# T-Cell-Driven Immunopathology and Fibrotic Remodeling in Hypertrophic Cardiomyopathy: A Translational Scoping Review

## TL;DR

This review suggests that hypertrophic cardiomyopathy involves immune and genetic changes, not just heart muscle defects, and could benefit from precision immunotherapy.

## Contribution

The study identifies novel immunogenetic mechanisms and potential drug targets for personalized treatment of HCM.

## Key findings

- HCM involves immune cell shifts and RNA regulation linked to fibrosis and heart dysfunction.
- Diagnostic gene panels and machine learning biomarkers show high accuracy for HCM detection.
- Ruxolitinib and celecoxib are predicted as potential immunometabolic modulators for HCM.

## Abstract

What are the main findings?
Hypertrophic cardiomyopathy (HCM) involves coordinated genetic, epigenetic, and immune remodeling, redefining it as an immunogenetic disorder rather than solely a sarcomeric disease.Key molecular drivers and immune cell shifts link RNA regulation, m6A methylation, and inflammatory pathways to myocardial fibrosis and diastolic dysfunction.

Hypertrophic cardiomyopathy (HCM) involves coordinated genetic, epigenetic, and immune remodeling, redefining it as an immunogenetic disorder rather than solely a sarcomeric disease.

Key molecular drivers and immune cell shifts link RNA regulation, m6A methylation, and inflammatory pathways to myocardial fibrosis and diastolic dysfunction.

What are the implications of the main finding?
Identified diagnostic gene panels and hub genes support transcriptome-based precision diagnostics for HCM.Immunometabolic drug targets and integration of biomarkers with imaging may guide personalized immunotherapy and risk stratification.

Identified diagnostic gene panels and hub genes support transcriptome-based precision diagnostics for HCM.

Immunometabolic drug targets and integration of biomarkers with imaging may guide personalized immunotherapy and risk stratification.

Background: Hypertrophic cardiomyopathy (HCM) is increasingly recognized as a disorder shaped not only by sarcomeric mutations but also by complex immunogenetic and metabolic interactions. Emerging transcriptomic and single-cell analyses implicate immune dysregulation, RNA methylation, and necroptosis as critical modulators of myocardial remodeling. Objectives: This scoping review synthesizes bioinformatic, transcriptomic, and experimental data to delineate the immunogenetic architecture of HCM and identify candidate molecular targets for immune–metabolic modulation. Methods: Following Joanna Briggs Institute and PRISMA-ScR guidelines, we systematically searched PubMed, Embase, Web of Science, and GEO through September 2025 for studies evaluating immune infiltration, RNA regulation, and necroptosis in human HCM. Data were narratively synthesized across histologic, clinical, and multi-omics domains. Results: Among 8191 screened records, 25 studies met the inclusion criteria. Key immune–epigenetic regulators included the lncRNA–mRNA pair MIR210HG–BPIFC, m6A readers IGFBP3 and YTHDC1, and necroptosis gene JAK2. The HCM myocardium exhibited the depletion of reparative M2 macrophages and Tregs; enrichment of cytotoxic CD8+ T cells; and activation of the TNFα–NFκB, IL-6–JAK–STAT3, and PI3K–Akt pathways. Machine learning biomarkers (RASD1, FCN3, and PIK3R1) exhibited diagnostic accuracy (AUC > 0.85). Drug target predictions identified ruxolitinib and celecoxib as potential immunometabolic modulators (agents predicted to modulate both immune and metabolic pathways based on gene expression signatures). Conclusions: These findings support a hypothesis that HCM may involve immunogenetic mechanisms, rather than being exclusively sarcomeric in nature, although this remains to be validated. The integration of molecular and imaging biomarkers may enable precision immunotherapy, redefining HCM from a structural cardiomyopathy to a biologically stratified condition.