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.

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.

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.

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).

Perinatal outcomes following early prenatal diagnosis: insights from a single-center experience with Ebstein anomaly and tricuspid valve dysplasia.

PURPOSE: Ebstein anomaly (EA) and tricuspid valve dysplasia (TVD) represent uncommon congenital malformations of the tricuspid valve. The purpose of this study is to report on current perinatal outcomes of EA/TVD in our center and to investigate clinical and fetal echocardiographic predictors of perinatal mortality. METHODS AND RESULTS: We performed a retrospective study among fetuses diagnosed from January 2014 to December 2023. Clinical and echocardiographic data were obtained from hospital records of Research and Education Hospital. The primary outcome was perinatal mortality. Of 21 fetuses diagnosed, there were 1 lost to follow-up, 1 termination, and 7 demises. In the live-born cohort of 12 live-born patients, 2 died before discharge, yielding an overall perinatal mortality of 50%. The median gestational age at diagnosis was 23 for non-survivors and 24 weeks for survivors. Birth weight was lower in non-survivors (2430 g vs 2990 g). Tricuspid insufficiency severity varied insignificantly. Non-survivors exhibited higher rates of hydrops, functional atresia, and absent antegrade flow (p < 0.05). Two infants with severe tricuspid insufficiency and congenital abnormalities died postnatally. The limited dataset enables further analysis for a predictive model. Notably, all non-survivors displayed hydrops, functional atresia, and absent antegrade flow, hindering definitive determination of the most impactful parameter on survival estimation. CONCLUSION: Perinatal mortality remains notably elevated in fetuses with EA/TVD. The individuals at the highest risk are those with antegrade flow loss and functional atresia of pulmonary valve, this high-risk subgroup could benefit from targeted interventions, such as novel prenatal therapies or a more comprehensive perinatal approach involving optimized timing of delivery and postnatal interventional strategies.

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.

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.

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.

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.

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.

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.

Case Report of a 33-year-old with Ebstein malformation of tricuspid valve and hypertrophic cardiomyopathy.

Ebstein malformation of tricuspid valve is a congenital disease of tricuspid valve with associated right ventricular cardiomyopathy. Hypertrophic cardiomyopathy is a form of inherited left ventricular cardiomyopathy caused by sarcomeric protein gene mutations with inherent risks of sudden cardiac death. Here we report a rare case with co-occurrence of Ebstein malformation of tricuspid valve and hypertrophic cardiomyopathy in a young patient.

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.

An echocardiographic finding mimicking tricuspid atresia in a neonate with dilated cardiomyopathy.

We report a neonate with dilated cardiomyopathy and have echocardiographic findings consistent with "functional" tricuspid atresia. There was an echo-bright, plate-like tissue at the tricuspid valve position with no forward flow across it. This report underscores the role of right ventricle intracavitary haemodynamic influence on the tricuspid valve leaflet excursion and demonstrates a phenomenon of "pseudo or functional tricuspid atresia" mimicking tricuspid atresia in a patient with acute presentation of cardiomyopathy.

Tricuspid Valve Dysplasia at Fetal Autopsy.

Introduction: Tricuspid valve abnormalities detected in fetal life include Ebstein anomaly and tricuspid valve dysplasia. The differentiation between these 2 entities can sometimes be challenging in the 2nd trimester fetus. We report a case of tricuspid valve dysplasia diagnosed on fetal autopsy. Case Report: A primigravida was diagnosed at 22 weeks' gestation to have Ebstein anomaly with severe tricuspid regurgitation. There was intra-uterine fetal demise. On fetal autopsy, the tricuspid valve leaflets were not apically displaced and the leaflets were nodular with rolled up edges. This supported a diagnosis of tricuspid valve dysplasia. Conclusion: The difficulties in differentiating Ebstein anomaly from tricuspid valve dysplasia due to inherent limitations in fetal imaging can be resolved by fetal autopsy. Valvular dysplasia will not have apical displacement of the valve leaflets.

FRS2α-dependent cell fate transition during endocardial cushion morphogenesis.

Atrioventricular valve development requires endothelial-to-mesenchymal transition (EndMT) that induces cushion endocardial cells to give rise to mesenchymal cells crucial to valve formation. In the adult endothelium, deletion of the docking protein FRS2α induces EndMT by activating TGFß signaling in a miRNA let-7-dependent manner. To study the role of endothelial FRS2α during embryonic development, we generated mice with an inducible endothelial-specific deletion of Frs2α (FRS2αiECKO). Analysis of the FRS2αiECKO embryos uncovered a combination of impaired EndMT in AV cushions and defective maturation of AV valves leading to development of thickened, abnormal valves when Frs2α was deleted early (E7.5) in development. At the same time, no AV valve developmental abnormalities were observed after late (E10.5) deletion. These observations identify FRS2α as a pivotal controller of cell fate transition during both EndMT and post-EndMT valvulogenesis.

Canine infantile left ventricular noncompaction.

BACKGROUND: Left ventricular noncompaction (LVNC) is a rare form of cardiomyopathy currently described in humans and cats. It consists of a spongy myocardium characterized by prominent trabeculation and deep recesses involving more than 50% of the ventricular thickness. We describe the clinical and pathological features of LVNC combined with tricuspid valve dysplasia, double-orifice tricuspid valve and severe pulmonary stenosis in a puppy. In addition, we briefly review the LVNC causes, pathogenesis, forms and current diagnostic criteria. CASE PRESENTATION: A seven-week-old intact German Shorthaired Pointer-cross male was presented with a poor body condition, exercise intolerance and dyspnea. Clinical exam identified a bilateral systolic murmur (grade IV/VI over the right heart base and grade III/VI over the left heart base). Echocardiography identified tricuspid valve dysplasia, mild mitral regurgitation, and severe pulmonic stenosis with a trans-valvar systolic pressure gradient of 106 mmHg. Left ventricular noncompaction was diagnosed by necropsy and further confirmed histopathologically by the presence of two distinct myocardial layers: an inner noncompacted zone covering more than 50% of ventricular thickness containing prominent trabeculation and deep recesses, and an outer zone of compact myocardium. CONCLUSIONS: This is the first case describing LVNC in a canine patient, supporting the introduction of this form of heart disease as a differential diagnosis for cardiomyopathies in juvenile and adult dogs.

Ebstein's anomaly of tricuspid valve with aortic stenosis and coarctation of aorta: Successful single-stage repair of a rare adult congenital heart disease.

Ebstein's anomaly of the tricuspid valve is infrequently associated with left heart anomalies. The association of aortic stenosis in Ebstein's anomaly has been reported to be extremely rare and the association of coarctation of aorta is even rarer especially in adults. The combination of all three of these lesions is virtually unknown without any references in literature. We report here an unusual case of Ebstein's anomaly of the tricuspid valve and severe aortic stenosis with coarctation of aorta in an adult who presented to us with exertional dyspnoea in the third decade and underwent a successful single-stage intracardiac repair.

Anterior Tricuspid Leaflet Cleft in an Adult Male: An Autopsy Case Report.

The deceased was a 44-year-old male who was treated for a suspected Ebstein's anomaly observed using transthoracic echocardiogram. He was found dead in his bed at home. Autopsy revealed that the septal tricuspid leaflet was intact; however, a large anterior tricuspid leaflet cleft and right atrioventricular cavity dilation were observed. Pathological examination revealed a normal tricuspid valve, except for the presence of a cleft with local fibrosis of the left ventricle papillary muscle and hemosiderin-containing macrophages at both lungs. There were no other abnormalities that may have led to death. It was concluded that he died a cardiac death based on the right heart overload associated with the anterior tricuspid leaflet cleft. This case indicates the possibility that the anterior tricuspid leaflet cleft can cause death and also highlights the necessity of a detailed autopsy to accurately diagnose the cause of death.