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The hERG channel activator, RPR260243, enhances protective IKr current in early refractory reducing arrhythmogenicity in zebrafish hearts.

HERG 通道激活剂 RPR260243 增强斑马鱼心脏早期难治性减少心律失常性的保护性 IKr 电流。

  • 影响因子:3.66
  • DOI:10.1152/ajpheart.00038.2020
  • 作者列表:"Shi YP","Pang Z","Venkateshappa R","Gunawan M","Kemp J","Truong E","Chang CE","Lin E","Shafaattalab S","Faizi S","Rayani K","Tibbits GF","Claydon VE","Claydon T
  • 发表时间:2020-06-19
Abstract

:hERG K+ channels are important in cardiac repolarization and their dysfunction causes prolongation of the ventricular action potential, Long QT Syndrome, and arrhythmia. As such, approaches to augment hERG channel function, such as activator compounds, have been of significant interest due to their marked therapeutic potential. Activator compounds that hinder channel inactivation abbreviate action potential duration (APD), but carry risk of over-correction leading to Short QT Syndrome. Enhanced risk by over-correction of the APD may be tempered by activator-induced increased refractoriness, however investigation of the cumulative effect of hERG activator compounds on the balance of these effects in whole organ systems is lacking. Here, we have investigate the antiarrhythmic capability of a hERG activator, RPR260243, which augments channel function by slowing deactivation kinetics, in ex vivo zebrafish whole hearts. We show that 30 mM RPR260243 abbreviates the ventricular APD, reduces triangulation, and steepens the slope of the electrical restitution curve. In addition, RPR260243 increases the post-repolarization refractory period. We provide evidence that this latter effect arises from RPR260243-induced enhancement of hERG channel protective currents flowing early in refractory. Finally, the cumulative effect of RPR260243 on arrhythmogenicity in whole organ zebrafish hearts is demonstrated by the restoration of normal rhythm in hearts presenting dofetilide-induced arrhythmia. These findings in a whole organ model demonstrate the antiarrhythmic benefit of hERG activator compounds that modify both APD and refractoriness. Furthermore, our results demonstrate that targeted slowing of hERG channel deactivation and enhancement of protective currents may provide an effective antiarrhythmic approach.

摘要

: HERG K + 通道在心脏复极中很重要,其功能障碍导致心室动作电位延长、长 QT 综合征和心律失常。因此,增强 hERG 通道功能的方法,如激活剂化合物,由于其显著的治疗潜力而引起了人们的极大兴趣。阻碍通道失活的激活剂化合物缩短动作电位时程 (APD),但携带过度校正导致短 QT 综合征的风险。通过 APD 的过度校正增强的风险可能会被活化剂诱导的增加的耐火度所缓和,然而,目前缺乏 hERG 激活剂化合物对整个器官系统中这些效应平衡的累积效应的研究。在这里,我们研究了 hERG 激活剂 RPR260243 的抗心律失常能力,它通过减缓失活动力学来增强通道功能,在离体斑马鱼整个心脏中。我们发现 30 mM RPR260243 可缩短心室 APD,减少三角测量,并使电恢复曲线的斜率变陡。此外,RPR260243 增加复极后不应期。我们提供的证据表明,后一种效应源于耐火材料早期流动的 hERG 通道保护电流的 RPR260243-induced 增强。最后,RPR260243 对整个器官斑马鱼心脏致心律失常性的累积作用通过恢复呈现多非利特诱导的心律失常的心脏的正常节律来证明。这些在整个器官模型中的发现证明了 hERG 活化剂化合物的抗心律失常作用,这些化合物同时改变了 APD 和难治性。此外,我们的结果证明靶向减缓 hERG 通道失活和增强保护电流可能提供一种有效的抗心律失常方法。

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DOI:10.1093/europace/euz244
作者列表:["Berte B","Hilfiker G","Moccetti F","Schefer T","Weberndörfer V","Cuculi F","Toggweiler S","Ruschitzka F","Kobza R"]

METHODS:AIMS:Pulmonary vein isolation (PVI) using ablation index (AI) incorporates stability, contact force (CF), time, and power. The CLOSE protocol combines AI and ≤6 mm interlesion distance. Safety concerns are raised about surround flow ablation catheters (STSF). To compare safety and effectiveness of an atrial fibrillation (AF) ablation strategy using AI vs. CLOSE protocol using STSF.,METHODS AND RESULTS:First cluster was treated using AI and second cluster using CLOSE. Procedural data, safety, and recurrence of any atrial tachycardia (AT) or AF >30 s were collected prospectively. All Classes 1c and III anti-arrhythmic drugs (AAD) were stopped after the blanking period. In total, all 215 consecutive patients [AI: 121 (paroxysmal: n = 97), CLOSE: n = 94 (paroxysmal: n = 74)] were included. Pulmonary vein isolation was reached in all in similar procedure duration (CLOSE: 107 ± 25 vs. AI: 102 ± 24 min; P = 0.1) and similar radiofrequency time (CLOSE: 36 ± 11 vs. AI: 37 ± 8 min; P = 0.4) but first pass isolation was higher in CLOSE vs. AI [left veins: 90% vs. 80%; P < 0.05 and right veins: 84% vs. 73%; P < 0.05]. Twelve-month off-AAD freedom of AF/AT was higher in CLOSE vs. AI [79% (paroxysmal: 85%) vs. 64% (paroxysmal: 68%); P < 0.05]. Only four patients (2%) without recurrence were on AAD during follow-up. Major complications were similar (CLOSE: 2.1% vs. AI: 2.5%; P = 0.87).,CONCLUSION:The CLOSE protocol is more effective than a PVI approach solely using AI, especially in paroxysmal AF. In this off-AAD study, 79% of patients were free from AF/AT during 12-month follow-up. The STSF catheter appears to be safe using conventional CLOSE targets.

翻译标题与摘要 下载文献
影响因子:2.45
发表时间:2020-01-01
DOI:10.1111/jce.14268
作者列表:["Qin M","Jiang WF","Wu SH","Xu K","Liu X"]

METHODS:OBJECTIVE:To investigate the role of driver mechanism and the effect of electrogram dispersion-guided driver mapping and ablation in atrial fibrillation (AF) at different stages of progression.,METHODS:A total of 256 consecutive patients with AF who had undergone pulmonary vein isolation (PVI) plus driver ablation or conventional ablation were divided into three groups: paroxysmal atrial fibrillation (PAF; group A, n = 51); persistent atrial fibrillation (PsAF; group B, n = 38); and long standing-persistent atrial fibrillation (LS-PsAF; group C, n = 39). PVI was performed with the guidance of the ablation index. The electrogram dispersion was analyzed for driver mapping.,RESULTS:The most prominent driver regions were at roof (28.0%), posterior wall (17.6%), and bottom (21.3%). From patients with PAF to those with PsAF and LS-PsAF: the complexity of extra-pulmonary vein (PV) drivers including distribution, mean number, and area of dispersion region increased (P < .001). Patients who underwent driver ablation vs conventional ablation had higher procedural AF termination rate (76.6% vs 28.1%; P < .001). With AF progression, the termination rate gradually decreased from group A to group C, and the role of PVI in AF termination was also gradually weakened from group A to group C (39.6%, 7.4%, and 4.3%; P < .001) in patients with driver ablation. At the end of the follow-up, the rate of sinus rhythm maintenance was higher in patients with driver ablation than those with conventional ablation (89.1% vs 70.3%; P < .001).,CONCLUSION:The formation of extra-PV drivers provides an important mechanism for AF maintenance with their complexity increasing with AF progression. Electrogram dispersion-guided driver ablation appears to be an efficient adjunctive approach to PVI for AF treatment.

翻译标题与摘要 下载文献
影响因子:1.65
发表时间:2020-01-06
DOI:10.1007/s10840-019-00700-1
作者列表:["Takamiya T","Nitta J","Inaba O","Sato A","Ikenouchi T","Murata K","Inamura Y","Takahashi Y","Goya M","Hirao K"]

METHODS:PURPOSE:Whether or not pulmonary vein isolation (PVI) plus left atrial posterior wall isolation (PWI) using contact force (CF) sensing improves the ablation outcome for persistent atrial fibrillation (AF) is unclear. This study compared the outcome of PVI plus PWI and additional non-PV trigger ablation for persistent AF with/without CF sensing. METHODS:This retrospective cohort study analyzed 148 propensity score-matched persistent AF patients (median duration of persistent AF, 8 months (interquartile range, 3-24 months); left atrial diameter, 43 ± 7 mm) undergoing PVI plus PWI and ablation of non-PV triggers provoked by high-dose isoproterenol, including 74 with CF-sensing catheters (CF group) and 74 with conventional catheters (non-CF group). PVI plus PWI with no additional ablation but cavotricuspid isthmus ablation was performed without non-PV triggers in 48 CF patients (65%) and 54 non-CF patients (73%) (P = 0.38). In all other patients, we performed additional ablation of provoked non-PV triggers. RESULTS:The Kaplan-Meier estimate of the rate of freedom from atrial tachyarrhythmia recurrence of antiarrhythmic drugs at 12 months after the single procedure was higher in the CF group than in the non-CF group (85 vs. 70%, log-rank P = 0.030). A multivariable analysis revealed that using CF sensing and non-inducibility of AF from a non-PV trigger after PVI and PWI were significantly associated with a reduced rate of atrial tachyarrhythmia recurrence. CONCLUSIONS:Compared with non-CF sensing, PVI plus PWI and additional non-PV trigger ablation using CF-sensing catheters for persistent AF can reduce the rate of atrial tachyarrhythmia recurrence.

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