臺灣博碩士論文加值系統

背景：
心肌炎是心肌的炎症，顯著增加了心室性心律不整（ventricular arrhythmia，VA）的風險。這些異常的心律可能導致嚴重併發症，包括猝死。估計約30%的心肌炎患者的心室性心律不整病例來自右心室流出通道（right ventricular outflow tract，RVOT），該區域特別容易出現異常電活動。然而，核苷酸寡聚化結構域樣受體家族蛋白3 (nucleotide oligomerization domain-like receptor family protein 3，NLRP3）訊號在右心室流出通道心律不整生成中的確切機制仍不清楚。此外，心肌炎還與心房性心律不整（如心房顫動 (atrial fibrillation，AF））的增加有關，這可能是由於肺靜脈（pulmonary vein，PV）的放電所致，但導致心肌炎中心房顫動的具體途徑尚未完全闡明。
方法：
本研究使用肌球蛋白肽誘導的心肌炎大鼠模型。實驗組的大鼠接受核苷酸寡聚化結構域樣受體家族蛋白3 (NLRP3）抑制劑MCC950（每天10 mg/kg，持續14天）治療，或未經治療。為了評估心肌炎和治療的影響，我們對大鼠進行了心電圖和心臟超音波檢查。從右心室流出通道、右心室肌心尖（right ventricular apex，RVA）和左心室（left ventricular，LV）收集心臟組織樣本，進行結構和功能分析。進一步的電生理學研究包括全細胞膜片鉗技術測量離子電流，使用共軛焦熒光顯微鏡觀察細胞內鈣離子水準，以及西方點墨法 (western blotting)評估涉及鈣調控的蛋白表達。此外，還對肺靜脈組織進行分析，研究心肌炎如何影響與心房顫動相關的電生理改變。
結果：
我們的結果揭示了心肌炎對心功能的多個關鍵影響。在心肌炎組，左心室射血分率顯著降低，提示心臟功能受損。此外，心肌炎組的心室早期收縮（premature ventricular contraction，PVC）頻率更高。組織學分析顯示，炎症細胞浸潤增加，特別是在右心室流出通道和右心室肌心尖，並且核苷酸寡聚化結構域樣受體家族蛋白3 (NLRP3）表達上調，提示這些區域存在強烈的炎症反應。MCC950治療改善了左心室射血分率並減少了心室早期收縮頻率，顯示其潛在的治療效果。在心律不整方面，實驗顯示心肌炎大鼠更容易在右心室流出通道中發展出異常自動性（自發電活動）和心室性心搏過速（ventricular tachycardia，VT），這表明右心室流出通道特別容易受到心肌炎誘發的電生理變化的影響。在細胞層面上，心肌炎大鼠的右心室流出通道心肌細胞顯示出更低的肌漿網（sarcoplasmic reticulum，SR）鈣水準、更小的細胞內鈣離子瞬變、L型鈣電流減少、晚鈉電流增加和鈉鈣交換蛋白（Na+–Ca2+ exchanger，NCX）電流增強。這些變化伴隨著活性氧類（reactive oxygen specie，ROS）水準升高和鈣/鈎蛋白依賴性蛋白激酶II（Ca2+/calmodulin-dependent protein kinase II，CaMKII）活性增加，表明氧化壓力和鈣處理失調。值得注意的是，這些病理變化在接受MCC950治療的大鼠中有所緩解，表明核苷酸寡聚化結構域樣受體家族蛋白3 (NLRP3）抑制有助於恢復正常的鈣動力學，減少心律不整風險。除了心室性心律不整，心肌炎還導致肺靜脈中出現顯著的電生理異常，包括自發活動增加、跳動頻率升高和頻繁的爆發性放電，這提示心肌炎增加了肺靜脈的心律不整風險，可能進一步導致心房顫動。對心肌炎大鼠進行快速起搏時，成功觸發了心房顫動，而在對照組大鼠中則未觀察到這一現象，表明心肌炎為心房顫動的發生提供了更有利的條件。MCC950治療降低了肺靜脈跳動頻率、自發觸發活動和爆發性放電，表明核苷酸寡聚化結構域樣受體家族蛋白3 (NLRP3）抑制能夠降低心肌炎在心房中的致心律不整潛力。
結論：
心肌炎可能通過電生理和結構重塑促進右心室流出通道和肺靜脈的致心律不整改變。核苷酸寡聚化結構域樣受體家族蛋白3 (NLRP3）訊號在這些過程中扮演著核心角色，通過MCC950抑制該途徑可能有助於減輕心肌炎對心律的有害影響。我們的研究結果強調了核苷酸寡聚化結構域樣受體家族蛋白3 (NLRP3）抑制在減少心肌炎患者中心室性和心房性心律不整（包括心房顫動）的治療潛力。

Background:
Myocarditis, an inflammation of the heart muscle, significantly increases the risk of ventricular arrhythmias (VA), which are abnormal heart rhythms that can lead to severe complications, including sudden cardiac death. It is estimated that approximately 30% of VA cases in myocarditis patients originate from the right ventricular outflow tract (RVOT), a region of the heart that is particularly prone to abnormal electrical activity. Despite this, the exact mechanisms, particularly the role of NLRP3 (Nucleotide Oligomerization Domain-Like Receptor Family Protein 3) signaling in RVOT arrhythmogenesis, remain unclear. Furthermore, myocarditis is associated not only with VA but also with atrial arrhythmias, such as atrial fibrillation (AF), which may be caused by electrical remodeling in the pulmonary veins (PVs). However, the specific pathways leading to AF in the context of myocarditis are not fully understood.
Methods:
In this study, we used a rat model of myocarditis, induced by injecting rats with myosin peptide. These rats (experimental group) either received treatment with MCC950 (an inhibitor of NLRP3, administered at 10 mg/kg daily for 14 days) or were left untreated. To assess the effects of myocarditis and treatment, we conducted electrocardiography and echocardiography on the rats. We collected tissue samples from the RVOT, right ventricular apex (RVA), and left ventricle (LV) to examine the structure and function of the heart. Further investigations were carried out using techniques such as whole-cell patch-clamp recordings to measure electrical activity, confocal fluorescence microscopy to visualize calcium levels in heart cells, and Western blotting to assess the levels of specific proteins involved in calcium regulation. Additionally, PV tissue samples were analyzed by whole-cell patch-clamp to determine how myocarditis influences AF-related electrical changes in the PVs.
Results:
Our findings revealed several key effects of myocarditis on heart function. In the myocarditis group, the left ventricular ejection fraction was significantly reduced compared to the control group, indicating impaired heart function. Furthermore, the frequency of premature ventricular contractions (PVCs), was higher in the myocarditis group. Histological analysis showed increased infiltration of inflammatory cells into heart tissues, particularly in the RVOT and RVA, and upregulated expression of NLRP3, suggesting a strong inflammatory response in these areas. Treatment with MCC950 improved the left ventricular ejection fraction and reduced the frequency of PVCs, demonstrating its therapeutic potential. In terms of arrhythmia, we found that rats with myocarditis were more likely to develop abnormal automaticity (spontaneous electrical activity) and ventricular tachycardia (VT) in the RVOT than in the RVA or LV. These findings suggest that the RVOT is particularly vulnerable to myocarditis-induced electrical changes. At the cellular level, RVOT myocytes (heart muscle cells) from myocarditis rats exhibited lower calcium levels in the sarcoplasmic reticulum (SR), smaller calcium transients, reduced L-type calcium currents, elevated late sodium currents, and increased activity of the Na+–Ca2+ exchanger (NCX). These changes were accompanied by higher levels of reactive oxygen species (ROS) and increased activity of Ca2+/calmodulin-dependent protein kinase II (CaMKII), indicating oxidative stress and disrupted calcium handling in the heart. Notably, these pathological changes were mitigated in the group treated with MCC950, suggesting that NLRP3 inhibition helps restore normal calcium dynamics and reduces the risk of arrhythmia. In addition to VA, myocarditis also caused significant electrical abnormalities in the PVs, including increased spontaneous activity, higher beating frequency, and frequent burst firing. These findings suggest that myocarditis increases the risk of pulmonary vein arrhythmogenesis, potentially leading to AF. When rapid pacing was applied to the myocarditis rats, AF was successfully triggered, whereas no such response was observed in control rats. This indicates that myocarditis creates more favorable conditions for the development of AF. Treatment with MCC950 reduced the beating frequency, spontaneous trigger activity, and burst firing in PVs, demonstrating that NLRP3 inhibition can reduce the arrhythmogenic potential of myocarditis in the atria.
Conclusion:
Myocarditis appears to promote arrhythmogenic changes in both the RVOT and pulmonary veins, possibly through a combination of electrical and structural remodeling. NLRP3 signaling plays a central role in these processes, and inhibiting this pathway with MCC950 may help mitigate the harmful effects of myocarditis on heart rhythm. Our findings highlight the potential of NLRP3 inhibition as a therapeutic strategy for reducing both ventricular and atrial arrhythmias, including AF, in myocarditis patients.

1 中文摘要(Abstract in Chinese) …………………………………… i-iii
2 英文摘要(Abstract in English) …………………………………… iv-vii
3 緒論(introduction)
3-1 心肌炎的病因與臨床表現概述……………………………………… 1-2
3-2 心肌炎與右心室流出道心律不整的關聯性………………………… 3-4
3-3 心肌炎與心房顫動之間的關聯……………………………………… 4-7
3-4 心房顫動與肺靜脈的關聯性………………………………………… 7-9
3-5 COVID-19與心肌炎的關聯性及其臨床意涵……………………… 9-10
3-6 核苷酸寡聚化結構域樣受體家族蛋白3( NLRP3)在心肌炎心房
顫動及心室性心搏過速中的關鍵角色….…………………………… 11-13
4 實驗材料與方法(Materials and Methods)
研究目的………………………………………………………………… 14
4-1 急性心肌炎的大鼠模型…………………………………………… 15
4-2 心電圖和心臟超音波……………………………………………… 15-16
4-3 右心室流出道組織電生理學分析………………………………… 16-17
4-4 肺靜脈組織電生理學分析………………………………………… 17-18
4-5 免疫組織學分析…………………………………………………… 18
4-6 右心室流出道中單個心肌細胞的分離……..…………………… 18-19
4-7 細胞內鈣離子瞬變的測量……………………………………… 19
4-8 單個心肌細胞的全細胞膜片鉗記錄……………………………… 20
4-9 晚期鈉離子電流測量……………………………………………… 20
4-10 L型鈣離子電流測量……………………………………………… 21
4-11 鈉鈣交換蛋白電流的測量……………………………………… 21
4-12 細胞內活性氧類和鈉離子水準的測量…………………………… 21-22
4-13 西方點墨法(western blotting)………………………………… 22-23
4-1 統計分析……………………………………………………………… 23
5 結果(result)
5-1 核苷酸寡聚化結構域樣受體家族蛋白3( NLRP3)抑制減輕了心肌功能
障礙並預防了心肌炎大鼠的心室性心律不整 .………………………… 24-25
5-2 肌球蛋白肽誘發大鼠早期心肌炎的炎症反應……………………… 25-26
5-3 心肌炎引發肺靜脈電生理異常與心房顫動風險增加……………… 27-28
5-4 右心室心尖、右心室流出道和左心室的動作電位形態…………… 28-30
5-5 心肌炎對右心室流出道電活動及細胞內活性氧類產生的影響…… 30-31
5-6 MCC950對心肌炎大鼠鈣水準的影響………………………………… 32-33
5-7 MCC950對心肌炎大鼠鈣調控蛋白的影響…………………………… 33-34
6 討論(Discussion) …………………………………………………… 34-47
7 結論與展望(Conclusion and Perspective)………………………… 48
8 參考文獻(References) ……………………………………………… 49-59
9 圖(Figures)…………………………………………………………… 60-87

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