O’Leary, Patrick

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.

Abstract Congenital heart diseases (CHDs) requiring surgical palliation mandate new treatment strategies to optimize long-term outcomes. Despite the mounting evidence of cardiac regeneration, there are no long-term safety studies of autologous cell-based transplantation in the pediatric setting. We aimed to establish a porcine pipeline to evaluate the feasibility and long-term safety of autologous umbilical cord blood mononuclear cells (UCB-MNCs) transplanted into the right ventricle (RV) of juvenile porcine hearts. Piglets were born by caesarean section to enable UCB collection. Upon meeting release criteria, 12 animals were randomized in a double-blinded fashion prior to surgical delivery of test article (n = 6) or placebo (n = 6). The UCB-MNC (3 × 106 cells per kilogram) or control (dimethyl sulfoxide, 10%) products were injected intramyocardially into the RV under direct visualization. The cohorts were monitored for 3 months after product delivery with assessments of cardiac performance, rhythm, and serial cardiac biochemical markers, followed by terminal necropsy. No mortalities were associated with intramyocardial delivery of UCB-MNCs or placebo. Two animals from the placebo group developed local skin infection after surgery that responded to antibiotic treatment. Electrophysiological assessments revealed no arrhythmias in either group throughout the 3-month study. Two animals in the cell-therapy group had transient, subclinical dysrhythmia in the perioperative period, likely because of an exaggerated response to anesthesia. Overall, this study demonstrated that autologous UCB-MNCs can be safely collected and surgically delivered in a pediatric setting. The safety profile establishes the foundation for cell-based therapy directed at the RV of juvenile hearts and aims to accelerate cell-based therapies toward clinical trials for CHD.

BackgroundTricuspid 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.MethodsEchocardiographic 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.ResultsA 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.ConclusionMM‐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.

AbstractSirolimus 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.

AbstractPosterior 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.

Irreparable mitral pathology may lead to early mitral valve replacement (MVR) in children. Often, a small mechanical prosthesis (<23 mm) is required, raising concerns about annular growth in patients who may eventually require subsequent mitral valve re-replacement (MVRR). The aim of this study was to evaluate interval mitral annular growth in this cohort. Between January 1972 and December 2006, 164 children underwent MVR with a mechanical prosthesis; 110 of these children (median age, 4 years; range, 7 days to 14 years) received a small mechanical prosthesis (<23 mm). The most common diagnoses were congenital mitral stenosis (10%), regurgitation (46%), and left atrioventricular valve dysfunction after previous atrioventricular septal defect repair (44%). The cohort was analyzed for age, body surface area (BSA), prosthesis size, and Z score at the time of MVR and MVRR. At the time of MVR, 78 patients had a BSA of 0.77 ± 0.06 m2, had an annular size of 24 ± 0.62 mm ( Z score, 2.91 ± 0.23), and ultimately did not require MVRR. Another cohort, who eventually did require MVRR (n = 24), had an initial BSA at the time of MVR of 0.62 ± 0.05 m2 ( P = NS vs MVR only) and an annular size of 20 ± 0.49 mm ( Z score, 1.85 ± 0.22) ( P = .008 vs MVR only). In the interval between MVR and MVRR (7.8 ± 1.1 years), BSA increased to 1.12 ± 0.07 m2, and annulus size increased to 24 ± 0.47 mm ( Z score, 1.80 ± 0.28). These data suggest growth of the mitral annulus following MVR with a small mechanical prosthesis, as evidenced by an unchanged Z score in the setting of normal interval increase in BSA. Additionally, there was a statistically significant difference in initial Z scores between the cohorts requiring MVRR and those who have not needed re-replacement, suggesting that the feasibility of placement of a slightly larger prosthesis may be associated with a decreased need for MVRR.