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Patent foramen ovale (PFO) may be an underlying factor in the pathogenesis of migraine, vasospastic angina, and Takotsubo cardiomyopathy. This article reviews the role that PFO may play in each of these clinical entities and discusses potential interventions. It also proposes a novel clinical syndrome wherein PFO may be the unifying link among migraine, coronary vasospasm, and Takotsubo cardiomyopathy in predisposed individuals.

Acute mountain sickness (AMS) commonly plagues people who travel to high altitude and can be life threatening. Clinically, AMS is defined by a constellation of symptoms as outlined in the Lake Louise Criteria. The underlying etiology is thought to be related to a decrease in partial pressure of oxygen leading to tissue hypoxia. Patent foramen ovale (PFO) has been postulated to play a role in AMS through right-to-left shunt, which can worsen hypoxemia. Recent data demonstrate a higher prevalence of PFO in hikers with AMS. Future studies are needed to further elucidate the relationship between PFO and AMS.

BackgroundPatients who had a cryptogenic stroke (CS) suspected to be causally related to a patent foramen ovale (PFO) are candidates for percutaneous PFO closure. In such patients, it is important to screen for atrial fibrillation (AF). Limited guidance is available regarding AF monitoring strategies in CS patients with PFO addressing optimal monitoring technology and duration.AimTo provide a narrative review of cardiac rhythm monitoring in CS patients considered for PFO closure, including current practices, stroke recurrences after CS, findings from monitoring studies in CS patients, and predictors for AF detection published in the literature. To propose a personalized strategy for cardiac monitoring in CS patients, accounting for aspects predicting AF detection.Summary of reviewAF detection in CS patients is predicted by age, left atrial enlargement, prolonged PR interval, frequent premature atrial contractions, interatrial conduction block, diabetes, prior brain infarctions, leukoaraiosis, elevated B-type natriuretic peptide (BNP)/N-terminal pro B-type natriuretic peptide (NT-proBNP) levels, and a family history of AF, as well as composed scores (e.g. CHA2DS2-VASc, atrial fibrillation in embolic stroke of undetermined source (AF-ESUS)). The causal role of the PFO may be accounted for by the risk of paradoxical embolism (RoPE) score and/or the PFO-Associated Stroke Causal Likelihood (PASCAL) classification.ConclusionA personalized approach to AF detection in CS patients is proposed, accounting for the likelihood of AF detection and aimed at obtaining sufficient confidence regarding the absence of AF in patients considered for PFO closure. In addition, the impact of high-risk PFO features on the monitoring strategy is discussed.

PurposeThe mechanisms of brain metastasis are incompletely understood. Circulating tumor cells travel to the right heart and through the pulmonary circulation, where they may become lung metastases, and can circulate further to the left heart and brain. In patients who develop brain metastases without lung involvement, we hypothesized that cancer cells may travel directly from the right atrium to left atrium via a patent foramen ovale (PFO), akin to paradoxical embolism. If the prevalence of PFO is greater in these individuals compared to the general population (20-30%), PFO may play a role in brain metastasis, and prophylactic closure may provide benefit. Accordingly, we investigated the prevalence of PFO in patients with brain metastases without prior lung involvement.MethodsWe prospectively identified patients with brain metastases from a non-lung primary cancer with no preceding or concurrent lung involvement. Nine eligible participants underwent a transcranial Doppler study with intravenous agitated saline to assess for PFO.ResultsAmong nine participants, primary cancers were breast (n = 6), upper gastrointestinal (n = 2), and thyroid (n = 1). A positive bubble study was identified in 2/9 (22.2%) participants: one female with breast cancer and one male with duodenal adenocarcinoma. No participants developed lung metastases on subsequent chest imaging.ConclusionIn this prospective pilot study, we found a similar prevalence of PFO in patients who developed brain metastases without preceding lung involvement compared to estimates for the general population. Through a larger study is needed, the development of brain metastases in these individuals may primarily reflect tumor-specific biological factors diecting metastasis organotropism.

BackgroundAlthough observational studies have shown percutaneous patent foramen ovale (PFO) closure to be a safe means of reducing the frequency and duration of migraine, randomized clinical trials have not met their primary efficacy endpoints.ObjectivesThe authors report the results of a pooled analysis of individual participant data from the 2 randomized trials using the Amplatzer PFO Occluder to assess the efficacy and safety of percutaneous device closure as a therapy for episodic migraine with or without aura.MethodsThe authors analyzed individual patient-level data from 2 randomized migraine trials (the PRIMA [Percutaneous Closure of Patent Foramen Ovale in Migraine With Aura] and PREMIUM [Prospective Randomized Investigation to Evaluate Incidence of Headache Reduction in Subjects with Migraine and PFO Using the Amplatzer PFO Occluder Compared to Medical Management] studies). Efficacy endpoints were mean reduction in monthly migraine days, responder rate (defined as ≥50% reduction in monthly migraine attacks), mean reduction in monthly migraine attacks, and percentage of patients who experienced complete cessation of migraine. The safety endpoint was major procedure- and device-related adverse events.ResultsAmong 337 subjects, 176 were randomized by blocks to device closure and 161 to medical treatment only. At 12-month follow-up, the analysis met 3 of the 4 efficacy endpoints: mean reduction of monthly migraine days (-3.1 days vs. -1.9 days; p = 0.02), mean reduction of monthly migraine attacks (-2.0 vs. -1.4; p = 0.01), and number of subjects who experienced complete cessation of migraine (14 [9%] vs. 1 [0.7%]; p

BackgroundPatent foramen ovale (PFO) is implicated in the pathogenesis of clinical conditions such as cryptogenic stroke and migraine with aura. This study evaluated the challenges of sizing a PFO with different contemporary imaging modalities and assessed the relationship between PFO size and severity of the right-to-left shunt (RLS).MethodsPatients who were referred to interventional cardiology with the diagnosis of a PFO and had undergone intra-procedural balloon sizing (n = 147), transesophageal echocardiogram (TEE) imaging (n = 67), or intracardiac echocardiogram (ICE) imaging (n = 73) at the time of workup were included in this study. TEE and ICE were used to obtain PFO length and height during normal respiration. A sizing balloon was used to obtain PFO width and height after the septum primum was opened with balloon inflation.ResultsThe mean PFO length measured by TEE and ICE differed significantly (n = 27, 13.0 ± 4.1 vs. 9.9 ± 3.2 mm, p = .001). The mean PFO height measured by TEE and ICE (n = 27, 1.4 ± 0.6 vs. 1.7 ± 0.6 mm, p = .04), TEE and sizing balloon (n = 56, 1.5 ± 1.2 vs. 10.5 ± 4.2 mm, p

Background and purposeIn patients with cryptogenic stroke and patent foramen ovale (PFO), the Risk of Paradoxical Embolism (RoPE) Score has been proposed as a method to estimate a patient-specific "PFO-attributable fraction"-the probability that a documented PFO is causally-related to the stroke, rather than an incidental finding. The objective of this research is to examine the relationship between this RoPE-estimated PFO-attributable fraction and the effect of closure in 3 randomized trials.MethodsWe pooled data from the CLOSURE-I (Evaluation of the STARFlex Septal Closure System in Patients With a Stroke and/or Transient Ischemic Attack due to Presumed Paradoxical Embolism through a Patent Foramen Ovale), RESPECT (Randomized Evaluation of Recurrent Stroke Comparing PFO Closure to Established Current Standard of Care Treatment), and PC (Clinical Trial Comparing Percutaneous Closure of Patent Foramen Ovale [PFO] Using the Amplatzer PFO Occluder With Medical Treatment in Patients With Cryptogenic Embolism) trials. We examine the treatment effect of closure in high RoPE score (≥7) versus low RoPE score (

Percutaneous patent foramen ovale (PFO) closure is recommended for secondary prevention of paradoxical embolism through a PFO. In the United States, two Food and Drug Administration-approved PFO closure devices are currently available, and the choice depends on operator preference and PFO anatomy. Although these devices are easy to implant, there are several potential complications. As opposed to the Amplatzer PFO Occluder, there has been no published case of atrial erosion with Gore closure devices. This report describes two cases of pericardial tamponade due to perforation of the atrial wall induced by a wire frame fracture of the Gore Helex and Cardioform devices.

ImportanceRecent epidemiologic and therapeutic advances have transformed understanding of the role of and therapeutic approach to patent foramen ovale (PFO) in ischemic stroke. Patent foramen ovale is likely responsible for approximately 5% of all ischemic strokes and 10% of those occurring in young and middle-aged adults.ObservationsRandomized clinical trials have demonstrated that, to prevent recurrent ischemic stroke in patients with PFO and an otherwise-cryptogenic index ischemic stroke, PFO closure is superior to antiplatelet medical therapy alone; these trials have provided some evidence that, among medical therapy options, anticoagulants may be more effective than antiplatelet agents.Conclusions and relevanceThese new data indicate a need to update classification schemes of causative mechanisms in stroke, developed in an era in which an association between PFO and stroke was viewed as uncertain. We propose a revised general nomenclature and classification framework for PFO-associated stroke and detailed revisions for the 3 major stroke subtyping algorithms in wide use.

BackgroundResidual shunt is observed in up to 25% of patients after patent foramen ovale (PFO) closure, but its long-term influence on stroke recurrence currently is unknown.ObjectiveTo investigate the association of residual shunt after PFO closure with the incidence of recurrent stroke and transient ischemic attack (TIA).DesignProspective cohort study comparing stroke or TIA recurrence in patients with and without residual shunt after PFO closure.SettingSingle hospital center.Participants1078 consecutive patients (mean age, 49.3 years) with PFO-attributable cryptogenic stroke who were undergoing percutaneous PFO closure were followed for up to 11 years.MeasurementsResidual shunt was evaluated by transthoracic echocardiography with saline contrast. Primary outcome was a composite of the first recurrent ischemic stroke or TIA after PFO closure.ResultsCompared with complete closure, the presence of residual shunt after PFO closure was associated with an increased incidence of recurrent stroke or TIA: 2.32 versus 0.75 events per 100 patient-years (hazard ratio [HR], 3.05 [95% CI, 1.65 to 5.62]; P < 0.001). This result remained robust after adjustment for important covariates, namely age; study period; device; presence of atrial septal aneurysm, hypertension, hyperlipidemia, diabetes, hypercoagulability, or hypermobile septum; and medication use (HR, 3.01 [CI, 1.59 to 5.69]; P < 0.001). Further stratification based on shunt size revealed that moderate or large residual shunts were associated with a higher risk for stroke or TIA recurrence (HR, 4.50 [CI, 2.20 to 9.20]; P < 0.001); the result for small residual shunts was indeterminate (HR, 2.02 [CI, 0.87 to 4.69]; P = 0.102).LimitationNonrandomized study with potential unmeasured confounding.ConclusionAmong patients undergoing PFO closure to prevent future stroke, the presence of residual shunt, particularly a moderate or large residual shunt, was associated with an increased risk for stroke or TIA recurrence.Primary funding sourceNational Institutes of Health.

ObjectivesTo compare residual shunt rate and complications associated with six different devices used for PFO closure.BackgroundTranscutaneous PFO closure is an effective treatment for preventing recurrent stroke in patients with a history of cryptogenic stroke. The rate of residual shunt is one metric by which the technical success of PFO closure can be measured.MethodsPatients who underwent PFO closure at a single center between February 2001 and July 2019 were retrospectively enrolled in the study. Right-to-left shunt at baseline and during follow-up was assessed using transcranial Doppler (TCD) or transthoracic echocardiography (TTE). Periprocedural and device-related complications, including atrial fibrillation, were also assessed.ResultsOf 467 PFO closures performed during this period, 320 patients received quantitative assessment of right-to-left shunting both before and after percutaneous closure. The highest effective closure was achieved with the Cardioform device (100%, n = 104), followed by the Amplatzer Cribriform (93%, n = 14), Helex (90%, n = 137), Amplatzer ASO (88%, n = 17), CardioSEAL (86%, n = 14), and Amplatzer PFO (85%, n = 33) devices. The most common significant adverse event was atrial fibrillation, which was more common with the Cardioform device (13%) than the Helex (4%) or the Amplatzer PFO (4%) devices.ConclusionsThe Gore Cardioform Septal Occluder provides more robust closure of a PFO when compared to other devices but its effectiveness is offset by the higher prevalence of transient atrial fibrillation.

Over 50% of patients who rapidly ascend to extreme altitudes develop various symptoms known as acute mountain sickness (AMS), which rarely can be life threatening. It is unclear why some patients are more susceptible to AMS than others. Our objective was to determine whether patent foramen ovale (PFO) is a risk factor for AMS. Subjects who had hiked to altitudes above 10,000' (∼3,000 meters) on the John Muir Trail in California were recruited. Participants completed a questionnaire and 2-physician adjudication was performed in regard to AMS status. A transcranial Doppler with agitated saline contrast injection was performed to evaluate the presence or absence of PFO. The primary outcome was the development of AMS. From 2016 to 2018, 137 hikers were recruited into the study. There was a higher prevalence of PFO in hikers with AMS 15 of 24 (63%) compared with hikers without AMS 44 of 113 (39%); p = 0.034. In the multivariate model, the presence of a PFO significantly increased the risk for developing AMS: odds ratio 4.15, 95% confidence intervals 1.14 to 15.05; p = 0.030. In conclusion, hikers with a PFO had significantly higher risk of developing AMS relative to hikers without a PFO. Clinicians should consider PFO a risk factor in patients who plan to hike to high altitudes.

"Observational studies have identified a relationship between patent foramen ovale (PFO) and migraine headache. In people who have migraine with aura, 40% to 60% have a PFO, compared with 20% to 30% in the general adult population. It is hypothesized that migraine, especially migraine with aura, may be triggered by hypoxemia or vasoactive chemicals (eg, serotonin), which are ordinarily metabolized during passage through the lungs. Although PFO closure is currently not a FDA-approved therapy for migraines, randomized trials suggest that this intervention may benefit a subgroup of migraineurs."

In the presence of a patent foramen ovale (PFO), a transient ischemic attack is indistinguishable from a complex migraine. Both have transient neurologic deficits with a normal MRI. The size of a PFO by echo should not be a criterion for closure. A stroke or peripheral embolus associated with a PFO is the indication for closure. Informed consent for PFO closure should include the warning that about 1 in 500 cases require device removal through open-heart surgery.

Until recently, evidence to support Patent Foramen Ovale (PFO) closure for secondary prevention of recurrent stroke has been controversial. Publication of high-quality evidence from randomized clinical trials and the subsequent FDA approval of two devices for percutaneous PFO closure is expected to increase the volume of PFO closure procedures not only in the United States but worldwide. As this technology is disseminated broadly to the public, ensuring the safe and efficacious performance of PFO closure is essential to mitigate risk and avoid unnecessary procedures. This document, prepared by a multi-disciplinary writing group convened by the Society for Cardiovascular Angiography and Interventions and including representatives from the American Academy of Neurology, makes recommendations for institutional infrastructure and individual skills necessary to initiate and maintain an active PFO/stroke program, with emphasis on shared decision making and patient-centered care.

Patent foramen ovale (PFO), an embryonic remnant of the fetal circulation, is present in 20-25% of adults. Although recent observational studies and clinical trials have established the link between PFO-mediated right-to-left shunting with cryptogenic stroke and migraine with aura, the role of a PFO in exacerbating hypoxemic medical conditions (ie, sleep apnea, chronic obstructive pulmonary disease, pulmonary hypertension, platypnea-orthodeoxia, pulmonary arteriovenous malformation, high-altitude pulmonary edema, and exercise desaturation) remains less understood. PFO-mediated hypoxemia occurs when deoxygenated venous blood from the right atrium enters and mixes with oxygenated arterial blood in the left atrium. Patients with an intracardiac right-to-left shunt may have profound hypoxemia out of proportion to underlying primary lung disease, even in the presence of normal right-sided pressures. The presence of right-to-left cardiac shunting can exacerbate the degree of hypoxemia in patients with underlying pulmonary disorders. In a subset of these patients, percutaneous PFO closure may result in marked improvement in dyspnea and hypoxemia. This review discusses the association between PFO-mediated right-to-left shunting with medical conditions associated with hypoxemia and explores the role of percutaneous PFO closure in alleviating the hypoxemia.

BACKGROUND AND PURPOSE:Individuals with migraine are at higher risk for stroke, but the mechanism has not been established. On the basis of the association between migraine and intracardiac right-to-left shunt, it has been proposed that stroke in migraineurs could be caused by a paradoxical embolus passing through a patent foramen ovale (PFO) or pulmonary arteriovenous malformation. The aim of this study was to determine the prevalence of PFO with right-to-left shunt in patients who presented with cryptogenic stroke and had a history of migraine. METHODS:Patients between 18 and 60 years old who presented with an ischemic stroke were characterized based on ASCOD phenotyping (atherosclerosis; small-vessel disease; cardiac pathology; other causes; dissection). A migraine diagnosis was identified by reviewing physician notes, and frequent aura was defined if present in at least 50% of attacks. A PFO with right-to-left shunt diagnosis was identified by the presence of a positive bubble contrast study with either transcranial Doppler, transthoracic, or transesophageal echocardiography. RESULTS:Of the 712 patients who presented with ischemic stroke, 127 (18%) were diagnosed as cryptogenic; 68 patients had adequate testing for PFO and a documented migraine history. The prevalence of PFO in patients with cryptogenic stroke without migraine was elevated (59%) compared with the general population (18%). Patients with both cryptogenic stroke and migraine had a higher prevalence of PFO (79%). In patients with cryptogenic stroke who had migraine with frequent aura, the prevalence of PFO was 93%. Only 5 patients (4%) had a history compatible with migrainous infarction. CONCLUSIONS:In patients with cryptogenic stroke who have migraine, there is a high prevalence (79%) of PFO with right-to-left shunt. The timing of the stroke in migraineurs is usually not related to a migraine attack. These observations are consistent with the hypothesis that the mechanism of stroke in migraineurs is most likely because of a paradoxical embolus. Future cryptogenic stroke classification schemes should consider including PFO as a separate etiologic category.

Nearly one-half of patients with cryptogenic stroke have a patent foramen ovale (PFO). The dilemma of whether to close these PFOs percutaneously, in an effort to reduce the risk of recurrent paradoxical embolism, has been a matter of ongoing debate for more than a decade. Early randomized clinical trials failed to demonstrate a significant benefit of percutaneous PFO closure for secondary prevention of cryptogenic stroke in an intention-to-treat analysis. The long-term follow-up data from the RESPECT trial and 2 new randomized trials (CLOSE and REDUCE) have clarified these findings. They showed that with good patient selection, transcatheter PFO closure significantly reduces the risk of recurrent stroke compared with medical therapy in patients with cryptogenic stroke, with no increased risk of serious adverse events or influence on major bleeding.

BackgroundMigraine is a prevalent and disabling disorder. Patent foramen ovale (PFO) has been associated with migraine, but its role in the disorder remains poorly understood.ObjectivesThis study examined the efficacy of percutaneous PFO closure as a therapy for migraine with or without aura.MethodsThe PREMIUM (Prospective, Randomized Investigation to Evaluate Incidence of Headache Reduction in Subjects With Migraine and PFO Using the AMPLATZER PFO Occluder to Medical Management) was a double-blind study investigating migraine characteristics over 1 year in subjects randomized to medical therapy with a sham procedure (right heart catheterization) versus medical therapy and PFO closure with the Amplatzer PFO Occluder device (St. Jude Medical, St. Paul, Minnesota). Subjects had 6 to 14 days of migraine per month, had failed at least 3 migraine preventive medications, and had significant right-to-left shunt defined by transcranial Doppler. Primary endpoints were responder rate defined as 50% reduction in migraine attacks and adverse events. Secondary endpoints included reduction in migraine days and efficacy in patients with versus without aura.ResultsOf 1,653 subjects consented, 230 were enrolled. There was no difference in responder rate in the PFO closure (45 of 117) versus control (33 of 103) groups. One serious adverse event (transient atrial fibrillation) occurred in 205 subjects who underwent PFO closure. Subjects in the PFO closure group had a significantly greater reduction in headache days (-3.4 vs. -2.0 days/month, p = 0.025). Complete migraine remission for 1 year occurred in 10 patients (8.5%) in the treatment group versus 1 (1%) in the control group (p = 0.01).ConclusionsPFO closure did not meet the primary endpoint of reduction in responder rate in patients with frequent migraine. (Prospective, Randomized Investigation to Evaluate Incidence of Headache Reduction in Subjects With Migraine and PFO Using the AMPLATZER PFO Occluder to Medical Management [PREMIUM]; NCT00355056).

A patent foramen ovale (PFO) is a common anatomic finding in 20% of the normal population. Significant hypoxemia can occur in circumstances in which hemodynamic or anatomic changes predispose to increased right-to-left intra-atrial shunting. The subsequent hypoxemia produces substantial dyspnea that may affect the patient's quality of life, independent of underlying pulmonary disease. Profound hypoxemia caused by right-to-left shunt across the interatrial septum usually responds to percutaneous PFO closure. An important impediment to successful treatment is the lack of awareness of the potential role of a PFO in this condition.

Once deemed benign, patent foramen ovale (PFO)-mediated right-to-left shunting has now been linked to stroke, migraine, and hypoxemia. Contrast transesophageal echocardiography is considered the standard technique for identifying a PFO, allowing visualization of the atrial septal anatomy and differentiation from non-PFO right-to-left shunts. Transthoracic echocardiography is the most common method for PFO imaging, being cost-effective, but has the lowest sensitivity. Transcranial Doppler is highly sensitive but is unable to differentiate cardiac from pulmonary shunts; it is the best method to quantitate shunt severity, being more sensitive than transthoracic or transesophageal echocardiography so is our preferred screening method for PFO.

Patent foramen ovale has been associated with multiple pulmonary diseases, such as pulmonary hypertension, platypnea-orthodeoxia syndrome, and chronic obstructive pulmonary disease. A connection between patent foramen ovale and chronic pulmonary disease was first described more than 2 decades ago in case reports associating patent foramen ovale with more severe hypoxemia than that expected based on the severity of the primary pulmonary disease. It has been suggested that patients with both chronic pulmonary disease and patent foramen ovale are subject to severe hypoxemia because of the right-to-left shunt. Furthermore, investigators have reported improved systemic oxygenation after patent foramen ovale closure in some patients with chronic pulmonary disease. This review focuses on the association between chronic pulmonary disease and patent foramen ovale and on the dynamics of a right-to-left shunt, and it considers the potential benefit of patent foramen ovale closure in patients who have hypoxemia that is excessive in relation to the degree of their pulmonary disease.

A patent foramen ovale (PFO) is a communication across the inter-atrial septum and a right atrial septal pouch (RASP) is an indentation of the atrial septum caused by an incomplete fusion of the septum primum and septum secundum with its base opening into the right atrium. A 63-year-old male who had a history of two strokes and episodes of transient neurological deficit was diagnosed to have a small right-to-left shunt. At the time of PFO closure, an angiogram of the atrial septum revealed a small PFO associated with a RASP. The small PFO was crossed with a straight-tipped guide wire and was closed using a 25-mm GORE CARDIOFORM Septal Occluder (W.L. Gore and Associates, AZ). It is hypothesized that stagnant blood in the RASP may generate a clot that can cross the PFO and cause an infarct. © 2015 Wiley Periodicals, Inc.

IntroductionPatent foramen ovale (PFO) is a common congenital cardiac abnormality and that has been associated with several disease processes including transient ischemic attacks (TIA), stroke, migraine headaches with aura, decompression sickness, platypnea-orthodeoxia syndrome, and shunt induced cyanosis. Controversy exists regarding closure of PFO as a therapeutic treatment modality for these disease processes. This review addresses the contemporary clinical indications for PFO closure. Areas covered: We conducted a comprehensive literature search of contemporary research studies focusing on randomized trials and meta-analyses comparing medical therapy and device closure of PFOs for the treatment of PFO associated clinical syndromes. We synthesized this literature into a review addressing indications for PFO closure in stroke, TIA, migraine headaches with aura, decompression sickness, platypnea-orthodeoxia syndrome, and shunt induced cyanosis. Expert commentary: Because in many PFO associated conditions it can be difficult to determine the degree to which the PFO is a causative factor in the disease process, we recommend a comprehensive diagnostic evaluation to exclude other obvious etiologies of PFO associated conditions before implicating the PFO and proceeding with closure. However in the properly selected patient population there is growing clinical experience and experimental evidence suggesting that closure of PFO is a safe and effective treatment modality.

BackgroundTranscranial Doppler (TCD) with agitated saline has been shown to be an alternative for the detection of right-to-left shunts (RLS) with similar diagnostic accuracies as transesophageal echocardiography (TEE). It is hypothesized that the addition of blood to agitated saline increases the sensitivity of TCD for the detection of RLS. The aim of this meta-analysis was to determine whether agitated saline with blood increases the sensitivity of TCD for the detection of RLS compared to agitated saline alone and other contrast agents.MethodA systematic review of Medline, Cochrane, and Embase was performed to look for all prospective studies assessing intracardiac RLS using TCD compared with TEE as the reference; both tests were performed with a contrast agent and a maneuver to provoke RLS in all studies.ResultsA total of 27 studies (29 comparisons) with 1,968 patients met the inclusion criteria. Of 29 comparisons, 10 (35%) used echovist contrast during TCD, 4 (14%) used a gelatin-based solution, 12 (41%) used agitated saline, and 3 (10%) utilized 2 different contrast agents. The addition of blood to agitated saline improved the sensitivity of TCD to 100% compared to agitated saline alone (96% sensitivity, P = 0.161), echovist (94% sensitivity, P = 0.044), and gelatin-based solutions (93% sensitivity, P = 0.041).ConclusionThe addition of blood to agitated saline improves the sensitivity of TCD for the detection of RLS to 100% when compared to other conventional contrast agents; these findings support the addition of blood to agitated saline during TCD bubble studies.

In patients who have a cryptogenic stroke and have their PFO closed, the recurrence rate of "cerebral ischemia" is much greater in patients who are older than 55 years. Most of these recurrent events (2 strokes and 4TIAs) in the older age group were due to identifiable causes. These findings corroborate the long-term results from the RESPECT randomized clinical trial of PFO closure versus medical therapy.

The foramen ovale is a remnant of the fetal circulation that remains patent in 20-25% of the adult population. Although long overlooked as a potential pathway that could produce pathologic conditions, the presence of a patent foramen ovale (PFO) has been associated with a higher than expected frequency in a variety of clinical syndromes including cryptogenic stroke, migraines, sleep apnea, platypnea-orthodeoxia, deep sea diving associated decompression illness, and high altitude pulmonary edema. A unifying hypothesis is that a chemical or particulate matter from the venous circulation crosses the PFO conduit between the right and left atria to produce a variety of clinical syndromes. Although observational studies suggest a therapeutic benefit of PFO closure compared to medical therapy alone in patients with cryptogenic stroke, 3 randomized controlled trials (RCTs) did not confirm the superiority of PFO closure for the secondary prevention of stroke. However, meta-analyses of these RCTs demonstrate a significant benefit of PFO closure over medical therapy alone. Similarly, observational studies provide support for PFO closure for symptomatic relief of migraines. But one controversial randomized study failed to replicate the results of the observational studies while another two demonstrated a partial benefit. The goal of this review is to discuss the clinical conditions associated with PFO and provide internists and primary care physicians with current data on PFO trials, and clinical insight to help guide their patients who are found to have a PFO on echocardiographic testing.

ObjectivesTo assess the presence of right-to-left shunting (RLS) in patients with obstructive sleep apnea (OSA), and compare clinical characteristics and parameters of the sleep studies of patients with and without RLS.BackgroundThe most common cause of RLS is due to intermittent flow through a patent foramen ovale (PFO). PFO occurs more frequently in patients with OSA and may be involved in the exacerbation of OSA.MethodsPatients with an abnormal polysomnogram seen at UCLA-Santa Monica Sleep Medicine Clinic were enrolled. A diagnosis of RLS was made using a transcranial Doppler (TCD) bubble study. Gender and age-matched controls were drawn from patients referred for cardiac catheterization who underwent a TCD. The frequency of RLS in OSA patients and the controls was evaluated. Clinical characteristics and polysomnogram parameters were compared between OSA patients with and without a RLS.ResultsA total of 100 OSA patients and 200 controls participated in the study. The prevalence of RLS was higher in patients with OSA compared to the control group (42% versus 19%; p < 0.0001). Patients with OSA and a RLS had a lower apnea-hypopnea index (AHI), less obstructive apnea, and fewer hypopnea episodes than patients with OSA without a RLS. The baseline and nadir SpO2 were similar in both groups and did not correlate with the level of RLS assessed by TCD. The degree of desaturation for a given respiratory disturbance, as measured by oxygen desaturation index (ODI)/AHI ratio, was higher in OSA patients with RLS versus OSA patients without RLS (0.85 ± 0.07 versus 0.68 ± 0.04; p < 0.0001).ConclusionRLS, most commonly due to a PFO, occurs 2.2 times more frequently in OSA patients compared to a control population that was matched for age and gender. The severity of sleep apnea is not greater in OSA patients who have a PFO. However, patients with OSA and a PFO are more likely to become symptomatic at a younger age with an equivalent decrease in nocturnal SpO2, and have greater arterial desaturation in proportion to the frequency of respiratory disturbances.

BackgroundPlatypnea-orthodeoxia syndrome is a rare condition characterized by hypoxemia in the upright position that is improved in the supine position. Although several etiologies of platypnea-orthodeoxia exist, it is frequently associated with right-to-left shunting of blood at the cardiac or pulmonary level, usually via a patent foramen ovale (PFO). The aim of this study was to evaluate the incidence of platypnea-orthodeoxia syndrome in a select patient population with right-to-left shunting and to describe the outcomes after PFO closure.MethodsPatients with platypnea-orthodeoxia were prospectively identified from a population of patients who had a PFO and were referred to UCLA from 2001 to 2012. Those patients who elected to have their PFO closed were assessed for the severity of their symptoms and interval SaO2 changes. The changes in SaO2 before and after closure were compared in the supine and upright position. Patients were classified depending on the result of PFO closure as having "improved SaO2 " or "no change."ResultsOf 683 patients with PFO-associated conditions, 17 (2.5%) had platypnea-orthodeoxia and elected to close their PFO. The results in 11 of 17 patients (64.8%) were classified as having "improved SaO2 "; they experienced improvement or complete resolution of their dyspnea and hypoxemia (improved SaO2 from baseline 5.2 ± 4.7% when recumbent and 15.6 ± 3.0% when upright, P = 0.03 and P < 0.0001, respectively). Patients with no change after PFO closure predominantly had a pulmonary etiology for their hypoxia, with elevated mean pulmonary pressures measured before closure (51.4 ±16.8 mmHg, P = 0.06).ConclusionPFO closure may resolve symptomatic postural dyspnea and hypoxemia and is an effective method for treating platypnea-orthodeoxia, but is not effective when the primary etiology of the hypoxemia is due to a pulmonary cause.

BackgroundTranscranial Doppler (TCD) can detect a right-to-left shunt (RLS) with high sensitivity but has a 5% chance of a false negative study. TCD is usually performed with injection of agitated saline into an arm vein. We compared the sensitivity of TCD performed from the brachial versus femoral veins.MethodsPatients presenting to the cardiac catheterization laboratory for percutaneous closure of a patent foramen ovale (PFO) were enrolled. Power M-mode Transcranial Doppler (Terumo 150 PMD) was conducted. After injection of a mixture of 8 cc of agitated saline, 0.5 cc of air, and 1 cc of blood into the brachial vein, embolic tracks were counted over the middle cerebral arteries. The degree of RLS was evaluated by TCD at rest, and with Valsalva at 40 mmHg aided by visual feedback with a manometer device. The test was repeated using femoral venous injections.ResultsSixty five patients were enrolled, mean age 52, 43% male. TCD grades were significantly higher with femoral injections compared to brachial injections at rest (p

BackgroundParadoxical embolization through a right-to-left shunt (RLS), often from a patent foramen ovale (PFO), has been associated with cryptogenic stroke. While transesophageal echo (TEE) bubble study is the current standard reference for diagnosing PFO, transthoracic echo (TTE) remains the most commonly used screening test for RLS due to its noninvasiveness and easy availability. The aim of this meta-analysis was to determine the accuracy of TTE compared to TEE as the reference.Methods and resultsA systematic review of Medline, Cochrane, and Embase was done to look for all the prospective studies assessing for intracardiac RLS using conventional TTE compared to TEE as the reference; both TTE and TEE were performed with a contrast agent and a maneuver to provoke RLS in all studies. A total of 13 studies with 1436 patients fulfilled the inclusion criteria. The weighted mean sensitivity and specificity for TTE were 46% and 99%, respectively. Likewise, the positive likelihood ratio and negative likelihood ratio were 20.85 and 0.57, respectively. Using different contrast agents, different microbubble cutoffs for a positive TTE/TEE, and different cardiac cycle cutoffs for a positive TTE/TEE did not affect the accuracy of TTE. In a population of patients with cryptogenic stroke, a TTE that tests positive for RLS has a 95% probability of being a true positive.ConclusionTransthoracic echocardiogram has a low sensitivity and extremely high specificity, making it a poor rule out test but an excellent rule in test for the detection of intracardiac RLS.

BackgroundPostmenopausal hormone therapy (HT) increases the risk of venous thrombosis and ischemic stroke.ObjectivesWe postulated that HT might increase the risk of ischemic stroke by promoting venous clots that travel to the brain through a right to left shunt (RLS).MethodsA total of 2,389 records were studied. After eliminating the premenopausal patients, and those with TIAs and non-ischemic strokes, the medical records of 1846 postmenopausal women hospitalized at four institutions for ischemic stroke were reviewed to identify those who had undergone an adequate study to assess for RLS. The proportion of women with a shunt in users and non-users of HT was compared in stroke patients and in a reference population consisting of postmenopausal women undergoing elective cardiac catheterization.ResultsThere were 363 (20%) records that had complete data and were included in the analysis. A shunt was more prevalent in patients with a cryptogenic stroke than in patients with a stroke of known cause (55/88 (63%) vs. 53/275 (19%), P

ObjectivesTo assess the effective closure rate among devices used for transcatheter patent foramen ovale (PFO) closure, and to discuss the management of patients with large residual shunts.BackgroundSeveral devices are used off-label for transcatheter closure of a PFO in the United States. The rate of residual shunting after PFO closure varies by device. Failure of effective closure poses risk of a recurrent cerebrovascular event, persistent migraine, or recurrent orthodeoxia.MethodsPatients who underwent PFO closure in the Cardiac Catheterization Laboratory at UCLA between 2001 and 2013 and had baseline and adequate follow-up transcranial Doppler studies following device placement were enrolled in the study.ResultsOf 167 patients whose records were analyzed, effective PFO closure occurred in 90% (150/167) of patients. The highest effective closure rate was with the Amplatzer Septal Occluder (ASO; 100%), followed by the Amplatzer Cribriform (93%), Gore Helex (90%), Amplatzer PFO (86%), and CardioSEAL (86%) device. The highest rate of residual shunting was observed after placement of the 30-mm Gore Helex device (55%). Of the 17 patients with a residual shunt, three required a repeat PFO closure procedure due to a significant residual shunt associated with recurrent pulmonary emboli or profound orthodeoxia. All three patients received an ASO which successfully closed the residual shunt.ConclusionsTranscatheter PFO closure has a high success rate, but a moderate residual shunt occurs in about 10% of cases. The observed incidence of residual shunting after PFO closure is significantly larger with the 30-mm Helex device. © 2014 Wiley Periodicals, Inc.