Patent foramen ovale: The current state of play

Abstract

### Learning objectives

Patent foramen ovale (PFO) is a common finding, occurring in up to 25% of people.1 ,2 An association between PFO and stroke has consistently been seen in up to 50% of patients without an identifiable cause, that is, the so-called cryptogenic stroke (CS) and only in 20% with an identified cause.3 ,4 Many studies have been published testing the hypothesis that paradoxical emboli through a PFO may be implicated, however the available evidence is mixed and conflicting,5 ,6 perhaps in part due to the low recurrence rate and long-term nature of these events. PFOs are associated with numerous other conditions including migraine with aura, decompression sickness, other venoarterial embolic phenomena and platypnoea orthodeoxia.

In this review we will describe the embryological development of the interatrial septum, discuss the diagnosis and clinical associations of PFO, as well as evaluate the available data for and against closure.

The embryological development of the interatrial septum and foramen ovale is complex, starting at 4–5 weeks post conception with fusion of ventral and dorsal endocardial cushions. Closure of the atrioventricular canal creates two cavities that develop into atria and ventricles and divide into left and right sides. Initially the septum primum grows from the roof of the atria towards the fused endocardial cushion (figure 1A), while the gap, the ostium primum, allows interatrial flow. Before complete atrial separation, a new communication, the ostium secundum, develops by fenestration of the superior region (figure 1B ), allowing continuous right-to-left shunting of oxygenated blood from the umbilical arteries bypassing the fetal pulmonary circulation (figure 1 …

Full text

Patent foramen ovale: the current state of play
Kaleab N Asrress, Maciej Marciniak, Anna Marciniak, Ronak Rajani, Brian Clapp
Curriculum topic: Congenital heart disease in adult patients
Department of Cardiology,
Guy’s and St Thomas’NHS
Foundation Trust, London, UK
Correspondence to
Dr Brian Clapp, Department of
Cardiology, St Thomas’
Hospital, Westminster Bridge
Road, London SE1 7EH, UK;
Brian.Clapp@gstt.nhs.uk
KNA and MM contributed
equally to this study.
Received 12 June 2015
Revised 19 August 2015
Accepted 13 September 2015
Published Online First
20 October 2015
To cite: Asrress KN,
Marciniak M, Marciniak A,
et al.Heart
2015;101:1916–1925.
INTRODUCTION
Patent foramen ovale (PFO) is a common finding,
occurring in up to 25% of people.
12
An associ-
ation between PFO and stroke has consistently
been seen in up to 50% of patients without an
identifiable cause, that is, the so-called cryptogenic
stroke (CS) and only in 20% with an identified
cause.
34
Many studies have been published testing
the hypothesis that paradoxical emboli through a
PFO may be implicated, however the available evi-
dence is mixed and conflicting,
56
perhaps in part
due to the low recurrence rate and long-term
nature of these events. PFOs are associated with
numerous other conditions including migraine with
aura, decompression sickness, other venoarterial
embolic phenomena and platypnoea orthodeoxia.
In this review we will describe the embryological
development of the interatrial septum, discuss the
diagnosis and clinical associations of PFO, as well as
evaluate the available data for and against closure.
ANATOMY AND EMBRYOLOGY
The embryological development of the interatrial
septum and foramen ovale is complex, starting at
4–5 weeks post conception with fusion of ventral
and dorsal endocardial cushions. Closure of the
atrioventricular canal creates two cavities that
develop into atria and ventricles and divide into
left and right sides. Initially the septum primum
grows from the roof of the atria towards the fused
endocardial cushion (figure 1A), while the gap, the
ostium primum, allows interatrial flow. Before com-
plete atrial separation, a new communication, the
ostium secundum, develops by fenestration of the
superior region (figure 1B), allowing continuous
right-to-left shunting of oxygenated blood from the
umbilical arteries bypassing the fetal pulmonary cir-
culation (figure 1C). Infolding of the atrial wall on
the right aspect of the septum primum produces
the septum secundum to overlap the ostium secun-
dum (figure 1D). The two septae partially fuse and
leave an uncovered part of the septum primum
forming the fossa ovalis and anterosuperiorly the
foramen ovale (figure 1E). Reversal of the pressure
gradient on birth approximates the remaining flap
and in the majority of the population the linings of
ostium primum and ostium secundum fuse perman-
ently closing the foramen.
PREVALENCE
PFO is believed to be present in up to one in four
adults, from postmortem studies. One study of 965
normal hearts documented an increasing size and
decreasing prevalence of PFO with age (34.3% up
to 30 years, 25.4% in the fourth decade and
20.2% in the ninth and tenth decades).
1
In 500
subjects who died due to acquired cardiovascular
pathology PFO occurred in 15% of cases.
7
Similarly, a PFO prevalence of 24% was found with
transoesophageal echocardiography (TOE) among
585 subjects, age 45 years in a stroke prevention
study.
8
A larger, 1000 patient, TOE study found a
lower prevalence of PFO of 9.2%, although this
confirmed increasing frequency with age (12.96%
vs 6.15% in patients aged 40–49 years vs
70–79 years).
9
DIAGNOSIS
As most individuals with a PFO are asymptomatic,
it is usually an incidental finding at autopsy,
10
while
antemortem presentation is often with a clinically
associated condition and subsequent identification
by one of the following methods.
TRANSCRANIAL DOPPLER
Transcranial Doppler (TCD) studies flow patterns in
the middle cerebral artery and, following the per-
ipheral intravenous injection of agitated saline,
monitors for air bubbles during normal respiration
and manoeuvres that promote right-to-left shunting,
such as a sniff and Valsalva. Valsalva manoeuvre
increases intrathoracic pressure reducing systemic
venous return resulting, on release, in a temporary
increase in right atrial pressure producing a gradient
allowing right-to-left shunting with a PFO.
11
TCD
with contrast has a greater sensitivity than transthor-
acic echocardiography (TTE) with contrast at identi-
fying PFO with reduced specificity
12
as it is unable
to differentiate atrial, ventricular and pulmonary
arteriovenous malformations (pAVMs).
TRANSTHORACIC ECHOCARDIOGRAPHY
TTE may identify a PFO using colour flow
mapping; however, if suspected, TTE should be
performed with air/saline or air/saline/blood con-
trast preferably injected from the femoral vein,
with a recent meta-analysis suggesting little differ-
ence between agents.
13
A PFO is confirmed by
Learning objectives
▸Understand the anatomy and embryology of
the interatrial septum and patent foramen
ovale (PFO).
▸Develop an overview of the many clinical
associations of a PFO.
▸Appraise the clinical evidence for and against
closure of PFO.
1916 Asrress KN, et al.Heart 2015;101:1916–1925. doi:10.1136/heartjnl-2015-307639
Education in Heart
group.bmj.com on January 19, 2016 - Published by http://heart.bmj.com/Downloaded from

contrast in the left atrium within three cardiac
cycles following opacification of the right atrium
(figure 2); any longer than five cardiac cycles is
suggestive of an intrapulmonary shunt.
14 15
Shunt
size can be quantified based by the number of
bubbles seen in a single still frame (small: <10;
moderate: 10–20; large: >20 bubbles) at rest and
after provocative manoeuvres.
16
Data is emerging
that 3D TTE with contrast may be more effective
than 2D, and similar to TOE with contrast at iden-
tifying PFO.
14 17
TRANSOESOPHAGEAL ECHOCARDIOGRAPHY
Closer proximity of the TOE probe to the intera-
trial septum improves anatomical resolution
although the invasive nature impairs Valsalva per-
formance and reproducibility. Given the higher
yield in some studies TOE may be used if PFO is
not found non-invasively where there is a high clin-
ical suspicion or to confirm the anatomy, including
the location of the pulmonary veins, once the PFO
has been demonstrated on TTE (figures 3 and 4).
OTHER MODALITIES
Alternative imaging modalities such CT
18
(figure 5)
and cardiac MRI
19
can be used to identify PFO,
although ultrasound based techniques remain the
cornerstone of diagnosis.
ASSOCIATIONS OF PFO
Although striking images of large thrombi strad-
dling a PFO following CS lend causality support
Figure 1 Embryological development of the interatrial septum. (A) Septum primum grows from the roof of the atria. (B) Fenestrations develop
within the septum primum creating a channel, the ostium secundum (C), through which oxygenated blood passes from right to left bypassing the
fetal pulmonary circulation. (D) The septum secundum develops by infolding of the atrial wall on the right of the septum primum and overlapping the
ostium secundum. (E) The septum secundum partially covers the septum primum creating a thick arch over the ostium secundum with the uncovered
part of the septum primum forming the fossa ovalis. (F) The two septae fuse, apart from the anterosuperior aspect of the fossa ovalis creating a
tunnel, namely the foramen ovale. IVC, inferior vena cava; LA, left atrium; PFO, patent foramen ovale; RA, right atrium; SVC, superior vena cava.
Figure 2 Transthoracic echocardiogram during bubble contrast injection. Bubble
contrast transthoracic echocardiogram showing right-to-left shunting of contrast
medium during a Valsalva manoeuvre. PFO, patent foramen ovale; RA, right atrium.
Asrress KN, et al.Heart 2015;101:1916–1925. doi:10.1136/heartjnl-2015-307639 1917
Education in Heart
group.bmj.com on January 19, 2016 - Published by http://heart.bmj.com/Downloaded from

(figure 6) numerous other conditions have been
associated with an increased prevalence of PFO.
EMBOLIC PHENOMENA
Cryptogenic stroke
The first documented stroke in the presence of
PFO was a young woman reported by Cohnheim in
1877.
20
Subsequently, numerous studies have
shown a significantly higher prevalence of PFO
(averaging 40%) among subjects with CS compared
with the general population—a significant effect
irrespective of age.
421–26
Studies suggest the size of
PFO is correlated with risk in CS—suspected para-
doxical embolisation was more common with a
larger PFO than control or in those with known
stroke aetiology.
27
A large meta-analysis compared
CS with strokes of known causes and demonstrated
an OR for PFO of 3.16 (95% CI 2.30 to 4.35), for
atrial septal aneurysms (ASAs) 3.65 (95% CI 1.34
to 9.97) and for PFO plus ASA 23.26 (95% CI
5.24 to 103.20).
28
Whether anatomical variants,
such as a persistent Eustachian valve, aneurysmal
septum and prolonged PFO tunnel, are correlated
with increased risk simply as they reflect a larger
PFO is not clear.
Non-cerebral arterial embolisation
Systemic arterial embolisation to the limbs, gut and
kidneys has been reported in association with
PFO.
29–33
The presence of PFO has been associated
with young patients, without cardiovascular risk
factors and non-atheromatous arteries, presenting
with thrombotic ST elevation myocardial infarction
in some,
34 35
although not all, studies.
36 37
Published cases of myocardial infarction with
PFO often report the presence of pulmonary
emboli,
38–40
with the raised right-sided pressures
increasing right-to-left shunting. A cardiac MRI
study of patients with CS found 1 in 10 had sub-
clinical myocardial infarctions on late gadolinium
enhancement
41
—suggesting that this may be a
more common manifestation than previously
thought.
Septic embolisation
Thrombotic emboli travelling to the systemic circu-
lation via PFO bypass the mechanical filter of the
lung vasculature. Paradoxical infections are well
recognised complications among children with con-
genital intracardiac shunts or adult patients with
pAVMs
42
Similarly, cerebral abscesses have been
reported in patients with sepsis with a previously
silent PFO.
43
MIGRAINE WITH AURA
Migraines affect approximately 13% of the popula-
tion aged 20–64 years, with 36% preceded by
aura,
44
and PFO is associated with migraine with
aura in 40–60% compared with 20–30% con-
trols.
145–47
A PFO allows bypassing of the
Figure 3 Transoesophageal
echocardiogram of the interatrial
septum. (A) Transoesophageal
echocardiogram of the interatrial
septum showing a ‘slit-like’
communication between the left
atrium (LA) and right atrium (RA).
(B) Colour flow mapping of the
spontaneous left-to-right shunt. PFO,
patent foramen ovale.
Figure 4 Transoesophageal echocardiography (TOE) of
the interatrial septum showing a significant atrial septal
aneurysm (ASA). LA, left atrium; RA, right atrium.
1918 Asrress KN, et al.Heart 2015;101:1916–1925. doi:10.1136/heartjnl-2015-307639
Education in Heart
group.bmj.com on January 19, 2016 - Published by http://heart.bmj.com/Downloaded from

filtration activity of the lungs perhaps leading to
increased systemic concentration of nitric oxide,
kinins, serotonins or other vasoactive substances
triggering migraine attacks.
48 49
Alternative propo-
sitions include deoxygenation of arterial blood
causing attacks and long-term shunting, lowering
the threshold for migraine attacks.
50
DECOMPRESSION SICKNESS
Decompression sickness can occur following diving
or at high altitudes in pilots and astronauts.
51
Inert
gas bubbles formed during depressurisation may
cause decompression sickness. Usually these
migrate through capillaries or lymphatics to the
pulmonary circulation and are expired. However,
when present in large numbers, they swamp this
filter to enter the arterial circulation and, after
amplification by further inert gases within periph-
eral tissues, cause the acute vascular effects of
decompression sickness. A PFO or pAVM facilitates
the entry of inert bubbles in the arterial circulation.
Decompression sickness following a normal non-
provocative dive profile, where ascent is at an
appropriate pace, is more often associated with a
right-to-left shunt than following a provocative
dive.
52
The risk of decompression sickness also
depends on the size of the PFO.
53
OTHER CONDITIONS ASSOCIATED WITH PFO
Obstructive sleep apnoea
It has been suggested that the presence of elevated
right heart pressure induces right-to-left shunting
across the PFO contributing to hypoxia,
54
and an
increased severity of nocturnal episodes of hypoxia
among patients with Obstructive sleep apnoea
(OSA) with PFO may worsen the adverse vascular
effects of this condition.
55
Similarly desaturation
can arise in a patient with transiently raised pul-
monary artery pressures, such as following a pul-
monary emboli or severe pneumonia.
Platypnoea orthodeoxia
An interesting entity strongly associated with
PFO,
56 57
platypnoea orthodeoxia is defined as an
association of dyspnoea and arterial oxygen desat-
uration induced by upright posture and relieved by
recumbency. The pathology is complex involving
an intracardiac shunt, such as a PFO, combined
with a mechanism to redirect flow through it—for
instance, a persistent Eustachian valve and dilated
aortic root causing stretching of the foramen
increasing right-to-left shunting. In patients who
exhibit such symptoms, closure of the PFO has
been shown to be an effective treatment.
10
Patients
with severe liver dysfunction may develop platyp-
noea and orthodeoxia due to the hepatopulmonary
syndrome, differentiated from a PFO with a bubble
study (potentially while standing), which alters the
urgency of treatment.
58
RECURRENCE
In addition to associations in prevalence of PFO
and events, studies have looked at stroke recurrence
rates in the PFO population.
Cryptogenic stroke
Mas et al
59
prospectively examined 581 patients,
aged 18–55 years, who suffered an ischaemic stroke
Figure 5 (A) Sagittal view (B) axial 5 chamber view. Patent foramen ovale (PFO)
identified on cardiac CT. Ao, ascending aorta; AV, aortic valve; LA, left atrium; RA, right
atrium.
Figure 6 Thrombus across the
interatrial septum. (A) Subcostal view
of the right and left atria with a large
mobile mass straddling the interatrial
septum in a patient that had suffered
a large stroke. Subsequent
pathological specimen (B) confirmed
the presence of a large thrombus
straddling the atria and is likely to
have been the cause of the stroke. LA,
left atrium; PFO, patent foramen ovale;
RA, right atrium.
Asrress KN, et al.Heart 2015;101:1916–1925. doi:10.1136/heartjnl-2015-307639 1919
Education in Heart
group.bmj.com on January 19, 2016 - Published by http://heart.bmj.com/Downloaded from

without a definite cause. All received secondary
prevention with aspirin and underwent TTE and
TOE assessment for PFO and ASA at rest; follow-
ing provocative manoeuvres, 37% were found to
have a PFO, 2% an ASA and 9% had both. After a
mean follow-up of 3.1 years, recurrent stroke
occurred in 4.2% of patients with no interatrial
septal abnormality, compared with 2.3% with a
PFO alone. However, the rate was increased signifi-
cantly to 15.2% with both a PFO and ASA. This
low recurrence rate and parity without a combined
PFO and ASA is consistent with smaller retrospect-
ive studies.
60–62
Although retrospective studies have shown a
strong association between the presence of PFO
and CS, prospective studies, looking at the risk of
first-time ischaemic stroke, have not shown PFO as
an independent risk factor.
863
INTERVENTIONAL STUDIES
Embolic Phenomena.
Trials on PFO closure versus medical treatment in
cryptogenic stroke
Non-randomised studies
By accepting that material crossing a PFO can cause
a stroke, treatment can work to reduce clot forma-
tion with medication or occlude the PFO (figures 7
and 8).
Medical approaches include the use of antiplate-
lets like aspirin, clopidogrel, dipyridamole or antic-
oagulants such as warfarin or novel oral
anticoagulants. Some evidence favours anticoagu-
lants in the presence of ASA and PFO,
60
however
with a higher risk of bleeding.
64 65
A recent system-
atic review and meta-analysis of 15 clinical studies
of medical treatment following CS or TIA
Figure 7 Fluoroscopic views of percutaneous patent foramen ovale (PFO) closure. Fluoroscopic guidance of
percutaneous PFO closure. (A) Although rarely required, balloon sizing of the PFO with a compliant balloon can help
in selecting the correct device. A stiff wire remains in place ideally in the left upper pulmonary vein avoiding the left
atrial appendage. (B) The left atrial and right atrial discs of this Amplatzer multifenestrated occluder are being held in
position by the introducer catheter. (C) Following release, the device takes up a more physiological position. IVC,
inferior vena cava; LA, left atrium; RA, right atrium; TOE, transoesophageal echocardiography;
Figure 8 Transoesophageal
echocardiography (TOE) images of
device deployment. TOE guidance to
aid device positioning and deployment.
(A) Prerelease position; (B) post release
in 2D as well as 3D imaging (C, D).
AV, aortic valve; LA, left atrium; RA,
right atrium.
1920 Asrress KN, et al.Heart 2015;101:1916–1925. doi:10.1136/heartjnl-2015-307639
Education in Heart
group.bmj.com on January 19, 2016 - Published by http://heart.bmj.com/Downloaded from

demonstrated an absolute rate of recurrent ischae-
mic stroke of 1.6 events per 100 person-years
(95% CI 1.1 to 2.1).
66
In contrast, a retrospective
analysis of 10 non-randomised studies of 1355
patients with PFO closure indicated a risk of recur-
rent stroke of 0–4.9% compared with a signifi-
cantly increased rate of 3.8–12% in 895 medically
managed patients from six trials.
67
A large single-
centre non-randomised trial by Windecker et al
found the risk of stroke over 4 years following PFO
closure had a non-significant trend towards fewer
events compared with medical treatment (7.8% vs
22.2%, p=0.08). Analysis of patients with more
than one cerebrovascular event at baseline found
PFO closure was associated with a significantly
lower risk of TIA or recurrent stroke (7.3% vs
33.2%, p=0.01).
68
A propensity-matched compari-
son after median follow-up of 9 years showed a
reduction in the composite end point (11% vs
21%, p=0.033) driven by a reduction in transient
ischaemic attacks in the closure group.
69
Randomised studies
To date three prospective randomised trials have
looked at the comparison of percutaneous closure
of PFO versus medical treatment for secondary
stroke prevention. A summary of these studies is
presented in table 1. First, the CLOSURE 1 trial
included 909 patients (age 18–60 years) who
suffered CS or TIA within 6-months prior to
recruitment and were randomised to PFO closure
with a STARFlex device (NMT Medical) (n=447)
or best medical treatment (n=462) and followed
up for 2 years. The primary end point, a composite
of stroke/TIA during 2 years of follow-up, death
from any cause during the first 30 days, or death
from neurological causes between 31 days and
2 years was 5.5% in the closure group compared
with 6.8% in the medical-therapy group
(HR=0.78, p=0.37).
5
The respective rates were
2.9% vs 3.1% for stroke (p=0.79) and 3.1% vs
4.1% for TIA (p=0.44). The authors concluded
that device closure did not offer a greater benefit
than medical therapy alone for stroke/TIA preven-
tion. Subsequently, the PC trial studied 414 patients
under the age of 60 years who had suffered a
previous stroke, TIA or peripheral embolic event.
A total of 204 patients were randomised to
Amplatzer PFO Occluder (St Jude Medical,
Minnesota, USA) and compared with medical treat-
ment in 210 subjects. The primary end point was a
composite of death, non-fatal stroke, TIA or per-
ipheral embolism with a mean 4-year follow-up.
This end point occurred in 3.4% (7 device patients)
vs 5.2% (11 medically treated subjects) (HR 0.63;
95% CI 0.24 to 1.62, p=0.34). Outcome for non-
fatal stroke (1 vs 5: HR 0.2; 95% CI 0.02 to 1.72,
p=0.14) and TIA (5 vs 7: HR 0.71; 95% CI 0.23
to 2.24, p=0.56) was also non-significant.
70
Finally, the RESPECT trial enrolled 980 subjects
(age 18–60 years) with PFO and CS within
270 days, randomised to medical therapy (n=481)
with one or more antiplatelet (74.8%) or warfarin
(25.2%) or PFO closure using the Amplatzer device
(n=499). The primary outcome was recurrence of
non-fatal stroke, fatal ischaemic stroke or early
postrandomisation death defined as all-cause mor-
tality. The mean follow-up was 2.6 years during
which a target of 25 of events had occurred.
Analysis was complicated by increased dropout in
the medical arm resulting in a significantly lower
patient/years follow-up. No deaths occurred and in
the intention-to-treat cohort, 9 device patients and
16 medically treated patients had a recurrent stroke
(HR 0.49; 95% CI 0.22 to 1.11, p=0.08).
However, a significant difference was observed in
the ‘as-treated’analysis (5 vs 16; HR 0.27; 95% CI
0.10 to 0.75, p=0.007) as three strokes in the
device arm occurred between randomisation and
closure.
6
These large multicentre randomised trials
provide invaluable information, however all three
had some important issues and limitations.
71
First,
all three encountered problems in recruitment due
to off-label PFO closure highlighted by the fre-
quency of non-research device closure; an esti-
mated 1 000 000 implants occurred over the same
time but only 2203 were recruited to studies. All
studies suffered long recruitment times (CLOSURE
1 9 years, PC 13 years and RESPECT 10 years).
CLOSURE 1 had to reduce its sample size poten-
tially leading to underpowering, while with
RESPECT and PC trials more dropouts occurred in
the medical arm, some due to off-label PFO closure
(table 1). The power of the PC trial was affected by
Table 1 Summary of randomised studies on patent foramen ovale (PFO) closure
for cryptogenic stroke (CS)
Closure Respect PC trial
Inclusion 18–60 years, PFO, CS or TIA
within 6 months
18–60 years, PFO, CS
within 270 days
<60 years, PFO, CS
Primary
outcome
Composite: Stroke or TIA,
death from any cause within
30 days, death from
neurological causes between
31 days and 2 years
Recurrence of
non-fatal stroke, fatal
ischaemic stroke or
all-cause mortality
Composite: death from
any cause, non-fatal
stroke, TIA, peripheral
embolism
Patients
recruited
909 980 414
Follow-up 2 years Mean 2.6 years Mean 4 years
Device STARFlex Amplatzer PFO
Occluder
Amplatzer PFO
Occluder
Device closure
effectiveness
86% 93.5% 95.9
Closure Medical Closure Medical Closure Medical
Dropouts 15% 19% 10% 19% 16% 20%
Kaplan-Meier ITT 5.5% 6.8% 1.8% 3.3% 3.4% 5.2%
HR 0.78 (0.45 to 1.35)
p=0.37
0.49 (0.22 to 1.11)
p=0.08
0.63 (0.24 to 1.62)
p=0.34
Stroke ITT 2.9% 3.1% 1.8% 3.3% 0.5% 2.4%
HR 0.90 (0.41 to 1.98)
p=0.79
0.53 (0.23 to 1.22)
p=0.16
0.20 (0.02 to 1.72)
p=0.14
As treated Not presented 1.0% 3.3% Not presented
HR 0.27 (0.10 to 0.75)
p=0.01
ITT, intention-to-treat.
Asrress KN, et al.Heart 2015;101:1916–1925. doi:10.1136/heartjnl-2015-307639 1921
Education in Heart
group.bmj.com on January 19, 2016 - Published by http://heart.bmj.com/Downloaded from

a smaller observed (5.2%) than expected (12%)
event rate in the medically treated patients.
Observational data suggests that patients with
large PFO and coexisting ASA are at greater risk,
however the CLOSURE 1 and PC trials recruited
significant numbers with small shunts and relatively
few with ASAs. In the CLOSURE 1 trial, only
52.9% of participants had a moderate or large shunt
and only 36.6% had a coexistent ASA. The PC trial
included 61% of patients with moderate or large
shunts, and only less than a quarter with an ASA
(23% in the device group and 24.3% in the medical
group). The greater effect seen in the RESPECT
trial may reflect the inclusion of 78% large or mod-
erate shunts.
Early studies showed that complete PFO closure
reduces risk of recurrent stroke,
68
however in the
CLOSURE 1 trial almost 14% had a significant
degree of shunting at 6 months and at 2 years.
Other concerns regarding this device arose as
nearly a quarter of the strokes were in the first
30 days, 5.7% suffered postprocedural AF and
major bleeding was noted in 2.6%; this could mask
any potential benefits. The RESPECT study had sig-
nificantly lower risk of residual shunt (6%) at
6 months while rates of atrial fibrillation and bleed-
ing were 0.6% and 1.6%, respectively. In the
CLOSURE 1 study an alternate cause of stroke or
TIA was apparent in 87% of the closure group and
76% of the medically treated group, questioning
the original patient workup.
Two recent meta-analyses have been published.
The first, by Agarwal et al
72
of 10 studies including
CLOSURE 1 with 1886 patients compared device
closure and medical therapy for recurrent neuro-
logical events. Overall recurrence rates were esti-
mated at 0.79/100 patient years (CI 0.48 to 1.05)
for device closure and 4.39 (CI 3.20 to 5.59) for
medical management (relative risk 0.25 (CI 0.11 to
0.58)).
72
A meta-analysis of the randomised control
trials found a significant ‘intention-to-treat’risk
reduction for stroke and/or TIA in the device
group (pooled HR=0.59; 95% CI 0.36 to 0.97,
p=0.04).
73
In summary there appears to be a real, albeit
small, signal for reduced recurrent neurological
events with device closure in carefully selected
patients, which is reflected in the recommendations
of the UK National Institute for Health and Care
Excellence.
74
Finally, although PFO closure is associated with
higher initial expenditure there is data suggesting it
is cost-effective in the long term, although this is
based on a clear efficacy model.
75
The hope is that
the ongoing REDUCE and CLOSE trials, with
more targeted inclusion criteria proposed by the
RoPE investigators, will help better differentiate
those for optimal medical therapy or device
closure.
76
Migraine
Patients undergoing PFO closure for non-migraine
indications have reported symptomatic improve-
ment.
77
A non-randomised study in refractory
migraines demonstrated a significant improvement
in symptoms and a total elimination of aura in
patients undergoing PFO closure.
78
The only pub-
lished randomised study is the Migraine
Intervention with STARFlex Technology (MIST)
trial.
79
This prospective sham-controlled study
using the STARFlex device (NMT Medical)
included patients with migraine with aura and a
moderate or larger right-to-left shunt. The study
failed to reach the primary end point of diary
recorded headache cessation 6 months after ran-
domisation. Furthermore, no significant difference
was found for the secondary end points, assessing
the frequency and severity of migraines over
3 months. A post hoc analysis revealed, when two
extreme outliers were removed, a significant reduc-
tion in the median total headache days following
PFO closure.
This negative result could reflect an overly ambi-
tious primary end point or the likely multifactorial
nature of migraine triggers, obscuring the effect of
reduction of one mechanism. As before, the efficacy
of the device has been questioned. Studies in this
area are further complicated the fluctuant nature of
presentation and severity of by this condition,
particularly when a short follow-up is used.
80
A follow-up study, the MIST II trial, started recruit-
ment in 2006 but was halted due to poor uptake in
2008.
81
Provisional presentation of the PRIMA
study, using the Amplatzer occluder device, also
failed to show a significant reduction in headache
days at 1 year, although very few subjects were ran-
domised to device closure (Transcatheter
Therapeutics, 2014, unpublished data). Given the
current evidence base, closure of PFO primarily for
migraine reduction is not recommended outside of
a trial, and should only be considered after thor-
ough workup by an independent neurologist.
Decompression illness
There are no prospective randomised studies of
PFO closure in divers. A longitudinal study
performed by Billinger et al
82
followed up 104
recreational divers with a history of major decom-
pression illness (DCI); 39 without PFO, 26 with a
PFO who chose to undergo closure and 39 with a
PFO who decided against closure. Over 5.3 years’
follow-up of 81 654 dives there were 5 major
neurological DCI events—none in the non-PFO
group, 0.5 ±2.5/10 000 dives in the PFO closure
group and 35.8±102.5/10 000 dives in the PFO
non-closure group. An experimental study evaluat-
ing 34 divers (19 with PFOs and 15 who had
undergone device closure) in a hyperbaric chamber
found the same number of venous bubbles was
detected by TTE and TCD with complete elimin-
ation of arterial bubbles after simulated dives in the
closure group.
83
Although the data supports
closure, it is advised that a cardiologist with a spe-
cialist interest in diving medicine reviews patients
prior to attribution of causality to a potentially
incidental PFO, because differentiation of alterna-
tive aetiologies of DCI is complex.
1922 Asrress KN, et al.Heart 2015;101:1916–1925. doi:10.1136/heartjnl-2015-307639
Education in Heart
group.bmj.com on January 19, 2016 - Published by http://heart.bmj.com/Downloaded from

Platypnoea orthodeoxia
This is a rare condition and there are no pub-
lished series comparing shunt closure versus con-
servative management. However, as reported
reversal of the documented haemodynamic com-
promise on closure of the shunt is so clear, device
closure is highly recommended in symptomatic
individuals.
56
FUTURE PERSPECTIVES
Ideally, to improve the quality of the available data,
we need the cooperation of clinicians, device com-
panies and regulatory bodies to design and carry
out an adequately powered study. This should aim
to better risk-stratify patients, to identify the truly
CS population, as well as predict risk of future
events based on anatomy and shunt dynamics.
Device closure with the current technology is asso-
ciated with serious but infrequent complications
and some residual shunt work should continue on
better device design to reduce malpositioning,
embolisation, clot formation and atrial tachyar-
rhythmias. Intracardiac echocardiography may
allow for shorter procedure times and hospital
stays by avoiding sedation and anaesthesia.
84
Bioabsorbable technologies or the development of
effective radiofrequency ablation techniques may
reduce complications such as erosion. There
remains an inextricable link between migraine with
aura and the presence of PFO,
85
and future
research in this area would be valuable.
Given the need for careful consideration of
numerous factors spanning cardiology, neurology
and haematology for individual patients, there is a
critical role for the multidisciplinary process in the
optimisation of care. Recent developments of the
heart team for complex valvular and coronary dis-
orders have laid the essential groundwork for this
new multidisciplinary group working.
CONCLUSION
A PFO is present in up to one in four people and is
associated with a host of conditions including CS,
DCI, OSA, migraine, paradoxical myocardial
infarction and other distal embolisations. A large
body of observational data point towards the
benefit of device closure, however three rando-
mised controlled trials have failed to send a conclu-
sive answer. There were limitations in study design,
recruitment process, inclusion criteria and device
characteristics. An adequately powered study
including a high proportion of patients with high-
risk features using an efficacious device and careful
inclusion criteria is still required. As all the current
evidence favours intervention, the balance points
towards improved outcomes with device closure
versus medical therapy in carefully selected patients
with CS.
Contributors KNA and MM are equal first authors having
provided the original draft and required revisions. AM provided
editorial support and wrote the required questions. RR provided
editorial support and specific assistance with the images. BC was
the overall senior author providing the idea, guidance and editorial
support.
Competing interests BC has received speaking fees from St Jude
Medical and has worked on advisory boards for Boston Scientific
and Medtronic.
Provenance and peer review Commissioned; externally peer
reviewed.
REFERENCES
1 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:
17–20.
2 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.
Mayo Clin Proc 1999;74:862–9.
3 Handke M, Harloff A, Olschewski M, et al. Patent foramen ovale
and cryptogenic stroke in older patients. N Engl J Med
2007;357:2262–8.
Key messages
▸Patent foramen ovale (PFO) is present in up to 25% of individuals.
▸There is a strong association between the presence of a PFO and
cryptogenic stroke (CS), defined as a stroke without an identifiable cause.
▸Transoesophageal echocardiography with bubble contrast remains the first
line of investigation in suspected cases.
▸The recurrence rate following a CS in those on optimal medical therapy is
low.
▸Three randomised studies of device closure versus medical therapy in
secondary prevention following CS have been completed: CLOSURE I,
RESPECT and PC trials. All missed their primary end point of reducing the
rate of recurrent stroke.
▸All three studies struggled with slow recruitment, high rate of off-label use
of devices, and a heterogeneous study population in terms of PFO size and
rate of atrial septal aneurysms.
▸In the largest study published to date, RESPECT, there was a signal towards
improved outcomes with device closure. However further studies are
required, and are ongoing, to clarify matters.
You can get CPD/CME credits for Education in Heart
Education in Heart articles are accredited by both the UK Royal College of
Physicians (London) and the European Board for Accreditation in Cardiology—you
need to answer the accompanying multiple choice questions (MCQs). To access
the questions, click on BMJ Learning: Take this module on BMJ Learning from
the content box at the top right and bottom left of the online article. For more
information please go to: http://heart.bmj.com/misc/education.dtl
▸RCP credits: Log your activity in your CPD diary online (http://www.
rcplondon.ac.uk/members/CPDdiary/index.asp)—pass mark is 80%.
▸EBAC credits: Print out and retain the BMJ Learning certificate once you
have completed the MCQs—pass mark is 60%. EBAC/ EACCME Credits can
now be converted to AMA PRA Category 1 CME Credits and are recognised
by all National Accreditation Authorities in Europe (http://www.ebac-cme.
org/newsite/?hit=men02).
Please note: The MCQs are hosted on BMJ Learning—the best available learning
website for medical professionals from the BMJ Group. If prompted, subscribers
must sign into Heart with their journal’s username and password. All users must
also complete a one-time registration on BMJ Learning and subsequently log in
(with a BMJ Learning username and password) on every visit.
Asrress KN, et al.Heart 2015;101:1916–1925. doi:10.1136/heartjnl-2015-307639 1923
Education in Heart
group.bmj.com on January 19, 2016 - Published by http://heart.bmj.com/Downloaded from

4 Lechat P, Mas JL, Lascault G, et al. Prevalence of patent foramen
ovale in patients with stroke. N Engl J Med 1988;318:1148–52.
5 Furlan AJ, Reisman M, Massaro J, et al. Closure or medical
therapy for cryptogenic stroke with patent foramen ovale. N Engl J
Med 2012;366:991–9.
6 Carroll JD, Saver JL, Thaler DE, et al. Closure of patent foramen
ovale versus medical therapy after cryptogenic stroke. N Engl J
Med 2013;368:1092–100.
7 Penther P. [Patent foramen ovale: An anatomical study. Apropos
of 500 consecutive autopsies]. Arch Mal Coeur Vaiss
1994;87:15–21.
8 Meissner I, Khandheria BK, Heit JA, et al. Patent foramen ovale:
Innocent or guilty? Evidence from a prospective population-based
study. J Am Coll Cardiol 2006;47:440–5.
9 Fisher DC, Fisher EA, Budd JH, et al. The incidence of patent
foramen ovale in 1,000 consecutive patients. A contrast
transesophageal echocardiography study. Chest J
1995;107:1504–9.
10 Kerut EK, Norfleet WT, Plotnick GD, et al. Patent foramen ovale:
A review of associated conditions and the impact of physiological
size. J Am Coll Cardiol 2001;38:613–23.
11 Zanette EM, Mancini G, De Castro S, et al. Patent foramen ovale
and transcranial doppler: comparison of different procedures.
Stroke 1996;27:2251–5.
12 Stendel R, Gramm HJ, Schröder K, et al. Transcranial doppler
ultrasonography as a screening technique for detection of a
patent foramen ovale before surgery in the sitting position.
Anesthesiology 2000;93:971–5.
13 Mojadidi MK, Winoker JS, Roberts SC, et al. Two-dimensional
echocardiography using second harmonic imaging for the
diagnosis of intracardiac right-to-left shunt: a meta-analysis of
prospective studies. Int J Cardiovasc Imaging 2014;30:911–23.
14 Bhatia N, Abushora MY, Donneyong MM, et al. Determination of
the optimum number of cardiac cycles to differentiate
intra-pulmonary shunt and patent foramen ovale by saline contrast
two- and three-dimensional echocardiography. Echocardiography
2014;31:293–301.
15 Di Tullio MR. Patent foramen ovale: echocardiographic detection
and clinical relevance in stroke. J Am Soc Echocardiogr
2010;23:144–55; quiz 220.
16 Homma S, Sacco RL. Patent foramen ovale and stroke. Circulation
2005;112:1063–72.
17 Monte I, Grasso S, Licciardi S, et al. Head-to-head comparison of
real-time three-dimensional transthoracic echocardiography with
transthoracic and transesophageal two-dimensional contrast
echocardiography for the detection of patent foramen ovale.
Eur J Echocardiogr 2010;11:245–9.
18 Kim YJ, Hur J, Shim CY, et al. Patent foramen ovale: diagnosis
with multidetector ct—comparison with transesophageal
echocardiography. Radiology 2009;250:61–7.
19 Hamilton-Craig C, Sestito A, Natale L, et al. Contrast
transoesophageal echocardiography remains superior to
contrast-enhanced cardiac magnetic resonance imaging for the
diagnosis of patent foramen ovale. Eur J Echocardiogr
2011;12:222–7.
20 Conheim J. Thrombose und embolie in: Vorlesungen uber
allgemeine pathologie. Vol. 1. Berlin: Hirschwald, 1877;134.
21 Webster MW, Smith HJ, Sharpe DN, et al. Patent foramen ovale in
young stroke patients. Lancet 1988;332:11–12.
22 Cabanes L, Mas JL, Cohen A, et al. Atrial septal aneurysm and
patent foramen ovale as risk factors for cryptogenic stroke in
patients less than 55 years of age. A study using transesophageal
echocardiography. Stroke 1993;24:1865–73.
23 de Belder MA, Tourikis L, Leech G, et al. Risk of patent foramen
ovale for thromboembolic events in all age groups. Am J Cardiol
1992;69:1316–20.
24 Di Tullio M, Sacco RL, Gopal A, et al. Patent foramen ovale as a
risk factor for cryptogenic stroke. Ann Intern Med
1992;117:461–5.
25 Hausmann D, Mügge A, Becht I, et al. Diagnosis of patent
foramen ovale by transesophageal echocardiography and
association with cerebral and peripheral embolic events.
Am J Cardiol 1992;70:668–72.
26 Jones EF, Calafiore P, Donnan GA, et al. Evidence that patent
foramen ovale is not a risk factor for cerebral ischemia in the
elderly. Am J Cardiol 1994;74:596–9.
27 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;105:2625–31.
28 Overell JR, Bone I, Lees KR. Interatrial septal abnormalities and
stroke: a meta-analysis of case-control studies. Neurology
2000;55:1172–9.
29 Ahmed S, Sadiq A, Siddiqui AK, et al. Paradoxical arterial
emboli causing acute limb ischemia in a patient with
essential thrombocytosis. Am J Med Sci 2003;326:
156–8.
30 Ronco F, Rigatelli G, Dell’Avvocata F, et al. Embolic renal infarct,
patent foramen ovale and coronary artery dissection: a strange
case of cardio-renal connection. Cardiovasc Revasc Med
2011;12:67.e5–7.
31 NikolićS, ZivkovićV, BabićD, et al. Systemic fat embolism and
the patent foramen ovale—a prospective autopsy study. Injury
2012;43:608–12.
32 Iwasaki M, Joki N, Tanaka Y, et al. A suspected case of
paradoxical renal embolism through the patent foramen ovale.
Clin Exp Nephrol 2011;15:147–50.
33 Caretta G, Robba D, Bonadei I, et al. Multiorgan paradoxical
embolism consequent to acute pulmonary thromboembolism
with patent foramen ovale: a case report. Cases J 2009;
2:8358.
34 Namazi MH, Biglari M, Khani M, et al. Acute myocardial
infarction secondary to suspected paradoxical emboli through
patent foramen ovale in a young woman. Am Heart Hosp J
2011;9:122–4.
35 Galiuto L, Giubilato S, De Caterina AR, et al. Patent foramen
ovale and hypercoagulable state in the pathogenesis of acute
thrombotic myocardial infarction. BMJ Case Rep 2009;2009:pii:
bcr11.2008.1211.
36 Sastry S, Riding G, Morris J, et al. Young adult myocardial
infarction and ischemic stroke: the role of paradoxical embolism
and thrombophilia (the YAMIS study). J Am Coll Cardiol
2006;48:686–91.
37 Crump R, Shandling AH, Van Natta B, et al. Prevalence of patent
foramen ovale in patients with acute myocardial infarction and
angiographically normal coronary arteries. Am J Cardiol
2000;85:1368–70.
38 Ramineni R, Daniel GK. Association of a patent foramen
ovale with myocardial infarction and pulmonary emboli in
a peripartum woman. Am J Med Sci 2010;340:
326–8.
39 Zimmermann FM, Peels KH. Simultaneous massive pulmonary
embolism and acute myocardial infarction, associated with patent
foramen ovale. Eur Heart J 2014;35:2046.
40 Smith CE. Understanding the role of patent foramen ovale in
stroke. Nursing 2013;43:52–5.
41 Wöhrle J, Kochs M, Hombach V, et al. Prevalence of myocardial
scar in patients with cryptogenic cerebral ischemic events and
patent foramen ovale. JACC Cardiovasc Imaging 2010;3:
833–9.
42 Tse KC, Ooi GC, Wu A, et al. Multiple brain abscesses in a
patient with bilateral pulmonary arteriovenous malformations
and immunoglobulin deficiency. Postgrad Med J 2003;79:
597–9.
43 Stathopoulos GT, Mandila CG, Koukoulitsios GV, et al. Adult brain
abscess associated with patent foramen ovale: a case report.
J Med Case Rep 2007;1:68.
44 Lipton RB, Stewart WF, Diamond S, et al. Prevalence and burden
of migraine in the united states: data from the american migraine
study II. Headache 2001;41:646–57.
45 Del Sette M, Angeli S, Leandri M, et al. Migraine with aura and
right-to-left shunt on transcranial doppler: a case-control study.
Cerebrovasc Dis 1998;8:327–30.
46 Schwerzmann M, Nedeltchev K, Lagger F, et al. Prevalence and
size of directly detected patent foramen ovale in migraine with
aura. Neurology 2005;65:1415–18.
47 Schwedt TJ, Demaerschalk BM, Dodick DW. Patent foramen ovale
and migraine: a quantitative systematic review. Cephalalgia
2008;28:531–40.
48 Ailani J. Migraine and patent foramen ovale. Curr Neurol Neurosci
Rep 2014;14:426.
49 Lip PZ, Lip GY. Patent foramen ovale and migraine attacks:
a systematic review. Am J Med 2014;127:411–20.
50 Wilmshurst P, Nightingale S. The role of cardiac and pulmonary
pathology in migraine: a hypothesis. Headache 2006;46:
429–34.
1924 Asrress KN, et al.Heart 2015;101:1916–1925. doi:10.1136/heartjnl-2015-307639
Education in Heart
group.bmj.com on January 19, 2016 - Published by http://heart.bmj.com/Downloaded from

51 Foster PP, Boriek AM, Butler BD, et al. Patent foramen ovale and
paradoxical systemic embolism: a bibliographic review. Aviat Space
Environ Med 2003;74(6 Pt 2):B1–64.
52 Wilmshurst PT, Byrne JC, Webb-Peploe MM. Relation between
interatrial shunts and decompression sickness in divers. Lancet
1989;334:1302–6.
53 Germonpre P, Balestra C. Risk of decompression illness among
230 divers in relation to the presence and size of patent foramen
ovale. Eur Heart J 2004;25:2173–4.
54 Beelke M, Angeli S, Del Sette M, et al. Obstructive sleep apnea
can be provocative for right-to-left shunting through a patent
foramen ovale. Sleep 2002;25:856–62.
55 Kar S. Cardiovascular implications of obstructive sleep apnea
associated with the presence of a patent foramen ovale. Sleep
Med Rev 2014;18:399–404.
56 Cheng TO. Platypnea-orthodeoxia syndrome: etiology, differential
diagnosis, and management. Catheter Cardiovasc Interv
1999;47:64–6.
57 Robin ED, Laman D, Horn BR, et al. Platypnea related to
orthodeoxia caused by true vascular lung shunts. N Engl J Med
1976;294:941–3.
58 Goldberg DS, Fallon MB. Lung and heart disease secondary to
liver disease. Clin Gastroenterol Hepatol 2015. April 28,
pii S1542–3565.
59 Mas JL, Arquizan C, Lamy C, et al. Recurrent cerebrovascular
events associated with patent foramen ovale, atrial septal
aneurysm, or both. N Engl J Med 2001;345:1740–6.
60 Mas J-L, Zuber M. Recurrent cerebrovascular events in patients
with patent foramen ovale, atrial septal aneurysm, or both and
cryptogenic stroke or transient ischemic attack. French study group
on patent foramen ovale and atrial septal aneurysm. Am Heart J
1995;130:1083–8.
61 Bogousslavsky J, Garazi S, Jeanrenaud X, et al. Stroke recurrence
in patients with patent foramen ovale: the lausanne study.
Lausanne stroke with paradoxal embolism study group. Neurology
1996;46:1301–5.
62 De Castro S, Cartoni D, Fiorelli M, et al. Morphological and
functional characteristics of patent foramen ovale and their
embolic implications. Stroke 2000;31:2407–13.
63 Di Tullio MR, Sacco RL, Sciacca RR, et al. Patent foramen ovale
and the risk of ischemic stroke in a multiethnic population.
J Am Coll Cardiol 2007;49:797–802.
64 Messé SR, Silverman IE, Kizer JR, et al. Practice parameter:
Recurrent stroke with patent foramen ovale and atrial septal
aneurysm: report of the quality standards subcommittee of the
american academy of neurology. Neurology 2004;62:
1042–50.
65 Kutty S, Sengupta PP, Khandheria BK. Patent foramen ovale:
the known and the to be known. J Am Coll Cardiol
2012;59:1665–71.
66 AlmekhlafiMA, Wilton SB, Rabi DM, et al. Recurrent cerebral
ischemia in medically treated patent foramen ovale:
a meta-analysis. Neurology 2009;73:89–97.
67 Khairy P, O’Donnell CP, Landzberg MJ. Transcatheter closure
versus medical therapy of patent foramen ovale and presumed
paradoxical thromboemboli: a systematic review. Ann Intern Med
2003;139:753–60.
68 Windecker S, Wahl A, Nedeltchev K, et al. Comparison of medical
treatment with percutaneous closure of patent foramen ovale in
patients with cryptogenic stroke. J Am Coll Cardiol 2004;
44:750–8.
69 Wahl A, Jüni P, Mono ML, et al. Long-term propensity
score-matched comparison of percutaneous closure of patent
foramen ovale with medical treatment after paradoxical embolism.
Circulation 2012;125:803–12.
70 Meier B, Kalesan B, Mattle HP, et al. Percutaneous closure of
patent foramen ovale in cryptogenic embolism. N Engl J Med
2013;368:1083–91.
71 Rhone E, Chung N, Clapp B. Current evidence for closure of a
patent foramen ovale for cryptogenic stroke prevention. Int J Clin
Pract 2014;68:551–6.
72 Agarwal S, Bajaj NS, Kumbhani DJ, et al. Meta-analysis of
transcatheter closure versus medical therapy for patent foramen
ovale in prevention of recurrent neurological events after presumed
paradoxical embolism. JACC Cardiovasc Interv 2012;5:777–89.
73 Rengifo-Moreno P, Palacios IF, Junpaparp P, et al. Patent foramen
ovale transcatheter closure vs. Medical therapy on recurrent
vascular events: a systematic review and meta-analysis of
randomized controlled trials. Eur Heart J 2013;34:3342–52.
74 NICE interventional procedure guidance 472. https://www.nice.
org.uk/guidance/ipg472/resources/guidance-percutaneous-closure-
of-patent-foramen-ovale-to-prevent-recurrent-cerebral-embolic-
events-pdf (accessed 4 May 2015).
75 Pickett CA, Villines TC, Ferguson MA, et al. Cost effectiveness of
percutaneous closure versus medical therapy for cryptogenic stroke
in patients with a patent foramen ovale. Am J Cardiol
2014;114:1584–9.
76 Kent DM, Thaler DE, RoPE Study Investigators. The risk of
paradoxical embolism (rope) study: developing risk models for
application to ongoing randomized trials of percutaneous patent
foramen ovale closure for cryptogenic stroke. Trials 2011;12:185.
77 Wilmshurst PT, Nightingale S, Walsh KP, et al. Effect on migraine
of closure of cardiac right-to-left shunts to prevent recurrence of
decompression illness or stroke or for haemodynamic reasons.
Lancet 2000;356:1648–51.
78 Rigatelli G, Cardaioli P, Dell’Avvocata F, et al. Transcatheter patent
foramen ovale closure is effective in reducing migraine
independently from specific interatrial septum anatomy and
closure devices design. Cardiovasc Revasc Med 2010;11:29–33.
79 Dowson A, Mullen MJ, Peatfield R, et al. Migraine intervention with
starflex technology (MIST) trial: a prospective, multicenter, double-
blind, sham-controlled trial to evaluate the effectiveness of patent
foramen ovale closure with starflex septal repair implant to resolve
refractory migraine headache. Circulation 2008;117:1397–404.
80 Butera G, Biondi-Zoccai GG, Carminati M, et al. Systematic review
and meta-analysis of currently available clinical evidence on
migraine and patent foramen ovale percutaneous closure: Much
ado about nothing? Catheter Cardiovasc Interv 2010;75:494–504.
81 https://clinicaltrials.gov/ct2/show/NCT00283738 (accessed May
2015).
82 Billinger M, Zbinden R, Mordasini R, et al. Patent foramen ovale
closure in recreational divers: effect on decompression illness and
ischaemic brain lesions during long-term follow-up. Heart
2011;97:1932–7.
83 Honěk J, Srámek M, Sefc L, et al. Effect of catheter-based patent
foramen ovale closure on the occurrence of arterial bubbles in
scuba divers. JACC Cardiovasc Interv 2014;7:403–8.
84 Asrress KN, Mitchell AR. Intracardiac echocardiography. Heart
2009;95:327–31.
85 Wilmshurst P, Nightingale S. Relationship between migraine and
cardiac and pulmonary right-to-left shunts. Clin Sci (Lond)
2001;100:215–20.
Asrress KN, et al.Heart 2015;101:1916–1925. doi:10.1136/heartjnl-2015-307639 1925
Education in Heart
group.bmj.com on January 19, 2016 - Published by http://heart.bmj.com/Downloaded from

play
Patent foramen ovale: the current state of
Brian Clapp
Kaleab N Asrress, Maciej Marciniak, Anna Marciniak, Ronak Rajani and
doi: 10.1136/heartjnl-2015-307639
2015 101: 1916-1925 originally published online October 20, 2015Heart
http://heart.bmj.com/content/101/23/1916
Updated information and services can be found at:
These include:
References #BIBLhttp://heart.bmj.com/content/101/23/1916
This article cites 80 articles, 14 of which you can access for free at:
service
Email alerting box at the top right corner of the online article.
Receive free email alerts when new articles cite this article. Sign up in the
Collections
Topic Articles on similar topics can be found in the following collections
(2061)Echocardiography (4660)Clinical diagnostic tests
(499)Education in Heart
Notes
http://group.bmj.com/group/rights-licensing/permissions
To request permissions go to:
http://journals.bmj.com/cgi/reprintform
To order reprints go to:
http://group.bmj.com/subscribe/
To subscribe to BMJ go to:
group.bmj.com on January 19, 2016 - Published by http://heart.bmj.com/Downloaded from