Dilated cardiomyopathy (DCM) is a leading cause of heart failure (HF), yet molecular signatures that are detectable in blood and mechanistically anchored in myocardial pathology remain limited. Adenosine-to-inosine (A-to-I) RNA editing is an important post-transcriptional regulator in the heart, but its biomarker potential in human DCM and its reflection in the circulation are not well defined. We performed comprehensive RNA editome profiling of human myocardium from DCM patients and non-failing donors, and integrated these results with peripheral blood RNA editing profiles from HF patients and controls, using a SPRINT-based pipeline with stringent in-house post-postprocessing and quality filtering. Global editing distributions and site-level differential editing were assessed, and shared heart–blood candidates were evaluated for directionality and functional enrichment. Cardiac RNA editing was dominated by ADAR-mediated A-to-I events and was significantly increased in DCM, with prominent enrichment in Alu elements and a higher number of unique editing sites compared with controls. Site-level analysis identified a predominantly hyper-edited DCM signature, mapping to genes and pathways linked to cardiomyopathy and cellular stress, including hypoxia and apoptosis. Cross-tissue comparison revealed 107 shared differentially edited sites between DCM heart and HF blood, with subsets showing concordant directionality. Shared targets were enriched for innate immune and type I interferon signaling, RIG-I pathway regulation, hypoxia-related responses, and apoptosis. DCM is associated with global myocardial A-to-I hyper-editing and a robust, multi-locus editing program. Importantly, a subset of these disease-associated editing events is detectable in peripheral blood from heart failure patients, supporting the feasibility of HF-associated circulating RNA editing signatures that reflect myocardial pathology.
Karagianni et al. (Sun,) studied this question.