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into the left atrium afterward. Only rarely, with tight tunnel PFOs, the dilator has to be introduced for readvance-
ment. Once the sheath is placed in the left atrium, even more attention must be paid to keep the outside end of
the sheath low (below the level of the heart), to avoid air aspiration and always ascertain back-bleeding.
DEVICE DEPLOYMENT
The device/loader assembly is ideally prepared according to Fig. 16.9 before sheath introduction to minimize the
delivery sheath indwelling time. It is subsequently connected to the delivery sheath at the lowest possible point be-
tween or lateral to the patient’s legs. Sufficient sheath backflow and the nose of the device peeking out of the loader
euqilbOroiretnAtfeLroiretnaoretsoP
ALALAL
ARARAR
SS
SS
SS
SP
SP
SP
FIGURE 16.8 Angiographic Assessment of a PFO After Wire Passage. Injections of less than 10 mL of contrast medium through a 9 French
TorqVue sheath show the width (left panel, frontal view) and the transesophageal echocardiography-like aspect (center panel, left anterior oblique
view) of the PFO. A later, identical injection shows a standard 25 Amplatzer PFO Occluder in place with some residual shunt, likely to disappear
over the following weeks. LA, left atrium; RA, right atrium; SP, septum primum; SS, septum secundum.
Loader
FIGURE 16.9 Device Preparation. Top panel: With the left hand resting on the table, the device is held perpendicular to the straight pusher
cable which is then screwed into the connector on the device like a regular screw into a nut. Once tightened, the screw is loosened half a turn
(dashed arrow). This is typically audible as a click and assures that the device will come off when one wants to release it rather than simply
pivoting with the pusher cable. Bottom panel: With the loader tip under water, the device has been pulled back into the loader once, pushed out
once, and pulled back in to a point that the nose is just peeking out (arrow). This position avoids introducing a leading air bubble when connecting
to the delivery sheath.
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(Fig. 16.9) assure that there will be no air pushed into the left atrium. Air behind the device is of no concern because
the delivery sheath is left open and no fluid can be injected. Before the device is deplo yed, partial untightening of the
screw is reassured on fluoroscopy (Fig. 16.10). This is important to prevent the device from simply rotating with the
pusher cable when trying to unscrew it. At the same time, inadvertent detachment of the device from the pusher
cable by faulty manipulations or spontaneous rotations of the device will be detecte d during the travel through
the delivery sheath (Fig. 16.10).
The fluoroscopic view is now changed from posteroanterior to left anterior oblique and the left disc is deployed in
the center of the left atrium. The open disc may not always be plainly visible, but it can be assumed to be completely
unfolded once the waist between the discs arrives at the end of the delivery sheath (Fig. 16.11). The delivery sheath
and the pusher cable are then pulled back as a unit until resistance is felt when the cranial part of the left disc is
stopped and conforms to the vertical septum secundum. At this moment even a hitherto poorly visible left disc reli-
ably comes into focus and pivots upwards. Maintaining a slight pull on the pusher cable, the delivery sheath is
further withdrawn until it has passed the attachment screw. At this moment, the sheath and the pusher cable are
relaxed to let the right disc assume its original shape as it approaches the septum and the left disc.
The Y-connector is attached, unless done earlier. The delivery sheath is purged and an angiogram is obtained with
5e15 mL of contrast medium. For this, the view is adjusted to the left anterior oblique projection with a cranial or
caudal tilt that shows the device in per fect profile without any overlap of the discs (Fig. 16.12, Video 16.8). If the Pac-
man sign [8] requirements (septum secundum at least halfway inside the disc mouth or, ideally, touching the disc
waist) are not met, the right disc of the device is repositioned by pulling and releasing again or by torqueing the
delivery sheath counterclockwise. If that fails, a larger device is used. Fig. 16.13 shows some cases that needed
correction.
Once a satisfactory occluder position is ascertained, the device is released by counterclockwise unscrewing of the
pusher cable. The provided torquer is rarely required for this. Upon detachment, the device can change its orienta-
tion considerably, if an atrial septal aneurysm is present. A contrast medium angiogram in an adjusted orientation
FIGURE 16.10 Checking the Required Partial Loosening of the Screw Before Deploying the Device. The partial loosening of the screw
described in Figure 16.9 may have been forgotten or the screw may have been retightened during advancement through the body by spontaneous
rotation of the device in the delivery sheath. If the required small gap (proximal end of the screw) as shown by the arrow in the left panel is not
present (center and right bottom panels), the pusher cable should be rotated counterclockwise before pushing the device out until the gap appears
(usually felt by a click). If the gap is too large (center and right top panels), it should be made smaller by clockwise rotation. Once the device is
pushed out, the device rotates freely with the pusher cable and adjustments are no longer possible, unless the device is again partially or totally
retracted into the sheath. The bottom right insert shows a detached screw within the sheath (arrow). While it may be possible to reattach the screw
while still in the sheath, the device can be secured with a gooseneck snare around the collar of the connector and pulled out for outside recon-
nection or, alternatively, pushed out by the unattached pusher with the snare functioning as a safety line.
VII. SAFETY, TECHNICAL ASPECTS TO PFO CLOSURE, AND FUTURE OUTLOOK
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FIGURE 16.11 Incomplete Deployment of Left Disc During Pullback to the septum. The waist between the discs (opposing arrows) should
have been advanced to the end of the sheath (dashed arrow) before pulling the left disc against the atrial septum to avoid the insufficiently
deployed disc with its still small diameter to be pulled through the PFO.
PFO
ASA
SS
LA
FIGURE 16.12 Angiography of PFO Closure Device Position (Pacman Sign). With an injection of about 10 mL of contrast medium in a left
anterior oblique view perfectly separating the 2 discs, all features of the PFO, such as PFO channel (PFO), atrial septal aneurysm of the septum
primum (ASA), and septum secundum (SS) are depicted. The fluoroscopic image is reminiscent of the arcade figure Pacman (bottom insert). The
contrast medium may be followed to the levophase to also document the left atrium (LA) and the position of the left disc (top insert).
VII. SAFETY, TECHNICAL ASPECTS TO PFO CLOSURE, AND FUTURE OUTLOOK
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perfectly perpendicular to the device (Fig. 16.14) may be made to document the final position. The left anterior obli-
que view commonly needs to be adapted at least slightly to again perfectly separate the 2 discs in the profile view. A
residual shunt at this time has little predictive value regarding complete closure later. A snug hugging of the septum
by the device heralds good long-term tightness (Fig. 16.4, Fig. 16.12, Fig. 16.13, Fig. 16.14, Video 16.1, Video 16.2,
Video 16.8, Video 16.9, Video 16.10). The sheath, when unhinged from the device, may fall into the hepatic vein
or behind the Thebesian ledge (or ridge) [9]. The Thebesian ledge may be deceiving at a final angiogram. Not to
confuse the Thebesian ledge with the atrial septum, the position of the sheath may have to be adapted or a larger
bolus of contrast medium may have to be injected (Fig. 16.15). An alternative to a second contrast injection is waiting
for the contrast medium to appear in the left atrium after passing through the pulmonary circulation (levophase),
which will clarify the position of the left disc.
RA
SS
SS
SS
SS
SS
LA
RA
SS
SS
RA
LA
A1 2A1AA2
B1CB2C1CC2
D1D1
D2D2
E1 2E1EE2
E3E3
ASA
SP
SS
SS
LA
RA
LA
RA
LA
RA
FIGURE 16.13 Corrections for Suboptimal Device Placements for PFO Closure. (A) An Amplatzer PFO Occluder 25 is first placed incor-
rectly, not biting into the septum secundum (SS) with part of the right disc in the PFO channel to the anatomical left of the SS (A1, Pacman sign
negative). This was corrected with the same device by pulling and re-releasing the right disc (A2). (B) An Amplatzer PFO Occluder 25 only
minimally bites into the SS because of too much pivoting into the atrial septal aneurysm (ASA). The SS only reaches partially into the Pacman
mouth. After counterclockwise torque of the delivery sheath, the device was finally released in a more perpendicular position with satisfactory
result (not shown). An Amplatzer PFO Occluder 35 would have been a better device choice. (C) A similar situation with an Amplatzer PFO
Occluder 25 in the presence of an excessively flimsy septum primum (SP). The device sits like an arrow in a drawn bow (C1, small arrows). As
expected, the device shot into a vertical position upon release from the pusher cable, now biting into the SS more deeply and correctly (C2). (D) An
Amplatzer PFO Occluder 25 fails to catch the SS (D1, Pacman sign negative, large residual shunt). After replacement with an Amplatzer PFO
Occluder 35, the Pacman sign is visible (D2). (E) An Amplatzer PFO Occluder 25 fails to sufficiently catch the SS (E1, Pacman sign negative). After
replacement with an Amplatzer Cribriform Occluder 35, the Pacman sign is improved but still borderline in spite of the largest device fitting
through the 9 F sheath having been employed (E2). Transesophageal echocardiography 15 months later documents complete occlusion (E3). LA,
left atrium; RA, right atrium.
VII. SAFETY, TECHNICAL ASPECTS TO PFO CLOSURE, AND FUTURE OUTLOOK
DEVICE DEPLOYMENT 213
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RA
LA
SS
SP
SS
SP
FIGURE 16.14 Final Angiogram After Release of the Device. Left panel: A 15 mL contrast medium injection from the entry of the right
atrium (RA), in a left anterior oblique view optimized for complete disc separation, fills the RA completely to document the position of the
Amplatzer PFO Occluder 25 compared with the septum secundum (SS) and the septum primum (SP). A few seconds later, the levophase of the
angiogram (insert) also depicts the contour of the left atrium (LA). Right panel: Sufficient delineation can also be achieved with 5 mL of contrast
medium injected close to the device (Amplatzer Cribriform 25 Occluder).
Septum
Secundum
Septum Primum
Left
Atrium
Right
Atrium
FIGURE 16.15 Thebesian Ledge Mistaken as Atrial Septum During Final Angiography [9]. The Thebesian ledge is a fold in the right atrium
(RA, top panel) that looks like a septum on angiography when contrast medium is injected beyond it. Correcting the position of the injecting
delivery sheath or injecting a larger amount of contrast medium, the real atrial septum can be correctly delineated (bottom panels). LA, left atrium;
SS, septum secundum.
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SECOND OCCLUDER FOR RESIDUAL SHUNT AT FOLLOW-UP[10]
Any residual shunt considered clinically relevant enough for repeat closure at follow-up echocardiography is
looked for angiographically in a left anterior oblique projection separating the 2 discs. If the shunt is large, it is
crossed with a wire and closed, usually with a standard Amplatzer PFO Occluder 25 (preferably through an 8 F de-
livery sheath), just like a native PFO (Fig. 16.16). If there is only a small tunnel tapering toward the exit into the left
atrium, a coil [11] or an Am platzer Vascular Plug can be deployed without the need to catheterize the left atrium
(Fig. 16.16). This has several advantages. No new material in the left atrium means antiplatelet agents do not
have to be continued or resumed. There is no need to exchange the diagnostic catheter for a delivery sheath. This
saves additional cost to the lower price of a coil or an Amplatzer Vascular Plug compared to PFO occluders.
CONCLUSION
The beauty of percutaneous PFO device closure mainly resides in its simplicity and safety combined with a huge
potential yield [12]. On the other hand, the procedure is mainly preventive, as if it were a mechanical vaccination
[12,13]. Therefore, comfort and safety of the patient during (and after) the intervention are of paramount importance.
The technique described here is kept as easy as fixing a tooth. When you go to the dentist, you expect some discom-
fort while injecting the local anesthetic but no pain thereafter. You also expect a swift procedure and you count on
100% success and no complications. Finally, you want to go to work or to whatever you wanted to do that day imme-
diately after the treatment without any restrictions and with at the most minimal local discomfort. Percutaneous PFO
LA LA
LA
RA
RA
1
2
1
2
1
2
SS
LA
RA
1
2
FIGURE 16.16 Second Amplatzer Occluder for Residual Shunt at Follow-up After PFO Closure. Top left panel: The first device (1,
Amplatzer Cribriform Occluder 25) did not completely cover the PFO slit. The second device (2, Amplatzer PFO Occluder 25) sits next to it,
straddling it partly. Top center panel: An Amplatzer PFO Occluder 18 (1, both discs 18 mm) was incorrectly implanted not biting into the septum
secundum (SS, Pacman sign negative). The second device (2, Amplatzer PFO Occluder 25) squeezes both, the first device and the SS. Top right
panel: There was a residual leak through the first device between the discs (1, Amplatzer PFO Occluder 25). The second device (2, Amplatzer PFO
Occluder 25) fills out that space with the right disc maintaining a cucumber configuration. In such cases, often an Amplatzer Vascular Plug can be
introduced through a diagnostic catheter as small as 4 French into the remaining tunnel between the discs. Bottom panels: Residual shunt (arrow,
left) of an Amplatzer Cribriform Occluder 35 (1), corrected with an Amplatzer Vascular Plug 8/5 mm through a 6 French diagnostic catheter (2,
right). LA, left atrium; RA, right atrium.
VII. SAFETY, TECHNICAL ASPECTS TO PFO CLOSURE, AND FUTURE OUTLOOK
CONCLUSION 215
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closure can offer all that. Even the few patients who come back for a reintervention due to a residual shunt are rarely
reluctant to consent to it. Some even demand a reintervention although the residual shunt is probably clinically irrel-
evant. They want that hole closed that caused their initial problem [14].
The facility of percutaneous PFO closure comes closest to the adage of “see one, do one, teach one” in interven-
tional cardiology. Echocardiography is intimately involved; however, it is the appetizer and dessert, but not part of
the main course.
SUPPLEMENTARY MATERIALS
Supplementary data related to this article can be found online at https://doi.org/10.1016/B978-0-12-816966-7.
00016-6.
Conflicts of interest
Both authors have received speaker and tutor fees from Abbott.
References
[1] Nietlispach F, Meier B. Percutaneous closure of patent foramen ovale: safe and effective but underutilized. Expert Rev Cardiovasc Ther 2015;
13:121e3.
[2] Madhkour R, Meier B. Patent foramen ovale closure, a contemporary review. Structural Heart 2018;2:114e20.
[3] Meier B. Patent foramen ovale e Amplatzer PFO occluders. In: Sievert H, Qureshi AS, Wilson N, Hijazi Z, editors. Percutaneous interventions
for congenital heart Disease. London: Informa Healthcare UK Ltd; 2007. p. 289e309.
[4] Salaun E, Carles S, Bigand E, Pankert M, Aldebert P, Jaussaud N, Theron A, Cuisset T, Lambert M, Grisoli D, Franceschi F, Avierinos JF,
Collart F, Deharo JC, Bonnet JL, Habib G. High radiation exposure of the imaging specialist during structural heart interventions with echo-
cardiographic guidance. JACC Cardiovasc Interv 2017;10:626e7.
[5] Taramasso M, Nietlispach F, Maisano F, Meier B. Patent foramen ovale: indications for closure and techniques. EuroIntervention 2016;
12(Suppl. X):X7e12.
[6] Meier B. Closure of patent foramen ovale: technique, pitfalls, complications, and follow up. Heart 2005;91:444e8.
[7] Bonvini RF, Sigwart U, Verin V. Interatrial septum rupture during balloon measurement of a patent foramen ovale in a young patient pre-
senting cryptogenic stroke. Cathet Cardiovasc Interv 2007;69:274e6.
[8] Meier B. Pacman sign during device closure of the patent foramen ovale. Cathet Cardiovasc Interv 2003;60:221e3.
[9] Tobis J, Shenoda M. Percutaneous treatment of patent foramen ovale and atrial septal defects. J Am Coll Cardiol 2012;60:1722e32.
[10] Susuri N, Obeid S, Ulmi M, Siontis GCM, Wahl A, Windecker S, Nietlispach F, Meier B, Praz F. Second transcatheter closure for residual shunt
following percutaneous closure of patent foramen ovale. EuroIntervention 2017;13:858e66.
[11] Meier B. Coil closure of residual shunt after Amplatzer PFO occlusion. Cathet Cardiovasc Interv 2011;77:720e1.
[12] Nietlispach F, Meier B. Percutaneous closure of patent foramen ovale: an underutilized prevention? Eur Heart J 2016;37:2023e8.
[13] Meier B. Closure of the patent foramen ovale with dedicated Amplatzer occluders: Closing in on a mechanical vaccination. Cathet Cardiovasc
Interv 2008;72:80e1.
[14] Meier B. Second device for a patent foramen ovale: life saver and psychotherapy. Cathet Cardiovasc Interv 2010;76:151e2.
VII. SAFETY, TECHNICAL ASPECTS TO PFO CLOSURE, AND FUTURE OUTLOOK
16. HOW I DO IT: FLUOROSCOPY-GUIDED TECHNIQUE FOR PERCUTANEOUS PFO CLOSURE216
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CHAPTER
17
PFO Closure: History, Final Thoughts, and
Future Outlook
Stefan Bertog, Horst Sievert
Cardiovascular Center, Frankfurt, Germany
OUTLINE
History and Lessons Learned 217
Final Thoughts and Future Outlook 219
References 219
HISTORY AND LESSONS LEARNED
There are a number of lessons to be learned from the journey of patent foramen ovale (PFO) closure. First, it can
take centuries from the discovery of the anatomy and first description of the pathophysiology of a conditio n to the
demonstration that a treatment is effective. A PFO may initially have been described by Galen with first detailed
drawings (of the circulatory system in pigs and ox) by DaVinci in 1490 depicting a communication between the atria.
Eustachi described the physiologic importance of the structure in the fetal circulation in 1570 and Virchow first
mentioned the phenomenon of embolization in the vascular system. This was the prelude to the first description
of paradoxical embolism through a PFO by one of his students, Julius Cohnheim, in 1877 [1].
“So habe ich noch ku
¨
rzlich einen Fall von frischer, to
¨
dlicher Embolie einer A. foss. Sylvii bei einer 35 ja
¨
hrigen Frau zu beobachten Gele-
genheit gehabt, wo Herzklappen, Aorta ascendens, kurz alle in Betracht kommenden Arterien absolut intact waren, dagegen in den Venen
der unteren Extremita
¨
t sich eine ausgedehnte Thrombose fand. Sie werden glauben, dass ich zuna
¨
chst entfernt nicht daran dachte, beides in
Zusammenhang miteinander zu bringen, bis ich bei genauerer Besichtigung des Herzens ein so grosses Foramen ovale auffand, dass ich
mit Leichtigkeit drei Finger durch dasselbe hindurchbringen konnte. Jetzt konnte ich nicht la
¨
nger die Mo
¨
glichkeit von der Hand weisen,
dass hier ein abgerissener Thrombus aus der Vena cruralis bei der Passage durch das Herz aus dem rechten in den linken Vorhof und von
da in die A. Foss. Sylvii geraten ist.”
The translation of this text is the following: “I recently have had the opportunity to observe a case of a fresh,
deadly embolus in the medial cerebral artery in a 35-year-old female whose heart valves, aorta, in short, all her ar-
teries were intact. However, there was extensive thrombosis found in the veins of the lower limb. You may imagine
that, at first, I did not remotely think to make a connection between the 2 findings until, after closer inspection of the
heart, I found a large PFO through which it did not require any effort to advance 3 fingers at a time. Now I could no
longer ignore the possibility that a dislodged thrombus from the leg veins made its way, via the PFO, into the medial
cerebral artery.”
Shortly thereafter Litten, a student of Cohnheim, described paradoxical embolism via a PFO to the lower extrem-
ity arterial system causing critical limb ischemia, gangrene, and ultimately the death of a 45-year-old woman [2]. The
PFO proved its potential to kill already in the first 2 cases. Following these initial reports, paradoxical embolism into
217
PFO Closure for Stroke, Myocardial Infarction, Peripheral Embolism, Migraine, and Hypoxemia
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other vascular territories (Chapter 9), including the coronary arteries causing myocardial infarction (Chapter 8), has
been reported. Hence, the connection of a PFO and paradoxical embolism was recognized over 100 years ago.
Contemporary studies further support the connection between a PFO and paradoxical embolism. For example, in
a cohort of w 25,000 patients with pulmonary embolism or deep venous thrombosis, the risk of developing a stroke
was twice as high in individuals with a PFO compared to those without [3]. Furthermore, in patients with pulmo-
nary embolism, the likelihood of silent cerebral infarctions (detected by magnetic resonance imaging) is substantially
higher in those with a PFO (33%) compared to those without (2%) [4]. Adding to the pathophysiological plausibility
is the observation of thrombus in transit, lodged within a PFO [5e8], and the correlation of PFO size and risk of
stroke from no other apparent cause [9e12]. The first surgical closures were performed in 1939 by Blakemore and
1948 by Murray [13]. The first percutaneous closure of an interatrial septal defect, using 2 discs, was conducted
by King and Mills in 1974 [14], and the first percutaneous PFO closures were performed by Lock [15]. This triggered
the era of percutaneous PFO closure. The anatomical and physiological plausibility (Chapter 1), the observation that
in young patients with otherwise cryptogenic stroke the prevalence of a PFO was higher than in the general popu-
lation [16,17], and the first nonrandomized studies suggesting a lower recurrence rate after PFO closure [18,19]
(Chapter 5) led to a rapid increase in the number of device closures. Results of the first randomized controlled trial,
CLOSURE I (Evaluation of the Starflex Septal Closure System in Patients With a Stroke or Transient Ischemic Attack
Due to the Possible Passage of a Clot of Unknown Origin Through a PFO) in 2012, however, showed no significant
advantage of PFO closure [20] and dampened the enthusiasm for PFO closure tremendously (Chapter 6). How was
this possible, if our understanding of the pathophysiology and ability to occlude the PFO fit together so perfectly?
This illustrates the second lesson in our journey.
Not all devices designed to solve a medical problem perform equally well. The STARFlex Septal Closure System
(NMT Medical Inc., Boston, Massachusetts) of the CLOSURE I trial demonstrated lower implantation success and
closure rates (89% and 86%, respectively) than other PFO occluding devices at that time, and the incidence of post-
implant atrial fibrillation was relatively high (5.7%) [20]. Moreover, the rate of left atrial thrombus formation at
6 months was 1.1%, and half of the patients with a thrombus had a stroke [20]. It has later become clear that other
PFO occluders outperform the aforementioned device. For example, in a randomized controlled trial including 660
patients comparing Amplatzer devices (Abbott, Chicago, Illinois) to the STARFlex device and Helex Septal Occluder
(W.L. Gore and Associates, Flagstaff, Arizona), the event rate at 5-year follow-up was significantly lower in patients
who received an Amplatzer device compared with the STARFlex and Helex occluders [21].
The third lesson relates to the need for long-term follow-up in trials examining the effectiveness of devices for the
prevention of an event, the risk of which is low at baseline and cumulative over time. This was well demonstrated in
the RESPECT (Randomized Evaluation of Recurrent Stroke Comparing PFO Closure to Established Current Stan-
dard of Care) trial which randomized 980 stroke patients to PFO closure versus medical management [22]. In the
initial analysis (2.6-year median follow-up), there was a strong trend toward a benefit after PFO closure that did
not reach statistical significance (P ¼ .08). However, after a median follow-up of 5.9 years, RESPECT showed a
more pronounced, now statistically significant stroke risk reduction with PFO closure compared to medical therapy
(Chapter 6). There are similarities to other trials examining the utility of devices used for event prevention, the inci-
dence of which is relatively low. For example, it took a long-term (3.8 years) follow-up in the Percutaneous Left
Atrial Appendage Closure vs. Warfarin for Atrial Fibrillation trial to demonstrate a mortality benefit of left atrial
appendage closure compared with long-term warfarin therapy [23].
The fourth lesson is the importance of appropriate patient selection. Although CLOSURE I did not mandate
confirmed neuroimaging for strokes and accepted patients with lacunar strokes, in RESPECT, only individuals
who had objective evidence of a stroke by neuroimaging were enrolled. In all 3 subsequent randomized trials
showing a benefit of PFO closure compared with medical therapy (Chapter 7), 1 inclusion criterion was a brain
defect by neuroimaging consistent with a stroke and features that increase the likelihood that the PFO was, in
fact, the culprit for the initial event [24e26]. For example, in REDUCE (PFO Closure or Antiplatelet Therapy for
Cryptogenic Stroke), patients with evidence for small vessel ischemic disease, i.e., prior lacunar infarct(s), uncon-
trolled diabetes mellitus or hypertension, autoimmune disease, or alcohol abuse were excluded [25]. In CLOSE
(PFO Closure or Anticoagulation vs. Antiplatelets after Stroke), only patients with an atrial septal aneurysm or large
shunt [24] were included; in DEFENSE-PFO (Cryptogenic Stroke and High-Risk PFO), only those with a hypermo-
bile interatrial septum, atrial septal aneurysm, or a separation of the septum primum from secundum of 2mm
were enrolled (Chapter 7) [26].
Where do we currently stand? We now have data on over 3000 patients from randomized trials demonstrating
that PFO closure with contemporary devices is superior to medical therapy alone for secondary prevention of
strokes from no underlying source other than the PFO. For example, in the most recent meta-analysis, despite
17. PFO CLOSURE: HISTORY, FINAL THOUGHTS, AND FUTURE OUTLOOK218
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including an outdated device (from the CLOSURE I trial), at latest follow-up, recurrent strokes occurred in 1.96% of
patients treated by PFO closure compared with 4.6% in those without a device [27]. Under these circumstances, PFO
closure should be recommended for all patients with stroke and no identifiable source other than a PFO, particularly
in those with high-risk features that suggest paradoxical embolism as the cause of the index stroke (cortical infarcts,
large PFOs and/or hypermobile interatrial septum or aneurysm, Eustachian valve or Chiari network, history of
venous thromboembolism). The devices that were rigorously tested in the randomized trials include the Amplatzer
PFO Occluder (Abbott, Chicago, Illinois) in RESPECT, CLOSE, and DEFENSE-PFO and the Helex Septal Occluder/
Cardioform Septal Occluder (W.L. Gore and Associates, Flagstaff, Arizona) in REDUCE (Chapter 14). This, of course,
does not imply that other devices do not work equally well.
FINAL THOUGHTS AND FUTURE OUTLOOK
Does all this mean the chapter of PFO closure can now be closed? Though tempting, this is not a time to become
complacent. There are a number of aspects that need improvements. First, no current device provides a 100% guar-
antee for effective closure; device-associated thrombus formation has been reported with virtually every device
studied in large randomized trials [28e30] and the incidence of atrial fibrillation shortly after device implantation
increases (4% vs. 0.72% in the aforementioned meta-analysis [27]), all of which potentially offset the benefit of the
procedure. Hence, innovation must continue with special focus on low-profile devices or techniques that maintain
high closure rates while further minimizing risks of thrombus formation and atrial fibrillation. Although implanta-
tion risk already is close to zero, device improvements further facilitating implantation remain possible and war-
ranted. Second, how large does an interatrial right-to-left shunt have to be in order to close it? Is 1 bubble seen
on echocardiography enough? How thoroughly does one have to investigate for the presence of an interatrial shunt
prior to and after closure? Is a transthoracic echocardiogram with bubble study via an antecubital vein injection
enough, or is it necessary to proceed with more aggressive investigations, such as femoral vein bubble injections
and transesophageal imaging, if initia l testing is negative (Chapter 2)? Third, although we have established the util-
ity of PFO device closure in young high-risk patients, should we not close a PFO for a patient who does not fit these
criteria? [31] Finally, is it time to study the utility of PFO closure for primary prevention? [32,33]
Regardless of the biochemistry and physiology of atherosclerotic plaque development and thrombus formation,
the devastating final event culminating in cortical ischemic strokes is most often of mechanical nature, i.e., emboli-
zation to the cerebral circulation. Despite many open questions and opportunities for further research, it is clear that
PFO closure [22,24e26], next to left atrial appendage closure [23] and carotid intervention [34,35], is one more impor-
tant tool at our disposal in the interventional armamentarium for the prevention of embolic events. Proof of the util-
ity of aforementioned procedures comes at a time when recognition that interventional management of acute
embolic cortical strokes is, when feasible, best performed by percutaneous mechanical thrombectomy [36e40].
Thus, interventional treatment options have revolutionized our approach to stroke prevention and therapy. The
key will be to give patients easy access to these treatments, provide physicians with the training needed to perform
the procedures, and for the device manufacturers and researchers to continue improving the technology.
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VII. SAFETY, TECHNICAL ASPECTS TO PFO CLOSURE, AND FUTURE OUTLOOK
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