Katsuhide Maeda

Molecular Diagnosis of Long-QT syndrome at 10 Days of Life by Rapid Whole Genome Sequencing

BACKGROUND The advent of clinical next generation sequencing is rapidly changing the landscape of rare disease medicine. Molecular diagnosis of long QT syndrome (LQTS) can affect clinical management, including risk stratification and selection of pharmacotherapy on the basis of the type of ion channel affected, but results from the current gene panel testing requires 4-16 weeks before return to clinicians. OBJECTIVE A term female infant presented with 2:1 atrioventricular block and ventricular arrhythmias consistent with perinatal LQTS, requiring aggressive treatment including epicardial pacemaker and cardioverter-defibrillator implantation and sympathectomy on day of life 2. We sought to provide a rapid molecular diagnosis for the optimization of treatment strategies. METHODS We performed Clinical Laboratory Improvement Amendments-certified rapid whole genome sequencing (WGS) with a speed-optimized bioinformatics platform to achieve molecular diagnosis at 10 days of life. RESULTS We detected a known pathogenic variant in KCNH2 that was demonstrated to be paternally inherited by follow-up genotyping. The unbiased assessment of the entire catalog of human genes provided by WGS revealed a maternally inherited variant of unknown significance in a novel gene. CONCLUSION Rapid clinical WGS provides faster and more comprehensive diagnostic information at 10 days of life than does standard gene panel testing. In selected clinical scenarios such as perinatal LQTS, rapid WGS can provide more timely and clinically actionable information than can a standard commercial test.

Intermediate-term outcomes after combined heart-liver transplantation in children with a univentricular heart.

For patients with end-stage hepatic failure secondary to failing hemodynamics, combined heart-liver transplant (H-LT) remains the only option for long-term survival. We report a series of three pediatric patients who successfully underwent orthotopic H-LT for failed single-ventricle palliation. All three patients are currently living, now two, three, and five years post-transplant, and remain completely free of cardiac cellular allograft rejection despite reduced immunosuppression protocols. One patient, however, did develop acute antibody-mediated rejection in the immediate post-transplant period, suggesting that this protective effect may be less effective in attenuating humoral mechanisms of rejection.

Lower socioeconomic status is associated with worse outcomes after both listing and transplanting children with heart failure.

The relationship between SES and outcomes surrounding pediatric cardiac transplantation is complex and influenced by recipient race. Broad‐based studies of SES have not been performed. A retrospective review of all 5125 primary pediatric heart transplants performed in the United States between 2000 and 2011. Patients were stratified by SES based on zip code of residence and U.S. census data (low SES: 1637; mid‐SES: 2253; high SES: 1235). Survival following listing and transplantation was compared across strata. Risk‐adjusted long‐term mortality on the waitlist was higher among low SES patients (hazard 1.32, CI 1.07–1.63). The relationship between SES and outcomes varied by race. Early risk‐adjusted post‐transplant outcomes were worst among high SES patients (10.8% vs. low SES: 8.9%, p < 0.05). The incidence of non‐compliance was higher among low SES patients (p < 0.0001). Long‐term risk‐adjusted patient survival was poorer among low (hazard 1.41, CI 1.10–1.80) and mid‐SES (1.29, 1.04–1.59) groups. Low SES is associated with worse outcomes on both the waitlist and late following transplantation. Higher SES patients had more complex transplants with higher early mortality. Further research should be directed at identifying and addressing underlying causal factors for these disparities.

Early somatic mosaicism is a rare cause of long-QT syndrome

Significance Most genetic studies and clinical genetic testing do not look for the possibility of mosaic variation. The genetic form of long-QT syndrome (LQTS) can result in life-threatening arrhythmias, but 30% of patients do not have a genetic diagnosis. We performed deep characterization of a mosaic variant in an infant with perinatal LQTS and developed a computational model showing how abnormal cellular repolarization in only 8% of heart cells may cause arrhythmia. Finally we looked at the prevalence of mosaicism among patients with LQTS; in a population of 7,500 individuals we found evidence of pathogenic early somatic mosaicism in approximately 0.17% of LQTS patients without a genetic diagnosis. Together these data establish an unreported mechanism for LQTS and other genetic arrhythmias. Somatic mosaicism, the occurrence and propagation of genetic variation in cell lineages after fertilization, is increasingly recognized to play a causal role in a variety of human diseases. We investigated the case of life-threatening arrhythmia in a 10-day-old infant with long QT syndrome (LQTS). Rapid genome sequencing suggested a variant in the sodium channel NaV1.5 encoded by SCN5A, NM_000335:c.5284G > T predicting p.(V1762L), but read depth was insufficient to be diagnostic. Exome sequencing of the trio confirmed read ratios inconsistent with Mendelian inheritance only in the proband. Genotyping of single circulating leukocytes demonstrated the mutation in the genomes of 8% of patient cells, and RNA sequencing of cardiac tissue from the infant confirmed the expression of the mutant allele at mosaic ratios. Heterologous expression of the mutant channel revealed significantly delayed sodium current with a dominant negative effect. To investigate the mechanism by which mosaicism might cause arrhythmia, we built a finite element simulation model incorporating Purkinje fiber activation. This model confirmed the pathogenic consequences of cardiac cellular mosaicism and, under the presenting conditions of this case, recapitulated 2:1 AV block and arrhythmia. To investigate the extent to which mosaicism might explain undiagnosed arrhythmia, we studied 7,500 affected probands undergoing commercial gene-panel testing. Four individuals with pathogenic variants arising from early somatic mutation events were found. Here we establish cardiac mosaicism as a causal mechanism for LQTS and present methods by which the general phenomenon, likely to be relevant for all genetic diseases, can be detected through single-cell analysis and next-generation sequencing.

Ventricular assist devices in a contemporary pediatric cohort: Morbidity, functional recovery, and survival

BACKGROUND Limited availability of donor organs has led to the use of ventricular assist devices (VADs) to treat heart failure in pediatric patients, primarily as bridge to transplantation. How effective VAD therapy is in promoting functional recovery in children is currently not known. METHODS We report morbidity and mortality as defined by the Interagency Registry for Mechanically Assisted Circulatory Support Modified for Pediatrics (PediMACS) and the use of the Treatment Intensity Score to assess functional status for 50 VAD patients supported at a single pediatric program from 2004 to 2013. RESULTS In this cohort, 30-day survival on VAD was 98%, and 180-day survival was 83%. Stroke occurred in 11 patients (22%), with 8 (16%) resulting in persistent neurologic deficit or death. The adverse event rate was 2-fold to 3-fold higher in the first 7 days of support compared with the subsequent support period. Functional status, as measured by the Treatment Intensity Score, improved with duration of support. Successful bridge to transplantation was associated with fewer adverse events during support and greater improvement in the Treatment Intensity Score during the period of support. CONCLUSIONS Overall survival in this cohort is excellent. The risk of serious adverse events decreases over the first month of support. However, a clinically significant risk of morbidity and mortality persists for the duration of pediatric VAD support. Measures of functional status improve with duration of support and are associated with survival to transplantation.

An inpatient rehabilitation program utilizing standardized care pathways after paracorporeal ventricular assist device placement in children

BACKGROUND Structured rehabilitation programs in adults after ventricular assist device (VAD) placement result in improvements in physical function and exercise capacity, and have been shown to improve survival and accelerate post-transplant recovery. The objective of this study was to determine the safety and feasibility of an acute inpatient rehabilitation program for children utilizing standardized, age-appropriate, family-centered care pathways after paracorporeal VAD placement in both the ICU and acute-care inpatient settings. METHODS Between November 12, 2010 and March 15, 2013, 17 patients were referred to therapy after VAD implantation, 14 of whom were medically stable enough to participate. Beginning in the ICU, a structured physical and occupational therapy program was implemented utilizing novel age-appropriate, standardized care pathways for infants (age <1 year) and children (age 1 to 12 years). The infant and child pathways consisted of 8 and 10 goals, respectively. Retrospective review was conducted to ascertain the number of phases achieved per patient. Adverse events, defined as bleeding, physiologic instability, stroke, or device disruption during therapy, were also analyzed. RESULTS The median age was 1.1 (range 0.5 to 14.4) years in the 14 patients considered medically stable enough to participate in rehabilitation. Nine of them were female. Eight patients participated in the infant standardized care pathway (SCP) and 6 participated in the child SCP. Seven patients were on biventricular support. Twelve patients were transplanted and survived. Two patients died while awaiting transplantation. There were 1,473 total days on the VAD (range 40 to 229 days). The median time to extubation was 2 days (range 1 to 8) and the median ICU stay was 6.5 days (range 3 to 152). Eleven patients achieved all goals of the SCP, including all of the patients in the child group. For the infant group, 5 patients achieved all goals of the SCP (range 5 to 8), and all but 1 patient achieved at least 7 goals of the SCP. There were no adverse events related to therapy. CONCLUSIONS Standardized, family-centered inpatient rehabilitation care paths are safe for infants and children after paracorporeal device placement. Structured rehabilitation goals can be achieved by the majority of pediatric patients during VAD support. Early mobilization and inpatient rehabilitation in this cohort promotes normalization of function while awaiting cardiac transplantation.

Midterm Results of the Modified Ross/Konno Procedure in Neonates and Infants

BACKGROUND The management of congenital aortic stenosis in neonates and infants continues to be a surgical challenge. We have performed the modified Ross-Konno procedure for patients who have severe aortic insufficiency or significant residual stenosis after balloon aortic dilation. The midterm results of this procedure were evaluated in this subset of patients. METHODS Between 1994 and 2010, a total of 24 patients younger than 1 year of age underwent the modified Ross-Konno procedure. The diagnoses were aortic stenosis with or without subaortic stenosis (n = 16), Shones complex (n = 7), and interrupted aortic arch with subaortic stenosis (n = 1). The aortic root was replaced with a pulmonary autograft, and the left ventricular outflow tract (LVOT) was enlarged with a right ventricular infundibular free wall muscular extension harvested with the autograft. RESULTS Age at operation ranged from 1 to 236 days (median 28 days). The median follow-up period was 81 months (range 1-173 months). There was 1 early death and no late mortality. Overall the 1-, 2-, and 5-year survival rate was 95% ± 4.5%. Freedom from aortic stenosis was 94.7% ± 5.1% at 1, 2, and 5 years. Less than mild aortic insufficiency was 93.3% ± 6.4% at 2 years, and 74.7% ± 12.9% at 5 years. In total, 23 reoperations and reinterventions were performed; 14 were allograft conduit replacements. Two patients required aortic valve plasty. None required valve replacement. The reintervention-free rate was 64.6% ± 10.8% at 2 years and 36.9% ± 11.3% at 5 years. CONCLUSIONS Pulmonary autografts demonstrated good durability with low mortality and morbidity. This study shows that the modified Ross-Konno procedure can be a practical choice in selective cases for complex LVOT stenosis in neonates and infants.

Use of the Impella 5.0 as a bridge from ECMO to implantation of the HeartMate II left ventricular assist device in a pediatric patient

A 10-yr-old previously healthy boy presented in cardiogenic shock after collapsing at school was subsequently diagnosed with a dilated cardiomyopathy at an outside hospital. Within hours following transfer to our cardiovascular intensive care unit (CVICU), the patient quickly decompensated, necessitating emergent V-A ECMO cannulation. Social service issues initially precluded listing for cardiac transplantation. On hospital day no. 14, an Impella 5.0 device was surgically implanted via the right femoral artery leading to successful weaning from ECMO (Fig. 1). The Impella required replacement 10 days after implantation because of mechanical failure. On hospital day no. 27, the Impella was removed and a HeartMate II LVAD was implanted for long-term management (Fig. 2). The procedure was complicated by pericardial tamponade requiring emergent chest exploration and evacuation of a large pericardial hematoma. The patient was extubated on hospital day no. 56 and weaned off all inotropic infusions. Demonstrating consistently appropriate hemodynamics, the patient was discharged from the CVICU to the acute care floor, and on hospital day no. 139, the patient was transferred to another institution closer to his father s home for continuing care. After further rehabilitation, the patient was listed for and subsequently underwent successful cardiac transplantation. Ventricular assist devices are used with increasing frequency in children for the treatment of cardiogenic shock (INTERMACS indication 1) or progressive decline, while on inotropic support (INTERMACS indication 2) (1). A recent report of 99 patients in the Pediatric Heart Transplant Study database reported 77% patients surviving to transplantation and 5% being successfully weaned from support (2). Fig. 1. The Impella 5.0 is seen in long axis on transesophageal echocardiogram. Fig. 2. The HeartMate II (LV apical cannula) is seen in four-chamber view on transthoracic echocardiogram. Pediatr Transplantation 2012: 16: 205–206 2011 John Wiley & Sons A/S.

Recovery during mid-term mechanical support of fontan circulation in sheep.

Total cavopulmonary connection (CPC) has a significant incidence of late failure due to increased systemic venous pressure and low cardiac output. Mechanical support could prevent failure by correcting hemodynamics. We established a model of inferior CPC using an axial flow pump (Thoratec HeartMate II, Thoratec Corp. Pleasanton, CA) in a group of ten 47–57 kg sheep and assessed hemodynamics and metabolism as a potential chronic treatment option for failed Fontan circulation. After pilot studies (n = 7), three animals underwent pump-supported inferior CPC to assess hemodynamic and metabolic responses. Pump inflow was connected to the inferior vena cava (IVC) and outflow to the main pulmonary artery. The IVC was ligated at the right atrium. Hemodynamic and biochemical parameters were recorded over four days. The first seven animals died from pump-related causes (graft kinking, three; pump thrombosis, one) or other causes (GI bleeding, one; suspected stroke, two). The subsequent three animals were electively euthanized on postoperative day four due to IRB requirements. Over the four day postoperative period, pump flow was 3.43 ± 0.62 L/min and IVC pressure 4.05 ± 3.21 mm Hg (mean ± SD). Lactate levels remained normal. Low pressure and high-volume IVC flow was sustained by mechanical support. We will next attempt chronic pump implantation.

Outpatient Outcomes of Pediatric Patients with Left Ventricular Assist Devices.

Outpatient experience of children supported with continuous-flow ventricular assist devices (CF-VAD) is limited. We reviewed our experience with children discharged with CF-VAD support. All pediatric patients <18 years old with CF-VADs implanted at our institution were included. Discharge criteria included a stable medication regimen, completion of a VAD education program and standardized rehabilitation plan, and presence of a caregiver. Hospital readmissions (excluding scheduled admissions) were reviewed. Adverse events were defined by Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) criteria. Of 17 patients with CF-VADs, 8 (47%) were discharged from the hospital (1 HeartWare ventricular assist device (Heartware Inc., Framingham, MA), 7 HeartMate II (Thoratec Corp, Pleasanton, CA)). Median age was 15.3 (range 9.6–17.1) years and weight was 50.6 (33.6–141) kg. Device strategies were destination therapy (DT; n = 4) and bridge to transplant (n = 4). Patients spent a median 49 (26–107) days hospitalized postimplant and had 2 (1–5) hospital readmissions. Total support duration was 3,154 patient-days, with 2,413 as outpatient. Most frequent adverse events were device malfunction and arrhythmias. There was one death because of pump thrombosis and no bleeding or stroke events. Overall adverse event rate was 15.22 per 100 patient-months. Early experience suggests that children with CF-VADs can be safely discharged. Device malfunction and arrhythmia were the most common adverse events but were recognized quickly with structured outpatient surveillance.