Brugada syndrome in Japan and Europe: a genome-wide association study reveals shared genetic architecture and new risk loci.

BACKGROUND AND AIMS: Brugada syndrome (BrS) is an inherited arrhythmia with a higher disease prevalence and more lethal arrhythmic events in Asians than in Europeans. Genome-wide association studies (GWAS) have revealed its polygenic architecture mainly in European populations. The aim of this study was to identify novel BrS-associated loci and to compare allelic effects across ancestries. METHODS: A GWAS was conducted in Japanese participants, involving 940 cases and 1634 controls, followed by a cross-ancestry meta-analysis of Japanese and European GWAS (total of 3760 cases and 11 635 controls). The novel loci were characterized by fine-mapping, gene expression, and splicing quantitative trait associations in the human heart. RESULTS: The Japanese-specific GWAS identified one novel locus near ZSCAN20 (P = 1.0 × 10-8), and the cross-ancestry meta-analysis identified 17 association signals, including six novel loci. The effect directions of the 17 lead variants were consistent (94.1%; P for sign test = 2.7 × 10-4), and their allelic effects were highly correlated across ancestries (Pearson's R = .91; P = 2.9 × 10-7). The genetic risk score derived from the BrS GWAS of European ancestry was significantly associated with the risk of BrS in the Japanese population [odds ratio 2.12 (95% confidence interval 1.94-2.31); P = 1.2 × 10-61], suggesting a shared genetic architecture across ancestries. Functional characterization revealed that a lead variant in CAMK2D promotes alternative splicing, resulting in an isoform switch of calmodulin kinase II-δ, favouring a pro-inflammatory/pro-death pathway. CONCLUSIONS: This study demonstrates novel susceptibility loci implicating potentially novel pathogenesis underlying BrS. Despite differences in clinical expressivity and epidemiology, the polygenic architecture of BrS was substantially shared across ancestries.

Diverse Phenotypic Manifestations in a Family with a Novel RYR2 E4107A Variant.

Cardiac ryanodine receptor (RyR2) gain-of-function mutations cause catecholaminergic polymorphic ventricular tachycardia (CPVT). Conversely, RyR2 loss-of-function mutations cause a new disease entity, termed calcium release deficiency syndrome (CRDS), which may include RYR2-related long QT syndrome (LQTS). Importantly, unlike CPVT, patients with CRDS do not always exhibit exercise- or epinephrine-induced ventricular arrhythmias, which precludes a diagnosis of CRDS. Here we report a boy and his father, who both experienced exercise-induced cardiac events and harbor the same RYR2 E4107A variant. In the boy, an exercise stress test (EST) and epinephrine provocation test (EPT) did not induce any ventricular arrhythmias. QTc was slightly prolonged (QTc: 474 ms), and an EPT induced QTc prolongation (QTc-baseline: 466 ms, peak: 532 ms, steady-state: 527 ms). In contrast, in his father, QTc was not prolonged (QTc: 417 ms), and neither an EST nor EPT induced QTc prolongation. However, an EST induced multifocal premature ventricular contraction (PVC) bigeminy and bidirectional PVC couplets. Thus, they exhibited distinct clinical phenotypes: the boy exhibited LQTS (or CRDS) phenotype, whereas his father exhibited CPVT phenotype. These findings suggest that, in addition to the altered RyR2 function, other unidentified factors, such as other genetic, epigenetic, and environmental factors, and aging, may be involved in the diverse phenotypic manifestations. Considering that a single RYR2 variant can cause both CPVT and LQTS (or CRDS) phenotypes, in cascade screening of patients with CPVT and CRDS, an EST and EPT are not sufficient and genetic analysis is required to identify individuals who are at increased risk for life-threatening arrhythmias.

Postmortem genetic analysis of 17 sudden cardiac deaths identified nonsense and frameshift variants in two cases of arrhythmogenic cardiomyopathy.

Sudden death, or unexpected natural death of a healthy individual, is a serious problem in all nations. Sudden cardiac death (SCD) mainly due to ischemic heart diseases is the top cause of sudden death. However, there are pathophysiological conditions, referred to as sudden arrhythmic death syndrome, in which no apparent lesion can be identified even after complete conventional or ordinary autopsy. While postmortem genetic analyses have accumulated evidence about underlying genetic abnormality in such cases, the precise relationships between genetic background and the phenotype have been largely elusive. In this study, a retrospective investigation of 17 autopsy cases in which lethal arrhythmia was suspected to be the cause of death was carried out. Genetic analysis focusing on 72 genes reported to be associated with cardiac dysfunctions was performed, in combination with detailed histopathological and postmortem imaging examination, and a family study. As a result, in two cases of suspected arrhythmogenic cardiomyopathy (ACM), we found a nonsense variant in PKP2 and frameshift variant in TRPM4 gene. In contrast, the other 15 cases showed no morphological changes in the heart despite the presence of a frameshift variant and several missense variants, leaving the clinical significance of these variants obscure. The findings of the present study suggest that nonsense and frameshift variants could be involved in the morphological abnormality in cases of SCD due to ACM, while missense variants alone rarely contribute to massive structural changes in the heart.

Mechanisms of fever-induced QT prolongation and torsades de pointes in patients with KCNH2 mutation.

AIMS: Patients with particular mutations of type-2 long QT syndrome (LQT2) are at an increased risk for malignant arrhythmia during fever. This study aimed to determine the mechanism by which KCNH2 mutations cause fever-induced QT prolongation and torsades de pointes (TdP). METHODS AND RESULTS: We evaluated three KCNH2 mutations, G584S, D609G, and T613M, in the Kv11.1 S5-pore region, identified in patients with marked QT prolongation and TdP during fever. We also evaluated KCNH2 M124T and R269W, which are not associated with fever-induced QT prolongation. We characterized the temperature-dependent changes in the electrophysiological properties of the mutant Kv11.1 channels by patch-clamp recording and computer simulation. The average tail current densities (TCDs) at 35°C for G584S, WT+D609G, and WT+T613M were significantly smaller and less increased with rising temperature from 35°C to 40°C than those for WT, M124T, and R269W. The ratios of the TCDs at 40°C to 35°C for G584S, WT+D609G, and WT+T613M were significantly smaller than for WT, M124T, and R269W. The voltage dependence of the steady-state inactivation curve for WT, M124T, and R269W showed a significant positive shift with increasing temperature; however, that for G584S, WT+D609G, and WT+T613M showed no significant change. Computer simulation demonstrated that G584S, WT+D609G, and WT+T613M caused prolonged action potential durations and early afterdepolarization formation at 40°C. CONCLUSION: These findings indicate that KCNH2 G584S, D609G, and T613M in the S5-pore region reduce the temperature-dependent increase in TCDs through an enhanced inactivation, resulting in QT prolongation and TdP at a febrile state in patients with LQT2.

Discrimination of atypical atrioventricular nodal reentrant tachycardia from atrial tachycardia by the V-A-A-V response.

INTRODUCTION: The electrophysiological discrimination between fast-slow (F/S-) atrioventricular (AV) nodal reentrant tachycardia (NRT) and atrial tachycardia (AT) originating from the interatrial septum remains challenging. While a V-A-A-V response may occur immediately after ventricular induction or entrainment of either tachycardia, the electrophysiological dissimilarities in that response between the two tachycardias remain unclear. The purpose of this study was to identify a diagnostic indicator discriminating F/S-AVNRT from AT by examining the difference in the V-A-A-V response between the two tachycardias. METHODS: This retrospective study included 17 patients with F/S-AVNRT [seven with common-form F/S-AVNRT using a typical slow pathway (SP) and 10 with superior type F/S-AVNRT using a superior SP] and 10 patients with reentrant AT. All 27 patients presented with long RP supraventricular tachycardia and an initial V-A-A-V response upon ventricular induction or entrainment. The V-A-A-V response in patients with F/S-AVNRT was due to dual atrial responses. We measured the interval between the first (A1) and second atrial electrogram (A2) of V-A-A-V and calculated ΔAA by subtracting A1-A2 from the tachycardia cycle length. RESULTS: V-A-A-V responses were observed most often upon ventricular induction of F/S-AVNRT (6 ± 5 times) as well as AT (6 ± 6 times; p = .87). The V-A-A-V response upon ventricular entrainment was observed in a single patient with F/S-AVNRT versus 10 all patients with AT (p < .001). ΔAA ranged between -80 and 228 ms in F/S-AVNRT and between -184 and 26 ms in AT. A ΔAA > 26 ms predicted a diagnosis of F/S-AVNRT with a 76% sensitivity and 100% specificity, while a ΔAA <-80 ms predicted a diagnosis of AT with a 50% sensitivity and 100% specificity. CONCLUSIONS: ΔAA is a useful, confirmatory, diagnostic indicator of F/S-AVNRT versus AT associated with the V-A-A-V response.

Functionally validated SCN5A variants allow interpretation of pathogenicity and prediction of lethal events in Brugada syndrome.

AIMS: The prognostic value of genetic variants for predicting lethal arrhythmic events (LAEs) in Brugada syndrome (BrS) remains controversial. We investigated whether the functional curation of SCN5A variations improves prognostic predictability. METHODS AND RESULTS: Using a heterologous expression system and whole-cell patch clamping, we functionally characterized 22 variants of unknown significance (VUSs) among 55 SCN5A mutations previously curated using in silico prediction algorithms in the Japanese BrS registry (n = 415). According to the loss-of-function (LOF) properties, SCN5A mutation carriers (n = 60) were divided into two groups: LOF-SCN5A mutations and non-LOF SCN5A variations. Functionally proven LOF-SCN5A mutation carriers (n = 45) showed significantly severer electrocardiographic conduction abnormalities and worse prognosis associated with earlier manifestations of LAEs (7.9%/year) than in silico algorithm-predicted SCN5A carriers (5.1%/year) or all BrS probands (2.5%/year). Notably, non-LOF SCN5A variation carriers (n = 15) exhibited no LAEs during the follow-up period. Multivariate analysis demonstrated that only LOF-SCN5A mutations and a history of aborted cardiac arrest were significant predictors of LAEs. Gene-based association studies using whole-exome sequencing data on another independent SCN5A mutation-negative BrS cohort (n = 288) showed no significant enrichment of rare variants in 16 985 genes including 22 non-SCN5A BrS-associated genes as compared with controls (n = 372). Furthermore, rare variations of non-SCN5A BrS-associated genes did not affect LAE-free survival curves. CONCLUSION: In vitro functional validation is key to classifying the pathogenicity of SCN5A VUSs and for risk stratification of genetic predictors of LAEs. Functionally proven LOF-SCN5A mutations are genetic burdens of sudden death in BrS, but evidence for other BrS-associated genes is elusive.

Pacing site- and rate-dependent shortening of retrograde conduction time over the slow pathway after atrial entrainment of fast-slow atrioventricular nodal reentrant tachycardia.

INTRODUCTION: We tested our hypothesis that atrial entrainment pacing (EP) of a) the common-type (com-) fast-slow (F/S-) atypical atrioventricular nodal reentrant tachycardia (AVNRT) using a typical slow pathway (SP), or b) the superior-type (sup-) F/S-AVNRT using a superior SP, both modify the retrograde conduction time across the SP immediately after termination of EP (retro-SP-time). METHODS: We measured the difference in the His-atrial interval (HA difference) immediately after cessation of EP, performed at 2 ± 2 rates from the high right atrium (HA[1]-HRA) versus from the proximal coronary sinus (HA[1]-CS) in 17 patients with com-F/S-AVNRT and 11 patients with sup-F/S-AVNRT. We also measured the atrial-His and HA intervals of the first and second cycles immediately after cessation of EP and during stable tachycardia. RESULTS: Unequal responses, defined as a ≥ 20-ms HA difference at ≥1 EP rates, were observed in 16 patients (57%), including 7 with com- and 9 with sup-F/S-AVNRT. Irrespective of the EP rate, all unequal responses of com-F/S-AVNRT were due to a shorter HA[1]-CS than HA[1]-HRA, with a mean 34 ± 11 ms HA difference, whereas all unequal responses of sup-F/S-AVNRT were due to a longer HA[1]-CS than HA[1]-HRA, with a mean 49 ± 25 ms HA difference. The unequal responses resolved within two cycles after the cessation of EP. CONCLUSIONS: We have identified a little-known pacing site- and pacing rate-dependent shortening of the retro-SP-time.

Reduced current density, partially rescued by mexiletine, and depolarizing shift in activation of SCN5A W374G channels as a cause of severe form of Brugada syndrome.

BACKGROUND: SCN5A-related Brugada syndrome (BrS) can be caused by multiple mechanisms including trafficking defects and altered channel gating properties. Most SCN5A mutations at pore region cause trafficking defects, and some of them can be rescued by mexiletine (MEX). OBJECTIVE: We recently encountered symptomatic siblings with BrS and sought to identify a responsible mutation and reveal its biophysical defects. METHODS: Target panel sequencing was performed. Wild-type (WT) or identified mutant SCN5A was transfected into tsA201 cells. After incubation of transfected cells with or without 0.1 mM MEX for 24-36 hr, whole-cell sodium currents (INa ) were recorded using patch-clamp techniques. RESULTS: The proband was 29-year-old male who experienced cardiopulmonary arrest. Later, his 36-year-old sister, who had been suffering from recurrent episodes of syncope since 12 years, was diagnosed with BrS. An SCN5A W374G mutation, located at pore region of domain 1 (D1 pore), was identified in both. The peak density of W374G-INa was markedly reduced (WT: 521 ± 38 pA/pF, W374G: 60 ± 10 pA/pF, p < .01), and steady-state activation (SSA) was shifted to depolarizing potentials compared with WT-INa (V1/2 -WT: -39.1 ± 0.8 mV, W374G: -30.9 ± 1.1 mV, p < .01). Incubation of W374G-transfected cells with MEX (W374G-MEX) increased INa density, but it was still reduced compared with WT-INa (W374G-MEX: 174 ± 19 pA/pF, p < .01 versus W374G, p < .01 versus WT). The SSA of W374G-MEX-INa was comparable to W374G-INa (V1/2 -W374G-MEX: -31.6 ± 0.7 mV, P = NS). CONCLUSIONS: Reduced current density, possibly due to a trafficking defect, and depolarizing shift in activation of SCN5A W374G are underlying biophysical defects in this severe form of BrS. Trafficking defects of SCN5A mutations at D1 pore may be commonly rescued by MEX.

Multiple arrhythmic and cardiomyopathic phenotypes associated with an SCN5A A735E mutation.

BACKGROUND: SCN5A mutations are associated with multiple arrhythmic and cardiomyopathic phenotypes including Brugada syndrome (BrS), sinus node dysfunction (SND), atrioventricular block, supraventricular tachyarrhythmias (SVTs), long QT syndrome (LQTS), dilated cardiomyopathy and left ventricular noncompaction. Several single SCN5A mutations have been associated with overlap of some of these phenotypes, but never with overlap of all the phenotypes. OBJECTIVE: We encountered two pedigrees with multiple arrhythmic phenotypes with or without cardiomyopathic phenotypes, and sought to identify a responsible mutation and reveal its functional abnormalities. METHODS: Target panel sequencing of 72 genes, including inherited arrhythmia syndromes- and cardiomyopathies-related genes, was employed in two probands. Cascade screening was performed by Saner sequencing. Wild-type or identified mutant SCN5A were expressed in tsA201 cells, and whole-cell sodium currents (INa) were recorded using patch-clamp techniques. RESULTS: We identified an SCN5A A735E mutation in these probands, but did not identify any other mutations. All eight mutation carriers exhibited at least one of the arrhythmic phenotypes. Two patients exhibited multiple arrhythmic phenotypes: one (15-year-old girl) exhibited BrS, SND, and exercise and epinephrine-induced QT prolongation, the other (4-year-old boy) exhibited BrS, SND, and SVTs. Another one (30-year-old male) exhibited all arrhythmic and cardiomyopathic phenotypes, except for LQTS. One male suddenly died at age 22. Functional analysis revealed that the mutant did not produce functional INa. CONCLUSIONS: A non-functional SCN5A A735E mutation could be associated with multiple arrhythmic and cardiomyopathic phenotypes, although there remains a possibility that other unidentified factors may be involved in the phenotypic variability of the mutation carriers.

Towards Mutation-Specific Precision Medicine in Atypical Clinical Phenotypes of Inherited Arrhythmia Syndromes.

Most causal genes for inherited arrhythmia syndromes (IASs) encode cardiac ion channel-related proteins. Genotype-phenotype studies and functional analyses of mutant genes, using heterologous expression systems and animal models, have revealed the pathophysiology of IASs and enabled, in part, the establishment of causal gene-specific precision medicine. Additionally, the utilization of induced pluripotent stem cell (iPSC) technology have provided further insights into the pathophysiology of IASs and novel promising therapeutic strategies, especially in long QT syndrome. It is now known that there are atypical clinical phenotypes of IASs associated with specific mutations that have unique electrophysiological properties, which raises a possibility of mutation-specific precision medicine. In particular, patients with Brugada syndrome harboring an SCN5A R1632C mutation exhibit exercise-induced cardiac events, which may be caused by a marked activity-dependent loss of R1632C-Nav1.5 availability due to a marked delay of recovery from inactivation. This suggests that the use of isoproterenol should be avoided. Conversely, the efficacy of ß-blocker needs to be examined. Patients harboring a KCND3 V392I mutation exhibit both cardiac (early repolarization syndrome and paroxysmal atrial fibrillation) and cerebral (epilepsy) phenotypes, which may be associated with a unique mixed electrophysiological property of V392I-Kv4.3. Since the epileptic phenotype appears to manifest prior to cardiac events in this mutation carrier, identifying KCND3 mutations in patients with epilepsy and providing optimal therapy will help prevent sudden unexpected death in epilepsy. Further studies using the iPSC technology may provide novel insights into the pathophysiology of atypical clinical phenotypes of IASs and the development of mutation-specific precision medicine.

[Current Clinical Practice Pattern for Castration-Resistant Prostate Cancer(CRPC)in Japan].

Although various agents are reported against castration-resistant prostate cancer(CRPC), little is known about their actual clinical use in Japan. In this study, 484 patients diagnosed with CRPC during androgen-deprivation therapy were selected from Japan's leading multicenter collaborative research real-world database. The treatment details and prognosis were analyzed. It was observed that the castration treatment represented by the use of LH-RH agonists and antagonists was continued in almost all cases even after CRPC diagnosis. First-line non-castration agents for the CRPC treatment including certain novel agents approved from 2010 onwards and conventional agents used before that were selected for use in 76.5% and 23.5% of cases, respectively, with the 1-year continuation rates being 57.7%, and 52.4%, respectively. The 1.5-year overall survival rate from CRPC was 63.7%(90.0% in the conventional agents' group and 58.8% in the novel agents' group). Previously, conventional agents were sometimes selected for the CRPC treatment; hence, they still seemed to play a role in clinical practice in Japan.

Unique electrophysiological properties of fast-slow atrioventricular nodal reentrant tachycardia characterized by a shortening of retrograde conduction time via a slow pathway manifested during atrial induction.

INTRODUCTION: Electrophysiological properties of reentry circuits of fast-slow atrioventricular nodal reentrant tachycardia (F/S-AVNRT) may contribute to cyclic variability after atrial induction. METHODS: In 156 atrial inductions of 33 patients with F/S-AVNRT, we measured the atrio-His (AH) and His-atrial (HA) intervals in the first cycle after the induction (AH[1] and HA[1], respectively), those in the second cycle (AH [2] and HA [2], respectively), and those during tachycardia that maintained a stable cycle length AH[T] and HA[T], respectively), and calculated the value of AH(1) minus AH(T) [ΔAH] and the value of HA(1) minus HA(T) [ΔHA] in each induction. According to the sum of ΔAH and ΔHA, tachycardia variability was classified as incremental (<-20), balanced (-20 to 20), or decremental (>20). RESULTS: ΔAH and ΔHA were significantly different between the three responses: 6 ± 28 and -67 ± 39 in 55 inductions (35%) with an incremental response, 20 ± 10 and -23 ± 28 in 59 (38%) with a balanced response, and 54 ± 44 and 4 ± 50 in 42 (27%) with a decremental response, respectively. Incremental response was reproducibly and consistently observed in 33% of patients. HA(2) was similar to HA(T) in inductions with an incremental response. These results suggest that incremental response can be manifested only in the first cycle when HA(1) is excessively shortened, approximating a retrograde conduction time over a slow pathway, in contrast, and far superior to a decremental delay of AH(1). CONCLUSION: In specific patients with F/S-AVNRT, poorly recognized, electrophysiological properties of shortening a retrograde conduction time over a slow pathway was manifested during atrial induction.

Biophysical defects of an SCN5A V1667I mutation associated with epinephrine-induced marked QT prolongation.

BACKGROUND: The epinephrine infusion test (EIT) typically induces marked QT prolongation in LQT1, but not LQT3, while the efficacy of ß-blocker therapy is established in LQT1, but not LQT3. We encountered an LQT3 family, with an SCN5A V1667I mutation, that exhibited epinephrine-induced marked QT prolongation. METHODS: Wild-type (WT) or V1667I-SCN5A was transiently expressed into tsA-201 cells, and whole-cell sodium currents (INa ) were recorded using patch-clamp techniques. To mimic the effects of epinephrine, INa was recorded after the application of protein kinase A (PKA) activator, 8-CPT-cAMP (200 µM), for 10 minutes. RESULTS: The peak density of V1667I-INa was significantly larger than WT-INa (WT: 469 ± 48 pA/pF, n = 20; V1667I: 690 ± 62 pA/pF, n = 19, P < .01). The steady-state activation (SSA) and fast inactivation rate of V1667I-INa were comparable to WT-INa . V1667I-INa displayed a significant depolarizing shift in steady-state inactivation (SSI) in comparison to WT-INa (V1/2 -WT: -88.1 ± 0.8 mV, n = 17; V1667I: -82.5 ± 1.1 mV, n = 17, P < .01), which increases window currents. Tetrodotoxin (30 µM)-sensitive persistent V1667I-INa was comparable to WT-INa . However, the ramp pulse protocol (RPP) displayed an increased hump in V1667I-INa in comparison to WT-INa . Although 8-CPT-cAMP shifted SSA to hyperpolarizing potentials in WT-INa and V1667I-INa to the same extent, it shifted SSI to hyperpolarizing potentials much less in V1667I-INa than in WT-INa (V1/2 -WT: -92.7 ± 1.3 mV, n = 6; V1667I: -85.3 ± 1.6 mV, n = 6, P < .01). Concordantly, the RPP displayed an increased hump in V1667I-INa , but not in WT-INa . CONCLUSIONS: We demonstrated an increase of V1667I-INa by PKA activation, which may provide a rationale for the efficacy of ß-blocker therapy in some cases of LQT3.

Simple differential entrainment screens ablation strategy for slow-fast atrioventricular nodal reentrant tachycardia.

BACKGROUND: Ablation of slow-fast atrioventricular nodal reentrant tachycardia (S/F-AVNRT) is occasionally refractory. We hypothesized that the site of ablation for curing S/F-AVNRT can be screened by simple differential atrial entrainment pacing (EP) from the high right atrium (HRA) and proximal coronary sinus (prox-CS). METHODS: We enrolled 43 patients with S/F-AVNRT who underwent successful differential atrial EP followed by successful ablation of slow pathway (SP) using step-wise approach, and compared the atrio-His (A-H) interval at the recording of His bundle immediately after EP from the HRA [A-H(HRA)], with the interval between atrial deflection at the prox-CS and His bundle electrogram after EP at an identical cycle length from the prox-CS [A-H (prox-CS)]. RESULTS: A typical A-H(CS) shorter than A-H(HRA), consistent with typical SP conduction, was observed in 39 patients (91%), and an atypical A-H(HRA) shorter than A-H(CS) was observed in 4 patients (9%). Successful ablation was obtained at the posteroseptum/midseptum in 32/7 patients with typical responses but only at the midseptum in all 4 patients with atypical responses (P = .0027). The atypical responses predicted a necessity for ablation at the midseptum, with positive and negative predictive values of 100% and 82%, respectively. The mechanism of an atypical response remains unclear but may involve an anatomical variation of Koch's triangle and/or the participation of a variant of the SP, including the superior SP, over which retrograde conduction was observed more frequently in patients with atypical responses (P = .0013). CONCLUSIONS: Differential atrial EP predicts the ablation site for successfully curing S/F-AVNRT.

Atypical Slow-Slow Atrioventricular Nodal Reentrant Tachycardia with Use of a Superior Slow Pathway.

We report a case of atypical slow-slow atrioventricular nodal reentrant tachycardia (AVNRT) utilizing a superior slow pathway as a retrograde limb. The standard electrophysiological criteria confirm the diagnosis of this AVNRT by successfully excluding a diagnosis of atrial tachycardia and atrioventricular reentrant tachycardia. The earliest atrial activation during tachycardia was found at the interatrial septum 17.5 mm superior to the site identified during retrograde conduction with the fast pathway. The tachycardia was not inducible after ablation at the right posterior septum, consistent with successful ablation of the typical slow pathway.

Novel Cardiocerebral Channelopathy Associated with a KCND3 V392I Mutation.

While a KCND3 V392I mutation uniquely displays a mixed electrophysiological phenotype of Kv4.3, only limited clinical information on the mutation carriers is available. We report two teenage siblings exhibiting both cardiac (early repolarization syndrome and paroxysmal atrial fibrillation) and cerebral phenotypes (epilepsy and intellectual disability), in whom we identified the KCND3 V392I mutation. We propose a link between the KCND3 mutation with a mixed electrophysiological phenotype and cardiocerebral phenotypes, which may be defined as a novel cardiocerebral channelopathy.

Enhanced closed-state inactivation of mutant cardiac sodium channels (SCN5A N1541D and R1632C) through different mechanisms.

BACKGROUND: SCN5A variants can be associated with overlapping phenotypes such as Brugada syndrome (BrS), sinus node dysfunction and supraventricular tachyarrhythmias. Our genetic screening of SCN5A in 65 consecutive BrS probands revealed two patients with overlapping phenotypes: one carried an SCN5A R1632C (in domain IV-segment 4), which we have previously reported, the other carried a novel SCN5A N1541D (in domain IV-segment 1). OBJECTIVE: We sought to reveal whether or not these variants are associated with the same biophysical defects. METHODS: Wild-type (WT) or mutant SCN5A was expressed in tsA201-cells, and whole-cell sodium currents (hNav1.5/INa) were recorded using patch-clamp techniques. RESULTS: The N1541D-INa density, when assessed from a holding potential of -150 mV, was not different from WT-INa as with R1632C-INa, indicating that SCN5A N1541D did not cause trafficking defects. The steady-state inactivation curve of N1541D-INa was markedly shifted to hyperpolarizing potentials in comparison to WT-INa (V1/2-WT: -82.3 ±â€¯0.9 mV, n = 15; N1541D: -108.8 ±â€¯1.6 mV, n = 26, P < .01) as with R1632C-INa. Closed-state inactivation (CSI) was evaluated using prepulses of -90 mV for 1460 ms. Residual N1541D-INa and R1632C-INa were markedly reduced in comparison to WT-INa (WT: 63.8 ±â€¯4.6%, n = 18; N1541D: 15.1 ±â€¯2.3%, n = 19, P < .01 vs WT; R1632C: 5.3 ±â€¯0.5%, n = 15, P < .01 vs WT). Entry into CSI of N1541D-INa was markedly accelerated, and that of R1632C-INa was weakly accelerated in comparison to WT-INa (tau-WT: 65.8 ±â€¯7.4 ms, n = 18; N1541D: 13.7 ±â€¯1.1 ms, n = 19, P < .01 vs WT; R1632C: 39.5 ±â€¯2.9 ms, n = 15, P < .01 vs WT and N1541D). Although N1541D-INa recovered from closed-state fast inactivation at the same rate as WT-INa, R1632C-INa recovered very slowly (tau-WT: 1.90 ±â€¯0.16 ms, n = 10; N1541D: 1.72 ±â€¯0.12 ms, n = 10, P = .41 vs WT; R1632C: 53.0 ±â€¯2.5 ms, n = 14, P < .01 vs WT and N1541D). CONCLUSIONS: Both N1541D-INa and R1632C-INa exhibited marked enhancement of CSI, but through different mechanisms. The data provided a novel understanding of the mechanisms of CSI of INa. Clinically, the enhanced CSI of N1541D-INa leads to a severe loss-of-function of INa at voltages near the physiological resting membrane potential (~-90 mV) of cardiac myocytes; this can be attributable to the patient's phenotypic manifestations.

Identification of a novel exon3 deletion of RYR2 in a family with catecholaminergic polymorphic ventricular tachycardia.

BACKGROUND: RYR2, encoding cardiac ryanodine receptor, is the major responsible gene for catecholaminergic polymorphic ventricular tachycardia (CPVT). Meanwhile, KCNJ2, encoding inward-rectifier potassium channel (IK1 ), can be the responsible gene for atypical CPVT. We recently encountered a family with CPVT and sought to identify a responsible gene variant. METHODS: A targeted panel sequencing (TPS) was employed in the proband. Copy number variation (CNV) in RYR2 was identified by focusing on read numbers in the TPS and long-range PCR. Cascade screening was conducted by a Sanger method and long-range PCR. KCNJ2 wild-type (WT) or an identified variant was expressed in COS-1 cells, and whole-cell currents (IK1 ) were recorded using patch-clamp techniques. RESULTS: A 40-year-old female experienced cardiopulmonary arrest while cycling. Her ECG showed sinus bradycardia with prominent U-waves (≥0.2 mV). She had left ventricular hypertrabeculation at apex. Exercise induced frequent polymorphic ventricular arrhythmias. Her sister died suddenly at age 35 while bouldering. Her father and paternal aunt, with prominent U-waves, received permanent pacemaker due to sinus node dysfunction. The initial TPS and cascade screening identified a KCNJ2 E118D variant in all three symptomatic patients. However, after focusing on read numbers, we identified a novel exon3 deletion of RYR2 (RYR2-exon3 deletion) in all of them. Functional analysis revealed that KCNJ2 E118D generated IK1 indistinguishable from KCNJ2 WT, even in the presence of catecholaminergic stimulation. CONCLUSIONS: Focusing on the read numbers in the TPS enabled us to identify a novel CNV, RYR2-exon3 deletion, which was associated with phenotypic features of this family.

Atypical Fast-Slow Atrioventricular Nodal Reentrant Tachycardia Using a Slow Pathway Extending to the Superoanterior Right Atrium.

We report a case of atypical fast-slow atrioventricular nodal reentrant tachycardia (AVNRT) using a slow pathway variant extending to the superoanterior right atrium. The AVNRT diagnosis was confirmed by using standard electrophysiological criteria that exclude a diagnosis of atrial tachycardia and atrioventricular reentrant tachycardia. The earliest atrial activation during tachycardia was found in the superoanterior right atrium adjacent to the tricuspid annulus, where the first delivery of radiofrequency energy terminated and eliminated the inducibility of the tachycardia.

Atypical Fast-Slow Atrioventricular Nodal Reentrant Tachycardia Incorporating a "Superior" Slow Pathway: A Distinct Supraventricular Tachyarrhythmia.

BACKGROUND: The existence of an atypical fast-slow (F/S) atrioventricular nodal reentrant tachycardia (AVNRT) including a superior (sup) pathway with slow conductive properties and an atrial exit near the His bundle has not been confirmed. METHODS AND RESULTS: We studied 6 women and 2 men (age, 74 ± 7 years) with sup-F/S-AVNRT who underwent successful radiofrequency ablation near the His bundle. Programmed ventricular stimulation induced retrograde conduction over a superior SP with an earliest atrial activation near the His bundle, a mean shortest spike-atrial interval of 378 ± 119 milliseconds, and decremental properties in all patients. sup-F/S-AVNRT was characterized by a long-RP interval; a retrograde atrial activation sequence during tachycardia identical to that over a sup-SP during ventricular pacing; ventriculoatrial dissociation during ventricular overdrive pacing of the tachycardia in 5 patients or atrioventricular block occurring during tachycardia in 3 patients, excluding atrioventricular reentrant tachycardia; termination of the tachycardia by ATP; and a V-A-V activation sequence immediately after ventricular induction or entrainment of the tachycardia, including dual atrial responses in 2 patients. Elimination or modification of retrograde conduction over the sup-SP by ablation near the right perinodal region or from the noncoronary cusp of Valsalva eliminated and confirmed the diagnosis of AVNRT in 4 patients each. CONCLUSIONS: sup-F/S-AVNRT is a distinct supraventricular tachycardia, incorporating an SP located above the Koch triangle as the retrograde limb, that can be eliminated by radiofrequency ablation.