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

In 30 seconds

This systematic translational review examined whether fibro-inflammatory signaling, fibrosis, and microvascular ischemia converge as substrates for ventricular arrhythmia and sudden cardiac death in hypertrophic cardiomyopathy (HCM). Searches identified 11 included studies from 167 records. Fibrosis was the most clinically mature substrate marker, while microvascular ischemia appeared to amplify electrical instability, especially in remodeled myocardium. Molecular and tissue studies implicated fibroblast activation, extracellular-matrix dysregulation, and several signaling pathways. The authors conclude that prospective studies linking these biological features to outcomes are needed before they can improve risk stratification beyond established clinical and imaging markers.

Key findings

• The review included 11 studies, selected after 37 full-text reports were assessed from 167 records.
• Fibrosis emerged as the most clinically mature substrate marker for arrhythmic vulnerability in HCM.
• Microvascular ischemia appeared to amplify electrical instability, particularly in remodeled myocardium.
• Molecular and tissue studies implicated fibro-inflammatory signaling, including SMAD/TGF-beta and CRLF1/LIFR-JAK-STAT pathways.

Why it matters

The review brings together tissue, molecular, and translational evidence to frame HCM arrhythmic vulnerability as a potentially interconnected process rather than a single substrate. This may help guide research into how fibrosis, ischemia, and inflammatory signaling relate to sudden-death risk. However, the evidence does not yet establish that these biological layers add predictive value to current clinical and imaging assessment.

What to keep in mind

Only 11 studies were included, and the review identifies a need for prospective, outcome-validated studies.