Key result
TNNI3-R145W cardiomyocytes show ~50% lower EV release and shift cargo toward inflammatory and fibrotic signatures.
Why the study?
The pathways linking sarcomeric mutations in HCM to myocardial fibrosis and immune cell infiltration remain incompletely defined, and the contribution of cardiomyocyte-derived extracellular vesicles to disease progression is not well established.
Does the TNNI3-R145W hypertrophic cardiomyopathy variant alter cardiomyocyte extracellular vesicle output and cargo to promote inflammation and extracellular matrix remodelling in cardiac cells?
Does the TNNI3-R145W hypertrophic cardiomyopathy variant alter cardiomyocyte extracellular vesicle output and cargo to promote inflammation and extracellular matrix remodelling in cardiac cells?
TNNI3-R145W cardiomyocytes secrete fewer extracellular vesicles, but their cargo shifts toward an early inflammatory and later fibrotic signature that activates fibroblasts and macrophages, identifying EVs as potential mechanistic biomarkers and therapeutic targets in hypertrophic cardiomyopathy.
Hypertrophic cardiomyopathy (HCM) is a prevalent inherited cardiac disease (≈1:200) marked by left-ventricular hypertrophy and most commonly driven by pathogenic variants in sarcomeric genes, including cardiac troponin I (TNNI3). In addition to cardiomyocyte dysfunction, HCM is frequently accompanied by myocardial fibrosis and immune cell infiltration, yet the pathways linking sarcomeric mutations to these non-cardiomyocyte features remain incompletely defined. Extracellular vesicles (EVs) released by cardiomyocytes provide a mechanism for intercellular signalling in HCM, but their contribution to disease progression is not well established. Left ventricular–like cardiomyocytes (LV-CMs) derived from induced pluripotent stem cells carrying the TNNI3-R145W variant, alongside isogenic controls, were generated (N=5). Longitudinal phenotyping was performed using immunofluorescence, transcriptomics, proteomics, SarcTrack-based contractility analysis, and Seahorse metabolic profiling. EVs were isolated via size-exclusion chromatography and characterised by Nanoparticle Tracking Analysis, ExoView, electron microscopy, Western blotting, and proteomics in accordance with MISEV2023 guidance. To assess translational relevance, UK Biobank plasma proteomics (≈50,000 participants) were queried for HCM cases and integrated with cellular and EV proteomic signatures from the R145W model. Compared with controls, R145W LV-CMs demonstrated cellular hypertrophy (P=0.0043), increased contraction amplitude (P=0.0027), and prolonged contraction duration (P=0.0001). Metabolic assessment showed elevated basal oxygen consumption (P=0.0286). Transcriptomic profiling identified 1,080 differentially expressed genes, enriched for hypertrophic extracellular matrix (ECM) remodelling and vesicle/EV-related signalling pathways. Longitudinal proteomics revealed stage-dependent perturbations, with 713 differentially expressed proteins at Day 20 and 1,080 at Day 44, repeatedly highlighting disrupted vesicle-transport programmes. EV release was reduced two-fold in R145W LV-CMs (P<0.0001). At Day 44, EV proteomics indicated enrichment of ECM/fibrosis and metabolic cargo alongside depletion of sarcomeric proteins, consistent with altered ECM organisation and vesicle-mediated transport (P=6.3×10⁻⁵). Overlap with UK Biobank HCM plasma proteomics highlighted histidine-rich calcium-binding protein and stanniocalcin-2 (P<0.05). Functionally, early-stage R145W LV-CM EVs triggered IL-6–linked inflammatory activation in left-ventricular fibroblasts and primary monocyte-derived macrophages (P<0.05). Collectively, TNNI3-R145W cardiomyocytes secrete fewer EVs, but their EV cargo shifts toward an early inflammatory programme and a later fibrotic signature. These EV-mediated signals promote inflammatory activation in other cardiac cell populations, supporting EVs as mechanistic biomarkers and potential therapeutic targets in HCM progression.
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Seddiq et al. (2026) studied Hypertrophic cardiomyopathy (HCM) (n=5). TNNI3-R145W variant vs. Isogenic controls was evaluated on Extracellular vesicle (EV) release and proteomic cargo composition (2-fold reduction in EV release, p=<0.0001). TNNI3-R145W cardiomyocytes showed a two-fold reduction in EV release (P<0.0001) and shifted EV cargo toward inflammatory (P<0.05) and fibrotic ECM signatures (P=6.3x10^-5) versus isogenic controls.
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