在新陳代謝症候群及肥胖病人身上可觀察到心房顫動發生頻率增加之情形，已知肺靜脈及左心房在心房顫動的誘發或維持扮演重要的角色，而心臟周邊脂肪恰位於肺靜脈及左心房常見的誘發點附近，已知心臟周邊脂肪具有促發炎能力，而發炎可能引起心房顫動發生，故脂肪細胞可能在心房心律不整的發生扮演重要的角色，然而其造成心房顫動之機轉尚未完全清楚了解，關於脂肪細胞在心肌細胞電生理及各種離子調控之分子生物機轉則未有研究。再則左心房肌已知是造成心房顫動之重要病灶所在，且左心房也是造成持續性心房顫動之的重要解剖構造且其前後壁具有相當之電生理差異。異常的離子調控已知是造成心房顫動以及肺靜脈引發心律不整之重要原因也是造成左心房前後壁電生理差異之原因。此外，疾病如心衰竭會增加心房顫動的發生，其機轉除心衰竭導致之心臟腔室肥厚或擴大及壓力變化外，是否會透過調控心臟周邊脂肪，改變其成分而促使心房容易產生心律不整，而哪種脂肪激素是我們想要尋找脂肪細胞與心房顫動之間相連結的可能機轉?。本實驗主要在探討一:脂肪細胞是否能直接調控左心房心肌細胞鈣離子調控蛋白、離子流與動作電位之作用，及其引發調控心肌細胞之鈣離子分子生物機轉；二: 心衰竭是否會透過調控心臟周邊脂肪，改變其成分而促使心房容易產生心律不整；三: 脂肪激素-瘦體素(leptin) 是否會調控心房細胞離子流進而影響心臟顫動的產生。實驗材料與方法: 一: 以兔子的心房細胞進行全細胞箝定之基礎電生理試驗方法，測試加入心周脂肪細胞後是否會影響心房細胞的電生理特性及離子流進而增加其致心律不整性；二: 兔子的左右心房加上正常或心衰竭心周脂肪測試是否會影響心房的電生理特性進而增加其致心律不整性；三:以兔子的心房細胞進行全細胞箝定之基礎電生理試驗方法，測試加入瘦體素(leptin)後是否會影響心房細胞的電生理特性及離子流進而增加其致心律不整性。

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia seen in clinical practice. Obesity and metabolic syndrome are independent risk factors of AF which were proposed partially by enhanced inflammation and oxidative stress. Moreover adipocyte can produce inflammatory cytokine and adipocytokine. Epicardial adipose tissues are highly associated with the genesis of atrial fibrillation. Local interactions between epicardial adipose tissue and adjacent myocardium may induce myocardial electrical or anatomical remodeling and give rise to AF occurrence. There was study demonstrated that discrepant electrophysiological characteristics and calcium homeostasis between anterior wall and posterior wall of left atrium (LA). Moreover, disease such as heart failure (HF) could increase the occurrence of AF. The mechanism o underlying HF related AF could be chamber dilatation or pressure overload induced electrophysiological change. However adipocytes mediated AF occurrence through the modulation of epicardial fat by HF should be considered. Furthermore, which adipokine is responsible for the adipocyte-atria interaction and atrial electrophysiological characteristics change? Therefore we hypothesized that epicardial adipocytes contain distinctive arrhythmogenicity through increase of inflammatory cytokines, adipocytokines, and adipocyte-cardiomyocyte interactions to induce atrial fibrillation. The purposes of this study are to investigate: First - could adipocytes modulate LA myocytes electrophysiological characteristics, ionic currents, calcium homeostasis and increase atrial arrhythmogenesis? Second - could HF modulate epicardial fat and increase atrial arrhythmogenesis through changing fat content? Third - could adipokine (leptin) induce ionic current change of atrial cells and influence the occurrence of atrial arrhythmia ? The material and method would be as follows: First - we will co-culture of isolated LA myocytes and isolated adipocytes of retrosternal epicardial fat, then test the electrophysiological property, ionic currents and calcium modulating properties and proteins of LA myocytes, and adipokines profile of retrosternal fat. Second: we will use conventional microelectrodes recording to record the action potential in LA and right atria (RA) of healthy (control) rabbits before and after application of epicardial fat from control or HF (ventricular pacing of 360-400 bpm for 4 weeks) rabbits. Adipokine profiles will be checked in epicardial fat of control and HF rabbits. Third: we will exam the electrophysiological effects inclucing action potential, ionic currents, and calcium modulating properties and proteins of leptin 100 nM on LA myocytes.

中文摘要 (Abstract in Chinese) ----------------------- i
英文摘要 (Abstract in English) ----------------------- ii
假說 (Hypothesis)--------------------------------------iii
第一章 緒論 (Introduction)
1. Epicardial fat and atrial fibrillation - 1
2. Heart failure and atrial fibrillation - 2
3. Leptin and atrial fibrillation - 3
第二章 研究方法與材料 (Materials and Methods)
4. Isolation of single cardiomyocytes and single adipocytes - 4
5. Electrophysiological study - 5
6. Generation and composition of supernatant - 8
7. Measurement of inflammatory cytokines and adipokines - 8
8. Statistical analysis - 8
9. Rabbit PV and atria tissue preparations - 9
10. Electrophysiological study - 10
11. Measurement of inflammatory cytokines and adipokines - 11
12. Histology of epicardial fat and measurement of adipocyte size - 11
13. Statistical analysis - 11
14. Isolation of single LA myocytes - 12
15. Electrophysiological study - 13
16. Measurement of the changes in the intracellular calcium concentration - 15
17. Statistical analysis - 16
第三章 研究結果 (Results)
18. Effects of adipocytes on the electrical activity of LA myocytes - 17
19. Effects of adipocytes on the membrane currents of LA myocytes - 17
20. Effects of adipocytes on the isoproterenol-induced arrhythmogenic activity of LA cardiomyocytes - 18
21. Profiles of adipokines in the supernatants of LA myocytes alone, adiopocytes alone, and co-incubated adipocytes and LA myocytes - 18
22. Effects of epicardial fat on the electrical activity of LA and RA myocytes - 18
23. Adipokines profile and adipocyte morphology from control and HF epicardial fat - 19
24. Effects of leptin on the electrical activity of LA myocytes - 20
25. Effects of leptin on the membrane currents of LA myocytes - 20
26. Effects of leptin on calcium handling of LA myocytes - 20
第四章 討論 (Discussion)
27. Adipocytes modulate the electrophysiology of atrial myocytes: implications in obesity-induced atrial fibrillation - 21
28. Heart failure epicardial fat increases atrial arrhythmogenesis - 25
29. Leptin modulates electrophysiological characteristics and isoproterenol -induced arrhythmogenesis in atrial myocytes -28
第五章 結論與展望 (Conclusion and Perspective) - 31
參考文獻 (References) - 32
表及圖 (Table and Figures) - 46

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