The mineralocorticoid receptor (MR) is a key player in cardiac remodelling and MR antagonists are well-established in the therapy of left heart disease. MR inhibition slows atrial remodelling and reduces the risk of atrial fibrillation in patients with heart failure. Thus, the aim of this study was to explore the impact of aldosterone on atrial remodelling in an experimental model.

 

To investigate the impact of aldosterone on atrial remodelling and arrhythmia, C57BL/6 wildtype mice received aldosterone via osmotic minipumps (100 mg/kgBW/day) together with high-salt drinking water (1% NaCl). After two weeks, in vivo echocardiography (ECG) revealed left ventricular diastolic dysfunction and atrial remodelling in aldosterone-treated mice. 9 out of 14 mice showed atrial arrhythmia or AV conductance defects. Unexpectedly, we did not observe significant atrial or ventricular fibrosis in histological sections stained with sirius red. Ex vivo ECG of Langendorff perfused hearts combined with pacing and fluorescence based optical modelling of electrical excitation transmission revealed a lower Wenckebach pacing frequency, higher atrial effective refractory period, and lower maximum ventricular pacing frequency in aldosterone treated mice. Assessment of passive mechanical properties by nanoindentation revealed an about 2-fold increase of left ventricular stiffness after treatment. To gain further insight into the molecular mechanism involved, we performed single-nuclear RNAseq using a 10x genomics platform. Gene expression analysis suggested a transcriptional activation and proliferation of endothelial cells and fibroblasts after aldosterone treatment. 

 

Aldosterone infusion induces diastolic dysfunction and arrhythmia in mice in vivo. Ex vivo biophysical assays confirm a disturbed conductance and increase in tissue stiffness, notably before the onset of apparent fibrosis. Single-nuclear RNAseq suggests changes in endothelial cells and fibroblasts after aldosterone / high salt treatment.