Circular RNAs in cardiovascular disease: A paradigm shift in diagnosis and therapeutics

Cardiovascular diseases (CVDs) remain the leading cause of global mortality, accounting for 32 % of deaths worldwide in 2021. The increasing prevalence of CVDs highlights the urgent need for novel diagnostic and therapeutic approaches. Circular RNAs (circRNAs), a class of single-stranded RNA molecules produced via back-splicing, have gained attention as potential biomarkers and therapeutic targets due to their distinctive features. Unlike linear RNAs, circRNAs lack 5' caps and 3' poly(A) tails, making them highly resistant to exonuclease degradation and granting them an extended half-life of 19-24 h. Their stability, tissue- and disease-specific expression, evolutionary conservation, and responsiveness to pathological stimuli enable them to regulate key biological processes such as apoptosis, metabolism, and inflammation. Growing evidence links circRNAs to CVD pathogenesis: in cardiomyopathies, circHIPK3 and circFndc3b contribute to hypertrophy and diastolic dysfunction through miR-30a sponging and SERCA2a inhibition; in atherosclerosis, circANRIL exhibits protective effects by modulating ribosomal RNA synthesis and vascular smooth muscle cell proliferation; after myocardial infarction, circZNF609 reduces inflammation while circFndc3b helps prevent apoptosis; and in hypertension, downregulation of hsa-circ-0005870 serves as a specific biomarker. This review further explores circRNAs' diagnostic potential in biofluids, such as serum circHIPK3 for myocardial injury, and their therapeutic applications through silencing with antisense oligonucleotides or delivery of protective mimetics. Despite promising advances, challenges remain, including achieving tissue-specific delivery and addressing the complex pleiotropic effects of circRNAs. Successfully integrating circRNA-based tools into clinical practice could transform CVD management by enabling earlier detection and more personalized treatment strategies.