Lee Bo-Ching, Chang Chin-Chen, Kang Victor Jing-Wei, Huang Jia-Zheng, Lin Yu-Li, Chang Yi-Yao, Tsai Cheng-Hsuan, Chen Zheng-Wei, Liao Che-Wei, Pan Chien-Ting, Wu Vin-Cent, Hung Chi-Sheng, Chou Chia-Hung, Lin Yen-Hung
Departments of Medical Imaging, National Taiwan University College of Medicine, Taipei, Taiwan, ROC.
Departments of National Taiwan University Hospital and Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan, ROC.
Hypertens Res. 2025 Jan;48(1):366-377. doi: 10.1038/s41440-024-01935-w. Epub 2024 Nov 8.
Autonomous cortisol secretion (ACS) is not uncommon in patients with primary aldosteronism (PA). However, the cardiovascular burden of ACS due to its dysregulated cortisol secretion remains poorly understood. Thus, we examined the effects of ACS on vascular calcification in a hyperaldosteronism environment in vitro and in vivo. A total of 339 patients with PA with adrenal incidentaloma and low-dose dexamethasone suppression test data (cutoff level: cortisol > 1.8 μg/dL) from a prospectively maintained database were enrolled; abdominal aortic calcification (AAC) scores were quantitatively estimated. Human aortic smooth muscle cells (HAOSMCs) were used as in vitro model of vascular calcification. In this study, 65 of the 339 patients with PA had ACS; 274 did not. Patients with PA/ACS had a higher AAC score (1171.0 ± 2434.0 vs. 489.5 ± 1085.3, P = 0.012) than patients without ACS. ACS was independently associated with AAC score (β = 0.139, P = 0.004) in multivariate analysis, and post-suppression cortisol level was significantly correlated with the AAC score (P = 0.004). In the HAOSMC model, co-treatment with cortisol synergistically stimulated alkaline phosphatase activity and calcium deposition in a hyperaldosteronism environment. The stimulatory effect of cortisol was abolished by the mineralocorticoid receptor (MR) antagonist eplerenone, but not glucocorticoid receptor antagonist mifepristone, indicating a MR-dependent mechanism. In conclusion, the presence of ACS is associated with heavier vascular calcification in patients with PA. Aldosterone and cortisol synergistically activate HAOSMC calcification via MR signaling, via a process that can be attenuated by eplerenone.
自主性皮质醇分泌（ACS）在原发性醛固酮增多症（PA）患者中并不少见。然而，由于其皮质醇分泌失调，ACS对心血管的负担仍知之甚少。因此，我们在体外和体内的高醛固酮血症环境中研究了ACS对血管钙化的影响。我们纳入了一个前瞻性维护数据库中339例患有肾上腺偶发瘤的PA患者以及低剂量地塞米松抑制试验数据（临界值：皮质醇＞1.8μg/dL）；对腹主动脉钙化（AAC）评分进行了定量评估。用人主动脉平滑肌细胞（HAOSMCs）作为血管钙化的体外模型。在本研究中，339例PA患者中有65例存在ACS；274例不存在。PA/ACS患者的AAC评分（1171.0±2434.0 vs. 489.5±1085.3，P = 0.012）高于无ACS的患者。在多变量分析中，ACS与AAC评分独立相关（β = 0.139，P = 0.004），且抑制后皮质醇水平与AAC评分显著相关（P = 0.004）。在HAOSMC模型中，在高醛固酮血症环境下，皮质醇联合治疗可协同刺激碱性磷酸酶活性和钙沉积。盐皮质激素受体（MR）拮抗剂依普利酮可消除皮质醇的刺激作用，但糖皮质激素受体拮抗剂米非司酮则不能，这表明存在MR依赖性机制。总之，ACS的存在与PA患者更严重的血管钙化有关。醛固酮和皮质醇通过MR信号通路协同激活HAOSMC钙化，依普利酮可减弱这一过程。
