A Promising Biomarker for Predicting Cardiovascular Risk in Asymptomatic Familial Hypercholesterolemia Patients From The SAFEHEART Study

Background Familial hypercholesterolemia (FH) is an autosomal dominant disorder associated with a markedly increased risk of premature atherosclerotic cardiovascular disease (ASCVD). Genetic and molecular factors, including microRNAs (miRNAs), may serve as biomarkers to improve disease risk prediction. miRNAs are key regulators of biological processes involved in cardiovascular pathology. This study aimed to identify miRNAs that, combined with clinical variables, enhance ASCVD prediction in asymptomatic FH patients from the SAFEHEART cohort.

A total of 400 subjects diagnosed with FH were included. Coronary calcium score (Agatston score) was measured by computed tomography and stratified into three risk categories (0–99, 100–299, >300). Circulating plasma miRNA levels were quantified using the OpenArray platform. Statistical analyses characterized baseline features and assessed predictive performance using ROC curve analysis. Functional enrichment was explored through the MIENTURNET database.

Individuals carrying the null allele for the LDL-R gene showed significantly higher plasma miR-1 levels than those carrying the defective allele (p=0.042). Likewise, subjects with an Agatston score of 0–99 exhibited higher miR-1 levels than those with scores >300 (p=0.025). A predictive model based on clinical variables including age, sex, hypertension, smoking, BMI, LDL burden, and lipoprotein(a) achieved an AUC of 0.846 for ASCVD prediction. Incorporating miR-1 increased the AUC to 0.878, representing a statistically significant improvement (DeLong test, p=0.005).

miR-1 emerged as a promising biomarker for ASCVD risk prediction in FH patients. When integrated with conventional clinical variables, miR-1 improved the model’s predictive accuracy. These findings suggest that miR-1 could serve as a useful molecular marker for enhanced cardiovascular risk stratification in asymptomatic individuals with familial hypercholesterolemia. Competing Interest Statement Dr Pérez de Isla reports research grants, speaker fees, and consultant fees from Sanofi and Amgen. Dr Díaz-Díaz reports research grants, speaker fees, and consultant fees from Sanofi, Amgen, and Daiichi Sankyo. Dr Muñiz-Grijalvo reports speaker fees from Sanofi and Amgen. Dr Fuentes reports research grants, speaker fees, and consultant fees from Sanofi and Amgen. Dr Mata reports research grants from Sanofi and Amgen. The other authors report no conflicts. Clinical Trial ClinicalTrials.gov, number NCT02693548. Funding Statement This study was supported by the Fundación Hipercolesterolemia Familiar and the Instituto de Salud Carlos III (grants ISCIII PI12/01461 and PI17/01320). Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This study was approved by the ethic committee of the Fundación Jiménez Díaz and all eligible subjects gave written informed consent. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Footnotes Clinical Trial Registration: ClinicalTrials.gov, number NCT02693548 Data Availability The availability of data from the present study is subject to collaboration with the research group and authorisation from the Familial Hypercholesterolaemia Foundation. Collaborations are open to Biomedical Institutions, always after an accepted proposal for a scientific work. Non-standard Abbreviations and Acronyms - ASCVD - Atherosclerotic cardiovascular disease - AUC - Area under curve - CAC - Coronary Artery Calcification - CTA - Computed tomography angiography - FH - Familial hypercholesterolemia - LDL-R - LDL receptor - LLT - Lipid-lowering therapy - Lp(a) - Lipoproteina (a) - miRNA - MicroRNA - ROC - Receiver operating curve - SAFEHEART - Spanish Familial Hypercholesterolemia Cohort Study