AHA Scientific Sessions 2026 Abstract · Nov 2, 2026
Suppression of Systemic and Local Inflammation by NLRP3 Inhibition Reduces Atheroma Burden Independent of Circulating Lipids in a Mouse Model of Accelerated Atherosclerosis
By Bao W, Sen P, Montenont E et al.
Background: Despite intensive lipid-lowering therapy, patients with cardiovascular disease (CVD) remain at increased risk of recurrent events. The Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS) established inflammation as an independent causal factor in atherosclerotic cardiovascular disease (ASCVD), distinct from low-density lipoprotein (LDL) cholesterol. Post hoc analyses further showed that patients with clonal hematopoiesis of indeterminate potential (CHIP), particularly those with TET2 mutations, gained substantial benefit from anti-inflammatory therapy. However, the role of the NLRP3 inflammasome in TET2-driven ASCVD remains incompletely defined. We hypothesized that NLRP3 inhibition would reduce atheroma burden in this setting. Methods: To model clinically relevant disease conditions, Ldlr knockout mice were lethally irradiated and transplanted with bone marrow containing 10% TET2-deficient and 90% wild-type cells. Mice were fed with a Western diet and randomized to receive placebo or AZ’7773, a potent oral NLRP3 inhibitor (n = 12/group), beginning six weeks after diet initiation and continuing for six weeks as an interventional treatment. The atheroma burden was quantified by Oil Red O staining. Systemic and plaque inflammation were assessed by enzyme-linked immunosorbent assay (ELISA), Olink proteomics, and Western blotting. Single-cell RNA sequencing was also performed for transcriptomic profiling. Results: AZ’7773 significantly reduced plaque area by 73% (0.98 ± 0.648 mm ² vs. 0.27 ± 0.185 mm ² , p < 0.001). Circulating IL-6 was reduced by 43% (p < 0.05), while circulating IL-18 was reduced by 9% (p > 0.05); plaque IL-18 protein levels were reduced by 33% (p < 0.05). Transcriptomic analyses showed that inflammatory pathways including IL-6 and IL-17 were upregulated in placebo treated mice but significantly attenuated with AZ’7773 treatment (p<0.05). Furthermore, differentially expressed genes, such as S100A8 and S100A9, were significantly upregulated in Ldlr KO mice with TET2 deficiency compared to control Ldlr KO mice. Those differentially expressed genes were significantly downregulated with AZ’7773 treatment, further confirming that NLRP3 inhibition suppresses inflammatory genes and pathways. Plasma lipid analysis showed treatment with AZ’7773 did not affect total cholesterol, LDL cholesterol, or triglycerides. Conclusions: NLRP3 inhibition reduced atheroma burden and systemic and local inflammatory markers without affecting plasma lipids, supporting further investigation of NLRP3-targeted therapy for residual inflammatory risk in patients with ASCVD.