Citations

Background— A portion of sudden cardiac deaths can be attributed to structural heart diseases, such as hypertrophic cardiomyopathy (HCM) or cardiac channelopathies such as long-QT syndrome (LQTS); however, the underlying molecular mechanisms are distinct. Here, we identify a novel CACNA1C missense mutation with mixed loss-of-function/gain-of-function responsible for a complex phenotype of LQTS, HCM, sudden cardiac death, and congenital heart defects. Methods and Results— Whole exome sequencing in combination with Ingenuity variant analysis was completed on 3 affected individuals and 1 unaffected individual from a large pedigree with concomitant LQTS, HCM, and congenital heart defects and identified a novel CACNA1C mutation, p.Arg518Cys, as the most likely candidate mutation. Mutational analysis of exon 12 of CACNA1C was completed on 5 additional patients with a similar phenotype of LQTS plus a personal or family history of HCM-like phenotypes and identified 2 additional pedigrees with mutations at the same position, p.Arg518Cys/His. Whole cell patch clamp technique was used to assess the electrophysiological effects of the identified mutations in Ca V 1.2 and revealed a complex phenotype, including loss of current density and inactivation in combination with increased window and late current. Conclusions— Through whole exome sequencing and expanded cohort screening, we identified a novel genetic substrate p.Arg518Cys/His-CACNA1C, in patients with a complex phenotype including LQTS, HCM, and congenital heart defects annotated as cardiac-only Timothy syndrome. Our electrophysiological studies, identification of mutations at the same amino acid position in multiple pedigrees, and cosegregation with disease in these pedigrees provide evidence that p.Arg518Cys/His is the pathogenic substrate for the observed phenotype.

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.

Background— Long QT syndrome (LQTS) is a potentially lethal but highly treatable cardiac channelopathy. Treatment options include pharmacotherapy, device therapy, and left cardiac sympathetic denervation (LCSD). Here, we sought to determine the characteristics of LQTS patients who have had ≥1 LQTS-related breakthrough cardiac event (BCE) after LCSD. Methods and Results— We performed retrospective chart review for 52 consecutive patients (24 males; mean age at diagnosis, 10.0±10 years; mean QTc, 528±74 ms) with LQTS who underwent LCSD between 2005 and 2010 (mean age at LCSD, 14.1±10 years) and have been followed up for 3.6±1.3 years. A BCE was defined as either (1) an appropriate ventricular fibrillation-terminating implantable cardioverter defibrillator shock or (2) arrhythmogenic syncope, seizures, or aborted cardiac arrest after LCSD. Thirty-three patients (61%) had LCSD as primary prevention because of either high-risk assessment or β-blocker intolerance. So far, 12 of 52 (23%) patients (7 males) have experienced ≥1 BCE post LCSD. The clinical phenotype of patients with BCEs was significantly more severe than patients without a BCE. No BCEs were seen in patients undergoing LCSD for β-blocker intolerance (0/12 versus 17/40; P <0.001). Conclusions— Although a marked reduction in number of cardiac events is usually seen after LCSD, ≈50% of high-risk LQTS patients have experienced ≥1 post-LCSD breakthrough. Therefore, LCSD must not be viewed as curative or as an alternative in implantable cardioverter defibrillator for high-risk patients. Prophylactic LCSD may provide another option to counter a suboptimal quality of life resulting from medication-related side effects.