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研究生：	李威杰 Lee, Wei-Chieh
論文名稱：	長期右心室起搏相關的心房心肌病變－從臨床實務到動物模型研究 Long-term right ventricular pacing related atrial cardiomyopathy - From clinical practice to animal model
指導教授：	劉秉彥 Liu, Ping-Yen
學位類別：	博士 Doctor
系所名稱：	醫學院 - 臨床醫學研究所 Institute of Clinical Medicine
論文出版年：	2024
畢業學年度：	112
語文別：	英文
論文頁數：	115
中文關鍵詞：	左心房擴大、左心房纖維化、右心室起搏、雙心室同步起搏、不同步、完全房室傳導阻滯、Sirtuin signaling pathway 、SIRT1 、GADD45G
外文關鍵詞：	left atrial enlargement, left atrial fibrosis, right ventricular pacing, biventricular pacing, dyssynchrony, complete atrioventricular block, Sirtuin signaling pathway, SIRT1, GADD45G
相關次數：	點閱：33 下載：1
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隨著人口老齡化，症狀性心動過緩的患病率增加，導致心臟節律器的使用增加，雖然在心律過緩治療方面取得長足進步，但臨床研究表明，長期的右心室起搏可能對左心室功能產生不利的影響，並導致左心房擴大，其左心房擴大與心臟衰竭和心房性心動過速的風險增加有關，特別是在完全房室傳導阻滯患者中，其中心房顫動的發病率超過了一般人群，然而長期右心室起搏後心房擴大和結構重構的分子和遺傳機制仍然知之甚少。
研究首先利用臨床數據觀察了由於長期右心室起搏所引起的心室之間不同步收縮，了解左心房擴大的整體發生率及其導致的併發症，通過臨床資料庫觀察發現，完全房室傳導阻滯患者接受長期右心室起搏，其中20.8%病患產生明顯左心房擴大，而影響長期中風的發生風險。
利用完全房室傳導阻滯的實驗豬模型，進一步探討長期右心室起搏後引起心房擴大和結構重構的分子和相關基因機制，比較了長期右心室起搏模式和雙心室同步收縮節律器在心房大小和結構重構方面的差異，研究分為三組：對照組、六個月右心室起搏組以及三個月右心室起搏後再進行三個月雙腔同步起搏的組別，六個月後，收集心房組織以檢查不同起搏方式如何影響基因表達和完全房室傳導阻滯豬心房的結構重構，利用基因測序系統地探索對照組與右心室起搏組之間基因表達的差異，進行功能途徑分析，以確定導致心房結構重構的信號途徑，則發現在右心室起搏的豬隻中觀察到左心房增大和新房纖維化的顯著變化，而對Sirtuin信號的負控制和SIRT1基因及蛋白質的表現降低則對左心房纖維化有重要影響，雙腔同步起搏改善心室收縮同步性，並反向調節GADD45G的表現以回饋SIRT1以改善左心房纖維化。
這項研究通過臨床數據庫分析和完全房室傳導阻斷動物模組研究強調右心室起搏相關的心室不同步收縮所導致的左心房增大和相關纖維化表現，其中發現對於Sirtuin信號的負控制和SIRT1基因及蛋白質的表現降低控制了纖維化，並突顯了右心室起搏所引起的左心房增大和纖維化背後複雜的分子機制。

The prevalence of symptomatic bradycardia has increased with the aging of the population, resulting in a global rise in the implantation of cardiac pacemakers. The introduction of artificial permanent pacemakers has revolutionized arrhythmia treatment; however, clinical research indicates that prolonged right ventricular (RV) pacing results in a decline in left ventricular function and left atrial (LA) enlargement. A larger atrium is associated with an increased risk of heart failure and atrial tachyarrhythmia, particularly in patients with complete atrioventricular block (CAVB), who are at a higher risk of developing atrial fibrillation (AF) than the general population. Currently, the involved molecular and associated genetic mechanisms cause atrial enlargement and structural remodeling after long-term RV pacing are poorly explored.
This study utilized clinical data to observe the asynchronous contractions induced by prolonged RV pacing, the overall prevalence of LA enlargement, and its resultant complications. The complications of interventricular dyssynchrony-related LA enlargement and remodeling were observed in a clinical database. Long-term RV pacing cause 20.8% patients with an increase of greater than 20% from the baseline LA diameter. The patients with LA enlargement presented higher incidence of stroke at long-term follow-up period.
An experimental pig model of AV conduction block was used to explore the atrial remodeling involved molecular and genetic mechanisms following prolonged stimulation of RV pacing. Furthermore, the variations induced in atrial size and structural remodeling by the long-term pacing modes of the RV pacemaker and the biventricular synchronous contraction pacemaker were compared. Three groups were created by building upon clinical research data and employing an experimental pig model of CAVB: a control group, a six-month RV pacing group, and other group subjected to three-month RV pacing followed by three-month bi-ventricular (BiV) synchronous pacing. Atrial tissues were collected after six months to investigate the effect of how different pacing modalities on gene expression and structural remodeling in pig atria with CAVB. The differences of genetic expression between the control and RV pacing groups were systematically explored via next-generation sequencing (NGS). Furthermore, the genes potentially associated with pathological changes in the LA among significantly differentially expressed genes were identified. Enrichment and functional pathway analyses were performed to identify the signaling pathways involved in atrial structural remodeling. Larger LA size and fibrotic change was observed significantly in the RV pacing pig. Negative control of sirtuin signaling pathway and down regulation of SIRT1 have an important impact on LA fibrosis. BiV pacing improved interventricular synchrony and reverse GADD45G to improve LA fibrosis.
The finding of this study emphasizes RV pacing related interventricular dyssynchrony cause LA enlargement and fibrosis by clinical database and CAVB animal study. Sirtuin signaling pathway and SIRT1 regulate fibrosis and underscore the complex molecular mechanisms driving LA enlargement induced by RV pacing.

Abstract I
中文摘要 III
誌謝 V
Contents VII
Table list XI
Figure list XIII
Abbreviations XV
Chapter 1. Introduction 1
1 Long-term impact and complications of right ventricular pacing 1
2 Possible mechanisms of left atrial enlargement after long-term right ventricular pacing 2
3 Right ventricular pacing-induced mechanical dyssynchrony can induce mitral regurgitation and left atrial enlargement 3
Chapter 2. Objective and Specific Aims 5
Chapter 3. Materials and Methods 7
1 Clinic study design 7
1.1 Patient enrollment and ethical statement 7
1.2 Definition and study endpoint 8
1.3 Echocardiography assessment 8
2 Animal study design 9
2.1 Creation of CAVB models post RV septal-dependent pacing and biventricular pacing 9
2.2 Pacemaker implantation and achievement of atrioventricular block condition 9
2.3 Transthoracic echocardiograph for animal 11
2.4 Specimen storage or atrial tissue 11
2.5 Masson’s Trichrome Staining 12
2.6 Western blotting 13
2.7 Next-generation sequencing and quantitative determination of RNA of the lateral wall of LA myocardium 14
3 HL-1 cell culture and stretch model 18
4 Statistical analyses 19
Chapter 4. Results 20
1 Results of the clinical cohort study 20
1.1 Baseline characteristics and demographic characteristics of patients with and without significant LA enlargement after RV pacing 20
1.2 Initial and following echocardiographic parameters of the patients with and without significant LA enlargement 20
1.3 Receiver operating characteristic curves of significant LA enlargement and the duration of RV pacing (years) 21
1.4 Incidence of significant LA enlargement and the change in LA diameter during the follow-up period in patients with RV pacing duration of < 3.3 years and ≥ 3.3 years 22
1.5 Univariate and multivariate logistic regression analyses of the predictors of significant LA enlargement post RV pacing 22
1.6 Clinical outcomes of the patients with and without significant LA enlargement 23
1.7 Comparison between the clinical outcomes of patients with and without significant LA enlargement after propensity score matching 23
2 Results of the CAVB animal model 24
2.1 Change in LA area, volume, and performance 24
2.2 Comparative analysis of weight of heart and indexed weight of heart according to BMI 25
2.3 Atrial fibrosis developed in the LA myocardium following pacing 25
2.4 Increased expression of fibrotic and apoptosis markers in the LA myocardium following pacing 26
2.5 Functional enrichment analysis: down regulation of the Sirtuin signaling pathway in the lateral wall of LA myocardium following 6 months of RV pacing compared with that in the sham control 27
2.6 Comparison of the expression levels of the fifteen differentially expressed genes in the sirtuin signaling pathway among the three groups 28
2.7 Quantitative measurement of RNAs using real-time PCR for the fifteen differentially expressed genes in the sirtuin signaling pathway among the three groups 29
2.8 Expression levels of sirtuin subtypes (SIRT1-7) in control and GADD45G knockdown HL-1 cells 30
2.9 Decreased expression of SIRT1 and GADD45G protein in the LA myocardium after pacing 30
3 Stretching increases the TGF-β levels and decreases the SIRT-1 levels, whereas resveratrol reverses TGF-β expression 31
3.1 Effects of mechanical stretch on the SIRT1, TGF-β, and Collagen I expression levels in the HL-1 cells over time 31
3.2 Resveratrol mitigates the changes in the SIRT1, TGF-β, and Collagen I expression levels in the HL-1 cells induced by mechanical stretch 32
Chapter 5. Discussion 33
1 Increased incidence of stroke is associated with long-term RV pacing-induced LA enlargement and significant MR 33
2 Possible mechanisms of LA structural fibrosis and enlargement induced by RV pacing 33
3 The role of LA enlargement in cardiovascular risk and its assessment 34
4 Post-implant impaired LV performance and development of mitral regurgitation after RV-dependent pacing 35
5 The role of SIRT1 and GADD45G in LA fibrosis and enlargement 35
6 The Role of SIRT1 in Fibrosis 36
7 Managing Long-Term Stroke Risk After RV Pacing-Related interventricular Dyssynchrony 37
Chapter 6. Conclusion 40
Reference 41
Tables 50
Figures 62
                                    

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