AHA Scientific Sessions 2026 Abstract · Nov 2, 2026
Paired Single Cell Transcriptomics Reveals Immune Remodeling During PCSK9 Inhibition in Atherosclerotic Cardiovascular Disease
By Gupta M, Remala S, Marks K et al.
Background - Proprotein Convertase Subtilisin/Kexin Type 9 inhibitors (PCSK9i) lower LDL-C and reduce ASCVD events, but their effects on circulating immune composition and cell-specific transcriptional programs remain incompletely defined. Hypothesis: PCSK9 inhibition is associated with changes in monocyte transcriptional programs linked to lipid biology and innate immune activation, along with broader changes in PBMC composition and lymphocyte regulatory phenotypes. Methods: In this pilot analysis of an ongoing Mass General Brigham prospective mechanistic study of clinically indicated PCSK9i therapy (NCT05152888), four participants underwent baseline and one-year PBMC single-cell RNA sequencing (scRNA-seq) using the 10x Genomics Chromium platform. One participant was excluded after interval malignancy, leaving three paired participants. Participants were all female, aged 56-73, with baseline LDL-C of 147.67 ± 51.03 mg/dL (Figure 1A). After quality control, Harmony integration, clustering, and manual annotation, paired abundance changes were tested using MASC with participants as a random effect; cell-type differential expression was assessed between baseline and 1 year. Results: PCSK9i therapy reduced LDL-C from 147.7 +/- 51.0 to 98.7+/- 55.4 mg/dl (paired p = 0.01), whereas hsCRP did not change significantly (p = 0.47) (Figure 1A) . We profiled 45,287 PBMCs were profiled and annotated 14 immune populations (Figure 1B). Exploratory abundance modeling showed FDR<0.05 relative enrichment of classical and nonclassical monocytes, CD56 bright and CD56 dim NK cells, Mucosal-Associated Invariant T (MAIT) cells and CD8+ effector cells, with relative reductions in B-cells, total and naïve CD4+ T cells, naïve CD8+ T cells and plasma cells (Figure 1C) . Differential expression was most pronounced in classical monocytes (Figure 2A) , with increased expression of interferon-stimulated and innate immune genes, including GBP1/2/4/5, IFIT1/2/3, ZBP1 and CGAS (Figure 2B-C) . Total and naïve CD4+ T cells showed higher expression of negative regulatory/checkpoint-associated genes (VSIR, UBASH3A, PAG1) and increased expression of cytokine-signaling suppressors (SOCS1, SOCS2) (Fig 2D) . Conclusion: In this paired scRNA-seq pilot study, 1 year of PCSK9 inhibition in ASCVD patients was associated with LDL-C reduction and circulating immune remodeling, including innate immune activation signatures, and CD4+ T cell regulatory transcriptional features. These data support measurable cellular and transcriptional immune changes during PCSK9i therapy but do not establish a clear anti-inflammatory mechanism of CV benefit. Larger paired analyses and functional assays are needed for reproducibility and significance.