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

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

Screening for Sudden Cardiac Death in the Young

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Vigorous Exercise in Patients With Hypertrophic Cardiomyopathy

IMPORTANCE: Whether vigorous intensity exercise is associated with an increase in risk of ventricular arrhythmias in individuals with hypertrophic cardiomyopathy (HCM) is unknown. OBJECTIVE: To determine whether engagement in vigorous exercise is associated with increased risk for ventricular arrhythmias and/or mortality in individuals with HCM. The a priori hypothesis was that participants engaging in vigorous activity were not more likely to have an arrhythmic event or die than those who reported nonvigorous activity. DESIGN, SETTING, AND PARTICIPANTS: This was an investigator-initiated, prospective cohort study. Participants were enrolled from May 18, 2015, to April 25, 2019, with completion in February 28, 2022. Participants were categorized according to self-reported levels of physical activity: sedentary, moderate, or vigorous-intensity exercise. This was a multicenter, observational registry with recruitment at 42 high-volume HCM centers in the US and internationally; patients could also self-enroll through the central site. Individuals aged 8 to 60 years diagnosed with HCM or genotype positive without left ventricular hypertrophy (phenotype negative) without conditions precluding exercise were enrolled. EXPOSURES: Amount and intensity of physical activity. MAIN OUTCOMES AND MEASURES: The primary prespecified composite end point included death, resuscitated sudden cardiac arrest, arrhythmic syncope, and appropriate shock from an implantable cardioverter defibrillator. All outcome events were adjudicated by an events committee blinded to the patient\u27s exercise category. RESULTS: Among the 1660 total participants (mean [SD] age, 39 [15] years; 996 male [60%]), 252 (15%) were classified as sedentary, and 709 (43%) participated in moderate exercise. Among the 699 individuals (42%) who participated in vigorous-intensity exercise, 259 (37%) participated competitively. A total of 77 individuals (4.6%) reached the composite end point. These individuals included 44 (4.6%) of those classified as nonvigorous and 33 (4.7%) of those classified as vigorous, with corresponding rates of 15.3 and 15.9 per 1000 person-years, respectively. In multivariate Cox regression analysis of the primary composite end point, individuals engaging in vigorous exercise did not experience a higher rate of events compared with the nonvigorous group with an adjusted hazard ratio of 1.01. The upper 95% 1-sided confidence level was 1.48, which was below the prespecified boundary of 1.5 for noninferiority. CONCLUSIONS AND RELEVANCE: Results of this cohort study suggest that among individuals with HCM or those who are genotype positive/phenotype negative and are treated in experienced centers, those exercising vigorously did not experience a higher rate of death or life-threatening arrhythmias than those exercising moderately or those who were sedentary. These data may inform discussion between the patient and their expert clinician around exercise participation