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syndrome: a review. Prog Car99. Hirst Jr AE, Gore I. Marfan’s diovasc Dis 1973;16:187-98. 100. McKusick VA. The Weill-Marchesani syndrome. In: McKusick VA. Heritable disorders of connective tissue. St. Louis: The C. V. Mosby Company, 1972:282-91. 101. Am PH, Scherer LR, Haller Jr JA, Pyeritz RE. Outcome of pectus excavatum in patients with Marfan syndrome and in the general population. J Pediatr 1989;115:954-8. 102. Marsalese DL, Moodie DS, Vacante M, Lytle BW, Gill CC, Sterba R, Cosgrove DM, Passalacqua M, Goormastic M, Kovats A. Marfan’s syndrome: natural history and long-term follow-un of cardiovascular involvement. J Am Co11 Cardiol 1989;14:;122-8. 103. Murdoch JL, Walker BA, Halpern BL, Kuzma JW, McKusick VA. Life exnectancv and causes of death in the Marfan syndrome. N Engl J Med 1972;286:804-8. 104. Pyeritz RE. Propranolol retards aortic root dilation in the Marfan syndrome. Circulation 1983;68(suppl III):III-365. 105. Zahka KG, Hensley C, Glesby M, Pyeritz RE. The impact of medical and surgical therapy on the cardiovascular progno-

Atrial septal aneurysm: relevance Robert N. Belkin,

MD and Joseph Kisslo, MD. Valhalla,

From the Division of Cardiology. University Hospital at Westchester County Medical Center, New York Medical College, Valhalla, N.Y. and the Division of Cardiovascular Disease, Duke University Medical Center. Durham. N.C. Reprint vilion. 10595.

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sis of the Marfan syndrome in early childhood. J Am Co11 Cardiol 1989;13:119A. 106. Yin FCP, Brin KP, Ting C-T, Pyeritz RE. Arterial hemodynamic indexes in Marfan’s syndrome. Circulation 1989; 79:854-62. 107. Gott VL, Pyeritz RE, Magovern Jr GJ, Cameron DE, McKusick VA. Surgical treatment of aneurysms of the ascending aorta in the Marfan syndrome. Results of composite-graft repair in 50 patients. N Engl J Med 1986;314:1070-4. 108. Child JS, Perloff JK, Kaplan S. The heart of the matter: cardiovascular involvement in Marfan’s syndrome. J Am Co11 Cardiol 1989;14:429-31. 109. Svensson LG, Crawford ES, Coselli JS, Safi HJ, Hess KR. Impact of cardiovascular operation on survival in the Marfan patient. Circulation 1989;8O(suppl I):I-233-42. 110. Tsipouras P. A workshop on Marfan syndrome, 10 June 1989, Farmington, CT, USA. J Med Genet 1990;27:139-40. 111. Tsipouras P. Marfan syndrome: light at the end of the tunnel? Am J Hum Genet 1990;46:643-5.

Recognition

Pathologic descriptions of atria1 septal aneurysms (ASAs) in adults have appeared sporadically in the last 50 years.l-lO The clinical importance of ASA remains uncertain, though case reports have prompted speculation, particularly in regard to the embolic potential of this structure. ‘l-l4 With widespread use of two-dimensional echocardiography in recent years has come increasing recognition of this previously obscure entity.15-24 ASAs are usually readily apparent echocardiographically (and frequently striking in appearance when displaying a rapid oscillating movement), but their observation occurs most commonly as an incidental finding. Although the importance of identifying such a structure is not totally clear, earlier speculation about its clinical relevance has, in part, been substantiated. The purpose of this paper

requests: Robert N. Belkin, MD, Room EZX. Westchester County

Division Medical

of Cardiology, Macy Center, Valhalla,

PaNY

October 1990 Heart Journal

and clinical

N. Y., and Durham,

N.C.

is to review current knowledge concerning this increasingly recognized and frequently reported entity. ANATOMY

During embryonic development the septum secundum forms from superior and inferior propogation of tissue adjacent to the already formed septum primum. Incomplete closure of the septum secundum leads to the opening known as the foramen ovale.g> 25 An oblique communication between foramen ovale and ostium secundum (the defect present within the septum primum) ensures interatrial communication. After birth, fusion of the septum primum and septum secundum occurs. The depression seen on the right side of the septum at the site of the former foramen ovale is the fossa ovalis. The rim of the fossa ovalis, or limbus, represents the former free edge of the foramen ovale.g, 25 When postnatal fusion of the septum primum and septum secundum is incomplete, the oblique communication persists and a patent foramen ovale is present. Occasionally, early resorption of the septum primum causes an excessively large ostium secundum or insufficient growth of the septum secundum oc-

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curs. When either of these occur, the space formed by the foramen ovale will overlie the space formed by the ostium secundum and a defect will occur, in spite of complete fusion of the septum primum and septum secundum,26 which leads to an ostium secundum atria1 septal defect. When, in postnatal life, the region of the septum primum underlying the fossa ovalis bulges into either atrium, a so-called septum primum of fossa ovalis aneurysm is present. 3,gl lo This pathologic entity is recognized angiographically and echocardiographitally as an atria1 septal aneurysm.ll? 12,16127p 28 All aneurysms of the atria1 septum involve the fossa ovalis region. lo Silver and Dorseyg note that the fossa ovalis region in the normal heart is frequently taut but occasionally may be somewhat depressed and slightly redundant and wrinkled. Unlike a true ASA, it cannot be displaced far into either atrium. This normal variant should be distinguished from a true ASA both on pathologic and echocardiographic examination. PATHOGENSIS

An ASA may be classified as primary or secondary. lo Secondary ASAs develop as a consequence of excessive pressure differences between the atria. These most commonly occur in the setting of complex congenital heart disease. For example, newborns with certain forms of hypoplastic right heart syndrome, specifically pulmonary atresia with intact ventricular septum or tricuspid atresia, require patency of the interatrial septum to ensure blood flow from right to left. 28 This obligatory interatrial shunt will generally occur through an atria1 septal defect or a patent foramen ovale. In newborns who lack such a communication, excessively high right atria1 pressures develop. An ASA with bulging of the fossa ovalis region into the left atrium may then occur.28’ 2g The recognition of such a structure echocardiographically or angiographically represents a sign that emergent atria1 septectomy or balloon septostomy will be necessary.28, 2g ASA that is due to excessively high right atria1 pressures with resultant bulging into the left atrium similarly occurs in patients with severe pulmonic valve stenosis with intact ventricular septum.30 Secondary ASAs due to excessive left atria1 pressures, with protrusion of the aneurysm into the right atrium, have been noted in patients with aortic valve atresia.31 Primary ASAs are those that cannot be attributed to excessive pressure differences between the atria. Primary ASAs appear to be unusual in childhood. When they are noted in children without obstructive

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congenital lesions, they are often seen in association with ostium secumdum atria1 septal defects.21T 32The occurrence of an ASA after spontaneous closure of an atria1 septal defect has also been reported,33 possibly in analogy to the formation of a so-called “wind-sock deformity” after spontaneous closure of a membraneous ventricular septal defect. The pathogenesis of primary ASA in these patients is not known. Another group of children with ASA who do have hypoplastic right heart syndrome but who lack marked interatrial pressure differences has been reported.21 The cause of primary ASA in this group is also unknown. These patients displayed bulging of the entire interatrial septum, however, and for this reason may not have had have true fosssa ovalis aneurysms.21 Primary ASAs are most commonly observed in adults.‘O The occurrence of ASAs in this population has been shown to be unrelated to excessive pressure differences between the atria.gT 21,27 The pathogenesis of the entity in adults is not understood. As association between ASA and mitral valve prolapse has been reported in both echocardiographic21v 23*24 and autopsy studies. lo RobertslO notes that both these entities represent redundancy of endocardial tissue. He suggests that their association may represent a common congenital connective tissue defect, which is manifested only with time. Detailed histologic studies of ASA have not been reported. PREVALENCE

In a large study of patients who died in the hospital and underwent autopsy, 16 of 1578 were noted to have this structure.g Subjects who underwent autopsy represents a highly selected population, and this 1% prevalence may not represent the frequency of ASA in the general population. Between 1983 and 1986, approximately 5 in every 1000 patients who underwent echocardiography at Duke University Medical Center were noted to have an ASA. Other echocardiographic series similarly report prevalence rate of between 2 and 6 per 1000.21p 22,35 The slightly lower rates of echocardiographic recognition compared to that from autopsy may represent a lack of recognition of this entity by most echocardiographers until fairly recently.21 ECHOCARDIOGRAPHIC

CHARACTERISTICS

ASA may be detected with M-mode echocardiography as abnormal linear echoes behind the mitral valve or the tricuspid valve.16, 28Their differentiation from other structures with M-mode echocardiography is difficult. ASAs are readily identified with two-dimensional echocardiography and easily distinguished from other structures. They appear as thin,

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1. A, A somewhat oblique short-axis view at the level of the aortic valve is displayed. Bulging of the ASA from LA to RA is shown (arrow). B, The ASA displays an oscillating motion and is shown here in the LA at a later stage of the cardiac cycle. RVOT, Right ventricular outflow tract; RA, right atrium; LA, left atrium; A, aorta. Fig.

localized segments in the central portion of the interatrial septum that bulge into either atrium. The aneurysm often oscillates rapidly from atrium to atrium (Fig. 1). On other occasions it may remain fixed in the right or left atrium with no or only limited mobility (Fig. 2). There are no universally accepted dimensional criteria to make the diagnosis of ASA. Again, as Silver and Dorseyg note in their autopsy series, a slightly redundent fossa ovalis may be a normal variant. Unlike a true ASA, the fossa ovalis region in such patients cannot be “pushed far towards the center of the atrial cavity. g” These authors did not prospectively diagnose the presence of ASA on the basis of a predetermined set of dimensional criteria. They did report dimensions from ASAs that were diagnosed in this subjective manner. The diameter of the aneurysm at its base varied from 1.2 to 2.5 cm, and the maximal distance it projected into an atria1 chamber from 1.1 to 2.4 cm. In their echocardiographic study Hanley et a1.21 required a diameter of 1.5 cm or greater and a maximal projection of the aneurysm into an atria1 chamber of 1.5 cm or greater. 21 These criteria were considered more stringent than the dimensional results reported in the autopsy study, even after accounting for expected shrinkage of the atria1 septum with formalin fixation. 21 Longhini et a1.22 required a maximal excursion of at least 0.8 cm for echocardiographic diagnosis of ASA. This was “based on the maximal radius of the smallest aneurysm diagnosed by subcoastal two-dimensional echocardiography and confirmed by angiography.” Gallet et a1.35 required a maximum excursion of 0.6 cm. Other investigators have not employed dimensional criteria.

Considerable discussion has also been devoted to the direction of protrusion of the ASA and nature of its motion. Commonly, ASA in adults will protrude into the left atrium during early ventricular systole and rapidly swing into the right atrium or midposition in late ventricular systole and diastole.15T 22127*35 The pattern of motion is unchanged with respiration, though in some cases excursion into the left atrium will be accentuated during inspiration and excursion into the right atrium will be accentuated during expiration.17 In other cases, the pattern of motion appears heavily dependent on respiration. In these individuals the aneurysm will protrude into the right atrium and display leftward motion to he midposition or left atrium during inspiration.22p 35 Longhini et a1.22 report that this inspiratory leftward motion will occur only during early ventricular systole. On other occasions, the aneuryms protrude into the right or left atrium throughout the cardiac cycle and display either minimal or no movement.21v 27p34,35 Again, the direction of protrusion and patttern of motion of primary ASA cannot be attributed to marked pressure differences between the atria. The pattern of motion of the aneurysm may, nevertheless, be due in part to small transatrial pressure gradients that occur normally. 21p36 Such gradients might be expected to change with alterations in filling pressures that accompany inspiration and expiration. Flow through an associated atria1 septal defect21a 27 may similarly influence pressure differences, though hemodynamically significant shunts are absent in the majority of patients. 27 Other factors such as interactions between the ventricles and atria will play a part. For example, the ventricular septum and atria1 septum are not aligned in a striaght line. The angle be-

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2. A subcostalview displaying the ASA (arrow). This view most consistently displays the interatrial septum. LV left ventricle; RA, right atrium; LA, left atrium.

Fig.

tween them will determine the magnitude and direction of translational atrial septal motion that occurs as a result of systolic motion of the ventricular septum. The translational and rotation motion of the heart as a whole will also influence the observed pattern of motion of the ASA. All of these considerations notwithstanding, the spatial and motion characteristics of primary ASA remain poorly understood. ECHOCARDIOGRAPHIC

DIFFERENTIAL

DIAGNOSIS

ASAs must be carefully distinguished from other interatrial structures and other abnormalities of the interatrial septum. The thin-walled, protruding, and frequently rapidly oscillating aneurysm is generally easily distinguished from atrial myxoma.16 The latter has a characteristic dense appearance and is generally attached by a stalk to the interatrial septum. It will display a pattern of motion different than that of the ASA; that is, it will prolapse into the mitral or tricuspid valve orifice in diastole and back into the atrium with ventricular systole. On other occasions it will not move becasue it is pedunculated or beacuse it is too large.37 In spite of these differing characteristics, ASA will on occasion be confused with atria1 myxoma. Caution in this regard, especially in light of the embolic potential of both structures is important. For example, a patient was referred to Duke Medical Center with a new stroke and a diagnosis of atria) myxoma

made by two-dimensional echocardiography. Examination of the echocardiogram after referral showed a dense structure that appeared in the parasternal long-axis view in the anterior and superior left atrium during each systole. The density of echoes and dramatic motion of the structure superficially had the appearance of myxoma. Careful examination in other views showed the presence of ASA and the absence of myxoma. ASAs are generally poorly visualized in the parasternal long-axis view and may, as on this occasion, present with an atypical appearance suggestive of myxoma. Close observation of the timing of motion in this view and careful attention to other views are necessary under these circumstances. The eustachian valve, or valve of the inferior vena cava, is a immobile, linear echo in the lower portion of the right atrium. I6 It is generally seen in the apical four-chamber or the parasternal right ventricular inflow view. Injection of mirocavitation contrast medium helps to distinguish this structure from an ASA. In the latter case, the aneurysmal sac appears as a filling defect (Fig. 3). In the case of the eustachian valve, there is prompt appearance of contrast of either side of the structure. Chiari’s network is another structure that must be distinguished from ASA. Like the eustachian valve, it is a congenital remnant of the sinus venosus.38 It is a fenestrated, filamentous structure that adheres to the posterolateral aspect of the right atrium, and it

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Fig. 3. A short-axis truding ASA (arrow) technique may help tract; Ao, aorta; RA,

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October 1990 Heart Journal

view at the level of the aortic valve after microcavitation contrast injection. The progives rise to an aneurysmal region of negative contrast protruding into the RA. This distinguish ASA from other interatrial sturctures. RVOT, right ventricular outflow right atrium; LA, left atrium.

displays rapid and chaotic motion throughout the cardiac cycle. 3g Again, injec tion of microcavitation contrast medium will lead to prompt appearance of microbubbles on all sides of this structure. The thebesian valve, or valve of the coronary sinus, is another congenital remanant of the sinus venosus and may also be observed in the right atrium. Care must be taken to further differentiate ASA from a bulge of the entire interatrial septum. Such a bulge may be observed during pressure overload states.40 Lipomatous hypertrophy of the interatrial septum will lead to thickening of the superior and inferior portions of the interatrial septum will often spare the fossa ovalis region,41 giving rise to a dumbbell-like appearance. The fossa ovalis region is quite distinctive in this entity, but it is not aneurysmal. In car triatriatum, a linear membrane will be seen to insert anteriorly on the aortic wall and course posteriorly and laterally in the left atrium.38, 42 Its spatial orientation, lack of motion, and absent aneurysmal segment will distinguish it from ASA.

ASA will be missed on angiography. The relative sensitivity of angiography in comparison with twodimensional echocardiography when such injections are made is not known. In one report, only three or four echocardiographically recognized ASAs were identified with angiography.23 In each of these three, axial projections were employed. Because of its greater anatomic resolution for intracardiac structures, the specificity of two-dimensional echocardiography would be expected to be superior to that of angiography. For example, in one report an angiographically detected filling defect in the right atrium was identified as a tumor mass. Autopsy showed the presence of an ASA.‘” A recent report outlines the diagnosis of ASA in two patients by intravenous digital subtraction angiography.43 Of two patients identified by this relatively noninvasive technique, only one was reportedly identified by two-dimensional echocardiography. However, details regarding echocardiography in this case were not provided.

ANGlOGRAPHIC

Pathologic examinations of ASA suggest a frequent association of this entity with an interatrial communication of one kind of another.g2 lo, ~3 21,27 Eight of sixteen patients in autopsy study by Silver and Dorseyg displayed patent foramen ovale. Two of

DIAGNOSIS

A number of reports of angiographically detected ASA have appeared. I12 12,17.23 Angiographic diagnosis of ASA will generally require injection of dye into the atrium. Since this is not a routine procedure, most

INTERATRIAL

SHUNTING

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4. An apical four-chamber view after microcavitation contrast injection. Right-to-left shunting is demonstrated by the early appearanceof bubbles (small arrows) in LA and LV. LV, left ventricule; RV, right ventricle; kA, right-atr&k.r; LA, left atrium.

Fig.

these eight patients also displayed small atria1 septal defects. RobertslO reported autopsy findings on two patients with ASA, one of whom had a patent foramen ovale and the other an atria1 septal defect. In another study, in three patients who underwent surgery for ASA pathologic examination and hemodynamically significant shunts confirmed septal defects in the redundant fossa ovalis. In two of the three patients multiple fenestrations in the aneurysm were noted. Hanley et a1.21 noted clinical and invasive hemodynamic evidence for atrial septal defects in 12 patients with ASA in whom the presence of a defect was confirmed on visual inspection at surgery. Multiple fenestrations were identified at autopsy in the fossa ovalis aneurysm of a patient reported by Gondi and Nanda.16 From these data, it appears that interatrial communications in ASA may occur as a result of associated patent foramen ovale or associated atria1 septal defects. In some cases the septal defect may represent an associated congenital ostium secundum defect. Given the degree of tissue thinning that often accompanies the ASA, and the frequent identification of multiple

distinct

fenestrations within

the

fossa ovalis region, it appears that atria1 septal defects in this entity may also be acquired and occur as a result of severe tissue attenuation.g, 27 The question of interatrial communication in ASA can be addressed in large numbers of patients with

the use of microcavitation contrast echocardiography. This technique, in which agitated saline or another contrast agent is injected intravenously with simultaneous two-dimensional echocardiographic imaging is highly sensitive in the detection of interatrial shunts (Fig. 4). 44 Human and experimental studies have shown that all atria1 septal defects are bidirectional, that some degree of right-to-left shunt flow is present even if predominent flow is left to right.44-47 The identification of microbubbles in the left atrium after opacification of the right atrium has in fact been shown to be more sensitive in the detection of intratrial communication than either indicator dilution curves or oximetry.44 A recent study that employed contrast echocardiography has shown the presence of right-to-left interatrial

shunting in 28 of 31 (90%) consecutive

patients with ASA in whom technically adequate contrast studies could be performed (Fig. 4).27, 34 This number is much higher than the reported prevalence of positive shunting of 18% in normal subjects, even with Valsalva’s maneuver (attributed to patent foramen ovale.). 48 This finding corroborates the frequent pathologic identification of interatrial communication in patients with ASA.

Four of the patients with ASA and shunting in the study by Lynch et al. 48 showed clinical and hemodynamic evidence of an ostium secundum defect. An

association

between ASA and clinically

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ostium secundum atrial septal defects has also been reported by Hanley et al. x Five additional patients with positive contrast studies in that series underwent catheterization. Although two subjects (with arterial hypoxemia) demonstrated right-to-left shunting with green dye curves, none had significant shunts as demonstrated by oximetry. These five patients and the remainder of patients with positive contrast lacked any auscultatory, electrocardiographic, roentgenographic, or other echocardiographic evidence for atrial septal defects. Thus, although atrial communications were present in the majority of patients with ASA, they were generally not of hemodynamic consequence. Again, shunting of contrast in these patients probably represents patent foramen ovale or small congenital or acquired atrial septal defects. Microcavitation contrast studies have been employed by other groups to enhance echocardiographic recognition of the ASA, 16*23 though no other large seris of consecutively studied ASA patients who received echo contrast have appeared. Hauser et all9 report the absence of shunting in 3 of 11 patients studied with this technique. Wysham, McPherson, and Kerbe@ found no shunting in one patient who was studied. Iliceto et a1.23 performed contrast echocardiography in five patients but did not report whether shunting occurred. The lack of positive contrast studies in these reports may be the result of chance, given the small numbers of patients studied, or it may represent a difference in contrast technique.27 CEREBROVASCULARANDPERIPHERAL EMBOLIC EVENTS

A number of case reports of ASA found in association with putative embolic events have appeared. Thompson, Phillips, and Melmon12 in 1966 reported a 50-year-old woman with ASA proven by autopsy and a history of clinically suspected multiple pulmonary emboli. Pulmonary emboli were not, however, demonstrated at autopsy. Grosgogeat et all1 reported cerebrovascular events in two young patients (ages 33 and 39) with angiographically detected ASA. The diagnosis of ASA was confumed at surgery in one patient. Each patient underwent cerebral arteriography. An embolic occlusion of the internal carotid artery was noted in one patient. In the second, cerebral arteriography apparently revealed no atherosclerotic cause for the patients’s hemiparesis and aphasia. Consistent with presently accepted criteria for embolic stroke,4g this patient was considered to have an embolic event. Canny et a1.14 also reported a patient with angiographically proven embolic stroke and echocardiographically demonstrated ASA.

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Gallet et al.35 used two-dimensional echocardiography to identify 10 consecutive patients with ASA. Two patients had suspected embolic events. One was a 61-year-old man with sudden right hemiplegia. Cervical vessels were normal on intravenous digital subtraction angiography. On the basis of this finding, the absence of cerebrovascular risk factors, and the suddenness of his stroke, the patient was clinically considered to have had an embolic event. The second patient was a 43-year-old man with abrupt occlusion of both superficial femoral arteries visualized on arteriography, a finding consistent with embolic events. Guarino et al.13 reported the case of a 43-year-old man with an acute anterior myocardial infarction and an am&graphically detected ASA. Coronary arteriography showed a total occlusion of the proximal left anterior descending artery. His coronary arteries were otherwise free of disease, and the authors postulated that he experienced an embolic infarction. As pointed out elsewhere, the possiblity of coronary arterial spasm was not excluded in this case.i8 In a large series of patients with ASA at the Mayo Clinic, cerebrovascular events were noted in 16 of 80 (20% ).21 Clinical and cerebral angiographic data that corroborate or disprove embolic etiologies for these events are not presented. Nevertheless, 9 of 16 patients with such events had cardiac abnormalities other than ASA that might be implicated. The remaining four patients had no potentially embolic cardiac abnormalities with the exception of their ASAs (with atrial septal defect and documented right-to-left shunting in three). In addition, two patients in the Mayo Clinic series had definite or possible pulmonary emboli. Again, sufficient clinical detail is not provided to implicate ASA in these events. Further suggestive data for the association of ASA and embolic events comes from a recent series at Duke Medical Center.34 Of 36 consecutive patients with ASA, cerebrovascular events occurred in 10 (28% ). Seven of the ten had definite or highly probable embolic events. Cerebral arteriograms were performed in all but one of these patients and were consistent with embolic events in each (either visualizing the embolus or displaying no significant atherosclerotic disease in the vascular distribution of the stroke). The diagnosis of embolic stroke was considered secure in the one patient without cerebral arteriography on the basis of sudden onset of symtpoms with multiple lesions on computed tomography scan and insignificant atherosclerotic disease on carotid ultrasound. An additional patient in this series who had not had a cerebrovascular event had an embolic event to her right femoral artery (which required embolectomy) and a possible embolic myocardial infarction. Thus 8 of 36 (22% ) patients in this series of

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patients embolic found in ports of POSSIBLE

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with ASAs had data strongly suggestive of events. The high prevalance of such events this series appears to corroborate earlier resuch an association. MECHANISMS

FOR EMBOLI

Although a causal relationship between ASA and embolic events has not been demonstrated, plausible mechanisms that link the tow phenomena may be postulated. One such mechanism is the local association of aneurysm with thrombus. There is ample observation1 data to support such an association. In their autopsy series, Silver and Dorsey report “small fiber-thrombus tags on the convex surface”g of the ASA in a number of patients. Macroscopic thrombus within the ASA at its base was noted in one patient. Other authors report the presence of large thrombi (up to 5 cm long) within the ASA.5* 7, 8al8 The presence of organized thrombus detected microscopically in a patient with an embolic cerebrovascular event has also been noted.13 Echocardiographically detected thrombus within an ASA has not been reported. Another potential cause of ASA is paradoxical embolization through an interatrial communication, In fact, a recent report has demonstrated a high prevalence of contrast echocardiographically demonstrated patent foramen ovale in patients with otherwise unexplained strokes. 5~As noted earlier, a strong association between ASA and interatrial communication in the form of patent foramen ovale or atrial septal defect has been observed both on pathologic examination and with the use of echo-contrast techniques. In general, the diagnosis of paradoxical embolism is made in the setting of an otherwise unexplained arterial embolus when an interatrial communication is present and there is cause for increased right atrial pressures51p 52 It may occur with chronic elevations of right atrial pressure and significant hemodynamic right-to-left shunting, as in cyanotic congenital heart disease. Alternatively it may occur with transient increases in right atrial pressure due, for example, to emboli are frepulmonary emboli. 51f52 Pulmonary quently observed in cases of paradoxical embolism because they also imply the presence of venous thrombosis, a source for right-sided embolic material. It has been suggested that the clinical triad of pulmonary embolus or venous thrombosis, interatrial communication, and unexplained arterial embolus is necessary to make the diagnosis of paradoxical embolism ante mortem.52 Paradoxical embolism may be possible in the absence of clinically demonstrated pulmonary emboli or venous thrombosis. As noted before, all inter-

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atrial shunts are bidirectionaL4p 47 Transit from the right to the left atrium may occur in the absence of significant increases in right atrial pressure. Again, this is demonstrated by the passage of microcavitation contrast from right atrium to left atrium with patent foramen ovale or small atrial septal defects, despite the absence of increased right atrial pressure or hemodynamically detected shunts.26p 34*44r53 This phenomenon may even be associated with arterial oxygen desaturation. 27~53 Strunk et al. have addressed this issue of “water flowing uphil1.“53 They note several possible explanations. First, this phenomenon may occur as a result of transient instantaneous pressure differences (rather than mean atrial pressure differences) between atria in the course of the cardiac cycle. Second, such transit might occur as a result of the accentuation or production of interatrial gradients with Valsalva’s maneuver or with respiration. Third, such transit may occur as a result of preferential orientation of flow from the inferior vena cava toward the patent foramen ovale or atrial septal defect. What is the source of thrombotic material in a putative paradoxical embolus if no deep venous thrombophlebitis is demonstrated clinically? It is well known that deep venous thrombophlebitis is frequently unapparent in patients with pulmonary emboli54 and may similarly be clinically silent in patients with paradoxical embolus. Although the occurrence of paradoxical embolization in the absence of clinically demonstrated pulmonary emboli or deep venous thrombosis appears to be plausible, its role in the association of ASA with embolic events remains speculative at this time. A third potential mechanism for embolic events in ASA is the putative association of supraventricular tachyarrhythmias with this entity,lgl 21155 though data on this association are not compelling. Finally, ASAs have been associated with mitral valve prolapse, an entity itself associated with cerebral emboli.56 However, multiple cases of embolic events with ASA in the absence of prolapse have been reported.34 OTHER CLINICAL

ASSOCIATIONS

The association between ASA and mitral valve prolapse is commonly reported. Roberts” noted both of these entities in two patients at autopsy and suggested that their association is a consequence of a common congenital connective tissue defect that involves endocardial tissue. Iliceto et a1.23 noted both mitral valve prolapse and tricuspid valve prolapse in each of five patients with ASA as reported from their laboratory. Mitral valve prolapse was present in 3 of 10 patients reported by Gallet et a1.,35 11 of 23

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patients reported by Longhini et a1.22and 5 of 36 patients reported by Belkin et alz7t 34 In the latter series, 3 of 5 patients with mitral valve prolapse had hemodynamically significant atria1 septal defects. Mitral valve prolapse in these cases and others may be a consequence of atrial septal defect hemodynamics,57 rather than a direct relation to the ASA. In the Mayo Clinic series, 9 of 67 patients with fossa ovalis aneurysms had mitral valve prolapse; only one of these had a significant atria1 septal defect. Five of sixty-seven patients had tricuspid valve prolapse.‘l Taken together, these reports suggest that mitral valve prolapse (and tricuspid valve prolapse) may be observed in somewhat higher than usual frequency in patients with ASA. As in all studies of mitral valve prolapse, conclusions about putative associations must be drawn cautiously. Their validity will be importantly influenced by the lack of uniformly agreed upon diagnostic criteria for this entity.58 ASAs have also been reported to produce an auscultatory systolic click murmur in the absence of echocardiographic prolapse.15, ‘I With echophonocardiography, the click in one case was found to correspond to the sudden motion of the aneurysm from left atrium to right atrium in midsystole.15 In another echophonographic series, nonejection clicks were present in 11 patients, though all had prolFpse.22 Diastolic filling murmurs have also been infrequently noted and attributed to interference with flow through either the mitral or tricuspid valve due to close proximity of a large ASA.‘, lg Pulmonary venous obstruction has been shown in an infant with tricuspid atresia and ASA.5g As noted, supraventricular tachyarrhythmias have also been reported in some patients.21 It appears that the majority of such patients had other cardiac disorders that may have been responsible. One case of autopsy-proven marasmic endocarditis that involved an ASA has been noted.21 No cases of infective endocarditis that involves this structure have appeared in the literature, and it would thus appear to be rare. CONCLUSIONS

The identification of ASA in a patient should prompt careful examination of the echocardiogram for mitral valve prolapse. It should also prompt reexamination of clinical and echocardiographic features that may be suggestive of a hemodynamically significant atria1 septal defect. The finding of ASA in a patient with arterial hypoxemia in whom administration of 100 % oxygen does not lead to significant augmentation of arterial oxygen saturation is an indication for contrast echocardiography. If results

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Heart Journal

are positive, further invasive evaluation and possible surgical repair for right-to-left shunting might be required. The finding of ASA may have its greatest clinical relevance in patients with otherwise unexplained peripheral or cerebrovascular embolic events. Its identification in such patients may represent an indication for long-term anticoagulation therapy and possibly even surgical repair, particularly if shunting is demonstrated. Further study of these issues will be required. REFERENCES

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