Muhammad Y. Qureshi

Regenerative therapy for hypoplastic left heart syndrome: first report of intraoperative intramyocardial injection of autologous umbilical-cord blood-derived cells.

The current standard of care for neonates with hypoplastic left heart syndrome (HLHS) includes a series of cardiac operations culminating in a complete cavopulmonary connection. Given the increased workload placed on the right ventricle, development of ventricular dysfunction and heart failure are concerns. As this patient population ages, many may require cardiac transplantation. Cellbased strategies to treat heart failure in adults have been reported, but little is known about their feasibility and efficacy in children with congenital heart disease. In an effort to attenuate or prevent the progression of heart failure that leads to the need for cardiac transplantation, we have developed an autologous cell-based protocol for infants with HLHS. We present the first reported case of direct intramyocardial injection of umbilical-cord blood–derived mononuclear cells in an infant with HLHS undergoing stage-II surgical palliation.

Recessive MYH6 Mutations in Hypoplastic Left Heart With Reduced Ejection Fraction

Background—The molecular underpinnings of hypoplastic left heart are poorly understood. Staged surgical palliation has dramatically improved survival, yet eventual failure of the systemic right ventricle necessitates cardiac transplantation in a subset of patients. We sought to identify genetic determinants of hypoplastic left heart with latent right ventricular dysfunction in individuals with a Fontan circulation. Methods and Results—Evaluation of cardiac structure and function by echocardiography in patients with hypoplastic left heart and their first-degree relatives identified 5 individuals with right ventricular ejection fraction ⩽40% after Fontan operation. Whole genome sequencing was performed on DNA from 21 family members, filtering for genetic variants with allele frequency <1% predicted to alter protein structure or expression. Secondary family-based filtering for de novo and recessive variants revealed rare inherited missense mutations on both paternal and maternal alleles of MYH6, encoding myosin heavy chain 6, in 2 patients who developed right ventricular dysfunction 3 to 11 years postoperatively. Parents and siblings who were heterozygous carriers had normal echocardiograms. Protein modeling of the 4 highly conserved amino acid substitutions, residing in both head and tail domains, predicted perturbation of protein structure and function. Conclusions—In contrast to dominant MYH6 mutations with variable penetrance identified in other congenital heart defects and dilated cardiomyopathy, this study reveals compound heterozygosity for recessive MYH6 mutations in patients with hypoplastic left heart and reduced systemic right ventricular ejection fraction. These findings implicate a shared molecular basis for the developmental arrest and latent myopathy of left and right ventricles, respectively.

Two‐Dimensional Measurement of Tricuspid Annular Plane Systolic Excursion in Children: Can It Substitute for an M‐Mode Assessment?

Tricuspid annular plane systolic excursion measured by M‐mode (MM‐TAPSE) has been validated as a marker of right ventricular systolic performance. A similar measurement by 2D imaging (2D‐TAPSE) can be obtained. We sought to determine the correlation and strength of agreement between MM‐TAPSE and 2D‐TAPSE in children.

Prevalence and outcome of thrombotic and embolic complications in adults after Fontan operation

Background There are limited studies of thrombotic and embolic complications (TEC) in the adult Fontan population. The purpose of the study was to determine the prevalence, risk factors, and outcomes of TECs in this population. Methods Retrospective review of adults with a previous Fontan operation, with follow‐up at Mayo Clinic, 1994‐2014. Systemic TEC was defined as intracardiac thrombus, ischemic stroke, or systemic arterial embolus. Nonsystemic TEC was defined as Fontan conduit/right atrial thrombus or pulmonary embolus. Results We identified 387 patients with a mean (SD) age of 28 (7) years and a mean follow‐up of 8 (2) years. An atriopulmonary connection (APC) was done for 286 patients (74%). Atrial arrhythmias were present in 278 (72%). There were 121 TECs (systemic n = 36, nonsystemic n = 85) in 98 patients (25%). Risk factors for systemic TEC were atrial arrhythmia (hazard ratio 2.28, P = .001) and APC (hazard ratio 1.98, P = .02); nonsystemic TEC also had similar risk factors. All 98 patients received warfarin. Warfarin was discontinued in 10 of 98 because of bleeding, and 8 of these 10 subsequently had a second TEC. Among the 82 patients who had follow‐up imaging, 16 (20%) had resolution of thrombus. In total, 24 of 98 patients had a second TEC, most of whom had inadequate anticoagulation. Conclusions Thrombotic and embolic complication was not uncommon; risk factors for TEC were APC and atrial arrhythmias. Most patients were treated successfully with warfarin alone. A second TEC occurred in most patients whose anticoagulation was discontinued because of bleeding events.

Cardiac imaging in Ebstein anomaly

Ebstein anomaly is a congenital disorder of right ventricular myocardial development, which affects the tricuspid valve in addition to the right ventricular myocardium. Cardiac imaging by transthoracic echocardiography and cardiac magnetic resonance imaging are the key modalities used to assess timing and type of surgery. In this article, we review the current standards of echocardiographic and magnetic resonance imaging in Ebstein anomaly.

Whole Exome Sequencing, Familial Genomic Triangulation, and Systems Biology Converge to Identify a Novel Nonsense Mutation in TAB2-encoded TGF-beta Activated Kinase 1 in a Child with Polyvalvular Syndrome

OBJECTIVE To use whole exome sequencing (WES) of a family trio to identify a genetic cause for polyvalvular syndrome. METHODS AND RESULTS A male child was born with mild pulmonary valve stenosis and mild aortic root dilatation, and an atrial septal defect, ventricular septal defect, and patent ductus arteriosus that were closed surgically. Subsequently, the phenotype of polyvalvular syndrome with involvement of both semilunar and both atrioventricular valves emerged. His family history was negative for congenital heart disease. Because of hypotonia, myopia, soft pale skin, joint hypermobility, and mild facial dysmorphism, either Noonan syndrome- or William syndrome-spectrum disorders were suspected clinically. However, chromosomal analysis was normal and commercially available Noonan syndrome and William syndrome genetic tests were negative. Whole exome sequencing of the patient and both parents was performed. Variants were analyzed by sporadic and autosomal recessive inheritance models. A sporadic mutation, annotated as c.1491 T > A, in TAB2, resulting in a nonsense mutation, p.Y497X, in the TAB2-encoded TGF-beta activated kinase 1 (TAK1) was identified as the most likely disease-susceptibility gene. This mutation results in elimination of the terminal 197 amino acids, including the C-terminal binding motif critical for interactions with TRAF6 and TAK1. CONCLUSIONS The combination of WES, genomic triangulation, and systems biology has uncovered perturbations in TGF-beta activated kinase 1 signaling as a novel pathogenic substrate for polyvalvular syndrome.

Importance of absent ductus arteriosus in tetralogy of Fallot with absent pulmonary valve syndrome.

Tetralogy of Fallot without pulmonary valve syndrome is almost always associated with an absent ductus arteriosus. Patients with right aortic arch and retroesophageal left subclavian artery have a vascular ring if the left ductus arteriosus or its remnant and the Kommerell diverticulum are present. We report the cases of 2 infants in whom the role of an absent ductus arteriosus or its remnant is noteworthy. Both patients had a combination of tetralogy of Fallot with absent pulmonary valve syndrome and right aortic arch with retroesophageal left subclavian artery without a vascular ring. The absence of the ductus arteriosus has a role in the pathogenesis of tetralogy of Fallot with absent pulmonary valve syndrome. The absence of a ductus arteriosus in the right aortic arch with retroesophageal left subclavian artery precludes a vascular ring.

Surgically Constructed Double-Outlet Right Ventricle

A 32-year-old woman with a history of fibrosing mediastinitis attributable to histoplasmosis presented to Mayo Clinic with occlusion of her right pulmonary artery. She underwent bypass of the occluded pulmonary artery with a 26-mm CryoLife homograft conduit from the right ventricle to the right pulmonary artery. Her postoperative course was uncomplicated, and postoperative cardiac MRI showed a patent right ventricle (RV) to right pulmonary artery homograft conduit, normal perfusion of the lobar branches of the right pulmonary artery, and normal pulmonary venous return (Figure 1). The patient did well after surgery and had an uncomplicated pregnancy 2 years later. Figure 1. A , Computed tomography angiogram performed before the first surgical intervention, showing severe calcification (arrow) in …

Biventricular Repair After Stage II Univentricular Surgery: Palliation Is Not a One-Way Path

Surgical decision in mild forms of hypoplastic left heart syndrome can be challenging. Once a univentricular pathway has been chosen, it can be difficult to reconsider a biventricular repair. A commitment to a palliative pathway is usually considered irreversible after initial univentricular repair. We present this case as an example in which the primary surgical palliation pathway was altered, and eventually a successful biventricular repair was performed in a mild variant of hypoplastic left heart syndrome, despite the fact that maneuvers to promote left ventricular growth were not recruited at the time of initial surgery.

Progressive right ventricular enlargement due to pulmonary regurgitation: Clinical characteristics of a “low-risk” group

Background: The optimal interval between serial cardiac magnetic resonance imaging (CMRI) scans for monitoring right ventricular (RV) enlargement in the setting of severe pulmonic valve regurgitation (PR) is unknown. The purposes of this study were to (1) determine the annual change in RV volume on serial CMRI scans and (2) identify the risk factors for rapid progression of RV enlargement. Methods: A retrospective study of adults with postintervention native valve PR and ≥2 CMRI scans at Mayo Clinic Rochester from 2000 to 2015 was conducted. Rapid progression of RV enlargement was defined as first upper quartile of annual increase in RV end‐diastolic volume index (RVEDVi) for the cohort. Results: Of the 63 patients (age, 36 ± 9 years) in the study, 43 (68%) had tetralogy of Fallot, whereas 20 (32%) had valvular pulmonic stenosis. Right ventricular outflow tract interventions that resulted in PR were balloon pulmonary valvuloplasty (n = 4; 7%), transannular patch repair (n = 30; 58%), and nontransannular patch repair (n = 18; 35%). Interval between baseline and second CMRI was 2 (1‐4) years. In comparison to baseline CMRI, RVEDVi increased from 130 (109‐141) to 135 (126‐155) mL/m2 and median annual change in RVEDVi was 3.1 (1.7‐5.9) mL/m2. Univariate risk factors for rapid progression of RV enlargement (annual increase in RVEDVi >6 mL/m2) were ≥moderate tricuspid regurgitation and RVEDVi >130 mL/m2. Among the 24 patients without these risk factors (low‐risk subgroup), RVEDVi increased by only 3 (0‐7) mL/m2 over 7 (5‐9) years. Conclusions: Patients with PR without RVEDVi >130 mL/m2 and/or ≥moderate tricuspid regurgitation represent a low‐risk subgroup that may be appropriate for clinical and echo follow‐up but may potentially require infrequent CMRI follow‐up.