Human 3D Cardiac Microtissue Model to Investigate Aldosterone-Induced Fibrosis and Electrical Dysfunction.

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.