7/5/23, 11:48 AM Patent foramen ovale - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Patent foramen ovale : Hidehiko Hara, MD : Heidi M Connolly, MD, FACC, FASE : Susan B Yeon, MD, JD, FACC All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Aug 24, 2022. INTRODUCTION Patent foramen ovale (PFO) is a congenital cardiac lesion that frequently persists into adulthood [1-3]. Although most patients with a PFO are asymptomatic, a variety of clinical manifestations may be associated with PFO, most importantly cryptogenic stroke. (See 'Clinical manifestations' below.) Issues related to the prevalence, anatomy, associations with other defects, clinical manifestations, and detection of PFO will be reviewed here. Clinical manifestations of atrial septal defects, including PFO, and the indications for and techniques of closure of a PFO are discussed separately. (See "Clinical manifestations and diagnosis of atrial septal defects in adults" and "Atrial septal abnormalities (PFO, ASD, and ASA) and risk of cerebral emboli in adults" and "Stroke associated with patent foramen ovale (PFO): Evaluation" and "Isolated atrial septal defects (ASDs) in children: Classification, clinical features, and diagnosis" and "Isolated atrial septal defects (ASDs) in children: Management and outcome".) PREVALENCE AND PATHOPHYSIOLOGY PFO was found in 25 to 30 percent of individuals in an autopsy study and in a community-based transesophageal echocardiography (TEE) study [4,5]. The following findings were noted in the autopsy study of 965 normal hearts [4]: https://www.uptodate.com/contents/patent-foramen-ovale/print 1/19 7/5/23, 11:48 AM Patent foramen ovale - UpToDate Probe-patent PFO was present in 27 percent; the prevalence and size were similar in males and females. The prevalence of PFO declined progressively with age, from 34 percent up to age 30, to 25 percent between ages 30 and 80, to 20 percent over age 80. Among patients who have a PFO, the mean size increased progressively with age, from 3.4 mm up to age 10 to 5.8 mm over age 90. This trend may reflect size selection, as larger defects remain patent while smaller defects close spontaneously. A similar overall prevalence of PFO (26 percent) was noted in a series of 581 subjects 45 years of age who underwent TEE as part of an evaluation of potential stroke risk factors in the community [5]. However, the incidence was stable with increasing age in contrast to the modest decline in the autopsy study [4]. The prevalence of PFO is higher in patients with cryptogenic stroke, particularly those under age 55 years in whom PFO is more likely to play a causal role. Approximately 40 percent of ischemic strokes in adults under 55 are cryptogenic. In the prospective PFO-ASA study of 581 patients with cryptogenic stroke (mean age 42), 37 percent had a PFO alone and another 9 percent had a PFO with an atrial septal aneurysm [6]. A similar prevalence of PFO (39 percent) was noted among 250 older patients (mean age 59) with cryptogenic stroke in the Patent Foramen Ovale in Cryptogenic Stroke Study [7]. In addition, the patients with cryptogenic stroke had a significantly higher rate of a large PFO compared with patients with a stroke of known cause (20 versus 9.7 percent). (See 'Cryptogenic stroke' below.) Although most individuals with PFO are asymptomatic, a PFO can serve as a pathway for venous to arterial transit of emboli (paradoxical emboli) via right-to-left shunting when the pressure in the right atrium exceeds that in the left atrium. A transient right-to-left gradient is sufficient to induce shunting and commonly occurs in patients without net right-to-left shunting (ie, those with no net shunt or a net left-to-right shunt). (See "Atrial septal abnormalities (PFO, ASD, and ASA) and risk of cerebral emboli in adults", section on 'Paradoxical emboli'.) A transient right-to-left gradient occurs in normal individuals during early ventricular systole and with Valsalva maneuver (eg, straining to defecate, coughing, lifting or pushing heavy objects). Among 148 patients with a PFO in the community-based series cited above, 57 percent had right-to-left shunting at rest, and 92 percent had right-to-left shunting with straining or coughing [5]. EMBRYOLOGY https://www.uptodate.com/contents/patent-foramen-ovale/print 2/19 7/5/23, 11:48 AM Patent foramen ovale - UpToDate During fetal development, a PFO is required for oxygenated blood to flow from the right to the left atrium. Starting at week four of pregnancy, the septum primum and septum secundum form and fuse in the following sequence ( figure 1) [8,9]: The septum primum grows from the primordial atrial roof toward the endocardial cushions. The endocardial cushions grow toward each other and then fuse, dividing the atrioventricular canal into right and left sides. The net effect is creation of the foramen primum. As the septum primum continues to grow toward the endocardial cushions, perforations develop in the septum primum. These perforations then fuse, forming the foramen secundum, which allows oxygenated blood to flow from the right to the left atrium. The foramen primum closes. A second membrane, the septum secundum, grows from the right side of the septum primum. The septum secundum eventually overlaps part of the foramen secundum, forming an incomplete septal partition that becomes the foramen ovale. The remaining septum primum forms a flap-like valve over the foramen ovale. Oxygenated blood from the inferior vena cava crosses the PFO, providing oxygenated blood for the systemic circulation. In contrast, most blood from the superior vena cava flows through the tricuspid valve and enters the right ventricle. At birth, either or both of two factors contribute to flap closure against the septum secundum: Oxygen filling the alveoli causes the pulmonary arterioles to open, resulting in reductions in right heart pressure and pulmonary vascular resistance; and the increasing amount of blood returning from the pulmonary circulation may raise left atrial pressure. Flap fusion is complete by age two in 70 to 75 percent of children, with the remaining 25 to 30 percent having a PFO. Why PFOs fail to close is not known, but familial and genetic factors may be important. This possibility was suggested in a study that compared 62 patients under age 60 with an ischemic stroke and 62 matched controls [10]. The prevalence of a PFO in female siblings of patients with a PFO was 77 percent, compared with 25 percent in female siblings of those without a PFO (odds ratio 9.8); there was no such association in men. ASSOCIATION WITH OTHER DEFECTS PFO is often associated with other cardiac anomalies, including atrial septal aneurysm and Chiari networks. https://www.uptodate.com/contents/patent-foramen-ovale/print 3/19 7/5/23, 11:48 AM Patent foramen ovale - UpToDate Atrial septal aneurysm An atrial septal aneurysm (ASA) is defined as redundant and mobile interatrial septal tissue in the region of the fossa ovalis with phasic excursion of at least 10 to 15 mm during the cardiorespiratory cycle. ASAs are frequently associated with PFOs and/or atrial septal defects (ASDs). The prevalence and potential clinical significance of ASAs are discussed separately. (See "Atrial septal abnormalities (PFO, ASD, and ASA) and risk of cerebral emboli in adults", section on 'ASA' and "Cryptogenic stroke and embolic stroke of undetermined source (ESUS)", section on 'Atrial septal abnormalities'.) Eustachian valve and Chiari network The Eustachian valve is located at the junction of the inferior vena cava and the right atrium and is prominent in some individuals. A Chiari network is a more fenestrated mobile structure consisting of a network of filamentous structures and fibers in the right atrium that originate from the region of the Eustachian and thebesian valves at the orifice of the inferior vena cava, with attachments to the upper wall of the right atrium or atrial septum [11,12]. A Chiari network is present in 2 to 3 percent of normal hearts [11,13]. (See "Echocardiographic evaluation of the atria and appendages", section on 'Structure'.) These structures are not generally thought to be clinically significant. However, a prominent Eustachian valve or Chiari network may maintain an embryonic right atrial flow pattern into adulthood with blood from the inferior vena cava being preferentially directed toward the interatrial septum. As a result, these structures may favor persistence of a PFO and formation of an ASA or flow through a PFO, indirectly facilitating paradoxical embolism. The association between Chiari network and PFO was illustrated in a review of 1436 consecutive patients referred for transesophageal echocardiography (TEE) [11]: A Chiari network was found in 29 patients (2 percent): 24 (83 percent) had a PFO and seven (24 percent) had an ASA. Transthoracic echocardiography detected only eight of these networks. A PFO with a large right-to-left shunt occurred with greater frequency in patients with Chiari networks (55 versus 12 percent). Chiari networks were more common in patients undergoing TEE for cryptogenic stroke than in those evaluated for other indications (4.6 versus 0.5 percent). Among the 24 patients with cryptogenic stroke and a Chiari network, 15 had a PFO as the only risk factor. In a study of patients undergoing PFO closure, the presence of Eustachian valve or Chiari network was associated with history of recurrent embolic events [14]. Atrial septal defect PFOs are occasionally associated with ASDs. In a review of 103 patients referred for transcatheter closure for a presumed paradoxical embolism, PFO alone was present https://www.uptodate.com/contents/patent-foramen-ovale/print 4/19 7/5/23, 11:48 AM Patent foramen ovale - UpToDate in 81, an ASD alone in 12, and both a PFO and ASD in 10 [15]. Ebstein anomaly Defects of the interatrial septum are present in most patients with Ebstein anomaly. In a series of 106 patients, 79 percent had either a persistent or previously closed PFO or ASD [16]. (See "Clinical manifestations and diagnosis of Ebstein anomaly".) CLINICAL MANIFESTATIONS Most patients with a PFO remain asymptomatic. The most important potential manifestation is ischemic stroke due to a paradoxical embolism. The following is a brief summary, since most of these manifestations are discussed in detail separately. Cryptogenic stroke Cryptogenic stroke, which accounts for approximately 20 to 40 percent of ischemic strokes, is defined as a stroke that occurs in the absence of an identified cardioembolic or large vessel source and with a distribution that is not consistent with small vessel disease. Most of these strokes are presumed to be embolic based upon imaging features, as discussed separately (see "Cryptogenic stroke and embolic stroke of undetermined source (ESUS)", section on 'Brain imaging'). There is an increased prevalence of PFO in patients who have had a cryptogenic stroke; thus, paradoxical embolism via PFO is likely one mechanism for stroke in this population. (See "Atrial septal abnormalities (PFO, ASD, and ASA) and risk of cerebral emboli in adults", section on 'Prospective studies' and "Cryptogenic stroke and embolic stroke of undetermined source (ESUS)", section on 'Atrial septal abnormalities'.) Of note, patients with an embolic-appearing ischemic stroke in the setting of a PFO with a right- to-left interatrial shunt and no other source of stroke or other risk factors for stroke despite a comprehensive evaluation are recognized as having a PFO-associated stroke. (See "Atrial septal abnormalities (PFO, ASD, and ASA) and risk of cerebral emboli in adults", section on 'Risk of embolic stroke' and "Stroke associated with patent foramen ovale (PFO): Evaluation".) Migraine and vascular headache Migraine and vascular headache may be associated with PFO and right-to-left cardiac shunting. As a result, PFO closure has been evaluated as a treatment for migraine headache. Routine screening for PFO in patients with migraine is not recommended. (See "Preventive treatment of episodic migraine in adults", section on 'Other interventions not recommended'.) Decompression sickness and air embolism Decompression sickness in scuba divers can result in air embolism through a PFO. The risk is increased with larger PFOs and in patients who travel by air within 12 to 48 hours after diving. PFOs can also permit paradoxical embolization from other causes of air embolism. (See "Complications of SCUBA diving" and "Air embolism".) https://www.uptodate.com/contents/patent-foramen-ovale/print 5/19 7/5/23, 11:48 AM Patent foramen ovale - UpToDate Platypnea-orthodeoxia syndrome The platypnea-orthodeoxia syndrome is a rare disorder characterized by both dyspnea (platypnea) and arterial desaturation (orthodeoxia) in the upright position with improvement in the supine position [17,18]. In addition to PFO and other interatrial defects, this syndrome has also been described with intrapulmonary shunting and with disorders such as pericardial effusion, constrictive pericarditis, emphysema, amiodarone pulmonary toxicity, pneumonectomy, and cirrhosis [18]. Two components are required [19]: An interatrial shunt, such as PFO, atrial septal defect, or fenestrated atrial septal aneurysm (ASA), or intrapulmonary shunting as in the hepatopulmonary syndrome and pulmonary arteriovenous malformations that may occur in patients with cirrhosis. (See "Hepatopulmonary syndrome in adults: Prevalence, causes, clinical manifestations, and diagnosis" and "Pulmonary arteriovenous malformations: Epidemiology, etiology, and pathology in adults".) A functional component that promotes abnormal shunting when the patient rises from a recumbent to an upright position. This could be mediated by a deformity in the atrial septum (that promotes shunt flow) and/or the right atrium that increases streaming of blood from the inferior vena cava through the defect. An elevation in right atrial pressure causing right-to-left shunting is usually required, although blood may flow from right to left even when right atrial pressure is normal, as typically occurs with persistent Eustachian valves [18-20]. Other A variety of less common manifestations have been described in patients with a PFO. These include: Acute myocardial infarction [21,22]. (See "Coronary artery disease and myocardial infarction in young people", section on 'Paradoxical embolism'.) Systemic embolization, such as renal infarction [23]. (See "Renal infarction".) Fat embolism [24]. (See "Fat embolism syndrome".) Right atrial tumors causing increased right atrial pressure can promote paradoxical embolization, including tumor embolism [22]. (See "Cardiac tumors", section on 'Right atrial tumors'.) Left-sided valve disease in carcinoid syndrome [25]. (See "Carcinoid heart disease".) https://www.uptodate.com/contents/patent-foramen-ovale/print 6/19 7/5/23, 11:48 AM Patent foramen ovale - UpToDate DIAGNOSIS AND EVALUATION Evaluation for PFO is indicated in patients with cryptogenic stroke or other embolic event as well as in patients with other clinical manifestations of PFO such as platypnea-orthodeoxia syndrome. Ultrasound techniques A variety of ultrasound modalities have been used to diagnose a PFO, including transthoracic echocardiography (TTE), transesophageal echocardiography (TEE) [5,26-30], transcranial Doppler (TCD) [30-38], transmitral Doppler (TMD) [39], and intracardiac echocardiography (ICE) [40]. TTE, TEE, TCD, TMD, and ICE generally in conjunction with injection of agitated saline contrast (a "bubble study") as well as color Doppler imaging (for TTE, TEE, and ICE), can all detect a right-to- left shunt associated with a PFO. PFO is much more common than other lesions causing intracardiac right-to-left shunting [5]. As noted above, transient right to left shunting is sufficient to cause a positive bubble study and occurs in individuals with PFO with normal intracardiac pressures during early ventricular systole or during Valsalva release. PFO detection can be augmented by cough or releasing a sustained Valsalva maneuver. These maneuvers, which are part of standard echocardiographic (TEE and TTE) testing, open the PFO when the right atrium fills with blood from the abdomen, increasing right-to-left shunting [5,41]. In a TEE study that included 148 patients with a PFO, right-to-left shunting was noted in 57 percent at rest compared with 92 percent with straining or coughing [5]. (See 'Prevalence and pathophysiology' above.) TEE, TTE, and ICE Among the ultrasound methods for detection of right-to-left shunts, only TEE and ICE enable visualization of the site of the shunt (eg, PFO, atrial septal defect [ASD], or pulmonary arteriovenous malformation) ( movie 1 and movie 2). Echocardiography (TTE or TEE) can also detect other cardiac abnormalities associated with embolic events such as ASA ( movie 3 and movie 4), intracardiac mass (eg, vegetation, tumor, or thrombus). TEE is generally more sensitive than TTE for identifying potential sources of cardiac embolus including ASA, vegetations, atrial mass, or thrombus and thoracic aortic plaque. (See "Echocardiography in detection of cardiac and aortic sources of systemic embolism".) TEE and ICE enable visualization of the flap of the atrial septum covering the foramen ovale as well as passage of agitated saline contrast through the foramen. Contrast that has passed through a pulmonary arteriovenous malformation may be visualized entering the left atrium via the pulmonary veins. In addition, color Doppler imaging on TEE or ICE (and occasionally on TTE) https://www.uptodate.com/contents/patent-foramen-ovale/print 7/19 7/5/23, 11:48 AM Patent foramen ovale - UpToDate may reveal flow through a PFO at rest and/or with maneuvers [42,43]. In a small series, PFO detection by contrast and color Doppler TEE correlated well with autopsy findings [42]. The timing of the appearance of agitated saline contrast (bubbles) in the left heart on echocardiography (TTE, ICE, or TEE) can help distinguish intracardiac shunting (via PFO or ASD) from pulmonary arteriovenous shunting. Early contrast appearance in the left heart (within three beats of contrast appearance in the right heart) suggests intracardiac shunting, while late shunting (after three to five beats) is more consistent with pulmonary arteriovenous shunting. However, the data supporting this timing rule are limited [44-46] and exceptions occur [46,47]. The relative efficacy of TTE and TEE has been evaluated in a number of comparative studies. In general, TEE and ICE have been found to be more sensitive than TTE for PFO detection, although the reported sensitivity of TEE has varied widely (11 to 85 percent of shunts detected by TEE) [28-30,48]. Variation in the sensitivity of TTE is likely related to variation in image quality. Some later studies have reported that TTE with second harmonic imaging (now routinely employed) had greater sensitivity than TEE for shunt detection [49,50]. Potential causes of reduced sensitivity of TEE include ineffective Valsalva maneuver in sedated patients with the TEE probe interfering with glottic closure and reduced right atrial pressures due to fasting and sedation [50]. A limitation of these studies is that a positive TTE or TEE served as the standard for shunt detection, so the rate of false positive results cannot be ascertained. A separate concern is reduction in sensitivity of echocardiography when images are stored digitally rather than on analog videotape. Although digital acquisition and storage of echocardiographic images are generally recommended by the American Society of Echocardiography [51], digital data compression by the approved Joint Photographic Experts Group (JPEG) method may result in loss of some visual information. A study comparing digital TTE and analog TTE results found that digital TTE had poor sensitivity for detection of right to left shunts as compared with analog TTE (50, 63, and 39 percent for rest, Valsalva, and late shunts, respectively) [48]. Longer recorded clip length ( 13 seconds) was associated with only modest improvement in sensitivity (50, 67, and 46 percent, respectively). Other factors that influence the sensitivity of echocardiography for shunt detection are the site of injection of agitated saline contrast (greater sensitivity with femoral rather than brachial venous injection) [52] and the number of bubbles (typically three) required for test positivity. https://www.uptodate.com/contents/patent-foramen-ovale/print 8/19 7/5/23, 11:48 AM Patent foramen ovale - UpToDate In summary, TEE with contrast at rest, with cough, and following Valsalva is generally considered the most definitive diagnostic test, although second harmonic TTE in patients with good acoustic windows may offer equal or greater sensitivity. Among those with cryptogenic stroke or other clinical indication to evaluate for PFO, we suggest starting with TTE, with TEE performed if TTE is negative or nondiagnostic. Transcranial Doppler As noted above, TCD is a potential alternative to TEE [30,33-37,39]. TCD has advantages compared with TEE of being noninvasive and easy to perform at the bedside. On the other hand, TCD can only detect a right-to-left shunt, not the location of the shunt. TCD is performed by placing a probe against the side of the skull just above the zygomatic arch (ie, over the middle cerebral artery). A contrast agent (typically agitated saline) is injected and Doppler ultrasonography is performed at baseline and after a Valsalva maneuver [35]. (See "Contrast echocardiography: Contrast agents, safety, and imaging technique".) Although early studies suggested that TCD was highly specific but less sensitive than TEE [30,31], later studies [32,34,35,38] indicated that these studies are comparable for detection of right-to- left shunts, as concluded in a 2004 report from the American Academy of Neurology [37]. However, TEE and ICE are considered a better test because it also provides anatomic information about the site and size of the shunt and possible presence of an atrial septal aneurysm and other possible causes of stroke such as aortic atherosclerosis, intracardiac masses, and infective endocarditis. (See 'Atrial septal aneurysm' above and "Thromboembolism from aortic plaque" and "Embolism from atherosclerotic plaque: Atheroembolism (cholesterol crystal embolism)" and "Clinical manifestations and evaluation of adults with suspected left-sided native valve endocarditis".) Safety Although intravenous administration of agitated saline contrast for ultrasound detection of shunts has generally been considered safe, case reports suggest that cerebral ischemic events may rarely result from passage of bubbles into the systemic circulation (via an intracardiac shunt or pulmonary arteriovenous malformation) [53,54]. Although data on techniques to enhance safety are lacking, suggestions include thorough agitation to minimize bubble size, vertical position of the injecting syringe to aid withholding of large bubbles and avoidance of additional contrast injections once a large shunt has been identified [53,54]. The safety of TEE is discussed separately. (See "Transesophageal echocardiography: Indications, complications, and normal views", section on 'Safety of TEE examination'.) MDCT and CMR Preliminary reports suggest that PFO may also be detected by multidetector computed tomography (MDCT) [55] or cardiovascular magnetic resonance (CMR) [56-58], https://www.uptodate.com/contents/patent-foramen-ovale/print 9/19 7/5/23, 11:48 AM Patent foramen ovale - UpToDate although these methods may be less sensitive than TEE. Assessment of clinical significance Identification of PFO in a patient with an ischemic event does not prove a causal relationship. Since PFO is a common lesion, it may serve as "innocent bystander" in some patients with ischemic events. Evaluation of a patient with PFO with an embolic event should include careful assessment of the likelihood that the PFO is causally related to the event, including identification of other potential causes of thromboembolism and stroke. This assessment is discussed separately. (See "Stroke associated with patent foramen ovale (PFO): Evaluation" and "Stroke associated with patent foramen ovale (PFO): Management", section on 'Patient selection for PFO closure' and "Cryptogenic stroke and embolic stroke of undetermined source (ESUS)", section on 'Evaluation and diagnosis' and "Atrial septal abnormalities (PFO, ASD, and ASA) and risk of cerebral emboli in adults", section on 'Risk of embolic stroke'.) Evaluation of sources of venous thromboembolism is also suggested since identification of venous thrombosis provides further support for paradoxical embolism as the mechanism of the embolic event and has treatment implications. (See "Atrial septal abnormalities (PFO, ASD, and ASA) and risk of cerebral emboli in adults", section on 'Diagnosis' and "Stroke associated with patent foramen ovale (PFO): Management", section on 'Patient selection for PFO closure'.) MANAGEMENT Management varies depending upon the clinical presentation. An incidentally detected PFO generally requires no follow-up or treatment. Evidence from randomized trials suggests that PFO device closure is more effective than medical therapy alone for select patients aged 60 years with a cryptogenic nonlacunar ischemic stroke who have a PFO with a right-to-left interatrial shunt. The selection of patients with cryptogenic stroke for PFO closure, and the lack of benefit and possible harm from closing incidentally discovered PFOs at the time of cardiac surgery, are discussed separately. (See "Atrial septal abnormalities (PFO, ASD, and ASA) and risk of cerebral emboli in adults" and "Stroke associated with patent foramen ovale (PFO): Evaluation" and "Stroke associated with patent foramen ovale (PFO): Management", section on 'Patient selection for PFO closure'.) Definitive treatment for platypnea-orthodeoxia syndrome is closure of the atrial shunt [59,60]. INFORMATION FOR PATIENTS https://www.uptodate.com/contents/patent-foramen-ovale/print 10/19 7/5/23, 11:48 AM Patent foramen ovale - UpToDate UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) Basics topic (see "Patient education: Patent foramen ovale (The Basics)") SUMMARY AND RECOMMENDATIONS Prevalence Patent foramen ovale (PFO) occurs in 25 to 30 percent of the general population. The prevalence of PFO is higher in patients with cryptogenic stroke, particularly those under age 55 years in whom PFO is more likely to play a causal role. (See 'Prevalence and pathophysiology' above.) Clinical manifestations Most individuals with PFO are asymptomatic, although some have clinical manifestations such as cryptogenic stroke, air embolism, or platypnea- orthodeoxia. (See 'Clinical manifestations' above.) When to check for PFO Testing for PFO is indicated in patients with a cerebral ischemic event of uncertain origin or other clinical manifestations of PFO such as platypnea- orthodeoxia. (See 'Diagnosis and evaluation' above.) Diagnosis of PFO Agitated saline contrast with ultrasound techniques (echocardiography or transcranial Doppler) enables shunt identification. On agitated saline contrast echocardiography, appearance of at least three bubbles of contrast in the left heart within three beats after contrast opacification of the right atrium suggests the presence of intracardiac shunt. (See 'Ultrasound techniques' above.) TTE Among those with cryptogenic stroke or other clinical indication for evaluation for PFO, we suggest starting with transthoracic echocardiography (TTE), with transesophageal echocardiography (TEE) performed if TTE is negative or nondiagnostic. https://www.uptodate.com/contents/patent-foramen-ovale/print 11/19 7/5/23, 11:48 AM Patent foramen ovale - UpToDate TEE TEE with contrast at rest, with cough, and following Valsalva is generally considered the most definitive diagnostic test for PFO. TEE and transcranial Doppler methods have similar sensitivity and specificity for detection of right-to-left shunts, although echocardiography also permits evaluation of cardiac structure and function. Since digital data compression may reduce the sensitivity of agitated saline contrast study, we suggest analog (videotape) recording and review of TTE and TEE contrast studies. (See 'TEE, TTE, and ICE' above.) Assessing clinical significance of PFO Identification of PFO in a patient with an embolic event does not prove a causal relationship. The evaluation of patients with PFO with an embolic event should include careful assessment of the likelihood that the PFO is causally related to the event, including identification of other potential causes of thromboembolism and stroke and of potential sources of venous thromboembolism. (See 'Assessment of clinical significance' above and "Stroke associated with patent foramen ovale (PFO): Evaluation" and "Stroke associated with patent foramen ovale (PFO): Management", section on 'Patient selection for PFO closure'.) Management An incidentally detected PFO generally requires no follow-up or treatment. Selected patients with cryptogenic stroke are candidates for PFO closure, as discussed separately. (See "Atrial septal abnormalities (PFO, ASD, and ASA) and risk of cerebral emboli in adults" and "Stroke associated with patent foramen ovale (PFO): Evaluation" and "Stroke associated with patent foramen ovale (PFO): Management", section on 'Patient selection for PFO closure'.) ACKNOWLEDGMENT The UpToDate editorial staff acknowledges Robert S Schwartz, MD, FACC, who contributed to earlier versions of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Hara H, Virmani R, Ladich E, et al. Patent foramen ovale: current pathology, pathophysiology, and clinical status. J Am Coll Cardiol 2005; 46:1768. 2. Wu LA, Malouf JF, Dearani JA, et al. Patent foramen ovale in cryptogenic stroke: current understanding and management options. Arch Intern Med 2004; 164:950. https://www.uptodate.com/contents/patent-foramen-ovale/print 12/19 7/5/23, 11:48 AM Patent foramen ovale - UpToDate 3. Kerut EK, Norfleet WT, Plotnick GD, Giles TD. Patent foramen ovale: a review of associated conditions and the impact of physiological size. J Am Coll Cardiol 2001; 38:613. 4. Hagen PT, Scholz DG, Edwards WD. Incidence and size of patent foramen ovale during the first 10 decades of life: an autopsy study of 965 normal hearts. Mayo Clin Proc 1984; 59:17. 5. Meissner I, Whisnant JP, Khandheria BK, et al. Prevalence of potential risk factors for stroke assessed by transesophageal echocardiography and carotid ultrasonography: the SPARC study. Stroke Prevention: Assessment of Risk in a Community. Mayo Clin Proc 1999; 74:862. 6. Lamy C, Giannesini C, Zuber M, et al. Clinical and imaging findings in cryptogenic stroke patients with and without patent foramen ovale: the PFO-ASA Study. Atrial Septal Aneurysm. Stroke 2002; 33:706. 7. Homma S, Sacco RL, Di Tullio MR, et al. Effect of medical treatment in stroke patients with patent foramen ovale: patent foramen ovale in Cryptogenic Stroke Study. Circulation 2002; 105:2625. 8. Konstantinides S, Geibel A, Kasper W, et al. Patent foramen ovale is an important predictor of adverse outcome in patients with major pulmonary embolism. Circulation 1998; 97:1946. 9. Moore KL. The Developing Human: Clinically Oriented Embryology, 6th ed, Saunders, Philad elphia 1998. 10. Arquizan C, Coste J, Touboul PJ, Mas JL. Is patent foramen ovale a family trait? A transcranial Doppler sonographic study. Stroke 2001; 32:1563. 11. Schneider B, Hofmann T, Justen MH, Meinertz T. Chiari's network: normal anatomic variant or risk factor for arterial embolic events? J Am Coll Cardiol 1995; 26:203. 12. Chiari, H . About network development in the right side of the heart. Beitr Pathol Anat 1897; 22:1. 13. Werner JA, Cheitlin MD, Gross BW, et al. Echocardiographic appearance of the Chiari network: differentiation from right-heart pathology. Circulation 1981; 63:1104. 14. Rigatelli G, Dell'avvocata F, Braggion G, et al. Persistent venous valves correlate with increased shunt and multiple preceding cryptogenic embolic events in patients with patent foramen ovale: an intracardiac echocardiographic study. Catheter Cardiovasc Interv 2008; 72:973. 15. Khositseth A, Cabalka AK, Sweeney JP, et al. Transcatheter Amplatzer device closure of atrial septal defect and patent foramen ovale in patients with presumed paradoxical embolism. Mayo Clin Proc 2004; 79:35. 16. Attenhofer Jost CH, Connolly HM, O'Leary PW, et al. Left heart lesions in patients with Ebstein anomaly. Mayo Clin Proc 2005; 80:361. https://www.uptodate.com/contents/patent-foramen-ovale/print 13/19 7/5/23, 11:48 AM Patent foramen ovale - UpToDate 17. Seward JB, Hayes DL, Smith HC, et al. Platypnea-orthodeoxia: clinical profile, diagnostic workup, management, and report of seven cases. Mayo Clin Proc 1984; 59:221. 18. Cheng TO. Platypnea-orthodeoxia syndrome: etiology, differential diagnosis, and management. Catheter Cardiovasc Interv 1999; 47:64. 19. Cheng TO. Mechanisms of platypnea-orthodeoxia: what causes water to flow uphill? Circulation 2002; 105:e47. 20. Cheng TO. Reversible orthodeoxia. Ann Intern Med 1992; 116:875. 21. Agostoni P, Gasparini G, Destro G. Acute myocardial infarction probably caused by paradoxical embolus in a pregnant woman. Heart 2004; 90:e12. 22. Diaz Castro O, Bueno H, Nebreda LA. Acute myocardial infarction caused by paradoxical tumorous embolism as a manifestation of hepatocarcinoma. Heart 2004; 90:e29. 23. Iwasaki M, Joki N, Tanaka Y, et al. A suspected case of paradoxical renal embolism through the patent foramen ovale. Clin Exp Nephrol 2011; 15:147. 24. Pell AC, Hughes D, Keating J, et al. Brief report: fulminating fat embolism syndrome caused by paradoxical embolism through a patent foramen ovale. N Engl J Med 1993; 329:926. 25. Pellikka PA, Tajik AJ, Khandheria BK, et al. Carcinoid heart disease. Clinical and echocardiographic spectrum in 74 patients. Circulation 1993; 87:1188. 26. M gge A, Daniel WG, Angermann C, et al. Atrial septal aneurysm in adult patients. A multicenter study using transthoracic and transesophageal echocardiography. Circulation 1995; 91:2785. 27. Pinto FJ. When and how to diagnose patent foramen ovale. Heart 2005; 91:438. 28. Pearson AC, Labovitz AJ, Tatineni S, Gomez CR. Superiority of transesophageal echocardiography in detecting cardiac source of embolism in patients with cerebral ischemia of uncertain etiology. J Am Coll Cardiol 1991; 17:66. 29. Konstantinides S, Kasper W, Geibel A, et al. Detection of left-to-right shunt in atrial septal defect by negative contrast echocardiography: a comparison of transthoracic and transesophageal approach. Am Heart J 1993; 126:909. 30. Di Tullio M, Sacco RL, Venketasubramanian N, et al. Comparison of diagnostic techniques for the detection of a patent foramen ovale in stroke patients. Stroke 1993; 24:1020. 31. Job FP, Ringelstein EB, Grafen Y, et al. Comparison of transcranial contrast Doppler sonography and transesophageal contrast echocardiography for the detection of patent foramen ovale in young stroke patients. Am J Cardiol 1994; 74:381. 32. Nemec JJ, Marwick TH, Lorig RJ, et al. Comparison of transcranial Doppler ultrasound and transesophageal contrast echocardiography in the detection of interatrial right-to-left https://www.uptodate.com/contents/patent-foramen-ovale/print 14/19 7/5/23, 11:48 AM Patent foramen ovale - UpToDate shunts. Am J Cardiol 1991; 68:1498. 33. Teague SM, Sharma MK. Detection of paradoxical cerebral echo contrast embolization by transcranial Doppler ultrasound. Stroke 1991; 22:740. 34. Blersch WK, Draganski BM, Holmer SR, et al. Transcranial duplex sonography in the detection of patent foramen ovale. Radiology 2002; 225:693. 35. Droste DW, Lakemeier S, Wichter T, et al. Optimizing the technique of contrast transcranial Doppler ultrasound in the detection of right-to-left shunts. Stroke 2002; 33:2211. 36. Schwarze JJ, Sander D, Kukla C, et al. Methodological parameters influence the detection of right-to-left shunts by contrast transcranial Doppler ultrasonography. Stroke 1999; 30:1234. 37. Sloan MA, Alexandrov AV, Tegeler CH, et al. Assessment: transcranial Doppler ultrasonography: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology 2004; 62:1468. 38. Droste DW, Schmidt-Rimpler C, Wichter T, et al. Right-to-left-shunts detected by transesophageal echocardiography and transcranial Doppler sonography. Cerebrovasc Dis 2004; 17:191. 39. Kerr AJ, Buck T, Chia K, et al. Transmitral Doppler: a new transthoracic contrast method for patent foramen ovale detection and quantification. J Am Coll Cardiol 2000; 36:1959. 40. Fenster BE, Curran-Everett D, Freeman AM, et al. Saline contrast echocardiography for the detection of patent foramen ovale in hypoxia: a validation study using intracardiac echocardiography. Echocardiography 2014; 31:420. 41. Lynch JJ, Schuchard GH, Gross CM, Wann LS. Prevalence of right-to-left atrial shunting in a healthy population: detection by Valsalva maneuver contrast echocardiography. Am J Cardiol 1984; 53:1478. 42. Schneider B, Zienkiewicz T, Jansen V, et al. Diagnosis of patent foramen ovale by transesophageal echocardiography and correlation with autopsy findings. Am J Cardiol 1996; 77:1202. 43. Schuchlenz HW, Weihs W, Hackl E, Rehak P. A large Eustachian valve is a confounder of contrast but not of color Doppler transesophageal echocardiography in detecting a right-to- left shunt across a patent foramen ovale. Int J Cardiol 2006; 109:375. 44. Woods TD, Patel A. A critical review of patent foramen ovale detection using saline contrast echocardiography: when bubbles lie. J Am Soc Echocardiogr 2006; 19:215. 45. Gazzaniga P, Buscarini E, Leandro G, et al. Contrast echocardiography for pulmonary arteriovenous malformations screening: does any bubble matter? Eur J Echocardiogr 2009; 10:513. https://www.uptodate.com/contents/patent-foramen-ovale/print 15/19 7/5/23, 11:48 AM Patent foramen ovale - UpToDate 46. Zukotynski K, Chan RP, Chow CM, et al. Contrast echocardiography grading predicts