KCNJ5體細胞突變在原發性皮質醛酮症單側腺瘤患者的心臟血管系統結構與功能的角色

The association between KCNJ5 somatic mutations and cardiovascular structure and functions in aldosterone-producing adenoma

張藝耀(Yi-Yao Chang)

指導教授 ： 林彥宏

共同指導教授 ： 劉力瑜(Li-yu Liu)

國立臺灣大學/醫學院/臨床醫學研究所/博士(2021年)

https://doi.org/10.6342/NTU202104574

摘要

原發性皮質醛酮症(primary aldosteronism, PA)是次發性高血壓疾病中最常見的，其致病機轉為腎上腺腫瘤或不正常增生而產生過量的皮質醛酮所致，盛行率約佔所有高血壓患者的 5-10%。單側皮質醛酮腺瘤(aldosterone producing adenoma; APA)是原發性皮質醛酮症的兩大主要亞型之一，此類型的病症可藉由切除腎上腺獲得痊癒。這些不正常產生的過量皮質醛酮會造成心臟結構的改變和傷害，包含左心室心肌肥厚、心肌纖維化、左心室舒張功能異常、以及血管硬化。在過去研究中，發現 PA 患者有相較於原發性高血壓(essential hypertension, EH)患者有較嚴重的左心室心肌肥厚、心肌纖維化以及較差的左心室舒張功能。而 APA 的發生在近年研究發現與體細胞突變發生相關，其中又以 KCNJ5 最常見，一旦突變會造成CYP11B2 基因過度活化使皮質醛酮合成酶(aldosterone synthase)的製造增加，進而造成皮質醛酮產出過剩而導致原發性皮質醛酮症。有 KCNJ5 突變的 APA 患者在亞洲(台灣、日本)有高達約 55-75%的 APA 病患有 KCNJ5 基因突變，但在西方國家則僅約 25-50%患者有突變，顯現 KCNJ5 基因突變在東西方族群有不同的臨床表徵。目前發現有 KCNJ5 體細胞突變患者較年輕，術前皮質醛酮濃度較高，術後血壓恢復正常的比例較多，但性別差異和腫瘤大小差異則在歐洲團隊的研究較顯著。
而 KCNJ5 突變對於心臟血管系統的影響過往僅有較零星的研究，對於左心室心肌肥厚的影響結果仍分歧，而對於心臟舒張功能以及開刀治療後血管硬度變化的研究更是稀少或無定論，其中可能的重要原因在於 KCNJ5 體基因有突變的患者年紀較輕且主要為女性，血壓亦有一定的差距，這些因素皆對心肌與血管的結構和功能有相當影響。因此本研究希望藉由較足夠的病患總量，藉由傾向分數匹配(propensity score matching)的統計方式，排除年紀、性別、以及血壓等干擾因子的影響，減少組間個案基本資料的落差，來探討 KCNJ5 突變對於心臟結構(心肌質量指數[LVMI，left ventricular mass index]，及不適當過度增加的左心室質量指數[ieLVMI，inappropriate excess LVMI])、左心室舒張功能(e’與 E/e’)、以及動脈血管硬度(baPWV，brachial-ankle pulse wave velocity)的影響，並追蹤其開刀一年後的變化。
在第一部分心臟結構與功能方面的研究，發現在年紀、性別、血壓嚴重程度作配對後，有 KCNJ5 突變的原發性皮質醛酮患者，其左心室質量指數(LVMI)仍較沒突變的患者高，且其增加的左心室心肌質量的組成中，不適當過度增加的左心室質量指數(ieLVMI，代表除血壓外其他因子所造成的左心室肥厚變化)，有KCNJ5 突變患者的 ieLVMI 仍顯著高於沒有突變的患者，顯示有突變的患者其較高的皮質醛酮濃度可能會造成除卻血壓影響外的左心室增厚，且 LVMI 和ieLVMI 與 KCNJ5 突變顯著相關。開刀後，有 KCNJ5 突變的患者其開刀前後的LVMI 以及 ieLVMI 均顯著下降，而 E/e’亦顯著下降，顯示舒張功能的改善；這些變化在沒有突變的患者均無顯著改變。而 LVMI 和 ieLVMI 的術後的降幅與KCNJ5 突變顯著相關。因此 KCNJ5 突變對皮質醛酮患者心臟結構和舒張功能及其術後恢復均具有顯著的影響。在第二部分血管功能方面的研究，發現在年紀、性別、血壓嚴重程度作配對後，有 KCNJ5 突變的原發性皮質醛酮患者，其baPWV 與沒有突變的患者無明顯差異，但開刀術後 baPWV 的降幅，有突變的患者顯著大於沒有突變的患者，且術後 baPWV 的降幅經年紀、性別、血壓嚴重度的校正後仍與 KCNJ5 突變顯著相關。因此 KCNJ5 突變對術後的血管硬度恢復有顯著影響。
高血壓影響心血管健康甚鉅，而原發性皮質醛酮症本身是一種可治癒的高血壓疾病，KCNJ5 體基因突變為單側皮質醛酮腺瘤在亞洲族群常見且重要的致病機轉，本研究結果有助於了解 KCNJ5 突變在原發性皮質醛酮症患者中對心臟結構、舒張功能、以及血管硬度的影響。

關鍵字

原發性皮質醛酮症 ； 皮質醛酮 ； KCNJ5 體基因突變 ； 左心室肥大 ； 左心室舒張功能 ； 血管硬度

並列摘要

Primary aldosteronism (PA) resulted from excessive aldosterone production is a curable disease with a prevalence of 5-10% in hypertensive population. Aldosterone producing adenoma (APA) is one of the most common subtype of PA and could be cured by adrenalectomy. Compare to patients with essential hypertension, patients with PA have higher prevalence of cardiovascular diseases, including left ventricular hypertrophy, cardiac fibrosis, diastolic dysfunction, and vascular stiffness. Somatic mutations play an important role on the pathogenesis of APA. KCNJ5 mutations is the most common mutation, which resulting in over-activation of CYP11B2 gene, increase of aldosterone synthase production and then over-production of aldosterone. In Asian countries (Taiwan, Japan), 55-75% of patients with APA have KCNJ5 somatic mutations. In contrast, only 25-50% of APA patients have KCNJ5 mutations in Western countries. This revealed the different clinical characteristics between Asian and Western countries. In previous studies, APA patients with KCNJ5 mutations are younger, have higher baseline serum aldosterone level, and higher percentage of hypertension cure rate compare to patients without mutations. However, the difference of gender and tumor sizes between groups with and without KCNJ5 mutations only noted in Western countries.
There are few studies discussing about the role of somatic mutations on cardiovascular structure and function. The effects of KCNJ5 mutations on left ventricular hypertrophy are still diverse in different studies. Besides, the effects of KCNJ5 mutations on left ventricular diastolic function and vascular largely remains unknown. The possible causes of the diversity maybe resulted from the patients with KCNJ5 mutations are younger, female dominant, and higher blood pressure compared with patients without mutations. All of these difference interfere the cardiovascular structure and function. Therefore, the current study investigate the effects of KCNJ5 mutations on cardiac structure (LVMI, left ventricular mass index; ieLVMI, inappropriate excess LVMI), left ventricular diastolic function (e’ and E/e’), and arterial stiffness (baPWV, brachial-ankle pulse wave velocity) by propensity score matching analysis to decrease the interference of age, sex, and blood pressure.
For the cardiac structure and function, after matching for age, sex, and blood pressure severity, the results revealed the patients with KCNJ5 somatic mutations had higher LVMI and ieLVMI, which represent the interaction of genetic and neurohumoral factors other than blood pressure, compared with patients without mutations. The LVMI and ieLVMI correlated with KCNJ5 mutations. After adrenalectomy, the decrease of LVMI and ieLVMI in patients with KCNJ5 mutations were significantly higher compared with patients without mutations. The APA patients with KCNJ5 mutations also benefited from adrenalectomy with regard to LV diastolic function (E/e’), but this was not found in patients without mutations. The decrease of LVMI and ieLVMI correlated with KCNJ5 mutations. Therefore, the KCNJ5 mutations affect the cardiac structure, diastolic function, and their reversal after adrenalectomy in PA patients. For the arterial stiffness, after matching for age, sex, and blood pressure severity, the results revealed the patients with KCNJ5 mutations had similar baPWV compared with patients without mutations. However, after adrenalectomy, the decrease of baPWV was significantly higher in the patients with KCNJ5 mutations compared with patients without mutations. Besides, the decrease of baPWV correlated with KCNJ5 mutations even after adjustment of age, sex, severity of hypertension. Therefore, KCNJ5 mutations affect the reversal of arterial stiffness after adrenalectomy.
Hypertension plays an important role in cardiovascular health. Primary aldosteronism is a curable hypertensive disease. KCNJ5 somatic mutations is one of the major pathogenesis in APA patients, especially in Asian countries. The results of the current study is indispensable for the effect of KCNJ5 somatic mutations on cardiac structure, diastolic function, and arterial stiffness.

並列關鍵字

primary aldosteronism ； aldosterone ； KCNJ5 somatic mutation ； left ventricular hypertrophy ； left ventricular diastolic function ； pulse wave velocity

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