Mineralocorticoid axis activity and cardiac remodeling in patients with ACTH-dependent Cushing’s syndrome

Background: Arterial hypertension and left ventricular hypertrophy and remodeling are independent cardiovascular risk factors in patients with Cushing's syndrome. Changes in the renin-angiotensin system and in the mineralocorticoid axis activity could be involved as potential mechanisms in their pathogenesis, in addition to cortisol excess. Methods: In this ancillary study of our previous study prospectively investigating patients with ACTH-dependent Cushing's syndrome by cardiac magnetic resonance imaging (NCT02202902), 11 patients without any interfering medication were cross-sectionally compared to 20 control subjects matched for age, sex and body mass index. Angiotensin metabolites and adrenal steroids were measured by liquid chromatography tandem mass spectrometry, and their relation to blood pressure and cardiac structure was evaluated. Results: Concentrations of angiotensin I and angiotensin II were comparable, but the angiotensin-converting enzyme activity was significantly lower (2.19 (1.67; 3.08) vs 4.07 (3.1; 5.6); P < 0.001) in patients compared to controls. Aldosterone concentrations were significantly lower (6.9 (6.9; 124.1) vs 239.9 (181.4; 321.9) pmol/L; P < 0.001) in the group of patients, but adrenal aldosterone precursor metabolites were comparable between patients and controls. Inverse correlations were observed for 24 h urinary free cortisol and aldosterone with the ratio of left ventricular mass to end-diastolic volume (r = 0.470, P = 0.012 and r = -0.367, P = 0.046, respectively). Conclusions: We describe a disease-specific profile of angiotensin metabolites in patients with ACTH-dependent Cushing's syndrome. Low levels of aldosterone in the presence of unchanged precursor metabolites indicate a direct inhibitory action of cortisol excess on the aldosterone synthase. Furthermore, glucocorticoid excess per se drives cardiac muscle remodeling.