Circulating microRNAs as biomarkers of cardiovascular disease: A systematic review

Abstract

BACKGROUND

MicroRNAs (miRNAs) are small, non-coding RNAs that play essential roles in various biological processes. Numerous miRNAs have been identified as biomarkers for various pathologies, including cardiovascular diseases (CVDs). Circulating miRNAs specifically have potential as non-invasive biomarkers, reflecting pathological changes at the cellular level in CVDs. Despite substantial advances in identifying circulating miRNAs associated with CVDs, considerable uncertainty remains regarding their clinical utility, consistency across studies, and integration into standardized diagnostic and prognostic workflows.

AIM

To summarize the identified circulating miRNAs used in the diagnosis or prognosis of CVD.

METHODS

In accordance with PRISMA 2020 guidelines and a registered protocol (PROSPERO CRD420251011773), we conducted comprehensive search of PubMed and CENTRAL from inception to March 2025. Records were screened in duplicate, and we included observational studies or clinical trials evaluating blood-based miRNAs in CVD. Data extraction was performed independently by two reviewers.

RESULTS

We identified 34 studies, comprising approximately 17642 participants, spanning diverse cardiovascular conditions, including acute coronary syndromes, coronary artery disease (CAD), heart failure (HF)/cardiomyopathy, stroke, cardiogenic shock (CS), and hypertension. Diagnostic findings included the upregulation of miR-133a and miR-328 in acute myocardial infarction (AMI), with miR-208b showing an area under the curve (AUC) of 0.76; a miR-132/150/186 panel for unstable angina (AUC = 0.91); and decreased miR-423-3p (AUC = 0.80) along with female-specific elevation of miR-18a in CAD. Prognostic associations included the miR-19 family with cardiovascular mortality in CAD; miR-26b-5p, miR-320a, miR-660-5p, and miR-122-5p/miR-133b ratio, with major adverse cardiovascular events after ST-segment elevation myocardial infarction; miR-328, miR-134, and miR-192 with incident HF after AMI; and miR-423-5p with higher mortality and miR-20b-5p with better survival in CS. Reported diagnostic accuracy varied (AUC values shown where available), and results were influenced by variation in sampling matrix, timing, normalization strategies, and assay platforms.

CONCLUSION

Although circulating miRNAs show potential for CVD diagnosis and risk stratification, study heterogeneity and limited external validation constrain their clinical utility. Future research should prioritize standardized pre-analytical procedures, harmonized reporting, and prospective multicenter validation to demonstrate incremental value over established clinical risk scores and biomarkers.

Keywords: Cardiovascular disease; MicroRNAs; Biomarkers; Extracellular biomarkers; Precision medicine

Core Tip: This systematic review summarizes current evidence on circulating microRNAs (miRNAs) as diagnostic and prognostic biomarkers across cardiovascular disease, including acute coronary syndromes, coronary artery disease, heart failure, stroke, cardiogenic shock, and hypertension. Several miRNAs showed promising disease-specific signals, including miR-133a, miR-328, miR-423-5p, miR-19a, and miR-21. However, clinical translation remains limited by heterogeneity in sampling methods, assay platforms, normalization strategies, and limited external validation. Standardized multicenter prospective studies are needed before circulating miRNAs can be incorporated into routine cardiovascular risk stratification.