Knockout of MD1 contributes to sympathetic hyperactivity and exacerbates ventricular arrhythmias following heart failure with preserved ejection fraction via NLRP3 inflammasome activation

Knockout of MD1 contributes to sympathetic hyperactivity and exacerbates ventricular arrhythmias following heart failure with preserved ejection fraction via NLRP3 inflammasome activation:

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.

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