Molecular Mechanisms of Inherited Arrhythmias

Inherited arrhythmias and conduction system diseases are known causes of sudden cardiac death and are responsible for significant mortality and morbidity in patients with congenital heart disease and electrical disorders. Knowledge derived from human genetics and studies in animal models have led to the discovery of multiple molecular defects responsible for arrhythmogenesis. This review summarizes the molecular basis of inherited arrhythmias in structurally normal and altered hearts

Prenatal diagnosis of long QT syndrome: Implications for delivery room and neonatal management

This case describes the prenatal diagnosis and integrated peripartum management of a foetus with 2:1 atrioventricular block and torsade de pointes due to congenital long QT syndrome. The unique issues related to the detection of intrauterine conduction abnormalities and ventricular arrhythmias, along with the immediate postnatal care, have been described as an interesting teaching case with successful outcome

Transvenous nonfluoroscopic pacemaker implantation during pregnancy guided by 3-dimensional electroanatomic mapping

Patients with congenital heart disease are at ongoing risk of developing both bradyarrhythmias and tachyarrhythmias decades after surgical repair. Rarely, arrhythmias can be exacerbated during pregnancy and require emergent intervention. Here, we report unique experience with nonfluoroscopic pacemaker implantation during pregnancy. Ionizing radiation, even in low doses, is associated with an increased risk of malignancy, and a fetus may be at particularly increased risk.1, 2 Over the past 2 decades, the use of fluoroscopy in cardiac ablation procedures has become nearly obsolete with the development of 3-dimensional (3D) electroanatomic mapping software such as CARTO (Biosense-Webster, Diamond Bar, CA) and NavX or EnSite (St. Jude Medical, Inc., St. Paul, MN).3 However, certain procedures, such as device implants, still commonly use fluoroscopy in most instances.2 Fluoroscopy use in patients with congenital heart disease is of utmost concern because of cumulative radiation exposure from multiple lifetime catheterization, radiographic and computed tomography imaging, and electrophysiological procedures

Mitral valve replacement in infants and children 5 years of age or younger: Evolution in practice and outcome over three decades with a focus on supra-annular prosthesis implantation

ObjectiveSuccessful mitral valve replacement in young children is limited by the lack of small prosthetic valves. Supra-annular prosthesis implantation can facilitate mitral valve replacement with a larger prosthesis in children with a small annulus, but little is known about its effect on the outcomes of mitral valve replacement in young children.MethodsOne hundred eighteen children underwent mitral valve replacement at 5 years of age or younger from 1976–2006. Mitral valve replacement was supra-annular in 37 (32%) patients.ResultsSurvival was 74% ± 4% at 1 year and 56% ± 5% at 10 years but improved over time (10-year survival of 83% ± 7% from 1994–2006). Factors associated with worse survival included earlier mitral valve replacement date, age less than 1 year, complete atrioventricular canal, and additional procedures at mitral valve replacement, but not supra-annular mitral valve replacement. As survival improved during our more recent experience, the risks of supra-annular mitral valve replacement became apparent; survival was worse among patients with a supra-annular prosthesis after 1991. A pacemaker was placed in 18 (15%) patients within 1 month of mitral valve replacement and was less likely in patients who had undergone supra-annular mitral valve replacement. Among early survivors, freedom from redo mitral valve replacement was 72% ± 5% at 5 years and 45% ± 7% at 10 years. Twenty-one patients with a supra-annular prosthesis underwent redo mitral valve replacement. The second prosthesis was annular in 15 of these patients and upsized in all but 1, but 5 required pacemaker placement for heart block.ConclusionsSupra-annular mitral valve replacement was associated with worse survival than annular mitral valve replacement in our recent experience. Patients with supra-annular mitral valve replacement were less likely to have operative complete heart block but remained at risk when the prosthesis was subsequently replaced

Rate Control of Atrial Arrhythmias Can Be Achieved by Selective Cardiac Neurostimulation

Introduction: Atrial arrhythmias (AA) occur in up to 40% of patients recovering from open-heart surgery (OHS). Pharmacologic treatment has been the main strategy used for the control of post-operative AA, but is associated with hypotension, pro-arrhythmia and myocardial dysfunction. There is a need for a reversible, modulated solution to rate control. We demonstrated the efficacy of vagal stimulation at inferior right fat pad (FP) to slow the ventricular response (VR) of atrial fibrillation (AF) and junctional ectopic tachycardia (JET). We hypothesized that the VR response to AA could be improved by alterations in 1) the site of stimulation (anterior right FP vs. inferior right FP), 2) site within the two FP regions tested, and 3) whether there was a relationship between stimulation voltage (V) and electrophysiologic effect. Methods: Eight mongrel dogs, age 8.7 ± 3.9 months and weighing 21.5 ± 2.5 kg, underwent open heart surgery replicating Tetralogy of Fallot repair. Stimulation of the anterior right (AR) and inferior right (IR) fat pad was used to control the VR of AF and JET. A 7-pole electrode was sutured to the AR and IR FP and used to deliver stimulation therapy. Tested parameters included: 1) FP site, 2) stimulation pole configuration, and 3) stimulation (1-25) V on the VR to AF and JET. Stimulation frequency was 30 Hz, and pulse width was 0.15 msec. Results: 1). The inferior right FP was more effective in slowing the VR response to AF (-0.43 ± 0.18 vs. -0.18 ± 0.11 %, p =0.03) and JET (-0.16 ± 0.06 vs. 0.0 ±0.0, p =0.06.) 2). Selective site stimulation within a FP region could augment the effect of stimulation during AF (-0.48 ± 0.21 (maximum effect) vs. 0.0 ± 0.0 % (least effect), p=0.01). Stimulation of electrodes 2+3 produced the greatest reduction in HR with a maximum percent VR reduction of 34.8% 3). FP stimulation at increasing V demonstrated a voltage-dependent effect (-0.12 ± 0.19 (low V) vs. -0.63 ± 0.21 (high V) %, p=0.01)

Cytoplasmic CUG RNA Foci Are Insufficient to Elicit Key DM1 Features

The genetic basis of myotonic dystrophy type I (DM1) is the expansion of a CTG tract located in the 3′ untranslated region of DMPK. Expression of mutant RNAs encoding expanded CUG repeats plays a central role in the development of cardiac disease in DM1. Expanded CUG tracts form both nuclear and cytoplasmic aggregates, yet the relative significance of such aggregates in eliciting DM1 pathology is unclear. To test the pathophysiology of CUG repeat encoding RNAs, we developed and analyzed mice with cardiac-specific expression of a beta-galactosidase cassette in which a (CTG)400 repeat tract was positioned 3′ of the termination codon and 5′ of the bovine growth hormone polyadenylation signal. In these animals CUG aggregates form exclusively in the cytoplasm of cardiac cells. A key pathological consequence of expanded CUG repeat RNA expression in DM1 is aberrant RNA splicing. Abnormal splicing results from the functional inactivation of MBNL1, which is hypothesized to occur due to MBNL1 sequestration in CUG foci or from elevated levels of CUG-BP1. We therefore tested the ability of cytoplasmic CUG foci to elicit these changes. Aggregation of CUG RNAs within the cytoplasm results both in Mbnl1 sequestration and in approximately a two fold increase in both nuclear and cytoplasmic Cug-bp1 levels. Significantly, despite these changes RNA splice defects were not observed and functional analysis revealed only subtle cardiac dysfunction, characterized by conduction defects that primarily manifest under anesthesia. Using a human myoblast culture system we show that this transgene, when expressed at similar levels to a second transgene, which encodes expanded CTG tracts and facilitates both nuclear focus formation and aberrant splicing, does not elicit aberrant splicing. Thus the lack of toxicity of cytoplasmic CUG foci does not appear to be a consequence of low expression levels. Our results therefore demonstrate that the cellular location of CUG RNA aggregates is an important variable that influences toxicity and support the hypothesis that small molecules that increase the rate of transport of the mutant DMPK RNA from the nucleus into the cytoplasm may significantly improve DM1 pathology

Developed in collaboration with and endorsed by the Heart Rhythm Society (HRS), the American College of Cardiology (ACC), the American Heart Association (AHA), and the Association for European Paediatric and Congenital Cardiology (AEPC). Endorsed by the Asia Pacific Heart Rhythm Society (APHRS), the Indian Heart Rhythm Society (IHRS), and the Latin American Heart Rhythm Society (LAHRS).

AbstractIn view of the increasing complexity of both cardiovascular implantable electronic devices (CIEDs) and patients in the current era, practice guidelines, by necessity, have become increasingly specific. This document is an expert consensus statement that has been developed to update and further delineate indications and management of CIEDs in pediatric patients, defined as ≤21 years of age, and is intended to focus primarily on the indications for CIEDs in the setting of specific disease categories. The document also highlights variations between previously published adult and pediatric CIED recommendations and provides rationale for underlying important differences. The document addresses some of the deterrents to CIED access in low- and middle-income countries and strategies to circumvent them. The document sections were divided up and drafted by the writing committee members according to their expertise. The recommendations represent the consensus opinion of the entire writing committee, graded by class of recommendation and level of evidence. Several questions addressed in this document either do not lend themselves to clinical trials or are rare disease entities, and in these instances recommendations are based on consensus expert opinion. Furthermore, specific recommendations, even when supported by substantial data, do not replace the need for clinical judgment and patient-specific decision-making. The recommendations were opened for public comment to Pediatric and Congenital Electrophysiology Society (PACES) members and underwent external review by the scientific and clinical document committee of the Heart Rhythm Society (HRS), the science advisory and coordinating committee of the American Heart Association (AHA), the American College of Cardiology (ACC), and the Association for European Paediatric and Congenital Cardiology (AEPC). The document received endorsement by all the collaborators and the Asia Pacific Heart Rhythm Society (APHRS), the Indian Heart Rhythm Society (IHRS), and the Latin American Heart Rhythm Society (LAHRS). This document is expected to provide support for clinicians and patients to allow for appropriate CIED use, appropriate CIED management, and appropriate CIED follow-up in pediatric patients