Aldosterone directly induced fibrosis and prolonged the QT interval in human 3D cardiac microtissues, effects that were blunted by the mineralocorticoid receptor antagonist eplerenone.
Does aldosterone induce fibrosis and electrical dysfunction in human 3D cardiac microtissue organoids, and can eplerenone reverse these effects?
Aldosterone directly induces fibrosis and QT interval prolongation in a human 3D cardiac microtissue model, providing a mechanistic basis for increased cardiovascular risk in primary aldosteronism that is reversible with mineralocorticoid receptor antagonists.
Objective: Aldosterone induces cardiac fibrotic remodelling and arrhythmogenic alterations. The lack of suitable pre-clinical models has hampered an in-depth investigation of the molecular mechanisms involved in aldosterone-induced cardiac damage. Our aim was to evaluate the effects of aldosterone on human 3D microtissue (hMT) cardiac organoids. Design and method: hMT were generated by co-culturing human cardiac fibroblasts, aortic endothelial cells and induced pluripotent stem cells-derived cardiomyocytes. hMT were treated with aldosterone, the mineralocorticoid receptor (MR) antagonist eplerenone, and serum from patients with primary aldosteronism (PA) or matched subjects with essential hypertension (EH). Immuno-fluorescence, histology, and western blot analyses were used to assess fibrosis; multielectrode array was employed to record extracellular field potentials of spontaneously beating human cardiomyocytes. Results: Levels of profibrotic markers increased after incubation with serum from PA patients, compared to untreated organoids and hMT incubated with EH patient-derived serum. Aldosterone treatment reproduced the same pro-fibrotic effect, in a dose-dependent manner and co-administration of eplerenone blunted these effects. Aldosterone treatment increased corrected field potential duration (an estimate of QT interval) and downregulated the expression levels of KCNQ1 and ATP2A2, responsible for the slow delayed rectifier potassium current and for calcium-handling in the sarcoplasmic reticulum. Eplerenone co-treatment reverted these electrical alterations. Conclusions: 3D hMT organoids offer a relevant in vitro model to study aldosterone mediated cardiac effects. Aldosterone directly induces fibrosis and prolongation of QT interval in this model, which may partially explain the increase of cardiovascular risk in patients with PA and underscores the benefit of MR antagonist therapy.
Burrello et al. (2026) studied Aldosterone-induced cardiac fibrosis and electrical dysfunction. Aldosterone vs. Untreated organoids and eplerenone co-treatment was evaluated on Fibrosis and corrected field potential duration. Aldosterone directly induced fibrosis and prolonged the QT interval in human 3D cardiac microtissues, effects that were blunted by the mineralocorticoid receptor antagonist eplerenone.