Authors reply regarding "A-V-V-A response to single atrial premature depolarization in a narrow QRS tachycardia: What is the mechanism?"

We respond to a letter by Dr. A. Goyal. If the tachycardia were junctional ectopic tachycardia (JET), the occurrence of the ventriculoatrial block following an atrial premature depolarization could not be explained. Therefore, we conclude that atrioventricular nodal reentrant tachycardia was more likely than JET.

Novel KCNQ1 Q234K variant, identified in patients with long QT syndrome and epileptiform activity, induces both gain- and loss-of-function of slowly activating delayed rectifier potassium currents.

Introduction: KCNQ1 and KCNE1 form slowly activating delayed rectifier potassium currents (IKs). Loss-of-function of IKs by KCNQ1 variants causes type-1 long QT syndrome (LQTS). Also, some KCNQ1 variants are reported to cause epilepsy. Segment 4 (S4) of voltage-gated potassium channels has several positively-charged amino acids that are periodically aligned, and acts as a voltage-sensor. Intriguingly, KCNQ1 has a neutral-charge glutamine at the third position (Q3) in the S4 (Q234 position in KCNQ1), which suggests that the Q3 (Q234) may play an important role in the gating properties of IKs. We identified a novel KCNQ1 Q234K (substituted for a positively-charged lysine) variant in patients (a girl and her mother) with LQTS and epileptiform activity on electroencephalogram. The mother had been diagnosed with epilepsy. Therefore, we sought to elucidate the effects of the KCNQ1 Q234K on gating properties of IKs. Methods: Wild-type (WT)-KCNQ1 and/or Q234K-KCNQ1 were transiently expressed in tsA201-cells with KCNE1 (E1) (WT + E1-channels, Q234K + E1-channels, and WT + Q234K + E1-channels), and membrane currents were recorded using whole-cell patch-clamp techniques. Results: At 8-s depolarization, current density (CD) of the Q234K + E1-channels or WT + Q234K + E1-channels was significantly larger than the WT + E1-channels (WT + E1: 701 ± 59 pA/pF; Q234K + E1: 912 ± 50 pA/pF, p < 0.01; WT + Q234K + E1: 867 ± 48 pA/pF, p < 0.05). Voltage dependence of activation (VDA) of the Q234K + E1-channels or WT + Q234K + E1-channels was slightly but significantly shifted to depolarizing potentials in comparison to the WT + E1-channels ([V1/2] WT + E1: 25.6 ± 2.6 mV; Q234K + E1: 31.8 ± 1.7 mV, p < 0.05; WT + Q234K + E1: 32.3 ± 1.9 mV, p < 0.05). Activation rate of the Q234K + E1-channels or WT + Q234K + E1-channels was significantly delayed in comparison to the WT + E1-channels ([half activation time] WT + E1: 664 ± 37 ms; Q234K + E1: 1,417 ± 60 ms, p < 0.01; WT + Q234K + E1: 1,177 ± 71 ms, p < 0.01). At 400-ms depolarization, CD of the Q234K + E1-channels or WT + Q234K + E1-channels was significantly decreased in comparison to the WT + E1-channels (WT + E1: 392 ± 42 pA/pF; Q234K + E1: 143 ± 12 pA/pF, p < 0.01; WT + Q234K + E1: 209 ± 24 pA/pF, p < 0.01) due to delayed activation rate and depolarizing shift of VDA. Conclusion: The KCNQ1 Q234K induced IKs gain-of-function during long (8-s)-depolarization, while loss of-function during short (400-ms)-depolarization, which indicates that the variant causes LQTS, and raises a possibility that the variant may also cause epilepsy. Our data provide novel insights into the functional consequences of charge addition on the Q3 in the S4 of KCNQ1.

Catheter Ablation Approach Targeting Epicardial Connections to the Right Pulmonary Vein Antrum Detected before Pulmonary Vein Isolation.

BACKGROUND: Epicardial connections from surrounding structures to the right pulmonary vein (PV) antrum impede PV isolation. OBJECTIVE: This study aimed to evaluate the efficacy of an ablation approach targeting epicardial connections for right PV isolation. METHODS: We prospectively enrolled 124 patients with atrial fibrillation undergoing initial PV isolation. We identified the activation breakthrough into the right PV antrum (BT-RPV) on the activation map created during high right atrial pacing before PV isolation. BT-RPV sites were targeted when right PV isolation was not achieved by wide antral circumferential ablation (WACA). RESULTS: BT-RPV was observed in 83 cases (67%). PV isolation was achieved by WACA in all 41 cases without BT-RPV. Among cases with BT-RPV, PV isolation was achieved by WACA in 48 cases when all BT-RPV sites were covered by the PV isolation line. Conversely, PV isolation was completed by WACA in only 5 out of 35 cases when not all BT-RPV sites were covered. In cases where WACA failed, 35 sites were targeted for BT-RPV ablation. Initial BT-RPV ablation led to PV isolation at 20 sites, while the remaining 15 BT-RPV sites required repeat BT-RPV ablation. The ablated area of successful BT-RPV ablation was 0.9 [0.6-1.2] cm2, corresponding to the area activated within 15 [14-16] ms after BT-RPV emergence. Ablating the area activated within 14 ms after BT-RPV emergence was associated with successful PV isolation (sensitivity 91% and specificity 100%). CONCLUSION: Ablation targeting BT-RPV sites is effective for right PV isolation. Extensive ablation is required to eliminate BT-RPV.

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.

The optimal slow pathway ablation site in atrioventricular nodal reentrant tachycardia cases with an inferiorly located His bundle.

INTRODUCTION: The optimal slow pathway (SP) ablation site in cases with an inferiorly located His bundle (HIS) remains unclear. METHODS AND RESULTS: In 45 patients with atrioventricular nodal reentrant tachycardia, the relationship between the HIS location and successful SP ablation site was assessed in electroanatomical maps. We assessed the location of the SP ablation site relative to the bottom of the coronary sinus ostium in the superior-to-inferior (SPSI), anterior-to-posterior (SPAP), and right-to-left (SPRL) directions. The HIS location was assessed in the same manner. The HIS location in the superior-to-inferior direction (HISSI), SPSI, SPAP, and SPRL were 17.7 ± 6.4, 1.7 ± 6.4, 13.6 ± 12.3, and -1.0 ± 13.0 mm, respectively. The HISSI was positively correlated with SPSI (R2 = 0.62; P < .01) and SPAP (R2 = 0.22; P < .01), whereas it was not correlated with SPRL (R2 = 0.01; P = .65). The distance between the HIS and SP ablation site was 17.7 ± 6.4 mm and was not affected by the location of HIS. The ratio of the amplitudes of atrial and ventricular potential recorded at the SP ablation site did not differ between the high HIS group (HISSI ≥ 13 mm) and low HIS group (HISSI < 13 mm) (0.10 ± 0.06 vs. 0.10 ± 0.06; P = .38). CONCLUSION: In cases with an inferiorly located HIS, SP ablation should be performed at a lower and more posterior site than in typical cases.