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eft Atrial Dysfunction in Patients With Patentoramen Ovale and Atrial Septal Aneurysmn Alternative Concurrent Mechanism for Arterial Embolism?

ianluca Rigatelli, MD,* Silvio Aggio, MD,† Paolo Cardaioli, MD,*abriele Braggion, MD,† Massimo Giordan, MD,* Fabio Dell’avvocata, MD,*auro Chinaglia, MD,‡ Giorgio Rigatelli, MD,§ Loris Roncon, MD,† Jack P. Chen, MD�

ovigo and Verona, Italy; and Atlanta, Georgia

bjectives We postulate that, in patients with large patent foramen ovales (PFO) and atrial septalneurysms (ASA), left atrial (LA) dysfunction simulating “atrial fibrillation (AF)-like” pathophysiologyight represent an alternate mechanism in the promotion of arterial embolism.

ackground Despite prior reports concerning paradoxical embolism through a PFO, the magnitudef this phenomenon as a risk factor for stroke remains undefined, because deep venous thrombosiss infrequently detected in such patients.

ethods To test our hypothesis, we prospectively enrolled 98 consecutive patients with previoustroke (mean age 37 � 12.5 years, 58 women) referred to our center for catheter-based PFO closure.aseline values of LA passive and active emptying, LA conduit function, LA ejection fraction, andpontaneous echocontrast (SEC) in the LA and LA appendage were compared with those of 50 AFatients as well as a sex/age/cardiac risk-matched population of 70 healthy control subjects.

esults Pre-closure PFO subjects demonstrated significantly greater reservoir function as well asassive and active emptying, with significantly reduced conduit function and LA ejection fraction,hen compared with AF and control patients. Furthermore, in PFO patients, 66.3% (65 of 98) hadoderate-to-severe ASA and basal shunt; SEC was observed in 52% of PFO plus ASA patients beforelosure. Multivariate stepwise logistic regression revealed moderate-to-severe ASA (odds ratio: 9.4,5% confidence interval: 7.0 to 23.2, p � 0.001) as the most powerful predictor of LA dysfunction.fter closure, all LA parameters normalized to the levels of control subjects: no SEC, device-relatedhrombosis, or aortic erosion were observed on follow-up echocardiography.

onclusions This study suggests that moderate-to-severe ASA might be associated with LA dys-unction in patients with PFO. The resultant similarities to the pathophysiology of AF might repre-ent an additional contributing mechanism for arterial embolism in such patients. (J Am Collardiol Intv 2009;2:655–62) © 2009 by the American College of Cardiology Foundation

rom the *Section of Adult Congenital and Adult Heart Disease, Cardiovascular Diagnosis and Endoluminal Interventions,Division of Cardiology, Echocardiography Lab, and the ‡Department of Neuroscience, Rovigo General Hospital, Rovigo, Italy;Department of Specialistic Medicine, Divisione of Cardiology, Legnago General Hospital, Verona, Italy; and the �Saint Joseph’sranslational Research Institute, Atlanta, Georgia.

anuscript received January 27, 2009; revised manuscript received April 24, 2009, accepted May 3, 2009.

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espite numerous reports regarding the association ofrterial embolism with patent foramen ovale (PFO) (1–3),he causality of paradoxical embolism remains speculative inany cases. The true impact of this phenomenon as a risk

actor for stroke in such patients with PFO is unknown,ecause deep vein thrombosis is frequently not identified inhese individuals (4). The diagnostic accuracy for detectionf small thrombi might, however, be limited by standardvailable techniques. Because patients with presumed para-oxical embolism frequently share functional features with

See page 663

hose with atrial fibrillation (AF), such as impairment of theeft atrial (LA) function, we postulate that an “AF-like”hysiology might contribute to LA thrombosis and subse-uent arterial embolism. Thus, we assessed the presence of

classical LA anatomic and func-tional predictors of AF andstroke such as LA dysfunction,LA spontaneous echocontrast(SEC) or thrombosis, and re-duced left atrial appendage(LAA) velocity amongst controlsubjects and AF and PFO pa-tients before and after percuta-neous closure.

Methods

We prospectively enrolled 98consecutive patients (mean age37 � 12.5 years, 58 women)with previous stroke who hadbeen referred to our center forcatheter-based closure of inter-atrial shunts according to stan-

ard indications (5) over a 36-month period (Table 1).ritten informed consent was obtained from all patients

nrolled in the study.chocardiographic protocols and definitions. TransthoracicTTE) and transesophageal echocardiography (TEE) wasonducted with a GE Vivid 7 (General Electric Corp.,orfolk, Virginia) 1 month before the procedure and

epeated 1 month after closure: LA volumes and function asell as shunt degree as assessed by contrast injection andalsalva maneuver under local anesthesia were recorded (6).The LA passive and active emptying, LA conduit func-

ion, and LA ejection fraction were evaluated by TTEefore and 1 month after PFO closure. Assessed parametersncluded: LA volumes as determined at the mitral valvepening (maximal, Vmax), at the onset of atrial systole

bbreviations andcronyms

F � atrial fibrillation

I � confidence interval

CE � intracardiacchocardiographic

A � left atrium/atrial

AA � left atrial appendage

R � odds ratio

FO � patent foramen ovale

EC � spontaneouschocontrast

CD � transcranial Doppler

EE � transesophagealchocardiography

TE � transthoracicchocardiography

P-wave of the electrocardiogram, Vp), and at mitral valve z

losure (minimal, Vmin) from the apical 2- and 4-chamberiews by means of the biplane area-length method viaoftware within the system. The following formula was usedo calculate LA volume (7,8): volume � 8 � 4 � AchA2ch/3�) � common length (where A4ch and A4ch �A area in 4- and 2-chamber views, respectively). The LA

unctional parameters were calculated as described in Table. The LA ejection fraction served as a measure of LAystolic performance; and acceleration and decelerationimes of systolic phase of pulmonary venous flow corre-ponded to LA relaxation and compliance, respectively.

The LAA peak flow velocity as well as SEC or throm-osis in LA and LAA were also evaluated among the 3roups, because low LAA peak flow velocity and SEC haveeen associated with risk of stroke (9,10). The pre- andost-operative echocardiographic findings were blindly eval-ated by 2 blinded physicians.ntracardiac echocardiography protocol. Patients who ful-lled the criteria for PFO closure underwent intraproce-ural intracardiac echocardiographic (ICE) assessment withhe mechanical 9-F 9-MHz UltraICE catheter (EP Tech-ologies, Boston Scientific Corporation, San Jose, Califor-ia). The ICE study was conducted as previously described11,12), by performing a manual pull-back from the supe-ior vena cava to the inferior vena cava through 5 sectionallanes. The ICE monitoring of the implantation procedureas conducted in the 4-chamber plane. Special attentionas posed in visualizing potential smoke-like phenomenon

n the LA before closure with standard gray-scale set-up,lthough the eventual thrombogenic process might be of ainor entity than in patients with AF or rheumatic disease

nd thus probably difficult to visualize by TEE.losure protocol. Combined antibiotic therapy (gentamicin0 mg plus ampicillin 1 g or Vancomicin 1 g if allergy hadeen recorded on anamnesis) was administered intrave-ously 1 h before the procedure. The right femoral vein wasatheterized through an 8-F sheath and used for pre-closureight heart catheterization; the sheath was subsequentlyeplaced with a 10- or 12-F long sheath for device implan-ation. The left femoral vein was catheterized with an 8-Fheath and replaced with a precurved 9-F long sheath forCE study.ntraoperative closure criteria and device selection. On theasis of ICE study and the presence/absence of moderate-o-large ASA and long tunnel-like PFO (tunnel length �12m), the operators selected either the Amplatzer Occluder

amily (PFO Occluder, Cribriform Occluder, AGA Medi-al Corporation, Golden Valley, Minnesota) or the Premerelosure System (St. Jude Medical Inc. GLMT, St. Paul,innesota), as previously described (13). The Amplatzer

amily, a well-known device composed of 2 parallel nitinolire-mesh disks was selected in cases of ASA, because itsore rigid design offered superior interatrial septal stabili-

ation, as previously suggested (14). The PFO Occluder was

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sed in cases of mild ASA (1 or 2 right/left [RL]-eft/right [LR], according to Olivares classification) (15)nd short tunnel, whereas the Amplatzer ASD Cribriformccluder was preferred in cases of moderate-to-severe ASA

3RL-3LR up to 5RL-5LR, according to Olivares classifi-ation). Finally, the Premere Occlusion system, a deviceomposed of 2 portions of a single nitinol wire (right isovered by tissue), connected by an adjustable length tender,as selected in cases of long tunnel PFO without ASA,ecause this device can be asymmetrically opened throughhe long channel.ollow-up protocol. All patients were administered aspirin00 mg/day for 6 months after the procedure. Follow-upvaluations consisted of TEE at 1 month, with repeat studyt 6 months if even minimal shunt was detected. Post-rocedural assessment further included TTE at 1, 6, and 12onths; transcranial Doppler (TCD) at 1 month; Holter

Table 1. Demographic, Clinical, and Echocardiographic Features of Enrolle

StudyPatients

Age (yrs) 37 � 12.5

Male/female 30/58

Heart rate 75.1 � 11.2

Body surface 1.74 � 0.2

VTDi (ml/m2) 68.6 � 15.4

Suga index 5.9 � 2.3

Systolic pulmonary pressure (mm Hg) 15.3 � 2.3

Migraine with aura 41/98 (41.8)

Migraine without aura 15/98 (15.3)

TCD shower pattern 55/98 (56.1)

TCD curtain pattern 43/98 (43.9)

Basal shunt on TEE without Valsalva 41/98 (41.8)

Atrial septal aneurysm (TEE) 52/98 (53.1)

Abnormalities of the coagulative cascade proteins:deficiency of anti-thrombin III, Factor V Leiden

36/98 (36.7)

Auto-antibodies: antiphospholipid or anticardiolipin 8/98 (8.2)

AF � atrial fibrillation; ASA � atrial septal aneurysm; PFO � patent foramen ovale; TCD � transcran

Table 2. Volumetrics and Measurement Points

VolumetricsMeasurement

Points

LA max Mitral opening

LA min Mitral closure

LA reservoir LA max-LA min

LA conduit LASV (Vmax–Vmin)

LA at atrial systole P wave

LA stroke volume (LASV, active emptying) LA at P-LA min

LA active emptying fraction LASV/LA at P

LA passive emptying LA max –LA at P

Left atrial (LA) volumes as determined at the mitral valve opening (maximal, Vmax), at the onset of

atrial systole (P wave of the electrocardiogram), and at mitral valve closure (minimal, Vmin).

bLASV � left atrium stroke volume.

onitoring at 1 month; and combined cardiologic andeurological visit at 1, 6, 12 months. Residual shunt wasssessed by contrast TEE and TCD (16).tatistical analysis. During transthoracic and TEE, basalalues were compared with those of a sex/age/heart rate-atched population of 70 healthy volunteers and 50 sex-atched AF patients. The latter were enrolled during the

ame study period; these subjects all demonstrated normaleft ventricular function and size and were optimally med-cated with respect to heart rate control and oral anticoag-lant levels (Table 1). Additionally, pre-procedural values ofFO patients were compared with those obtained at-month follow-up. All values were corrected for R-Rnterval and body surface area.

Chi-square, analysis of variance, and paired Student tests were used to compare frequencies and continuousariables between groups. Statistical analysis was performedith a statistical software package (SAS for Windows,ersion 8.2, SAS Institute, Cary, North Carolina). A prob-bility value of �0.05 was considered to be statisticallyignificant. Stepwise logistic regression analysis was used toetermine independent determinants of preoperative LAysfunction. We considered only patients with at least 1ltered parameter as patients with “LA dysfunction”. Theariables subject to analysis were: age, sex, moderate-severeSA (3RL, 3LR up to 5RL, according to Olivares classi-cation), shower pattern on TCD, curtain pattern on TCD,edium-to-large shunt with Valsalva on TEE, and basal

hunt without Valsalva on TEE. A dispersion graphic withinear regression was generated to determine the correlation

ents and Control Subjects

Healthy ControlSubjects AF Patients p Value

38 � 11.8 58 � 11.8 �0.01

30/44 17/33 NS

73.3 � 12.7 78.3 � 14 NS

1.78 � 0.2 1.71 � 0.4 NS

73.1 � 13.5 72.8 � 12.7 NS

6.36 � 2.1 6.24 � 2.3 NS

14.6 � 2.4 15.1 � 2.1 NS

4/70 (5.7) 2/50 (4.0) �0.01

11/70 (15.7) 8/50 (16) NS

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pler ultrasound; TEE � transesophageal echocardiography; VTDi � indexed teledistolic volume.

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esults

hen compared with healthy subjects, pre-procedural PFOatients demonstrated greater reservoir function and passivend active emptying but lower conduit function and LAjection fraction (Table 3). These abnormal values wereimilar to those found in AF subjects.

When compared with isolated PFO patients, those withFO plus ASA were observed to have worse functionalarameters and higher percentage of spontaneous right-to-

eft shunt (Fig. 1). Interestingly, patients with both PFOnd ASA had more coagulative abnormalities than PFOlone patients: 67.3% (35 of 52) versus 19.5% (9 of 46), p �.01. This observation might account for the more frequentistory of recurrent cerebral events (�2 stroke/transient

schemic events or multiple magnetic resonance imaging

Table 3. Echocardiographic Data of Healthy Subjects, Atrial Fibrillation Pat

Healthy SubjectsAtrial Fi

Pati

Systolic acceleration time 200.1 � 43.1 180.5

Systolic deceleration time 213.3 � 52.1 252.1

Reservoir function (ml/mq/s�0.5) 34.14 � 13.53 40.1

LA passive emptying (ml/mq/s�0.5) 24.19 � 13.26 31.14

LA conduit function (ml/mq/s�0.5) 30.82 � 11.63 26.3

LA active emptying (ml/mq/s�0.5) 13.97 � 10.48 17.10

LA passive emptying fraction (%) 0.32 � 0.17 0.22

LA conduit fraction (%) 1.10 � 0.72 0.83

LA active emptying fraction (%) 0.41�0.18 0.32

LA ejection fraction (%) 0.61�0.12 0.49

Not adjusted for type I error risk.

LA � left atrial.

Figure 1. PFO Versus PFO and ASA

Comparison of left atrial (LA) functional parameters and anatomical characteris

atrial septal aneurysms (ASA) versus those with isolated PFO, suggesting a higher ris

schemic foci) in the former versus latter groups: 78.8% (41f 52) versus 34.8% (16 of 46), p �0.01. In the PFO plusSA group, a smoke-like phenomenon was observed by at

east 1 imaging tool in the LA before closure of 27 of 52atients (52%, 22 of 27 patients by intraprocedural ICE)Fig. 2): all these patients had moderate-to-severe ASA. NoEC was observed in the PFO alone group (p � 0.01). TheAA peak flow velocity was not statistically different be-

ween the entire cohort of PFO patients and healthy controlubjects (48.1 � 21.0 cm/s vs. 49.8 � 23.2 cm/s, p � 0.18),ith both being higher than AF patients (21.8 � 8.2 cm/s,� 0.001).Multivariate stepwise logistic regression revealed moderate-

o-severe ASA (odds ratio [OR]: 9.4, 95% confidence intervalCI]: 7.0 to 23.2, p � 0.001) and basal shunt on TEE (OR:.6, 95% CI: 3.0 to 12.1, p � 0.001) as predictors of LA

, and Patent Foramen Ovale Patients Scheduled for Closure at Baseline

on Study PatientsBefore Closure

Study Patients AfterClosure p Value

185.5 � 51.2 199.1 � 42.1 0.03

250.1 � 65.0 215.2 � 51.7 0.02

38.61 � 10.89 35.71 � 10.41 0.04

30.35 � 10.05 26.35 � 9.92 0.04

27.95 � 10.54 29.01 � 10.07 0.04

16.70 � 4.87 14.45 � 3.68 0.02

0.23 � 0.07 0.32 � 0.09 0.02

0.84 � 0.55 1.04 � 0.50 0.04

0.34�0.10 0.29�0.09 0.01

0.51�0.6 0.61�0.6 0.03

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ysfunction, whereas moderate-to-severe ASA (OR: 11.7,5% CI: 8.0 to 29.2, p � 0.001) was the strongest predictor ofEC in the LA.All patients underwent successful PFO transcatheter

losure with the Premere Occlusion System in 28 patients,mplatzer Cribriform Occluder in 40 patients, and Am-latzer PFO Occluder in 30 patients. Complete PFOlosure was achieved in 90 patients (91.8%, 8 patients with

persistent small shunt, all with an Amplatzer ASDribriform Occluder) on TEE and TCD. Aside from 4

pisodes of AF lasting up to 48 h, no other perioperative orong-term complications—including ictus or transient isch-mic attack recurrence—were observed during meanollow-up of 26.1 � 6.7 months: in particular, no LA SEC,A thrombosis, or device-related thrombosis or aorticrosions were observed on follow-up echocardiography.

After closure, active and passive emptying as well asonduit function and LA ejection fraction tended to nor-alize (Table 3) to the levels of healthy subjects; moreover,

fter closure, LA functional parameters varied according toevice type. The Premere Occlusion System was associatedith a greater reduction of LA passive, LA conduit, and

ctive emptying as well as larger increase in LA ejectionraction, as compared with Amplatzer PFO and ASDribriform Occluders. This observation might well be

elated to the more favorable baseline anatomic featuresTable 4) (Fig. 3). The inter-observer agreement was 99.4%

Figure 2. ICE Study

(A) Intracardiac echocardiography (ICE) before closure in a 49-year-old man with awith the typical swirling inside the ASA on its left side. (B) Stabilization of the ASAGolden Valley, Minnesota) in the same patient: an electrophysiological procedurecomplete ASA stabilization with no demonstrable spontaneous echocontrast (SEC)� tricuspid valve.

lobally. t

iscussion

ur study suggests an alternative mechanism for arterialmbolism in patients with PFO and large ASA. Either withr without concurrent potential for paradoxical embolism,A dysfunction—simulating that of AF—might furtherredispose these patients to cardiogenic thrombosis. Similaro those found in patients with chronic AF, LA parametersf active and passive emptying as well as ejection fraction arelearly altered in PFO patients with large ASA.

Mechanistically, the isolated existence of a PFO is noter se a risk factor for stroke; paradoxical embolism requiresvenous source of thrombus, typically from the lower

xtremity deep veins (17). However, deep venous thrombo-is has been documented in only a small percentage ofresumed paradoxical embolic cases (4). Thus, the certaintyf this phenomenon as a cause of recurrent stroke in theFO patient without deep venous thrombosis remainsnclear. Alternative hypotheses in such cases have includedlatelet and fibrin aggregates on the ASA surface orndiagnosed deep venous thrombosis in atypical sites (suchs uterine or prostate venous plexus) (18). Although all orome might be contributory, the relative importance of eachs difficult to quantitate.

More recently, the impact of coagulation abnormalities inhe genesis of paradoxical embolism in PFO patients haseen evaluated (19). The importance of such coagulopa-

atrial septal aneurysms (ASA): note the smoke-like spontaneous echo-contrastan Amplatzer ASD Cribriform Occluder 25/25 mm (AGA Medical Corporation,ed 3 months later gave the occasion for an ICE control that demonstratedguidewire across the PFO; MV � mitral valve; rim � septum secundum rim; TV

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ology of arterial embolism in PFO patients is not dimin-shed by our findings; such pro-coagulable states furthernhance the thrombogenicity of the dysfunctional LA.

The role of LA function in the modulation of leftentricular diastolic filling is well-described (20). The LAunctions as a reservoir for the collection and storage oflood during left ventricular systole and as a conduit for thelood passage from the pulmonary veins to the left ventricleuring early left ventricular diastole. In addition to servings a passive conduit and reservoir for pulmonary venousnflow, the LA further augments left ventricular end-iastolic filling through active contraction (21).Grant et al. (22) estimated that 42% of the left ventricular

troke volume is stored in the LA during ventricular systole;he subsequent dissipation of this potential energy acts to

Table 4. Comparison of Post-Closure LA Functional Parameters According

Amplatzer PFO(n � 28)

A

Reservoir function (ml/mq/s�0.5) 32.7 � 11.4

LA active emptying (ml/mq/s�0.5) 13.8 � 4.6

LA passive emptying (ml/mq/s�0.5) 23.3 � 9.8

LA conduit function (ml/mq/s�0.5) 32.1 � 16.7

LA passive emptying fraction (%) 0.41 � 0.12

LA conduit fraction (%) 1.18 � 0.71

LA active emptying fraction (%) 0.23 � 0.12

LA ejection fraction (%) 57 � 10

All values are indexed and corrected for heart rate and body surface. *Premere versus Amplatzer PF

Abbreviations as in Tables 1 and 3.

Figure 3. LA Function Before and After Closure

Comparison of left atrial (LA) passive emptying fraction and LA volume max bclosure with various occlusion devices: the LA compliance and global function

after closure. Max ind. s.c. and RR � indexed for body surface and RR interval.

ccentuate left ventricular filling during diastole. The effi-iency of this mechanism is governed by atrial distensibilityuring ventricular systole. The LA conduit function occursrimarily but not exclusively during ventricular diastole andepresents the blood volume passing through the LA, whichs not attributable to reservoir or booster pump function.his amount accounts for 35% of LA flow (23). The boosterump function represents LA contraction and is dependentn several factors, including timing of atrial systole, vagaltimulation, magnitude of venous return, left ventricularnd-diastolic pressures, and left ventricular systolic reserve24).

On the basis of these considerations, it is likely that someegree of LA dysfunction, such as impairment of active orassive emptying or perhaps conduit function, might be

ice Type

zer ASD Cribriform(n � 40)

Premere Occlusion(n � 30) p Value

40.5 � 21.6 29.9 � 9.8 *0.43, †0.18

20.0 � 19.1 10.9 � 4.9 *0.45, †0.04

29.8 � 19.1 18.5 � 9.3 *0.04, †0.03

33.4 � 7.9 30.3 � 9.4 *0.58, †0.47

0.31 � 0.07 0.29 � 0.08 *0.37, †0.18

1.16 � 0.85 1.05 � 0.63 *0.01, †0.01

0.26 � 0.11 0.26 � 0.11 *0.02, †0.94

56 � 12 64 � 10 *0.93, †0.02

mere versus Amplatzer ASD Cribriform Occluder.

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resent in patients with PFO, especially those withoderate-large ASA. Our study further suggests that, after

ercutaneous closure, these functional aberrations return toevels observed in healthy subjects. The pathophysiologicimilarities to AF patients are particularly provocative. Lefttrial wall stiffness resulting from loss of active and passivemptying as well as contraction and reservoir functions haveeen correlated with long-term risk of LA thrombosis andubsequent arterial embolism (9,10,25). The presence ofEC alone versus that of frank LA or LAA thrombosisight be dependent upon the degree and form of LA

unctional alterations. Although some measurable impair-ents were insufficient to produce visible thrombus, theyight nonetheless promote platelet-fibrin aggregation andicro-thrombi, manifested as SEC. This phenomenonight be further augmented in patients with pro-

oagulative tendencies.The presence of moderate-to-large ASA seemed to be

he most important determinant of impaired LA function,s further suggested in a recent small study by Goch et al.26). This hypothesis is additionally substantiated by anal-sis of results based upon device types, which were selectedccording to the presence or absence of moderate-to-largeSA. The apparent superior results achieved by the Pre-ere Occlusion system might be attributable to the more

avorable pre-selection anatomic features at baseline (be-ause they were implanted in patients with no ASA),hereas the septal rigidity caused by use of the Amplatzerccluder family might account for the trend to near

ormalization of LA functional parameters. The apparentssociation with basal right-to-left shunt is more difficult toxplain but might be attributable to slight alterations in LAolumes and function resulting from increased volume.

Moreover, the subsequent post-closure improvements inA functional parameters suggest that PFO closure or ASA

tabilization might be beneficial not only in protection fromecurrent paradoxical embolism but also in preservation ofA function. Given the similarities to findings in AF,revention of such sequelae by prophylactic or primaryercutaneous closure might reduce the risk of LA throm-osis in the long-term. Although chronic anticoagulationight be proposed as a more conservative treatment in these

ituations, such therapy is clearly not without associatedorbidity. Furthermore, actual reversal of the atrial patho-

hysiology as reported in our evaluation might be, at leastntuitively, a more attractive option.tudy limitations. Although our study was a prospectivevaluation, the relatively small sample size, lack of random-zation, and short-term follow-up all tend to limit theidespread applicability of our findings. A placebo PFO

rm was not ethically possible in our study, because all PFOubjects had history of minor or major recurrent stroke andere referred for percutaneous closure. Moreover, in con-

ordance with present indications, all closures were per-

ormed for secondary prevention in patients who havelready suffered a stroke. Finally, the visualization of smoke-ike phenomenon by TEE or ICE might be somewhatuestionable, depending on different equipment set-up,perators’ skill, and probably has limited significance com-ared with LA dysfunction parameters.

onclusions

o our knowledge, the present study is the first to suggestn alternative mechanism, involving AF-like LA patho-hysiology, for arterial embolism in patients with PFO.urthermore, large prospective randomized trials mightelp elucidate any potential benefits of PFO closure forrimary stroke prevention in asymptomatic patients withFO and moderate-to-large ASA.

eprint requests and correspondence: Dr. Gianluca Rigatelli,ardiovascular Diagnosis and Endoluminal Intervention, Rovigoeneral Hospital, Via WA Mozart, 9, 37040 Legnago, Verona,

taly. E-mail: jackyheart@libero.it.

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ey Words: cardiac anatomy � echocardiography � em-

olism � patent foramen ovale � stroke.