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 ±â€¯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.

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

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.

Low recurrence rate in treating atrioventricular nodal reentrant tachycardia with triple freeze-thaw cycles.

BACKGROUND: Cryoablation is an alternative to radiofrequency ablation in treating atrioventricular nodal reentrant tachycardia (AVNRT). However, its long-term effectiveness is in question when compared to radiofrequency ablation. We reviewed the results of cryoablation in children with AVNRT at our institute. METHODS: We performed a retrospective single-center chart review of consecutive patients ≤18 years of age with AVNRT who underwent cryoablation between January 2007 and August 2009. During cryoablation, a 6-mm-tip cryocatheter was used with temperature set to -80°C. Test lesions were performed at the presumed slow pathway location based on combined anatomic and electrophysiologic approach. If successful, ablation was then continued with triple freeze-thaw cycles (FTC) of 4 minutes each. RESULTS: A total of 53 patients (age range: 6.1-18.4 years, mean: 13.6 years, median: 13.2 years) underwent slow pathway modification with cryoablation. Acute success was achieved in 51 (96.2%) cases. Transient atrioventricular block was seen in 19 cases. The block occurred during FTC in eight patients (15%). The number of FTC was three in 47 (92.2%) patients. Less than three FTC were given in two patients due to transient heart block and four FTC were given in two patients with suspected catheter movement. Procedure duration was 177 ± 56 minutes; fluoroscopic time was 14 ± 11 minutes. Mean follow-up was 30.7 ± 10 (range 12-52, median 31) months. Recurrence of supraventricular tachycardia was seen in only one (1.96%) patient. CONCLUSIONS: Triple FTC cryoablation lesions resulted in a low recurrence rate comparable to RF ablation in treating AVNRT without increased complications.

Autologous Umbilical Cord Blood-Derived Mononuclear Cell Therapy Promotes Cardiac Proliferation and Adaptation in a Porcine Model of Right Ventricle Pressure Overload.

Congenital heart diseases, including single ventricle circulations, are clinically challenging due to chronic pressure overload and the inability of the myocardium to compensate for lifelong physiological demands. To determine the clinical relevance of autologous umbilical cord blood-derived mononuclear cells (UCB-MNCs) as a therapy to augment cardiac adaptation following surgical management of congenital heart disease, a validated model system of right ventricular pressure overload due to pulmonary artery banding (PAB) in juvenile pigs has been employed. PAB in a juvenile porcine model and intramyocardial delivery of UCB-MNCs was evaluated in three distinct 12-week studies utilizing serial cardiac imaging and end-of-study pathology evaluations. PAB reproducibly induced pressure overload leading to chronic right ventricular remodeling including significant myocardial fibrosis and elevation of heart failure biomarkers. High-dose UCB-MNCs (3 million/kg) delivered into the right ventricular myocardium did not cause any detectable safety issues in the context of arrhythmias or abnormal cardiac physiology. In addition, this high-dose treatment compared with placebo controls demonstrated that UCB-MNCs promoted a significant increase in Ki-67-positive cardiomyocytes coupled with an increase in the number of CD31+ endothelium. Furthermore, the incorporation of BrdU-labeled cells within the myocardium confirmed the biological potency of the high-dose UCB-MNC treatment. Finally, the cell-based treatment augmented the physiological adaptation compared with controls with a trend toward increased right ventricular mass within the 12 weeks of the follow-up period. Despite these adaptations, functional changes as measured by echocardiography and magnetic resonance imaging did not demonstrate differences between cohorts in this surgical model system. Therefore, this randomized, double-blinded, placebo-controlled pre-clinical trial establishes the safety of UCB-MNCs delivered via intramyocardial injections in a dysfunctional right ventricle and validates the induction of cardiac proliferation and angiogenesis as transient paracrine mechanisms that may be important to optimize long-term outcomes for surgically repaired congenital heart diseases.

Determinants of Left Ventricular Diastolic Function and Exertional Symptoms in Adults With Coarctation of Aorta.

BACKGROUND: Coarctation of aorta (COA) results in chronic left ventricular (LV) pressure overload and subsequently leads to LV diastolic dysfunction and heart failure over time. The goal of COA intervention is to prevent these complications. The timing of COA interventions is based on the presence of these COA severity indices: doppler mean COA gradient, systolic blood pressure, upper-to-lower-extremity SBP gradient, aortic isthmus ratio, presence of collaterals, and exercise-induced hypertension. Although these indices are physiologically intuitive, the relationship between these indices and LV diastolic dysfunction and exertional symptoms has not been studied. The purpose of this study was to evaluate the association between the indices of COA severity and LV diastolic function and symptoms. METHODS: In this cross-sectional study, multivariate linear and logistic regression analyses were used to assess the correlation between indices of COA severity, LV diastolic function (average e' and E/e'), and exertional symptoms (NYHA II-IV and peak oxygen consumption). RESULTS: Of all the COA indices analyzed in 546 adult COA patients, aortic isthmus ratio had the strongest correlation with e' (ß [95% CI]: 3.11 [2.02-4.31]; P=0.014) per 1 cm/second; E/e' (-13.4 [-22.3 to -4.81]; P=0.009) per 1 unit; peak oxygen consumption (4.05 [1.97-6.59] per 1% change, P=0.019), and NYHA II to IV symptoms (odds ratio, 2.16 [1.65-3.18]; P=0.006). CONCLUSIONS: Of all the COA severity indices stipulated in the guidelines, aortic isthmus ratio had the strongest correlation with LV diastolic function and exertional symptoms. As LV diastolic dysfunction typically precede heart failure symptoms, we anticipate that the results of this study will improve and simplify patient selection for COA intervention and potentially improve long-term outcomes.

The Congenital Tricuspid Valve Spectrum: From Ebstein to Dysplasia.

Ebstein anomaly has a breadth of presentations, including "typical" and "atypical," and can be confused with congenital tricuspid dysplasia. We summarize how to differentiate within this spectrum of disease. Both typical and atypical Ebstein have an underlying failure of delamination, but atypical Ebstein does not have ≥8mm/m2 apical septal leaflet displacement. In congenital tricuspid dysplasia, delamination is normal, while the leaflets and subvalvar apparatus are abnormal. To summarize, the sine qua non feature of Ebstein anomaly, present in both typical and atypical, is the failure of delamination. These are distinct from congenital tricuspid valve dysplasia in which the pathology is in the leaflet itself.

Dysregulated ribonucleoprotein granules promote cardiomyopathy in RBM20 gene-edited pigs.

Ribonucleoprotein (RNP) granules are biomolecular condensates-liquid-liquid phase-separated droplets that organize and manage messenger RNA metabolism, cell signaling, biopolymer assembly, biochemical reactions and stress granule responses to cellular adversity. Dysregulated RNP granules drive neuromuscular degenerative disease but have not previously been linked to heart failure. By exploring the molecular basis of congenital dilated cardiomyopathy (DCM) in genome-edited pigs homozygous for an RBM20 allele encoding the pathogenic R636S variant of human RNA-binding motif protein-20 (RBM20), we discovered that RNP granules accumulated abnormally in the sarcoplasm, and we confirmed this finding in myocardium and reprogrammed cardiomyocytes from patients with DCM carrying the R636S allele. Dysregulated sarcoplasmic RBM20 RNP granules displayed liquid-like material properties, docked at precisely spaced intervals along cytoskeletal elements, promoted phase partitioning of cardiac biomolecules and fused with stress granules. Our results link dysregulated RNP granules to myocardial cellular pathobiology and heart failure in gene-edited pigs and patients with DCM caused by RBM20 mutation.

Cell-Based Therapy for Myocardial Dysfunction After Fontan Operation in Hypoplastic Left Heart Syndrome.

Myocardial dysfunction after Fontan palliation for univentricular congenital heart disease is a challenging clinical problem. The medical treatment has a limited impact, with cardiac transplant being the ultimate management step. Cell-based therapies are evolving as a new treatment for heart failure. Phase 1 clinical trials using regenerative therapeutic strategies in congenital heart disease are ongoing. We report the first case of autologous bone marrow-derived mononuclear cell administration for ventricular dysfunction, 23 years after Fontan operation in a patient with hypoplastic left heart syndrome. The cells were delivered into the coronary circulation by cardiac catheterization. Ventricular size decreased and several parameters reflecting ventricular function improved, with maximum change noted 3 months after cell delivery. Such regenerative therapeutic options may help in delaying and preventing cardiac transplant.

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.

Thrombotic and Embolic Complications Associated With Atrial Arrhythmia After Fontan Operation: Role of Prophylactic Therapy.

BACKGROUND: There are limited data about the risk of thrombotic and embolic complication (TEC) in adults with atrial arrhythmia after Fontan operation. OBJECTIVES: This study sought to determine the risk of TEC in this population and the role of anticoagulation therapy in TEC prevention. METHODS: This was a retrospective review of adults with atrial arrhythmia after Fontan operation who were evaluated at the Mayo Clinic between 1994 to 2014. TEC was classified into 2 groups: systemic TEC, defined as intracardiac thrombus, ischemic stroke, or systemic arterial embolus; and nonsystemic TEC, defined as Fontan conduit/right atrial thrombus or pulmonary embolus. Patients were divided into 3 groups: anticoagulation, antiplatelet, and no therapy cohorts. RESULTS: We followed 278 patients, mean age 31 ± 9 years, for 88 ± 14 months (1,464 patient-years). Patient groups included antiplatelet (n = 181), anticoagulation (n = 91), and no therapy (n = 6). There were 97 TEC in 81 patients (29%); 32 were systemic, yielding an event rate of 2.1 systemic TEC per 100 patient-years, and 65 were nonsystemic TEC, yielding an event rate of 4.4 nonsystemic TEC per 100 patient-years. Prevalence of TEC was 18% and 55% at 5 and 10 years, respectively. Atriopulmonary connection was a risk factor for TEC (hazard ratio: 2.31; 95% confidence interval: 1.61 to 4.64), and TEC were associated with higher risk of death and hospitalization (p < 0.0001). Anticoagulation was protective against TEC and resulted in a reduction of TEC risk by 2.5 TEC per 100 patient-years. Anticoagulation was also associated with lower risk of death and hospitalization (p = 0.02). Bleeding complications occurred in 21 (7%) patients and were similar in all groups. CONCLUSIONS: Anticoagulation was associated with lower TEC rate and lower risk of death and hospitalization, without a significant increase in bleeding risk. Perhaps anticoagulation should be the preferred preventive strategy.

Familial Incidence of Cardiovascular Malformations in Hypoplastic Left Heart Syndrome.

Obstructive left-sided congenital heart lesions exhibit familial clustering, and familial echocardiographic screening for bicuspid aortic valve has become standard practice. Hypoplastic left heart syndrome (HLHS) is a severe left-sided obstructive lesion; however, familial screening is not universally recommended. The purpose of this study was to define the incidence of cardiovascular malformations (CVMs) in first-degree relatives of HLHS probands. First-degree relatives were screened for CVM by transthoracic echocardiography. Screening was completed in 152 family members (97 parents and 55 siblings) of 52 probands. Of these, 17 of 152 (11%) had CVM. Anomalies detected included: bicuspid aortic valve in 5 (3%), isolated dilated ascending aorta in 4 (3%), coarctation of the aorta in 1, partial anomalous pulmonary venous connection in 1, anomalous, intramural coronary artery in 1, bicuspid pulmonary valve in 1, and other anomalies in 4. Most were previously undiagnosed (11 of 17, 65%). Fourteen of 52 families (27%) had ≥1 relative with CVM. Overall, 7 of 55 siblings (13%), 5 of 46 fathers (11%) and 5 of 51 mothers (10%) had CVM. Although the incidence of CVM in first-degree relatives of HLHS probands was lower in this cohort than previously reported, it remained substantial, with at least one additional member having CVM in 27% of families. The frequent occurrence of undiagnosed CVM highlights the importance of routine familial screening in HLHS. In fact, even if screening was done in childhood, it may be appropriate to screen again in the third or fourth decade to exclude isolated enlargement of the ascending aorta.

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.