Ebstein's anomaly of the tricuspid valve

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor-In-Chief: Cafer Zorkun, M.D., Ph.D. [2]}; Claudia P. Hochberg, M.D.; Maneesha Nandimandalam, M.B.B.S.[3] Priyamvada Singh, MBBS [4]

Ebstein’s anomaly is a congenital heart defect in which the opening of the tricuspid valve is displaced towards the apex of the right ventricle of the heart (congenital apical displacement of the tricuspid valve that typically causes significant tricuspid regurgitation).

Ebstein anomaly was named after Wilhelm Ebstein, who in 1866 first described it the heart of a 19 year old patient Joseph Prescher.

The pathophysiology of Ebstein’s anomaly depends on the morphology of tricuspid valve and the right ventricle. The annulus of the valve is in normal position. The valve leaflets however, are to a varying degree attached to the walls and septum of the right ventricle. There is subsequent atrialization of a portion of the morphologic right ventricle (which is then contiguous with the right atrium). This causes the right atrium to be large and the anatomic right ventricle to be small in size. 50% of cases involve an atrial shunt (either a PFO or an ASD). Mutations in MYH7, which a sarcomere gene encoding the cardiac beta-myosin heavy chain have been linked in the occurence of familial Ebstein anomaly. Commonly associated conditions include Aortic coarctation, Cleft anterior leaflet of the mitral valve, Coarctation of the aorta, corrected transposition of the great arteries, Hypoplastic pulmonary arteries, Left ventricular outflow obstruction etc.

Lithium ingestion in first trimester of pregnancy, Benzodiazepine use by the mother,varnishing substances exposure.

Disorders that Ebstein’s anomaly must be distinguished from include Accessory pathway-mediated WPW syndrome and SVT,Atrial septal defect (ASD), Cyanotic congenital heart diseases, Isolated, severe tricuspid regurgitation, L-transposition of the great vessels, Severe right heart failure with dilation of the anulus.

Ebstein’s anomaly is a rare congenital heart disease (observed in 5/100,000 newborns in the United States) with no gender predilection, but a higher incidence in Caucasians.

Administration of lithium carbonate or benzodiazepines during pregnancy is associated with a higher risk of Ebstein’s anomaly.

The symptoms of Ebstein’s anomaly vary in severity, with some patients experiencing either no symptoms or very mild symptoms and others experiencing symptoms that may worsen over time such as (cyanosis), heart failure, heart block, or other tachyarrhythmias or bradyarrhythmias. Paradoxical embolization, brain abscesses and pulmonary embolism may also occur.

The symptoms of Ebstein’s anomaly depend upon the degree of apical displacement of the tricuspid valve leaflet as well as the degree of dysfunction of the tricuspid valve. If the tricuspid valve is severely deformed, fetal hydrops may occur. If the valve is functioning, patients may remain symptom free for many years.

• Exertional dyspnea
• Failure to grow
• Fatigue and cyanosis
• Heart failure
• Murmur
• Palpitations may occur secondary to SVTs (supraventricular tachycardia) and WPW (Wolff-Parkinson-White syndrome).
• Paradoxical embolization may cause brain abscesses (right to left shunting due to interatrial communication)

Ebstein’s anomaly is characterized by tricuspid regurgitation and variable degrees a cyanosis depending upon the magnitude of right to left shunting. And elevation of the jugular venous pressure is often present.

The EKG is abnormal in 50 to 60% of patients, and will often show signs of right atrial enlargement, including “Himalayan” P waves which are P waves greater than 2.5 mm in height in leads 2, 3, and aVF. First-degree AV block, low QRS voltage, an atypical right bundle branch block, T wave inversions, and Wolff-Parkinson-White syndrome may also be present.

The chest x-ray in Ebstein’s anomaly of the tricuspid valve may demonstrate cardiomegaly, a dilated right atrium and a pruned pulmonary vasculature.

Computed tomography can be helpful as a diagnostic tool in conditions where the echocardiographic findings are inconclusive.

Magnetic resonance imaging can be helpful as a diagnostic tool in conditions where the echocardiographic findings are inconclusive.^[1]

Electrophysiologic testing may be done in Ebstein’s anomaly patients who have rhythm disturbances such as tachyarrhythmias, or Wolff-Parkinson-White syndrome. An electrophysiology study helps in identifying accessory pathways prior to an ablation procedure.

Medical management of patients with Ebstein’s anomaly consists of supportive care such as:

• Control of the heart rhythm with antiarrhythmic drugs
• Inotropic agents and diuretics for heart failure
• Anticoagulation in patients with atrial fibrillation and paradoxical embolization

Some Ebstein’s anomaly patients present with an (antidromic) AV nodal reentrant tachycardia with associated pre-excitation. Among these patients, the preferred pharmacological treatment agent is procainamide. Since AV-blockade may promote conduction over the accessory pathway, drugs such as beta blockers, calcium channel blockers and digoxin are contraindicated.

If there is atrial fibrillation with pre-excitation, treatment options include procainamide, flecainide, propafenone, dofetilide and ibutilide since these medications slow conduction in the accessory pathway causing the tachycardia and should be administered before considering electrical cardioversion. Intravenous amiodarone may also convert atrial fibrillation and/or slow the ventricular response.

Tricuspid valve repair is indicated in patients in which there is symptoms or deteriorating exercise capacity, cyanosis (oxygen saturation less than 90%), paradoxical embolism, progressive cardiomegaly on chest x-ray or progressive right ventricular dilation or reduction of right ventricular systolic function. When possible, repair is favored over replacement.

In so far as lithium and benzodiazepines have been associated with an increased risk of Ebstein’s anomaly, these drugs should be avoided if possible in the first trimester of pregnancy.

Class IIa

“1.Antibiotic prophylaxis before dental procedures that involve manipulation of gingival tissue or the periapical region of the teeth or perforation of the oral mucosa is reasonable in cyanotic patients with Ebstein’s anomaly and postoperative patients with a prosthetic cardiac valve. (Level of Evidence: C)”

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor-In-Chief: Cafer Zorkun, M.D., Ph.D. [2]; Claudia P. Hochberg, M.D.; Priyamvada Singh, MBBS [3]

Ebstein anomaly was named after Wilhelm Ebstein, who in 1866 first described it the heart of a 19 year old patient Joseph Prescher.

• In the year 1866, Dr. Ebstein published his first case report named, “A very rare case of tricuspid regurgitation caused by a congenital defect“.^[1][2][3]
• Later in year 1867, Hermann Lebert, a professor of medicine in Breslau, was probably the first to catalogue Ebstein’s seminal publication.
• It is only after 1927 that the term “Ebstein’s disease” appeared in the medical literature.
• Soloff and his colleagues in the yaer 1951 reported the case of ebstein anomaly in a patient using cardiac catheterization and angiocardiography.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor-In-Chief: Cafer Zorkun, M.D., Ph.D. [2]; Claudia P. Hochberg, M.D. [3];Priyamvada Singh, MBBS [4],Associate Editor(s)-in-Chief: Maneesha Nandimandalam, M.B.B.S.[5]

The pathophysiology of Ebstein’s anomaly depends on the morphology of tricuspid valve and the right ventricle. The annulus of the valve is in normal position. The valve leaflets however, are to a varying degree attached to the walls and septum of the right ventricle. There is subsequent atrialization of a portion of the morphologic right ventricle (which is then contiguous with the right atrium). This causes the right atrium to be large and the anatomic right ventricle to be small in size. 50% of cases involve an atrial shunt (either a PFO or an ASD). Mutations in MYH7, which a sarcomere gene encoding the cardiac beta-myosin heavy chain have been linked in the occurence of familial Ebstein anomaly. Commonly associated conditions include Aortic coarctation, Cleft anterior leaflet of the mitral valve, Coarctation of the aorta, corrected transposition of the great arteries, Hypoplastic pulmonary arteries, Left ventricular outflow obstruction etc.

• Pathophysiology mainly involves the right ventricle, right atrium and tricuspid valve.^[1][2][3][4]
• They include:

1. Failure of TV(tricuspid valve) leaflet delamination
2. Apical descent of the functional tricuspid orifice
3. Right ventricular dilation and “atrialization”
4. Anterior leaflet abnormal fenestrations and tethering
5. Right atrioventricular junction dilation

Source: National Library Of Medicine.

• The superficial layer of the right myocardium usually delaminates to form the septal and posterior leaflets of the tricuspid valve.
• Any Delamination failure might result in adherence of the leaflets to the ventricular myocardium as a result causes apical displacement of the tricuspid valve leaflets.
• The tricuspid valve orifice is in normal position.
• The anterior leaflet of the tricuspid valve is attached to the tricuspid valve annulus or to the right ventricular endocardium.
• The septal and posterior leaflets of the tricuspid valve are absent most of the time.
• Due to these changes, the tricuspid valve may become funnel-shaped and incompetent or leaky.

The right ventricle changes secondary to the malformed tricuspid valves. The right ventricle can be divided into two parts by the malformed valve:

• The downward extension of the tricuspid valve causes ‘atrialization’ of the proximal part of the right ventricle.
• The small distal part, the right ventricle proper, thus is reduced in size and sometimes comprises only of the right ventricular outflow tract.

• Till now the genetic basis for this condition is largely unknown or very little is known about this.^[5][6]
• Mutations in MYH7, which a sarcomere gene encoding the cardiac beta-myosin heavy chain have been linked in the occurence of familial Ebstein anomaly.
• It is formulated that embryonic cell migration may be impaired by these MYH7 mutations.
• Cardiac transcription factors NK2 homeobox 5 (NKX2-5) and GATA binding protein 4 (GATA4) mutations have also been described in some cases.

Commonly associated conditions include:^{[7][8][9][10]}

• 50% of patients have an ASD or patent foramen ovale.
• 25% have an accesory pathway such as Wolff-Parkinson-White syndrome.

Listed below are the other associated conditions:

• Aortic coarctation
• Cleft anterior leaflet of the mitral valve
• Coarctation of the aorta
• Corrected transposition of the great arteries
• Hypoplastic pulmonary arteries
• Left ventricular outflow obstruction
• Mitral valve prolapse
• Parachute mitral valve
• Partial atrioventricular canal
• Patent ductus arteriosus
• Pulmonary atresia with an intact ventricular septum
• Pulmonary stenosis
• Subaortic stenosis
• Tetralogy of Fallot
• Ventricular septal defect (VSD)
• Downs syndrome

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] and Claudia P. Hochberg, M.D. [2]

Associate Editor-In-Chief: Cafer Zorkun, M.D., Ph.D. [3]}; Keri Shafer, M.D. [4] Priyamvada Singh, MBBS [[5]] Assistant Editor-In-Chief: Kristin Feeney, B.S. [[6]]

The genetic or molecular mechanism causing Ebstein’s anomaly is largely unknown. However, the incidence is increased in infants born to mothers who have taken lithium during first trimester of pregnancy and those taking benzodiazepines.

• Lithium ingestion in first trimester of pregnancy.^[1][2]
• Benzodiazepine use by the mother.
• Varnishing substances exposure.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor-In-Chief: Cafer Zorkun, M.D., Ph.D. [2]; Claudia P. Hochberg, M.D. Maneesha Nandimandalam, M.B.B.S.[3]

Disorders that Ebstein’s anomaly must be distinguished from include:

• Accessory pathway-mediated WPW syndrome and SVT
• Atrial septal defect (ASD)
• Cyanotic congenital heart diseases
• Isolated, severe tricuspid regurgitation
• L-transposition of the great vessels
• Severe right heart failure with dilation of the anulus

Ebstein’s anomaly should be differentiated from other cynotic diseases and others^[1][2][3]

Disorders	Etiology	Clinical Presentation	Laboratory Findings	Electrocardiogram	Echocardiography
Tetralogy of Fallot	Multifactorial Genetic polymorphisms Maternal rubella Poor prenatal nutrition Maternal alcohol use Maternal diabetes	Cyanosis on exertion Exertional dyspnea Palpitations Fatigue	CBC: Anemia or polycythemia. Coagulation profile. Arterial blood gas: Low oxygen saturation and acidosis	Right ventricular hypertrophy Right bundle branch block Tachycardia Rate of QRS change predicts ventricular arrhythmia	Echocardiography may show: Residual VSD or ASD RV outflow tract obstruction Abnormal valvular anatomy
Total Anomalous Pulmonary Venous Connection	Multifactorial Genetic polymorphisms Maternal rubella Poor prenatal nutrition Maternal alcohol use Maternal diabetes	Tachypnea Palpitations Cyanosis Failure to thrive	Arterial blood gas: Low oxygen saturation and acidosis Coagulation profile.	Right ventricular hypertrophy with a qR pattern	Right ventricular hypertrophy Right ventricular loading Paradoxical septal motion
Tricuspid Atresia	Multifactorial Genetic polymorphisms Maternal rubella Poor prenatal nutrition Maternal alcohol use Maternal diabetes	Respiratory difficulties as nasal flaring or muscle retractions Cyanosis Growth retradation	Arterial blood gases CBC: Polycythemia Coagulation profile	Tall P waves indicate atrial enlargement. First-degree atrioventricular block. Frontal plane QRS axis may be leftward.	Echocardiography may show Defect size Pulmonary blood flow Ventricular function Valve abnormalities
Transposition of the Great Arteries	Multifactorial Genetic polymorphisms Poor prenatal nutrition Maternal alcohol use Maternal diabetes	Prominent cyanosis within hours of birth Congestive heart failure	Arterial blood gases: Hypoxemia Hyperoxia test	Right ventricular hypertrophy Right axis deviation Varying degrees of AV block Q waves	Echocardiography may show: Relationship between great vessels Associated anatomic lesions Coronary artery origin and branches

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor-In-Chief: Cafer Zorkun, M.D., Ph.D. [2]; Claudia P. Hochberg, M.D.

The development of Ebstein’s anomaly is associated with the administration of Lithium Carbonate during the first trimester or benzodiazepines during pregnancy. Maternal exposure to varnishing substances is also a risk factor as is a previous history of fetal loss in the mother.

• Lithium exposure during pregnancy.^[1][2][3]
• Benzodiazepine use.
• Second-hand cigarette smoke exposure at home.
• Family history of congenital heart defect(CHD).

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