| Summary: | 博士 === 國立臺灣大學 === 臨床醫學研究所 === 100 === Growing evidence has shown that high plasma aldosterone level leads to a risk of cardiovascular diseases (CVD), including fatal stroke and sudden cardiac death. In addition, long-term exposure to increased aldosterone levels resulted in renal and metabolic sequelae independently of the blood pressure level. This phenomenon is best demonstrated in patients with primary aldosteronism (PA) who have excessive and inappropriate production of aldosterone. The excessive production of aldosterone in PA is associated with a high incidence of cardiovascular events, in comparison with essential hypertension (EH).
A total of 113 PA patients (87 patients with a diagnosis of aldosterone-producing adenoma, 26 with idiopathic hyperaldosteronism) and 55 patients with EH were enrolled. PA patients had higher arterial stiffness than EH patients (p = 0.006). However, lower numbers of circulating EPC and endothelial colony forming units (CFU) were observed in PA patients than in EH patients (p<0.05), which was ameliorated at six months after adrenalectomy or treatment with spironolactone. Expression of MR was identified in EPC. The plasma aldosterone concentration was inversely correlated with the number of circulating EPC (p =0.021) by the general additive model. The circulating number of EPC was inversely correlated with arterial stiffness (p=0.029) and the Framingham risk score (p=0.001). Serum high sensitively C-reactive protein was inversely correlated with the circulating EPC number (p=0.03) and decreased in patients after operation. Among the 45 patients who went through unilateral adrenalectomy, 32 (71%) were cured of hypertension. Preoperative number of circulation of EPC (Log[EPC number%] > -3.6) could predicted the curability of hypertension after adrenalectomy. (p=0.003).
There was a biphasic effect of aldosterone on EPC proliferation. Incubation of early EPC with a low aldosterone level (10-9 and 10-8 M) for 5 days significantly increased the number of early EPC. However, higher dosage of aldosterone (10-6M) decreased the EPC number. EPC also showed a biphasic response to aldosterone, i.e., an increase of cell proliferation at low aldosterone level (10-9 and 10-8M), and a decrease at high aldosterone level (10-5 and 10-6M). Both effects were blunted by adding spironolactone. Aldosterone, in either a low or high dose, did not affect the percentage of senescence-associated β-galactosidase-positive EPC or apoptosis of EPC.
After 5 days’ incubation with 10-6 M aldosterone, the functional capacity for tube formation of late EPC was significantly reduced (p<0.01). In contrast, a low dosages of aldosterone (10-8~10-9M) increased tube formation. This effect of aldosterone was dose-dependent (average total length and nodes number, all < 0.001).
Our study clearly showed that human EPC express MR both at gene and protein levels. The expression of MR and 11β-HSD2 in EPC, therefore, indicates that EPC have the capacity to modulate gene expression in response to aldosterone specifically. In accordance with the animal experiments, our study reveals a long-term in vivo effect of high aldosterone level on the number of circulating EPC in PA patients, with an inverse association between PAC and EPC numbers. A correlation of PAC with oxidative stress and endothelial inflammation was observed in PA patients, and the oxidative stress was attenuated after adrenalectomy. Increased intracellular ROS may result in EPC mobilization and impaired neovascularization capacity. Accordingly, CRP augments the effect of aldosterone on endothelial cell stiffness. In our study, a significant correlation between CRP level and aldosterone was noted in PA patients. Moreover, there was an inverse correlation between CRP and EPC numbers, and a reduction of CRP level accompanied by an increase of EPC number was noted in APA patients after adrenalectomy. Chronic aldosterone excess leads to vascular morphological change (wall thickening and carotid artery fibrosis) and vascular dysfunction (central stiffness), independent of blood pressure (BP). In the present study, we further demonstrate that the lower the preoperative EPC number, the higher the risk of residual hypertension after adrenalectomy. The finding indicates that EPC play an important role in both normal endothelial function and vasculature.
The inverse correlation between PAC and EPC number and the change of EPC numbers in response to the treatment of PA indicates that aldosterone contributes to the decreased EPC number in PA patients. The mechanisms accounting for low EPC numbers in PA patients are the direct activation of MR on EPC proliferation and an indirect effect through a high CRP level and oxidative stress caused by an excess of aldosterone. Low EPC numbers in PA plays a crucial role in the high incidence of arterial stiffness and in predicting residual hypertension in APA patients after adrenalectomy.
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