From Old to Bold: Advancing microRNA Studies in Sudden Cardiac Death Through Molecular Analysis of FFPE Heart Tissue

Background/Objectives: Sudden cardiac death (SCD) is a natural death of cardiac origin, accounting for an estimated 6–9 million deaths worldwide each year and representing a major public health challenge. Despite its clinical and forensic relevance, the molecular investigation of SCD remains limited. Peripheral blood or fresh tissue, the preferred specimens for post-mortem genetic testing, are not always available, and DNA extracted from formalin-fixed paraffin-embedded (FFPE) tissues is often suboptimal for conventional genetic analyses. This review evaluates the potential of archived FFPE cardiac tissue as a source for microRNA (miRNA) analysis in molecular autopsy. Methods: A narrative review was conducted by collecting studies investigating miRNA expression in FFPE cardiac tissue relevant to SCD. Ten studies met the inclusion criteria and were critically analyzed. Results: Although the available evidence remains limited, recent studies have identified several differentially expressed miRNAs associated with cardiac diseases relevant to SCD. Owing to their small size and remarkable stability, miRNAs remain detectable in FFPE tissues despite fixation and long-term storage, making them attractive molecular biomarkers. While most available studies were conducted in clinical rather than forensic settings, they demonstrate the feasibility and analytical robustness of miRNA profiling in archived FFPE cardiac specimens. Conclusions: This review underlines the importance of reconsidering archived FFPE tissues not merely as historical or morphological resources, but as promising matrices for molecular autopsy of SCD supporting the identification and validation of novel molecular biomarkers.