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

Abstract

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 MD1knockout (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 min ), increased , 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-1 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. K E Y W O R D Sheart failure with preserved ejection fraction, inflammation, sympathetic nerve 1 966wileyonlinelibrary.com/journal/eph Experimental Physiology. 2020;105:966-978.

Silenced SOX2‐OT alleviates ventricular arrhythmia associated with heart failure by inhibiting NLRP3 expression via regulating miR‐2355‐3p

“…The inflammatory markers, IL‐1β and TGF‐β1 promote extracellular matrix remodeling and cardiac collagen expression and aggravate VA induced by ischemia 4,7,8 . Caspase‐1 NLRP3 and ASC are components of NLRP3 inflammasomes that can cause cardiac inflammation and cardiac dysfunction via IL‐1β and TGF‐β1 release 13–16 . Inhibiting TGF‐β and IL‐1β expression can alleviate cardiac dysfunction in ischemic VA‐HF 9–11 .…”

“…Abnormal activation of NLRP3 inflammasomes can lead to cardiac inflammation and heart dysfunction 13,14 . The activation of NLRP3 inflammasomes increases IL‐1β release to promote myocardial inflammation, systolic dysfunction, and VA 15,16 . Additionally, silencing NLRP3 inflammasomes can reduce inflammation and improve cardiac dysfunction 17 .…”

Shensong Yangxin Protects Against Metabolic Syndrome-Induced Ventricular Arrhythmias by Inhibiting Electrical Remodeling

“…The ventricular effective refractory period (ERP) was measured via an S1S2 stimulation protocol, 8 consecutive S1 stimulations with cycle length (CL) of 200 ms were followed by a stimulus S2, the CL was progressively reduced by 10 ms starting from 200 ms and ending at 20 ms, then reduced by 10 ms from 20 ms to the conduction block, and finally reduced in steps of 1 ms from the last conducted S2 to ERP ( Yang et al., 2020 ).…”

“…Burst pacing protocols were conducted to determine susceptibility to ventricular arrhythmias (VAs) as previously described ( Yang et al., 2020 ). Briefly, VA was induced through the last 2-s burst pacing which repeated for three times.…”

“…Briefly, VA was induced through the last 2-s burst pacing which repeated for three times. VAs were defined as consecutive premature ventricular contractions at least 2 s. And sustained VA were defined as the VA last more than 30 s. Susceptibility to VAs was evaluated based on the VA incidence and the ratio of sustained to nonsustained VAs ( Yang et al., 2020 ).…”