Rapid pacing and angiotensin II drove divergent mitochondrial and fibrotic remodeling in human atrial organoids, recapitulating key features of atrial fibrillation patient datasets.
Do rapid pacing and angiotensin II induce distinct mitochondrial and fibrotic remodeling in human atrial organoids?
Human atrial organoids exposed to rapid pacing or angiotensin II recapitulate distinct mitochondrial and fibrotic remodeling signatures seen in AF patient datasets, providing a translational platform for testing interventions.
Abstract Background Atrial fibrillation (AF) remains a major clinical burden because structural and metabolic remodeling, particularly mitochondrial dysfunction and fibrosis, often persists beyond rhythm control. Human-relevant models that disentangle these axes and connect them to patient data are limited. Methods Human atrial organoids were exposed to two AF-relevant stressors: rapid pacing (FP) and angiotensin II (AngII). We assessed mitochondrial and fibrotic remodeling by transcript/protein analyses, imaging, and contractility readouts, and benchmarked organoid responses against four public AF transcriptomic datasets (GEO: GSE128188, GSE138252, GSE222793, GSE239321). Statistical analyses used predefined contrasts versus matched controls with multiple-testing correction. Results FP predominantly suppressed mitochondrial biogenesis/oxidative programs and increased stress-response features, resembling signatures observed in AF with heart failure (e.g., downregulation of mitochondrial regulators and altered cytochrome c patterns). AngII elicited stronger profibrotic signaling with a mixed mitochondrial response, mirroring profiles more typical of AF without heart failure. Both stressors impaired organoid contractility. Protein and immunostaining corroborated mitochondria–fibrosis crosstalk, with changes in PGC1α and cytochrome c alongside increased extracellular matrix deposition and myofibroblast markers (COL1A1, αSMA), consistent with stimulus-specific but partially overlapping remodeling trajectories. Conclusion Distinct AF-relevant stressors drive divergent mitochondrial and fibrotic remodeling in human atrial organoids that recapitulate key features of patient datasets. These organoid models provide a translational platform to prioritize mitochondria-targeted and antifibrotic interventions and to inform biomarker development for residual dysfunction in AF.
Won et al. (Sat,) conducted a other in Atrial fibrillation. Rapid pacing (FP) and angiotensin II (AngII) vs. Matched controls was evaluated on Mitochondrial and fibrotic remodeling. Rapid pacing and angiotensin II drove divergent mitochondrial and fibrotic remodeling in human atrial organoids, recapitulating key features of atrial fibrillation patient datasets.
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