Key result
TTR amyloid fibrils impair contraction, disrupt sarcomeres, and alter calcium transients in engineered cardiac tissue.
Why the study?
Transthyretin amyloid cardiomyopathy (ATTR-CM) lacks an optimal therapy due to the absence of representative models to identify the early mechanisms underlying disease progression.
Does exposure to transthyretin amyloid fibrils impair viability, functionality, structure, electrophysiology, and gene expression in 3D hiPSC-derived cardiac tissue models?
Does exposure to transthyretin amyloid fibrils impair viability, functionality, structure, electrophysiology, and gene expression in 3D hiPSC-derived cardiac tissue models?
This preclinical study establishes an advanced 3D biofabricated human cardiac tissue model that recapitulates early structural, functional, and electrophysiological changes of transthyretin amyloid cardiomyopathy to aid in drug discovery.
Supports 3D hiPSC cardiac models for early TTR amyloid mechanisms; leaves open clinical translation pending validation.
Objectives Transthyretin (TTR) amyloid cardiomyopathy (ATTR-CM) is a progressive, fatal multisystem disease, lacking an optimal therapy, stemming from the absence of representative models. Our work aims to provide advanced 3D disease models, for identifying the early mechanisms underlaying disease progression, contributing to the development of more precise and personalised effective treatments and potential cures. Methods Human induced pluripotent stem cell (hiPSC)-derived cardiac cells were embedded at high, physiological relevant densities in fibrin hydrogels, incorporating TTR amyloid fibrils and casted into 3D printed scaffolds using Melt Electro Writing (MEW) technology. Response to exposure to different increasing doses of TTR was analyzed. Tissues were maintained for over 4 weeks with a multiparametric analysis conducted on a weekly basis to determine viability, functionality, structure, electrophysiology, and genomic expression profiling. Results Biomimetic functional cardiac tissues can be generated using 3D printed MEW scaffolds. The presence of fibrils directly affects human cardiomyocyte function in 3D cardiac constructs, leading to sarcomere disruption and reducing the amplitude and speed of contraction. No differences were found in the cardiac tissues in terms of cell viability after 4 weeks of exposure to the concentrations used. Genes related to cardiac structural organization and function, such as MYL2, SCN5A1, CACNA1C, COL1A1, NPPA and NPPB, were significantly downregulated in tissues exposed to TTR. Interestingly, tissues showed shortened calcium transients after TTR exposure compared to unexposed tissues, suggesting a proarrhythmic behaviour of fibrils, which could correlate with the presence of arrhythmias in some ATTR-CM patients. Conclusions We have provided an advanced model of ATTR-CM capable of recapitulating the early stages of the disease, by applying frontline technologies in cell reprogramming, biofabrication and biomaterials, which will contribute to advancing our understanding of the mechanisms of the disease, and help discovering and formulating new treatments.
No takes yet. Share an insight, caveat, or question.
Garcia et al. (2026) studied Transthyretin amyloid cardiomyopathy (ATTR-CM). Transthyretin (TTR) amyloid fibrils vs. Unexposed tissues was evaluated on Viability, functionality, structure, electrophysiology, and genomic expression profiling of 3D cardiac constructs. TTR amyloid fibril exposure for 4 weeks disrupted sarcomeres, reduced contraction, shortened calcium transients, and downregulated structural genes without altering cell viability in 3D hiPSC tissues.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: