**4. Anatomy of tricuspid valve**

Normally, the TV has three valvar leaflets referred to as the anterosuperior, the septal and the mural leaflets. However, in EA, the anterosuperior is the largest, redundant anterior leaflet, which contains fenestrations. It stretches from the infundibulum anteriorly to the inferolateral wall posteriorly, whereas the septal leaflet, the smallest, arises medially from the annulus above the interventricular septum. Mural or posterior leaflet attaches along the posterior margin of the tricuspid annulus from the septum to the inferolateral wall [10]. The leaflets of TV develop equally from the endocardial cushion tissues and the myocardium [10]. EA is a myopathy of the RV with abnormalities in both myocardial structure and function, besides the characteristic valvar deformities [9, 11]. Embryonic failure of delamination of the septal, inferior and anterior leaflets of the TV results in the apical displacement of the tricuspid leaflets to the underlying RV myocardium. Such failure in delamination creates the characteristic downward (apical) displacement of the functional orifice and dilation of the atrialized right ventricle (aRV), with various degrees of hypertrophy and thinning of the wall. This malformation is characterized by the displacement of the points of attachment, or the hinges, of the septal and mural leaflets into the right ventricle, away from the atrioventricular junction. As the anterosuperior leaflet has a different developmental origin, its junctional hinge usually retains a normal position [8, 13, 14].

The failure in delamination also results in various degrees of displacement of TV leaflets, and the movement of the tricuspid hinge points both anteriorly and toward the right ventricular apex. The adherent portions of the valvar leaflets usually have little or no motion. This generally leads to tricuspid regurgitation or rarely to stenosis. [10–13]. Chordae tendinea of anterior leaflets are generally short, tethered, poorly formed and severely deformed. Therefore, the only mobile leaflet tissue is displaced into the right ventricular outflow tract (RVOT), where it may cause obstruction or forms a large sail-like intracavitary curtain. The septal and mural leaflets are usually rudimentary, dysplastic or may be absent due to failure of delamination. These leaflets may be freely mobile or adhered (tethered) to the endocardium [9, 13].

The maximal displacement is at the commissure level between the mural and septal leaflets of the TV [14]. Apical displacement of the septal leaflet by at least 8 mm/m<sup>2</sup> of body surface area is considered as a diagnostic feature of EA in the echocardiographic evaluation [12]. The spectrum of the malformation in EA may range from a minimal displacement of the septal and mural leaflets to an imperforate membrane or muscular shelf between the inlet and trabecular zones of the right ventricle. There is often a marked dilatation of the true TV annulus, and the aRV separating this true annulus from the functional right ventricle (fRV) [6, 12].

#### **4.1. Atrium and atrioventricular sulcus**

The right atrium is usually very dilated, and the right atrioventricular junction, or true annulus of the TV, is enlarged circumferentially. The valve of the inferior vena cava (eustachian valve) is often very prominent.

#### **4.2. Coronary arteries**

symptomless throughout life. There is a genetic heterogeneity; most of the cases are sporadic, familial ones are rare. Asymptomatic patients with EA can be conservatively treated and kept under close follow-up, whereas surgical operation is indicated for those with the evidence of right heart dilation and progressively impaired ventricular systolic function. A biventricular repair is suitable for most of the patients. While 1.5-ventricular repair (bidirectional Glenn shunt) is indicated for the patients with poor right ventricular function, heart transplantation

This anomaly was first described by Wilhelm Ebstein, a German physician, in a report titled "Concerning a very rare case of insufficiency of the tricuspid valve caused by a congenital malformation" [1, 2]. Ebstein's own description of the malformation in 1866, with illustrations by Dr. Weiss, was based upon the anatomical findings related to the heart of Joseph Prescher, a 19-year-old cyanotic laborer with dyspnea, palpitations, jugular venous distension, and cardiomegaly [1, 2]. Ebstein described an enlarged and fenestrated anterior leaflet of the tricuspid valve in the findings of the autopsy. The posterior and septal leaflets were hypoplastic, thickened, and adherent to the right ventricle. There was also a thinned and dilated atrialized portion of the right ventricle, an enlarged right atrium, and a patent foramen ovale [3, 4]. The first case described in the English literature was not published until 1900 years [5–7]. In the

EA occurs in about 1/200.000 live births. It accounts for no more than 0.3–0.5% of congenital

Normally, the TV has three valvar leaflets referred to as the anterosuperior, the septal and the mural leaflets. However, in EA, the anterosuperior is the largest, redundant anterior leaflet, which contains fenestrations. It stretches from the infundibulum anteriorly to the inferolateral wall posteriorly, whereas the septal leaflet, the smallest, arises medially from the annulus above the interventricular septum. Mural or posterior leaflet attaches along the posterior margin of the tricuspid annulus from the septum to the inferolateral wall [10]. The leaflets of TV develop equally from the endocardial cushion tissues and the myocardium [10]. EA is a myopathy of the RV with abnormalities in both myocardial structure and function, besides the characteristic valvar deformities [9, 11]. Embryonic failure of delamination of the septal, inferior and anterior leaflets of the TV results in the apical displacement of the tricuspid leaflets to the underlying RV myocardium. Such failure in delamination creates the characteristic downward (apical) displacement of the functional orifice and dilation of the atrialized right ventricle (aRV), with

is suggested for the patients with severe left ventricular dysfunction.

1950s, successful surgical palliation was achieved.

**4. Anatomy of tricuspid valve**

heart disease [8, 9]. The male–female incidence is equal [9].

**2. History**

134 Structural Insufficiency Anomalies in Cardiac Valves

**3. Prevalence**

In the usual form of Ebstein's anomaly, the coronary arteries are normal except the right coronary artery (RCA). It may be displaced superiorly and posteriorly because of an aneurysmatic dilatation of aRV. Therefore, the surgeon should carefully follow the course of the RCA during the operation. It demarcates the level of the true annulus and may become kinked during plication annuloplasty procedures or TV replacement [12].

#### **4.3. Right ventricle**

Because of the displaced TV, the RV is divided into two regions in Ebstein's anomaly: the inlet portion [atrialized right ventricle (aRV)] and the trabecular or outlet portion [functional ventricle (fRV)]. The inlet portion, directly involved with the malformation, is functionally integrated with the right atrium, whereas the outlet portion constitutes the functional RV. The aRV usually has a thinner wall than the fRV and may account for more than half of the RV volume in extreme cases, instead of its usual location in one-third of the RV [8, 9]. There is often a marked dilatation of the true TV annulus and a large chamber separating this annulus from the functional RV. Two-thirds of EA cases possess dilated RV, which commonly involve the functional RV apex and outflow tract. In some cases, RV dilatation is so significant that the ventricular septum bulges leftward, compressing the left ventricular (LV) chamber, and may cause episodic left ventricular outflow tract (LVOT) obstruction [8]. In such cases, the shortaxis view demonstrates a circular right ventricle and a crescentic left ventricle.

#### **4.4. Conduction tissue**

EA cases have specialized conduction tissues [9, 14]. The sinoatrial node appears to be normally positioned, but various abnormalities of the right bundle branch have been reported. It may be located superficially in the subendocardium of the atrialized ventricle and encased in fibroelastic tissue. Arrhythmias such as accessory conduction pathways (Wolff-Parkinson-White (WPW) syndrome), atrial fibrillation or flutter are common. They occur with increasing frequency with advancing age [15]. Patients who have accessory conduction pathways are diagnosed and treated by catheter ablation technique with high succession rates.

important when considering repair versus replacement of the TV [10]. In 1988, according to the classification of Carpentier, EA was divided into four types. Type A: The volume of the true RV is adequate. Type B: Large atrialized component of the RV exists, but the anterior leaflet of the TV moves freely. Type C: The anterior leaflet is severely restricted in its movement and may cause significant obstructions of the RVOT. Type D: Almost complete atrialization of

100 (cyanotic)

Ebstein's Anomaly

137

http://dx.doi.org/10.5772/intechopen.78067

The Celermajer classification [28] of EA was according to echocardiographic measurements calculating the ratio of the combined area of the right atrium and aRV to that of the fRV and the left heart in a four-chamber view at the end diastole (GOSE = RA + aRV/fRV + LV + LA). There is an echocardiographic grading score for neonates with Ebstein's anomaly, The Great Ormond Street Echocardiography (GOSE) score, with grades 1 to 4. Increasing severity, that is, a higher grade, was associated with a high mortality rate. This classification is particularly helpful with neonatal Ebstein's anomaly [28]. The Great Ormond Street Echocardiography

No specific cause has been consistently associated with EA. Based on retrospective case reporting, treatment with lithium during the first trimester of pregnancy was thought to be strongly associated, a 400-fold relative risk, with the occurrence of EA in the fetus. However, recent cohort and case–control epidemiologic studies have not confirmed these initial findings.

There are heterogeneous genetic factors in EA. Most cases are sporadic; familial ones are rare. Duplication of 15q affects the early morphogenesis of cardiac structures, including the normal formation of TV. Therefore, the gene located on the long arm (q) of chromosome 15 is likely to be involved in the development of EA [29, 30]. Distinct rearrangements of the chromosomal region 11q arm and deletion of 10p13–p14 and 1p34.3–p36.11 have also been described in association with EA. Genetic bases of this anomalies may be associated with the mutations in the genes MYH7 and NKX2.5 and among others [31–38]. Moreover, heterozygous mutations of NKX2.5 have been identified in the EA cases accompanied by atrioventricular (AV) block, atrial septal defect (ASD), ventricular septal defect (VSD), tetralogy of Fallot or double-outlet

the ventricle except for a small infundibular component [27].

**GOSE score Ratio Mortality rate (%)**

Grade 3 1–1.49 45 (acyanotic)

**Table 1.** The Great Ormond Street Echocardiography (GOSE) score and mortality rate are seen.

Grade 1 <0.5 5–8 Grade 2 0.5–0.99 8–10

Grade 4 >1.5 100

(GOSE) score and mortality rate are demonstrated in the **Table 1**.

**6. Causation and genetics**

RV, and other TV abnormalities [39].

### **4.5. Left ventricle**

Histology of the left LV in patients with EA has shown variable degrees of fibrosis, hypertrophy, and nonspecific dysplasia [14]. LV dysfunction leads to abnormal leftward bowing of the ventricular septum and mitral valve prolapse. Regional dysfunction of LV may also develop secondary to RV dilatation.

#### **4.6. Associated cardiac defects**

The most commonly associated cardiac defects are atrial septal defect and patent foramen ovale, present in 80–94% of EA patients [16]. Other associated anomalies include bicuspid or atretic aortic valves, pulmonary atresia or hypoplastic pulmonary artery, subaortic stenosis, coarctation, mitral valve prolapse, accessory mitral valve tissue or muscle bands of the left ventricle, ventricular septal defects (VSD), and pulmonary stenosis [17]. Abnormalities of LV morphology and function, as well as other left-sided heart lesions, may also occur in EA [9, 10, 16–23]. Most patients with congenitally corrected transposition of the great arteries have an abnormal systemic TV, which fulfills the criteria for EA in 15–50% of cases. It is unclear whether the fundamental nature of the anomaly is identical in concordant and discordant atrioventricular connections [24–26]. The morphological RV is rarely dilated in congenitally corrected transposition.

### **5. Classifications**

There are two approaches in the description of the anatomic severity of EA. The first approach is based on the echocardiographic appearance. The abnormality is described anatomically as mild, moderate, or severe. The amount of displacement and tethering of the leaflets and the degree of RV dilatation are assessed. This classification is imprecise but simple. The second approach is to describe the exact anatomy of each of the involved cardiac structures as visualized at operation. This nomenclature system emphasizes the characteristics that surgeons find


**Table 1.** The Great Ormond Street Echocardiography (GOSE) score and mortality rate are seen.

important when considering repair versus replacement of the TV [10]. In 1988, according to the classification of Carpentier, EA was divided into four types. Type A: The volume of the true RV is adequate. Type B: Large atrialized component of the RV exists, but the anterior leaflet of the TV moves freely. Type C: The anterior leaflet is severely restricted in its movement and may cause significant obstructions of the RVOT. Type D: Almost complete atrialization of the ventricle except for a small infundibular component [27].

The Celermajer classification [28] of EA was according to echocardiographic measurements calculating the ratio of the combined area of the right atrium and aRV to that of the fRV and the left heart in a four-chamber view at the end diastole (GOSE = RA + aRV/fRV + LV + LA). There is an echocardiographic grading score for neonates with Ebstein's anomaly, The Great Ormond Street Echocardiography (GOSE) score, with grades 1 to 4. Increasing severity, that is, a higher grade, was associated with a high mortality rate. This classification is particularly helpful with neonatal Ebstein's anomaly [28]. The Great Ormond Street Echocardiography (GOSE) score and mortality rate are demonstrated in the **Table 1**.

### **6. Causation and genetics**

the functional RV apex and outflow tract. In some cases, RV dilatation is so significant that the ventricular septum bulges leftward, compressing the left ventricular (LV) chamber, and may cause episodic left ventricular outflow tract (LVOT) obstruction [8]. In such cases, the short-

EA cases have specialized conduction tissues [9, 14]. The sinoatrial node appears to be normally positioned, but various abnormalities of the right bundle branch have been reported. It may be located superficially in the subendocardium of the atrialized ventricle and encased in fibroelastic tissue. Arrhythmias such as accessory conduction pathways (Wolff-Parkinson-White (WPW) syndrome), atrial fibrillation or flutter are common. They occur with increasing frequency with advancing age [15]. Patients who have accessory conduction pathways are

Histology of the left LV in patients with EA has shown variable degrees of fibrosis, hypertrophy, and nonspecific dysplasia [14]. LV dysfunction leads to abnormal leftward bowing of the ventricular septum and mitral valve prolapse. Regional dysfunction of LV may also develop

The most commonly associated cardiac defects are atrial septal defect and patent foramen ovale, present in 80–94% of EA patients [16]. Other associated anomalies include bicuspid or atretic aortic valves, pulmonary atresia or hypoplastic pulmonary artery, subaortic stenosis, coarctation, mitral valve prolapse, accessory mitral valve tissue or muscle bands of the left ventricle, ventricular septal defects (VSD), and pulmonary stenosis [17]. Abnormalities of LV morphology and function, as well as other left-sided heart lesions, may also occur in EA [9, 10, 16–23]. Most patients with congenitally corrected transposition of the great arteries have an abnormal systemic TV, which fulfills the criteria for EA in 15–50% of cases. It is unclear whether the fundamental nature of the anomaly is identical in concordant and discordant atrioventricular connections [24–26]. The morphological RV is rarely dilated in

There are two approaches in the description of the anatomic severity of EA. The first approach is based on the echocardiographic appearance. The abnormality is described anatomically as mild, moderate, or severe. The amount of displacement and tethering of the leaflets and the degree of RV dilatation are assessed. This classification is imprecise but simple. The second approach is to describe the exact anatomy of each of the involved cardiac structures as visualized at operation. This nomenclature system emphasizes the characteristics that surgeons find

axis view demonstrates a circular right ventricle and a crescentic left ventricle.

diagnosed and treated by catheter ablation technique with high succession rates.

**4.4. Conduction tissue**

136 Structural Insufficiency Anomalies in Cardiac Valves

**4.5. Left ventricle**

secondary to RV dilatation.

**4.6. Associated cardiac defects**

congenitally corrected transposition.

**5. Classifications**

No specific cause has been consistently associated with EA. Based on retrospective case reporting, treatment with lithium during the first trimester of pregnancy was thought to be strongly associated, a 400-fold relative risk, with the occurrence of EA in the fetus. However, recent cohort and case–control epidemiologic studies have not confirmed these initial findings.

There are heterogeneous genetic factors in EA. Most cases are sporadic; familial ones are rare. Duplication of 15q affects the early morphogenesis of cardiac structures, including the normal formation of TV. Therefore, the gene located on the long arm (q) of chromosome 15 is likely to be involved in the development of EA [29, 30]. Distinct rearrangements of the chromosomal region 11q arm and deletion of 10p13–p14 and 1p34.3–p36.11 have also been described in association with EA. Genetic bases of this anomalies may be associated with the mutations in the genes MYH7 and NKX2.5 and among others [31–38]. Moreover, heterozygous mutations of NKX2.5 have been identified in the EA cases accompanied by atrioventricular (AV) block, atrial septal defect (ASD), ventricular septal defect (VSD), tetralogy of Fallot or double-outlet RV, and other TV abnormalities [39].
