A High-Protein Diet Promotes Atrial Arrhythmogenesis via Absent-in-Melanoma 2 Inflammasome

Area of Science:

• Cardiology
• Molecular Biology
• Dietary Science

Background:

• High-protein diets (HPDs) are linked to weight management and metabolic improvements.
• The impact of HPDs on cardiac arrhythmogenesis, particularly atrial fibrillation (AF), is not well understood.
• Inflammasome activation, specifically involving Absent-in-Melanoma 2 (AIM2), is implicated in AF but its role in HPD-induced AF is unexplored.

Purpose of the Study:

• To investigate the effect of HPD on AF susceptibility.
• To determine the role of AIM2 inflammasome signaling in HPD-induced AF.
• To elucidate the mechanisms linking HPD, AIM2 activation, and AF.

Main Methods:

• Wildtype and Aim2-deficient mice were fed either normal chow or HPD for four weeks.
• Inflammasome activity, cytoplasmic DNA levels, mitochondrial reactive oxygen species (ROS), and sarcoplasmic reticulum (SR) Ca2+ release were assessed.
• AF susceptibility was evaluated in the different mouse groups.

Main Results:

• HPD significantly increased susceptibility to AF in wildtype mice.
• Inflammasome activity and cytoplasmic double-strand DNA levels were elevated in the atria of HPD-fed wildtype mice.
• Genetic inhibition of AIM2 in Aim2-deficient mice attenuated HPD-induced AF, reduced cytoplasmic dsDNA, mitochondrial ROS, and normalized SR Ca2+ release.

Conclusions:

• HPD promotes AF development by activating the AIM2 inflammasome pathway.
• AIM2 activation by HPD is associated with mitochondrial oxidative stress and proarrhythmic SR Ca2+ release.
• Targeting the AIM2 inflammasome may represent a novel therapeutic strategy for AF in specific patient populations.