Yung R. Lau

Catecholaminergic Polymorphic Ventricular Tachycardia in Children Analysis of Therapeutic Strategies and Outcomes From an International Multicenter Registry

Background—Catecholaminergic polymorphic ventricular tachycardia is an uncommon, potentially lethal, ion channelopathy. Standard therapies have high failure rates and little is known about treatment in children. Newer options such as flecainide and left cardiac sympathetic denervation are not well validated. We sought to define treatment outcomes in children with catecholaminergic polymorphic ventricular tachycardia. Methods and Results—This is a Pediatric and Congenital Electrophysiology Society multicenter, retrospective cohort study of catecholaminergic polymorphic ventricular tachycardia patients diagnosed before 19 years of age. The cohort included 226 patients, including 170 probands and 56 relatives. Symptomatic presentation was reported in 176 (78%). Symptom onset occurred at 10.8 (interquartile range, 6.8–13.2) years with a delay to diagnosis of 0.5 (0–2.6) years. Syncope (P<0.001), cardiac arrest (P<0.001), and treatment failure (P=0.008) occurred more often in probands. &bgr;-Blockers were prescribed in 205 of 211 patients (97%) on medication, and 25% experienced at least 1 treatment failure event. Implantable cardioverter defibrillators were placed in 121 (54%) and was associated with electrical storm in 22 (18%). Flecainide was used in 24% and left cardiac sympathetic denervation in 8%. Six deaths (3%) occurred during a cumulative follow-up of 788 patient-years. Conclusions—This study demonstrates a malignant phenotype and lengthy delay to diagnosis in catecholaminergic polymorphic ventricular tachycardia. Probands were typically severely affected. &bgr;-Blockers were almost universally initiated; however, treatment failure, noncompliance and subtherapeutic dosing were often reported. Implantable cardioverter defibrillators were common despite numerous device-related complications. Treatment failure was rare in the quarter of patients on flecainide. Left cardiac sympathetic denervation was not uncommon although the indication was variable.

Spectrum and Prevalence of CALM1-, CALM2-, and CALM3-Encoded Calmodulin (CaM) Variants in Long QT Syndrome (LQTS) and Functional Characterization of a Novel LQTS-Associated CaM Missense Variant, E141G

Background—Calmodulin (CaM) is encoded by 3 genes, CALM1, CALM2, and CALM3, all of which harbor pathogenic variants linked to long QT syndrome (LQTS) with early and severe expressivity. These LQTS-causative variants reduce CaM affinity to Ca2+ and alter the properties of the cardiac L-type calcium channel (CaV1.2). CaM also modulates NaV1.5 and the ryanodine receptor, RyR2. All these interactions may play a role in disease pathogenesis. Here, we determine the spectrum and prevalence of pathogenic CaM variants in a cohort of genetically elusive LQTS, and functionally characterize the novel variants. Methods and Results—Thirty-eight genetically elusive LQTS cases underwent whole-exome sequencing to identify CaM variants. Nonsynonymous CaM variants were over-represented significantly in this heretofore LQTS cohort (13.2%) compared with exome aggregation consortium (0.04%; P<0.0001). When the clinical sequelae of these 5 CaM-positive cases were compared with the 33 CaM-negative cases, CaM-positive cases had a more severe phenotype with an average age of onset of 10 months, an average corrected QT interval of 676 ms, and a high prevalence of cardiac arrest. Functional characterization of 1 novel variant, E141G-CaM, revealed an 11-fold reduction in Ca2+-binding affinity and a functionally dominant loss of inactivation in CaV1.2, mild accentuation in NaV1.5 late current, but no effect on intracellular RyR2-mediated calcium release. Conclusions—Overall, 13% of our genetically elusive LQTS cohort harbored nonsynonymous variants in CaM. Genetic testing of CALM1-3 should be pursued for individuals with LQTS, especially those with early childhood cardiac arrest, extreme QT prolongation, and a negative family history.

Prevalence and clinical, electrocardiographic, and electrophysiologic characteristics of ventricular arrhythmias originating from the noncoronary sinus of Valsalva.

BACKGROUND Idiopathic ventricular arrhythmias (VAs) can be rarely ablated from the noncoronary cusp (NCC) of the aorta. OBJECTIVE The purpose of this study was to investigate the prevalence and the clinical, electrocardiographic, and electrophysiologic characteristics of idiopathic NCC VAs. METHODS We studied 90 consecutive patients who underwent successful catheter ablation of idiopathic aortic root VAs (left coronary cusp [LCC] 33, right coronary cusp [RCC] 32, junction between LCC and RCC 19, NCC = 6). RESULTS NCC VAs occurred in significantly younger patients (all <40 years old) and exhibited a shorter QRS duration (all but one <150 ms), smaller R-wave amplitude ratio in leads II and III (III/II), earlier ventricular activation in the His bundle (HB) region (all but one preceded QRS onset by >25 ms), and larger atrial to ventricular electrogram amplitude ratio (A/V) at the successful ablation site (all but one >1) than the other VAs. QRS morphology of the NCC VAs was similar to that of RCC VAs, but NCC VAs always exhibited a left bundle branch block and left superior (n = 1) or inferior axis (n = 5). All NCC VAs exhibited ventricular tachycardias, although premature ventricular contractions were dominant in the other VAs. CONCLUSION NCC VAs were very rare (7%) and occurred in significantly younger patients than those among the other aortic root VAs. In a limited set of six patients, the ECG and electrophysiologic characteristics of NCC VAs were similar to those of RCC VAs but were characterized by narrower QRS duration, smaller III/II ratio, earlier ventricular activation in the HB region, and A/V ratio >1 at the successful ablation site.

Successful transbaffle catheter ablation of pulmonary vein tachycardia.

A 46-year-old woman with a history of transposition of the great arteries, Mustard operation, and tricuspid valve (TV) replacement underwent catheter ablation …

The clinical and genetic spectrum of catecholaminergic polymorphic ventricular tachycardia: findings from an international multicentre registry

Aims Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an ion channelopathy characterized by ventricular arrhythmia during exertion or stress. Mutations in RYR2-coded Ryanodine Receptor-2 (RyR2) and CASQ2-coded Calsequestrin-2 (CASQ2) genes underlie CPVT1 and CPVT2, respectively. However, prognostic markers are scarce. We sought to better characterize the phenotypic and genotypic spectrum of CPVT, and utilize molecular modelling to help account for clinical phenotypes. Methods and results This is a Pediatric and Congenital Electrophysiology Society multicentre, retrospective cohort study of CPVT patients diagnosed at <19 years of age and their first-degree relatives. Genetic testing was undertaken in 194 of 236 subjects (82%) during 3.5 (1.4-5.3) years of follow-up. The majority (60%) had RyR2-associated CPVT1. Variant locations were predicted based on a 3D structural model of RyR2. Specific residues appear to have key structural importance, supported by an association between cardiac arrest and mutations in the intersubunit interface of the N-terminus, and the S4-S5 linker and helices S5 and S6 of the RyR2 C-terminus. In approximately one quarter of symptomatic patients, cardiac events were precipitated by only normal wakeful activities. Conclusion This large, multicentre study identifies contemporary challenges related to the diagnosis and prognostication of CPVT patients. Structural modelling of RyR2 can improve our understanding severe CPVT phenotypes. Wakeful rest, rather than exertion, often precipitated life-threatening cardiac events.

Adenosine can improve the intra-atrial conduction block along the mitral annulus during accessory pathway ablation

A 10-year-old boy with a supraventricular tachycardia was referred for catheter ablation. An electrophysiologic study revealed a left lateral concealed accessory pathway (AP). A few radiofrequency (RF) applications targeting the AP resulted in an inadvertent intra-atrial conduction block at the mitral isthmus without any damage to the AP. Adenosine was then administered during left ventricular pacing. Soon after that, the conduction at the mitral isthmus recovered partially, and that change disappeared soon. Those findings suggested that the administration of adenosine may transiently recover the conduction at the mitral isthmus damaged by RF ablation.

Successful catheter ablation of a focal atrial tachycardia originating from the coronary sinus ostium in a patient with a history of Fontan conversion and dextrocardia

A 44-year-old man with a history of complex congenital heart disease, including a functionally univentricular heart, dextrocardia, and situs ambiguous with the right atrium (RA) and superior vena cava to inferior vena cava (IVC) on the left, and the left atrium (LA) on the right and posteriorly, and multiple cardiac surgeries, developed an atrial tachycardia (AT), and underwent electrophysiological testing. He had undergone right Blalock–Taussig shunt at the age of 4, modified Fontan at the age of 15, and conversion of the Fontan to a total cavopulmonary connection (TCPC) with an extra-anatomic conduit from the IVC to pulmonary artery (PA), bidirectional Glenn shunt, and right and limited left Maze procedure at the age of 36. The pre-procedural computed tomography images revealed that the RA was completely separated into two components after the TCPC with the internal baffle (Figure 1). This finding suggested that a transvenous approach could not reach the pulmonary venous atrium (PVA). During the electrophysiological study, a decapolar catheter was placed in the PA through the baffle to record the LA electrogram as a reference for 3D mapping. Activation mapping was performed with a contact force sensing ablation

Supraventricular Tachycardia With Something Missing

A 7-year-old girl was referred for electrophysiological study and catheter ablation for incessant supraventricular tachycardia that was terminated with intravenous adenosine but was refractory to oral metoprolol and sotalol (Figure 1). There were cycles in which no atrial activation could be observed in leads I and V1 without a change in the R-R interval (Figure 2). For this supraventricular tachycardia (SVT) with intermittently missing P waves, can you determine the mechanism? Figure 1. Twelve-lead ECG demonstrating a regular, narrow complex supraventricular tachycardia at a rate of 183 bpm. The RP interval measures 125 ms and the PR interval measures 195 ms. Figure 2. Twelve-lead ECG demonstrating the occasional absence of retrograde P waves (arrows). Note that the R-R interval remains constant despite the lack of retrograde P waves (arrows). The presence of persistent tachycardia with fewer P waves than QRS complexes rules out atrial tachycardia or orthodromic atrioventricular reciprocating tachycardia, because these arrhythmias are dependent on atrial activation. The differential diagnosis of a regular, narrow QRS tachycardia with VA block includes an accelerated junctional tachycardia or AV nodal reentrant tachycardia (AVNRT). The RP interval of 125 ms is not typical of slow antegrade-fast retrograde AVNRT, which usually has an RP interval of ≤70 ms. Neither is this tachycardia typical of fast antegrade–slow retrograde AVNRT, because the PR interval is considerably longer than the RP interval. …