Department of Cardiology, Renmin Hospital of Wuhan University, Wuchang, Wuhan, China.
Cardiovascular Research Institute, Wuhan University, Wuchang, Wuhan, China.
Exp Physiol. 2020 Jun;105(6):966-978. doi: 10.1113/EP088390. Epub 2020 May 6.
What is the central question of this study? In this study, we investigated whether MD1 interacted with the sympathetic nerves in ventricular arrhythmia (VA) during heart failure with preserved ejection fraction (HFpEF). What is the main finding and its importance? Mice with HFpEF showed increased susceptibility to VA, adverse electrical remodelling, impaired heart rate variability, enhanced sympathetic hyperactivity, activation of the NLRP3 inflammasome and increased interleukin-1β release. These changes induced by HFpEF were exacerbated by MD1 deficiency.
Sympathetic hyperactivity can promote malignant ventricular arrhythmia (VA), and myeloid differentiation 1 (MD1) has been reported to play an important role in obesity-induced VA. However, it is not known whether an interaction of MD1 with sympathetic hyperactivity contributes to the VA induced by heart failure with preserved ejection fraction (HFpEF). The aim of this study was to investigate the potential interaction between MD1 and sympathetic hyperactivity in HFpEF-induced VA and the underlying mechanism. Eight-week-old MD1-knockout (MD1-KO) and wild-type (WT) mice were subjected to a model of HFpEF induced by uninephrectomy, a continuous saline or d-aldosterone infusion and provision of drinking water containing 1.0% sodium chloride for 4 weeks. Echocardiography and haemodynamics were used to verify the model of HFpEF. An isolated electrophysiological study was performed to assess the susceptibility to VA. Four weeks later, the mice with HFpEF showed an increased heart weight to tibia length ratio, decreased left ventricular minimum rates of pressure rise (dP/dt ), increased τ, lung weight to tibia length ratio and preserved left ventricular ejection fraction compared with WT mice. The mice with HFpEF exhibited increased susceptibility to VA, as shown by the shortened effective refractory period, prolonged action potential duration (APD), increased APD alternans threshold and higher incidence of VA. Moreover, we also found that mice with HFpEF showed impaired heart rate variability, sympathetic hyperactivity, activation of the NLRP3 inflammasome and increased interleukin-1β release. These changes induced by HFpEF were exacerbated by MD1 deficiency. We conclude that MD1-KO contributes to sympathetic hyperactivity and facilitates VA in HFpEF via activation of the NLRP3 inflammasome. Treatment targeting MD1 and NLRP3 might decrease the risk of HFpEF-induced VA.
本研究的核心问题是什么？在这项研究中，我们研究了在射血分数保留心力衰竭（HFpEF）期间，MD1 是否与室性心律失常（VA）中的交感神经相互作用。主要发现及其重要性是什么？HFpEF 小鼠表现出对 VA、不良电重构、心率变异性降低、交感神经活性增强、NLRP3 炎性小体激活和白细胞介素-1β释放增加的易感性增加。HFpEF 引起的这些变化因 MD1 缺乏而加剧。
交感神经活性可促进恶性室性心律失常（VA），髓样分化因子 1（MD1）已被报道在肥胖诱导的 VA 中发挥重要作用。然而，尚不清楚 MD1 与交感神经活性的相互作用是否有助于射血分数保留心力衰竭（HFpEF）引起的 VA。本研究旨在探讨 MD1 与 HFpEF 诱导的 VA 中交感神经活性之间的潜在相互作用及其潜在机制。将 8 周龄的 MD1 敲除（MD1-KO）和野生型（WT）小鼠进行单侧肾切除术、连续生理盐水或 d-醛固酮输注以及提供 1.0%氯化钠饮用水 4 周的 HFpEF 模型。使用超声心动图和血流动力学来验证 HFpEF 模型。进行离体电生理研究以评估对 VA 的易感性。4 周后，与 WT 小鼠相比，HFpEF 小鼠的心脏重量/胫骨长度比增加，左心室最小压力上升率（dP/dt）降低，τ延长，肺重量/胫骨长度比增加，左心室射血分数保持不变。HFpEF 小鼠表现出对 VA 的易感性增加，表现为有效不应期缩短、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 小鼠的心率变异性降低、交感神经活性增强、NLRP3 炎性小体激活和白细胞介素-1β释放增加。HFpEF 引起的这些变化因 MD1 缺乏而加剧。我们得出结论，MD1-KO 通过激活 NLRP3 炎性小体促进 HFpEF 中的交感神经活性并促进 VA。针对 MD1 和 NLRP3 的治疗可能会降低 HFpEF 诱导的 VA 风险。
