Michael P. Carboni

Long QT syndrome, Brugada syndrome, and conduction system disease are linked to a single sodium channel mutation

The function of the 12 positive charges in the 53-residue III/IV interdomain linker of the cardiac Na(+) channel is unclear. We have identified a four-generation family, including 17 gene carriers with long QT syndrome, Brugada syndrome, and conduction system disease with deletion of lysine 1500 (DeltaK1500) within the linker. Three family members died suddenly. We have examined the functional consequences of this mutation by measuring whole-cell and single-channel currents in 293-EBNA cells expressing the wild-type and DeltaK1500 mutant channel. The mutation shifted V(1/2)h( infinity ) to more negative membrane potentials and increased k(h) consistent with a reduction of inactivation valence of 1. The shift in h( infinity ) was the result of an increase in closed-state inactivation rate (11-fold at -100 mV). V(1/2)m was shifted to more positive potentials, and k(m) was doubled in the DeltaK1500 mutant. To determine whether the positive charge deletion was the basis for the gating changes, we performed the mutations K1500Q and K1500E (change in charge, -1 and -2, respectively). For both mutations, V(1/2)h was shifted back toward control; however, V(1/2)m shifted progressively to more positive potentials. The late component of Na(+) current was increased in the DeltaK1500 mutant channel. These changes can account for the complex phenotype in this kindred and point to an important role of the III/IV linker in channel activation.

Radiofrequency catheter ablation of supraventricular tachycardia substrates after mustard and senning operations for d-transposition of the great arteries

OBJECTIVES The purpose of this study was to determine the efficacy and risks of radiofrequency ablation of various forms of supraventricular tachycardia after Mustard and Senning operations for d-transposition of the great arteries. BACKGROUND In this patient group, the reported success rate of catheter ablation of intraatrial reentry tachycardia is about 70% with a negligible complication rate. There are no reports of the use of radiofrequency ablation to treat other types of supraventricular tachycardia. METHODS Standard diagnostic criteria were used to determine supraventricular tachycardia type. Appropriate sites for attempted ablation included 1) intraatrial reentry tachycardia: presence of concealed entrainment with a postpacing interval similar to tachycardia cycle length; 2) focal atrial tachycardia: a P-A interval < or =-20 ms; and 3) typical variety of atrioventricular (AV) node reentry tachycardia: combined electrographic and radiographic features. RESULTS Nine Mustard and two Senning patients underwent 13 studies to successfully ablate all supraventricular tachycardia substrates in eight (73%) patients. Eight of eleven (73%) patients having intraatrial reentry tachycardia, 3/3 having typical AV node reentry tachycardia, and 2/2 having focal atrial reentry tachycardia were successfully ablated. Among five patients having intraatrial reentry tachycardia (IART) and not having ventriculoatrial (V-A) conduction, two suffered high-grade AV block when ablation of the systemic venous portion of the medial tricuspid valve/inferior vena cava isthmus was attempted. CONCLUSIONS Radiofrequency catheter ablation can be effectively and safely performed for certain supraventricular tachycardia types in addition to intraatrial reentry. A novel catheter course is required for slow pathway modification. High-grade AV block is a potential risk of lesions placed in the systemic venous medial isthmus.

Quinidine in the treatment of KCNT1-positive epilepsies

We report 2 patients with drug‐resistant epilepsy caused by KCNT1 mutations who were treated with quinidine. Both mutations manifested gain of function in vitro, showing increased current that was reduced by quinidine. One, who had epilepsy of infancy with migrating focal seizures, had 80% reduction in seizure frequency as recorded in seizure diaries, and partially validated by objective seizure evaluation on EEG. The other, who had a novel phenotype, with severe nocturnal focal and secondary generalized seizures starting in early childhood with developmental regression, did not improve. Although quinidine represents an encouraging opportunity for therapeutic benefits, our experience suggests caution in its application and supports the need to identify more targeted drugs for KCNT1 epilepsies. Ann Neurol 2015;78:995–999

The ventricular volume variability study of the Pediatric Heart Network: study design and impact of beat averaging and variable type on the reproducibility of echocardiographic measurements in children with chronic dilated cardiomyopathy.

BACKGROUND Clinical trials often rely on echocardiographic measures of left ventricular size and function as surrogate end points. However, the quantitative impact of factors that affect the reproducibility of these measures is unknown. To address this issue, the National Heart, Lung, and Blood Institute-funded Pediatric Heart Network designed a longitudinal observational study of children with known or suspected dilated cardiomyopathy aged 0 to 22 years from eight pediatric clinical centers. METHODS Clinical data were collected together with 150 echocardiographic indices of left ventricular size and function. Separate observers performed duplicate echocardiographic imaging. Multiple observers performed measurements from three cardiac cycles to enable assessment of intraobserver and interobserver variability. The impacts of beat averaging (BA), observer type (local vs core), and variable type (areas, calculations, dimensions, slopes, time intervals, and velocities) on measurement reproducibility were studied. The outcome measure was percentage error (100 × difference/mean). RESULTS Of 173 enrolled subjects, 131 met criteria for dilated cardiomyopathy. BA, variable type and observer type all influenced percentage error (P < .0001). Core interobserver percentage error (medians, 11.4%, 10.2%, and 9.3% for BA using one, two, and three beats, respectively) was approximately twice the intraobserver percentage error (medians, 6.3%, 4.9%, and 4.2% for BA using one, two, and three beats, respectively). Slopes and calculated variables exhibited high percentage error despite BA. Chamber dimensions, areas, velocities, and time intervals exhibited low percentage error. CONCLUSIONS This comprehensive evaluation of quantitative echocardiographic methods will provide a valuable resource for the design of future pediatric studies. BA and a single core lab observer improve the reproducibility of echocardiographic measurements in children with dilated cardiomyopathy. Certain measurements are highly reproducible, while others, despite BA, are poorly reproducible.

Brugada-Like Syndrome in Infancy Presenting With Rapid Ventricular Tachycardia and Intraventricular Conduction Delay

Background— Brugada syndrome is a potentially serious channelopathy that usually presents in adulthood and has only rarely been described in infancy. In the absence of metabolic or structural cardiac disease, rapid ventricular tachycardia (>200 bpm) and primary cardiac conduction disease are uncommon in infancy. We hypothesized that infants having rapid ventricular tachycardia and conduction abnormalities and not having structural or metabolic pathogeneses were likely to have mutations in depolarizing current channels. Methods and Results— A retrospective review of all clinical materials from a single institution over a 9-year period from all infants <2 years old and having a discharge diagnosis of ventricular tachycardia or ventricular fibrillation was performed. Among 32 infants fulfilling inclusion criteria, 12 had a structurally normal heart, and 9 of them had either prolonged QRS duration or Brugada pattern while in sinus rhythm. Of those 5 infants not having a definitive pathogenesis, electrophysiological testing had been performed in 4, and genetic testing had been performed in all 5 of those infants. During electrophysiological testing, a prolonged HV interval was present in 2 of 4, inducible ventricular tachycardia was present in 1 of 4, and a type 1 Brugada pattern was induced by intravenous procainamide in 3 of 4. Genetic testing revealed disease-causing mutations in depolarizing sodium (SCN5A) or calcium (CaCNB2b) channels in all 5 infants. Conclusions— Infants having rapid ventricular tachycardia and conduction abnormalities in the absence of structural or metabolic abnormalities are likely to have disease-causing mutations in cardiac depolarizing channels.

Ventricular Arrhythmia in the X-linked Cardiomyopathy Barth Syndrome

Barth syndrome is an X-linked disorder characterized by dilated cardiomyopathy, cyclic neutropenia, skeletal myopathy, abnormal mitochondria, and growth deficiency. The primary defect is a mutation in the TAZ gene on the X chromosome at Xq28, resulting in abnormal phospholipid biosynthesis and cardiolipin deficiency. To date, there has been no systematic evaluation of the cardiac phenotype. We report five cases of cardiac arrest and/or placement of an internal cardiac defibrillator with documented ventricular arrhythmia. We suggest that ventricular arrhythmia is part of the primary phenotype of the disorder and that patients should be screened accordingly.

Block of Wild-Type and Inactivation-Deficient Cardiac Sodium Channels IFM/QQQ Stably Expressed in Mammalian Cells

The role of inactivation as a central mechanism in blockade of the cardiac Na(+) channel by antiarrhythmic drugs remains uncertain. We have used whole-cell and single channel recordings to examine the block of wild-type and inactivation-deficient mutant cardiac Na(+) channels, IFM/QQQ, stably expressed in HEK-293 cells. We studied the open-channel blockers disopyramide and flecainide, and the lidocaine derivative RAD-243. All three drugs blocked the wild-type Na(+) channel in a use-dependent manner. There was no use-dependent block of IFM/QQQ mutant channels with trains of 20 40-ms pulses at 150-ms interpulse intervals during disopyramide exposure. Flecainide and RAD-243 retained their use-dependent blocking action and accelerated macroscopic current relaxation. All three drugs reduced the mean open time of single channels and increased the probability of their failure to open. From the abbreviation of the mean open times, we estimated association rates of approximately 10(6)/M/s for the three drugs. Reducing the burst duration contributed to the acceleration of macroscopic current relaxation during exposure to flecainide and RAD-243. The qualitative differences in use-dependent block appear to be the result of differences in drug dissociation rate. The inactivation gate may play a trapping role during exposure to some sodium channel blocking drugs.

Endocardial Atrial Pacing Lead Implantation and Midterm Follow-Up in Young Patients with Sinus Node Dysfunction After the Fontan Procedure

The purpose of the study was to investigate the results of endocardial lead implantation, lead performance, and follow‐up in young patients after the Fontan procedure. A retrospective study was conducted with patients who had endocardial atrial pacing for SND and intact AVN function after Fontan from two pediatric centers. Patient demographics, pacing, and sensing data of endocardial atrial leads were analyzed at the time of pacemaker implantation and follow‐up visits. Fifteen patients (weight 42.6 ± 35 kg) had transvenous endocardial atrial lead implantation at an average age of 11.4 ± 6.5 years. Active‐fixation leads were used in all patients and steroid elution was present in 12 (80%) patients. Adequate P wave sensing was obtained in patients with sinus rhythm (n = 10); the remaining four patients had junctional rhythm without measurable P waves. Lead failure was not observed in any patient during the follow‐up period of 2.9 ± 2.1 years. The energy threshold at implantation was 1.46 ± 1.5 μJ, 1.54 ± 0.75 μJ at 3 months, 0.62 ± 0.45 μJ at 1 year, 0.72 ± 0.65 μJ at 2 years, 0.75 ± 0.55 μJ at 3 years, and 0.8 ± 0.85 μJ at 5 years postimplant. The lead impedance was 648 ± 298 Ω at implantation, 714 ± 163 Ω at 3 months, 744 ± 195 Ω at 1 year, 734 ± 198 Ω at 2 years, 800 ± 142 Ω at 3 years and 830 ± 200 Ω 5 years postimplant. Anticoagulation therapy (aspirin n = 5, warfarin n = 8) was continued by 13 patients. Complications consisted of a pneumothorax at implantation and a transient ischemic attack in one patient 4 years after pacemaker implant. Endocardial atrial leads offer low energy thresholds and can be implanted relatively safely in Fontan patients. (PACE 2004; 27:949–954)

Ambulatory electrocardiogram analysis in infants treated with recombinant human acid alpha-glucosidase enzyme replacement therapy for Pompe disease.

Purpose: Infantile Pompe disease is caused by deficiency of lysosomal acid α-glucosidase. Trials with recombinant human acid α-glucosidase enzyme replacement therapy (ERT) show a decrease in left ventricular mass and improved function. We evaluated 24-hour ambulatory electrocardiograms (ECGs) at baseline and during ERT in patients with infantile Pompe disease.Methods: Thirty-two ambulatory ECGs were evaluated for 12 patients with infantile Pompe disease from 2003 to 2005. Patients had a median age of 7.4 months (2.9–37.8 months) at initiation of ERT. Ambulatory ECGs were obtained at determined intervals and analyzed.Results: Significant ectopy was present in 2 of 12 patients. Patient 1 had 211 and 229 premature ventricular contractions (0.2% of heart beats) at baseline and at 11.5 weeks of ERT, respectively. Patient 2 had 10,445 premature ventricular contractions (6.7% of heart beats) at 11 weeks of therapy.Conclusion: Infantile Pompe disease may have preexisting ectopy; it may also develop during the course of ERT. Therefore, routinely monitoring patients using 24-hour ambulatory ECGs is useful. Periods of highest risk may be early in the course of ERT when there is a substantial decrease in left ventricular mass and an initial decrease in ejection fraction.

Fontan-associated protein-losing enteropathy and heart transplant: A Pediatric Heart Transplant Study analysis

BACKGROUND Post-Fontan protein-losing enteropathy (PLE) is associated with significant morbidity and mortality. Although heart transplantation (HTx) can be curative, PLE may increase the risk of morbidity before and after HTx. This study analyzed the influence of PLE influence on waiting list and post-HTx outcomes in a pediatric cohort. METHODS Fontan patients listed for HTx and enrolled in the Pediatric Heart Transplant Study from 1999 to 2012 were stratified by a diagnosis of PLE, and the association of PLE with waiting list and post-HTx mortality, rejection, and infection was analyzed. RESULTS Compared with non-PLE Fontan patients (n = 260), PLE patients listed for HTx (n = 96) were older (11.9 years vs 7.6 years; p = 0.003), had a larger body surface area (1.1 m(2) vs 0.9 m(2); p = 0.0001), had lower serum bilirubin (0.5 vs 0.9 mg/dl; p = 0.01), lower B-type natriuretic peptide (59 vs 227 pg/ml; p = 0.006), and were less likely to be on a ventilator (3% vs 13%; p = 0.006). PLE patients had lower waiting list mortality than non-PLE Fontan patients (p < 0.0001). There were no intergroup differences for post-HTx survival or times to the first infection or rejection. PLE was not independently associated with increased post-HTx mortality at any time point. CONCLUSIONS In this multicenter cohort, the diagnosis of PLE alone was not associated with increased waiting list mortality or post-HTx morbidity or mortality. Given the limitations of our data, this analysis suggests that PLE patients in the pediatric age group have outcomes similar to their non-PLE counterparts. Additional multicenter studies of PLE patients with targeted collection of PLE-specific information will be necessary to fully delineate the risks conferred by PLE for HTx.