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.

Study on the correlation between retrograde ductus arteriosus flow and right ventricular function evaluated by Z-score of tricuspid annular plane systolic excursion in fetuses with Ebstein anomaly.

PURPOSE: To analyze the influence of RV dysfunction evaluated by Free-angle M-mode (FAM) TAPSE Z-score on retrograde ductus arteriosus flow (RDAF) in fetuses with Ebstein anomaly (EA). METHODS: A retrospective cohort study of 30 EA and 60 normal fetuses were enrolled. The EA group was divided into two groups: with RDAF (EA-RDAF group) and without RDAF (EA-NRDAF group). FAM was used to measure TAPSE of EA and normal fetuses, and Z-scores were calculated. The differences of FAM-TAPSE Z-score, gestational week (GW), maternal age (MA), and mitral valve-tricuspid valve distance (MTD) between three groups were compared. The correlation and binary logistic regression between FAM-TAPSE Z-score, GW, MA, MTD, and RDAF were analyzed. RESULTS: FAM-TAPSE Z-score was significantly lower in EA-RDAF group compared to other groups (p < 0.05). FAM-TAPSE Z-score, GW, and MA were negatively correlated with RDAF (p < 0.05), but no correlation was found between TR, MDT, and RDAF (p > 0.05). Multivariate logistic regression showed that FAM-TAPSE Z-score was an independent influencing factor for RDAF (OR = 0.102, p < 0.05). CONCLUSION: RV dysfunction is an independent factor leading to RDAF in EA fetus, which provides a feasible theoretical basis for further study on improvement of RV function through intrauterine treatment to delay and prevent the RDAF, to avoid death cycle and improve live-birth rate.

First in man right atrial appendage implantation of a Micra leadless pacemaker.

INTRODUCTION: Pacemaker implantation can be challenging in patients with congenital heart disease. METHODS AND RESULTS: In a patient with Ebstein disease and symptomatic sinus node dysfunction, despite multiple attempts, the Micra® pacemaker could not be implanted in the severely dilated right ventricle. In that context, and after iodine injection to confirm the appropriate location, the Micra® pacemaker was successfully implanted in the right appendage at the first attempt. CONCLUSION: Despite the recent development of dedicated dual-chamber leadless pacemaker, to the best of our knowledge, this case is the first off-label Micra® implantation in a right appendage.

Ebstein's anomaly: an electrophysiological perspective.

Ebstein's anomaly of the tricuspid valve (EA) is an uncommon congenital cardiac malformation. It can present with atrioventricular tachycardia (AVRT), atrioventricular nodal re-entrant tachycardia (AVNRT), atrial arrhythmias, and rarely with ventricular tachycardia. The 12-lead electrocardiogram (ECG) is critically important and often diagnostic even prior to an electrophysiology study (EPS). Due to its complex anatomy, it poses particular challenges for mapping and ablation, even for an experienced electrophysiologist. In this review, we aim to provide insight into the electrophysiological perspective of EA and an in-depth analysis of the various arrhythmias encountered in diverse clinical scenarios.

Myocardial Fibrosis in Pediatric Patients With Ebstein's Anomaly.

BACKGROUND: Left ventricular dysfunction in Ebstein's anomaly (EA) is associated with higher mortality. The health of the left ventricular myocardium in children and adolescents with EA has not been investigated in detail. METHODS: Patients with unrepaired EA who had undergone cardiac magnetic resonance imaging including T1 mapping were retrospectively reviewed. Patients were compared with age- and sex-matched controls. EA severity index was calculated using volumetric measurements at end diastole ([right atrial+atrialized right ventricular volumes]/[functional right ventricular+left atrial+left ventricular volumes]). Global circumferential and radial strain and as well as strain rate were examined using cardiac magnetic resonance feature tracking. RESULTS: Twelve EA patients and an equal number of controls were included. Functional and atrialized right ventricular end-diastolic volumes were 84±15 and 21±13 mL/m2, respectively. Late gadolinium enhancement, confined to the right ventricle, was found in 2 patients (16%). Left ventricular native T1 values and extracellular volume fractions were higher in patients compared with controls (1026±47 versus 956±40 ms, P=0.0004 and 28.5±3.4% versus 22.5±2.6%, P<0.001, respectively). Native T1 times correlated inversely with patients' age, body surface area, and O2 saturations (r=-0.63, -0.62, and -0.91, respectively; P=0.02, P=0.02, and P<0.0001, respectively). EA severity index ranged between 0.15 and 0.94 and correlated with T1 values (r=0.76, P=0.003). Native T1 correlated with global circumferential strain (r=0.58, P=0.04) but not ejection fraction (EF). EA patients had reduced maximum oxygen uptake (Vo2max). Vo2max correlated inversely with T1 values (r=-0.79, P=0.01). CONCLUSIONS: Children and adolescents with EA experience an abnormal degree of diffuse myocardial fibrosis. Its association with O2 saturation points toward a role of hypoxemia in the pathogenesis of fibrosis. Larger and prospective studies are needed to evaluate the value of T1 mapping for risk stratification and monitoring in EA.

Hemodynamics and Clinical Implications of Occult Left Ventricular Dysfunction in Adults Undergoing Ebstein Anomaly Repair.

BACKGROUND: Left ventricular global longitudinal strain (LVGLS) can detect early phases of LV systolic dysfunction, but its application has not been studied in Ebstein anomaly. We hypothesized that LVGLS can detect early phases of LV systolic dysfunction and that patients with occult LV systolic dysfunction will have worse hemodynamics, end-organ dysfunction, and suboptimal postoperative LV reverse remodeling after tricuspid valve surgery in comparison to patients with normal LV systolic function. METHODS: In this retrospective cohort study, 371 Ebstein patients that underwent tricuspid valve surgery were divided into 3 groups: normal LV systolic function (normal LVGLS and LV ejection fraction; n=244, 77%), occult LV systolic dysfunction (abnormal LVGLS with normal LV ejection fraction; n=44, 14%), and overt LV systolic dysfunction (abnormal LVGLS and LV ejection fraction; n=27, 9%). RESULTS: Compared with the normal LV function group, the occult group had smaller LV volume and cardiac output (2.1±0.4 versus 2.9±0.6 L/min per m2, P<0.001), worse end-organ dysfunction (glomerular filtration rate, 78±14 versus 91±18 mL/min per 1.73 m2, P=0.01), and suboptimal postoperative LV reverse remodeling. Although both the occult and overt groups had a similar degree of end-organ dysfunction (glomerular filtration rate, 78±14 versus 82±16 mL/min per 1.73 m2, P=0.3), the occult group was less likely to be on heart failure therapy (48% versus 96%, P<0.001). CONCLUSIONS: Abnormal LVGLS was associated with suboptimal postoperative LV reverse remodeling. These data suggest that LVGLS can potentially be used for risk stratification and provides a foundation for further studies to determine whether optimal heart failure therapy or tricuspid valve intervention can improve outcomes for LV systolic dysfunction in patients with Ebstein anomaly.

Cone reconstruction for Ebstein anomaly: Late biventricular function and possible remodeling.

OBJECTIVES: To evaluate late-term tricuspid valve competence and biventricular function following cone reconstruction for Ebstein anomaly, and to explore biventricular remodeling. METHODS: Consecutive adult and pediatric patients who underwent cone reconstruction from 2009 to 2019 were reviewed for inclusion in this retrospective cardiac magnetic resonance imaging study. Tricuspid valve competence was assessed with tricuspid regurgitation fraction. Biventricular systolic function was assessed by ejection fraction, cardiac index, indexed stroke volume, and indexed aortic and pulmonary artery beat volume. Biventricular remodeling was assessed by planimetered areas (right atrium, functional right ventricle, left heart), and indexed end-diastolic and end-systolic ventricular volumes. Paired t tests or Wilcoxon signed-rank tests were used for analyses. RESULTS: Of 58 included patients, 50 underwent cardiac magnetic resonance imaging. Twelve patients had both preoperative and late postoperative cardiac magnetic resonance imaging with a median follow-up of 5.11 years (interquartile range, 3.12-6.07 years). Focusing on these, tricuspid regurgitation fraction decreased (from 69% to 10%; P = .014), right ventricle ejection fraction remained stable, and antegrade pulmonary artery beat volume increased (from 26.7 to 41.6 mL/beat/m2; P = .037). The left ventricle stroke volume (from 30.4 to 44.1 mL/m2; P = .015) and antegrade aortic beat volume (from 28.5 to 41.1 mL/beat/m2; P = .014) also increased, and the left ventricle stroke volume improved progressively with time since surgery (P = .048). Whereas the right atrium area decreased (P = .004), the functional right ventricle and left heart area increased (cm2, P = .021 and P = .004). Right ventricle volumes showed a tendency to normalize and left ventricle indexed end-diastolic volume increased (from 50 to 69 mL/m2; P = .03) over time. CONCLUSIONS: Cone valve integrity was sustained. Biventricular function improved progressively during follow-up, and there are positive signs of biventricular remodeling late after cone reconstruction.

Effect of In Utero Non-Steroidal Anti-Inflammatory Drug Therapy for Severe Ebstein Anomaly or Tricuspid Valve Dysplasia (NSAID Therapy for Fetal Ebstein anomaly).

Ebstein anomaly (EA) and tricuspid valve dysplasia (TVD) are rare congenital malformations associated with nearly 50% mortality when diagnosed in utero. The diseases often produce severe tricuspid regurgitation (TR) in the fetus and in some cases, pulmonary regurgitation (PR) and circular shunting ensue. Since the ductus arteriosus (DA) plays a critical role in the circular shunt and may be constricted by transplacental nonsteroidal anti-inflammatory drugs (NSAIDs), we sought to assess the effect of NSAIDs on fetuses with EA/TVD. We reviewed mothers of singleton fetuses with EA/TVD and PR, indicative of circular shunting, who were offered NSAIDs at multiple centers from 2010 to 2018. Initial dosing consisted of indomethacin, followed by ibuprofen in most cases. Twenty-one patients at 10 centers were offered therapy at a median gestational age (GA) of 30.0 weeks (range: 20.9 to 34.9). Most (15/21 = 71%) mothers received NSAIDs, and 12 of 15 (80%) achieved DA constriction after a median of 2.0 days (1.0 to 6.0). All fetuses with DA constriction had improved PR; 92% had improved Doppler patterns. Median GA at pregnancy outcome (live-birth or fetal demise) was 36.1 weeks (30.7 to 39.0) in fetuses with DA constriction versus 33 weeks (23.3 to 37.3) in fetuses who did not receive NSAIDs or achieve DA constriction (p = 0.040). Eleven of 12 patients (92%) with DA constriction survived to live-birth, whereas 4 of 9 patients (44%) who did not receive NSAIDs or achieve DA constriction survived (p = 0.046). In conclusion, our findings demonstrate the proof of concept that NSAIDs mitigate circular shunt physiology by DA constriction and improve PR among fetuses with severe EA/TVD. Although the early results are encouraging, further investigation is necessary to determine safety and efficacy.

Haemodynamic determinants of improved aerobic capacity after tricuspid valve surgery in Ebstein anomaly.

BACKGROUND: Although tricuspid valve surgery improves functional capacity in patients with Ebstein anomaly, it is not always associated with improvement in aerobic capacity. The purpose of this study was to identify the determinants of improved aerobic capacity after tricuspid valve surgery in adults with Ebstein anomaly with severe tricuspid regurgitation. METHODS: Retrospective study of patients with severe tricuspid regurgitation due to Ebstein anomaly that had tricuspid valve surgery at Mayo Clinic Rochester (2000-2019) and had preoperative and postoperative cardiopulmonary exercise tests and echocardiograms. The patients were divided into aerobic capacity(+) and aerobic capacity(-) groups depending on whether they had postoperative improvement in %-predicted peak oxygen consumption (VO2). RESULTS: Of 76 patients with severe tricuspid regurgitation due to Ebstein anomaly, 28 (37%) and 48 (63%) were in aerobic capacity(+) and aerobic capacity(-) groups, respectively. The average improvement in peak VO2 was 2.1±1.4 mL/kg/min and -0.9±0.4 mL/kg/min in the in aerobic capacity(+) and aerobic capacity(-) groups, respectively. Although both groups had similar severity of residual tricuspid regurgitation, the aerobic capacity(+) group had more postoperative improvement in right atrial (RA) function, left atrial (LA) function and left ventricular preload and stroke volume. Of the preoperative variables analysed, RA reservoir strain (relative risk 1.12; 95% CI 1.06 to 1.18); LA reservoir strain (relative risk 1.09; 95% CI 1.04 to 1.14) and LV stroke volume index (OR 1.04; 95% CI 1.01 to 1.07) were predictors of postoperative improvement in peak VO2. CONCLUSIONS: One-third of patients with severe tricuspid regurgitation due to Ebstein anomaly had postoperative improvement in aerobic capacity, and atrial function indices were the best predictors of postoperative improvement in aerobic capacity. These data provide new insight into the haemodynamic determinants of exercise capacity and lay the foundation for further studies to determine whether postoperative improvement in aerobic capacity translates to improved long-term survival, and whether timing of tricuspid valve surgery based on these echocardiographic indices will improve long-term outcomes.

Prognostic Role of Hepatorenal Function Indexes in Patients With Ebstein Anomaly.

BACKGROUND: Hepatorenal dysfunction is a risk factor for mortality in patients with chronic tricuspid regurgitation due to acquired heart disease. Ebstein anomaly is the most common cause of primary tricuspid regurgitation in adults with congenital heart disease, but the prevalence and prognostic implications of hepatorenal dysfunction are unknown in this population. OBJECTIVES: The purpose of this study was to determine the risk factors and prognostic implications of hepatorenal dysfunction, as measured primarily by the use of model for end-stage liver disease excluding international normalized ratio (MELD-XI score), as well as looking at other associated factors. METHODS: This was a retrospective study of adults with Ebstein anomaly who received care at Mayo Clinic from 2003 to 2018. RESULTS: Of 692 patients, the median MELD-XI score was 10.2 (interquartile range: 9.4 to 13.3); 53 (8%) died and 3 (0.4%) underwent heart transplant. MELD-XI was an independent predictor of death/transplant (hazard ratio: 1.32; 95% confidence interval: 1.11 to 2.06; p < 0.001). In the subset of patients with serial MELD-XI scores (n = 416), temporal change in MELD-XI score (ΔMELD-XI) was also a predictor of death/transplant. In the subset of patients who underwent tricuspid valve surgery (n = 344), a post-operative improvement in MELD-XI score (ΔMELD-XI) was associated with improved long-term survival. Impaired right atrial (RA) reservoir strain and elevated estimated RA pressure were associated with worse baseline MELD-XI and ΔMELD-XI scores. CONCLUSIONS: Hepatorenal dysfunction is a predictor of mortality in Ebstein anomaly, and RA dysfunction and hypertension are hemodynamic biomarkers that can identify patients at risk for deterioration in hepatorenal function and mortality. These data highlight the prognostic importance of noncardiac organ-system dysfunction, and provide complementary clinical risk stratification metrics for management of these patients.

Strain and Strain Rate To Evaluate Right Heart Function of Ebstein Anomaly (EA) Patients Before and After Operation.

OBJECTIVE: This study was aimed to elucidate the feasibility of using right ventricular (RV) strain and strain rate to evaluate right heart function of Ebstein anomaly (EA) patients before and after operation. METHODS: Sixty EA patients and 30 healthy controls underwent echocardiography (UCG) for evaluation of right heart function. Preoperative UCG and 1-week and 3-month postoperative UCG were performed in EA patients. RV strain and strain rate were measured on the four-chamber section of tissue Doppler imaging (TDI). RESULTS: The strain and strain rate representative of right ventricle systolic function were reduced prior to operation. RV strain and strain rate improved after the operation (P < .001), most significantly in the basal segment and middle segment of the free wall of the right ventricle as well as the basal segment of the interventricular septum (P < .001). CONCLUSIONS: The measurement of RV strain and strain rate on tissue Doppler imaging can be employed to assess the preoperative and postoperative RV function, proves the positive effect of tricuspid valve repair on right heart function, and offers more insight on right heart function evaluation.

Ebstein Anomaly in the Adult Patient.

Ebstein anomaly is a congenital malformation involving primarily the tricuspid valve, with failure of delamination from the underlying myocardium and right ventricular myopathy. Echocardiography is diagnostic in most patients and demonstrates apical displacement of the septal leaflet and variable tethering of leaflet tissue to the right ventricular myocardium. Operative intervention is considered for exertional symptoms, progressive right ventricular enlargement, or right ventricular dysfunction. Tricuspid valve cone repair is the preferred surgical approach. Tricuspid valve replacement and bidirectional cavopulmonary shunt also are considered in patients with advanced disease. Pregnancy generally is well tolerated. Patients with Ebstein anomaly require lifelong follow-up.

Ebstein anomaly associated with cri du chat (cat's cry) syndrome and 20q duplication.

Ebstein anomaly is a congenital heart defect with a low prevalence and high mortality in the early stages of life. In medical literature, there is no reported association between Ebstein anomaly and cri du chat syndrome. Here, we report the case of a full-term newborn with a low weight for his age and who had a prenatal diagnosis of Ebstein anomaly and a postnatal diagnosis of cri du chat syndrome and 20q duplication detected on array CGH. The patient required medical treatment with inotropic support, high-frequency ventilation and nitric oxide, with an adequate response. Surgical intervention was not needed.

Heart failure in the adult Ebstein patient.

Ebstein anomaly comprises approximately 1% of all congenital heart diseases. It occurs when the tricuspid valve fails to properly delaminate from the right ventricle, resulting in a clinical spectrum of abnormal tricuspid valve morphology and right ventricular dysfunction. Due to the anatomy of the tricuspid valve and right ventricle, as well as associated right- and left-sided pathology, patients are at risk for both right and left ventricular failure and the associated symptoms of each. Ebstein patients are also at risk for atrial arrhythmias, due to the atrial enlargement intrinsic to the anatomy, as well as the presence of potential accessory pathways. Arrhythmias are generally poorly tolerated, particularly in the setting of ventricular dysfunction. Cyanosis may also be present in Ebstein patients, due to the common occurrence of atrial communications, which can exacerbate other symptoms of heart failure. Treatment of heart failure can be through pharmacologic and procedural interventions, depending on the underlying cause of heart failure. While early heart failure symptoms may be treated with medical management, most Ebstein patients will require surgery. Various surgical and catheter-based interventions targeting the tricuspid valve and the atrialized right ventricular tissue have been developed to help treat the underlying cause of the heart failure. The optimal timing of transcatheter and surgical intervention in the Ebstein patient to prevent or treat heart failure needs further study.

Cone repair for Ebstein's anomaly and atrial fibrillation ablation in an adult patient.

We present a 52-year-old woman with Ebstein's anomaly not previously treated. In this subset of patients, there are no clear guidelines regarding the best surgical strategy for treating the tricuspid valve: replace it or repair it.  In this case, extensive repair of the tricuspid valve and the right ventricle is achieved using the cone repair technique popularized by Dr. José Pedro Da Silva. Because the patient also presented with symptomatic paroxysmal atrial fibrillation, a right atrial maze procedure combined with isolation of the pulmonary veins was performed using both radiofrequency and cryotherapy. At the last follow-up, 2 years after the repair, the patient is asymptomatic and maintains sinus rhythm. The last echocardiogram showed mild tricuspid regurgitation with normal right ventricular function.

Permanent Pacing in a Patient With Fontan Circulation: Use All You Have at Your Discretion.

Patients with Fontan circulation post significant technical challenges at the time of permanent pacemaker implantation, as majority of them are treated with surgically implanted epicardial pacemakers. However, transvenous pacemaker implantation is technically feasible, and the treating physician should be aware of each individual's anatomy and available treatment options.