Human Genetics of Ebstein Anomaly.

Ebstein anomaly (EA) is a rare, congenital cardiac defect of the tricuspid valve with a birth prevalence between 0.5 and 1 in 20,000 [1]. It is characterized by displacement of the tricuspid valve toward the apex of the right ventricle (RV) and "atrialization" of the RV (Fig. 57.1) [2]. EA accounts for about 0.5% of all congenital heart diseases (CHD) [2]. Depending on severity of the defect and due to heterogeneity of the disease, patient's presentation varies from severe heart failure symptoms and arrhythmia in neonatal life to asymptomatic adults.

Clinical Presentation and Therapy of Ebstein Anomaly.

Ebstein anomaly is a rare congenital heart defect, accounting for less than 1% of cardiac malformations and occurring in approximately 1 out of 210,000 live births. It is characterized by an abnormality of the tricuspid valve, where the valve is positioned lower than normal in the right ventricle. Although primarily a tricuspid valve defect, the right ventricle itself is often structurally abnormal and weakened (myopathic).

Molecular Pathways and Animal Models of Ebstein's Anomaly.

Ebstein's anomaly is a congenital malformation of the tricuspid valve characterized by abnormal attachment of the valve leaflets, resulting in varying degrees of valve dysfunction. The anatomic hallmarks of this entity are the downward displacement of the attachment of the septal and posterior leaflets of the tricuspid valve. Additional intracardiac malformations are common. From an embryological point of view, the cavity of the future right atrium does not have a direct orifice connected to the developing right ventricle. This chapter provides an overview of current insight into how this connection is formed and how malformations of the tricuspid valve arise from dysregulation of molecular and morphological events involved in this process. Furthermore, mouse models that show features of Ebstein's anomaly and the naturally occurring model of canine tricuspid valve malformation are described and compared to the human model. Although Ebstein's anomaly remains one of the least understood cardiac malformations to date, the studies summarized here provide, in aggregate, evidence for monogenic and oligogenic factors driving pathogenesis.

Tricuspid atresia with atrial and ventricular septal defects in a kitten.

A 45-days-old mixed-breed female cat was referred to a veterinary specialty hospital for evaluation due to poor general condition, dyspnea of possible cardiac origin, and a heart murmur. The results of the physical examination, thoracic radiography, and echocardiography led to a diagnosis of hypotrophy of the right ventricle, tricuspid atresia, and atrial septal defect. Cardiovascular pathological findings confirmed the clinical diagnosis in addition to the observation of a ventricular septal defect. To the authors' knowledge, this is the first report of tricuspid atresia with atrial septal defect and ventricular septal defect in a cat.

Biventricular repair in an infant with transposition of the great arteries and straddling of the tricuspid valve.

Biventricular repair is challenging in patients with transposition of the great arteries and straddling of the atrioventricular valves. Biventricular repair is the preferred option because of its anatomical and physiological advantages. However, in cases where biventricular repair carries operative risks that are too high or cases with unsuitable intracardiac anatomy, univentricular heart repair may have to be chosen. We report a five-month-old male patient with transposition of the great arteries, an inlet ventricular septal defect and anomalous coronary anatomy who had previously undergone a pulmonary banding operation and balloon atrial septostomy. Successful biventricular repair was performed while the patient had straddling of the tricuspid valve.

Sequential percutaneous tricuspid and pulmonary valve implantation in a young child operated previously for Ebstein Anomaly.

We report a successful percutaneous tricuspid valve implantation followed by a percutaneous pulmonary valve implantation in a young child with Ebstein's anomaly of tricuspid valve and pulmonary stenosis who was previously treated surgically at 1 year of age with tricuspid ring annuloplasty and a transannular outflow patch. This article shows the feasibility of sequential implantation of two valves in young patients with severe tricuspid and pulmonary valve insufficiency.

Tricuspid valve repair with papillary muscle approximation for congenital tricuspid valve regurgitation due to tricuspid valve dysplasia.

We experienced a case of a 1-year-old female with congenital tricuspid valve regurgitation caused by tricuspid valve dysplasia. The anterior and septal leaflets were particularly dysplastic, and leaflet tethering was observed. The anterior papillary muscle was approximated to the interventricular septum, and a commissural edge-to-edge suture was inserted on the anteroseptal commissure. Tricuspid valve regurgitation improved to be trivial after surgery and has not worsened 1 year later. Papillary muscle approximation could be one of the feasible reparative techniques for congenital tricuspid valve regurgitation.

An Unguarded Tricuspid Valve Orifice Diagnosed by Autopsy.

Introduction: Fetal unguarded tricuspid valve orifice (UTVO) is characterized by a complete or partial absence of the tricuspid valvular tissue or sub-valvular apparatus and only case reports are available at present. We report a UTVO diagnosed by fetal autopsy. Case report: An 18-week fetus was diagnosed by prenatal ultrasound with tricuspid dysplasia with 'to-and-fro' flow across the right-sided heart. Fetal autopsy showed partial agenesis of tricuspid valve instead of valvular dysplasia. This supported a diagnosis of UTVO. Conclusion: Fetal autopsy can differentiate UTVO form other valve abnormalities. The 'to-and-fro' flow pattern across the right atrioventricular orifice could be used to differentiate UTVO from other valve dysplasias on echocardiography.

Differential requirement for DICER1 activity during the development of mitral and tricuspid valves.

Mitral and tricuspid valves are essential for unidirectional blood flow in the heart. They are derived from similar cell sources, and yet congenital dysplasia affecting both valves is clinically rare, suggesting the presence of differential regulatory mechanisms underlying their development. Here, we specifically inactivated Dicer1 in the endocardium during cardiogenesis and found that Dicer1 deletion caused congenital mitral valve stenosis and regurgitation, whereas it had no impact on other valves. We showed that hyperplastic mitral valves were caused by abnormal condensation and extracellular matrix (ECM) remodeling. Our single-cell RNA sequencing analysis revealed impaired maturation of mesenchymal cells and abnormal expression of ECM genes in mutant mitral valves. Furthermore, expression of a set of miRNAs that target ECM genes was significantly lower in tricuspid valves compared to mitral valves, consistent with the idea that the miRNAs are differentially required for mitral and tricuspid valve development. We thus reveal miRNA-mediated gene regulation as a novel molecular mechanism that differentially regulates mitral and tricuspid valve development, thereby enhancing our understanding of the non-association of inborn mitral and tricuspid dysplasia observed clinically.

Acute Liver Failure due to Altered Fontan Circulation in a Patient With Tricuspid Atresia: A Case Report.

Tricuspid atresia is a congenital malformation of the tricuspid valve resulting in a lack of blood flow between the right atrium and the right ventricle. Management generally involves staged surgical intervention enabling affected individuals to survive into adulthood. Although surgical intervention greatly improves morbidity and mortality in this patient population, there are many long-term complications associated with the creation of a surgical shunt. We report a case of a 33-year-old male with tricuspid atresia who underwent Fontan surgery as a child and presented to our hospital with acute liver failure.

Transposition physiology in the setting of concordant ventriculo-arterial connections.

BACKGROUND AND AIM: To review the anatomical details, diagnostic challenges, associated cardiovascular anomalies, and techniques and outcomes of management, including re-interventions, for the rare instances of transposition physiology with concordant ventriculo-arterial connections. METHODS: We reviewed clinical and necropsy studies on diagnosis and surgical treatment of individuals with transposition physiology and concordant ventriculo-arterial connections, analyzing also individuals with comparable flow patterns in the setting of isomerism. RESULTS: Among reported cases, just over two-thirds were diagnosed during surgery, after initial palliation, or after necropsy. Of the patients, four-fifths presented in infancy with either cyanosis or congestive cardiac failure, with complex associated cardiac malformations. Nearly half had ventricular septal defects, and one-fifth had abnormalities of the tricuspid valve, including hypoplasia of the morphologically right ventricle. A small minority had common atrioventricular junctions We included cases reported with isomerism when the flow patterns were comparable, although the atrioventricular connections are mixed in this setting. Management mostly involved construction of intraatrial baffles, along with correction of coexisting anomalies, either together or multistaged. Overall mortality was 25%, with one-fifth of patients requiring pacemakers for surgically-induced heart block. The majority of survivors were in good functional state. CONCLUSIONS: The flow patterns produced by discordant atrioventricular and concordant ventriculo-arterial connections remain an important, albeit rare, indication for atrial redirection or hemi-Mustard's procedure with bidirectional Glenn. The procedure recruits the morphologically left ventricle in the systemic circuit, producing good long-term functional results. The approach can also be used for those with isomeric atrial appendages and comparable hemodynamic circuits.

Surgical treatment of tricuspid valve dysplasia in children.

OBJECTIVES: Congenital tricuspid valve dysplasia (TVD) is a rare cardiac disease, often discussed in the same way as Ebstein's anomaly. Though the morphology of TVD is different, the clinical appearance is similar. The indication for surgical treatment depends on the morphology of the tricuspid valve (TV) and the clinical presentation. METHODS: We reviewed all patients below 18 years of age who underwent TV repair between 2005 and 2019 and identified 9 with a TVD. The diagnosis was verified with the operative notes and patients were excluded if the septal leaflet was displaced as in Ebstein's anomaly. The aim of the study was to describe the morphology of the TV and analyse the surgical possibilities and their results. RESULTS: The median age at surgery was 2.3 years (5 days to 14 years), 3 patients were neonates with a duct-dependent pulmonary circulation. Morphology of the TV showed a tethering of at least 1 leaflet in all patients, a restrictive septal leaflet in 8, a large anterior leaflet in 7 and a small posterior leaflet in 4. Surgical techniques included an annuloplasty in 7 patients, a leaflet procedure in 6 patients, an edge-to-edge stitch in 5 patients and a primary Starnes procedure in 1 neonate. During a median follow-up time of 2.8 years (5 months to 15 years), 1 valve replacement and 1 conversion to univentricular palliation were necessary. CONCLUSIONS: Unequal leaflet size and tethering are the most common features of TVD. A variety of surgical techniques is available to achieve good results beyond the neonatal period.

New trend: Surgical correction of Ebstein's anomaly using modified cone repair and a combination of different techniques.

BACKGROUND: Ebstein's anomaly,a rare cardiac disease that accounts for <1% of all congenital heart diseases, is a right ventricular myopathy with varying degrees of delamination in the endocardium under the tricuspid valve. Cone reconstruction, first described by da Silva in 2004, is a modification of the Carpentier technique. An alternative surgical treatment for Ebstein's anomaly, it is now the preferred surgical corrective technique. AIMS: This study demonstrates that our modifications of the cone repair procedure to correct Ebstein's anomaly improve valve coaptation and stabilization in the early and midterm. MATERIALS AND METHODS: Of the 134 patients diagnosed with Ebstein's anomaly in our clinic between January 2012 and October 2020, 10 underwent a cone procedure and its modifications and were thus included in the study. The mean age of these patients was 28.6 ± 18.79 years and ranged from 1 to 61 years. Thirty percent of the patients were male and 70% were female. RESULTS: The additional procedures performed were an isolated cone procedure (two patients), anomalous pulmonary venous return repair in addition to a cone procedure (one patient), single-vessel coronary artery bypass (one patient), Glenn procedure (two patients), and tricuspid ring annuloplasty (four patients). CONCLUSION: Based on the results of this study, which assesses the outcomes of patients who underwent cone repairs with surgical modifications, we argue that right ventricular oblique plication, tricuspid valve delamination, surgical valve rotation, and tricuspid ring annuloplasty protect valve coaptation and function in the early and midterm, thereby having beneficial effects on right ventricle remodeling.

Impact of fetal haemodynamics on surgical and neurodevelopmental outcomes in patients with Ebstein anomaly and tricuspid valve dysplasia.

OBJECTIVES: To evaluate the impact of fetal haemodynamics on surgical and neurodevelopmental outcomes in severe Ebstein anomaly and tricuspid valve dysplasia. METHODS: Thirty-four fetuses with Ebstein anomaly/tricuspid valve dysplasia were referred from 2013 to 2019 for fetal echocardiography and clinical management. Nineteen fetuses with Ebstein anomaly/tricuspid valve dysplasia and 30 controls underwent cardiovascular magnetic resonance to quantify the fetal blood flow and to calculate cerebral oxygen delivery (cDO2) and consumption (cVO2). The 3D steady-state free precession acquisition was used to measure fetal brain volume. Surgical outcome, brain MRI, and neurodevelopmental follow-up were reviewed. RESULTS: Twenty-six fetuses were live born (76%) and survival (65%) at a mean follow-up of 4 years. Nine fetuses had a brain MRI before discharge, and all had clinically silent injuries and volume loss. At 18 months, five single-ventricle patients had a neurodevelopmental delay in cognition and language (mean percentile: 11th), with gross-motor skills more affected than fine-motor skills (mean percentiles: 4th and 34th). Fetuses with Ebstein anomaly/tricuspid valve dysplasia had smaller brains, lower combined ventricular output, ascending aorta, superior caval vien and umbilical vein flows, lower oxygen saturation in ascending aorta and superior caval vien, lower cDO2 and cVO2 (p < 0.05). Superior caval vien/combined ventricular output and descending aorta/combined ventricular output ratios were lower in fetuses with circular shunt (p < 0.05). Fetuses requiring the Starnes procedure tended to have smaller brains, lower combined ventricular output, superior caval vien, descending aorta, and umbilical vein flows. CONCLUSIONS: All patients with Ebstein anomaly/tricuspid valve dysplasia are at high risk of neurodevelopmental delay and warrant follow-up. Fetal cardiovascular magnetic resonance revealed impaired brain growth with diminished cerebral blood flow and cDO2, the extenting dependent on the severity of the haemodynamic compromise.

A case of double-chambered right ventricle due to cap-like fibrous tissue and aberrant chordal insertion of tricuspid valve in adult.

BACKGROUND: A double-chambered right ventricle is a rare congenital heart disease where an anomalous structure divides the right ventricle into two cavities. CASE: A 78-year-old man with dyspnea was referred to our institution for a double-chambered right ventricle (DCRV) and ventricular septal defect (VSD). Echocardiography showed normal left ventricular function, right ventricular hypertrophy, and mild tricuspid regurgitation. On parasternal short-axis views, color-flow Doppler studies showed a mosaic pattern through the stenotic right ventricular outflow tract (RVOT). Cardiac catheterization showed a 122 mmHg pressure gradient between the high-pressure chamber and the low-pressure chamber of the RVOT. Computed tomography showed a cap-like structure consisting of fibrous tissue, with moderate stenosis, which divided the right ventricle into two cavities. The aberrant tendinous chords supporting the anterior leaflet of the tricuspid valve were found inserted into the anterior wall of the RV (Figure 1). Resection of the cap-like fibrous tissue and abnormal muscle (Figure 2), detachment of aberrant tendinous chords of the tricuspid valve, closure of VSD by direct suture, and tricuspid valve plasty (TVP) were performed. TVP was achieved using an artificial chordae replacement with expanded polytetrafluoroethylene (CV-5) suture and a 32-mm Physio Tricuspid annuloplasty ring (Edwards Lifeline). Postoperative echocardiography revealed no RVOT pressure gradient and a normal right ventricular pressure of 21 mmHg. DISCUSSION: In conclusion, we report a rare case of DCRV secondary to a cap-like structure fibrous tissue with anomalous chordal insertion of a tricuspid valve leaflet.

Congenital Tricuspid Valve Calcification Necessitating Neonatal Surgical Intervention.

We report a case of isolated idiopathic congenital tricuspid valve calcification that necessitated urgent neonatal surgical intervention. Hemodynamic analysis revealed circular shunt caused by severe tricuspid regurgitation, pulmonary regurgitation, and a hypoplastic right ventricle. The patient successfully underwent tricuspid valve repair at postnatal day 10. Although intervention for neonatal tricuspid valve is challenging, hemodynamic evaluation and early surgical intervention are necessary in patients with this rare cardiac calcification.

The Association of Age and Repair Modification with Outcome after Cone Repair for Ebstein's Malformation.

Cone repair (CR) uses native tissue for tricuspid valve (TV) repair and provides potential for growth. Results after CR were investigated in different age groups including several surgical modifications. Single institution retrospective analysis of all CR excluding neonatal procedures. Endpoints included TV reoperation, late tricuspid regurgitation (TR) and death. Between April 2006 and August 2019, 157 patients underwent CR at a median age of 11.7 years (range, 0.3-57.2). 20% (n=32) of patients had previous surgery. Repair modifications included atrial reduction (n=111,71%), right ventricular plication (n=85,55%), leaflet augmentation (n=36,23%), papillary muscle repositioning (n=50,32%), ring annuloplasty (n=70,45%). Early re-operation for recurrent TR occurred in 11 patients. Median follow-up time was 4.3 years (range, 9d-12.3y). There was no significant association between age at repair and time to TV reoperation (p=0.25). However, age <4 years at CR was identified as the most discriminating binary age threshold for the patients with TV reoperation (25.0% in <4y group vs 9.3% in the ≥4y group). Placement of an annuloplasty ring was protective against ≥moderate TR (OR=0.39, 95% CI 0.16-0.95, p=0.039). Freedom from late TV re-operation was 94.1% at 7 years. Survival was 97.9% at 6 years. Repair after age 18 years was associated with mortality in early follow-up (p=0.037). Mid-term results for CR are favorable in children and adults. Time to TV reoperation may be shorter when CR is performed before age four years, but this result requires confirmation in a larger sample. An annuloplasty ring should be considered when appropriate.