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.

Altered contractility, Ca2+ transients, and cell morphology seen in a patient-specific iPSC-CM model of Ebstein's anomaly with left ventricular noncompaction.

Patients with two congenital heart diseases (CHDs), Ebstein's anomaly (EA) and left ventricular noncompaction (LVNC), suffer higher morbidity than either CHD alone. The genetic etiology and pathogenesis of combined EA/LVNC remain largely unknown. We investigated a familial EA/LVNC case associated with a variant (p.R237C) in the gene encoding Kelch-like protein 26 (KLHL26) by differentiating induced pluripotent stem cells (iPSCs) generated from affected and unaffected family members into cardiomyocytes (iPSC-CMs) and assessing iPSC-CM morphology, function, gene expression, and protein abundance. Compared with unaffected iPSC-CMs, CMs containing the KLHL26 (p.R237C) variant exhibited aberrant morphology including distended endo(sarco)plasmic reticulum (ER/SR) and dysmorphic mitochondria and aberrant function that included decreased contractions per minute, altered calcium transients, and increased proliferation. Pathway enrichment analyses based on RNASeq data indicated that the "structural constituent of muscle" pathway was suppressed, whereas the "ER lumen" pathway was activated. Taken together, these findings suggest that iPSC-CMs containing this KLHL26 (p.R237C) variant develop dysregulated ER/SR, calcium signaling, contractility, and proliferation.NEW & NOTEWORTHY We demonstrate here that iPSCs derived from patients with Ebstein's anomaly and left ventricular noncompaction, when differentiated into cardiomyocytes, display significant structural and functional changes that offer insight into disease pathogenesis, including altered ER/SR and mitochondrial morphology, contractility, and calcium signaling.

Cardiac remodeling after tricuspid valve repair in Ebstein's anomaly: a magnetic resonance study.

OBJECTIVES: We aimed to evaluate immediate and midterm cardiac remodeling after surgery by cardiac magnetic resonance (CMR) in Ebstein's anomaly (EA), and also to investigate preoperative predictors of right ventricular (RV) normalization. METHODS: We retrospectively analyzed CMR parameters of the whole heart in adult patients with EA before surgery, at discharge and follow-up. RESULTS: A total of 26 patients were included and performed CMR at 7 days (interquartile range, 3-13 days) before surgery. Immediate postoperative CMR was finished at discharge (median: 8 [7-9] days; n = 18) and follow-up CMR at 187 days (interquartile range, 167-356 days; n = 17). RV and right atrial (RA) volumes promptly decreased immediately after surgery and at follow-up (all p < 0.05). RV ejection fraction decreased significantly at discharge (p < 0.05) but recovered at follow-up (p = 0.18). However, RV global longitudinal strain and RA reservoir strain were significantly impaired immediately and midterm after surgery (all p < 0.05). Indexed left ventricular (LV) end-diastolic volume, stroke volume, as well as global longitudinal strain increased from preoperative to follow-up (all p < 0.05). Patients who achieved normalization of RV volumes after surgery had smaller severity index and RV and RA volumes and higher LV ejection fraction and RA reservoir strain at baseline than patients without RV normalization (all p < 0.05). CONCLUSIONS: Reverse biventricular remodeling took place in EA after tricuspid valve surgery. Tricuspid valve reconstruction should be performed before deterioration of RV volume overload and LV function to achieve reverse RV remodeling. Key Points • After removing the volume load of tricuspid regurgitation in Ebstein's anomaly, reverse remodeling was detected by CMR in both left and right heart at midterm follow-up. • Tricuspid valve reconstruction should be performed before deterioration of RV volume overload and LV function to achieve reverse RV remodeling.

Effect of concomitant atrial septal defect on left ventricular function in adult patients with unrepaired Ebstein's anomaly: a cardiovascular magnetic resonance imaging study.

BACKGROUND: Due to the heterogeneity of anatomic anomalies in Ebstein's anomaly (EA), particularly in the subset of patients with atrial septal defect (ASD), hemodynamic changes, which ultimately cause left ventricular (LV) deterioration remain unclear. The current study aimed to investigate the effect of concomitant ASD on LV function using cardiovascular magnetic resonance (CMR) imaging in patients with EA. METHODS: This study included 31 EA patients with ASD, 76 EA patients without ASD, 35 patients with simple ASD and 40 healthy controls. Left/right ventricular (RV, the RV was defined as a summation of the functional RV and atrialized RV in EA patients) volumes and functional parameters, LV strain parameters, and echocardiogram indices were compared among the four groups. Associations between variables were evaluated via Spearman or Pearson correlation analyses. The association between risk factors and LV ejection fraction (EF) was determined via multivariate linear regression analysis. RESULTS: Both EA patients and ASD patients had a higher RV/LV end-diastolic volume (RVEDV/LVEDV) as well as lower LV and RV ejection fractions (LVEF/RVEF) compared to healthy controls (all p < 0.05). Moreover, the EA patients with ASD had a significantly higher RVEDV/LVEDV and a lower LVEF and RVEF than those without ASD (all p < 0.05). Multivariate linear regression analysis revealed that the presence of ASD was independently associated with LVEF (ß = - 0.337, p < 0.001). The RVEDV/LVEDV index was associated with LVEF (r = - 0.361, p < 0.001). Furthermore, the LV longitudinal peak diastolic strain rate (PDSR) was lower in EA patients with ASD than those without ASD, patients with simple ASD, and healthy controls (p < 0.05). CONCLUSION: Concomitant ASD is an important risk factor of LV dysfunction in patients with EA, and diastolic dysfunction is likely the predominate mechanism related to LV dysfunction.

A rare combination of Ebstein's anomaly with left ventricular outflow tract obstruction.

We describe a rare case of Ebstein's anomaly (EA) combined with left ventricular outflow tract obstruction in a 54-year-old man that was accurately identified by echocardiography, cardiac magnetic resonance imaging (CMR). The imaging result was ultimately validated by surgery. We emphasize the clinical importance of using echocardiography and CMR together to provide a thorough, noninvasive explanation of these results.

Inadvertent irreversible closure of arterial duct following therapeutic use of transplacental indomethacin in a fetus with severe Ebstein's anomaly and circular shunt.

We report on a fetal case of Ebstein's anomaly with severe tricuspid regurgitation, functional pulmonary atresia and progressive circular shunting (CS) across a widely patent ductus arteriosus (DA) and regurgitant pulmonary valve, contributing to significant systemic hypoperfusion. To mitigate the extent of CS and allow the pregnancy to continue, maternal non-steroidal anti-inflammatory drug (NSAID) therapy with indomethacin was started at 33 + 5 weeks to induce DA constriction. Rather than achieving the desired narrowing of the DA, the treatment led to its complete closure and only minimal antegrade flow across the pulmonary valve. While closure of the DA resulted in the anticipated improvement in fetal hemodynamics, at birth, the child was at risk of severe hypoxemia and its consequences due to the lack of adequate pulmonary perfusion. Reduction and eventual discontinuation of the NSAID treatment did not result in DA reopening. Our experience illustrates the risk of unintended irreversible DA closure when NSAIDs are used to treat CS. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

Histological examination of the potential arrhythmic substrates in the setting of Ebstein's malformation.

Cardiac arrhythmias, notably Wolff-Parkinson-White syndrome, are known to represent a major issue in patients with Ebstein's malformation of the tricuspid valve. Abnormal conducting circuits, however, can also be produced by pathways extending either from the atrioventricular node or the ventricular components of the atrioventricular conduction axis, direct to the crest of the muscular ventricular septum. We hoped to provide further information on the potential presence of such pathways by investigations of six autopsied examples of Ebstein's malformation. All were studied by histological sectioning on the full extent of the atrioventricular conduction axis, with limited sectioning of the right atrioventricular junction supporting the inferior and antero-superior leaflets of the deformed tricuspid valve. We used the criteria established by Aschoff (Verhandlungen der Deutschen Gesellschaft für Pathologie, 14, 1910, 3) and Mönckeberg (Verhandlungen der Deutschen Gesellschaft für Pathologie, 14, 1910, 64) over a century ago to define abnormal connections across the atrioventricular junctions, as these definitions retain their validity for the identification of gross myocardial connections across the insulating tissues of the atrioventricular junctions. In one specimen, we found two discrete accessory myocardial connections across the parietal right atrioventricular junction. In all of the hearts, we found so-called nodoventricular connections, and in one heart we also observed a well-formed connection originating from the penetrating atrioventricular bundle. In addition to accessory myocardial connections across the parietal right atrioventricular junction, therefore, our histological findings demonstrate a potential role for direct connections between the atrioventricular conduction axis and the ventricular myocardium in the setting of Ebstein's malformation.

Cardiovascular magnetic resonance evidence of myocardial fibrosis and its clinical significance in adolescent and adult patients with Ebstein's anomaly.

BACKGROUND: Myocardial fibrosis is a common pathophysiological process that is related to ventricular remodeling in congenital heart disease. However, the presence, characteristics, and clinical significance of myocardial fibrosis in Ebstein's anomaly have not been fully investigated. This study aimed to evaluate myocardial fibrosis using cardiovascular magnetic resonance (CMR) late gadolinium enhancement (LGE) and T1 mapping techniques, and to explore the significance of myocardial fibrosis in adolescent and adult patients with Ebstein's anomaly. METHODS: Forty-four consecutive patients with unrepaired Ebstein's anomaly (34.0 ± 16.2 years; 18 males), and an equal number of age- and gender-matched controls, were included. A comprehensive CMR protocol consisted of cine, LGE, and T1 mapping by modified Look-Locker inversion recovery (MOLLI) sequences were performed. Ventricular functional parameters, native T1, extracellular volume (ECV), and LGE were analyzed. Associations between myocardial fibrosis and disease severity, ventricular function, and NYHA classification were analyzed. RESULTS: LGE was found in 10 (22.7%) patients. Typical LGE in Ebstein's anomaly was located in the endocardium of the septum within the right ventricle (RV). The LV ECV of Ebstein's anomaly were significantly higher than those of the controls (30.0 ± 3.8% vs. 25.3 ± 2.3%, P < 0.001). An increased ECV was found to be independent of the existence of LGE. Positive LGE or higher ECV (≥30%) was associated with larger fRV volume, aRV volume, increased disease severity, and worse NYHA functional class. In addition, ECV was significantly correlated with the LV ejection fraction (P <  0.001). CONCLUSIONS: Both focal and diffuse myocardial fibrosis were observed in adolescent and adult patients with Ebstein's anomaly. Increased diffuse fibrosis is associated with worse LV function, increased Ebstein's severity, and worse clinical status.

EBSTEIN ANOMALY IN THE TSUSHIMA LEOPARD CAT (PRIONAILURUS BENGALENSIS EUPTILURUS).

Ebstein anomaly is a rare congenital heart disease that has been described in domestic dogs, a meerkat, a pygmy goat, and a lion. An 11-mo-old Tsushima leopard cat presented to Osaka Prefecture University Veterinary Hospital for diagnosis and treatment of right-sided congestive heart failure. Echocardiography showed a dilated right atrium and ventricle with an enlarged tricuspid valve annulus and apical displacement of the tricuspid valve leaflets. The cat was diagnosed with Ebstein anomaly. To the best of our knowledge, this is the first report of this type of congenital heart disease in a Tsushima leopard cat.

Natural Course of Adult Ebstein Anomaly When Treated according to Current Recommendation.

The objectives of this study were to assess the clinical outcomes of adults with Ebstein Anomaly (EA) according to their treatment modalities. All adult EA patients diagnosed between October 1994 and October 2014 were retrospectively evaluated by medical record review. Total 60 patients were categorized into 3 groups according to their treatment strategy, i.e. non-operative treatment (Group I, n = 23), immediate operative treatment (Group II, n = 27), and delayed operative treatment (Group III, n = 10). A composite of major adverse cardiac and cerebrovascular events (MACCE) and factors associated with MACCE were assessed in each treatment group. MACCE occurred in 13.0% patients in Group I, 55.6% patients in Group II and 50% in Group III (P = 0.006). Event free survivals at 5 years were 90% in Group I, 52.7% in Group II, 50.0% in Group III (P = 0.036). Post-operatively, most patients showed improvement on clinical symptoms. However, event free survival rate was lower in patients with operation compared to those with non-operative treatment (58.7% vs. 90.9%; P = 0.007). Major arrhythmic event occurred more frequently even after surgical ablation (50.0% vs. 20.0%; P = 0.034). Re-operation was more frequent in patients underwent delayed surgery compared to those with immediate surgery (50.0% vs. 18.5%; P = 0.001). Current guideline to decide patient's treatment strategy appeared to be appropriate in adult patients with EA. However, surgical ablation for arrhythmia was not enough so that concomitant medical treatment should be considered. Therefore, attentive risk stratification and cautious decision of treatment strategy by experienced cardiac surgeon are believed to improve clinical outcome.

Right ventricular endomyocardial fibrosis mimicking Ebstein anomaly in a patient with Behçet's disease: case report and review of the literature.

Behçet's disease is a multisystemic, chronic inflammatory disorder with diffuse clinical manifestations including the cardiovascular system. Endomyocardial fibrosis is a rarely seen complication of Behçet's disease leading to progressive heart failure. We report a case of right ventricular endomyocardial fibrosis mimicking Ebstein anomaly in a 26-year-old male Turkish patient with Behçet's disease, who had heart failure symptoms. In addition, the previously reported cases of endomyocardial fibrosis complicating Behçet's disease are reviewed in this article.

[Diagnosis and prognosis of fetal ebstein anomaly]. / Diagnóstico y pronóstico fetales de la anomalía de Ebstein.

BACKGROUND: Fetal echocardiography is possible to confirm with great certainty the diagnosis, in utero, Ebstein's anomaly, as well as determine its perinatal prognosis. OBJECTIVE: Review the experience of 16 cases diagnosed with Ebstein's anomaly, using fetal echocardiography, analyzing "forecast echocardiographic parameters" set by Pavlova, Huhta and Barre. MATERIAL AND METHOD: retrospective and descriptive analysis. We analysed echocardiographic parameters and its correlation with the perinatal development of 16 cases diagnosed with Ebstein's anomaly. RESULTS: Maternal age of our patients was 27.94 +/- 5.7 years, gestational age 31.3 +/- 3.6.) Mortality: in-utero 37.5% (n = 6), neonatal 50% (n = 8), survived 12.5% (n = 2). Cardiothoracic index 0.61 +/- 0.074, relationship foramen oval/heart atrial 0.6 +/- 0.015; obstruction to the way out of the right ventricle in 14 cases (87.5%). The deceased 81% presented degree of valvular displacement > 2.5; relationship RV/LV 2.24 +/- 0.37). CONCLUSIONS: Cardiothoracic index fetal stage > 0.55, relationship oval foramen/interatrial septum < 0.3, obstruction to the way out and a degree of valvular displacement > 2.5, absence of back flow in arteriosus ductus and a ratio RV/LV > 2 are poor prognostic factors for Ebstein's anomaly.

[Structural features of cardiomyocytes in the atrialized right ventricle in patients with Ebstein anomaly].

Intraoperative biopsy specimens were used to analyze the sizes and ultrastructure of cardiomyocytes (CMC) in the atrialized right ventricle (ARV) versus those in the right ventricle (RV) and right atrium (RA) in 32 patients aged 9 months to 57 years with Ebstein anomaly. The mean CMC diameter in ARV, RV, and RA did not differ significantly in patients less than 10 years; that was equal in ARV and RV, but higher in RA in patients over 10 years of age. No specific atrial granules were found in the CMC of ARV, RV, and RA; but T system channels and multiple intercalated disks were encountered significantly more frequently than in the RA cells. Individual CMCs showed abnormal myofibrils with specific accumulations of Z-band material (more commonly in RA), as well as nuclear displacement under the sarcolemma (more commonly in ARV and RV). Conclusion. ARV cardiomyocytes preserve ventricular specificity in patients with Ebstein anomaly.

Complex Ebstein's malformation: defining preoperative cardiac anatomy and function.

INTRODUCTION: Ebstein's malformation is a congenital malformation of the tricuspid valve and right ventricle, with a highly variable morphology, and clinical presentation, accounting for less than 1% of all congenital heart diseases, and about 40% of congenital malformations of the tricuspid valve. METHOD: Systematic review of English language literature regarding the morphogenesis and progress of imaging techniques, especially echocardiography and cardiac magnetic resonance imaging, in the preoperative planning of Ebstein's malformation, using the MEDLINE database with the PubMed Entre interface. RESULTS: Technological developments of the recent years, with 3D echocardiographic and cardiac magnetic resonance imaging evolution, have resulted in better understanding of the malformed tricuspid valve and right ventricle in vivo anatomy. Through a better understanding of Ebstein's malformation, there is a continuous trend of surgical techniques favoring tricuspid valve sparing procedures, with a constant decrease in early and late postoperative mortality. CONCLUSIONS: Although imaging methods to investigate Ebstein's malformation have continuously evolved, standardization of assessment protocols by 3D echocardiographic imaging, speckle tracking imaging, and cardiac magnetic resonance imaging is required.

Right ventricular exclusion and univentricular palliation for failed one and a half ventricle repair for Ebstein's anomaly.

A 20 year-old male was diagnosed to have Ebstein's anomaly with severe right ventricular dysfunction. He was taken up for 1.5 ventricle repair. Post procedure, there was difficulty in weaning from cardiopulmonary bypass due to progressive right ventricular dilatation compromising the systemic output. An atrial septectomy did not help. Progressive right ventricular dilatation compressing the left ventricle, demonstrated on transoesophageal echocardiogram, prompted us to perform a right ventricular exclusion and univentricular palliation. The patient was successfully weaned off cardiopulmonary bypass and had a smooth postoperative recovery. Judicious use of right ventricular exclusion and univentricular palliation could be an effective bailout strategy in difficult surgical scenarios in Ebstein's anomaly.

Fetal Ebstein's anomaly: early and late appearance.

OBJECTIVE: To present sonographic findings in early and late appearance of fetal Ebstein's anomaly. METHODS: Fetal sonography was performed in 53,447 consecutive pregnant women at 14 to 16 weeks' gestation. RESULTS: Ebstein's anomaly was detected in eight fetuses, in four of them additional anomalies were observed. All eight pregnancies were terminated. In an additional fetus, a normal four-chamber view without valvular regurgitation was visualized at 15 weeks' gestation. At 24 weeks, a normal four-chamber view was depicted. No Doppler examination was performed at that time. The newborn was found to have Ebstein's anomaly with pulmonary stenosis. A balloon pulmonary valvuloplasty was performed with a good outcome at three months of age. CONCLUSION: Fetal Ebstein's anomaly may be detected in early pregnancy. The incidence is higher than what is reported in newborns. Depiction of a normal fetal heart in early and midpregnancy does not exclude the possibility of subsequent development of Ebstein's anomaly.

Ebstein's anomaly of the tricuspid valve: the cone repair.

Ebstein's anomaly is a cardiac malformation affecting the tricuspid valve and right ventricle with a wide range of anatomic and pathophysiologic presentations. The cone repair technique is described in detail, as applied to several types of this complex congenital heart disease. The importance of extensive mobilization of displaced and tethered tricuspid leaflets to permit a good leaflet-to-leaflet coaptation after the cone construction is highlighted. This technique was performed in 100 patients with a hospital mortality rate of 3.0%, good clinical outcome, and no need for tricuspid valve replacement. Echocardiograph results showed good anatomic and functional tricuspid valves at immediate and long-term postoperative follow-up.

Ebstein's anomaly of the tricuspid valve in association with tetralogy of fallot and absent pulmonary valve syndrome.

Ebstein's anomaly and absent pulmonary valve syndrome belong to the rarest congenital heart defects. Their association has never been reported so far. We present the unusual case of a fetus at 23 weeks of gestation with Ebstein's anomaly, tetralogy of Fallot, absent pulmonary valve and agenesis of the arterial duct. The main diagnostic features were apical displacement of the septal leaflet of the tricuspid valve with an offset from the mitral valve of 8 mm, a pronounced atrialization of the right ventricle, a large malalignment ventricular septal defect with overriding aorta in combination with absence of the pulmonary valve leaflets, to and fro flow pattern over the stenotic pulmonary valve annulus, turbulent flow in the pulmonary trunk, massive dilatation of the pulmonary trunk plus the pulmonary arteries and a right aortic arch with retroesophageal course of an aberrant left subclavian artery. The arterial duct and the thymus were absent. The remaining fetal anatomy was unremarkable. Amniocentesis revealed a normal male karyotype; 22q11 microdeletion was ruled out. After being counseled on the unfavorable prognosis, the parents opted for termination of pregnancy. The prenatal cardiac findings were confirmed at autopsy; however, a severely hypoplastic thymus was found instead of the suspected aplasia.

Multiplanar review of three-dimensional echocardiography gives new insights into the morphology of Ebstein's malformation.

INTRODUCTION: We aimed to assess the ability of the multiplanar review modality of three-dimensional echocardiography to examine the dynamic morphology and the functional characteristics of malformed tricuspid valves in patients previously identified as having Ebstein's malformation. Based on these characteristics, we attempted to differentiate Ebstein's malformation from tricuspid valvar dysplasia. METHODS: Using three-dimensional multiplanar review, analysed with either Qlab 6.0 or Tomtech Image Arena 3.0, we studied 23 patients, aged from 1 day to 70 years, previously diagnosed using cross-sectional echocardiography as having Ebstein's malformation. RESULTS: Using the features of rotational abnormality, and the orientation, of the effective tricuspid valvar orifice as diagnostic features of Ebstein's malformation, we reclassified 11 patients (48 per cent) as exhibiting tricuspid valvar dysplasia. In addition, we studied the dynamic morphology as well as the function of the tricuspid valve. Surgical treatment was undertaken on 10 patients, revealing good correlation with the findings obtained using three-dimensional multiplanar review. In those with Ebstein's malformation, we found varying degrees of rotation, with the effective valvar orifice always directed towards the right ventricular outflow tract. The opening of the orifice of dysplastic tricuspid valves, in contrast, was towards the apex of the right ventricle. The degree of delamination, and abnormalities of subcordal apparatus, were similar in the two groups. DISCUSSION: Three-dimensional multiplanar review permits accurate definition of the dynamic morphology of Ebstein's malformation, permitting clear differentiation from tricuspid valvar dysplasia.

Mirror syndrome: a systematic review of fetal associated conditions, maternal presentation and perinatal outcome.

INTRODUCTION: Mirror syndrome, also referred to as Ballantyne's syndrome, is normally defined as the development of maternal edema in association with fetal hydrops. The incidence of mirror syndrome is low and few cases have been published. We describe a case report in association with fetal Ebstein anomaly and provide a systematic review on the fetal associated conditions, maternal presentation and perinatal outcome reported for mirror syndrome. DATA SOURCES: A PubMed database search was done until December 2008 (English, French or German) without any restriction of publication date or journal, using the following key words: Ballantyne syndrome, Mirror syndrome, Triple edema, Pseudotoxemia, Maternal hydrops syndrome, Pregnancy toxemia, Acute second trimester gestosis, and Early onset preeclampsia. Reported cases were considered eligible when fetal associated conditions, maternal symptoms and fetal outcome were clearly described. RESULTS: Among 151 publications a total of 56 reported cases satisfying all inclusion criteria were identified. Mirror syndrome was associated with rhesus isoimmunization (29%), twin-twin transfusion syndrome (18%), viral infection (16%) and fetal malformations, fetal or placental tumors (37.5%). Gestational age at diagnosis ranged from 22.5 to 27.8 weeks of gestation. Maternal key signs were edema (80-100%), hypertension (57-78%) and proteinuria (20-56%). The overall rate of intrauterine death was 56%. Severe maternal complications including pulmonary edema occurred in 21.4%. Maternal symptoms disappeared 4.8-13.5 days after delivery. DISCUSSION: Mirror syndrome is associated with a substantial increase in fetal mortality and maternal morbidity.