臺灣博碩士論文加值系統

隨著社會人口年齡結構老化，心血管疾病日益增加，心肌梗塞與心臟衰竭是心臟科急診與門診住院常見的二種疾病。心衰竭是公共衛生的一大挑戰，治療心衰竭耗費龐大的醫療資源，因為心衰竭造成的社會經濟生產力損失亦極為可觀。因為心肌缺氧梗塞與不同原因造成之心肌損傷心臟功能異常，身體會啟動種種的代償系統企圖補償之；心室的心肌細胞及間質組織也會不斷地因為各種不同的分子機轉進行代償作用(適應過程)，即心室重塑作用。當心室功能不足以達到身體的需要或代償作用過度活化時，心衰竭隨之而來。近年來我們對心室重塑作用的分子機轉，心衰竭的致病機轉及治療不斷地在擴展與進步。在前者近年來學者認為心肌細胞的計劃性死亡可能是心室重塑過程的重要因子之一，因為它會造成有收縮功能的組織減少、心肌細胞代償性肥大及心肌修復性纖維化。在後者我們目前對心肌梗塞及心衰竭的治療已能提供多種早期有效的治療方式及選擇，但是心衰竭仍是一極為棘手的普遍問題；在現有的藥物、非藥物、電氣、器械、手術治療選擇之外，醫學界仍盼望更新有效而實際的治療方式，近年來研究不同生長因子在心臟疾病的變化及應用不同生長因子治療心血管疾病的努力不斷。本論文即在探討第一型類胰島素生長因子在急性心肌梗塞時之變化及其與左心室重塑作用及患者臨床預後之相關性，和應用第一型類胰島素生長因子治療動物擴大性心肌病變心衰竭與探索其對心肌細胞計劃性死亡之影響及此種影響與心臟解剖及功能的相關性。在第一章中我首先回顧心衰竭的流行病學、致病機轉及代償作用，並探討心肌重塑作用發生的分子機轉及在細胞階層、心臟解剖結構及心室功能造成之影響。在本章中我也說明了心肌細胞的特殊死亡方式 - 細胞計劃性死亡，其變化特色、分子機轉、辨認方法，發生心肌細胞計劃性死亡的臨床心臟疾病種類及發生機轉。我亦詳細探討了心肌細胞計劃性死亡如何參與心室重塑作用的機轉。第二章則仔細回溯了目前我們對第一型類胰島素生長因子及其結合蛋白的認識，並說明第一型類胰島素生長因子在心肌細胞之多重細胞信號傳導路徑及分子作用機轉。我也探討了第一型類胰島素生長因子在心臟血管組織的正常生理作用及不同心血管疾病狀況下此生長因子表現及控制之改變。在第本章中我也回顧第一型類胰島素生長因子與各種不同心臟疾病及心室重塑作用關係之研究並發掘應用第一型類胰島素生長因子治療心肌損傷及心臟衰竭之研究。第三章則呈現作者研究人類急性心肌梗塞後第一型類胰島素生長因子系統之變化及其與左心室早期重塑作用之關係，我發現急性心肌梗塞後第一型類胰島素生長因子參與了早期的心室重塑過程並可能決定患者的臨床預後。血清第一型類胰島素生長因子愈低則重塑作用愈大而預後愈差。第四章則是作者應用第一型類胰島素生長因子治療動物因慢性心室快速電刺激引發心肌病變心衰竭的研究結果。第一型類胰島素生長因子可有效部份回復心衰竭之血流力學異常，降低體循環阻力及抑制心肌細胞計劃性死亡。心肌細胞計劃性死亡與心臟結構及功能有直接而明顯之因果關係。
結論：第一型類胰島素生長因子在急性心肌梗塞及心肌病變心衰竭之心室重塑作用佔有重要角色，未來可能可應用此生長因子治療人類急性心肌梗塞及心肌病變心衰竭，改善心室重塑作用，回復心臟功能，甚至延長患者壽命，這些有待未來繼續研究証實之。

As life expectancy of the general population increases and the structure of population hierarchy ages, the incidence and prevalence of cardiovascular diseases increase concomitantly. Acute myocardial infarction and congestive heart failure are two commonly seen diseases in cardiology practices. Congestive heart failure, the end stage of many cardiac diseases, becomes a significant public health issue. The resources required to take care of heart failure represent a major burden for our health care system and the loss of productivity resulting from heart failure is significant.
When myocardial function fails to function properly after myocardial injuries, multiple compensatory systems in the body are activated. In the meantime, cardiac myocytes and interstitial tissue continuously undergo adaptive processes, the so-called ventricular remodeling, to maintain its pumping function. When the cardiac function could not meet the body need or the compensatory systems were over-activated, heart failure appears. In recent years our knowledge of the molecular and cellular mechanisms of ventricular remodeling and treatment of congestive heart failure have been expanded. A new paradigm during the development of heart failure was recently identified and programmed cell death (apoptosis) of cardiomyocytes is considered one of the major factors contributing to ventricular remodeling. This is because loss of cardiomyocytes leads to loss of cardiac contractile tissue, compensatory hypertrophy of cardiac myocytes, and subsequent fibrosis of cardiac tissue. Congestive heart failure and myocardial infarction are the two major public health issues in cardiology awaiting to be conquered. Despite the recent advancements of various pharmacological and interventional treatments, current therapeutic modalities are quite limited. Among the new strategies, growth factors have been proposed as potential agents that may be used to treat various heart diseases.
In this thesis, I address the role of one recently reappraised growth factor, insulin-like growth factor I (IGF I), in cardiac remodeling of two commonly seen cardiac disorders, acute myocardial infarction and cardiomyopathic congestive heart failure. First, I reviewed the epidemiology, pathogenesis and compensatory mechanisms of congestive heart failure in Chapter 1. In this chapter we also explored the molecular mechanisms of cardiac remodeling and the results and consequences of ventricular remodeling on cardiac myocyte, interstitial tissue, cardiac anatomical structure and ventricular performance. Chapter 1 also illustrates a pathognomonic way of cardiomyocyte cell loss: programmed cell loss, its characteristic membranous, nuclear and cytoplasmic alterations, molecular mechanisms and ways of identification. I reviewed the cardiac diseases in which programmed cell deaths of cardiomyocytes occurred and the possible mechanisms. I also looked at how apoptosis of cardiac myocytes participated in the ventricular remodeling. In Chapter 2 I went over the current understandings of IGF I and IGF binding proteins, and scrutinized the multiple intracellular signaling pathways and molecular mechanisms of IGF I actions. I also looked into the normal physiological actions of IGF I in cardiovascular cell cultures and tissues, and altered expression and control of IGF I in different cardiovascular diseases. In this chapter I also probed the relationships between IGF I expression, cardiovascular disorders and ventricular remodelings. Moreover, I examined all the published works studying the effects of IGF I on cardiac diseases. I presented the results of my study on the changes of serum IGF I and its relationship to left ventricular remodeling and patient clinical outcome in human acute myocardial infarction in Chapter 3. I discovered that IGF I took part in the ventricular remodeling early after acute myocardial infarction and potentially thereby influenced later clinical outcome. The lower the serum level of IGF I was after acute myocardial infarction, the worse the patient outcome became. Chapter 4 presents the results of my other another study exploring the therapeutic effects of IGF I in pacing-induced congestive heart failure. IGF I effectively restored the ventricular hemodynamic function, normalized elevation of systemic vascular resistance and suppressed apoptosis of cardiac myocyte in heart failure. There was statistically significant relationship between the extent of cardiomyocyte apoptosis and cardiac structure and function.
In conclusion, IGF I plays an important role in the ventricular remodeling of both human acute myocardial infarction and canine dilated cardiomyopathy. IGF I remains a possible candidate to be used as a therapeutic agent in human acute myocardial infarction and dilated cardiomyopathy with heart failure. The effect of IGF I may be mediated through improving ventricular remodeling and hemodynamic alteration, thus recovering cardiac function and extending subject life span. The results of my studies provide a strong argument for the potential therapeutic value of IGF I in human heart failure.

封面
目錄
中文摘要
英文摘要
中英文對照表
第一章 心臟衰竭，心室重塑作用與心肌戀胞計劃性死亡
心臟衰竭行病學
心臟衰竭的代償機轉
心室重塑作用
心肌細胞計劃性死亡
第二章 第一型類胰島素生長因子
第一型類胰島素生長因子系統與心臟血管疾病之關係
第一型類胰島素生長因子與心室重塑作用關係
第三章 人類急性心肌梗塞後第一型類胰島素生長因子系統之變化及其與左心室重塑過程之關係
第四章 應用第一型類胰島素生長因子治療狗快速心室電剌激心肌病變心衰竭
第五章 結論
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