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Title: | 原發性皮質醛酮症患者的心臟結構重塑之研究 Remodeling of cardiac structure in patients with primary aldosteronism. |
Authors: | Yen-Hung Lin 林彥宏 |
Advisor: | 謝豐舟,何奕倫 |
Keyword: | 原發性皮質醛酮症,皮質醛酮,左心室肥大,心肌纖維化,IL-6,galectin-3, primary aldosteronism,aldosterone,left ventricular hypertrophy,cardiac fibrosis,IL-6,galectin-3, |
Publication Year : | 2011 |
Degree: | 博士 |
Abstract: | 原發性皮質醛酮症是一個可以治癒的常見高血壓疾病(Wu, Chen 2001)(Wu, Chen 2001)(Wu, Chen 2001)(Wu, Chen 2001)(Wu, Chen 2001),它是由於因腎上腺有腫瘤或不正常增生而分泌過多之皮質醛酮所造成;其盛行率約佔了高血壓病人中百分之五到十。原發性皮質醛酮症最常見有兩種亞型,第一型單側皮質醛酮素瘤及第二型雙側腎上腺增生。
原發性皮質醛酮症較原發性高血壓的患者有更高的心血管疾病的罹病率及心房顫動的發生率,而這現象與血壓影響無關;此外,原發性皮質醛酮症患者較原發性高血壓的患者有較厲害的左心室肥厚、左心室舒張功能異常及心肌纖維化之現象。近來研究顯示皮質醛酮之所以造成心肌纖維化,巨噬細胞所媒介的低密度系統性發炎反應扮演著極為重要的角色,然而其中的媒介物仍不清楚。 在第一部份的研究發現原發性皮質醛酮症患者的血鉀濃度和左心室質量指數呈現著獨立性的負相關;原發性皮質醛酮症患者比原發性高血壓患者有較差的左心室舒張功能,此現象與患者血鉀濃度無關。在第二部份的研究發現腎上腺切除術可顯著改善原發性皮質醛酮症患者的左心室肥大;術前左心室質量指數及手術前後收縮壓差異與左心室質量指數降幅有顯著相關。在第三及第四部份的研究發現單側原發性皮質醛酮症患者較原發性高血壓患者有著較明顯的心臟結構及心肌質地的變化,這個發現支持前人所提到的皮質醛酮有著和血壓無關的導致心肌纖維化效果;單側原發性皮質醛酮症患者在腎上腺切除後,心臟結構及心肌質地均有改善,這暗示著,原發性皮質醛酮症患者的心肌纖維化在腎上腺切除後是可以改善的。第五部份的研究是從細胞研究探討皮質醛酮是否刺激巨噬細胞分泌galectin-3及其作用之機轉,研究發現皮質醛酮的確刺激THP-1細胞分泌galectin-3且經由礦物類皮質激素(鹽)受體途徑及PI3K/Akt所調控之細胞訊息傳遞途徑;其中NF-kB為其基因表現的重要轉錄分子。第六部份的研究是從基礎的細胞研究探討皮質醛酮是否刺激巨噬細胞分泌IL-6及其作用之機轉;研究中發現皮質醛酮的確刺激THP-1細胞分泌IL-6,而皮質醛酮誘發IL-6的表現是經由礦物類皮質激素(鹽)受體途徑,其與PI3K/Act及p38所調控之細胞訊息傳遞途徑有關;NF-kB及NF-IL-6是調控的重要轉錄分子。在第七部份的研究發現單側皮質醛酮素瘤患者較原發性高血壓患者有著較高的IL-6,但galectin-3兩組並無顯著差別;術後一年的追蹤,IL-6有明顯的下降,但galectin-3沒有變化。 而高血壓本身即為心臟血管疾病的一個十分重要的因子,而原發性皮質醛酮症是一個有機會可以治癒的常見高血壓疾病,它的重要性與日俱增,希望能藉由這些研究,讓大家更了解原發性皮質醛酮症及其對心血管系統的影響。 Primary aldosteronism (PA) is a curable and common hypertensive disease, and is characterized by an inappropriate production of aldosterone. PA, the prevalence of which is around 5-10% of patients with hypertension, consists of two subtypes: aldosterone-producing adenoma (APA) and idiopathic hyperaldosteronism (IHA). Patients with PA have been shown to have a higher prevalence of cardiovascular events and atrial fibrillation than patients with essential hypertension (EH), which are independent of blood pressure effects. In addition, patients with PA have a more prominent left ventricular (LV) mass, and a higher degree of LV diastolic function impairment and myocardial fibrosis than those with EH. In recent studies, macrophage-mediated low grade inflammation has been shown to play an important role in aldosterone-inducing cardiac fibrosis. However, the mediators of this process are still unclear. In order to investigate the change of cardiac structure and texture in PA patients and their relation to macrophage, we designed a series of studies. In the part, we found that serum potassium level was negatively associated with LV mass index (LVMI) in PA patients. Compared with patients with EH, PA patients had a greater impairment of cardiac diastolic function, which was independent of serum potassium level. In the second part, we found that LV hypertrophy in PA patients could be significantly reversed by adrenalectomy. Pre-operative LVMI and change of systolic blood pressure were associated with the degree of LVMI decrease. In the third and fourth part, we found that adrenalectomy reversed not only LV geometry but also altered myocardial texture in patients with unilateral hyperaldosteronism. This suggests that increases in collagen content in the myocardium of patients with unilateral hyperaldosteronism might be reversed by adrenalectomy. In the fifth part, we investigated whether aldosterone induced macrophage to secret galectin-3 and its mechanisms. We found that aldosterone induced the THP-1 cell to secret galectin-3 via mineralocorticoid receptors. The induced secretion occurred through the PI3K/Akt pathway, and NF-kB was an important transcriptional factor in this pathway. In the sixth part, we investigated whether aldosterone induced macrophage to secret IL-6 and its mechanisms. We found that aldosterone induced the THP-1 cell to secret IL-6 via mineralocorticoid receptors. The induced secretion was achieved through the PI3K/Akt and p38 pathway, and NF-kB and NF-IL-6 were important transcriptional factors in this pathway. In the seventh part, we found that patients with APA had higher plasma IL-6 levels than EH patients’ and the increased plasma IL-6 concentration decreased significantly one year after adrenalectomy in the APA patients. However, plasma galectin-3 levels were comparable in both groups, and there was also no change one year after adrenalectomy in the APA patients. As hypertension is an important risk factor of cardiovascular disease, and as PA is a curable and common hypertensive disease, the issues of PA are becoming increasingly important. It is hoped that these studies will promote a greater understanding of PA and its effect on the cardiovascular system. Key words: primary aldosteronism; aldosterone; left ventricular hypertrophy; cardiac fibrosis; IL-6; galectin-3 |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/66444 |
Fulltext Rights: | 有償授權 |
Appears in Collections: | 臨床醫學研究所 |
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