patent foramen ovale: a review of associated conditions ... · review article patent foramen ovale:...

REVIEW ARTICLE

Patent Foramen Ovale: A Review of AssociatedConditions and the Impact of Physiological SizeEdmund K. Kerut, MD, FACC,* William T. Norfleet, MD,† Gary D. Plotnick, MD, FACC,‡Thomas D. Giles, MD, FACC*New Orleans, Louisiana; Houston, Texas; and Baltimore, Maryland

Patent foramen ovale (PFO) is implicated in platypnea-orthodeoxia, stroke and decompres-sion sickness (DCS) in divers and astronauts. However, PFO size in relation to clinical illnessis largely unknown since few studies evaluate PFO, either functionally or anatomically. Theautopsy incidence of PFO is approximately 27% and 6% for a large defect (0.6 cm to 1.0 cm).A PFO is often associated with atrial septal aneurysm and Chiari network, although theseanatomic variations are uncommon. Methodologies for diagnosis and anatomic and func-tional sizing of a PFO include transthoracic echocardiography (TTE), transesophagealechocardiography (TEE) and transcranial Doppler (TCD), with saline contrast. Salineinjection via the right femoral vein appears to have a higher diagnostic yield for PFO than viathe right antecubital vein. Saline contrast with TTE using native tissue harmonics ortransmitral pulsed wave Doppler have quantitated PFO functional size, while TEE ispresently the reference standard. The platypnea-orthodeoxia syndrome is associated with alarge resting PFO shunt. Transthoracic echocardiography, TEE and TCD have been used inan attempt to quantitate PFO in patients with cryptogenic stroke. The larger PFOs(approximately $4 mm size) or those with significant resting shunts appear to be clinicallysignificant. Approximately two-thirds of divers with unexplained DCS have a PFO that maybe responsible and may be related to PFO size. Limited data are available on the incidenceof PFO in high altitude aviators with DCS, but there appears to be a relationship. A largedecompression stress is associated with extra vehicular activity (EVA) from spacecraft. Afterfour cases of serious DCS in EVA simulations, a resting PFO was detected by contrast TTEin three cases. Patent foramen ovales vary in both anatomical and functional size, and theclinical impact of a particular PFO in various situations (platypnea-orthodeoxia, thrombo-embolism, DCS in underwater divers, DCS in high-altitude aviators and astronauts) may bedifferent. (J Am Coll Cardiol 2001;38:613–23) © 2001 by the American College ofCardiology

Patent foramen ovale (PFO) has been implicated in severalpathologic processes, including paradoxical embolism incryptogenic stroke (1–6) and venous-to-arterial gas embo-lism (AGE) in serious forms of decompression sickness(DCS) (an occupational hazard for underwater divers [7–9]and high altitude aviators and astronauts [10–13]). En-hanced right-to-left shunting of venous blood through aPFO in certain pathologic states (14–16), including theplatypnea-orthodeoxia syndrome (17–24), may cause sys-temic hypoxemia. Only a few studies have attempted toquantitate the size of a PFO, either functionally or anatom-ically.

The availability of noninvasive techniques for assessmentof PFO provides the opportunity for clinicians to diagnosepathologic states that were heretofore difficult to diagnose.

These techniques assess PFO risk based on anatomic andfunctional size.

EMBRYOLOGY

Patent foramen ovale is a remnant of the fetal circulation.Oxygenated placental blood enters the right atrium (RA) viathe inferior vena cava (IVC) and crosses the valve of theforamen ovale to enter the systemic arterial system (25). TheIVC flow preferentially flows toward the interatrial septum(IAS) and foramen ovale. The crista interveniens directssuperior vena cava flow away from the IAS. Coronary sinusflow is also directed away from the IAS (26). At birth,pulmonary vascular resistance and right-sided cardiac pres-sures drop with a reversal of the RA-to-left atrium (LA)pressure gradient. The flap of the foramen ovale (septumprimum) closes against the atrial septum (septum secun-dum), with fusion usually occurring within the first twoyears of life. Fusion is incomplete in about 25% of people,resulting in an oblique slit-like defect. Termed a PFO, itfunctions as a valve-like structure with the “door-jam” onthe LA side of the atrial septum (25) (Fig. 1).

From the *Cardiovascular Research Laboratory, Division of Cardiology, LouisianaState University Health Sciences Center, New Orleans, Louisiana; †National Aero-nautics and Space Administration, Johnson Space Center, Houston, Texas; ‡Divisionof Cardiology, University of Maryland Hospitals, Baltimore, Maryland. Supported, inpart, by unrestricted funds from the Cardiovascular Research Laboratory, LSU HealthSciences Center, New Orleans, Louisiana, and Toshiba America Medical Systems,Tustin, California.

Manuscript received October 3, 2000; revised manuscript received May 4, 2001,accepted May 21, 2001.

Journal of the American College of Cardiology Vol. 38, No. 3, 2001© 2001 by the American College of Cardiology ISSN 0735-1097/01/$20.00Published by Elsevier Science Inc. PII S0735-1097(01)01427-9

INCIDENCE

Two autopsy studies determined PFO incidence, with thefirst (n 5 1,100) revealing a “probe” patent PFO (0.2 cm to0.5 cm maximum dimension) in 29% and “pencil” patentPFO (0.6 cm to 1.0 cm) in 6% (27). The second study (n 5965) recorded a PFO incidence of 27.3%, with PFOsvarying in size from 1 mm to 19 mm (mean 4.9 mm). The

incidence of PFO declined with age, suggesting that ana-tomic closure may occur even in adulthood (28).

ASSOCIATED ANATOMICAL STRUCTURES

Atrial septal aneurysm (ASA) (29,30) (Fig. 2) and Chiarinetwork (31) (Fig. 3) are associated with PFO. Atrial septalaneurysm incidence is 1% by an autopsy study (32) and 1.9%by transthoracic echocardiography (TTE) (10,803 subjects)(33), defining ASA as a septal excursion of $10 mm, witha base diameter of $15 mm. Another TTE study using anexcursion of $15 mm found an ASA incidence of 0.22%(34).

A monoplane transesophageal echocardiography (TEE)study (30) defined ASA excursion $11 mm and basediameter of 15 mm to compare patients with embolic stroke(n 5 133) with controls (n 5 277). An ASA was present in15% of the stroke group and 4% of controls. A PFO wasdiagnosed by saline contrast injection in 70% of strokepatients with an ASA and 75% of controls with an ASA. Ofthe 32 ASAs in this study, six had an associated Chiarinetwork. Notably, TTE identified only 12/32 (37.5%) ofthe ASAs. A biplane TEE study (29) found an ASA in28/355 (7.9%) of stroke patients and 8/363 (2.2%) ofcontrols. A PFO was found by saline contrast in 56% ofASA patients. No other possible source of embolism wasfound in 24/28 (86%) of the stroke patients with an ASA. Inanother study, if a mobile IAS or fossa ovalis measured$14 mm, there appeared to be an increased PFO incidence(35). These data indicate that an ASA occurs commonly inpatients with unexplained stroke and is more frequentlydetected by TEE than by TTE.

The Chiari network is a remnant of the septum spuriumand the right valve of the sinus venosus resulting fromincomplete resorption of these structures (36). Lace-likeremnants of the original septum may persist and be evidentas coarse or fine fibers in the RA. These fibers originatefrom either the Eustachian or Thebesian valve and haveattachments to the upper wall of the RA or IAS. TheEustachian valve may also be relatively mobile and fenes-trated but does not attach to the upper wall of the rightatrium or IAS and, therefore, should not be termed a“Chiari network.”

The autopsy incidence of the Chiari network has beenreported as 2% to 3% (37). A TEE study found a Chiarinetwork in 29/1,436 (2%), whereas TTE identified only 8.A TEE-determined PFO was found in 24/29 (83%) ofthese, with more “intense” right-to-left shunting noted. AnASA was found by TEE in 33/1,436 (2.3%), with 7/33having a coexistent Chiari network (31).

DIAGNOSIS OF A PFO

Before the advent of echocardiography, diagnosis of aright-to-left shunt was problematic. A PFO without asignificant resting right-to-left shunt is generally not asso-ciated with any abnormality of the patient history, physical

Abbreviations and AcronymsAGE 5 arterial gas embolismASA 5 atrial septal aneurysmASD 5 atrial septal defectDCS 5 decompression sicknessEMU 5 extravehicular mobility unitEVA 5 extravehicular activity (spacewalk)IAS 5 interatrial septumISS 5 International Space StationIVC 5 inferior vena cavaLA 5 left atriumMRI 5 magnetic resonance imagingNTH 5 native tissue harmonicsPAVS 5 pulmonary arteriovenous shuntPFO 5 patent foramen ovalePV 5 pulmonary veinRA 5 right atriumTCD 5 transcranial DopplerTEE 5 transesophageal echocardiographyTMD 5 transmitral DopplerTTE 5 transthoracic echocardiography

Figure 1. Longitudinal imaging transesophageal echocardiography in themidupper esophagus. A large patent foramen ovale (PFO) is evident. Thearrow illustrates how to measure the PFO width. LA 5 left atrium; RA 5right atrium.

614 Kerut et al. JACC Vol. 38, No. 3, 2001Patent Foramen Ovale: Size and Clinical Significance September 2001:613–23

examination, electrocardiogram or chest radiograph. Heartcatheterization is generally inadequate for diagnosis of PFO,unless a right heart catheter crosses the IAS into the LA.On occasion, a transvenous pacemaker wire or pulmonaryartery catheter may inadvertently cross into the LA via anatrial septal defect (ASD) or PFO. Dye dilution methodsare cumbersome and invasive (38). A relatively noninvasivemethod using peripherally injected indocyanine with gen-

eration of a dye dilution curve from a dichromatic earpiecedensitometer was reported in patients with cryptogenicstroke. A right-to-left shunt was detected in 24/59 (41%);however, it was not compared with any other diagnosticmodality (39).

Echocardiographic techniques have emerged as the prin-ciple means for diagnosis and assessment of PFO (Table 1).In particular, TTE, TEE and transcranial Doppler (TCD)are commonly used. Peripherally injected agitated salinemay be utilized with TTE to diagnose a right-to-left shunt,but the yield is rather low compared with TEE. Transcra-nial Doppler has been used for PFO diagnosis by detectionof air microemboli in a middle cerebral artery after periph-eral injection of agitated saline. With TTE, the Valsalvamaneuver may enhance color Doppler or agitated salinecontrast detection of a right-to-left shunt, but the acousticwindow may be lost during the maneuver.

Transmitral Doppler (TMD) of mitral flow using periph-eral injection of agitated saline was compared with TEEusing both contrast and color Doppler for PFO detection(40). Transesophageal echocardiography detected PFO in17/44 subjects (39%), with 16 detected by contrast and 1only by color, the latter having a left-to-right shunt.Transthoracic echocardiography (TTE) was positive in only12 of 17 positive TEE-detected PFOs, but all 16 contrastpositive TEEs were positive by TMD. An additionalpositive TMD was not detected by TEE. A TMD “bubblescore” and automated quantitative power score correlatedwith PFO size measured by TEE.

Transthoracic echocardiography, TTE with native tissueharmonics (NTH) and TEE were performed with salinecontrast and the Valsalva maneuver in a consecutive group

Figure 2. M-mode (left) and two-dimensional (right) transesophageal echocardiography longitudinal image in the midupper esophagus. The M-modedemonstrates marked interatrial septum (IAS) mobility, with an excursion .15 mm. By definition this is an atrial septem aneurysm. LA 5 left atrium;RA 5 right atrium; SVC 5 superior vena cava.

Figure 3. Transesophageal echocardiography in the midupper esophagus at105°. The arrow points to the mobile Chiari network. IAS 5 interatrialseptum; LA 5 left atrium; RA 5 right atrium; SVC 5 superior vena cava.

615JACC Vol. 38, No. 3, 2001 Kerut et al.September 2001:613–23 Patent Foramen Ovale: Size and Clinical Significance

of patients referred to an echocardiography laboratory (n 5109) for TEE (41). Criteria for PFO detection includedcontrast found in the LA within three cardiac cycles afterRA opacification, and “significant” shunts were categorizedas .20 bubbles in the LA. Patent foramen ovale wasidentified by TTE in 9/109 subjects (8%), NTH in 21/109subjects (19%) and TEE in 21/109 subjects (19%). A“significant” PFO shunt was found in 8 subjects (7%) byTTE, 17 (16%) by NTH and 12 (11%) by TEE. Two“significant” shunts detected by NTH were not detected byTEE. Native tissue harmonics failed to detect four nonsig-nificant PFOs that were detected by TEE. The advantage ofNTH over TEE was explained by the difficulty patients hadin performing the Valsalva maneuver due to the presence ofan endoscope.

Transesophageal echocardiography is currently consid-ered the reference standard for PFO diagnosis, allowingdirect imaging of the IAS and saline contrast shuntingthrough a PFO. If color flow Doppler or peripheral salinecontrast injection detect right-to-left flow during normalrespiration, this is termed a resting PFO. Enhanced right-to-left flow may be noted upon release of the Valsalvamaneuver.

A methodologic study (n 5 70) in patients with arterialembolism compared antecubital vein to femoral vein con-trast injection (Table 2) (42). These data suggest that cough

or the Valsalva maneuver increase the sensitivity of TEEPFO detection and that contrast injections via the femoralvein approach are superior to the antecubital route. Asecond study comparing the antecubital and femoral veinapproach used TEE and TCD in young patients (n 5 44)with unexplained neurologic events (Table 3) (43). Al-though the incidence of PFO by antecubital injection wasmuch lower than that generally reported by other investi-gators, contrast injections via the femoral approach had ahigher PFO detection rate.

A false-negative or false-positive TEE for PFO mayoccur. A false-negative TEE may result from inadequatevisualization within the esophagus, elevated LA pressurespreventing right-to-left passage of contrast (44,45), IVC-directed flow along the IAS preventing impingement ofantecubital bubbles against the IAS (42) (Fig. 4) or animproperly performed Valsalva maneuver.

A TEE false-positive contrast study may occur with atrue ASD (Fig. 5) or a pulmonary arteriovenous shunt(PAVS). Contrast that has a delayed appearance (.3cardiac cycles) within the LA after opacification of the RAmay result from a PAVS in which contrast may also beobserved traversing one or more pulmonary veins (PVs).So-called “debris” entering the LA from PVs may result ina false-positive TEE (46). Thought to be related to tran-sient PV stasis, especially during Valsalva maneuver release,flow was noted to enter the LA. This debris was usuallynoted with high gain settings.

PFO SIZE AND CLINICAL SIGNIFICANCE

Autopsy correlation. Patients (n 5 35) were examined forPFO with both TEE and at subsequent autopsy (47).Patent foramen ovale size was measured with TEE aided bycolor flow Doppler and by quantitating LA contrast usingperipheral venous injections. Nine PFOs found at autopsyhad all been correctly identified ante mortem by colorDoppler TEE. Contrast TEE was negative in one subjectdescribed as having a long interatrial channel. Severalpatients with anatomically confirmed PFO had TEE de-tected left-to-right shunts. All had evidence of high LApressures. Color flow Doppler slightly overestimated PFOsize as determined by autopsy. Left atrium contrast wasgraded by the maximum number of microbubbles appearingin a single frame and subsequently compared with autopsyfindings (Table 4).The platypnea-orthodeoxia syndrome. The platypnea-orthodeoxia syndrome describes both dyspnea (platypnea)and arterial desaturation in the upright position with im-

Table 1. Evaluation of Patients for Both Anatomical andFunctional PFO Size

TTEAnatomy Chiari network

Interatrial septal mobility/atrial septal aneurysmDiameter of fossa ovalis

Color Doppler Evaluate IVC flow directionRight-to-left shuntLeft-to-right shunt

Saline contrast (Quantitate bubbles in left heart)Resting injectionValsalva injection

TEEAnatomy Chiari network

Interatrial septal mobility/atrial septal aneurysmDiameter of fossa ovalisEvaluate fossa ovalis for ASDMeasure slit between septum primum and

septum secundumResting and Valsalva

Color Doppler Evaluate IVC flow directionRight-to-left shuntLeft-to-right shuntMeasure slit between septum primum and

septum secundumResting and Valsalva

Saline contrast (Timing of contrast arrival into LA)(Quantitate bubbles in LA)Resting injectionValsalva injection

TCD Performed in conjunction with TTE and TEE

ASD 5 atrial septal defect; IVC 5 inferior vena cava; LA 5 left atrium; PFO 5patent foramen ovale; TCD 5 transcranial Doppler; TEE 5 transesophagealechocardiography; TTE 5 transthoracic echocardiography.

Table 2. TTE PFO Detection by Site of Injection (42)

SpontaneousRespiration Cough Valsalva Total

Arm 1/70 (1%) 4/70 (6%) 9/70 (13%) 9/70 (13%)Femoral vein 7/70 (10%) 14/70 (20%) 22/70 (31%) 22/70 (33%)

PFO 5 patent foramen ovale; TTE 5 transthoracic echocardiography.


provement in the supine position (orthodeoxia) (48,49).The syndrome occurs with an intracardiac or intrapulmo-nary shunt and often with some form of lung disease. Thepost-pneumonectomy patient (usually the right lung[18,20]) may develop symptoms many months after thesurgical procedure (17,18,50). A ventilation-perfusion lungscan, obtained for dyspnea and hypoxia, will reveal systemicuptake of isotope (21,22,50).

Diagnosis of a PFO with platypnea-orthodeoxia has beenmade with a tilt table and saline contrast TTE (17) andTEE (24). A typical patient history with a significant dropin oxygen saturation while in the upright position, alongwith a large PFO by TEE found as the only source of ashunt, has been considered diagnostic (22).Cryptogenic stroke. Efforts to determine anatomical sizeand functional significance of a PFO have been expendedmost often in patients with embolic stroke (Fig. 6). Patients(n 5 49) with stroke were evaluated by TTE, TEE andTCD (51). Transesophageal echocardiography diagnosedPFO in 19/49 subjects (39%). Transthoracic echocardiog-raphy was positive in 9/49 subjects (18%) and TCD in13/49 subjects (27%). No PFOs were detected by TTE and

TCD that were not detected by TEE. All six PFOs notdiagnosed by TCD measured #2 mm by TEE, suggestingthat TCD may only miss small defects.

Another study used TCD and monoplane TEE tocompare 63 controls, 33 patients with stroke that wasexplained or “clarified” and 41 patients with cryptogenicstroke (52). Shunts were sized by quantitating the numberof TCD detected spikes or TEE visualized microbubbles(Table 5). The TEE score distribution was relatively similaramong the three groups. By TCD, however, the normalgroup had a minimal shunt score, and the cryptogenic grouphad the largest shunt score, suggesting that TCD may findpredominately clinically significant shunts.

A TEE study with peripheral contrast injection (18 forsource of embolism) detected 34 resting PFOs (53). Thesewere divided into a small shunt subgroup (n 5 18) with $3and ,20 LA microbubbles and a large shunt subgroup (n 516) with 20. All patients were treated with aspirin orwarfarin and were followed for 21 months. Of the largeshunt subgroup (5/16), 31% had an ischemic event, whereasthere were none in the small shunt subgroup.

Patients ,60 years of age with unexplained neurologic

Table 3. TTE and TCD PFO Detection by Site of Injection (43)

Normal Respiration Valsalva Maneuver

TEE TCD TEE TCD

Arm 5/44 (11.4%) 2/44 (4.5%) 8/44 (18%) 6/44 (13.6%)Femoral vein 17/44 (38.6%) 16/44 (36%) 22/44 (50%) 22/44 (50%)

PFO 5 patent foramen ovale; TCD 5 transcranial Doppler; TEE 5 transesophageal echocardiography; TTE 5 transthoracicechocardiography.

Figure 4. Longitudinal transesophageal echocardiography imaging in the midupper esophagus with color Doppler. Blue color is inferior vena cava (IVC)flow directed along the interatrial septum (IAS). Prominent IVC flow may prevent contrast injected in an upper extremity from opacifying the septum alongthe IAS.


events were compared with normal controls by multiplaneTEE (54) (Table 6). A PFO was diagnosed using peripheralcontrast injection and by direct visualization of the IAS.Shunt size was measured during normal respiration andwith the Valsalva. Patients with neurologic events had asignificantly higher PFO incidence and size compared withcontrols. The large PFO size was found more commonly inthe multiple cerebrovascular accident subgroup. An ASAwas more common in the neurologic event group (12%)

compared with controls (2%), and 19 of the 21 patients withan ASA had a large PFO (5 6 2 mm). Peripheral salinecontrast shunts were quantitated as minimal (few bubbles inLA), moderate (“cloud” in LA) or severe (intense opacifi-cation). Although contrast identified patients with PFO,there was no significant correlation between measured sizeand contrast shunt severity.Underwater diving and DCS. Decompression sicknessresults from the formation of bubbles in body fluids as

Figure 5. Longitudinal transesophageal echocardiography (TEE) imaging in the midupper esophagus. A 32-year-old male presented with an embolicstroke. He was found to have occult thrombi in both calf veins. Transthoracic echocardiography with peripheral saline contrast during normal respirationand Valsalva were negative for a right-to-left shunt. (A) TEE revealed a small restrictive secundum atrial septal defect (ASD) (arrow). Note how thisappearance is different from that of a patent foramen ovale. (B) Color Doppler demonstrates a left-to-right shunt with a color mosaic pattern from the shuntin the right atrium (RA). The ASD was subsequently surgically repaired. LA 5 left atrium; SVC 5 superior vena cava.


ambient pressure is reduced. Arterial gas embolism is usuallydue to air emboli arising from pulmonary barotrauma orfrom bubbles in the systemic venous circulation entering thearterial system. An AGE through an ASD in a scuba diverwas first reported in 1986 (55). Two TTE studies thendemonstrated a relationship between PFO and otherwiseunexplained DCS in divers (7,8). In the first study (n 5 30),11/30 subjects (37%) had a resting right-to-left shunt (8).Of the 30 divers, 18 had type II DCS (i.e., serious diseaseincluding neurologic or cardiopulmonary dysfunction asopposed to type I DCS in which only musculoskeletal painis present), and all 11 divers with a resting shunt were in thisgroup. None of the other 12 divers, who had type I DCS,had a shunt.

In the second study, antecubital injection was performedduring normal respiration and “modified” Valsalva (7). Theincidence of PFO was 23/53 (43%), but further quantifica-tion, by counting bubbles in the left ventricle, was notreproducible from one injection to the next.

A TTE, TEE and TCD study compared commercialdivers (n 5 26) with control subjects (n 5 30) (9). Diverswere categorized as “possible” DCS (transient nonspecificneurologic symptoms and a normal examination within 48 h

of surfacing), “probable” (significant neurologic dysfunctionbut with a normal neurologic examination within 48 h) and“definite” (significant neurologic dysfunction and an abnor-mal neurologic examination). A TTE was considered pos-itive if any bubble appeared in the left heart. By TEE, $3bubbles in the LA were required for an examination to beclassified as positive, and a study was considered “stronglypositive” if .5 bubbles were seen in a single video frame.With normal respirations, no difference in PFO detectionrate was noted. By Valsalva maneuver (Table 7), TCD hadthe best positive and negative predictive value for detectionof PFO in divers with DCS and was felt to be better thanTEE for delineation of a clinically significant shunt. Inaddition, all controls and divers with a strongly positiveTEE had a positive TCD, and all with a positive TCD hada strongly positive TEE.

Asymptomatic sport divers (n 5 87) were evaluated withbilateral TCD and a sonicated contrast medium injectedinto an antecubital vein (56). A shunt was considered to beof low relevance if ,20 signals occurred after the Valsalvamaneuver and high relevance if $20 signals were noted.Magnetic resonance imaging (MRI) brain scans were alsoperformed (Table 8). All MRI lesions were 2 mm to 3 mmin size and located in the distribution of the anterior cerebralcirculation. Of note, the three divers with many lesions hadhigh relevance signals by TCD.

A multiplane TEE study with peripheral agitated con-trast injection was performed in divers with DCS (n 5 37)and control divers (n 5 36) (57). Shunts were sized duringValsalva by quantitating microbubbles in the LA (Table 9).Of the 37 DCS divers, 20 had type II illness and, of these,14/20 (70%) had a grade II PFO.

From these studies, it appears that a PFO is associated

Table 4. TTE PFO Size Comparison by Contrast andMeasured Size (47)

Grade (Number ofLA Microbubbles)

Number ofPatients PFO Autopsy Size

I (1–5) 1 #2 mm2 .2 mm to ,10 mm

II (6–25) 2 .2 mm to ,10 mmIII (.25) 3 $10 mm

LA 5 left atrium; PFO 5 patent foramen ovale; TTE 5 transthoracic echocardio-graphy.

Figure 6. Longitudinal transesophageal echocardiographic imaging in the midupper esophagus. Arrows point to a thrombus wedged through a patentforamen ovale and lodged in both the right atrium (RA) and left atrium (LA). SVC 5 superior vena cava.


with unexplained DCS. A resting PFO and one found byTCD seem to be associated. Recreational divers without aclinical history of DCS, but with $20 signals detected byTCD on a single peripheral injection seemed to have ahigher likelihood of lesions in the anterior cerebral arteryterritory, as detected by MRI brain scan.DCS in high altitude aviators and astronauts. As theperformance of aircraft has evolved over the course of thelast century, both the achieved altitude and rate of climbhave increased. Therefore, hypobaric DCS became a prob-lem, particularly evidenced during high-altitude bomberflights in World War II. Several fatal cases occurred inwhich the pressure profile and postmortem findings weredocumented in some detail (58), with a PFO noted in 5/19cases. However, no comment was made on the integrity ofthe IAS in the reports of several of the remaining autopsies.Nevertheless, it is clear that a PFO is not invariably presentin all serious cases of altitude DCS.

Altitude exposures occur yearly in hypobaric chambersutilized by the armed forces of several nations to familiarizeaircrew with the physiologic phenomena associated withhypoxia and rapid decompression. Altitude DCS is anuncommon but persistent problem in these exposures; anoverall incidence of about 0.1% is experienced by the U.S.Armed Forces, with about 10% of these cases manifestingneurologic or other serious symptoms (59–61).

The contribution of a PFO to these cases of DCS is notclear, but the prevalence of PFO in U.S. Navy aviators with

serious DCS is reported to be no different from case controls(10,62). However, these data may not be applicable to alltypes of hypobaric pressure profiles. Specifically, the pres-sure profile used in physiologic training exercises involves ashort exposure (about 15 min) to a modest altitude (about7,600 m) with subjects at rest. A long hypobaric exposure,during which heavy work is performed, may be distinct fromthese physiologic training profiles and may render a PFOmore important. Presently, the relative risk for altitude DCSconferred by the presence of a PFO is not well character-ized.

A large decompression stress is associated with extrave-hicular activity (EVA) from spacecraft. During the era ofthe International Space Station (ISS) construction andmaintenance, two types of “space suits” were utilized, theExtravehicular Mobility Unit (EMU) developed by the U.S.and the Russian Orlan suit. To maximize space suit flexi-bility while maintaining an adequate alveolar oxygen partialpressure, the suits contain nearly pure oxygen at subatmo-spheric pressures. The absolute pressure within the EMU is29.6 kPa, while in the Orlan suit it is 38.6 kPa. Under mostconditions, the cabin atmosphere within all spacecraft uti-lized in this program (Space Shuttle, proposed “lifeboat”spacecraft, the Soyuz spacecraft and ISS itself) approximatessea-level conditions with a composition of 21% oxygen,balance nitrogen and trace gases, at an absolute pressure of101 kPa. Consequently, when a crew member transitionsfrom a spacecraft cabin into a space suit for EVA, there is asubstantial decompression. If this decompression were per-formed without specific preparation, serious DCS would bevirtually inevitable. To reduce risk of DCS during EVA,

Table 5. Contrast Comparison of TEE and TCD for PFO Shunt Size (52)

TEE

Normal (n 5 63) Clarified CVA (n 5 33) Cryptogenic CVA (n 5 41)

27/63 11/33 27/41

I II III I II III I II III

8/27 15/27 4/27 4/11 5/11 2/11 6/27 8/27 13/2730% 55% 15% 36% 46% 18% 22% 30% 48%

TCD 28/63 11/33 22/41

I II III I II III I II III

22/28 5/28 1/28 3/11 5/11 3/11 2/22 6/22 14/2279% 18% 3% 28% 45% 27% 9% 27% 64%

Transesophageal echocardiography microbubbles or TCD spikes were graded as score I: ,10, score II: 10–50 and score III: .50.CVA 5 cerebrovascular accident; PFO 5 patent foramen ovale; TCD 5 transcranial Doppler; TEE 5 transesophageal

echocardiography.

Table 6. Transesophageal Echocardiography Measured PFOSize in Otherwise Unexplained TIA, Single CVA and MultipleCVAs (54)

Control(n 5 123)

CNS Event (n 5 121)

TIA(n 5 55)

1 CVA(n 5 46)

>2 CVAs(n 5 20)

1PFO 38 (31%) 33 (60%) 37 (80%) 17 (85%)PFO size (mm) 2 6 1 3 6 1 4 6 2 5 6 2PFO 1–4 mm 28 (51%) 24 (52%) 4 (20%).4 mm 5 (9%) 13 (28%) 13 (65%)

CNS 5 central nervous system; CVA 5 cerebrovascular accident; PFO 5 patentforamen ovale; TIA 5 transient ischemic attack.

Table 7. TTE, TEE and TCD in Controls and Divers WithDCS (9)

Control(n 5 30)

Probable/Definite(n 5 15)

All Divers(n 5 26)

TTE 5 (17%) 3 (20%) 8 (31%)TEE 14 (47%) 9 (60%) 15 (58%)TCD 7 (23%) 7 (47%) 13 (50%)

DCS 5 decompression sickness; TCD 5 transcranial Doppler; TEE 5 transesoph-ageal echocardiography; TTE 5 transthoracic echocardiography.


several protocols are utilized that include reductions in cabinpressure or periods of oxygen breathing before decompres-sion.

Human terrestrial hypobaric chamber studies indicatethat significant gas phase evolution takes place in bodytissues with all decompression protocols. In particular,monitoring of the pulmonary artery with Doppler ultra-sonography reveals that heavy burdens of circulating gaseousemboli are present in from 6% to 39% of subjects, depend-ing on the protocol used (63–65) (J. Conkin, personalcommunication, 2000). In these studies, serious DCS hasbeen encountered, including unusual forms such as massivecutaneous “marbling,” orthostatic instability and severe ce-rebral dysfunction ([66], J. Conkin, personal communica-tion, 2000).

A PFO screening was performed after four cases ofserious DCS resulting from EVA-like simulations. A rest-ing PFO was detected by contrast TTE in three (J.Waligora, personal communication, 2000).Conclusions. Patent foramen ovale has been implicated inplatypnea-orthodeoxia, embolic stroke and paradoxical gasembolism in DCS. Few studies have attempted to quanti-tate PFO size. Current literature suggests that, whenevaluating a patient for source of embolism, the size of anydetected PFO should be considered since the risk oftrans-septal passage of emboli seems to be greater withlarger lesions.

During TTE and TEE examinations for PFO, oneshould evaluate for the presence of an ASA and a Chiarinetwork because of an association with significant PFOs.M-mode of the IAS helps facilitate measurement of septalexcursion.

Color flow Doppler by TTE and TEE should be per-formed to evaluate IVC flow direction into the RA, exam-ining in particular if IVC flow runs along and, therefore,potentially across, the IAS. Color flow Doppler should beused to look for both right-to-left and left-to-right shuntingduring normal respiration and after the Valsalva maneuver.

Agitated saline contrast injection should be performed

during normal respiration and the Valsalva maneuver, withattention to proper timing during the Valsalva maneuver. Itappears that femoral venous injection of contrast, as com-pared with antecubital injection, increases the incidence ofright-to-left shunt detection, especially during TTE studies.During a TEE study, observation of agitated contrastadjacent to the RA-side of the IAS after antecubital contrastinjection may be helpful in that the antecubital injectionprobably is accurate.

Individuals who have PFO can be subgrouped accordingto many PFO characteristics (large vs. small PFO, provokedvs. unprovoked trans-septal gas passage, associated anatom-ical structures). Which methodologic techniques for detec-tion of those characteristics that are clinically important inassessing risk of embolic stroke, diver’s DCS and altitudeDCS is not yet entirely clear. The size of PFO probablymatters in determining risk, as does the ease with whichtrans-septal passage of emboli occurs in relation to intratho-racic pressure excursions. Patent foramen ovales are verycommon, and not all PFOs are the same. The challenge thatremains is to determine which PFOs and clinical contextsconfer an increased risk of significant disease.

Reprint requests and correspondence: Dr. Thomas D. Giles,Louisiana State University Health Sciences Center, 1542 TulaneAvenue, Room 331E, New Orleans, Louisiana 70112-2822.E-mail: [email protected].

REFERENCES

1. Webster MW, Chancellor AM, Smith HJ, et al. Patent foramen ovalein young stroke patients. Lancet 1988;2:11–2.

2. Jones HR, Jr, Caplan LR, Come PC, et al. Cerebral emboli ofparadoxical origin. Ann Neurol 1983;13:314–9.

3. Lechat P, Mas JL, Lascault G, et al. Prevalence of patent foramenovale in patients with stroke. N Engl J Med 1988;318:1148–52.

4. Ranoux D, Cohen A, Cabanes L, et al. Patent foramen ovale: is strokedue to paradoxical embolism? Stroke 1993;24:31–4.

5. Hausmann D, Mugge A, Becht I, Daniel WG. Diagnosis of patentforamen ovale by transesophageal echocardiography and associationwith cerebral and peripheral embolic events. Am J Cardiol 1992;70:668–72.

6. Kasper W, Geibel A, Tiede N, Just H. Patent foramen ovale inpatients with hemodynamically significant pulmonary embolism. Lan-cet 1992;340:561–4.

7. Wilmshurst PT, Byrne JC, Webb-Peploe MM. Relation betweeninteratrial shunts and decompression sickness in divers. Lancet 1989;2:1302–6.

8. Moon RE, Camporesi EM, Kisslo JA. Patent foramen ovale anddecompression sickness in divers. Lancet 1989;1:513–4.

9. Kerut EK, Truax WD, Borreson TE, et al. Detection of right to leftshunts in decompression sickness in divers. Am J Cardiol 1997;79:377–8.

10. Gallagher DL, Hopkins EW, Clark JB, Hawley TA. U.S. Navyexperience with type II decompression sickness and the associationwith patent foramen ovale. Aviat Space Environ Med 1996;67:712.

11. Bendrick GA, Ainscough MJ, Pilmanis AA, Bisson RU. Prevalence ofdecompression sickness among U-2 pilots. Aviat Space Environ Med1996;67:199–206.

12. Conkin J, Bedahl SR, Van Liew HD. A computerized databank ofdecompression sickness incidence in altitude chambers. Aviat SpaceEnviron Med 1992;63:819–24.

13. Pilmanis AA, Meissner FW, Olson RM. Left ventricular gas emboli in

Table 8. TCD Detected Shunts Compared With MRI BrainLesions in Asymptomatic Sports Divers (56)

TCD Shunt(Microbubbles)

Number ofDivers

Divers WithMRI Lesions

None 62 7 (1 lesion in 7 divers)Low (,20) 12 1 (1 lesion in 1 diver)High ($20) 13 3 (39 lesions in 3 divers)

MRI 5 magnetic resonance imaging; TCD 5 transcranial Doppler.

Table 9. TEE Detected Shunts and Shunt Size in Divers Withand Without DCS (57)

Divers 1PFOGrade II PFO

(>20 Microbubbles)

DCS 22/37 (59.5%) 19/37 (51.3%)Controls 13/36 (36.1%) 9/36 (25.0%)

DCS 5 decompression sickness; PFO 5 patent foramen ovale; TEE 5 transesopha-geal echocardiography.


six cases of altitude-induced decompression sickness. Aviat SpaceEnviron Med 1996:67;1092–6.

14. Thompson RC, Finck SJ, Leventhal JP, Safford RE. Right-to-leftshunt across a patent foramen ovale caused by cardiac tamponade:diagnosis by transesophageal echocardiography. Mayo Clin Proc1991;66:391–4.

15. Bansal RC, Marsa RJ, Holland D, Beehler C, Gold PM. Severehypoxemia due to shunting through a patent foramen ovale: acorrectable complication of right ventricular infarction. J Am CollCardiol 1985;5:188–92.

16. Begin R, Gervais L, Bureau MA. Patent foramen ovale and hypoxemiain chronic obstructive pulmonary disease. Eur J Respir Dis 1981;62:373–5.

17. Seward JB, Hayes DL, Smith HC, et al. Platypnea-orthodeoxia:clinical profile, diagnostic workup, management, and report of sevencases. Mayo Clin Proc 1984;59:221–31.

18. Smeenk FW, Postmus PE. Interatrial right-to-left shunting develop-ing after pulmonary resection in the absence of elevated right-sidedheart pressures: review of the literature. Chest 1993;103:528–31.

19. Godart F, Rey C, Prat A, et al. Atrial right-to-left shunting causingsevere hypoxaemia despite normal right-sided pressures: report of 11consecutive cases corrected by percutaneous closure. Eur Heart J2000;21:483–9.

20. Bakris NC, Siddiqi AJ, Fraser CD, Jr, Mehta AC. Right-to-leftinteratrial shunt after pneumonectomy. Ann Thorac Surg 1997;63:198–201.

21. Murray KD, Kalanges LK, Weiland JE, et al. Platypnea-orthodeoxia:an unusual indication for surgical closure of a patent foramen ovale.J Card Surg 1991;6:62–7.

22. Dear WE, Chen P, Barasch E, et al. Sixty-eight-year-old woman withintermittent hypoxemia. Circulation 1995;91:2284–9.

23. Davidson A, Chandrasekaran K, Guida L, et al. Enhancement ofhypoxemia by atrial shunting in cystic fibrosis. Chest 1990;98:543–5.

24. Herregods MC, Timmermans C, Frans E, et al. Diagnostic value oftransesophageal echocardiography in platypnea. J Am Soc Echocar-diogr 1993;6:624–7.

25. Moore KL. The Developing Human: Clinically Oriented Embryol-ogy. 2nd ed. Philadelphia, PA: W.B. Saunders, 1977.

26. Heymann MA, Creasy RK, Rudolph AM. Quantitation of blood flowpatterns in the foetal lamb in utero. In: Proceedings of the Sir JosephBarcroft Centenary Symposium: Foetal and Neonatal Physiology.Cambridge, MA: Cambridge University Press, 1973:129–35.

27. Thompson T, Evans W. Paradoxical embolism. Q J Med 1930;23:135–52.

28. Hagen PT, Scholz DG, Edwards WD. Incidence and size of patentforamen ovale during the first 10 decades of life: an autopsy study of965 normal hearts. Mayo Clin Proc 1984;59:17–20.

29. Agmon Y, Khandheria BD, Meissner I, et al. Frequency of atrial septalaneurysms in patients with cerebral ischemic events. Circulation1999;99:1942–4.

30. Pearson AC, Nagelhout D, Castello R, et al. Atrial septal aneurysmand stroke: a transesophageal echocardiographic study. J Am CollCardiol 1991;18:1223–9.

31. Schneider B, Hofmann T, Justen MH, Meinertz T. Chiari’s network:normal anatomic variant or risk factor for arterial embolic events? J AmColl Cardiol 1995;26:203–10.

32. Silver MD, Dorsey JS. Aneurysms of the septum primum in adults.Arch Pathol Lab Med 1978;102:62–5.

33. Olivares-Reyes A, Chan S, Lazar EJ, et al. Atrial septal aneurysm: anew classification in two hundred five adults. J Am Soc Echocardiogr1997;10:644–56.

34. Hanley PC, Tajik AJ, Hynes JK, et al. Diagnosis and classification ofatrial septal aneurysm by two-dimensional echocardiography: report of80 consecutive cases. J Am Coll Cardiol 1985;6:1370–82.

35. Louie EK, Konstadt SN, Tao TLK, Scanlon PJ. Transesophagealechocardiographic diagnosis of patent foramen ovale in adults withoutprior stroke. Circulation 1991;84:II–451.

36. Corliss CE. Patten’s Human Embryology: Elements of ClinicalDevelopment. New York, NY: McGraw-Hill, 1976.

37. Chiari H. Uber netzbildungen im rechten vorhof des herzens BeitrPathol Anat 1897;22:1–10.

38. Cheng TO. Paradoxical embolism: a diagnostic challenge and itsdetection during life. Circulation 1976;53:565–8.

39. Karttunen V, Ventila M, Hillbom M, et al. Dye dilution and oximetry

for detection of patent foramen ovale. Acta Neurol Scand 1998;97:231–6.

40. Kerr AJ, Buck T, Chia K, et al. Transmitral Doppler: a newtransthoracic contrast method for patent foramen ovale detection andquantification. J Am Coll Cardiol 2000;36:1959–66.

41. Camp GV, Franken P, Melis P, et al. Comparison of transthoracicechocardiography with second harmonic imaging with transesophagealechocardiography in the detection of right to left shunts. Am J Cardiol2000;86:1284–7.

42. Gin KG, Huckell VF, Pollick C. Femoral vein delivery of contrastmedium enhances transthoracic echocardiographic detection of patentforamen ovale. J Am Coll Cardiol 1993;22:1994–2000.

43. Hamann GF, Schatzer-Klotz D, Frohlig G, et al. Femoral injection ofecho contrast medium may increase the sensitivity of testing for apatent foramen ovale. Neurology 1998;50:1423–8.

44. Siostrzonek P, Lang W, Zangeneh M, et al. Significance of left-sidedheart disease for the detection of patent foramen ovale by transesoph-ageal contrast echocardiography. J Am Coll Cardiol 1992;19:1192–6.

45. Movsowitz HD, Movsowitz C, Jacobs LE, Kotler MN. Negativeair-contrast test does not exclude the presence of patent foramen ovaleby transesophageal echocardiography. Am Heart J 1993;126:1031–2.

46. Camp GV, Cosyns B, Vandenbossche J. Non-smoke spontaneouscontrast in left atrium intensified by respiratory manoeuvres: a newtransesophageal echocardiographic observation. Br Heart J 1994;72:446–51.

47. Schneider B, Zienkiewicz T, Jansen V, et al. Diagnosis of patentforamen ovale by transesophageal echocardiography and correlationwith autopsy findings. Am J Cardiol 1996;77:1202–9.

48. Altman M, Robin ED. Platypnea (diffuse zone I phenomenon?).N Engl J Med 1969;281:1347–8.

49. Robin ED, Laman D, Horn BR, Theodore J. Platypnea related toorthodeoxia caused by true vascular lung shunts. N Engl J Med1976;294:941–3.

50. Durand E, Bussy E, Gaillard JF. Lung scintigraphy in postpneumo-nectomy dyspnea due to a right-to-left shunt. J Nucl Med 1997;38:1812–5.

51. Di Tullio M, Sacco RL, Venketasubramanian N, et al. Comparison ofdiagnostic techniques for the detection of a patent foramen ovale instroke patients. Stroke 1993;24:1020–4.

52. Job FP, Ringelstein EB, Grafen Y, et al. Comparison of transcranialcontrast Doppler sonography and transesophageal contrast echocardi-ography for the detection of patent foramen ovale in young strokepatients. Am J Cardiol 1994;74:381–4.

53. Stone DA, Godard J, Corretti MC, et al. Patent foramen ovale:association between the degree of shunt by contrast transesophagealechocardiography and the risk of future ischemic neurologic events.Am Heart J 1998;131:158–61.

54. Schuchlenz HW, Weihs W, Horner S, Quehenberger F. The associ-ation between the diameter of a patent foramen ovale and the risk ofembolic cerebrovascular events. Am J Med 2000;109:456–62.

55. Wilmshurst PT, Ellis BG, Jenkins BS. Paradoxical air embolism in ascuba diver with an atrial septal defect. BMJ 1986;293:1277.

56. Knauth M, Rica S, Pohimann S, et al. Cohort study of multiple brainlesions in sport divers: role of a patent foramen ovale. BMJ 1997:314;701–5.

57. Germonpre P, Dendale P, Unger P, Balestra C. Patent foramen ovaleand decompression sickness in sports divers. J Appl Physiol 1998;84:1622–6.

58. Dixon JP. Death from altitude-induced decompression sickness: majorpathophysiologic factors. In: Pilmanis AA, editor. Proceedings of the1990 Hypobaric Decompression Sickness Workshop. Brooks AirForce Base, TX: Air Force Systems Command, 1992:97–105.

59. Bason R, Yacavone D. Decompression sickness: U.S. Navy altitudechamber experience 1 October 1981 to 30 September 1988. AviatSpace Environ Med 1991;62:1180–4.

60. Weien RW. Altitude decompression sickness: the US Army experi-ence. In: Pilmanis AA, editor. Proceedings of the 1990 HypobaricDecompression Sickness Workshop. AL-SR-1992-0005. Brooks AirForce, TX: Air Force Systems Command, 1992:379–83.

61. Baumgartner N, Weien RW. Decompression sickness due to USAFaltitude chamber exposure (1985 to 1987). In: Pilmanis AA, editor.Proceedings of the 1990 Hypobaric Decompression Sickness Work-shop. AL-SR-1992-0005. Brooks Air Force Base, TX: Air ForceSystems Command, 1992:363–376.


62. Clark JB, Hayes GB. Patent foramen ovale and type II altitudedecompression sickness (abstr). Aviat Space Environ Med 1991;62:445.

63. Waligora JM, Horrigan D, Jr, Conkin J, Hadley AT, III. Verificationof an altitude decompression sickness prevention protocol for shuttleoperation utilizing a 10.2 psi pressure stage. NASA technical memo-randum 58259. Houston, TX: National Aeronautics and Space Ad-ministration, 1984.

64. Powell MR, Waligora JM, Norfleet W, Kumar KV. Project Argo-gas

phase formation in simulated microgravity. NASA technical memo-randum 104762. Houston, TX: National Aeronautics and SpaceAdministration, 1993.

65. Waligora JM, Horrigan DJ, Jr, Conkin J. The effect of extended O2prebreathing on altitude decompression sickness and venous gasbubbles. Aviat Space Environ Med 1987;58:A110–12.

66. Powell MR, Norfleet WT, Kumar KV, Butler BD. Patent foramenovale and hypobaric decompression. Aviat Space Environ Med 1995;66:273–5.


patent foramen ovale: a review of associated conditions ... · review article patent foramen ovale:...

Documents