Ebstein Anomaly: A Review Joseph Galea, MD Sarah Ellul, MD Aaron Schembri, MD Pierre Schembri-Wismayer, MD, PhD Jean Calleja-Agius, MD, MRCOG, MRCPI, PhD Continuing Nursing Education (CNE) Credit A total of 2 contact hours may be earned as CNE credit for reading the articles in this issue identified as CNE and for completing an online posttest and evaluation. To be successful the learner must obtain a grade of at least 80% on the test. Test expires three (3) years from publication date. Disclosure: The authors/planning committee have no relevant financial interest or affiliations with any commercial interes ts related to the subjects discussed within this article. No commercial support or sponsorship was provided for this educational activity. ANN/ANCC does not endorse any commercial products discussed/displayed in conjunction with this educational activity. The Academy of Neonatal Nursing is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center ’s Commission on Accreditation. Provider, Academy of Neonatal Nursing, approved by the California B oard of R egis tered Nursing, Provider #CEP 6261; and Florida Board of Nursing, Provider #FBN 3218, content code 2505. The purpose of this article is to outline the etiology and pathophysiology of Ebstein anomaly and to discuss the symptoms and treatment of this anomaly.
Accepted for publication April 2014.
Abstract Cardiac congenital abnormalities are a leading cause in neonatal mortality occurring in up to 1 in 200 of live births. Ebstein anomaly, also known as Kassamali anomaly, accounts for 1 percent of all congenital cardiac anomalies. This congenital abnormality involves malformation of the tricuspid valve and of the right ventricle. In this review, the causes of the anomaly are outlined and the pathophysiology is discussed, with a focus on the symptoms, management, and treatments available to date. Keywords: Ebstein anomaly; cardiac congenital abnormality; neonatal mortality
T
h e h u m a n h e a r t i s a m yoge n ic
uscular organ that is responsible m for the maintenance of blood f low circulation within the human body. Neonates may be born with congenital heart defects, which are very common, especially because of the complexity of the embryologic cardiac development. Congenital heart defects are a significant cause of neonatal morbidity and mortality, occurring in up to 1 in 200 live births.1 The causes for such anomalies are either genetic, thus involving mutations, or environmental, possibly involving infection during pregnancy or exposure to teratogens. Ebstein anomaly, first described by German physician Wilhelm Ebstein in 1866, 2 is one of many congenital cardiac defects that may occur during heart development. It involves an abnormality in the tricuspid valve leaflets— adherence of the posterior and septal leaflets of the valve underlying the myocardium. This right atrioventricular valve is found between the right atrium and right ventricle, which together collect venous blood and direct it to the lungs so that it can be oxygenated.1,3 To comprehend the structural defects involved in Ebstein anomaly together with its pathophysiology, manifestations, management, and prognosis, a good understanding
of the embryologic development of the heart is necessary. The embryologic development of the heart begins 18 days after fertilization through the formation of the cardiogenic plate and can be grouped into five stages (Figure 1).4,5
DEFINITION
Ebstein anomaly is a rare congenital cardiac malformation which is characterized by the apical displacement of the tricuspid valve leaflets. Such a displacement leads to the atrialization of the right ventricle; that is, the atrium and ventricle become one functional unit, giving rise to an atrialized segment. There is also a variable degree of malformation and displacement of the anterior tricuspid leaflet.6 This congenital disorder occurs in about 1–5 per 200,000 live births, thus accounting for about 1 percent of all congenital cardiac abnormalities.7 In patients with this anomaly, the leaflets are unusually stretched deep into the right ventricle and are often larger than normal. The defect usually causes the valve to work poorly, and blood may reverse and flow back into the right atrium. Such regurgitation of blood, ranging from mild to severe, can
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C
Cardiac mesoderm
Endoderm
Mesoderm
Ectoderm
The premature heart as viewed from the front with the atria on top of the ventricles
D
Communication between the tubes
Right ventricular chamber
Tricuspid valve
Right atrial chamber
Pulmonary valve
Left Right endocardial endocardial tube tube
B
Septum
Left ventricular chamber
Mitral valve
Left atrial chamber
Aortic valve
Single endocardial tube
Aortic sac Conotruncal segment Right ventricle Left ventricle Atria
A. Stage 1—Specification for cardiac precursor cells. The first stage involves the specification of cardiac precursor cells, which develop from the cardiac mesoderm. This is a derivative of the splanchnic mesoderm, which is the germ layer found between the endoderm and ectoderm in the embryo. These cells differentiate into endocardium, the layer of tissue lining the heart chambers, and myocardium, the functional tissue that contracts to circulate blood and the pericardium. These coalesce into two heart tubes. Numerous cardiogenic signals such as bone morphogenetic proteins and fibroblast growth factor control this development. B. Stage 2—Heart tube formation and their subsequent connection forming the primitive heart. The second stage involves the migration of cardiac precursor cells and fusion of the primordial cells. Cardiac precursor cells migrate and fuse into a single heart tube on each side of the pericardial cavity, and these connect and develop into various regions and chambers of the heart. C. Stage 3—Looping of the heart. Looping of the heart occurs in the third stage where the heart tube undergoes rightward looping, and, thus, the ventricles come to lie in front of the atria, and the atria lie above the ventricles. D. Stages 4 and 5— Heart chamber formation, septation, and valve formation. The fourth stage involves heart chamber formation, and the final stage involves septation and valve formation.
Rightward looping of the atrial portion of the premature heart to come to lie behind the ventricles
Endocardium, myocardium, and pericardium tubes
A
FIGURE 1 n The stages of embryologic development of the heart.
lead to hypertrophy of the heart and edema in the lungs or liver.8 In such an anomaly, the right ventricle is divided into two parts: the inlet portion being functionally integrated with the right atrium and the other portion constituting the functional right ventricle. This abnormality results in dilatation of the true tricuspid annulus and the presence of a large chamber. This will lead to the separation of the true tricuspid annulus from the functional right ventricle (Figure 2).9,10 Generally, patients also have an atrial septal defect, and, thus, blood flow across this defect causes oxygen-poor blood to shunt from right to left, bypassing the lungs and ending up in the systemic circulation. There may also be stenosis of the pulmonary valve. The wall of the right ventricle is generally thin, and the ventricular cavity itself is quite small compared with normal.11
PATHOPHYSIOLOGY
The partial deterioration present in the right ventricle together with the presence of the tricuspid valve regurgitation will hinder venous return from flowing into the pulmonary circulation. Apart from that, during atrial contraction, the atrialized part of the right ventricle inf lates and will behave as a passive reservoir. This will result in a diminished ejection fraction. The ultimate result is right atrial dilation, therefore increasing the interatrial communication through the atrial septal defect resulting in varying degrees of rightto-left shunting.12 The hemodynamic complications of Ebstein anomaly are directly related to the severity of the leaflet displacement and to the resultant tricuspid valve regurgitation.6 In the case of mild displacement and mild valve regurgitation, the patient
FIGURE 2 n Ebstein anomaly.
Atrial septal defect
Right atrium
Displaced tricuspid valve allows blood back into right atrium
may be asymptomatic for many years. If the leaflet displacement and valve regurgitation are severe, pulmonary blood flow decreases, the right atrium becomes dilated, and blood is shunted from right to left across an atrial septal defect.6 This dysfunction and dilation of the right atrium and right ventricle leads to progressive patchy myocardial atrophy and fibrosis, which leads to a conduction defect, resulting in an abnormal electrocardiogram (ECG).13 The abnormally developed tricuspid valve is also associated with conduction abnormalities which include delayed intra-atrial conduction, right bundle branch block, and ventricular preexcitation. This is because the downward displacement of the septal leaflet is related to discontinuity of the central fibrous body and the septal atrioventricular ring leading to direct muscular connection being formed. These create a potential substrate for accessory atrioventricular connections.12,14 In addition, although the atrioventricular system is situated normally, the atrioventricular node may become compressed by the abnormal formation of the central fibrous body. Thus, the right bundle branch may be damaged by marked fibrosis, leading to complete or incomplete right bundle branch blocks.5
GENETICS
Genetic research regarding Ebstein anomaly is lacking; however, very recent studies have shown that there is an association with the gene MYH7, located on chromosome 14q12. Patients with Ebstein anomaly also suffer from a myocardial disease known as left ventricular noncompaction (LVNC).15 This condition is brought about by abnormalities in structural proteins which are important for heart contraction. This malformation has been linked to the gene MYH7, where mutations result in spongelike muscle tissue protruding into the left ventricle, impairing contraction. In one study, 141 Ebstein patients were tested for the gene MYH7, 8 had a mutation in the gene, and 6 suffered from LVNC. Thus, genetic testing and family evaluation in case of MYH7 mutations is warranted.16
SIGNS AND SYMPTOMS Prenatal
Ebstein anomaly may at times be picked up as an abnormality in the development of the heart during routine prenatal sonography. It is associated with atrial septal defects, anatomic or functional pulmonary atresia, and rarely ventricular septal defects. It is possible that Ebstein anomaly results in severe tricuspid regurgitation and cardiac dysfunction in utero, which can lead to cardiomegaly, heart failure, pulmonary hypoplasia, tachyarrhythmias, and hydrops fetalis.12,17
Neonatal
These usually develop soon after birth and include cyanosis caused by low blood oxygen levels, right-sided congestive
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heart failure caused by tricuspid valve regurgitation, marked cardiomegaly caused by right heart dilatation, and arrhythmias. The cyanosis is usually associated with the right-to-left atrial shunt or severe heart failure. These symptoms range from mild to very severe.6,18 Cyanosis is markedly increased whenever the neonate has pulmonary hypertension because this further restricts pulmonary blood f low and oxygenation, which results in increased right ventricular pressures and right-sided failure. This will lead to progressive cardiac enlargement and hepatomegaly.7
Infancy and Adolescence
These usually include symptoms such as cough, failure to thrive, fatigue, rapid breathing, shortness of breath, and tachycardia. These symptoms can be caused by right ventricular failure and decreased left ventricular ejection fraction, which will make the heart beat faster to meet the body’s needs. 6 The clinical presentation is dependent on the age at which such patients present, the level of displacement of the tricuspid valve leaflets, the size of the right ventricle, and the degree of interatrial shunting present between the right and the left side because they all ultimately affect the level of hemodynamic disruption.19 Symptomatic children with Ebstein anomaly may also have progressive right heart failure, yet most will reach adulthood.7
Adulthood
In adulthood, patients who had mild degree of Ebstein anomaly–related cardiac abnormalities and so never developed any symptoms may present with arrhythmias, cyanosis, and an increasing right heart failure. Often in these patients, the right atrium and the atrialized right ventricle are quite dilated, at times even to extreme proportions.7 Irrespective of their age, in most patients with this anomaly, the ECG is abnormal. It may show tall and broad P waves because of right atrial enlargement, and the R waves of leads V1 and V2 are also found to be small.6 Ebstein anomaly is also associated with the presence of an abnormal electric connection between the right atrium and the right ventricle via a bundle called Kent’s bundle. Such a bundle will make the electric impulse bypass its usual path and predisposes the patient to develop Wolff-Parkinson-White syndrome. This arrhythmia is characterized by an irregular supraventricular tachycardia.20
DIAGNOSIS
In the fetus and neonate, a planned fetal echocardiography is extremely useful to distinguish the different severities of Ebstein anomaly.17
Prenatal
Sonographic imaging of the fetal heart in a four-chamber view during the second and even the third trimester
is essential in the detection of Ebstein anomaly. Apart from that, using a color Doppler, it is possible to detect a severely regurgitant tricuspid valve.17 A targeted echocardiogram on a fetus is recognized as being highly reliable to diagnose Ebstein anomaly and differentiate severity. Echocardiography can show whether the atrioventricular groove is of normal heart valve tissue and whether the valve is downwardly displaced. It is important to keep in mind that, because targeted echocardiography in obstetrics patients is not carried out on a regular basis, the need to recognize such an anomaly on a routine prenatal sonographic examination is essential.17 This is because Ebstein anomaly has a relatively poor prognosis during the neonatal period, where the mortality rate can be as high as 85 percent. 21 It is also essential to identify those neonates who will urgently require surgical intervention.22,23 Apart from that, it is essential that if such condition is suspected, close monitoring is performed for early detection of any hydrops and arrhythmias.17
Postnatal
Magnetic resonance imaging is a useful imaging technique in Ebstein anomaly. This is because the images that are acquired using this technique are not limited by acoustic windows, and the potential for a wider field of view allows a segmental, anatomic, and comprehensive view. This technique is also useful in assessing cardiac function, where it assesses wall motion, right and left ventricular ejection fraction, and blood flow. During a postnatal evaluation of these patients, one can obtain accurate functional and volumetric data for the right side of the heart. The ejection fraction can be equally quantified for the right ventricle. This will help to assess both the current and the expected right ventricular function after the valve replacement or repair. 24 Even though the best timing for an elective surgery in these patients is not known, symptomatology is a good indicator for surgery. However, patients with this condition are often unaware of their functional limitations; therefore, the use of exercise capacity can be used to assess prognostic implications. This is because right-to-left shunting can be easily increased with exercise. As such, progressive decline in the exercise performance must be taken as a relative indication for surgical management.25 Finally, surface ECG can show important clues regarding the patient’s anatomy, the presence of an accessory pathway, and any risk for developing atrioventricular reentry tachycardia. In fact, the surface ECG of a patient with Ebstein anomaly is nearly never normal. For example, a wide P wave that also has a prolonged PR interval demonstrates a slowed conduction in a dilated atrium. Also, a right bundle branch block is relatively common. Yet these patients might also have a right ventricular conduction delay related to hypertrophy or else overt excitation.25
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TREATMENT
Medical Treatment
Neonate. A neonate with Ebstein anomaly, who is symptomatic, is usually cyanotic because pulmonary blood flow is ductus dependent, and, therefore, a prostaglandin infusion is administered to maintain the pulmonary circulation. Complete anatomic evaluation with echocardiography is done to assess the anomaly. If the right ventricle is unobstructed, a trial of weaning from prostaglandins is tried, and a trial of nitric oxide to decrease pulmonary vascular resistance may help. If there is no deterioration, no surgery is needed. However, if the wean is unsuccessful, surgery via a systemic–pulmonary artery shunt or tricuspid valvoplasty would be considered.26 Children and Adults. The patients who present with mild forms must have regular assessments by a cardiologist. These assessments should include evaluation of the patient’s heart rhythm to evaluate any new arrhythmias and exercise testing to quantify cardiac functional capacity. If the patients develop signs and symptoms of right-sided heart failure, standard heart failure treatment is initiated, yet there is little evidence for the actual efficacy of these treatments in patients with Ebstein anomaly.25 Medical management should be individualized and usually involves standard heart failure treatment, such as diuretics, digoxin, beta-blockers, and angiotensin-converting enzyme inhibitors so as to reduce the afterload. There has also been recent use of nesiritide, a recombinant human brain natriuretic peptide, which has resulted in improved hemodynamic actions, enhanced sodium excretion, and suppression of the renin-angiotensin-aldosterone pathway and sympathetic nervous system.19,27 Antibiotic prophylaxis is not usually necessary in those patients who are acyanotic and
unoperated. However, it is recommended before dental procedures if there is cyanosis and/or if the patient has a prosthetic heart valve.25 Recommendations for physical activity state that, in cases of mild Ebstein anomaly, nearly normal heart size, and no arrhythmias, there is no restriction from sports participation. In severe unrepaired Ebstein anomaly, patients are warned against sports.25
Surgical Treatment
Surgical repair may be needed, but this is dependent on age, anatomy, and symptoms of the patient. It is recommended for those cases with congestive heart failure because a leak in the tricuspid valve is present or there is severe cyanosis. Surgical procedures used to treat this anomaly are shown in Table 1. Surgery should also be considered if there is evidence of deterioration such as progressive right ventricular dilatation, hypertrophy of the heart on chest radiography, or appearance of premature ventricular contractions. The latter reflects stress on the myopathic right ventricle.10 Managing patients with this condition is quite challenging, and, therefore, it must be specific for each patient. The most common procedure is the tricuspid valve reconstruction because it is quite feasible; however, it needs to be carried out by a specialist surgeon in a tertiary referral unit.28 Such a procedure can consist of a valve reconstruction and even placation of the atrialized portion of the right ventricle. Also, the anterior leaflet of the tricuspid valve is incised and afterward repositioned along the tricuspid valve annulus to give rise to a monocuspid right atrioventricular annulus, which is the aim of the whole procedure.29 Alternatively, a biventricular repair is preferred when the right ventricular size and function are adequate. Symptomatic neonates with this condition tend to have unfavorable pathophysiologic and anatomic conditions, thus leading to a worse prognosis; therefore, an
TABLE 1 n Surgical Treatment for Ebstein Anomaly Tricuspid valve repair
It is a reduction of the size of the valve opening so as to allow the valve leaflets to come together and work as a functional unit.
Tricuspid valve replacement
This is often used when the existing valve cannot be repaired, so instead, a mechanical or bioprosthetic valve is used. Anticoagulants will be required postoperatively.
Atrial septal defect closure
Atrial septal defects are associated with Ebstein anomaly and should be considered for closure to avoid complications.
Maze procedure
Performed during tricuspid valve repair or replacement, this procedure helps reduce atrial tachyarrhythmias via a series of incisions or freezing in the right atrium. This leads to destruction of tissue in the right atrium, which during healing develops scarring, thus acting as a barrier to electrical signals leading to a normal heart beat.
Radiofrequency catheter ablation
This is another procedure used to treat tachyarrhythmias or Wolff-Parkinson-White syndrome. Several catheters are threaded through the blood vessels to the heart and placed strategically. Electrodes at the tip of these catheters are heated via radiofrequency energy that ablates small spots of heart tissue leading to electrical signal blocks and ceasing of the arrhythmia.
Heart transplantation
This is only used for severe cases involving severely malformed valves and poor heart function.
Adapted from van son JA, Falk V, Black MD, Haas GS, Mohr FW. Conversion of complex neonatal Ebstein’s anomaly into functional tricuspid or pulmonary atresia. Eur J Cardiothorac Surg. 1998;13(3):280-284.
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accurate planning and individualized strategy for treatment is required so as to achieve a successful surgical approach.30 In neonates, who initially require palliation using a systemicto-pulmonary shunt, a one and a half ventricle repair using a cavopulmonary anastomosis must be considered after about two to three months. In the case of children, they should have valve reconstruction as opposed to a valve replacement. If the patient has severe cyanosis, arrhythmia, or even cardiac failure, then atrial septal defect closure, valve repair, and valve replacement are performed.6
PROGNOSIS
4. Sadler TW, Leland J, Sadler-Redmond S, Tosney K, Chescheir N, Imseis H. Langman’s Medical Embryology. 12th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2011. 5. Anderson KR, Zuberbuhler JR, Anderson RH, Becker AE, Lie JT. Morphologic spectrum of Ebstein’s anomaly of the heart: a review. Mayo Clin Proc. 1979;54:174-180. 6. Lev M, Liberthson RR, Joseph RH, et al. The pathologic anatomy of Ebstein’s disease. Arch Pathol. 1970;90:334-343. 7. Cecile C, Debord S, Moustapha-Nadler N. Ebstein’s anomaly: a complex congenital heart defect. AORN J. 2009;9:1098-1100. 8. Perloff JK. The Clinical Recognition of Congenital Heart Disease. Philadelphia, PA: Saunders; 2003. 9. Dearani JA, Danielson GK. Congenital Heart Surgery Nomenclature and Database Project: Ebstein’s anomaly and tricuspid valve disease. Ann Thorac Surg. 2000;69:S106-S117.
This disease is notorious for having a poor prognosis in the neonatal period with a mortality rate of up to 85 percent. Spontaneous intrauterine death can be as high as 48 percent, with 35 percent of affected live births dying of hypoxia because of congestive heart failure. In view of this, an early presentation of such an anomaly is linked with more cardiac anomalies, mostly pulmonary stenosis or atresia. Therefore, generally, the earlier the patient shows up with the anomaly, the worse the prognosis. This variation is related to the downward displacement of the tricuspid valve, which leads into a large right atrium and a smaller hypoplastic right ventricle.17 Factors associated with increased mortality include hepatomegaly, pulmonary valve defects, ventricular septal defects, and a patent ductus arteriosus.29 However, if the anomaly is mild, patients tend to remain stable and possibly asymptomatic for decades. Yet most will generally develop late rhythm disorders nearly to the same level as patients with a more serious anatomic abnormality.31
13. Egidy Assenza G, Valente AM, Geva T, et al. QRS duration and QRS fractionation on surface electrocardiogram are markers of right ventricular dysfunction and atrialization in patients with Ebstein anomaly. Eur Heart J. 2013;34(3):191-200.
CONCLUSION
17. Melendres G, Ormsby EL, McGahan JP, Moon-Grady AJ, Towner D, Taylor D. Prenatal diagnosis of Ebstein’s anomaly: a potential pitfall. J Ultrasound Med. 2004;23(4):551-555.
Ebstein anomaly is a complicated form of congenital heart disease with variable clinical presentations. In this condition, the visualization of the apically displaced septal tricuspid leaflet is a good diagnostic feature. With a sound knowledge of the normal anatomy, accurate observation of pregnancy outcomes, and regular visits with the respective cardiologists and the multidisciplinary team, better management will ultimately improve the prognosis of such patients.
REFERENCES
1. University of Illinois at Chicago. Embryological development of the human: the primitive heart. http://www.uic.edu/com/surgery/embryo/ cardiovascular_11.htm. Published August 14, 2001. Accessed April 4, 2013. 2. Ebstein W. Über einen sehr seltenen Fall von Insufficienz der Valvula tricuspidalis, bedingt durch eine angeborene hochgradige Missbildung derselben. Arch Anat Physiol wiss Med. 1866;238-254. 3. Universities of Fribourg, Lausanne and Bern (Switzerland). Module 16. Chapter 16.1. Human embryology. http://www.embryology.ch/ anglais/pcardio/herzentwick01.html. Published June 21, 2005. Updated February 20, 2008. Accessed April 4, 2013.
10. Fuster V, ed. Hurst’s The Heart. 13th ed. New York, NY: McGraw-Hill; 2011. 11. Park MK, Troxler RG. Cyanotic congenital heart defects. In: Park MK, Troxler RG, eds. Pediatric Cardiology for Practitioners. 5th ed. St. Louis, MO: Mosby; 2008. 12. Attenhofer Jost CH, Connolly HM, Edwards WD, Dearani JA, Danielson GK. Congenital heart disease for the adult cardiologist: Ebstein’s anomaly. Circulation. 2007;115:277-285.
14. Ghosh S, Avari JN, Rhee EK, Woodard PK, Rudy Y. Noninvasive electrocardiographic imaging (ECGI) of epicardial activation before and after catheter ablation of the accessory pathway in a patient with Ebstein’s anomaly. Heart Rhythm. 2008;5(6):857-860. 15. van Engelen K, Postma AV, van de Meerakker JB, et al. Ebstein’s anomaly may be caused by mutations in the sarcomere protein gene MYH7. Neth Heart J. 2013;21:113-117. 16. Postma AV, van Engelen K, van de Meerakker J, et al. Mutations in the sarcomere gene MYH7 in Ebstein anomaly. Circ Cardiovasc Genet. 2010;4:43-50.
18. Cincinnati Children’s Hospital Medical Center. Ebstein anomaly. http://www.cincinnatichildrens.org/health/e/ebstein/. Published July 2009. Accessed April 4, 2013. 19. Attenhofer Jost CH, Connolly HM, Edwards WD, Hayes D, Warnes CA, Danielson GK. Ebstein’s anomaly—review of a multifaceted congenital cardiac condition. Swiss Med Wkly. 2005;135:269-281. 20. Daliento L, Angelini A, Ho SY, et al. Angiographic and morphologic features of the left ventricle in Ebstein’s malformation. Am J Cardiol. 1997;80:1051-1059. 21. Pavlova M, Fouron JC, Drblik SP, et al. Factors affecting the prognosis of Ebstein’s anomaly during fetal life. Am Heart J. 1998;135(6 Pt 1): 1081-1085. 22. Knott-Craig CJ, Overholt ED, Ward KE, Razook JD. Neonatal repair of Ebstein’s anomaly: indications, surgical technique, and medium-term follow-up. Ann Thorac Surg. 2006;69:1505-1510. 23. Chauvaud S, Berrebi A, d’Attellis N, Mousseaux E, Hernigou A, Carpentier A. Ebstein’s anomaly: repair based on functional analysis. Eur J Cardiothorac Surg. 2003;23:525-531. 24. Attenhofer Jost CH, Edmister WD, Julsrud PR, et al. Prospective comparison of echocardiography versus cardiac magnetic resonance imaging in patients with Ebstein’s anomaly. Int J Cardiovasc Imaging. 2012;28:1147-1159.
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25. Krieger EV, Valente AM. Diagnosis and management of Ebstein anomaly of the tricuspid valve. Curr Treat Options Cardiovasc Med. 2012;14(6):594-607. 26. Shinkawa T, Polimenakos AC, Gomez-Fifer CA, et al. Management and long-term outcome of neonatal Ebstein anomaly. J Thorac Cardiovasc Surg. 2010;139(2):354-358. 27. Tavakol M, Banko L, Schifter D. Use of nesiritide in Ebstein’s anomaly. Int J Angiol. 2008;17(1):47-49. 28. Ebaid M, Azeka E, Ikari NM, Sosa EA, Marcial MB, Atik E. Ebstein’s anomaly with coarctation of the aorta. An unusual association. Arq Bras Cardiol. 1999;73:219-224. 29. Pierpont ME, Basson CT, Benson DW Jr, et al. Genetic basis for congenital heart defects: current knowledge: a scientific statement from the American Heart Association Congenital Cardiac Defects Committee, Council on Cardiovascular Disease in the Young: endorsed by the American Academy of Pediatrics. Circulation. 2007;115:3015-3038. 30. Oxenius A, Attenhofer Jost CH, Pretre R, et al. Management and outcome of Ebstein’s anomaly in children. Cardiol Young. 2013;23:27-34. 31. Bhupali AN, Patankar KB, Paranjpe FS, Tamhane AU. Giant right atrium in a foetus. Indian Heart J. 2013;65(4):493-495.
About the Authors
Jean Calleja-Agius, MD, MRCOG, MRCPI, PhD, is an obstetrician and gynecologist, and she is a lecturer on Embryology and Reproductive Sciences at the University of Malta. Pierre Schembri-Wismayer, MD, PhD, is the head of the Department of Anatomy at the University of Malta. Joseph Galea, Sarah Ellul, and Aaron Schembri are final-year medical students who have been working on a project on congenital cardiac anomalies as part of their dissertation. For further information, please contact: Jean Calleja-Agius, MD, MRCOG, MRCPI, PhD (Lond.) Department of Anatomy Faculty of Medicine and Surgery University of Malta Tal-Qroqq, Msida MSD2080, Malta E-mail: [email protected]
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Accepted for publication April 2014.
Abstract Cardiac congenital abnormalities are a leading cause in neonatal mortality occurring in up to 1 in 200 of live births. Ebstein anomaly, also known as Kassamali anomaly, accounts for 1 percent of all congenital cardiac anomalies. This congenital abnormality involves malformation of the tricuspid valve and of the right ventricle. In this review, the causes of the anomaly are outlined and the pathophysiology is discussed, with a focus on the symptoms, management, and treatments available to date. Keywords: Ebstein anomaly; cardiac congenital abnormality; neonatal mortality
T
h e h u m a n h e a r t i s a m yoge n ic
uscular organ that is responsible m for the maintenance of blood f low circulation within the human body. Neonates may be born with congenital heart defects, which are very common, especially because of the complexity of the embryologic cardiac development. Congenital heart defects are a significant cause of neonatal morbidity and mortality, occurring in up to 1 in 200 live births.1 The causes for such anomalies are either genetic, thus involving mutations, or environmental, possibly involving infection during pregnancy or exposure to teratogens. Ebstein anomaly, first described by German physician Wilhelm Ebstein in 1866, 2 is one of many congenital cardiac defects that may occur during heart development. It involves an abnormality in the tricuspid valve leaflets— adherence of the posterior and septal leaflets of the valve underlying the myocardium. This right atrioventricular valve is found between the right atrium and right ventricle, which together collect venous blood and direct it to the lungs so that it can be oxygenated.1,3 To comprehend the structural defects involved in Ebstein anomaly together with its pathophysiology, manifestations, management, and prognosis, a good understanding
of the embryologic development of the heart is necessary. The embryologic development of the heart begins 18 days after fertilization through the formation of the cardiogenic plate and can be grouped into five stages (Figure 1).4,5
DEFINITION
Ebstein anomaly is a rare congenital cardiac malformation which is characterized by the apical displacement of the tricuspid valve leaflets. Such a displacement leads to the atrialization of the right ventricle; that is, the atrium and ventricle become one functional unit, giving rise to an atrialized segment. There is also a variable degree of malformation and displacement of the anterior tricuspid leaflet.6 This congenital disorder occurs in about 1–5 per 200,000 live births, thus accounting for about 1 percent of all congenital cardiac abnormalities.7 In patients with this anomaly, the leaflets are unusually stretched deep into the right ventricle and are often larger than normal. The defect usually causes the valve to work poorly, and blood may reverse and flow back into the right atrium. Such regurgitation of blood, ranging from mild to severe, can
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C
Cardiac mesoderm
Endoderm
Mesoderm
Ectoderm
The premature heart as viewed from the front with the atria on top of the ventricles
D
Communication between the tubes
Right ventricular chamber
Tricuspid valve
Right atrial chamber
Pulmonary valve
Left Right endocardial endocardial tube tube
B
Septum
Left ventricular chamber
Mitral valve
Left atrial chamber
Aortic valve
Single endocardial tube
Aortic sac Conotruncal segment Right ventricle Left ventricle Atria
A. Stage 1—Specification for cardiac precursor cells. The first stage involves the specification of cardiac precursor cells, which develop from the cardiac mesoderm. This is a derivative of the splanchnic mesoderm, which is the germ layer found between the endoderm and ectoderm in the embryo. These cells differentiate into endocardium, the layer of tissue lining the heart chambers, and myocardium, the functional tissue that contracts to circulate blood and the pericardium. These coalesce into two heart tubes. Numerous cardiogenic signals such as bone morphogenetic proteins and fibroblast growth factor control this development. B. Stage 2—Heart tube formation and their subsequent connection forming the primitive heart. The second stage involves the migration of cardiac precursor cells and fusion of the primordial cells. Cardiac precursor cells migrate and fuse into a single heart tube on each side of the pericardial cavity, and these connect and develop into various regions and chambers of the heart. C. Stage 3—Looping of the heart. Looping of the heart occurs in the third stage where the heart tube undergoes rightward looping, and, thus, the ventricles come to lie in front of the atria, and the atria lie above the ventricles. D. Stages 4 and 5— Heart chamber formation, septation, and valve formation. The fourth stage involves heart chamber formation, and the final stage involves septation and valve formation.
Rightward looping of the atrial portion of the premature heart to come to lie behind the ventricles
Endocardium, myocardium, and pericardium tubes
A
FIGURE 1 n The stages of embryologic development of the heart.
lead to hypertrophy of the heart and edema in the lungs or liver.8 In such an anomaly, the right ventricle is divided into two parts: the inlet portion being functionally integrated with the right atrium and the other portion constituting the functional right ventricle. This abnormality results in dilatation of the true tricuspid annulus and the presence of a large chamber. This will lead to the separation of the true tricuspid annulus from the functional right ventricle (Figure 2).9,10 Generally, patients also have an atrial septal defect, and, thus, blood flow across this defect causes oxygen-poor blood to shunt from right to left, bypassing the lungs and ending up in the systemic circulation. There may also be stenosis of the pulmonary valve. The wall of the right ventricle is generally thin, and the ventricular cavity itself is quite small compared with normal.11
PATHOPHYSIOLOGY
The partial deterioration present in the right ventricle together with the presence of the tricuspid valve regurgitation will hinder venous return from flowing into the pulmonary circulation. Apart from that, during atrial contraction, the atrialized part of the right ventricle inf lates and will behave as a passive reservoir. This will result in a diminished ejection fraction. The ultimate result is right atrial dilation, therefore increasing the interatrial communication through the atrial septal defect resulting in varying degrees of rightto-left shunting.12 The hemodynamic complications of Ebstein anomaly are directly related to the severity of the leaflet displacement and to the resultant tricuspid valve regurgitation.6 In the case of mild displacement and mild valve regurgitation, the patient
FIGURE 2 n Ebstein anomaly.
Atrial septal defect
Right atrium
Displaced tricuspid valve allows blood back into right atrium
may be asymptomatic for many years. If the leaflet displacement and valve regurgitation are severe, pulmonary blood flow decreases, the right atrium becomes dilated, and blood is shunted from right to left across an atrial septal defect.6 This dysfunction and dilation of the right atrium and right ventricle leads to progressive patchy myocardial atrophy and fibrosis, which leads to a conduction defect, resulting in an abnormal electrocardiogram (ECG).13 The abnormally developed tricuspid valve is also associated with conduction abnormalities which include delayed intra-atrial conduction, right bundle branch block, and ventricular preexcitation. This is because the downward displacement of the septal leaflet is related to discontinuity of the central fibrous body and the septal atrioventricular ring leading to direct muscular connection being formed. These create a potential substrate for accessory atrioventricular connections.12,14 In addition, although the atrioventricular system is situated normally, the atrioventricular node may become compressed by the abnormal formation of the central fibrous body. Thus, the right bundle branch may be damaged by marked fibrosis, leading to complete or incomplete right bundle branch blocks.5
GENETICS
Genetic research regarding Ebstein anomaly is lacking; however, very recent studies have shown that there is an association with the gene MYH7, located on chromosome 14q12. Patients with Ebstein anomaly also suffer from a myocardial disease known as left ventricular noncompaction (LVNC).15 This condition is brought about by abnormalities in structural proteins which are important for heart contraction. This malformation has been linked to the gene MYH7, where mutations result in spongelike muscle tissue protruding into the left ventricle, impairing contraction. In one study, 141 Ebstein patients were tested for the gene MYH7, 8 had a mutation in the gene, and 6 suffered from LVNC. Thus, genetic testing and family evaluation in case of MYH7 mutations is warranted.16
SIGNS AND SYMPTOMS Prenatal
Ebstein anomaly may at times be picked up as an abnormality in the development of the heart during routine prenatal sonography. It is associated with atrial septal defects, anatomic or functional pulmonary atresia, and rarely ventricular septal defects. It is possible that Ebstein anomaly results in severe tricuspid regurgitation and cardiac dysfunction in utero, which can lead to cardiomegaly, heart failure, pulmonary hypoplasia, tachyarrhythmias, and hydrops fetalis.12,17
Neonatal
These usually develop soon after birth and include cyanosis caused by low blood oxygen levels, right-sided congestive
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heart failure caused by tricuspid valve regurgitation, marked cardiomegaly caused by right heart dilatation, and arrhythmias. The cyanosis is usually associated with the right-to-left atrial shunt or severe heart failure. These symptoms range from mild to very severe.6,18 Cyanosis is markedly increased whenever the neonate has pulmonary hypertension because this further restricts pulmonary blood f low and oxygenation, which results in increased right ventricular pressures and right-sided failure. This will lead to progressive cardiac enlargement and hepatomegaly.7
Infancy and Adolescence
These usually include symptoms such as cough, failure to thrive, fatigue, rapid breathing, shortness of breath, and tachycardia. These symptoms can be caused by right ventricular failure and decreased left ventricular ejection fraction, which will make the heart beat faster to meet the body’s needs. 6 The clinical presentation is dependent on the age at which such patients present, the level of displacement of the tricuspid valve leaflets, the size of the right ventricle, and the degree of interatrial shunting present between the right and the left side because they all ultimately affect the level of hemodynamic disruption.19 Symptomatic children with Ebstein anomaly may also have progressive right heart failure, yet most will reach adulthood.7
Adulthood
In adulthood, patients who had mild degree of Ebstein anomaly–related cardiac abnormalities and so never developed any symptoms may present with arrhythmias, cyanosis, and an increasing right heart failure. Often in these patients, the right atrium and the atrialized right ventricle are quite dilated, at times even to extreme proportions.7 Irrespective of their age, in most patients with this anomaly, the ECG is abnormal. It may show tall and broad P waves because of right atrial enlargement, and the R waves of leads V1 and V2 are also found to be small.6 Ebstein anomaly is also associated with the presence of an abnormal electric connection between the right atrium and the right ventricle via a bundle called Kent’s bundle. Such a bundle will make the electric impulse bypass its usual path and predisposes the patient to develop Wolff-Parkinson-White syndrome. This arrhythmia is characterized by an irregular supraventricular tachycardia.20
DIAGNOSIS
In the fetus and neonate, a planned fetal echocardiography is extremely useful to distinguish the different severities of Ebstein anomaly.17
Prenatal
Sonographic imaging of the fetal heart in a four-chamber view during the second and even the third trimester
is essential in the detection of Ebstein anomaly. Apart from that, using a color Doppler, it is possible to detect a severely regurgitant tricuspid valve.17 A targeted echocardiogram on a fetus is recognized as being highly reliable to diagnose Ebstein anomaly and differentiate severity. Echocardiography can show whether the atrioventricular groove is of normal heart valve tissue and whether the valve is downwardly displaced. It is important to keep in mind that, because targeted echocardiography in obstetrics patients is not carried out on a regular basis, the need to recognize such an anomaly on a routine prenatal sonographic examination is essential.17 This is because Ebstein anomaly has a relatively poor prognosis during the neonatal period, where the mortality rate can be as high as 85 percent. 21 It is also essential to identify those neonates who will urgently require surgical intervention.22,23 Apart from that, it is essential that if such condition is suspected, close monitoring is performed for early detection of any hydrops and arrhythmias.17
Postnatal
Magnetic resonance imaging is a useful imaging technique in Ebstein anomaly. This is because the images that are acquired using this technique are not limited by acoustic windows, and the potential for a wider field of view allows a segmental, anatomic, and comprehensive view. This technique is also useful in assessing cardiac function, where it assesses wall motion, right and left ventricular ejection fraction, and blood flow. During a postnatal evaluation of these patients, one can obtain accurate functional and volumetric data for the right side of the heart. The ejection fraction can be equally quantified for the right ventricle. This will help to assess both the current and the expected right ventricular function after the valve replacement or repair. 24 Even though the best timing for an elective surgery in these patients is not known, symptomatology is a good indicator for surgery. However, patients with this condition are often unaware of their functional limitations; therefore, the use of exercise capacity can be used to assess prognostic implications. This is because right-to-left shunting can be easily increased with exercise. As such, progressive decline in the exercise performance must be taken as a relative indication for surgical management.25 Finally, surface ECG can show important clues regarding the patient’s anatomy, the presence of an accessory pathway, and any risk for developing atrioventricular reentry tachycardia. In fact, the surface ECG of a patient with Ebstein anomaly is nearly never normal. For example, a wide P wave that also has a prolonged PR interval demonstrates a slowed conduction in a dilated atrium. Also, a right bundle branch block is relatively common. Yet these patients might also have a right ventricular conduction delay related to hypertrophy or else overt excitation.25
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TREATMENT
Medical Treatment
Neonate. A neonate with Ebstein anomaly, who is symptomatic, is usually cyanotic because pulmonary blood flow is ductus dependent, and, therefore, a prostaglandin infusion is administered to maintain the pulmonary circulation. Complete anatomic evaluation with echocardiography is done to assess the anomaly. If the right ventricle is unobstructed, a trial of weaning from prostaglandins is tried, and a trial of nitric oxide to decrease pulmonary vascular resistance may help. If there is no deterioration, no surgery is needed. However, if the wean is unsuccessful, surgery via a systemic–pulmonary artery shunt or tricuspid valvoplasty would be considered.26 Children and Adults. The patients who present with mild forms must have regular assessments by a cardiologist. These assessments should include evaluation of the patient’s heart rhythm to evaluate any new arrhythmias and exercise testing to quantify cardiac functional capacity. If the patients develop signs and symptoms of right-sided heart failure, standard heart failure treatment is initiated, yet there is little evidence for the actual efficacy of these treatments in patients with Ebstein anomaly.25 Medical management should be individualized and usually involves standard heart failure treatment, such as diuretics, digoxin, beta-blockers, and angiotensin-converting enzyme inhibitors so as to reduce the afterload. There has also been recent use of nesiritide, a recombinant human brain natriuretic peptide, which has resulted in improved hemodynamic actions, enhanced sodium excretion, and suppression of the renin-angiotensin-aldosterone pathway and sympathetic nervous system.19,27 Antibiotic prophylaxis is not usually necessary in those patients who are acyanotic and
unoperated. However, it is recommended before dental procedures if there is cyanosis and/or if the patient has a prosthetic heart valve.25 Recommendations for physical activity state that, in cases of mild Ebstein anomaly, nearly normal heart size, and no arrhythmias, there is no restriction from sports participation. In severe unrepaired Ebstein anomaly, patients are warned against sports.25
Surgical Treatment
Surgical repair may be needed, but this is dependent on age, anatomy, and symptoms of the patient. It is recommended for those cases with congestive heart failure because a leak in the tricuspid valve is present or there is severe cyanosis. Surgical procedures used to treat this anomaly are shown in Table 1. Surgery should also be considered if there is evidence of deterioration such as progressive right ventricular dilatation, hypertrophy of the heart on chest radiography, or appearance of premature ventricular contractions. The latter reflects stress on the myopathic right ventricle.10 Managing patients with this condition is quite challenging, and, therefore, it must be specific for each patient. The most common procedure is the tricuspid valve reconstruction because it is quite feasible; however, it needs to be carried out by a specialist surgeon in a tertiary referral unit.28 Such a procedure can consist of a valve reconstruction and even placation of the atrialized portion of the right ventricle. Also, the anterior leaflet of the tricuspid valve is incised and afterward repositioned along the tricuspid valve annulus to give rise to a monocuspid right atrioventricular annulus, which is the aim of the whole procedure.29 Alternatively, a biventricular repair is preferred when the right ventricular size and function are adequate. Symptomatic neonates with this condition tend to have unfavorable pathophysiologic and anatomic conditions, thus leading to a worse prognosis; therefore, an
TABLE 1 n Surgical Treatment for Ebstein Anomaly Tricuspid valve repair
It is a reduction of the size of the valve opening so as to allow the valve leaflets to come together and work as a functional unit.
Tricuspid valve replacement
This is often used when the existing valve cannot be repaired, so instead, a mechanical or bioprosthetic valve is used. Anticoagulants will be required postoperatively.
Atrial septal defect closure
Atrial septal defects are associated with Ebstein anomaly and should be considered for closure to avoid complications.
Maze procedure
Performed during tricuspid valve repair or replacement, this procedure helps reduce atrial tachyarrhythmias via a series of incisions or freezing in the right atrium. This leads to destruction of tissue in the right atrium, which during healing develops scarring, thus acting as a barrier to electrical signals leading to a normal heart beat.
Radiofrequency catheter ablation
This is another procedure used to treat tachyarrhythmias or Wolff-Parkinson-White syndrome. Several catheters are threaded through the blood vessels to the heart and placed strategically. Electrodes at the tip of these catheters are heated via radiofrequency energy that ablates small spots of heart tissue leading to electrical signal blocks and ceasing of the arrhythmia.
Heart transplantation
This is only used for severe cases involving severely malformed valves and poor heart function.
Adapted from van son JA, Falk V, Black MD, Haas GS, Mohr FW. Conversion of complex neonatal Ebstein’s anomaly into functional tricuspid or pulmonary atresia. Eur J Cardiothorac Surg. 1998;13(3):280-284.
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accurate planning and individualized strategy for treatment is required so as to achieve a successful surgical approach.30 In neonates, who initially require palliation using a systemicto-pulmonary shunt, a one and a half ventricle repair using a cavopulmonary anastomosis must be considered after about two to three months. In the case of children, they should have valve reconstruction as opposed to a valve replacement. If the patient has severe cyanosis, arrhythmia, or even cardiac failure, then atrial septal defect closure, valve repair, and valve replacement are performed.6
PROGNOSIS
4. Sadler TW, Leland J, Sadler-Redmond S, Tosney K, Chescheir N, Imseis H. Langman’s Medical Embryology. 12th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2011. 5. Anderson KR, Zuberbuhler JR, Anderson RH, Becker AE, Lie JT. Morphologic spectrum of Ebstein’s anomaly of the heart: a review. Mayo Clin Proc. 1979;54:174-180. 6. Lev M, Liberthson RR, Joseph RH, et al. The pathologic anatomy of Ebstein’s disease. Arch Pathol. 1970;90:334-343. 7. Cecile C, Debord S, Moustapha-Nadler N. Ebstein’s anomaly: a complex congenital heart defect. AORN J. 2009;9:1098-1100. 8. Perloff JK. The Clinical Recognition of Congenital Heart Disease. Philadelphia, PA: Saunders; 2003. 9. Dearani JA, Danielson GK. Congenital Heart Surgery Nomenclature and Database Project: Ebstein’s anomaly and tricuspid valve disease. Ann Thorac Surg. 2000;69:S106-S117.
This disease is notorious for having a poor prognosis in the neonatal period with a mortality rate of up to 85 percent. Spontaneous intrauterine death can be as high as 48 percent, with 35 percent of affected live births dying of hypoxia because of congestive heart failure. In view of this, an early presentation of such an anomaly is linked with more cardiac anomalies, mostly pulmonary stenosis or atresia. Therefore, generally, the earlier the patient shows up with the anomaly, the worse the prognosis. This variation is related to the downward displacement of the tricuspid valve, which leads into a large right atrium and a smaller hypoplastic right ventricle.17 Factors associated with increased mortality include hepatomegaly, pulmonary valve defects, ventricular septal defects, and a patent ductus arteriosus.29 However, if the anomaly is mild, patients tend to remain stable and possibly asymptomatic for decades. Yet most will generally develop late rhythm disorders nearly to the same level as patients with a more serious anatomic abnormality.31
13. Egidy Assenza G, Valente AM, Geva T, et al. QRS duration and QRS fractionation on surface electrocardiogram are markers of right ventricular dysfunction and atrialization in patients with Ebstein anomaly. Eur Heart J. 2013;34(3):191-200.
CONCLUSION
17. Melendres G, Ormsby EL, McGahan JP, Moon-Grady AJ, Towner D, Taylor D. Prenatal diagnosis of Ebstein’s anomaly: a potential pitfall. J Ultrasound Med. 2004;23(4):551-555.
Ebstein anomaly is a complicated form of congenital heart disease with variable clinical presentations. In this condition, the visualization of the apically displaced septal tricuspid leaflet is a good diagnostic feature. With a sound knowledge of the normal anatomy, accurate observation of pregnancy outcomes, and regular visits with the respective cardiologists and the multidisciplinary team, better management will ultimately improve the prognosis of such patients.
REFERENCES
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10. Fuster V, ed. Hurst’s The Heart. 13th ed. New York, NY: McGraw-Hill; 2011. 11. Park MK, Troxler RG. Cyanotic congenital heart defects. In: Park MK, Troxler RG, eds. Pediatric Cardiology for Practitioners. 5th ed. St. Louis, MO: Mosby; 2008. 12. Attenhofer Jost CH, Connolly HM, Edwards WD, Dearani JA, Danielson GK. Congenital heart disease for the adult cardiologist: Ebstein’s anomaly. Circulation. 2007;115:277-285.
14. Ghosh S, Avari JN, Rhee EK, Woodard PK, Rudy Y. Noninvasive electrocardiographic imaging (ECGI) of epicardial activation before and after catheter ablation of the accessory pathway in a patient with Ebstein’s anomaly. Heart Rhythm. 2008;5(6):857-860. 15. van Engelen K, Postma AV, van de Meerakker JB, et al. Ebstein’s anomaly may be caused by mutations in the sarcomere protein gene MYH7. Neth Heart J. 2013;21:113-117. 16. Postma AV, van Engelen K, van de Meerakker J, et al. Mutations in the sarcomere gene MYH7 in Ebstein anomaly. Circ Cardiovasc Genet. 2010;4:43-50.
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25. Krieger EV, Valente AM. Diagnosis and management of Ebstein anomaly of the tricuspid valve. Curr Treat Options Cardiovasc Med. 2012;14(6):594-607. 26. Shinkawa T, Polimenakos AC, Gomez-Fifer CA, et al. Management and long-term outcome of neonatal Ebstein anomaly. J Thorac Cardiovasc Surg. 2010;139(2):354-358. 27. Tavakol M, Banko L, Schifter D. Use of nesiritide in Ebstein’s anomaly. Int J Angiol. 2008;17(1):47-49. 28. Ebaid M, Azeka E, Ikari NM, Sosa EA, Marcial MB, Atik E. Ebstein’s anomaly with coarctation of the aorta. An unusual association. Arq Bras Cardiol. 1999;73:219-224. 29. Pierpont ME, Basson CT, Benson DW Jr, et al. Genetic basis for congenital heart defects: current knowledge: a scientific statement from the American Heart Association Congenital Cardiac Defects Committee, Council on Cardiovascular Disease in the Young: endorsed by the American Academy of Pediatrics. Circulation. 2007;115:3015-3038. 30. Oxenius A, Attenhofer Jost CH, Pretre R, et al. Management and outcome of Ebstein’s anomaly in children. Cardiol Young. 2013;23:27-34. 31. Bhupali AN, Patankar KB, Paranjpe FS, Tamhane AU. Giant right atrium in a foetus. Indian Heart J. 2013;65(4):493-495.
About the Authors
Jean Calleja-Agius, MD, MRCOG, MRCPI, PhD, is an obstetrician and gynecologist, and she is a lecturer on Embryology and Reproductive Sciences at the University of Malta. Pierre Schembri-Wismayer, MD, PhD, is the head of the Department of Anatomy at the University of Malta. Joseph Galea, Sarah Ellul, and Aaron Schembri are final-year medical students who have been working on a project on congenital cardiac anomalies as part of their dissertation. For further information, please contact: Jean Calleja-Agius, MD, MRCOG, MRCPI, PhD (Lond.) Department of Anatomy Faculty of Medicine and Surgery University of Malta Tal-Qroqq, Msida MSD2080, Malta E-mail: [email protected]
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