Key result
Aldosterone induces fibrosis and QT prolongation in cardiac microtissues, explaining CV risk in primary aldosteronism.
Why the study?
Does aldosterone induce fibrosis and electrical dysfunction in 3D human cardiac microtissue organoids?
Does aldosterone induce fibrosis and electrical dysfunction in 3D human cardiac microtissue organoids?
A 3D human cardiac microtissue model demonstrates that aldosterone directly induces fibrosis and prolongs the QT interval, effects that are reversible with eplerenone.
Supports MRA therapy to reduce CV risk in primary aldosteronism; extends evidence for direct myocardial toxicity in human models.
BACKGROUND: Aldosterone induces cardiac fibrotic remodeling and arrhythmogenic alterations. The lack of suitable preclinical 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 3D human microtissue (hMT) cardiac organoids. METHODS: hMT were generated by coculturing human cardiac fibroblasts, aortic endothelial cells and induced pluripotent stem cell-derived cardiomyocytes. hMT were treated with aldosterone, the mineralocorticoid receptor antagonist eplerenone, and serum from patients with primary aldosteronism or matched subjects with essential hypertension. Immunofluorescence, histology, and Western blot analyses were used to assess fibrosis; a multielectrode array was used to record extracellular field potentials of spontaneously beating human cardiomyocytes. RESULTS: Levels of profibrotic markers increased after incubation with serum from primary aldosteronism patients, compared with untreated organoids and hMT incubated with essential hypertension patient-derived serum. Aldosterone treatment reproduced the same profibrotic effect in a dose-dependent manner, and coadministration of eplerenone blunted these effects. Aldosterone treatment increased corrected field potential duration (an estimate of the 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 cotreatment 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 the QT interval in this model, which may partially explain the increase of cardiovascular risk in patients with primary aldosteronism and underscores the benefit of mineralocorticoid receptor antagonist therapy.
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Burrello et al. (2026) studied Aldosterone-induced cardiac fibrosis and electrical dysfunction. Aldosterone and serum from patients with primary aldosteronism vs. Untreated organoids, essential hypertension serum, and eplerenone coadministration was evaluated on Profibrotic markers and corrected field potential duration. Aldosterone and serum from primary aldosteronism patients directly induced fibrosis and prolonged the QT interval in 3D human cardiac microtissues, effects which were blunted by eplerenone.
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