Negative Impact of the Left Ventricular Remnant Morphology on Systemic Right Ventricular Myocardial Deformation in Hypoplastic Left Heart Syndrome.

Left ventricular (LV) morphology may affect right ventricular (RV) function before and after Fontan palliation in patients with hypoplastic left heart syndrome (HLHS). We sought to assess the potential impact of LV morphology on RV function in patients with HLHS using cardiac magnetic resonance (CMR) imaging. A retrospective analysis of available CMR scans from all patients with HLHS was performed. LV morphology was categorized as absent/slit-like or globular/miniaturized. Volumetric analysis was performed using manual disc-summation method on steady-state free precession (SSFP) stack obtained in short-axis orientation of the ventricles. 4-chamber and short-axis SSFP images were used to measure strain on a semi-automated feature-tracking (FT) module. Two sample t-test was used to compare the groups. A total of 48 CMR scans were analyzed. Of those, 12 patients had absent/slit-like and 36 had globular/miniaturized LV morphology. Averaged 4-chamber longitudinal RV strain was significantly higher for absent/slit-like (- 17.6 ± 4.7%) than globular/miniaturized (- 13.4 ± 3.5; P = 0.002). Averaged 4-chamber radial RV strain was also significantly higher for absent/slit-like (33.1 ± 14.9%) than globular/miniaturized (21.6 ± 7.1; P = 0.001). For globular/miniaturized LV morphology, the decreases of 4-chamber longitudinal and radial strains were mainly attributable to the septal basilar and septal mid-ventricular segments. No differences were found in short-axis RV global circumferential strain between the morphologic subtypes (absent/slit-like - 15.0 ± 6.5, globular/miniaturized - 15.7 ± 4.7; P = 0.68). Larger LV remnants, with globular/miniaturized LV morphology, demonstrated diminished strain in the septal base and mid-ventricle segments. Patients with globular/miniaturized LV morphology may benefit with closer monitoring and lower threshold to start heart failure medications. These results exemplify the utility of including both septal and regional deformation in systemic RV strain analysis.

Inter-observer and Inter-vendor Variability in Strain Measurements in Patients with Single Right Ventricular Anatomy.

Myocardial strain offers new insights into ventricular performance, There are software packages from several different companies used to ascertain this, and little data is available in patients with single right ventricle (sRV) physiology. We aimed to compare the analysis of two strain software applications using a cohort of patients with sRV for both inter-vendor and inter-observer variability. Echocardiograms from 85 patients with sRV (122 separate studies) were prospectively evaluated. All had Glenn and/or Fontan palliation. Longitudinal 4-chamber (4LS), inflow/outflow (IO), circumferential, and radial strain were assessed using Velocity Vector Imaging (VVI, Seimens, Munich) and Automated Functional Imaging (AFI, General Electric, Boston) software. In a subset of 45 patients (61 separate studies), strain measurements were obtained by two sonographers so a paired "inter-observer" analysis could be performed. A moderate correlation between measurements made by the two systems was observed. Circumferential strain assessment had the highest R value (0.77) with all others having R values < 0.6. Both software packages showed modest inter-observer reproducibility for longitudinal and circumferential strain. VVI intraclass correlation coefficients (ICC) for 4LS and average circumferential strain (ACS) were 0.6 and 0.58, compared to 0.68 and 0.59 for AFI. Other than radial strain and VVI IO inferior strain, mean strain differences between AFI and VVI were ≤ 1%. Inter-observer variability is modest, however, mean differences are minimal suggesting reasonable clinical reliability. Inter-vendor variability is greater and not as clinically reliable. In patients with sRV, serial assessments with strain should be performed using the same software.

Ventriculotomy Decreases Agreement Between Assessment of Right Ventricular Function by Echocardiography and Cardiac Magnetic Resonance Imaging in Patients with Hypoplastic Left Heart Syndrome.

Accurate assessment of the right ventricular (RV) volume and function is important in patients with hypoplastic left heart syndrome (HLHS). We sought to investigate the effect of ventriculotomy on the correlation of RV functional assessments by two-dimensional echocardiography (2DE) to cardiac magnetic resonance (CMR)-derived RV ejection fraction (EF) in patients with HLHS. A retrospective re-analysis of CMR imaging with matched 2DE was performed from the institutional HLHS registry. Echocardiographic RV functional parameters were analyzed and correlated with CMR-derived EF. Intraclass correlation coefficient was used to determine interobserver reliability. A total of 58 matched echocardiograms and CMR imaging studies from 46 patients was evaluated. Median duration between CMR imaging and echocardiogram was 1 day (range 0-6 days). No significant difference was seen in CMR RV EF between patients with and without a ventriculotomy (EF - 43.6% vs 44.7%, p = 0.85). The presence of a ventriculotomy significantly decreased the correlation of biplane FAC (r = 0.86 vs 0.52; p = 0.02), triplane FAC (r = 0.84 vs 0.49; p = 0.03), and 2DE visually estimated EF (r = 0.83 vs 0.49; p = 0.02). The correlation of circumferential and longitudinal strains to CMR-derived EF was not significantly affected by the presence of a ventriculotomy. A prior ventriculotomy significantly affected correlation between 2DE FAC and visually estimated EF with CMR-derived EF. The dyskinetic myocardial segment due to ventriculotomy, which is often not visualized by 2DE, may be the reason for this discrepancy.

Hypoplastic Left Heart Syndrome: An Overview for Primary Care Providers.

Hypoplastic left heart syndrome is one of the most complex congenital heart diseases and requires several cardiac surgeries for survival. The diagnosis is usually established prenatally or shortly after birth. Each stage of surgery poses a unique hemodynamic situation that requires deeper understanding to manage common pediatric problems such as dehydration and respiratory infections. Careful multidisciplinary involvement in the care of these complex patients is improving their outcome; however, morbidity and mortality are still substantial. In this review, we focus on the hemodynamic aspects of various surgical stages that a primary care provider should know to manage these challenging patients.

Heart transplantation after Fontan: Results from a surgical Fontan cohort.

We performed a retrospective review of outcomes after heart transplantation during long-term follow-up of a surgical cohort of 1138 Fontan patients who were followed at the Mayo Clinic. Follow-up information was obtained from medical records and a clinical questionnaire that was mailed to patients not known to be deceased at the initiation of the study. Forty-four of 1138 Fontan patients with initial or subsequent evaluation at Mayo had cardiac transplantation between 1988 and 2014 (mean age at transplantation was 23.2 ± 12 yr, median was 19.8 yr; mean interval between Fontan and transplantation was 13.0 ± 7.7 yr, median was 13.1 yr). Two patients had combined organ transplantation (one heart-lung, one heart-liver). Twelve of the 44 (27%) patients had PLE prior to transplantation. There was no difference in post-bypass Fontan pressures or incidence of late reoperations for AVV repair/replacement between transplanted and non-transplanted patients. There were 16 (36%) deaths in the transplantation cohort; seven occurred within 30 days of transplantation. Overall one, five, 10, and 15 yr post-transplantation survival was 80%, 72%, 69%, and 55%, respectively. Although this is a challenging group of patients, intermediate-term results suggest that cardiac transplantation remains a reasonable option for patients with a failed Fontan circulation.

Electrocardiographic abnormalities in elite high school athletes: comparison to adolescent hypertrophic cardiomyopathy.

BACKGROUND: In athletes, ECG changes from physiological cardiac remodelling are common but can overlap with findings from a pathological disorder. We compared ECG findings in a group of elite high school athletes to a cohort of adolescents with hypertrophic cardiomyopathy (HCM). METHODS/RESULTS: We prospectively performed 15-lead ECGs and echocardiograms in 147 elite high school athletes. Student-athlete ECGs were compared in blinded fashion to ECGs of 148 adolescents with HCM of similar age and ethnicity. Standard ECG hypertrophy criteria and established expert opinion guidelines (European Society of Cardiology, ESC and Seattle criteria) were analysed. All student-athletes had normal echocardiograms. Overall, 77/147 (52%) of student-athletes met standard ECG criteria for ventricular hypertrophy compared to 126/148 (85%) adolescents with HCM (p<0.0001). There were 112/148 (76%) adolescents with HCM who had pathological Q-waves, T-wave inversion and/or ST-segment depression compared to 1/147 (1%) athletes (p<0.0001). Most patients with HCM (84%, 124/148) had ≥1 abnormal ECG finding(s) according to Seattle criteria, compared to 1% of student-athletes (2/147). Similarly, 130/148 (88%) patients with HCM met group-2 ESC criteria (abnormal), compared to 36/147 (24%) student-athletes (p<0.0001). CONCLUSIONS: Over 50% of elite high school athletes with echocardiographically confirmed normal hearts satisfied standard voltage criteria for ventricular hypertrophy. Pathological Q-waves, T-wave inversion or ST-segment depression were most helpful in distinguishing adolescents with HCM from normals. Both ESC and Seattle criteria successfully stratified the student-athlete and HCM cohorts, however each had a false-negative rate >10% for the HCM cohort. The Seattle criteria demonstrated a significantly lower false-positive rate (1%) than the ESC criteria (24%).

Compound heterozygous NOTCH1 mutations underlie impaired cardiogenesis in a patient with hypoplastic left heart syndrome.

Hypoplastic left heart syndrome (HLHS) is a severe congenital heart defect (CHD) that necessitates staged, single ventricle surgical palliation. An increased frequency of bicuspid aortic valve (BAV) has been observed among relatives. We postulated number of mutant alleles as a molecular basis for variable CHD expression in an extended family comprised of an HLHS proband and four family members who underwent echocardiography and whole-genome sequencing (WGS). Dermal fibroblast-derived induced pluripotent stem cells (iPSC) were procured from the proband-parent trio and bioengineered into cardiomyocytes. Cardiac phenotyping revealed aortic valve atresia and a slit-like left ventricular cavity in the HLHS proband, isolated bicuspid pulmonary valve in his mother, BAV in a maternal 4° relative, and no CHD in his father or sister. Filtering of WGS for rare, functional variants that segregated with CHD and were compound heterozygous in the HLHS proband identified NOTCH1 as the sole candidate gene. An unreported missense mutation (P1964L) in the cytoplasmic domain, segregating with semilunar valve malformation, was maternally inherited and a rare missense mutation (P1256L) in the extracellular domain, clinically silent in the heterozygous state, was paternally inherited. Patient-specific iPSCs exhibited diminished transcript levels of NOTCH1 signaling pathway components, impaired myocardiogenesis, and a higher prevalence of heterogeneous myofilament organization. Extended, phenotypically characterized families enable WGS-derived variant filtering for plausible Mendelian modes of inheritance, a powerful strategy to discover molecular underpinnings of CHD. Identification of compound heterozygous NOTCH1 mutations and iPSC-based functional modeling implicate mutant allele burden and impaired myogenic potential as mechanisms for HLHS.

Two-dimensional measurement of tricuspid annular plane systolic excursion in children: can it substitute for an m-mode assessment?

BACKGROUND: 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. METHODS: Echocardiographic studies performed for clinical indications were reviewed retrospectively. All consecutive subjects ≤18 years of age were included. The cohort was divided into those with normal echocardiographic findings and those with disorders affecting the right ventricle. Digitally recorded images were analyzed for both MM-TAPSE and 2D-TAPSE. Measurements of 2D-TAPSE were made in an apical four-chamber view, from the tricuspid valve annulus to a consistent point at the apex of the imaging sector at end-diastole and end-systole, with the difference representing the 2D-TAPSE value. RESULTS: A total of 329 subjects (mean age 9.0 ± 6.1 years) met entry criteria. Correlation coefficient between MM-TAPSE and 2D-TAPSE was 0.90. Bland-Altman analysis showed agreement between the two methods to be within 1.2 ± 2.6 mm (mean percentage difference of 6.5%). About 1 mm difference between MM-TAPSE and 2D-TAPSE was consistently observed in all diagnostic subgroups, and across all age categories. CONCLUSION: MM-TAPSE and 2D-TAPSE correlate strongly, with 2D-TAPSE being consistently about 1 mm less than values obtained by the M-mode technique. We conclude that 2D-TAPSE can provide a reliable alternative to MM-TAPSE to quantitatively measure right ventricular systolic function and may be especially useful in situations where retrospective comparisons are sought.

Posterior reversible encephalopathy syndrome and hemorrhage associated with tacrolimus in a pediatric heart transplantation recipient.

Posterior reversible encephalopathy syndrome (PRES) is a disorder characterized by gray and white matter abnormalities in the temporal, parietal, and occipital lobes of the brain. Its etiology has been attributed to renal failure, immunosuppressive drugs such as cyclosporine and tacrolimus, and other potential entities leading to acute hypertension. Clinical findings include headaches, altered mental status, seizures, visual changes, and focal neurologic deficits. We report the case of a child who developed PRES with intracerebral and subarachnoid hemorrhages associated with tacrolimus exposure 10 days after heart transplantation for restrictive cardiomyopathy. The patient initially presented with complex partial seizures, headache, agitation, and hypertension. Head MRI was suggestive of PRES along with intracerebral and subarachnoid hemorrhages. Tacrolimus was discontinued and blood pressure was controlled. The patient's encephalopathy resolved, but he has had ongoing neurologic symptoms secondary to hemorrhage. Generally, PRES is less common in children than in the adult population and is a rare complication of calcineurin inhibitors (CNI). Presentation with secondary hemorrhage also can occur. In children receiving CNIs presenting with new neurologic symptoms, PRES should be considered as prompt discontinuation of the offending agent can induce resolution of symptoms. Children can develop hemorrhage in the context of PRES, leading to increased morbidity.

Empiric switch from calcineurin inhibitor to sirolimus-based immunosuppression in pediatric heart transplantation recipients.

Sirolimus is used in heart transplant patients with CAV and CNI-induced nephropathy. However, little is known regarding the tolerability, rejection rate, and effect on renal function when used empirically in children. We describe our experience with the empiric use of a sirolimus-based immunosuppressive regimen in pediatric heart transplantation recipients. We reviewed records of patients in whom conversion was attempted to a CNI-free sirolimus-based regimen. Rejection episodes and measures of renal function were recorded. We attempted to convert 20 patients, of which 16 were successful. In total, six of 20 patients (30%) experienced adverse effects. Of the 16 converted, four patients converted to sirolimus due to CNI-induced disease (three nephropathy, one CAV), while 12 patients (mean age 5.5 yr, range 0.1-21 yr; 33% female; 33% with a history of congenital heart disease) were empirically switched to sirolimus at a mean of 2.3 yr after transplant. Follow-up was available for a mean of 2.5 yr after conversion (range 0.5-8.3 yr). The rate of rejection while taking CNIs was 0.18 rejection episodes per patient-year (total of five episodes), compared with 0.03 rejection episodes per patient-year (total of one episode) while on sirolimus. Renal function, in terms of GFR, significantly improved after sirolimus conversion at latest follow-up (from 86 ± 37 mL/min to 130 ± 49 mL/min, p = 0.02). Here, we demonstrate the potential benefit of empiric use of sirolimus in pediatric heart transplant patients in a CNI-free regimen. Larger and longer studies are needed to further clarify risks of rejection and adverse effect profiles.

How Does Cross-Sectional Imaging Impact the Management of Patients With Single Ventricle After Bidirectional Cavopulmonary Connection?

BACKGROUND: There is currently no consensus regarding the use of surveillance cross-sectional imaging in pediatric patients after bidirectional cavopulmonary connection (BDCPC). We sought to determine how computed tomography with angiography (CTA) and cardiac magnetic resonance (CMR) imaging impacted the clinical management of pediatric patients after BDCPC. METHODS: A single-center retrospective study including patients with single ventricle who had BDCPC between 2010 and 2019, and CTA/CMR studies obtained in these patients, at ≤5 years of age, and with Glenn physiology. Repeat studies on the same patient were included if the clinical situation had changed. The impact of CTA/CMR studies was categorized as major, minor, or none. RESULTS: Twenty-four patients (63% male) and 30 imaging studies (22 CTAs) were included. 60% were obtained in patients with hypoplastic left heart syndrome (HLHS); most common indication was Follow-up after an intervention (23%). 6 CMRs were performed on stable HLHS patients as part of a research protocol, with no clinical concerns. The overall impact of CTA/CMR studies was major in 13 cases (43.3%). CTA/CMR studies performed ≥1 year of age (62.5% vs 21.4%, P = .02) and in non-HLHS patients (66.7% vs 27.8%, P = .035) were associated with major impact. Also, 2/6 Research studies were associated with a major impact. CONCLUSIONS: CTA/CMR imaging in pediatric patients with SV after BDCPC was associated with significant clinical impact in over 40% of cases, with a higher impact if obtained in patients ≥1 year of age and in non-HLHS patients. We cannot disregard the possibility of CMR as a surveillance imaging modality in this population.

Optimizing Referral Timing of Patients With Fontan Circulatory Failure for Heart Transplant.

BACKGROUND: There are no criteria guiding the timing of heart transplant referral for Fontan patients, nor are there any characteristics of those deferred or declined listing reported. This study examines comprehensive transplant evaluations for Fontan patients of all ages, listing decisions, and outcomes to inform referral practices. METHODS: Retrospective review of 63 Fontan patients formally assessed by the advanced heart failure service and presented at Mayo Clinic transplant selection committee meetings (TSM) January 2006 to April 2021. The study is compliant with the Helsinki Congress and Declaration of Istanbul and included no prisoners. Statistical analysis was performed with Wilcoxon Rank Sum and Fisher's Exact tests. RESULTS: Median age at TSM was 26 years (17.5, 36.5). Most were approved (38/63 [60%]); 9 of 63 (14%) were deferred and 16 of 63 (25%) were declined. Approved patients more commonly were <18 years old at TSM (15/38 [40%] vs 1/25 [4%], P = .002) compared with those deferred/declined. Complications of Fontan circulatory failure were less common in approved vs deferred/declined patients: ascites (15/38 [40%] vs 17/25 [68%], P = .039), cirrhosis (16/38 [42%] vs 19/25 [76%], P = .01), and renal insufficiency (6/38 [16%] vs 11/25 [44%], P = .02). Ejection fraction and atrioventricular valve regurgitation did not differ between groups. Pulmonary artery wedge pressure was overall high normal (12 mm Hg [9,16]) but higher in deferred/declined vs approved patients, 14.5 (11, 19) vs 10 (8, 13.5) mm Hg, P = .015. Overall survival was significantly lower in deferred/declined patients (P = .0018). CONCLUSION: Fontan patient referral for heart transplant at younger age and before the onset of end-organ complications is associated with increased approval for transplant listing.

Vertically oriented intramural right coronary artery in complete transposition of the great arteries: prospective recognition and surgical implications.

This report describes a rare case of complete transposition of the great arteries (TGA) with an intramural right coronary artery arising well above the sinotubular junction. Additionally in this case, the left circumflex artery arose anomalously as a branch from the right coronary. Identification of this anatomic anomaly was made by transthoracic echocardiography before surgery. The patient underwent a successful arterial switch operation on day 6 of life. Due to the preoperative diagnosis of the unusual right intramural coronary artery, the coronary transfer technique during the arterial switch was altered, allowing preservation of the right coronary artery.

From Safety to Benefit in Cell Delivery During Surgical Repair of Ebstein Anomaly: Initial Results.

BACKGROUND: The objective of this study is to assess the safety and early impact of intramyocardial delivery of autologous bone marrow-derived mononuclear cells (BM-MNC) at time of surgical Ebstein repair. METHODS: Patients with Ebstein anomaly (ages 6 months to 30 years) scheduled to undergo repair of the tricuspid valve were eligible to participate in this open-label, non-randomized phase I clinical trial. BM-MNC target dose was 1-3 million cells/kg. Ten patients have undergone surgical intervention and cell delivery to the right ventricle (RV) and completed 6-month follow-up. RESULTS: All patients underwent surgical tricuspid valve repair and uneventful BM-MNC delivery; there were no ventricular arrhythmias and no adverse events related to study product or delivery. Echocardiographic RV myocardial performance index improved and RV fractional area change showed an initial decline and then through study follow-up. There was no evidence of delayed myocardial enhancement or regional wall motion abnormalities at injection sites on 6-month follow-up magnetic resonance imaging. CONCLUSIONS: Intramyocardial delivery of BM-MNC after surgical repair in Ebstein anomaly can be performed safely. Echocardiography variables suggest a positive impact of cell delivery on the RV myocardium with improvements in both RV size and wall motion over time. Additional follow-up and comparison to control groups are required to better characterize the impact of cell therapy on the myopathic RV in Ebstein anomaly.

Systemic Semilunar Valve Repair/Replacement With Fontan Circulation: The Mayo Clinic Experience.

Background: There is a paucity of literature regarding systemic semilunar valve (SSLV) dysfunction in patients with Fontan circulation. We sought to describe our center's 47-year experience with systemic semilunar valve replacement or repair (SSLVR) in patients with Fontan circulation. Methods: The Mayo Clinic Fontan Database is a comprehensive institutional database that stores clinical information of 1176 patients from 1973 to 2021. It was reviewed to identify patients who had a SSLV intervention at the time of or after Fontan. A cohort of 15 patients was identified and a retrospective review of their records was performed. Results: Fourteen patients had SSLV replacement (all mechanical) and one had a repair. SSLVR occurred up to 29 years following the Fontan (mean 11.3 ± 9 years, median 14 years). Thirteen of 14 with SSLVR were performed after Fontan and one was done at the time of initial Fontan. This was an older cohort and mean age at the time of Fontan was 8.7 ± 9.4 years (median 4 years). Indication for the operation was > moderate SSLV regurgitation in all patients. Six patients had decreased ventricular function (EF < 50%) prior to SSLVR and 8 had reduced function after SSLVR. Conclusion: Fortunately, the need for SSLV intervention after Fontan was rare, as evidenced by our small cohort extracted from a large single-institution database spanning a 47-year time period. Reduced preoperative and postoperative ejection fraction was common but did not seem to impact the outcome. Optimal timing for SSLV intervention after Fontan remains unclear.

Cone Reconstruction for Ebstein Anomaly: Ventricular Remodeling and Preliminary Impact of Stem Cell Therapy.

OBJECTIVE: To define the impact of tricuspid valve cone reconstruction (CR) on ventricular performance in Ebstein anomaly, both independently and after stem cell therapy. PATIENTS AND METHODS: The control group included 257 patients who had CR between June 2007 and December 2019. Ten subjects of a phase I stem cell therapy trial (May 2017 - March 2019) were compared with the controls to assess the echocardiographic impact on ventricular remodeling. RESULTS: After CR, right ventricular (RV) size decreased and left ventricular (LV) volume increased in all patients. Apical and biplane RV fractional area change (FAC) initially decreased, but rebounded by 6 months postoperation. Short-axis FAC increased early and was maintained at 6 months post-CR in the control group. At 6 months post-CR, cell therapy patients showed a significantly larger increase in short-axis FAC (24.4% vs 29.9%, P=.003). In addition, whereas LV ejection fraction (EF) was unchanged at 6 months post-CR in controls, cell therapy patients showed a significant increase in EF relative to baseline and to controls (55.6% vs 65.0%, P=.007). CONCLUSION: Cone reconstruction reduces tricuspid regurgitation and RV size, but is also associated with increased RV FAC and LV volume. Furthermore, injection of bone marrow-derived stem cells augmented the increase in RV FAC and was associated with improved LV EF at 6 months post-CR. This is evidence of a favorable interventricular interaction. These findings provide motivation for continued investigation into the potential benefits of stem cell therapy in Ebstein anomaly and other congenital cardiac malformations. TRIAL REGISTRATION: clinicaltrials.gov identifier: NCT02914171.

Clinical Impact of Autologous Cell Therapy on Hypoplastic Left Heart Syndrome After Bidirectional Cavopulmonary Anastomosis.

Preservation of right ventricle function (RV) is a key to favorable outcome in Hypoplastic Left Heart Syndrome (HLHS), but methods to preserve or improve RV function are limited. Our goal was to assess the clinical and functional impact of autologous umbilical cord blood-derived mononuclear cells (UCB-MNC) therapy when given to patients with HLHS at Stage II surgery. UCB-MNC patients were enrolled prospectively in a phase I, FDA monitored trial as previously described (Burkhart et al., 2019). Matched retrospective controls were identified by review of clinical databases. Growth and RV echocardiographic variables were assessed in both groups prestage II through the first 6 months postoperatively. Statistical comparisons between the groups at similar postoperative time points were made to define potential impact of the cell therapy. There were 7 UCB-MNC patients and 17 controls. Prestage II, most parameters showed no differences between groups, although median fractional area change (FAC) was slightly greater in the controls (FAC: controls = 45% vs UCB-MNC = 41% P= 0.02). At dismissal, FAC and estimated Ejection Fraction (EF) decreased in controls, while both were unchanged from baseline in UCB-MNC patients (ΔFAC: -5% vs -1%, P < 0.01; ΔEF: -8% vs 0%, P = 0.03, respectively). Subsequently, median FAC increased slightly in UCB-MNC patients over the 6 month follow-up period, while it decreased in controls (ΔFAC: UCB-MNC +3% vs control -5%, P = 0.03). Preoperative weight percentiles were similar in both groups (UCB-MNC 34%ile vs controls 22%ile, P = 0.93). However, by 6 months postoperative, median weight percentile improved to 63% in the UCB-MNC treated group, but declined to 8% in controls (P = 0.02). UCB-MNC therapy appears to limit the initial negative impact on RV FAC and EF seen after stage II surgery. During early follow up, FAC and weight percentile improved in UCB-MNC patients relative to controls, suggesting a beneficial effect of UCB-MNC therapy.

Genetic Association Between Hypoplastic Left Heart Syndrome and Cardiomyopathies.

BACKGROUND: Hypoplastic left heart syndrome (HLHS) with risk of poor outcome has been linked to MYH6 variants, implicating overlap in genetic etiologies of structural and myopathic heart disease. METHODS: Whole genome sequencing was performed in 197 probands with HLHS, 43 family members, and 813 controls. Data were filtered for rare, segregating variants in 3 index families comprised of an HLHS proband and relative(s) with cardiomyopathy. Whole genome sequencing data from cases and controls were compared for rare variant burden across 56 cardiomyopathy genes utilizing a weighted burden test approach, accounting for multiple testing using a Bonferroni correction. RESULTS: A pathogenic MYBPC3 nonsense variant was identified in the first proband who underwent cardiac transplantation for diastolic heart failure, her father with left ventricular noncompaction, and 2 fourth-degree relatives with hypertrophic cardiomyopathy. A likely pathogenic RYR2 missense variant was identified in the second proband, a second-degree relative with aortic dilation, and a fourth-degree relative with dilated cardiomyopathy. A pathogenic RYR2 exon 3 in-frame deletion was identified in the third proband diagnosed with catecholaminergic polymorphic ventricular tachycardia and his father with left ventricular noncompaction and catecholaminergic polymorphic ventricular tachycardia. To further investigate HLHS-cardiomyopathy gene associations in cases versus controls, rare variant burden testing of 56 genes revealed enrichment in MYH6 (P=0.000068). Rare, predicted-damaging MYH6 variants were identified in 10% of probands in our cohort-4 with familial congenital heart disease, 4 with compound heterozygosity (3 with systolic ventricular dysfunction), and 4 with MYH6-FLNC synergistic heterozygosity. CONCLUSIONS: Whole genome sequencing in multiplex families, proband-parent trios, and case-control cohorts revealed defects in cardiomyopathy-associated genes in patients with HLHS, which may portend impaired functional reserve of the single-ventricle circulation.

Diagnostic Accuracy of Echocardiography and Intraoperative Surgical Inspection of the Unicuspid Aortic Valve.

Unicuspid aortic valve (UAV) is a rare malformation that is often difficult to distinguish from a bicuspid aortic valve (BAV) with commissural fusion by echocardiography or intraoperative surgical inspection. This study assessed the accuracy of intraoperative surgical inspection and two-dimensional echocardiography in diagnosing UAV compared to a gold standard of pathological diagnosis. The Mayo Clinic echocardiographic database, tissue registry database and electronic medical record were searched for all patients assigned a diagnosis of UAV by any technique. Transthoracic (TTE), transesophageal (TEE) echocardiographic, and surgical diagnoses were compared to pathological diagnosis as the standard. A clinical diagnosis of UAV was applied to 380 patients by 1 or more method and in 196 (52%) a pathologic evaluation was available to compare to the clinical description given by TTE, TEE, or surgical inspection. Of these 196 patients, only 58 (30%) had a pathological diagnosis of UAV; the majority were found to be BAVs by pathologic evaluation (n = 132, 67%). For diagnosing UAV, the sensitivity and specificity were 15% and 87% for TTE, 28%, and 82% for TEE, and 52% and 51% for surgical inspection, respectively. Valves with bicuspid morphology and extensive commissural fusion were frequently misclassified as UAV by all methods. In conclusion, intraoperative surgical inspection and echocardiography have limitations for diagnosing UAV due to difficulties in accurately assigning a correct morphological diagnosis, which suggests that the current understanding of the natural history of UAV may be inaccurate.