References: Matthew Nayor et al. Contemporary Approach to Paradoxical Embolism. Circulation. 2014;129:1892-1897. Marco Hernandez-Enrıquez et al.  Current Indications for Percutaneous Closure of Patent Foramen Ovale.  Rev Esp Cardiol. 2014;67(8):603–607.

The debate on patent foramen ovale behavior in different clinical contexts remains open, no pun intended. Based on numerous observational studies and expert recommendations, when facing the risk of paradoxical embolism, closure used to be the gold standard. However, three fairly recent randomized controlled clinical studies seem to have eradicated this recommendation. 

In the past few days, two excellent reviews, one published in Circulation and the other in Revista Española de Cardiología, analyze this question.

 – Anatomy and physiology

Circulation change from fetal to postpartum is a real wonder of nature. Right-to-left shunt of blood flow via foramen ovale is an essential piece of fetal circulation, vital to life, since oxygen rich blood coming from the placenta through the inferior vena cava into the right atrium must be redirected to the left atrium and the aorta. 

The particular anatomy of the right atrium, with the Eustachian valve redirecting the flow of oxygen rich blood across the atrial septum, the strong fetal pulmonary resistance and the lower pressure of the left atrium facilitate such short circuit, through the foramen ovale, an advantage of the septum secundum. At the moment of birth, lungs are oxygenated, which drastically reduces pulmonary vascular resistance and, in time, elevates systemic vascular resistance, with the consequent inversion of inter atrial pressure (more pressure in the left atrium than in the right atrium), which interrupts the right to left shunt and forces the flexible and thin septum primum against the muscular and more rigid septum secundum, leading to closure of the foramen ovale. This initial closure (physiological) typically occurs by 2 years of age, when these tissues merge into one (anatomical closure). However, for unknown reasons, an important number of individuals do not succeed in growing the primum septum into the secundum, or may not grow it completely, resulting in a patent foramen ovale (PFO). Observational studies and autopsies reveal this occurs in 25% of cases.

– PFO diagnosis

PFO may be incidental and have no clinical consequences. Transesophageal echocardiography (TEE) is considered the most accurate method to identify the presence of PFO and to define its anatomy; its sensitivity increases with the use of intravenous contrast of micro bubbles with agitated saline. Transthoracic echocardiography (ETT) with Doppler and resting bubble contrast with Valsalva maneuver is also a useful tool. Transcranial Doppler can identify the presence of micro bubbles in the basal brain arteries to diagnose PFO; however, this should generally be completed with ETT or TEE to confirm findings and define shunt anatomy. Cardiac MRI and CT are the second, less accurate, alternatives to EET or TEE for PFO diagnosis.

Anatomical characteristics of the right atrium and the atrial septum, usually studied by TEE, provide crucial information: the size of cavities, possible aneurysms of the atrial septum (ASA), size of defect, location in relation to the aortic rim, magnitude and direction of shunt, etc. Certain anatomical features have been associated with a higher risk of paradoxical embolism: an important defect (>5 mm), a prominent Eustachian valve, right to left shunt  both at rest and with Vasalva, and the presence of accompanying ASA (defined as an excursion > 10 mm of septum in relation to septal plane, present in nearly one third of PFO cases).

 – Observational and epidemiological studies

In several observational series and case-controlled studies, PFO has been associated to the pathogenesis of cerebrovascular diseases, mainly transient ischemic attack, ischemic stroke and migraine headache. Even though it is known that PFO incidence in higher in patients with idiopathic stroke compared to normal subjects (up to 4 times higher, according to some series) their association has not yet been proved; a recent study with more than 1000 patients follow up at 11 years, PFO had no significant influence on the risk of suffering a first stroke. Nevertheless, when present, stroke in patients with PFO is hypothesized to involve paradoxical embolism. Percutaneous closure devices, effective and with a low rate of complications, are being valued as an alternative therapy in these cases. Moreover, after the issuing of several retrospective and observational studies suggesting an important benefit, a meta-analysis of these same studies suggest a reduction from 5 to 0.8 in the number of events every 100 patients a year for the intervention group, compared to the control group.

 – Randomized and controlled studies

Three randomized controlled studies on this issue have been recently published: CLOSURE I (N Engl J Med 2012;366:991–999), PC trial (N Engl J Med 2013;368:1083–1091) and RESPECT (N Engl J Med 2013;368:1092–1100).

Perhaps due to the seemingly suboptimal design of the chosen device, the CLOSURE I has been challenged because of its high complications rate and the nature of the intervened population (auricular fibrillation, and thrombosis), and a relatively low procedural success rate. PC and RESPECT trials used the Amplatzer device (St. Jude Medical), which showed better results with a lower incidence of AF, thrombosis and vascular complications. The PC trial was the only one to include patients with peripheral embolisms but in very low numbers (11 cases). The RESPECT had stricter inclusion criteria, since it only included stroke cases and excluded TIA cases; the studied population presented a low events rate, lower than expected, and it required 7 years to collect data on 25 primary events (recurrent stroke or death after procedure). No significant differences were seen in the primary analysis by treatment intention but differences were observed in the analysis by protocol or by treatment in favor of closure. From the subgroups, a major benefit of closure was observed in those subjects with large shunts (>20 bubbles) and ASAs.

Despite the negative results of these individual studies, several meta-analysis have been published on their data and, in most of them, outcomes seem to favor percutaneous closure, particularly when analyzing the Amplatzer outcomes alone.

A fourth trial called REDUCE comparing closure using a new percutaneous device (other than the Amplatzer) vs. medical treatment is currently in progress. 

 – Conclusions:

The initial enthusiasm that percutaneous closure devices had generated has largely declined since these studies were published and, at present, there is no conclusive evidence to indicate closure in patients undergoing cryptogenic stroke with PFO. 

So, when should PFO closure be indicated? The indication seems reasonable for Young patients (

Other less frequent indications would be: professional scuba divers with decompression conditions and patent foramen ovale (non-conclusive evidence), patients with platypnea-orthodeoxia, a rare condition characterized by dyspnea and hypoxemia in standing position that improves with horizontal position; produced by several  anatomical thoracic alterations in the context of PFO (aneurysm or aortic enlargement, thoracic surgery, serious emphysema, etc.) which alter the cava vein flow when standing, orienting the flow of blood towards the PFO and generating a right-to left shunt. Regarding migraine patients and PFO, at present there is no conclusive evidence to recommend closure.

Courtesy of del Dr. Alejandro Lakowsky.
MTSAC.

Alejandro Lakowsky