Fibro-Inflammatory Signaling, Fibrosis, and Microvascular Ischemia as Convergent Translational Substrates of Sudden Cardiac Death in Hypertrophic Cardiomyopathy: A Systematic Review.

Hypertrophic cardiomyopathy (HCM) remains an important cause of sudden cardiac death (SCD), but the biological determinants of ventricular arrhythmic vulnerability remain incompletely defined. This systematic translational review examined whether fibro-inflammatory signaling, fibrotic remodeling, and microvascular ischemia represent convergent components of the arrhythmogenic substrate in HCM. MEDLINE/PubMed, Embase, Web of Science Core Collection, and Cochrane Library were searched from inception to January 2026. Of 167 records, 37 full-text reports were assessed and 11 studies included. Fibrosis emerged as the most clinically mature substrate marker, while microvascular ischemia appeared to amplify electrical instability, particularly in remodeled myocardium. Molecular and tissue studies suggested upstream fibro-inflammatory programs involving activated fibroblasts, extracellular matrix dysregulation, SMAD/TGF-beta signaling, CRLF1/LIFR-JAK-STAT signaling, and altered multicellular communication. Overall, the evidence supports an integrated mechanism-to-substrate model, but prospective outcome-validated studies are needed before these biological layers can refine SCD risk stratification beyond established clinical and imaging markers in contemporary HCM practice.