Circular RNAs: a novel tool in cardiovascular biomarker development?

As we move towards cardiovascular personalised medicine, the development of novel biomarkers to assist in the decision-making process is a hot topic in translational research. In recent years, the non-coding transcriptome has emerged as a novel source of indicators with clinical applications. A vast number of publications have highlighted the potential of different members of this family as biomarkers, especially microRNAs and long non-coding RNAs. Recent advances in RNA sequencing and bioinformatic analysis have drawn attention to another promising class of non-coding RNAs: circular RNAs (circRNAs). CircRNAs are single-stranded and covalently closed RNA molecules that lack free caps or poly(A) tails. Initially discovered in plant viroids as early as the 1970s, circRNAs were originally considered splicing by-products or background noise. Nonetheless, transcriptome-wide analyses have identified and characterised thousands of circRNAs in diverse human cells, with key functions in the regulation of cellular processes. Indeed, various authors have proposed a causative role in a number of pathological conditions, including cardiovascular disease (CVD). Furthermore, circRNAs have the optimal chemical and biological properties to serve as interesting biomarkers. CircRNAs are free of exonuclease-mediated degradation and have a longer half-life than most linear RNAs, and their expression is cell- and developmental stage- and disease-specific. The presence of circRNAs has been demonstrated in clinical specimens, including whole blood, plasma and serum. Here, we review publications that have evaluated the potential of circRNAs as biomarkers for the diagnosis and prediction of cardiovascular conditions, including atherosclerosis, hypertension, aneurysm and the risk of adverse events. In addition, we discuss current methodological limitations and proposed future steps for their application as clinical indicators.