原發性醛固酮症對大小血管與身體組成之影響的探討

Abstract

原發性醛固酮症是導致心血管和腦血管損傷的重要因素，且其影響獨立於高血壓的傷害。因為鹽皮質激素受體廣泛存在於血管內皮細胞、血管平滑肌、脂肪細胞、骨骼肌細胞，當過多醛固酮異常刺激此類受體時，會造成受體細胞的氧化壓力與慢性發炎。而血管周邊脂肪細胞發炎與血管損傷之間存在雙向惡化循環，造成血管平滑肌收縮及血管壁硬化。因此，醛固酮透過鹽皮質激素受體在多器官同時造成相同的發炎、代謝與內皮功能障礙路徑，最終形成多系統血管損傷。這些損傷包含小血管病變（腦微血管、小動脈硬化）、大血管病變（主動脈壁增厚、血管硬化）、周血管脂肪功能失調（可能以脂肪肌肉身體組成變化表現）。

本論文整合了四項基礎到臨床研究成果，探討醛固酮對身體多系統血管的綜合影響，從小血管病變、大血管鈣化到與血管周圍脂肪組織相關的肌肉脂肪組成變化。第一項研究分析了高血壓性腦出血的患者，發現患有原發性醛固酮症的患者顯示更嚴重的腦部小血管病變，包括更多的微出血及擴張的腦周圍血管間隙，第一次在學術上顯示醛固酮可能加劇高血壓性小動脈病變。第二項研究聚焦於腎上腺醛固酮分泌瘤患者，發現自主性皮質醇分泌與肌肉脂肪浸潤增加、肌肉質量與密度下降相關，顯示其與肌肉脂肪變性及肌少症有關。值得注意的是，腎上腺切除手術可改善患者的肌肉組成，進一步支持皮質醇共分泌對肌肉退化的影響。第三四項研究探討原發性醛固酮症患者的大血管鈣化程度。結果顯示擁有KCNJ5體細胞突變患者的動脈鈣化程度較低，但擁有更高的大血管厚度，且能被手術阻止惡化。而自主性皮質醇分泌則是與動脈鈣化有著顯著相關性。進一步的細胞實驗證實，皮質醇與醛固酮共同促進血管鈣化，並透過礦物皮質類固醇受體途徑發揮作用，而此作用可透過礦物皮質類固醇受體拮抗劑加以抑制。整體而言，這些研究結果凸顯了醛固酮與皮質醇對腦血管健康、血管鈣化與肌肉退化的多方面影響，顯示了早期診斷與個人化治療策略在原發性醛固酮症患者處置中的重要性。

Primary aldosteronism (PA) is a major contributor to cardiovascular and cerebrovascular damage, independent of hypertension. The mineralocorticoid receptor (MR) is widely expressed in endothelial cells, vascular smooth muscle cells, adipocytes, and muscles. Chronic aldosterone excess can abnormally activate MR, triggering oxidative stress, endothelial dysfunction, inflammation, and fibrosis. In particular, inflammation within perivascular adipose tissue creates a bidirectional vicious cycle that further amplifies vascular injury. Consequently, excessive aldosterone induces a multi-level vascular injury including small vessel disease (cerebral small vessel disease or arteriosclerosis, large vessel remodeling (atherosclerosis or aortic wall thickening), and perivascular adipose tissue dysfunction (may be represented by adipose-muscle remodeling or altered body composition).

Our dissertation integrates findings from four investigations exploring the impact of aldosterone on small and large vessel injury, and perivascular adipose tissue-related body composition changes. The first study examined survivors of hypertensive intracerebral hemorrhage and found that those with PA exhibited more extensive cerebral small vessel disease, with a greater burden of microbleeds and dilated perivascular spaces, suggesting that aldosteronism may worsen hypertensive arteriopathy. The second study analyzed patients with adrenal aldosterone-producing adenomas and revealed that ACS was associated with increased fat infiltration in muscle and reduced muscle mass and density, indicative of myosteatosis and sarcopenia. Encouragingly, adrenalectomy led to improvements in muscle composition, reinforcing the link between cortisol co-secretion and muscle deterioration. The third study examined vascular calcification in PA patients, revealing that those with the KCNJ5 mutation exhibited less aortic calcification but a thicker aortic wall, with minimal progression after adrenalectomy. The final study found that patients with ACS had a greater degree of arterial calcifications. Further in vitro experiments showed that cortisol, in combination with aldosterone, promoted vascular calcification through mineralocorticoid receptor activation, a process that could be mitigated by mineralocorticoid receptor antagonists. Collectively, these findings highlight the multifaceted impact of aldosterone and cortisol on cerebrovascular health, muscle deterioration, and vascular calcification, underscoring the importance of early detection and tailored treatment strategies for patients with PA and ACS.