Citations

Dynamic QT Interval Monitoring Post‐LCSDBackgroundVideoscopic left cardiac sympathetic denervation (LCSD) is an adjunct therapy for reduction of arrhythmia‐induced events in patients with long‐QT syndrome (LQTS). LCSD reduces LQTS‐triggered breakthrough cardiac events. The temporal effects of QTc changes post‐LCSD have not been studied.MethodsWe utilized continuous QTc monitoring on 72 patients with LQTS. We evaluated acute and long‐term QTc changes in comparison to 12‐lead ECG‐derived QTc values prior to surgery, 24 hours postsurgery, and at follow up ≥3 months.ResultsSeventy‐two patients underwent LCSD at our institution (46% male, mean age at LCSD was 14 ± 10 years). The mean baseline, pre‐LCSD QTc was 505 ± 56 ms, which had decreased significantly at ≥3 months post‐LCSD to 491 ± 40 ms (P = 0.001). QTc monitoring revealed that the majority of the cohort (53/72; 74%) had a transient increase >30 ms in QTc from baseline, with an average maximum increase of 72 ± 30 ms. Resolution within 10 ms of baseline or less occurred in 57% (30/53) at 24 hours post‐LCSD.ConclusionsAlthough LQTS patients may have a paradoxically increased QTc post‐LCSD, the effects are transient in most patients. Importantly, no patients experienced any arrhythmias in the postoperative setting related to this transient rise in QTc.

Sudden Cardiac Arrest During Sex in Cardiac ChannelopathiesBackgroundPatients with catecholaminergic polymorphic ventricular tachycardia (CPVT) and long‐QT syndrome (LQTS) are susceptible to cardiac events during sympathetic nervous system activation. Herein, we sought to determine the risk of cardiac events associated with sex in CPVT and LQTS patients.Methods and ResultsWe reviewed the electronic medical record of patients seen in the Genetic Heart Rhythm Clinic. There were 445 patients ≥18 years diagnosed with LQTS (N = 402, age at diagnosis 30 ± 16 years) or CPVT (N = 43, age at diagnosis 25 ± 15 years). No sex‐induced cardiac events occurred in the LQTS population, and 2 occurred in the CPVT population. Sex‐induced events were more likely in CPVT (2/43, 4.7%) than LQTS (0/402, 0%, P = 0.008). One case involved a 22‐year‐old CPVT1 female with prior cardiac arrest, who experienced several appropriate implantable cardioverter defibrillator shocks during intercourse while taking β‐blockers. The second case was a 52‐year‐old CPVT1 male with history of recurrent exercise‐triggered syncope, who had syncope during sex in the setting of β‐blocker noncompliance. Extrapolating from published estimates of intercourse frequency by age, the overall event rate was only 0.0004%, and 0.005% among the CPVT cohort.ConclusionsPotentially life‐threatening cardiac events during sex in patients with CPVT are rare and even rarer in LQTS. Overall, the cardiac event per intercourse rate is extremely low. Patients and their partners should be reassured that sex is a low‐risk activity from a cardiac standpoint.

AbstractWe developed and implemented a ‘CPOE-QT Alert’ system, that is, clinical decision support integrated in the computerized physician order entry system (CPOE), in 2011. The system identifies any attempts to order medications with risk of torsade de pointes (TdP) for patients with a history of significant QT prolongation (QTc ≥500 ms) and alerts the provider entering the order. We assessed its impact by comparing orders and subsequent medication administration before and after activation of the system. We found a significant decrease in the proportion of completed order per ordering attempt after system activation (94% (1293/1379) vs 77% (1888/2453), difference 16.8%; p<0.001). This resulted in a 13.9% reduction in the administration of those medications to patients. A significant decrease was observed across all provider types, educational levels, and specialties. The CPOE-QT Alert system successfully reduced exposure to QT-prolonging medications in high risk patients.

Expression silencing of junctophilin-2 (JPH2) in mouse heart leads to ryanodine receptor type 2 (RyR2)-mediated sarcoplasmic reticulum (SR) Ca2+ leak and rapid development of heart failure. The mechanism and physiological significance of JPH2 in regulating RyR2-mediated SR Ca2+ leak remains elusive. We sought to elucidate the role of JPH2 in regulating RyR2-mediated SR Ca2+ release in the setting of cardiac failure. Cardiac myocytes isolated from tamoxifen-inducible conditional knockdown mice of JPH2 (MCM-shJPH2) were subjected to confocal Ca2+ imaging. MCM-shJPH2 cardiomyocytes exhibited an increased spark frequency width with altered spark morphology, which caused increased SR Ca2+ leakage. Single channel studies identified an increased RyR2 open probability in MCM-shJPH2 mice. The increase in spark frequency and width was observed only in MCM-shJPH2 and not found in mice with increased RyR2 open probability with native JPH2 expression. Na+/Ca2+-exchanger (NCX) activity was reduced by 50% in MCM-shJPH2 with no detectable change in NCX expression. Additionally, 50% inhibition of NCX through Cd2+ administration alone was sufficient to increase spark width in myocytes obtained from wild-type mice. Additionally, superresolution analysis of RyR2 and NCX colocalization showed a reduced overlap between RyR2 and NCX in MCM-shJPH2 mice. In conclusion, decreased JPH2 expression causes increased SR Ca2+ leakage by directly increasing open probability of RyR2 and by indirectly reducing junctional NCX activity through increased dyadic cleft Ca2+. This demonstrates two novel and independent cellular mechanisms by which JPH2 regulates RyR2-mediated SR Ca2+ leak and heart failure development.

Rationale : Semaphorin 3A ( SEMA3A )-encoded semaphorin is a chemorepellent that disrupts neural patterning in the nervous and cardiac systems. In addition, SEMA3A has an amino acid motif that is analogous to hanatoxin, an inhibitor of voltage-gated K + channels. SEMA3A -knockout mice exhibit an abnormal ECG pattern and are prone to ventricular arrhythmias and sudden cardiac death. Objective : Our aim was to determine whether SEMA3A is a naturally occurring protein inhibitor of K v 4.3 (I to ) channels and its potential contribution to Brugada syndrome. Methods and Results : K v 4.3, Na v 1.5, Ca v 1.2, or K v 4.2 were coexpressed or perfused with SEMA3A in HEK293 cells, and electrophysiological properties were examined via whole-cell patch clamp technique. SEMA3A selectively altered K v 4.3 by significantly reducing peak current density without perturbing K v 4.3 cell surface protein expression. SEMA3A also reduced I to current density in cardiomyocytes derived from human-induced pluripotent stem cells. Disruption of a putative toxin binding domain on K v 4.3 was used to assess physical interactions between SEMA3A and K v 4.3. These findings in combination with coimmunoprecipitations of SEMA3A and K v 4.3 revealed a potential direct binding interaction between these proteins. Comprehensive mutational analysis of SEMA3A was performed on 198 unrelated SCN5A genotype–negative patients with Brugada syndrome, and 2 rare SEMA3A missense mutations were identified. The SEMA3A mutations disrupted SEMA3A’s ability to inhibit K v 4.3 channels, resulting in a significant gain of K v 4.3 current compared with wild-type SEMA3A. Conclusions : This study is the first to demonstrate SEMA3A as a naturally occurring protein that selectively inhibits K v 4.3 and SEMA3A as a possible Brugada syndrome susceptibility gene through a K v 4.3 gain-of-function mechanism.

Background— The pathogenesis of sudden cardiac death in college athletes has not been defined by systematic case identification. Methods and Results— A total of 45 cases of sudden cardiac death were identified in National Collegiate Athletic Association (NCAA) athletes from 2004 to 2008 based on an internal reporting system and review of media reports. Autopsy reports were reviewed and adjudicated by a multidisciplinary panel. Cause of death could be reasonably determined in 36 cases; 3 athletes had no autopsy, 5 autopsy reports could not be obtained, and 1 autopsy had insufficient information to determine cause of death. The most common finding at death was a structurally normal heart or autopsy-negative sudden unexplained death (11, 31%), followed by coronary artery abnormalities (5, 14%), dilated cardiomyopathy (3, 8%), myocarditis related (3, 8%), aortic dissection (3, 8%), and idiopathic left ventricular hypertrophy/possible hypertrophic cardiomyopathy (HCM; 3, 8%). There was 1 case each (3%) of hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, long QT syndrome, commotio cordis, and Kawasaki disease. There was 1 case of death in a sickle cell positive athlete who also had left ventricular hypertrophy. The adjudicated diagnosis agreed with the official pathology report in only 59% of cases. Conclusions— Unexplained death with a structurally normal heart is the most common finding after suspected sudden cardiac death in NCAA athletes. Hypertrophic cardiomyopathy is infrequently seen, and conclusions in autopsy reports may not accurately reflect the pathological findings. Standardized protocols for cardiovascular autopsies in athletes are needed, including postmortem genetic testing, particularly in autopsy-negative cases.

For more than a decade there has been considerable interest in the role of QT interval prolongation in the pathogenesis of sudden infant death syndrome. It has been proposed that the QT interval is a surrogate marker for autonomic instability and can be used to identify infants at risk for significant morbidity and mortality, including sudden infant death syndrome. We present the case of an infant that experienced a significant increase in his QTc, as detected by continuous QTc monitoring in the NICU after repositioning from a supine to prone position. This increase from a 413 ± 6 millisecond baseline average to 500 milliseconds was sustained for 2 hours and associated with clinically relevant apnea that ultimately required repositioning of the infant back to the supine position. Repositioning resulted in an immediate decrease of the QTc back to the previous baseline and termination of the apneic events. This case demonstrates an example of how the use of continuous QTc monitoring in the NICU setting may be used to detect QTc-accentuating factors in real time and identify situations that cause perturbations in an infant’s autonomic nervous system.