Continuing Education Activity

Ebstein anomaly is a rare congenital abnormality involving the tricuspid valve and the right ventricle. Ebstein anomaly occurs when an apical displacement of the tricuspid valve with tethering of leaflet attachments. Both the tricuspid valve and the right ventricle are dysplastic, with it frequently described as "atrialization of the right ventricle." Ebstein anomaly often results in pathological tricuspid regurgitation, right ventricular failure, and arrhythmias. Common clinical manifestations include exertional dyspnea, palpitations, and cyanosis. This activity reviews the pathophysiology and presentation of Ebstein anomaly and highlights the role of the interprofessional team in its management.

Objectives:

• Describe the pathophysiology of Ebstein anomaly.
• Review the presentation of a patient with an Ebstein anomaly.
• Summarize the evaluation treatment for Ebstein anomaly.
• Outline the importance of improving care coordination among interprofessional team members to improve outcomes for patients affected by Ebstein anomaly.

Introduction

Ebstein anomaly is a rare congenital abnormality involving the tricuspid valve and the right ventricle.[1] It was first described by the pathologist Wilhelm Ebstein in 1866 when he performed an autopsy of a laborer who suffered from exertional dyspnea all his life, had evidence of cyanosis and died of a sudden cardiac arrest.[2] Ebstein anomaly occurs when there is an apical displacement of the tricuspid valve with tethering of leaflet attachments. Both the tricuspid valve and the right ventricle are dysplastic, with it frequently described as "atrialization" of the right ventricle.[3] 

Most commonly, patients present with exertional dyspnea, palpitations, and cyanosis and, depending on the severity of the defect, can present in childhood, adolescence, or early adulthood. Ebstein anomaly frequently results in pathological tricuspid regurgitation, right ventricular failure, and arrhythmias.[4] 

Etiology

Ebstein anomaly is thought to be associated with chromosome 15q, which is involved in the embryological development of the heart in utero. There are case reports suggesting a possible association of Ebstein anomaly with chromosome 11q. Furthermore, studies suggest that Ebstein malformation may be associated with mutations in myosin heavy chain 7 (frequently associated with cardiomyopathies) and NKX2.5 (associated with other congenital heart defects).[5][6]

Another known association of Ebstein anomaly is the teratogenic effect of Lithium. Case-control and cohort studies in the 1970s and 1980s of pregnant women taking Lithium demonstrated a risk of Ebstein anomaly in <2% of their newborns.[7] A small case-control study of 47 patients with Ebstein anomaly also suggested some association with maternal exposure to benzodiazepines and varnishing.[8] 

Epidemiology

Ebstein anomaly accounts for 0.3% to 0.6% of all congenital heart defects.[9] It is reported to occur at 0.2 to 0.7 per 10,000 live births.[10] The majority of cases are sporadic, with no identifiable etiology. Some studies suggest that there may be a familial inheritance, and monozygotic twins have been known to concurrently present from the same.[10]

There is a higher incidence of recurrence in the offspring of women (6%) than that seen in the offspring of men (0.6%).[9] About one-third of patients have been noted to have other congenital cardiac defects.[8] Case-control studies have also suggested a higher incidence of Ebstein anomaly in Caucasian patients.[8] 

Pathophysiology

Anatomic Abnormalities

The main pathophysiological abnormality of Ebstein anomaly is the failure of delamination of the tricuspid valve leaflets from the interventricular septum in utero.[11] The apical displacement mainly affects the posterior and septal leaflets, leading to the apical displacement of the tricuspid annulus and anteroapical displacement of the tricuspid orifice.[10][12] This apical displacement has also been described as a rotational displacement of the tricuspid leaflets towards the right ventricular outflow tract to account for the fact that the atrioventricular junction is not really horizontal.[13] The displacement is usually defined as > 8mm/m2 displacement of the septal leaflet from the anatomic tricuspid annulus.[13] The anterior leaflet of the tricuspid valve often has abnormal chordal attachments and becomes hypermobile, described as "sail-like." Alternately, there may be tethering of the anterior leaflet causing restricted motion.[11][12] There may also be fenestrations of the anterior leaflet.[3] 

The right ventricle becomes split into two portions. The first portion is the "atrialized" right ventricle, where the right ventricular inflow should typically be, extending from the undisplaced tricuspid annulus to the "functional" right ventricle. The second portion is the functional right ventricle. The first portion receives the regurgitant flow from the tricuspid regurgitation and becomes dilated along with the right atrium. The functional right ventricle can be very small and can often consist of only the right ventricular outflow tract in cases of severe apical displacement of the septal and posterior leaflets. 

More than 80% of patients with Ebstein anomaly also have a secundum atrial septal defect or a patent foramen ovale.[14] Paradoxical emboli can also occur across shunts in these patients. Ventricular septal defects and pulmonary atresia have also been concurrently found with Ebstein malformation.[10] In addition, Ebstein anomaly is associated with conduction system abnormalities thought to be due to compression of the atrioventricular node by the septal malformation and disruption of the atrioventricular node connection. This manifests in the form of accessory conduction pathways, and about one-third of patients with Ebstein anomaly have more than one accessory pathway.[13][15] Furthermore, 5 to 25% of patients with Ebstein anomaly have been reported to have Wolff Parkinson White syndrome, making it the most commonly found congenital heart defect associated with Wolff Parkinson White syndrome.[15] 

Functional Abnormalities

The abnormal coaptation of the tricuspid leaflets as a result of their anatomic displacement and tethering abnormalities leads to tricuspid. The severity of the apical displacement of the posterior and septal leaflets and degree of abnormality of the anterior leaflet attachments, and the integrity of the leaflets themselves determine the severity of the tricuspid regurgitation.[10][11] The "atrialized" right ventricle is often dyskinetic as a result of fibrosis and myopathy.[10] The functional right ventricle also becomes enlarged and myopathic due to severe tricuspid regurgitation.[16] The right ventricular volume overload can also lead to ventricular septal flattening and cause left ventricular dysfunction.[10] Another major hemodynamic abnormality that can occur in Ebstein anomaly is when there is a concurrent atrial septal defect or patent foramen ovale. The right ventricular volume overload can lead to a right to left shunting in these patients resulting in hypoxemia and cyanosis.[17]

Histopathology

The degree of tricuspid leaflet failure of delamination can vary from mild failure of delamination to no delamination.[13] The surgical pathology of patients who underwent tricuspid valve replacement has shown that tricuspid leaflets in Ebstein anomaly are usually large, irregular shaped, thin, transparent, and have abnormal insertion points due to short chordal attachments or due to direct myocardial insertion.[18][13] The septal leaflet can often have a fibrous ridge, and the leaflets can have muscularized portions as well.[13][18]

There is also atypical Ebstein anomaly whereby the displacement of the septal and posterior leaflets is less than 8 mm/m^2; the anterior leaflet is typically normal, and there is less severe tricuspid annular dilation, no abnormalities of the subvalvular apparatus, and no "atrialization" of the right ventricle.[13]

Surgical pathological studies of mitral valves in patients with Ebstein anomaly have shown primary mitral valve defects in most patients involving the mitral orifice, leaflets, papillary muscles, and cords. About half of the mitral abnormalities were noted to have functional significance.[19]  

History and Physical

Ebstein anomaly presents across a broad spectrum and can have a variable age at presentation. Most cases present in infancy or childhood but a significant percentage of patients present in adulthood.[3] Ebstein malformation can be very hard to detect in utero using transvaginal ultrasound, unlike some other congenital heart defects. Although an abnormal heart to chest ratio and abnormal cardiac axis in the fetus could be indicators that could help make the diagnosis.[20] Fetal demise and perinatal mortality have been reported as 20% and 45%, respectively, with Ebstein anomaly.[21] The most common physical examination finding in neonates and infants is cyanosis, occurring in about 50% of neonates.[22] Although those children without cyanosis are also at high risk for perinatal mortality, in the presence of tricuspid regurgitation and right ventricular dysfunction, they may be more likely to survive early childhood.[23] 

In early childhood, symptoms of heart failure can also be prominent. There may be a prominent v wave in jugular venous pulsation due to severe tricuspid regurgitation (although this may be absent in torrential tricuspid regurgitation due to rapid equalization of pressures across the tricuspid valve).[24] There may be a loud first heart sound due to anterior leaflet closure, referred to as the "sail sound," and the first heart sound can also be split due to delayed tricuspid valve closure.[10] A holosystolic murmur of tricuspid regurgitation is another common physical examination finding in these patients. Multiple ejection clicks can be heard in the case of a very mobile anterior leaflet. [10][22] 

In adults, the most common presenting symptoms are palpitations and exertional dyspnea. Studies suggest that slightly over half of adult patients with Ebstein anomaly present with palpitations and arrhythmias are the first presenting clinical manifestation in almost 40% of newly diagnosed adults with Ebstein anomaly.[10][23] Symptoms of exertional dyspnea, chronic fatigue, and lower extremity edema are other clinical symptoms in patients who develop heart failure. Dyspnea can also occur as a result of right to left shunting, causing hypoxemia.[10] Rarely can patients present with a stroke, brain abscess, or Type 2 myocardial infarction due to paradoxical emboli across an intracardiac shunt.[10] Physical examination findings in adults include the murmur of tricuspid regurgitation. In severe cases in adults, hyperdynamic precordium and thrill at the left lower sternal border may be present. The second heart sound may be widely split in the presence of an atrial septal defect.[22]

Sudden cardiac death due to ventricular arrhythmias has also been reported, with an 8.6% 50-year cumulative incidence from birth.[25]

Evaluation

Electrocardiogram

Findings on electrocardiogram include:

1. Right bundle branch block
2. Delta waves due to pre-excitation from the accessory pathway
3. Tall P waves (p pulmonale) suggest right atrial enlargement
4. First degree AV block due to atrioventricular nodal conduction abnormalities
5. Supraventricular tachyarrhythmias, most commonly atrioventricular re-entrant tachycardia, but also include atrial fibrillation, atrial flutter, and atrial tachycardia[13][26]

Cardiothoracic Imaging

Chest Radiography usually shows cardiomegaly with right heart enlargement, giving the cardiac silhouette a globular appearance. There is also an increase in cardiothoracic ratio due to right atrial enlargement.[24] 

Echocardiography is the imaging study of choice to evaluate Ebstein anomaly. The first echocardiographic criteria to detect Ebstein anomaly is the apical displacement of the septal leaflet of the tricuspid valve greater than 8 mm/m^2 in the apical 4-chamber view. The mitral valve annulus is used to calculate the hinge point of the nondisplaced tricuspid septal leaflet. [27] Right ventricular enlargement and interventricular septal flattening due to right ventricular volume overload can also be seen. Tricuspid regurgitation can also be detected on Color Doppler ultrasound. Although echocardiography can help to determine the severity of tricuspid regurgitation, it may be challenging due to the absence of systolic flow reversal in the hepatic veins (due to equalization of pressures between the right atrium and right ventricle) and the inability to calculate vena contracta and proximal isovelocity surface area (due to the possibility of more than one color jet).[13][16] 

Assessment of the right ventricular size and function can also be difficult using traditional methods. Typically, only a qualitative evaluation based on left ventricular function and septal motion is used to evaluate the right ventricle. [16] Right ventricular strain can be used for the assessment of right ventricular function. Transesophageal echocardiography can aid in better visualizing the tricuspid leaflet anatomy and evaluating the Color Doppler jet. It can also be of great utility for surgical planning. Furthermore, transesophageal echocardiography is superior to transthoracic echocardiography in detecting intracardiac shunts.[16] 

Cardiac magnetic resonance imaging can also add valuable information in evaluating tricuspid leaflet anatomy and is superior to echocardiography in assessing right ventricular function. It can help to quantify right ventricular ejection fraction, which correlates well with right ventricular strain measurements.[28]

Cardiac computed tomography is another modality that can assess right ventricular ejection fraction and tricuspid valve anatomy in patients who cannot undergo cardiac magnetic resonance imaging. In addition, it can be used for periprocedural imaging of coronary anatomy prior to surgical intervention on the tricuspid valve.[13]

Treatment / Management

Medical Management

In infants, the mainstay of treatment is supportive to help reduce pulmonary vascular resistance and hypoxemia. In symptomatic infants with either heart failure or cyanosis, inhaled nitric oxide can help reduce pulmonary vascular resistance.[29] In cases of extreme cyanosis, prostaglandin E1 infusion can be used to keep the patent ductus arteriosus open and lower pulmonary vascular resistance by increasing pulmonary vasodilation.[30] Newborns with heart failure and cardiogenic shock may need to be treated with inotropes, of which Milrinone is the drug of choice since it also helps with pulmonary vasodilation. Catecholamines like epinephrine and norepinephrine are avoided as they carry a high risk of tachyarrhythmias in these patients.[30]

Heart failure symptoms are treated with loop diuretics and guideline-directed medical therapy. Children with atrial arrhythmias can be managed with rate control medications like beta-blockers. Infrequently, anti-arrhythmic drugs like amiodarone can also be used. However, most of these patients usually need definitive ablative therapy for supraventricular arrhythmias.[31] 

Surgical Management

Due to high periprocedural mortality, surgery is usually delayed till age four and avoided in newborns unless they meet specific indications. Indications for surgery in a neonate include [30]:

• Right heart failure due to severe tricuspid regurgitation
• A cardiothoracic ratio of greater than 80 percent
• Severe cyanosis

In children and adults, indications for surgery are:

• Heart failure symptoms
• Evidence of right ventricular dysfunction or progressive dilation
• Evidence of paradoxical emboli
• Intractable atrial arrhythmia
• Cyanosis
• Severe tricuspid regurgitation[32][30]

The preferred surgical therapy is tricuspid valve repair along with the closure of the atrial septal defect. For atrial arrhythmias in these patients, catheter ablation carries risks of paradoxical emboli, given the high incidence of intratrial shunts. As a result, the recommendation is to undergo a surgical bi-atrial Maze procedure while getting surgical repair of the tricuspid valve.[33] Multiple surgical approaches have been described for the treatment of Ebstein anomaly. The da Silva Cone procedure, which is the currently preferred surgical approach in young children and adults, consists of mobilizing the anterior and posterior leaflets from their anomalous attachments, rotating the detached edges of these leaflets clockwise, and suturing them to the septal edge of the anterior leaflet at the level of the tricuspid valve annulus.[34] 

The Danielson repair consists of repairing the tricuspid valve by plication of the atrialized portion of RV, narrowing the size of the tricuspid valve, and creating a monoleaflet tricuspid valve that is competent.[35] The Carpentier repair consists of plicating the atrialized portion of RV and narrowing the tricuspid valve annulus but in the direction at right angles from that performed by Danielson.[36]

Prophylactic Management

Infective endocarditis antibiotic prophylaxis is recommended for patients with Ebstein anomaly and cyanosis and following surgical repair with prosthetic cardiac valves; prior to dental procedures.[37]

Although some experts suggest using oral anticoagulation for patients with Ebstein anomaly and atrial fibrillation or evidence of paradoxical embolus, there is no data to support the benefit of the same in this population.[38]

Differential Diagnosis

Congenital tricuspid atresia - This can be differentiated from Ebstein anomaly by the absence of apical displacement of the septal and/or posterior leaflets, no annular dilation, presence of thickened leaflets with rolled edges as well as foreshortened and fused chordae, and no "atrialization" of the right ventricle.[13]  

Uhl's anomaly - Congenital absence of right ventricular myocardium that leads to right ventricular failure. It is frequently associated with pulmonary atresia, right ventricular aneurysms, and thrombus, not found in Ebstein anomaly. There is no apical displacement of the septal leaflet. The major similarity is the right ventricular and right atrial dilation in neonates, making it hard to distinguish from Ebstein anomaly.[39]

Other cyanotic congenital heart conditions whose presentation can mimic Ebstein anomaly include transposition of the great arteries, tetralogy of Fallot, pulmonary atresia, hypoplastic left heart syndrome, and total anomalous pulmonary venous return. Echocardiography can help distinguish these conditions.[40]

Prognosis

The main predictors of mortality are the severity of tricuspid displacement, tricuspid regurgitation severity, and duration and degree of right ventricular dysfunction.[41] Cyanosis and pericardial effusions also have a high risk of fetal and perinatal mortality in Ebstein anomaly.[21] Concomitant pulmonary regurgitation with Ebstein anomaly in newborns carries a poor prognosis since it leads to a circular shunt and low cardiac output state.[30] 

In unoperated patients, it is estimated that survival declines significantly on follow-up, with survival at 1-year follow-up being 86% and decreasing to 41% at 20- year follow-up.[42] In patients that undergo surgical repair, significant right heart dysfunction is an independent predictor of early post-surgical mortality.[14]

The Celermajer index is an established score calculated using echocardiography that predicts mortality.[43] It is measured as the ratio of the area of the right atrium and the atrialized right ventricle to the combined area of the functional right ventricle, left atrium, and left ventricle at end-diastole. The higher the grade, the higher the mortality.

• Grade 1 (ratio less than 0.5) has a mortality of 0%. 
• Grade 2 (ratio of 0.5 to 0.99) has a mortality of 10%. 
• Grade 3 (ratio of 1.0 to 1.49) has a mortality of 4%.
• Grade 4 ( ratio greater than  1.5) has a 100% mortality.

The SAS (Simpson Andrews Sharland) score is another prognostic score that uses as a weighted model to predict mortality. Cardiothoracic ratio, the Celermajer index, pulmonary valve flow, duct flow, and left-right ventricular ratio are graded 0,1,2 points each to generate a score. In studies, a score of 5 predicted 100% mortality, and a score of less than or equal to 3 predicted 91% survival.[44]

Complications

The most common complications as a result of Ebstein anomaly are[3]:

• Heart failure, initially right ventricular and later biventricular
• Intractable atrial arrhythmias
• Paradoxical emboli
• Sudden cardiac death due to ventricular arrhythmia

Deterrence and Patient Education

Ebstein anomaly is a rare congenital heart defect with no apparent cause. Mild forms are asymptomatic. It can present as early as in fetal life and as late as early adulthood. Disease severity varies across a broad spectrum depending on the degree of the malformation. Most patients will require definitive management in the form of surgical intervention. 

Enhancing Healthcare Team Outcomes

The majority of infants with Ebstein anomaly come to attention soon after birth. These infants need NICU monitoring, and hence, the ICU nurse must be familiar with the management of congenital heart disorders. While some infants have an isolated heart anomaly, others may also have involvement of other organ systems, and hence appropriate consultations are required. Once the diagnosis is made, surgery is usually required. Post-surgery, these children usually require close monitoring for an extended period until all the pacing wires and chest tubes have been removed and the child is breathing without the aid of a mechanical ventilator.[31] As a result, management of Ebstein anomaly requires robust interdisciplinary coordination between congenital heart disease specialists, cardiothoracic and pediatric surgeons, and intensivists.