Knockout of MD1 contributes to sympathetic hyperactivity and exacerbates ventricular arrhythmias following heart failure with preserved ejection fraction via NLRP3 inflammasome activation.
敲除 MD1 有助于交感神经过度活跃，并通过 NLRP3 炎性体激活加剧射血分数保留的心力衰竭后室性心律失常。
- 作者列表："Yang HJ","Kong B","Shuai W","Zhang JJ","Huang H
NEW FINDINGS:What is the central question of this study? In this study, we investigated whether MD1 interacted with sympathetic nerve in ventricular arrhythmia (VA) following heart failure with preserved ejection fraction (HFpEF). What is the main finding and its importance? HFpEF mice depicted increased VA susceptibility, adversed electrical remodeling, impaired heart rate variability, enhanced sympathetic hyperactivity, activation of NLRP3 inflammasome and increased IL-1β release. These changes induced by HFpEF were exacerbated when MD1 deficiency. ABSTRACT:Background: Sympathetic hyperactivity could promotemalignant ventricular arrhythmias (VA), and myeloid differentiation 1 (MD1) has been reported to play an important role in obesity-induced VA. However, whether MD1 interacted with sympathetic hyperactivity contribute to heart failure with preserved ejection fraction (HFpEF) induced-VA was poorly understood. Hence, this study aims to investigate the potential interaction between MD1 and sympathetic hyperactivity in HFpEF-induced VA and the underlying mechanism. METHODS:8-week old MD1-knockout (MD1-KO) and wild-type (WT) mice subjected to model of HFpEF induced by uninephrectomy, a continuous saline or d-aldosterone infusion and given 1.0% sodium chloride drinking water for 4-weeks. Echocardiography and hemodynamics were used to verify the model of HFpEF, isolated electrophysiological study was performed to induced the incidence of VA. RESULTS:4-week later, HFpEF mice showed increased heart weight (HW) to tibia length (TL) ratio, decreased dp/dtmin, increased Tau, lung weight (LW) to tibia length (TL) ratio and preserved left ventricular ejection fraction compared to WT mice. HFpEF mice depicted increased VA susceptibility, as showed by the shortened effective refractory period (ERP), prolonged action potential duration (APD), increased APD alternans threshold and greater incidence of VA. Moreover, we also found that HFpEF mice showed impaired heart rate variability, sympathetic hyperactivity, activation of NLRP3 inflammasome and increased IL-1β release. These changes induced by HFpEF were exacerbated when MD1 deficiency. CONCLUSIONS:MD1-KO contributes to sympathetic hyperactivity and facilitates VA in HFpEF via NLRP3 inflammasome activation. Treatment targeting MD1-NLRP3 may decrease the risk of HFpEF-induced VA. This article is protected by copyright. All rights reserved.
新发现: 这项研究的中心问题是什么？在这项研究中，我们研究了射血分数保留的心力衰竭 (HFpEF) 后，MD1 是否与交感神经相互作用引起的室性心律失常 (VA)。主要发现及其重要性是什么？HFpEF 小鼠表现为 VA 易感性增加、电重构受阻、心率变异性受损、交感神经过度活跃增强、 NLRP3 炎性体激活和 il-1 β 释放增加。当 MD1 缺乏时，HFpEF 诱导的这些变化加剧。 摘要: 背景: 交感神经过度活跃可促进室性心律失常 (VA) 的发生，髓样分化 1 (MD1) 在肥胖引起的 VA 中起重要作用。然而，MD1 是否与交感神经过度活跃相互作用导致射血分数保留的心力衰竭 (HFpEF) 诱导的-VA 尚不清楚。因此，本研究旨在探讨 MD1 和交感神经过度活跃在 HFpEF 诱导的 VA 中的潜在相互作用及其潜在机制。 方法: 以 8 周龄 MD1-knockout (MD1-KO) 和野生型 (WT) 小鼠为模型鼠,持续输注生理盐水或 d-醛固酮并给予 1.0% 氯化钠饮用水 4 周。采用超声心动图和血流动力学方法验证 HFpEF 模型，进行离体电生理研究，诱导 VA 发生率。 结果: 4 周后，HFpEF 小鼠显示心脏重量 (HW) 与胫骨长度 (TL) 比值增加，dp/dtmin 降低，Tau 增加，肺重量 (LW) 与 WT 小鼠相比，胫骨长度 (TL) 比值和保留的左心室射血分数。HFpEF 小鼠描述了 VA 易感性增加，表现为有效不应期 (ERP) 缩短、动作电位持续时间 (APD) 延长、 APD 交替阈值增加和 VA 发生率增加。此外，我们还发现 HFpEF 小鼠表现出心率变异性受损、交感神经过度活跃、 NLRP3 炎症小体激活和 il-1 β 释放增加。当 MD1 缺乏时，HFpEF 诱导的这些变化加剧。 结论: MD1-KO 通过 NLRP3 炎性体激活促进 HFpEF 中的交感神经过度活跃和 VA。针对 MD1-NLRP3 的治疗可能会降低 HFpEF 诱导 VA 的风险。本文受版权保护。保留所有权利。
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.
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.
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.