Jeffrey M. Vinocur

Catecholaminergic Polymorphic Ventricular Tachycardia in Children Analysis of Therapeutic Strategies and Outcomes From an International Multicenter Registry

Background—Catecholaminergic polymorphic ventricular tachycardia is an uncommon, potentially lethal, ion channelopathy. Standard therapies have high failure rates and little is known about treatment in children. Newer options such as flecainide and left cardiac sympathetic denervation are not well validated. We sought to define treatment outcomes in children with catecholaminergic polymorphic ventricular tachycardia. Methods and Results—This is a Pediatric and Congenital Electrophysiology Society multicenter, retrospective cohort study of catecholaminergic polymorphic ventricular tachycardia patients diagnosed before 19 years of age. The cohort included 226 patients, including 170 probands and 56 relatives. Symptomatic presentation was reported in 176 (78%). Symptom onset occurred at 10.8 (interquartile range, 6.8–13.2) years with a delay to diagnosis of 0.5 (0–2.6) years. Syncope (P<0.001), cardiac arrest (P<0.001), and treatment failure (P=0.008) occurred more often in probands. &bgr;-Blockers were prescribed in 205 of 211 patients (97%) on medication, and 25% experienced at least 1 treatment failure event. Implantable cardioverter defibrillators were placed in 121 (54%) and was associated with electrical storm in 22 (18%). Flecainide was used in 24% and left cardiac sympathetic denervation in 8%. Six deaths (3%) occurred during a cumulative follow-up of 788 patient-years. Conclusions—This study demonstrates a malignant phenotype and lengthy delay to diagnosis in catecholaminergic polymorphic ventricular tachycardia. Probands were typically severely affected. &bgr;-Blockers were almost universally initiated; however, treatment failure, noncompliance and subtherapeutic dosing were often reported. Implantable cardioverter defibrillators were common despite numerous device-related complications. Treatment failure was rare in the quarter of patients on flecainide. Left cardiac sympathetic denervation was not uncommon although the indication was variable.

Letal, A tumor-associated NKG2D immunoreceptor ligand, induces activation and expansion of effector immune cells.

NKG2D serves as one of the most potent activating receptors for effector lymphocytes in peripheral tissues. Here we report the characterization of Letal, the first human transmembrane NKG2D ligand lacking an immunoglobulin-like a-3 ectodomain. Letal is constitutively expressed by a variety of normal tissues, and is up-regulated in tumor cells of different origins. Unlike other NKG2D ligands, Letal mRNA expression progressively decreased after treatment of tumor cells with retinoic acid. Simultaneous T-cell receptor activation and engagement of Letal stimulated proliferation of CD8+ cells and dramatically increased IL-2 and IFN-g secretion. In addition, Letal induced the killing of cancer cells by CD8+ and NK cells. These results suggest that Letal delivers activating signals to NK cells and promotes tumor immune surveillance by inducing the expansion of anti-tumor cytotoxic lymphocytes.

Putting the Pediatric Cardiac Care Consortium in Context Evaluation of Scope and Case Mix Compared With Other Reported Surgical Datasets

Collaborative multi-institutional clinical registries are critical in pediatric cardiology, with its diverse diagnoses and procedures and relatively low event rates.1,2 Founded in 1982 to support quality improvement,3 the Pediatric Cardiac Care Consortium (PCCC) contains clinical information on over 137 000 patients (through 2007). Centers participate voluntarily and membership has varied over time; of the 57 PCCC centers, 35 have contributed at least 10 years of data. Analyses of PCCC data have contributed to an understanding of cardiac surgical outcomes in children (see online-only Data Supplement Table I).4 Centers of the size range represented in the PCCC (< 500 operations/year) may vary systematically in their case mix relative to larger centers. To provide context for outcomes research reports from the PCCC, we analyzed (1) how the case mix at PCCC centers compares with that in published …

In‐Hospital Vital Status and Heart Transplants After Intervention for Congenital Heart Disease in the Pediatric Cardiac Care Consortium: Completeness of Ascertainment Using the National Death Index and United Network for Organ Sharing Datasets

Background The long‐term outcomes of patients undergoing interventions for congenital heart disease (CHD) remain largely unknown. We linked the Pediatric Cardiac Care Consortium (PCCC) with the National Death Index (NDI) and the United Network for Organ Sharing Dataset (UNOS) registries to study mortality and transplant occurring up to 32 years postintervention. The objective of the current analysis was to determine the sensitivity of this linkage in identifying patients who are known to have died or undergone heart transplant. Methods and Results We used direct identifiers from 59 324 subjects registered in the PCCC between 1982 and 2003 to test for completeness of case ascertainment of subjects with known vital and heart transplant status by linkage with the NDI and UNOS registries. Of the 4612 in‐hospital deaths, 3873 were identified by the NDI as “true” matches for a sensitivity of 84.0% (95% CI, 82.9–85.0). There was no difference in sensitivity across 25 congenital cardiovascular conditions after adjustment for age, sex, race, presence of first name, death year, and residence at death. Of 455 known heart transplants in the PCCC, there were 408 matches in the UNOS registry, for a sensitivity of 89.7% (95% CI, 86.9–92.3). An additional 4851 deaths and 363 transplants that occurred outside the PCCC were identified through 2014. Conclusions The linkage of the PCCC with the NDI and UNOS national registries is feasible with a satisfactory sensitivity. This linkage provides a conservative estimate of the long‐term death and heart transplant events in this cohort.

Development of Quality Metrics in Ambulatory Pediatric Cardiology

The American College of Cardiology Adult Congenital and Pediatric Cardiology (ACPC) Section had attempted to create quality metrics (QM) for ambulatory pediatric practice, but limited evidence made the process difficult. The ACPC sought to develop QMs for ambulatory pediatric cardiology practice. Five areas of interest were identified, and QMs were developed in a 2-step review process. In the first step, an expert panel, using the modified RAND-UCLA methodology, rated each QM for feasibility and validity. The second step sought input from ACPC Section members; final approval was by a vote of the ACPC Council. Work groups proposed a total of 44 QMs. Thirty-one metrics passed the RAND process and, after the open comment period, the ACPC council approved 18 metrics. The project resulted in successful development of QMs in ambulatory pediatric cardiology for a range of ambulatory domains.

Age-Dependent Sex Effects on Outcomes After Pediatric Cardiac Surgery

Background Sex has been linked to differential outcomes for cardiovascular disease in adults. We examined potential sex differences in outcomes after pediatric cardiac surgery. Methods and Results We retrospectively analyzed data from the Pediatric Cardiac Care Consortium (1982–2007) by using logistic regression to evaluate the effects of sex on 30‐day within‐hospital mortality after pediatric (<18 years old) cardiac operations and its interaction with age, risk category, z‐score for weight, and surgical year for the whole cohort. Of 76 312 operations, 55% were in boys. Unadjusted mortality was similar for boys and girls (5.2% versus 5.0%, P=0.313), but boys were more likely to have cardiac surgery as a neonate and to have more complex operations. After adjustment, the overall test of any association between postsurgical mortality and sex was significant (P=0.002), but the overall test of any interaction was not (P=0.503). However, a potential age‐dependent sex effect on postsurgical mortality was observed among infants subjected to high‐risk operations, with girls doing worse during the first 6 months of life. Conclusions Patient sex has a significant effect on mortality after pediatric cardiac operations, with an increased risk of death in early infancy for girls after high‐risk cardiac operations. This age‐dependent relationship supports a sex‐related biological effect on postoperative cardiovascular stress.

Surgical Placement of Permanent Epicardial Pacing Systems in Very Low-Birth Weight Premature Neonates A Review of Data From the Pediatric Cardiac Care Consortium (PCCC)

Few studies have characterized the surgical outcomes following epicardial pacemaker placement in very low-birth weight infants with congenital complete heart block. This study was undertaken to review the surgical experience with this patient population based on data from a large multi-institutional registry. Methods: The Pediatric Cardiac Care Consortium (PCCC) multi-institutional database was retrospectively reviewed to identify premature, low-birth weight neonates that underwent surgical placement of an epicardial pacing system for heart block. We reviewed 179 patients with birth weights less than 1.5 kg that underwent a major operative procedure. Of these, 10 patients underwent surgical placement of an epicardial pacing system for heart block. Patients had heart block in otherwise structurally normal hearts (n = 6) or heart block associated with complex structural congenital cardiac anomalies (n = 4). Results: There were no deaths directly related to the surgical placement of the epicardial pacing system. There were no immediate complications with either lead or generator placement. One generator pocket was revised three months following placement. Survival to discharge was 60%. The four deaths occurred at a mean of 11 days (range 1-45 days) following the procedure. Conclusions: Neonates born with prematurity and congenital heart block represent a challenging subset of patients with significant mortality. Generator pocket breakdown and infection have been considered barriers to optimal short- and long-term outcomes. Among cases in the PCCC, there were no deaths or major complications that could be attributed to permanent epicardial pacemaker placement. These data suggest that an aggressive surgical strategy may be justified.

The clinical and genetic spectrum of catecholaminergic polymorphic ventricular tachycardia: findings from an international multicentre registry

Aims Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an ion channelopathy characterized by ventricular arrhythmia during exertion or stress. Mutations in RYR2-coded Ryanodine Receptor-2 (RyR2) and CASQ2-coded Calsequestrin-2 (CASQ2) genes underlie CPVT1 and CPVT2, respectively. However, prognostic markers are scarce. We sought to better characterize the phenotypic and genotypic spectrum of CPVT, and utilize molecular modelling to help account for clinical phenotypes. Methods and results This is a Pediatric and Congenital Electrophysiology Society multicentre, retrospective cohort study of CPVT patients diagnosed at <19 years of age and their first-degree relatives. Genetic testing was undertaken in 194 of 236 subjects (82%) during 3.5 (1.4-5.3) years of follow-up. The majority (60%) had RyR2-associated CPVT1. Variant locations were predicted based on a 3D structural model of RyR2. Specific residues appear to have key structural importance, supported by an association between cardiac arrest and mutations in the intersubunit interface of the N-terminus, and the S4-S5 linker and helices S5 and S6 of the RyR2 C-terminus. In approximately one quarter of symptomatic patients, cardiac events were precipitated by only normal wakeful activities. Conclusion This large, multicentre study identifies contemporary challenges related to the diagnosis and prognostication of CPVT patients. Structural modelling of RyR2 can improve our understanding severe CPVT phenotypes. Wakeful rest, rather than exertion, often precipitated life-threatening cardiac events.

Long-Term Transplant-Free Survival After Repair of Total Anomalous Pulmonary Venous Connection

BACKGROUND Long-term survival, risk of transplantation, and causes of death after repair of total anomalous pulmonary venous connection (TAPVC) remain unknown. By linking the Pediatric Cardiac Care Consortium with the National Death Index and the United Network for Organ Sharing, we evaluated long-term transplant-free survival in children undergoing repair of TAPVC. METHODS We identified 777 infants within the Pediatric Cardiac Care Consortium who underwent TAPVC repair (median 21 days; interquartile range, 5 to 80) and had sufficient personal identifiers for linkage with the National Death Index and United Network for Organ Sharing. Sixty-six deaths, ten cardiac transplantations, and one bilateral lung transplantation had occurred by the end of 2014. Data collected included age and weight at time of procedure, TAPVC type, associated cardiac lesions, and postoperative length of stay. The study cohort was divided into simple and complex TAPVC based on the presence of an associated cardiac lesion. Parametric survival plots were constructed, and risk factor analyses were performed to identify demographic and clinical characteristics associated with long-term outcomes. RESULTS Mortality or need for transplantation was 9.7% with a median follow-up of 18.4 years and a median age of death or transplant of 0.74 years. The risk of mortality and transplant after TAPVC repair was highest during the first 18 months after hospital discharge. Cardiac causes accounted for the majority of deaths. Multivariate regression models for transplant-free survival demonstrated that complex TAPVC, mixed TAPVC, and postoperative length of stay were associated with increased risk of death/transplant. CONCLUSIONS Transplant-free survival after TAPVC repair is excellent, with most deaths or transplant events occurring early. Factors associated with the worst long-term outcomes included complex TAPVC, mixed TAPVC, and prolonged postoperative length of stay.

Brugada Phenocopy Associated with Diabetic Ketoacidosis in Two Pediatric Patients

Two patients without cardiac history demonstrated type 1 Brugada pattern during hospitalization for diabetic ketoacidosis (DKA). Both patients had normalization of their ECGs after treatment of marked electrolyte abnormalities and metabolic acidosis. In this report, we describe two cases of Brugada phenocopy associated with DKA in children.