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.

Novel CACNA1C R511Q mutation, located in domain â -â ¡ linker, causes non-syndromic type-8 long QT syndrome.

BACKGROUND: Gain-of-function mutations in CACNA1C encoding Cav1.2 cause syndromic or non-syndromic type-8 long QT syndrome (LQTS) (sLQT8 or nsLQT8). The cytoplasmic domain (D)Ⅰ-Ⅱ linker in Cav1.2 plays a pivotal role in calcium channel inactivation, and mutations in this site have been associated with sLQT8 (such as Timothy syndrome) but not nsLQT8. OBJECTIVE: Since we identified a novel CACNA1C mutation, located in the DⅠ-Ⅱ linker, associated with nsLQTS, we sought to reveal its biophysical defects. METHODS: Target panel sequencing was employed in 24 genotype-negative nsLQTS probands (after Sanger sequencing) and three family members. Wild-type (WT) or R511Q Cav1.2 was transiently expressed in tsA201 cells, then whole-cell Ca2+ or Ba2+ currents (ICa or IBa) were recorded using whole-cell patch-clamp techniques. RESULTS: We identified two CACNA1C mutations, a previously reported R858H mutation and a novel R511Q mutation located in the DⅠ-Ⅱ linker. Four members of one nsLQTS family harbored the CACNA1C R511Q mutation. The current density and steady-state activation were comparable to those of WT-ICa. However, persistent currents in R511Q-ICa were significantly larger than those of WT-ICa (WT at +20 mV: 3.3±0.3%, R511Q: 10.8±0.8%, P<0.01). The steady-state inactivation of R511Q-ICa was weak in comparison to that of WT-ICa at higher prepulse potentials, resulting in increased window currents in R511Q-ICa. Slow component of inactivation of R511Q-ICa was significantly delayed compared to that of WT-ICa (WT-tau at +20 mV: 81.3±3.3 ms, R511Q-tau: 125.1±5.0 ms, P<0.01). Inactivation of R511Q-IBa was still slower than that of WT-IBa, indicating that voltage-dependent inactivation (VDI) of R511Q-ICa was predominantly delayed. CONCLUSIONS: Delayed VDI, increased persistent currents, and increased window currents of R511Q-ICa cause nsLQT8. Our data provide novel insights into the structure-function relationships of Cav1.2 and the pathophysiological roles of the DⅠ-Ⅱ linker in phenotypic manifestations.

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.

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.

Superior-Type Fast-Slow Atrioventricular Nodal Reentrant Tachycardia Phenotype Mimicking the Slow-Fast Type.

BACKGROUND: Superior-type fast-slow (sup-F/S-) atrioventricular nodal reentrant tachycardia (AVNRT) is a rare AVNRT variant using a superior slow pathway (SP) as the retrograde limb. Its intracardiac appearance, characterized by a short atrio-His (AH) interval and the earliest site of atrial activation in the His-bundle, is an initial indicator for making a diagnosis. METHODS: Among 22 consecutive patients with sup-F/S-AVNRT, 3 (age, 68-81 years) patients had an apparent slow-fast (S/F-) AVNRT characterized by a long AH interval and the earliest site of atrial activation in or superior to the His-bundle region (tachy-long-AH). RESULTS: The diagnosis of sup-F/S-AVNRT was based on the standard criteria in 2 patients and on the occurrence of Wenckebach-type atrioventricular block during tachycardia, which was attributable to a block at the lower common pathway (LCP) below the circuit of the AVNRT, detected owing to the lower common pathway potentials, in one patient. As with the typical S/F-AVNRT, tachy-long-AH was induced after a jump in the AH interval. In contrast to typical S/F-AVNRT, fluctuation in the ventriculoatrial interval was observed during the tachy-long-AH. Ventricular overdrive pacing was unable to entrain or terminate the tachy-long-AH. Moreover, the tachy-long-AH reciprocally transited to/from sup-F/S-AVNRT spontaneously or was triggered by ventricular contractions while the atrial cycle length and earliest site of atrial activation remained unchanged. Both tachycardias were cured by ablation at a single site in the right-side para-Hisian region of 2 patients and the noncoronary aortic cusp of one patient. Collectively, the essential circuit of both tachycardias was identical, and the tachy-long-AH was diagnosed as another phenotype of sup-F/S-AVNRT accompanied by sustained antegrade conduction via another bystander slow pathway breaking through the His-bundle owing to the repetitive antegrade block at the lower common pathway, thus representing a long AH interval during the ongoing sup-F/S-AVNRT. CONCLUSIONS: An unknown sup-F/S-AVNRT phenotype exists that apparently mimics the typical S/F-AVNRT and is also an unknown subtype of apparent S/F-AVNRT.

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.

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.

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.

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.

Hippocampal GAD67 Transduction Using rAAV8 Regulates Epileptogenesis in EL Mice.

Gene therapy has been employed as a therapeutic approach for intractable focal epilepsies. Considering the potential of focal GABAergic neuromodulation in regulating epileptogenesis, the GABA-producing enzyme, γ-aminobutyric acid decarboxylase 67 (GAD67), is highly suitable for epilepsy therapy. The EL/Suz (EL) mouse is a model of multifactorial temporal lobe epilepsy. In the present study, we examined focal gene transduction in epileptic EL mice using recombinant adeno-associated virus serotype 8 (rAAV8) expressing human GAD67 to enhance GABA-mediated neural inhibition. Eight-week-old mice were bilaterally injected with rAAV8-GFP or rAAV8-GAD67 in the hippocampal CA3 region. After four weeks, the GAD67-transduced EL mice, but not the rAAV-GFP-treated EL mice, exhibited a significant reduction in seizure generation. The GAD67-mediated depression became stable after 14 weeks. The excitability of the CA3 region was markedly reduced in the GAD67-transduced EL mice, consistent with the results of the Ca2+ imaging using hippocampal slices. In addition, downregulation of c-Fos expression was observed in GAD67-transduced hippocampi. Our findings showed that rAAV8-GAD67 induced significant changes in the GABAergic system in the EL hippocampus. Thus, rAAV8-mediated GAD67 gene transfer is a promising therapeutic strategy for the treatment of epilepsies.

Spontaneous occlusion of the frontal arteriovenous malformation and the following progression of the associated aneurysm: a case report.

We report the case of a 59-year-old women with a cerebral arteriovenous malformation (AVM) in the right frontal lobe, which was detected incidentally. Additionally, an aneurysm was found at the feeding artery of the AVM. The patient was treated conservatively. Nine years later, the nidus of the AVM was no longer detectable. The angiography showed the associated aneurysm growing irregularly with a daughter sac. The spontaneous occlusion of an AVM and the following progression of an associated aneurysm are rare. The possible mechanisms leading to the occlusion of the AVM and the progression of the associated aneurysm are discussed.