Frailty exacerbates left atrial remodeling and dysfunction through activation of AIM2 and NLR inflammasome-dependent cardiomyocytes pyroptosis after myocardial infarction in aged mice

Myocardial infarction (MI) is a major driver of left atrial dysfunction and structural remodeling, substantially increasing the risks of heart failure and stroke. Frailty, a common geriatric syndrome, has been linked to adverse cardiovascular outcomes, but its mechanistic contribution remains poorly defined. This study examined the impact of frailty on left atrial remodeling after MI in aged mice and explored the underlying mechanisms. Frailty was modeled in 24-month-old IL-10 knockout mice, and MI was induced by permanent ligation of the left anterior descending coronary artery. Cardiac structure and function were evaluated by echocardiography and histological analysis. In vitro, frailty enhances the susceptibility of atrial cardiomyocytes to pathological remodeling under combined senescent and ischemic stress. RNA-seq of left atrial tissue from wild-type and frail mice after MI was performed, and key findings were validated by quantitative real-time polymerase chain reaction, Western blotting, and immunofluorescence. Although frailty had no baseline effect on left atrial structure or function, frail mice developed pronounced left atrial dilation, increased fibrosis and inflammation, and reduced survival 28 days after MI. Transcriptomic analysis showed enrichment of pyroptosis-, immune activation-, and cytokine signaling-related pathways, with robust activation of NLR and AIM2 inflammasomes. Pharmacological inhibition with the dual NLRP3 and AIM2 inflammasome inhibitor NLRP3/AIM2-IN-3 attenuated cardiomyocyte pyroptosis, reduced myocardial inflammation and pathological remodeling, and improved left atrial function. These findings demonstrate that frailty exacerbates post-MI left atrial remodeling and dysfunction in aged mice by promoting inflammasome-mediated pyroptosis and identify NLRP3/AIM2-IN-3 as a promising therapeutic strategy for frailty-associated left atrial injury.