Catecholaminergic polymorphic ventricular tachycardia patients with multiple genetic variants in the PACES CPVT Registry.

BACKGROUND: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is often a life-threatening arrhythmia disorder with variable penetrance and expressivity. Little is known about the incidence or outcomes of CPVT patients with ≥2 variants. METHODS: The phenotypes, genotypes and outcomes of patients in the Pediatric and Congenital Electrophysiology Society CPVT Registry with ≥2 variants in genes linked to CPVT were ascertained. The American College of Medical Genetics & Genomics (ACMG) criteria and structural mapping were used to predict the pathogenicity of variants (3D model of pig RyR2 in open-state). RESULTS: Among 237 CPVT subjects, 193 (81%) had genetic testing. Fifteen patients (8%) with a median age of 9 years (IQR 5-12) had ≥2 variants. Sudden cardiac arrest occurred in 11 children (73%), although none died during a median follow-up of 4.3 years (IQR 2.5-6.1). Thirteen patients (80%) had at least two RYR2 variants, while the remaining two patients had RYR2 variants plus variants in other CPVT-linked genes. Among all variants identified, re-classification of the commercial laboratory interpretation using ACMG criteria led to the upgrade from variant of unknown significance (VUS) to pathogenic/likely pathogenic (P/LP) for 5 variants, and downgrade from P/LP to VUS for 6 variants. For RYR2 variants, 3D mapping using the RyR2 model suggested that 2 VUS by ACMG criteria were P/LP, while 2 variants were downgraded to likely benign. CONCLUSIONS: This severely affected cohort demonstrates that a minority of CPVT cases are related to ≥2 variants, which may have implications on family-based genetic counselling. While multi-variant CPVT patients were at high-risk for sudden cardiac arrest, there are insufficient data to conclude that this genetic phenomenon has prognostic implications at present. Further research is needed to determine the significance and generalizability of this observation. This study also shows that a rigorous approach to variant re-classification using the ACMG criteria and 3D mapping is important in reaching an accurate diagnosis, especially in the multi-variant population.

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.

Spectrum and Prevalence of CALM1-, CALM2-, and CALM3-Encoded Calmodulin Variants in Long QT Syndrome and Functional Characterization of a Novel Long QT Syndrome-Associated Calmodulin 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 Ca(2+) 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 Ca(2+)-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.

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. ß-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. ß-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.

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.

Is the "perfect Fontan" operation routinely achievable in the modern era?

OBJECTIVE: In 1990, Fontan, Kirklin, and colleagues published equations for survival after the so-called "Perfect Fontan" operation. After 1988, we evolved a protocol using an internal or external polytetraflouroethylene tube of 16 to 19 millimetres diameter placed from the inferior caval vein to either the right or left pulmonary artery along with a bidirectional cava-pulmonary connection. The objective of this study was to test the hypothesis that a "perfect" outcome is routinely achievable in the current era when using a standardized surgical procedure. METHODS: Between 1 January, 1988, and 12 December, 2005, 112 patients underwent the Fontan procedure using an internal or external polytetraflouroethylene tube plus a bidirectional cava-pulmonary connection, the latter usually having been constructed as a previous procedure. This constituted 45% of our overall experience in constructing the Fontan circulation between 1988 and 1996, and 96% of the experience between 1996 and 2005. Among all surviving patients, the median follow-up was 7.3 years. We calculated the expected survival for an optimal candidate, given from the initial equations, and compared this to our entire experience in constructing the Fontan circulation. RESULTS: An internal tube was utilized in 61 patients, 97% of whom were operated prior to 1998, and an external tube in 51 patients, the latter accounting for 95% of all operations since 1999. At 1, 5, 10 and 15 years, survival of the entire cohort receiving polytetraflouroethylene tubes is superimposable on the curve calculated for a "perfect" outcome. Freedom from replacement or revision of the tube was 97% at 10 years. CONCLUSION: Using a standardized operative procedure, combining a bidirectional cavopulmonary connection with a polytetraflouroethylene tube placed from the inferior caval vein to the pulmonary arteries for nearly all patients with functionally univentricular hearts, early and late survival within the "perfect" outcome as predicted by the initial equations of Fontan and Kirklin is routinely achievable in the current era. The need for late revision or replacement of the tube is rare.

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.

Ventricular tachycardia with an outflow tract septal origin after repair of double outlet right ventricle.

A 12-year-old boy born with double outlet right ventricle (RV) developed sustained ventricular tachycardia (VT) 6 years after the corrective surgery and underwent electrophysiologic testing and catheter ablation. Electroanatomic mapping of the right and left ventricles during the VT revealed a centrifugal activation from the outflow tract septum. Though an excellent pace map was obtained in the RV, successful ablation was achieved on the left side. These findings suggested that the VT origin might have been located in the intramural region of the ventricular outflow tract septum with a preferential breakout site in the RV outflow tract.

Electrophysiological findings in adolescents with atrial fibrillation who have structurally normal hearts.

BACKGROUND: Atrial fibrillation (AF) is uncommon in children, and its mechanisms are unknown. This study describes the electrophysiological findings in children and adolescents with AF and the outcome of catheter ablation. METHODS AND RESULTS: Nine adolescents with symptomatic, lone AF who failed antiarrhythmic drug therapy were evaluated. All patients had ECG-documented AF and underwent invasive electrophysiological testing. Intracardiac mapping was performed to determine the site of spontaneous onset of AF and rapidly firing atrial foci. Only the triggering focus was targeted for ablation or isolation. The patients' mean age was 15.9+/-3.3 (range, 8 to 19 years). The most common finding was rapid, irregular atrial tachycardias in the region of the pulmonary veins (n=5), left atrium (n=2), or crista terminalis (n=3). One patient had foci in both the pulmonary veins and crista terminalis. The cycle lengths ranged from 108 to 280 ms. Catheter ablation was acutely successful in 8 patients (88.9%), whereas 1 patient with multiple left atrium foci was treated with the surgical maze operation. Over a mean of 35+/-22 months, 7 patients (77.8%) were arrhythmia free on no medications, while AF recurred in 2 patients who are controlled on antiarrhythmic medications. Two patients with tachycardia-induced cardiomyopathy had resolution of their left ventricular dysfunction after ablation. CONCLUSIONS: AF in adolescents with structurally normal hearts is usually due to foci in the pulmonary veins, crista terminalis, or left atrium. These foci usually induce irregular atrial tachycardias. Catheter ablation of the foci is effective in eliminating recurrent AF.

Clinical, genetic, and biophysical characterization of a homozygous HERG mutation causing severe neonatal long QT syndrome.

Previous studies have identified mutations in five ion channel genes as a cause of long QT syndrome, a heterogeneous disorder characterized by prolongation of the QT interval, multiform ventricular tachycardia (torsades de pointes), seizures, syncope, and sudden death. However, in these studies, the average age of initial symptoms is in the third decade of life or later, and few reports have described the genetic causes of long QT syndrome presenting in the prenatal or neonatal period. We used a candidate gene approach to identify the genetic cause of long QT syndrome in an infant whose initial manifestations were detected in utero. Direct bidirectional sequencing of long QT syndrome genes identified a previously unreported HERG missense mutation (R752Q). Three asymptomatic family members were heterozygous for R752Q, and the proband, who manifested ventricular tachycardia in utero, was homozygous. R752Q was not found in 100 normal unrelated chromosomes. Paternal DNA was unavailable for testing. Transient transfection of HERG generated robust IKr, but no current was observed for the mutant HERG. The HERG mutant, R752Q, is associated with a mild phenotype, inasmuch as family members with a heterozygous mutation appear unaffected. The homozygous mutation results in absence of functional IKr, causing a profound loss of HERG channel function, creating the equivalent of a "HERG knockout" and leading to a severe phenotype.