Background: Pacemaker-induced cardiomyopathy (PICM) is an increasingly recognized consequence of chronic right ventricular pacing. It is preceded by dyssynchrony-related myocardial dysfunction, a condition characterized by abnormal electrical activation, mechanical discoordination, adverse remodeling, fibrosis, perfusion abnormalities, and progressive ventricular dysfunction. Marked variability in PICM incidence and patient susceptibility suggests that the paced myocardium–dyssynchrony axis alone does not fully explain disease expression. This review aimed to synthesized current evidence regarding microRNA (miRNA)-related biomolecular mechanisms potentially involved in dyssynchrony-related cardiomyopathy and PICM, while proposing a translational framework for future biomarker identification and therapeutic development.

Methods: Half-narrative, half-translational review employing an original bioinformatic literature-based prioritization strategy integrating biological annotation through the GeneCards® database, validation in human studies indexed in PubMed/MEDLINE, Embase, and SciELO, and a mathematical prioritization model incorporating literature weight, disease attribution, and cross-descriptor consistency. Candidate miRNAs were mapped across descriptors including dilated cardiomyopathy, heart failure, cardiac dyssynchrony, ventricular pacing, pacemaker-related remodeling, and PICM.

Results: Dysregulated miRNAs may mediate key pathways involved in dyssynchrony-related cardiomyopathy and PICM, including fibrosis, hypertrophy, inflammation, ion-channel dysfunction, calcium-handling abnormalities, gap-junction disorganization, and arrhythmogenic remodeling. Our prioritization model implicated the following candidate miRNAs: miRNA-1, miRNA-21, miRNA-23a, miRNA-30, miRNA133a, miRNA-146a and miRNA146b, miRNA-155, miRNA-206, miRNA-210, miRNA-221/222/223, miRNA-17 and miRNA-328. These molecular signatures may explain why only a subset of chronically paced patients develop PICM despite comparable pacing exposure.

Conclusions: Distinct miRNA profiles may serve as mechanistic mediators, biomarkers for risk stratification and early detection, and potential therapeutic targets in dyssynchrony-related PICM. Additional multicenter studies are required to validate PICM-specific miRNA panels and clarify their causal contribution to disease pathogenesis.

To be updated