Comparison of transesophageal and intracardiac electrophysiologic studies in characterization of supraventricular tachycardia in pediatric patients

Objectives.This study sought to determine the accuracy of transesophageal electrophysiologic studies in diagnosing and characterizing various mechanisms of supraventricular tachycardia in pediatric patients.Background.Transesophageal electrophysiologic studies are a relatively noninvasive means of characterizing supraventricular tachycardia. Although widely used, to our knowledge no data exist that directly compare information obtained from transesophageal electrophysiologic studies with that from intracardiac electrophysiologic studies.Methods.We reviewed the records of 57 pediatric patients undergoing both transesophageal and intracardiac electrophysiologic studies at our institution. The results of these studies were compared with respect to mechanism of tachycardia, localization of accessory atrioventricular (AV) connections (if present) and characterization of anterograde accessory connection conduction properties.Results.Tachycardia mechanisms were concordant in 56 of 57 patients: orthodromic reciprocating tachycardia in 43, antidromic reciprocating tachycardia in 1, both orthodromic and antidromic tachycardia in 2, AV node reentrant tachycardia in 5, atrial reentrant tachycardia in 4 and ectopic atrial tachycardia in 2. Of 29 patients with orthodromic reciprocating tachycardia using a concealed accessory connection, transesophageal study predicted the accessory connection site through changes induced by transient bundle branch block in 12. By the Bland-Altman method in 14 patients with pre-excitation, the anterograde accessory connection effective refractory period determined by transesophageal study compared favorably with that determined by intracardiac study (mean difference 5.0 ms, limits of agreement −55 and 65 ms).Conclusions.Transesophageal electrophysiologic studies are a highly accurate means of diagnosing and characterizing various mechanisms of supraventricular tachycardia in pediatric patients

Prevention of recurrent sudden cardiac arrest: role of provocative electropharmacologic testing

This study evaluates the usefulness of serial provocative electropharmacologic testing for predicting the efficacy of prophylactic antiarrhythmic treatment regimens in patients resuscitated from sudden cardiac arrest in the absence of acute myocardial infarction. Testing was carried out in 34 consecutive patients (28 men and 6 women) who required cardiopulmonary resuscitation and direct current countershock for treatment of primary ventricular fibrillation (28 patients), ventricular tachycardia (5 patients) or excessively rapid heart rate during atrial fibrillation with preexcitation (1 patient).In 8 (24%) of the 34 patients, drug testing either was not feasible because of absence of inducible arrhythmia or was incomplete because of patient withdrawal from study; and 3 of these 8 patients had recurrent sudden cardiac arrest within 10 to 19 months. In an additional five patients, treatment regimens failed to prevent initiation of sustained ventricular tachyarrhythmias in the catheterization laboratory, and two of these five patients had cardiac arrest recurrences within 2 weeks to 25 months of follow-up. In the remaining 21 (62%) of the 34 patients, including 3 patients with preexcitation syndrome, a drug regimen or surgical treatment, or both, was found that prevented inducible life-threatening tachyarrhythmias in the laboratory. Subsequently, only 1 (5%) of these 21 patients died suddenly within a 7 to 38 month (mean ± standard deviation, 18 ± 8.3) follow-up period. Thus, provocative electropharmacologic testing appears to be useful in predicting response to therapy in survivors of sudden cardiac arrest

Loss of Function and Inhibitory Effects of Human CSX/NKX2.5 Homeoprotein Mutations Associated with Congenital Heart Disease

CSX/NKX2.5 is an evolutionarily conserved homeodomain-containing (HD-containing) transcription factor that is essential for early cardiac development. Recently, ten different heterozygous CSX/NKX2.5 mutations were found in patients with congenital heart defects that are transmitted in an autosomal dominant fashion. To determine the consequence of these mutations, we analyzed nuclear localization, DNA binding, transcriptional activation, and dimerization of mutant CSX/NKX2.5 proteins. All mutant proteins were translated and located to the nucleus, except one splice-donor site mutant whose protein did not accumulate in the cell. All mutants that had truncation or missense mutations in the HD had severely reduced DNA binding activity and little or no transcriptional activation function. In contrast, mutants with intact HDs exhibit normal DNA binding to the monomeric binding site but had three- to ninefold reduction in DNA binding to the dimeric binding sites. HD missense mutations that preserved homodimerization ability inhibited the activation of atrial natriuretic factor by wild-type CSX/NKX2.5. Although our studies do not characterize the genotype-phenotype relationship of the ten human mutations, they identify specific abnormalities of CSX/NKX2.5 function essential for transactivation of target genes

Role of Segregation for Variant Discovery in Multiplex Families Ascertained by Probands With Left Sided Cardiovascular Malformations

Cardiovascular malformations (CVM) are common birth defects (incidence of 2–5/100 live births). Although a genetic basis is established, in most cases the cause remains unknown. Analysis of whole exome sequencing (WES) in left sided CVM case and trio series has identified large numbers of potential variants but evidence of causality has remained elusive except in a small percentage of cases. We sought to determine whether variant segregation in families would aid in novel gene discovery. The objective was to compare conventional and co-segregation approaches for WES in multiplex families. WES was performed on 52 individuals from 4 multiplex families ascertained by probands with hypoplastic left heart syndrome (HLHS). We identified rare variants with informatics support (RVIS, minor allele frequency ≤0.01 and Combined Annotation Dependent Depletion score ≥20) in probands. Non-RVIS variants did not meet these criteria. Family specific two point logarithm of the odds (LOD) scores identified co-segregating variants (C-SV) using a dominant model and 80% penetrance. In families, 702 RVIS in 668 genes were identified, but only 1 RVIS was also a C-SV (LOD ≥ 1). On the other hand, there were 109 non-RVIS variants with LOD ≥ 1. Among 110 C-SV, 97% were common (MAF > 1%). These results suggest that conventional variant identification methods focused on RVIS, miss most C-SV. For diseases such as left sided CVM, which exhibit strong familial transmission, co-segregation can identify novel candidates

Impact of \u3cem\u3eMYH6\u3c/em\u3e Variants in Hypoplastic Left Heart Syndrome

Hypoplastic left heart syndrome (HLHS) is a clinically and anatomically severe form of congenital heart disease (CHD). Although prior studies suggest that HLHS has a complex genetic inheritance, its etiology remains largely unknown. The goal of this study was to characterize a risk gene in HLHS and its effect on HLHS etiology and outcome. We performed next-generation sequencing on a multigenerational family with a high prevalence of CHD/HLHS, identifying a rare variant in the α-myosin heavy chain (MYH6) gene. A case-control study of 190 unrelated HLHS subjects was then performed and compared with the 1000 Genomes Project. Damaging MYH6 variants, including novel, missense, in-frame deletion, premature stop, de novo, and compound heterozygous variants, were significantly enriched in HLHS cases (P \u3c 1 × 10−5). Clinical outcomes analysis showed reduced transplant-free survival in HLHS subjects with damaging MYH6 variants (P \u3c 1 × 10−2). Transcriptome and protein expression analyses with cardiac tissue revealed differential expression of cardiac contractility genes, notably upregulation of the β-myosin heavy chain (MYH7) gene in subjects with MYH6 variants (P \u3c 1 × 10−3). We subsequently used patient-specific induced pluripotent stem cells (iPSCs) to model HLHS in vitro. Early stages of in vitro cardiomyogenesis in iPSCs derived from two unrelated HLHS families mimicked the increased expression of MYH7 observed in vivo (P \u3c 1 × 10−2), while revealing defective cardiomyogenic differentiation. Rare, damaging variants in MYH6 are enriched in HLHS, affect molecular expression of contractility genes, and are predictive of poor outcome. These findings indicate that the etiology of MYH6-associated HLHS can be informed using iPSCs and suggest utility in future clinical applications