臺灣博碩士論文加值系統

原發性高醛固酮症，顧名思義就是體內自發性的產生過多的醛固酮所產生的病變。在所有原發性高醛固酮症的病人中，最常見的是腎上腺分泌性腺瘤及腎上腺過度增生；一些其他的基因突變也會造成原發性高醛固酮症。這些病人除了因為長期高血壓帶來的影響之外，心血管系統也會因為過多的醛固酮而比本態性高血壓的病人有更多結構上的病變，罹患心血管疾病的風險更高。
醛固酮對心血管系統的影響是可逆的。不管是腎上腺增生的病人接受藥物治療，抑或是分泌性腎上腺腫瘤的病人接受手術切除，在治療之後肇因高醛固酮引起的左心室肥大、心臟血管的纖維化和和動脈壁硬化等都會改善。
脈搏波速（pulse wave velocity, PWV）是一種量化動脈硬度的非侵襲性指標。雖然已有實驗證實腎上腺分泌性腺瘤的病人在開刀摘除腫瘤之後動脈硬化的程度會改善，但相關的細節付之闕如。本研究旨在於探討腎上腺醛固酮分泌性腺瘤病人在手術治療之後動脈硬化恢復的相關細節。
我們在2006年3月到2012年1月之間前瞻性的收案102位成年、罹患腎上腺醛固酮分泌性腺瘤準備接受切除手術的患者。我們在術前量測他們的肱踝脈搏波速（baPWV）、心踝脈搏波速（haPWV）及其他生化、生理指標，並在術後六個月及術後一年重複同樣的測量，再加以比較分析。
不論是baPWV或是haPWV皆在術後前六個月內有顯著下降（baPWV1636 ± 310 降至 1533 ± 278 cm/s, p <0.001, haPWV 1096 ±138降至1048 ±129 cm/s, p<0.001）。其他的生理生化指標包括血壓、血中鉀離子濃度及血中醛固酮濃度、腎素活性等也都有顯著的進步。然而，在後續六個月除了血中醛固酮濃度之外都沒有進一步的顯著改變。
經分析，治療前baPWV大小的決定性因子為高血壓病史長短、及治療前收縮壓。利用同樣的方法，得到治療前haPWV的決定性因子為年齡、高血壓病史長短、治療前收縮壓及治療前舒張壓。對baPWV前六個月變化量而言，決定因子為治療前baPWV（β = -0.292 , 95% C.I. -0.404~-0.179, p <0.001）及前六個月舒張壓變化量（β=9.137 , 95% C.I. 6.279~11.996, p <0.001)，而haPWV前六個月變化量的決定因子為治療前haPWV（β = -0.242 , 95% C.I. -0.373~-0.111, p <0.001）、前六個月舒張壓變化量（β = 5.781 , 95% C.I. 4.309~7254, p <0.001），及對數轉換後血漿腎素活性前六個月變化量（ β = -23.718, 95% C.I. -43.297~-4.140, p <0.018）。
腎上腺醛固酮分泌性腫瘤的病人在術後六個月內高醛固酮症的臨床指標性表徵，包括高血壓、低血鉀及動脈壁硬化等都有顯著改進，但之後除了血中醛固酮濃度有反彈性的上升之外其他表現就沒有進一步的顯著變化。術前PWV的決定性因子有高血壓病史長短及術前收縮壓等；PWV前六個月變化量的決定性因子為術前PWV及舒張壓前六個月的變化量等。由於PWV的高低和心血管疾病的風險有高度相關，藉由接受治療讓PWV下降或許意謂著同時降低高醛固酮病人相關的心血管疾病風險。不過這仍需要進一步的大規模臨床試驗來證實。

Primary aldosteronism (PA) was one of the most common causes of secondary hypertension. Exposure to excessive aldosterone led to increased arterial stiffness. The effect of adrenalectomy on arterial stiffness reversibility was seldom reported. Besides, the time course of arterial stiffness reversal and the actual predicting factors on arterial stiffness reversal were still unclear.
We prospectively enrolled 102 patients with aldosterone producing adenoma (APA) from March 2006 to January 2012. We measured the pulse wave velocity (PWV) between brachial-ankle (baPWV) and heart-ankle (haPWV) before, and 6 months and 12 months after adrenalectomy of all enrolled patients. All other physiological and biochemistry parameters were collected at the same time and analyzed after the 1-year follow-up.
The baseline baPWV averaged as 1636± 310 cm/s while haPWV as 1096±138cm/s. The determinant factors to baseline baPWV were age, duration of hypertension, and baseline systolic blood pressure (SBP) after multi-variable linear regression analysis. Similarly, the determinant factors for baseline haPWV were age, duration of hypertension, baseline systolic pressure and diastolic pressure (DBP). After treatment, the patients’ PWV decreased significantly during the first 6-month (baPWV 1533 ± 278 at 6-month, p < 0.001; haPWV 1048±129 at 6-month, p<0.001). No further reduction was noted during the following 6 month (baPWV 1562±31 at 12-month, p = 0.248; haPWV 1049±130 at 12-month, p=0.415). After multi-variable regression analysis, the determinants of baPWV decrement at 6 months (ΔbaPWV0-6mo) were decrement of diastolic blood pressure at 6 months (ΔDBP0-6mo) and the baseline baPWV. On the other hand, the determinants for the change of haPWV at 6 months (ΔhaPWV0-6mo) were baseline haPWV, ΔDBP0-6mo and the change of log-transformed plasma renin activity (ΔLogPRA0-6mo)
The arterial stiffness of APA patients could be reversed after surgical treatment in the first 6 months after adrenalectomy. The determinant factors of baseline PWV included age, duration of hypertension and baseline SBP, and baseline DBP (for haPWV). The determinant factors of ΔPWV are baseline PWV, ΔDBP0-6mo and ΔLogPRA0-6mo (for ΔhaPWV). Since higher PWV was closely correlated with higher cardiovascular risks, the decrease in PWV might also imply reducing CV disease risks. However, we needed a further large scale clinical trial focusing on the long-term outcomes to clarify this.

口試委員會審定書 …………………………………………………………………… i
誌謝 …………………………………………………………………………… ii
中文摘要 …………………………………………………………………………… iv
英文摘要 …………………………………………………………………………… vi
碩士論文內容
第一章 緒論 …………………………………………… 1
第二章 研究方法與材料 …………………………………………… 4
第三章 結果 …………………………………………… 6
第四章 討論 …………………………………………… 7
第五章 展望 …………………………………………… 10
第六章 論文英文簡述（Summary) …………………………………………… 12
第七章 參考文獻 …………………………………………… 19
第八章 圖表
表 1 …………………………………………… 23
表2 …………………………………………… 25
表3 …………………………………………… 26
表4 …………………………………………… 28
圖1 …………………………………………… 30

Asmar, R., et al., Assessment of arterial distensibility by automatic pulse wave velocity measurement. Validation and clinical application studies. Hypertension, 1995. 26(3): p. 485-90.
Bernini, G., et al., Arterial stiffness, intima-media thickness and carotid artery fibrosis in patients with primary aldosteronism. J Hypertens, 2008. 26(12): p. 2399-405.
Born-Frontsberg, E., et al., Cardiovascular and cerebrovascular comorbidities of hypokalemic and normokalemic primary aldosteronism: results of the German Conn''s Registry. J Clin Endocrinol Metab, 2009. 94(4): p. 1125-30.
Callera, G.E., et al., Aldosterone activates vascular p38MAP kinase and NADPH oxidase via c-Src. Hypertension, 2005. 45(4): p. 773-9.
Catena, C., et al., Long-term cardiac effects of adrenalectomy or mineralocorticoid antagonists in patients with primary aldosteronism. Hypertension, 2007. 50(5): p. 911-8.
Catena, C., et al., Cardiovascular outcomes in patients with primary aldosteronism after treatment. Arch Intern Med, 2008. 168(1): p. 80-5.
Catena, C., et al., Predictive factors of left ventricular mass changes after treatment of primary aldosteronism. Horm Metab Res, 2012. 44(3): p. 188-93.
Choo, J., et al., Regional pulse wave velocities and their cardiovascular risk factors among healthy middle-aged men: a cross-sectional population-based study. BMC Cardiovasc Disord, 2014. 14: p. 5.
Conn, J.W., Presidential address. I. Painting background. II. Primary aldosteronism, a new clinical syndrome. J Lab Clin Med, 1955. 45(1): p. 3-17.
Di Bello, V., et al., Severe aortic stenosis and myocardial function: diagnostic and prognostic usefulness of ultrasonic integrated backscatter analysis. Circulation, 2004. 110(7): p. 849-55.
Galmiche G, Pizard A, Gueret A, El Moghrabi S, Ouvrard-Pascaud A, et al. (2014) Smooth muscle cell mineralocorticoid receptors are mandatory for aldosterone-salt to induce vascular stiffness. Hypertension 63: 520-526Harvey, A., A.C. Montezano, and R.M. Touyz, Vascular biology of aging - implications in hypertension. J Mol Cell Cardiol, 2015.
Holaj, R., et al., Increased intima-media thickness of the common carotid artery in primary aldosteronism in comparison with essential hypertension. J Hypertens, 2007. 25(7): p. 1451-7.
Hung CS, Ho YL, Chang YY, Wu VC, Wu XM, et al. (2013) Twenty-four-hour urinary aldosterone predicts inappropriate left ventricular mass index in patients with primary aldosteronism. ScientificWorldJournal 2013: 294594Kozakova, M., et al., Myocardial ultrasonic backscatter in hypertension: relation to aldosterone and endothelin. Hypertension, 2003. 41(2): p. 230-6.
Kuo, C.C., et al., Relative kidney hyperfiltration in primary aldosteronism: a meta-analysis. J Renin Angiotensin Aldosterone Syst, 2011. 12(2): p. 113-22.
Kuo, C.C., et al., Verification and evaluation of aldosteronism demographics in the Taiwan Primary Aldosteronism Investigation Group (TAIPAI Group). J Renin Angiotensin Aldosterone Syst, 2011. 12(3): p. 348-57.
Levy, D., et al., Prognostic implications of echocardiographically determined left ventricular mass in the Framingham Heart Study. N Engl J Med, 1990. 322(22): p. 1561-6.
Lin, Y.H., et al., The association of serum potassium level with left ventricular mass in patients with primary aldosteronism. Eur J Clin Invest, 2011a. 41(7): p. 743-50.
Lin, Y.H., et al., Reversal of myocardial fibrosis in patients with unilateral hyperaldosteronism receiving adrenalectomy. Surgery, 2011b. 150(3): p. 526-33.
Lin, Y.H., et al., Adrenalectomy improves increased carotid intima-media thickness and arterial stiffness in patients with aldosterone producing adenoma. Atherosclerosis, 2012. 221(1): p. 154-9.
Lorenz, M.W., et al., Prediction of clinical cardiovascular events with carotid intima-media thickness: a systematic review and meta-analysis. Circulation, 2007. 115(4): p. 459-67.
Mattace-Raso, F.U., et al., Arterial stiffness and risk of coronary heart disease and stroke: the Rotterdam Study. Circulation, 2006. 113(5): p. 657-63.
Milliez, P., et al., Evidence for an increased rate of cardiovascular events in patients with primary aldosteronism. J Am Coll Cardiol, 2005. 45(8): p. 1243-8.
Minamino, T., et al., Endoplasmic reticulum stress as a therapeutic target in cardiovascular disease. Circ. Res, 2010. 107(9): p. 1071-82.
Nehme, J., et al., Differences between cardiac and arterial fibrosis and stiffness in aldosterone-salt rats: effect of eplerenone. J Renin Angiotensin Aldosterone Syst, 2006. 7(1): p. 31-9.
Nomura, K., et al., Plasma aldosterone response to upright posture and angiotensin II infusion in aldosterone-producing adenoma. J Clin Endocrinol Metab, 1992. 75(1): p. 323-7.
Novitsky, Y.W., et al., Clinical outcomes of laparoscopic adrenalectomy for lateralizing nodular hyperplasia. Surgery, 2005. 138(6): p. 1009-16; discussion 1016-7.
Rizzoni, D., et al., Changes in extracellular matrix in subcutaneous small resistance arteries of patients with primary aldosteronism. J Clin Endocrinol Metab, 2006. 91(7): p. 2638-42.
Rocha R, Rudolph AE, Frierdich GE, Nachowiak DA, Kekec BK, et al. (2002) Aldosterone induces a vascular inflammatory phenotype in the rat heart. Am J Physiol Heart Circ Physiol 283: H1802-1810.
Rosa, J., et al., Peripheral arterial stiffness in primary aldosteronism. Physiol Res, 2012. 61(5): p. 461-8.
Rossi, G.P., et al., Changes in left ventricular anatomy and function in hypertension and primary aldosteronism. Hypertension, 1996. 27(5): p. 1039-45.
Rossi, G.P., et al., Remodeling of the left ventricle in primary aldosteronism due to Conn''s adenoma. Circulation, 1997. 95(6): p. 1471-8.
Rossi, G.P., et al., Excess aldosterone is associated with alterations of myocardial texture in primary aldosteronism. Hypertension, 2002. 40(1): p. 23-7.
Rossi, G.P., T.M. Seccia, and A.C. Pessina, Primary aldosteronism - part I: prevalence, screening, and selection of cases for adrenal vein sampling. J Nephrol, 2008. 21(4): p. 447-54.
Rossi, G.P., et al., Primary aldosteronism: cardiovascular, renal and metabolic implications. Trends Endocrinol Metab, 2008. 19(3): p. 88-90.
Rossi, G.P., Prevalence and diagnosis of primary aldosteronism. Curr Hypertens Rep, 2010. 12(5): p. 342-8.
Rossi, G.P., et al., Long-term control of arterial hypertension and regression of left ventricular hypertrophy with treatment of primary aldosteronism. Hypertension, 2013. 62(1): p. 62-9.
Rossi, G.P., et al., KCNJ5 gene somatic mutations affect cardiac remodelling but do not preclude cure of high blood pressure and regression of left ventricular hypertrophy in primary aldosteronism. J Hypertens, 2014. 32(7): p. 1514-22.
Sechi, L.A., et al., Cardiovascular and renal damage in primary aldosteronism: outcomes after treatment. Am J Hypertens, 2010. 23(12): p. 1253-60.
Shapiro, J.I., et al., Hypokalemia potentiates ouabain''s effect on calcium cycling and cardiac growth. Cell Mol Biol (Noisy-le-grand), 2006. 52(8): p. 87-91.
Strauch, B., et al., Increased arterial wall stiffness in primary aldosteronism in comparison with essential hypertension. Am J Hypertens, 2006. 19(9): p. 909-14.
Strauch, B., et al., Adrenalectomy improves arterial stiffness in primary aldosteronism. Am J Hypertens, 2008. 21(10): p. 1086-92.
Tanabe, A., et al., Left ventricular hypertrophy is more prominent in patients with primary aldosteronism than in patients with other types of secondary hypertension. Hypertens Res, 1997. 20(2): p. 85-90.
Tsuchiya, K., T. Yoshimoto, and Y. Hirata, Endothelial dysfunction is related to aldosterone excess and raised blood pressure. Endocr J, 2009. 56(4): p. 553-9.
Tzamou, V., et al., Aldosterone Levels, Aortic Stiffness, and Wave Reflection in Essential Hypertensive Patients. Am J Hypertens, 2014.
Wu, V.C., et al., Endothelial progenitor cells in primary aldosteronism: a biomarker of severity for aldosterone vasculopathy and prognosis. J Clin Endocrinol Metab, 2011. 96(10): p. 3175-83.
Wu, V.C., et al., Primary aldosteronism: changes in cystatin C-based kidney filtration, proteinuria, and renal duplex indices with treatment. J Hypertens, 2011. 29(9): p. 1778-86.
Xie, Z., et al., Effects of hypokalemia on cardiac growth. Ren Fail, 2000. 22(5): p. 561-72.