親蛋白質尿毒素硫酸吲哚酚對於心臟細胞電生理之影響及其心律不整致病機轉之研究

The electrophysiological effect indoxyl sulfate on cardiomyocyte and its role in clinical arrhythmogenesis

陳偉華(Wei-Hua Tang)

指導教授 ： 賴文德

高雄醫學大學/醫學院/醫學研究所博士班/博士(2015年)

https://doi.org/10.6832/KMU.2015.00007

摘要

近年來，隨著慢性腎衰竭和血液透析病患的增加，慢性腎衰竭病患的心血管疾病及心律不整也逐漸被重視。根據以往的研究報告，心血管疾病亦是慢性腎衰竭和血液透析病患的主要死亡原因。
目前大家對為何慢性腎衰竭和血液透析病患的心血管疾病較為嚴重的原因，多歸咎於各式各樣的尿毒素。雖然目前血液透析可過濾出大多數病患血液中的尿毒素，但仍有部分的尿毒素因為分子量較大(大於>500D)或因為本身會和血液中蛋白質而無法經由血液透析有效的移除。
硫酸吲哚酚(Indoxyl sulfate)，是一種小分子親蛋白質尿毒素，目前發現會隨著腎臟衰竭的進展而逐漸累積在慢性腎衰竭的病患體內。並且，利用目前血液透析的方法是無法有效的過濾移除病患中的硫酸吲哚酚。根據過去研究文獻的報導，硫酸吲哚酚已被證實會引起心臟組織纖維化，發炎反應及心肌細胞的異常肥大。此外，硫酸吲哚酚對於心臟間質纖維化及心臟的代償性再造( cardiac remodeling)也有相當密切的關係。但直到如今，硫酸吲哚酚對於心肌細胞的電生理及心律不整的影響，還沒有確實的報告和研究。本研究的目的就是希望藉由心肌細胞的培養及硫酸吲哚酚的投予，分析心肌細胞離子通道蛋白的表現和心肌細胞電生理的影響，探討硫酸吲哚酚對心肌細胞的急性和慢性電生理變化和其在慢性腎衰竭病患心律不整的角色。
本研究發現硫酸吲哚酚對於心臟細胞鉀離子電流有明顯抑制效果。蛋白質分析亦發現此現象是由於硫酸吲哚酚抑制心臟細胞鉀離子通道蛋白KV2.1磷酸化造成的。

關鍵字

硫酸吲哚酚 ； 慢性腎衰竭 ； 心律不整 ； 細胞電生理

並列摘要

Cardiac arrhythmias and sudden cardiac death are highly prevalent in chronic kidney disease (CKD). In CKD patients, the protein-bound uremic retention solute indoxyl sulfate (IS) is independently associated with cardiovascular disease. However, the cardiac arrhythmogenic effect of IS have not been elucidated. The relationship between IS and cardiac electrocardiographic parameters was investigated in a prospective observational study among early CKD patients. IS arrhythmogenic effect was evaluated by in vitro cardiomyocyte electrophysiological study and mathematical computer simulation.
In a cohort of early CKD patients, patients with QTc prolongation had higher IS levels compared to the patients with normal QTc interval. Furthermore, serum IS level was independently associated with prolonged QTc interval. In vitro, the delay rectifier potassium current (IK) was found to be decreased significantly after the treatment of IS in a dose-dependent manner. The modulation of IS to the IK was through the regulation of the major potassium ion channel protein Kv 2.1 phosphorylation. In computer simulation, the decrease of IK by IS could prolong the cardiomyocyte action potential duration (APD) and induce early afterdepolarization, which is known to be a trigger mechanism of lethal ventricular arrhythmias. In conclusions, Serum IS level is independently associated with the prolonged QTc interval in early CKD patients. IS down-regulated IK channel protein phosphorylation and the IK current activity that in turn increase the cardiomyocyte APD and QTc interval in vitro and in the computer model. These findings suggest that IS may play a role in the arrhythmogenesis in CKD patients.

並列關鍵字

indoxyl sulfate ； chronic renal disease ； cardiac arrhythmias ； electrophysiology

參考文獻

References

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