ESC Congress 2026 Abstract · Oct 26, 2026
A blood-derived 5-microRNA signature of atherosclerotic cardiovascular disease resilience in genetically confirmed familial hypercholesterolemia
By Escate R, Vilahur G, Fuentes F et al.
Background: Familial hypercholesterolemia (FH) confers a markedly elevated risk of premature atherosclerotic cardiovascular disease (ASCVD) due to lifelong high LDL-cholesterol, yet clinical expression is highly variable even among carriers of the same pathogenic variant. Genotype and LDL-cholesterol levels only partially explain this heterogeneity. Circulating microRNAs (miRNAs), key post-transcriptional regulators of lipid metabolism, vascular inflammation, and thrombosis, may capture residual, individualized ASCVD risk in FH. Identifying miRNA signatures that characterize FH patients who remain free of cardiovascular events (CVE) over long-term follow-up versus those with early ASCVD could reveal endogenous cardioprotective pathways and biomarkers of ASCVD resilience. Purpose: In genetically confirmed FH patients from the SAFEHEART cohort with 14-year follow-up, we aimed to identify a circulating miRNA signature associated with lifelong ASCVD resilience in individuals who remained CVE-free up to 65 years (FH-nCVE) compared with those with early ASCVD events (FH-CVE: myocardial infarction, angina, or sudden death before 50 years). Methods: We included 197 FH patients from SAFEHEART with long-term follow-up. Differential miRNA profiling was analyzed in whole blood (PAX tubes) using Affymetrix arrays in a discovery set (FH-nCVE: 30, FH-CVE: 28). Differentially expressed candidates were validated by RT-qPCR in an independent cohort (FH-nCVE: 89, FH-CVE: 50). Bioinformatic analyses identified resilience-associated miRNA signatures and enriched pathways. Results: Global profiling in the discovery set (N=58) identified 9 miRNAs significantly increased in resilient FH-nCVE versus FH-CVE (>1.2-fold). When men and women were analysed separately, the resilience-associated signature expanded to 106 miRNAs (>1.5-fold; 86 in men, 20 in women). The top 10 candidates, selected by presence in coronary arteries (miTED), higher annotation scores (miRBase) and fold change, were taken forward for validation. In the validation cohort, a 5-miRNA signature (miR-27a-3p, miR-194-5p, miR-128-3p, miR-125b-5p, miR-941) was significantly elevated in resilient FH-nCVE patients (overall p=0.007), with each miRNA individually overexpressed. This pattern was also observed when comparing FH-nCVE with FH-CVE patients who experienced MACE during 14-year follow-up (p=0.02). Adding the 5-miRNA signature to the SAFEHEART risk score (SRsc-5y) improved ASCVD risk discrimination in FH (AUC 0.860 vs 0.807). In 14-year Kaplan-Meier analyses, CVE-free survival was associated with a hazard ratio of 9.51 for SRsc-5y alone and 11.23 when combined with the 5-miRNA signature. Conclusion: A specific 5-microRNA signature associates with ASCVD-resilient FH subjects, improves the performance of the SAFEHEART risk score, and highlights endogenous cardioprotective pathways that may guide more personalized prevention in familial hypercholesterolemia.