Key result
Specific miRNA shifts link to increased coronary fibrous plaque during PCSK9 inhibitor therapy in FH.
Why the study?
Does PCSK9 inhibitor therapy alter miRNA expression associated with coronary plaque remodelling in patients with familial hypercholesterolemia and subclinical atherosclerosis?
Cohort (n=77)
Does PCSK9 inhibitor therapy alter miRNA expression associated with coronary plaque remodelling in patients with familial hypercholesterolemia and subclinical atherosclerosis?
p-value: p=0.026 and 0.001
PCSK9 inhibitor therapy in familial hypercholesterolemia is associated with specific miRNA changes that correlate with coronary plaque stabilization and fibrous remodelling.
Background Patients with familial hypercholesterolemia (FH) exhibit lifelong elevated LDL-cholesterol levels and high risk of premature atherosclerotic cardiovascular disease despite lipid-lowering therapy. PCSK9 inhibitors reduce LDL-cholesterol and have shown to regress coronary atherosclerotic plaque burden in asymptomatic FH patients, but post-transcriptional miRNA mechanisms underlying these vascular effects remain unclear. Purpose This study was aimed to identify differentially expressed miRNAs associated with changes ) in coronary plaque volume and composition as assessed by computed tomographic angiography (CTA) in FH patients treated with PCSK9 inhibitors added to high-intensity statins. Methods Seventy-seven FH patients with subclinical atherosclerosis from the SAFEHEART cohort underwent CTA at baseline and after 78 weeks of PCSK9 inhibitors (150 mg every 14 days) plus high-intensity statins. Plaque components (fibrous, fibro-fatty, calcified, and necrotic) were quantified. miRNA changes were analyzed by real-time PCR and bioinformatic tools (miTED, TAM, miRWalk, ShinyGO, Cytoscape, IPA). Results An initial profiling of 375 miRNA was performed in a discovery subset (n=8), identifying 66 miRNAs consistently expressed in all subjects. Thirteen miRNAs with stable and quantifiable expression were selected for validation in the full cohort (n=77). Hierarchical clustering revealed two miRNA clusters [Cluster 1 (8 miRNAs) and Cluster 2 (5 miRNAs)] related to tissue remodelling processes (cell proliferation, innate immunity, and stem cell differentiation). The most relevant changes occurred in miRNAs miR-342-3p (immune-related source, Cluster 1) and miR-193a-5p (vascular-related source, Cluster 2). Changes in both miRNA positively correlated with the observed increase in the percentage of fibrous plaque at follow-up (P=0.026 and p=0.001, respectively). Moreover, miR-193a-5p changes were inversely correlated with reductions in fibro-fatty plaques (P=0.017). miR-342-3p changes were associated with PCSK9 inhibitor-induced lipid reductions, whereas miR-193a-5p changes appeared lipid-independent. Combined target gene predictions for the effects of the two miRNAs relate to FGF and PDGF signaling, including genes such as SOS1, PIK3CD, PPP2R1A, MAPK9, and RPS6KA5. Downregulation of SOS1, PIK3CD, MAPK9, and RPS6KA5, genes regulating inflammation, cell proliferation, and apoptosis, is linked to plaque stabilization. Conclusions FH patients treated with a PCSK9 inhibitor exhibited a differential miRNA signature. Predicted target genes for upregulated miR-320a-3p and miR-21-5p relate to cell functions involved in plaque remodelling and stabilization.
No takes yet. Share an insight, caveat, or question.
Chavez et al. (2026) conducted a cohort in Familial hypercholesterolemia with subclinical atherosclerosis (n=77). PCSK9 inhibitors plus high-intensity statins vs. Baseline was evaluated on Differentially expressed miRNAs associated with changes in coronary plaque volume and composition (p=0.026 and 0.001). In FH patients treated with PCSK9 inhibitors, changes in miR-342-3p and miR-193a-5p positively correlated with increased fibrous plaque percentage (P=0.026 and P=0.001, respectively).
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: