of embolic origin on the basis of brain imaging criteria, and PFO size ≥4 mm may be an independent risk factor for recurrent cerebrovascular events. The size of a shunt has been defined on the basis of the number of microbubbles counted in the left atrium in a single digital frame. A count > 10 has been considered large in some studies and moderate in others that have set the cutoff for a large shunt at 30 microbubbles. At this time, there is no evidence that either definition is more strongly associated with the stroke risk, but the >30 definition seems to have attained wide acceptance.
The presence of an ASA has also been associated with an increased risk for stroke, especially when it is associated with a PFO. Because this association is frequent, and PFO size tends to be larger in patients with ASAs, the stroke risk from an ASA is considered by many as secondary to the coexistent PFO. However, in a meta-analysis mentioned earlier in this section, the stroke risk was higher in subjects with PFOs plus ASAs than in those with either condition alone. Moreover, in patients with strokes aged <55 years treated with aspirin, the 4-year recurrent stroke rate in those with isolated PFOs (2.3%) was not significantly different from that of patients with PFOs (4.2%) but was markedly higher (15.2%) in those with combined PFOs and ASAs. Finally, a study with brain magnetic resonance imaging in 48 patients with cryptogenic strokes showed that patients with PFOs and ASAs more often had multiple acute brain lesions than patients with PFOs alone (53% vs 17%, P = .01) and that the difference persisted after adjustment for PFO size and degree of shunt and other vascular risk factors. Therefore, there may be more to the stroke risk associated with an ASA than the mere coexistence of a PFO. Other potential stroke mechanisms include in situ thrombus formation, which appears to be infrequent, and possibly a predisposition to the development of atrial arrhythmias, a circumstance that has been suggested but not definitely proved.
A prominent Eustachian valve (the remnant of the right valve of the fetal sinus venosus that directs the blood from the inferior vena cava to the fossa ovalis of the atrial septum) has been found to be more frequent in patients with suspected paradoxical embolism, although this has not been confirmed in other studies. A Chiari’s network (a network of threads and fibers variably connecting the Eustachian valve to other atrial structures, such as the Thebesian valve at the entrance of the coronary sinus and the crista terminalis in the upper portion of the atrium) is present in approximately 2% of the general population but is more frequently seen in patients with PFOs, ASAs, and unexplained arterial embolisms.
Hemodynamic conditions may also contribute in increasing the likelihood of a PFO to act as a conduit for paradoxical embolization. An increase in pressure in the right-sided cardiac chambers can enhance the risk for paradoxical embolization; therefore, conditions such as pulmonary embolism, right ventricular infarction, and severe tricuspid regurgitation have been associated with increased degree of shunting through a PFO. Patients on mechanical left ventricular assist device support also experience increased right-to-left shunting through the PFO, secondary to the decompression of the left-sided chambers.
Deep venous thrombosis may increase the risk for paradoxical embolization through a PFO. An increased prevalence of deep venous thrombosis in patients with cryptogenic strokes with PFOs has been reported but not confirmed in other studies. Pelvic vein thrombi were found more frequently in young patients with cryptogenic strokes than in those with defined causes of stroke. However, pelvic thrombi are not routinely sought in patients with cryptogenic stroke, therefore their actual frequency and relevance as a potential source for paradoxical embolization is uncertain. Also, the late performance of venous studies after a stroke and treatment with anticoagulation or thrombolysis immediately after a stroke may decrease the rate of detection of a venous thrombus. When a PFO and deep venous thrombosis coexist in a patient with acute ischemic stroke, systemic anticoagulation becomes mandatory, as discussed later in this review.
A prothrombotic state may increase the likelihood of thrombus formation and, consequently, of paradoxical embolization through the PFO. An increased prevalence of G20210A and factor V Leiden mutations has been reported in patients with cryptogenic stroke and PFOs. One of these two prothrombotic genotypes was significantly more frequent in young patients with cryptogenic strokes than in age-matched controls (10.3% vs 2.5%, P = .008), with prothrombin G20210A mutation being more frequent than factor V Leiden mutation (8.2% vs 2.1%). The association of either genotype with PFO increased the stroke risk in that study by 4.7-fold. An association between PFO size and the presence of antiphospholipid antibodies has been suggested. Other risk factors for venous thromboembolism, such as recent surgery, trauma, and the use of oral contraceptives, may increase the likelihood of paradoxical embolization through a PFO.
Prevention of Recurrent Stroke
The annual rate of stroke recurrence in patients with cryptogenic strokes and PFOs has been reported to be between 1.5% and 12%, depending on the population studied and the type of treatment used. Preventive options have included antithrombotic treatment, surgical closure of the PFO, and, more recently, percutaneous transcatheter PFO closure.
Antithrombotic Treatment
Oral anticoagulation with warfarin or treatment with antiplatelet agents, usually aspirin, has been used in patients with strokes and PFOs. In a pooled analysis of published studies on a total of 943 patients with strokes, the combined rate of recurrent stroke, death, and transient ischemic attack (TIA) for medical treatments was 4.86 events per 100 person-years. In a more recent meta-analysis of 15 published studies, the risk for stroke or TIA was estimated at 4.0 events per 100 person-years. Figure 7 summarizes the results of 3 large studies comparing patients with strokes with and without PFOs treated medically (aspirin in the French study; aspirin, warfarin, or both in the La Sapienza study; aspirin or warfarin in the Patent Foramen Ovale in Cryptogenic Stroke Study [PICSS]). From these data, it appears that patients with strokes and PFOs on antithrombotic treatment have an incidence of stroke and death that is not significantly different than in patients without PFOs. The age of the population studied, rather than the presence or absence of a PFO, seemed to drive the event rates seen across the 3 studies, and the combined hazard ratio for stroke and death of PFO versus no PFO was 0.95. The excess risk observed in the French study for patients with the combination of PFO and ASA was not confirmed by the results of PICSS. PICSS was the only randomized, double-blind study of the 3 and was conducted in 630 patients with noncardioembolic strokes. PICSS was a substudy of the Warfarin Aspirin Recurrent Stroke Study (WARSS), in which patients with noncardioembolic stroke were randomized to aspirin 325 mg or warfarin (target international normalized ratio, 1.4-2.8). After 2 years of follow-up, there were no significant differences in the rates of recurrent stroke or death among patients with or without PFOs, both in the entire study group (14.8% vs 15.4%; hazard ratio, 0.96; 95% confidence interval, 0.62-1.48; P = .84) and in the subgroup of patients with cryptogenic strokes (14.3% vs 12.7%; hazard ratio, 1.17; 95% confidence interval, 0.60-2.37; P = .65). Although the comparison between treatment types was not the main objective of the study, no significant differences in the rates of recurrent stroke or death were observed between patients treated with warfarin (9.5%) or aspirin (17.9%) (hazard ratio, 0.52; 95% confidence interval, 0.16-1.67; P = .28). In a multicenter study with TEE from Spain involving 200 patients with strokes and PFOs treated with warfarin or antiplatelet agents, the degree of right-to-left shunting and the coexistence of an ASA were also not associated with an increased risk for recurrent stroke.
