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研究生:何奕倫
研究生(外文):Ho Yi-Lwun
論文名稱:心臟衰竭時心肌功能之改變-從臨床影像檢查到動物模式之建立
論文名稱(外文):Myocardial Functional Changes in Heart Failure- From Clinical Image Studies to Animal Model
指導教授:黃博昭黃博昭引用關係謝豐舟謝豐舟引用關係
指導教授(外文):Huang Por-JauHsieh Fong-Jou
學位類別:博士
校院名稱:國立臺灣大學
系所名稱:臨床醫學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2003
畢業學年度:92
語文別:中文
論文頁數:104
中文關鍵詞:心臟衰竭心電圖壓力超音波鉈201心肌灌流掃描加成性超音波逆行散射細胞凋亡換心人斑馬魚
外文關鍵詞:Heart faliureelectrocardiogramstress echocardiographythallium-201 scintigraphycyclic variation of integrated backscatterapoptosisheart transplantationzebrafish
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心肌受損到心肌衰竭時的心臟變化是目前心臟醫學上最重要的課題。冠狀動脈缺血是造成心肌受損的最主要的原因;另一個重要的原因則為擴張性心肌病變。早期研究顯示,冠狀動脈血流受完全阻斷時,會導致心肌收縮功能的停止;並造成心肌細胞受損與心肌壞死。隨著血管重建治療 (revascularization) 的觀念發展,越來越多的資料顯示局部心肌收縮異常常在血管打通之後是可以回復的。在1978 年「冬眠性心肌」被提出來解釋心臟在血流減少後肌肉收縮異常的狀態可以被血管重建治療來復原。冬眠性心肌的診斷,對於冠狀動脈病病患的治療具有重要的意義;左心室功能異常如能藉由血管重建治療而恢復,則病人的預後可以大為改善。因此診斷冬眠性心肌的非侵襲性臨床影像檢查對心臟內外科醫師在決定病人治療計劃時,扮演了重要的角色。從上述冬眠性心肌的機轉得知,可以用下列的方式來診斷冬眠性心肌:第一、證明血液灌流與收縮狀態的吻合 (血液灌流減少的情況下,收縮功能也跟著降低);第二、證明血液灌流與代謝狀態的不吻合 (血液灌流減少的情況下,葡萄醣代謝率增加) ;第三、證明收縮功能改善的代價是心肌細胞代謝的惡化。目前臨床上較常被使用的方式有:一、多保它命壓力超音波 [dobutamine stress echocardiography]、二、超音波加成性逆行散射的週期性變化 [cyclic variation of integrated backscatter]、三、鉈-201心肌灌流掃描 [thallium-201 perfusion scintigraphy] 等。
在心電圖上有Q波心肌梗塞的導極,當增加心臟負荷時(如跑步或多保它命灌注時),常會有ST節段升高或T波偽正常化。這種心電圖的變化與殘存的心肌缺血、心室瘤形成、或冬眠性心肌有關;但是也有報告指出這種心電圖的變化只是與左心室收縮功能異常有關。因此心電圖上有Q波心肌梗塞的導極,當增加心臟負荷時(如跑步或多保它命灌注時), ST節段升高或T波偽正常化與冬眠性心肌之相關,仍為心臟學上有爭論的的一部份。本論文研究的重點之一:在多保它命灌注時,有Q波心肌梗塞的導極如發生ST節段升高或T波偽正常化時;與心肌存活度是否有相關? 一共有119位 (108位男性及11位女性,平均年齡59±12歲) Q波心肌梗塞病患接受多保它命壓力超音波及鉈-201心肌灌流檢查。第一組有58位病患有ST節段升高或T波偽正常化,第二組有61位病患無此變化。第一組與第二組的左心室射出分量則有明顯差異(第一組43±13%,第二組49±14%)。在未給予多保它命、給予低劑量及高劑量多保它命下兩組的整體心肌收縮狀態並無明顯分數上的差異。給予多保它命下引起ST節段升高及T波偽正常化來預測心肌缺血之敏感度、專一度、及準確度分別為47%, 48%,與47%(無統計學上差異)。給予多保它命下引起ST節段升高及T波偽正常化來預測心肌存活之敏感度、專一度、及準確度分別為50%, 53%,與 51% (無統計學上差異)。給予多保它命下引起ST節段升高及T波偽正常化與鉈-201可逆式灌流缺損無明顯之相關。本研究的研究結果支持這些心電圖的變化代表的是心臟扭轉變形及收縮功能降低所致,與存活或缺血的心肌組織無關。這些心電圖變化不能用來作為心臟血管重建決策之可靠參考。
細胞凋亡在擴張性心肌病變扮演的角色與缺血性心肌病變較不相同,細胞凋亡與擴張性心肌病變並未如細胞凋亡與缺血性心肌病變一樣,達到學界的共識。有論文指出,擴張性心肌病變患者使用多保它命時,如有局部左心室收縮功能改善時;代表這些部位仍有存活的組織,因此預後會較佳。本論文研究重點之二:分析末期擴張性心肌病變患者之心肌存活度時,特別著重在心肌細胞凋亡現象與細胞凋亡相關蛋白(bax, bcl2, p53)的表現,並分析這些變化與多保它命灌注後左心室局部改善之相關。一共有6位擴張性心肌病變病患共81塊擴張性心肌病左心室供多保它命超音波比較及細胞凋亡之研究,另有5位對照組病患。細胞凋亡蛋白(bcl2,bax and p53)以免疫組織化學呈色偵測,在組織上偵測細胞凋亡是用TUNEL法。一共有26塊左心室(32%)在低劑量多保它命給予下,出現左心室收縮改善的狀態。與對照組相較,bcl2大於第二級免疫化學組織呈色的左心室數目明顯增加(68%相對於0%,p=0.005)。與對照組相較,bax大於第二級免疫化學組織呈色的左心室數目明顯增加(70%相對於0%,p=0.003)。在研究組與對照組的檢體中,p53均未被發現。在81塊左心室中,TUNEL染色法呈現的細胞凋亡百分比為0.73% (296/40500)。在擴張性心肌病變患者左心室bax與bcl2蛋白的分布具有一致性。bcl2蛋白的免疫化學組織呈色與多保它命灌流下心肌收縮狀態改善有統計學上明顯之負相關 [第零級 (3/3); 第一級 (11/23); 第二級 (5/25); 第三級 (7/30); p <0.01]。然而bax蛋白的免疫化學組織呈色與多保它命灌流下心肌收縮狀態改善無統計學上明顯之相關。
有許多的文獻報告末期心肌衰竭患者接受心臟移植後,植入心臟會產生心肌肥厚的變化。這些變化會導致心肌細胞硬化、舒張功能異常、與收縮功能異常;這些心肌肥厚變化也與因環孢靈(cyclosporin)使用後引起高血壓無關。另一方面,近來在基因轉殖鼠的動物實驗中,活化T細胞所產生的第三細胞核因子(nuclear factor of activated T lymphocyte, NFAT-3)被發現與心臟肥厚有明顯的相關。在有calcineurin存在的情況下, calcineurin 可將活化T細胞所產生的第三細胞核因子去磷酸化,然後這去磷酸化的T細胞第三細胞核因子可以進入細胞核;在與GATA4結合後, 可以啟動心肌肥厚基因而產生一系列心臟肥大的現象。動物實驗指出如抑制 calcineurin的作用,可以減少心肌肥厚的發生;最常被使用的calcineurin抑制劑為環孢靈。本論文研究重點之三:末期心肌衰竭患者接受心臟移植後,植入心臟是否會產生心肌肥厚的變化? 而這些心肌肥厚的變化是否能用非侵襲性臨床影像檢查分析? 病人術後抑制排斥的環孢靈劑量是否與心肌肥厚之抑制有關? 一共有32位 (27位男性與5位女性) 接受心臟移植病患接受檢查,換心後無排斥現象或排斥等級為≦IA級的病人才被納入本次研究之中。所有的病人在接受加成性超音波逆行散射的檢查後,接著作多保它命超音波及鉈-201心肌灌流掃描檢查。血清生化檢查、環孢靈血中濃度、心導管檢查、及心肌切片都在二週內進行。另有十五位冠狀動脈血管攝影正常的病人接受加成性超音波逆行散射的檢查,作為加成性超音波逆行散射對照組。一位病患的冠狀動脈攝影呈現瀰漫性冠狀動脈狹窄,他的多保它命超音波、鉈-201心肌灌流掃描檢查、及加成性超音波逆行散射均呈現異常。其他31位冠狀動脈攝影均呈正常,這些病患中,有3位多保它命超音波呈現異常、19位加成性超音波逆行散射呈現異常、16位鉈-201心肌灌流掃描檢查呈現異常。共有25位病患有異常病理學檢查:14位病患有心肌細胞肥大、18位病患有間質纖維原沉積。在所有96塊換心人(32位病患)的心肌中,有63塊(第一組)加成性超音波逆行散射結果為正常(在正常對照組的平均值±2標準差以內);另外33塊(第二組) 加成性超音波逆行散射結果為異常(波幅、相差、或波幅進行相差的加權計算結果在正常對照組的平均值±2標準差以外)。鉈-201心肌灌流掃描檢查異常的比例在第二組明顯增加(第一組為21%,第二組為52%;p = 0.004)。有86%病理檢查正常的病患其加成性超音波逆行散射呈正常,而只有24%病理檢查異常的病患其加成性超音波逆行散射呈正常(p = 0.01)。在32位的換心人中,有20位的病患其加成性超音波逆行散射至少在受檢三塊心肌中有一塊心肌數值為異常(A組);有12位的病患其加成性超音波逆行散射在受檢三塊心肌中數值均為正常(B組)。多變項回歸分析發現異常加成性超音波逆行散射與血中環孢靈濃度呈明顯負相關(p = 0.028)。但本研究中發現,病人的心肌細胞肥厚有無與環孢靈血清濃度無關。
近來斑馬魚 (Danio rerio)已漸漸成為心臟研究者喜愛的工具。它是體外授精並且產生下一代的數量多及胚胎發育快速(胚胎從單一細胞發育成完整幼魚祇要三天便可觀察)。斑馬魚的胚胎全身是透明的,這讓研究者在基因轉殖後很容易的觀察魚心臟變化並且不需要犧牲動物以觀察心臟。斑馬魚的心臟雖然只有一心房及一心室;但它的功能與高等脊椎動物的二心房二心室心臟近似。斑馬魚的胚胎在無心臟循環系統下仍可生存數日,這方便研究者充分觀察基因轉殖後造成的心臟變化,而不致因心臟衰竭死亡影響觀察。另一方面已有非常多的突變基因導致心臟異常功能的模式魚,這讓轉殖基因的基因庫有非常充沛的資源可供比對。 斑馬魚的心臟突變基因造成的外在表現,最主要是造成心臟擴大或是心肌肥厚,這些變化提供了研究人類心臟衰竭與心律不整的資料。
利用斑馬魚心臟肌肉細胞中的 CMLC-2 (cardiac myosin light chain-2) 基因的調控區域當作心臟專一導子,加上一段綠螢光(GFP)基因當作轉殖判讀的標記,組合成pICMLE(-870/787)。這包含CMLC-2上游-870/+1、exon1 、intron 1與部分exon2。我們已成功地將綠螢光在心臟肌肉專一的表現。綠螢光基因在老鼠身上曾被報告無明顯不良作用,但綠螢光基因過量在老鼠心臟表現曾被報告造成老鼠心臟功能的惡化。這些心臟功能惡化包括:心臟擴大、收縮功能異常、及心肌肥厚。因此綠螢光蛋白在斑馬魚身上是否為一安全生物標記,成為本研究之重點之一。本動物實驗之研究重點另外針對甫孵化的幼魚及成魚,嘗試研發出一種可行的斑馬魚心臟功能評估工具?心肌細胞蛋白改變後心臟功能及心臟節律的變化又如何?簡述如下:
研發可行的斑馬魚心臟功能評估工具:共有20條斑馬魚作為研究之用,平均年齡為3-4個月大;平均體重及身長分別為562 ±173 毫克及4.6 ±0.7 公分。所有的魚均以2-phenoxyethanol作為麻醉劑 (100%, 每公升1微克)。水溫維持在室溫然後逐漸降至15℃。斑馬魚腹部朝上被置放在一個鋸齒狀橡膠板上,然後放入水中。超音波探頭(型號15L8)以一個機器手臂固定住,並直接靠近魚體。 超音波採用臨床心臟超音波機器(機型Acuson Sequoia);彩色杜卜勒及動量超音波血管攝影(power angiography)的頻率為8.5 及7.0百萬赫茲。心房到心室的血流包含兩個部分:早期舒張血流與晚期舒張血流。在25 and 15℃下,早期舒張血流均小於晚期舒張血流。在15℃時,心跳速度與心房流至心室的血流速度均降低。早期舒張血流的加速斜率明顯在15℃時變小,早期舒張血流的加速時間與晚期舒張血流的加速時間也明顯延長。不管是早期舒張或晚期舒張血流,加速與減速的杜卜勒面積比也明顯異常。因此本研究方式是一個可行的非侵襲性斑馬魚心臟超音波研究工具。
綠螢光蛋白在斑馬魚身上是否為一安全生物標記:在心臟專一導子cmlc-2引導下,綠螢光的表現在某些品系特別明亮。一共培養出兩種不同亮度的綠螢光心臟專一表現的斑馬魚(A26與A277);A277這個品系的心臟綠螢光亮度為A26這個品系的1.7倍。經過分析,不同亮度的綠螢光斑馬魚心臟表現,從心室收縮長、短徑、心室舒張長、短徑、心跳速率、心室射出分量都沒有差異。因此在這樣品系的斑馬魚中,可以以這樣的基因轉殖模式進行心臟功能改變的研究。
cTnC抑制表現後心臟的變化:在基因轉殖魚胚胎發育到12小時,添加入四環黴素衍生物 doxycycline。cTnC抑制表現後斑馬魚心臟心房、心室大小發生改變,在收縮及舒張末期的心室短徑都發生漲大的現象,心室射出分量也從48%降至25%。在孵化後第八天,明顯觀察到心跳變慢且不規則,這些心律不整有三種模式:第一種、心跳減緩 (平均每分鐘191次,相對於對照組每分鐘220次)。第二種、心室內傳導變慢,心尖部收縮後,心室側壁收縮延緩,整個心室收縮完成時間延長。第三種、心房心室傳導阻斷,心房收縮與心室收縮不相關,且心房速度快過心室速度。第一種心律不整對應至人體的竇房結(sino-atrial node)異常、第二種心律不整對應至人體的心室內傳導變慢(intra-ventricular conduction delay)、左束枝導阻滯 (left bundle branch block)或右束枝傳導阻滯 (right bundle branch block)、第三種心律不整對應至人體的房室傳導阻斷。從本研究發現cTnC抑制表現後,心房與心室心律不整均出現,因此推論在斑馬魚電氣傳導的過程中,鈣離子流扮演了一個角色。
心臟疾病是台灣居民住院及死亡的重要原因。心臟衰竭與心律不整又是心臟疾病中住院與死亡的最常見原因。但是臨床上對於重度心臟衰竭的預防與治療迄今並未有明顯的突破,換心治療卻又常苦無器官捐贈者。幸而分子生物學與基因轉殖的技術近來日益成熟。希望藉由這些研究開啟本土性心臟衰竭研究的新頁。

It has been known that total ischemia leads to a prompt cessation of contraction and eventually results in the appearance of cell damage and irreversible myocardial necrosis. Accordingly, in the mind of many cardiologists the discovery of an abnormal regional contraction in patients with coronary artery disease (CAD) has long been equated with the irreversible myocardial necrosis. With the advent of recanalization therapy, however, evidence progressively accumulated that prolonged regional ischemic dysfunction did not always arise from irreversible tissue damage and, to some extent, could be reversed by restoration of blood flow. The term ”hibernation” was first used by Diamond et al in 1978 to describe the chronic wall motion abnormalities of patients with CAD but no previous myocardial infarction and their reversibility after revascularization, and it was subsequently popularized by Rahimtoola and Braunwald and Rutherfold. The definition of hibernating myocardium, as formulated by Rahimtoola, thus implies that: (1) the heart can spontaneously adapt to chronic underperfusion (the “smart hear” hypothesis), (2) a new steady state between perfusion and contraction can be reached, and (3) this new equilibrium can be maintained for a long period of time.Clinical syndromes consistent with the existence of myocardial hibernation include unstable and stable angina, acute myocardial infarction, and left ventricular dysfunction and/or congestive heart failure.
The concept of chronic hibernation bears important implication for the management of patients with CAD. Identifying areas of myocardium with depressed but potentially reversible contractile function helps to formulate the therapeutic strategy and to predict the prognosis of patients with CAD and chronic left ventricular dysfunction. Consequently, the non-invasive assessment of dyssynergy but viable myocardium, which may contribute to the overall improvement in the left ventricular function after revasculariztion, has generated great interest among cardiologist and cardiac surgeon. There are several aspects to evaluate the hibernating myocardium: (1) demonstration of a perfusion-contraction matching (i.e. decreased contraction in the face of decreased perfusion), (2) demonstration of a perfusion-metabolism mismatch (i.e. increased glycolytic metabolism in the face of decreased perfusion), (3) demonstration of an inotropic reserve at the expense of worsening of myocardial metabolism. Among the techniques used for this purpose, dobutamine stress echocardiography (DSE), cyclic variation of integrated backscatter (CVIBS), and thallium-201 scintigraphy (using stress-redistribution-reinjection protocols) have been shown to be useful methods.
The clinical significance of stress-induced ST-segment elevation and T-wave pseudonormalization in infarct-related leads is still controversial. The possible mechanisms include ventricular asynergy, residual myocardial ischemia, and contractile reserve within infarct area. Since residual myocardial ischemia and viability within the infarct area is important for cardiologists to formulate the strategy of coronary intervention, the significance of these electrocardiographic changes need to be further validated. DSE and thallium-201 single-photon emission computed tomography (SPECT) are sensitive and specific in myocardial ischemia and viability detection. Both examinations also provide complementary information in the assessment of myocardial viability. However, there have been few reports about assessment of these electrocardiographic changes using simultaneous DSE and stress radionuclide imaging. The present study was designed to evaluate the functional significance of dobutamine-induced ST elevation and/or T pseudonormalization in patients with previous Q-wave myocardial infarction (MI) by simultaneous DSE and thallium-201 SPECT. A total of 119 patients with Q wave myocardial infarction were enrolled in this study. There were 58 patients with dobutamine-induced ST-T changes (group I) and 61 patients without (group II). The left ventricular ejection fraction was 43±13% in group I and 49±14% in group II (p<0.05). The baseline, low-dose and peak-dose global wall motion scores were similar between these 2 groups (26.2±6.1 vs 26.2±6.3 [p= non-significant];24.1±5.3 vs 23.5±5.7 [p = non-significant]; 26.4±5.7 vs 26.7±6.1 [p = non-significant]). The sensitivity, specificity, and accuracy of these ST-T changes for detecting residual myocardial viability and ischemia documented by DSE in total patients were 50%, 53%, and 51% (for viability); 47%, 48%, and 47% (for ischemia). The sensitivity, specificity, and accuracy of these ST-T changes for detecting reversible perfusion defect documented by thallium-201 SPECT were 51%, 54% and 52%, respectively. In conclusion, dobutamine-induced ST elevation and/or T-wave pseudonormalization is associated with poor resting left ventricular function. These ST-T changes are not associated with residual myocardial ischemia and viability in infarct area. Therefore, these electrocardiographic changes alone cannot be reliably considered as distinctive markers in the formulation of the therapeutic strategy of coronary intervention.
Apoptosis has been reported to be one of the possible mechanisms for the hemodynamic deterioration of congestive heart failure. There have been several studies exploring the existence of apoptosis in patients with heart failure. Although available data supports the above findings, studies about the relation between myocardial functional reserve and apoptosis-related proteins (bcl-2, bax, and p53) are lacking. Changes in left ventricular systolic performance during low dose dobutamine infusion are useful markers to predict the recovery of systolic function in patients with dilated cardiomyopathy (DCM). Therefore, we conducted this prospective study to evaluate the apoptosis-related proteins (bcl-2, bax, and p53) and apoptosis in myocardium of patients with DCM and to correlate these proteins with the dobutamine-induced myocardial contractile reserve. A total of 81 segments of left ventricles (from 6 patients with DCM) were collected in this study. Another 5 patients who had died of non-cardiac causes were used as the control group. Apoptosis related proteins (bax, bcl-2, and p53) and apoptosis were evaluated in these segments by immunocytochemical stain and terminal deoxynucleotidyl transferase-mediated DNA nick end-labeling assay (TUNEL). There were 26 segments with dobutamine-induced contractile reserve. There were significant differences in numbers of segments with over-expression of bcl-2 and bax in the study and control groups. However, p53 was not found in either group. The total TUNEL-positive nuclei in explanted hearts of DCM were 0.73%. The myocardial contractile reserve was inversely associated with an over-expression of bcl-2 (p<0.01) rather than bax. In conclusions, the expression of bax and bcl-2 proteins in patients with DCM is enhanced and independent of p53. Loss of contractile reserve is associated with over-expression of bcl-2 protein in failing myocardium.
Several studies have reported that cardiac allografts undergo some cardiomyocyte hypertrophy after heart transplantation. These histological alterations may contribute to the functional changes of the transplanted hearts, particularly myocardial stiffness, diastolic dysfunction, and, to a certain extent, systolic dysfunction. On the other hand, interstitial fibrin deposition in biopsies of transplanted hearts has been reported to identify patients at high risk for developing coronary artery disease or graft failure. Therefore, noninvasive detection of these myocardial changes has clinical significance. Ultrasonic tissue characterization with integrated backscatter (IBS) mode has been used to detect acute cardiac allograft rejection, myocardial ischemia and viability. The changes in IBS are caused by variations in myocardial collagen or water content, myofibril orientation relative to the incident ultrasound beam and myocardial contractile performance. Therefore, we hypothesized that IBS could assess cardiomyocyte hypertrophy and interstitial fibrin deposition in heart transplant recipients without evident acute myocardial rejection. The aims of this study were: (1) to evaluate the IBS of heart transplant recipients without or with minimal acute myocardial rejection (International Society of Heart and Lung Transplantation grade 0 or IA); (2) to compare the results of IBS with those of simultaneous DSE and thallium-201 perfusion imaging; and (3) to compare the results of IBS with pathology of endomyocardial biopsy. A total of 32 heart transplant recipients with either no or mild acute rejection (International Society of Heart and Lung Transplantation grade IA) were enrolled in this study. IBS data of myocardium were collected immediately prior to simultaneous DSE and thallium-201 imaging. Coronary angiography and endomyocardial biopsy were also performed. Coronary angiography showed diffuse narrowing in 1 patient who also had abnormal results of IBS, DSE and thallium results. In the other 31 patients with patent coronary arteries, there were 3 patients (10%) with abnormal DSE results, 19 patients (61%) with abnormal IBS patterns and 16 patients (52%) with reversible thallium perfusion defects. There were 44% patients with cardiomyocyte hypertrophy and 56% with interstitial fibrin deposition. There were significant differences in the prevalence of thallium-201 perfusion defects and serum cyclosporine levels between patients with and without abnormal IBS patterns. Pathological changes were also associated with abnormal IBS patterns (p = 0.01). However, there was no association between abnormal IBS and DSE results. By multiple logistic regression analysis, the abnormal IBS patterns were associated inversely with serum cyclosporine level (p = 0.028). In conclusion, abnormal IBS patterns are associated significantly with perfusion heterogeneity and pathological changes in heart transplant recipients without evident acute myocardial rejection. There is no association between abnormal IBS patterns and dobutamine-induced dyssynergy in these patients. IBS provides a noninvasive approach for detection of myocardial changes in transplanted hearts without evident acute rejection.
The zebrafish (Danio rerio) is a new animal model for cardiac researches. The zebrafish heart contains 4 components (sinus venosus, atrium, ventricle and bulbus arteriosus). Although it has a prototypic vertebrate heart, the studies of genetic control for zebrafish development can reveal some hints to solve human problems. On the other hand, the zebrafish mutations which principally disturb cardiac contractility fall into two broad phenotypic categories, 'dilated' and 'hypertrophic'. These correspond to the two primary types of heart failure in humans. The disorders of cardiac function provided candidate genes to be examined in complex human heart diseases, including arrhythmias and heart failure). Despite the simplicity of zebrafish heart, the objective parameters of cardiac performance are not easily available except morphological description. A lack of functional evaluation by either echocardiography or pressure tracing makes the diagnosis of heart failure phenotype in zebrafish less convincing than that in human.
As the zebrafish reached maturity (3 months post-fertilization), its atrial wall increased to 2 to 3 cells layers and the ventricle wall increased to 4 cells layers. The ventricle-to-body ratio decreased to 0.02 in adult fishes. The body length of adult zebrafish is around 5 cm. Therefore, the size of the ventricle is around 1.0 mm. These factors make the pressure tracing and two-dimension echocardiography for zebrafish hearts not easily feasible. Power Doppler imaging has become a popular ultrasonic angiography due to its high sensitivity. The frequency spectrum analysis also provides useful information about flow disturbance. Since the 4 components of a zebrafish heart are connected in series, we hypothesized that ultrasonic imaging methods for vascular system analysis could be used for the study of zebrafish hearts. The routine Doppler echocardiography, power angiography and the frequency spectrum analysis were used to evaluate the cardiac performance of the zebrafish by a clinical instrument. A total of 20 fishes that aged 3-4 months were studied. Their mean body weight and height were 562 ±173 mg and 4.6 ±0.7 cm, respectively. Power angiography and routine Doppler echocardiography were used to evaluate the cardiac performance of zebrafish at 25℃ and 15℃. The zebrafish hearts could be easily identified with color-Doppler (8.5 MHz) or power angiography (7 MHz). The ventricular filling flow contained 2 components (E and A-flow). The E-flow velocities were lower than the A-flow velocities at both 25 and 15℃. The cycle length was prolonged (p<0.05) and the velocities of ventricular filling and bulbus arteriosus decreased significantly at 15℃ (p<0.05). Significant decrease in early diastolic acceleration slope and significant prolongation in early-diastolic and late-diastolic acceleration times were found at a lower temperature (15℃). The acceleration/deceleration ratio for early and late diastole also showed significant difference at 15℃. In conclusion, the cardiac performance of the zebrafish could be approached using commercially available clinical instruments equipped with Doppler echocardiography and power angiography.
Green fluorescent protein (GFP) has been reported to cause dilated cardiomyopathy in mice. We tested the possible cardiac toxicity of GFP in zebrafish. Two lines with different GFP expression were breed (A26 and A277). The luminance of A277 was higher than A26 (1.7 folds). The short and long diameters of ventricle, ejection fraction and heart rates were all similar between these two groups. Under such luminance of GFP, the cardiac toxicity can be excluded.
We added doxycycline to cardiac troponin C (cTnC) anti-sense zebrafish 12 hours post fertilization. T cTnC anti-sense zebrafish showed dilated atrium, ventricle and impaired contractility. The ejection fraction decreased from 48% to 25%. Arrhythmia was observed 8 days post fertilization. There were 3 types of arrhythmia:The first type was bradycardia without affecting ventricular contractility. The second type was intra-ventricular conduction delay. The third type was complete atrio-ventricular block. Calcium channel may play a role in electric conduction in zebrafish.
Cardiac diseases are the main cause of death in Taiwan. We hope we can open a new window for basic research of heart failure in Taiwan.

目錄項目 頁次
中文摘要 7
緒論 12
冬眠性心肌的診斷 13
多保它命壓力超音波 13
超音波加成性逆行散射的週期性變化 14
鉈-201同位素心肌灌流造影 15
心電圖變化與冬眠心肌之相關 16
冬眠性心肌的構造變化 17
細胞凋亡在冬眠性心肌扮演的角色 17
細胞凋亡在擴張性心肌病變的角色 18
末期心肌衰竭患者接受心臟移植後,植入心臟之變化 19
利用斑馬魚建立心臟衰竭的動物模式 19
斑馬魚基因轉殖技術 20
研究方法與材料 22
第一部份 22
研究對象 22
多保它命灌注方式 22
心電圖分析 22
心臟超音波的執行與判讀 23
多保它命鉈-201心肌灌流掃描 23
冠狀動脈攝影及左心室射出分量 24
統計方法 24
第二部份 24
研究對象 24
多保它命心臟超音波的執行與判讀 24
細胞凋亡蛋白的免疫組織化學呈色偵測 25
組織切片上偵測細胞凋亡 26
統計方法 26
第三部份 26
研究對象 26
加成性超音波逆行散射檢查 27
加成性超音波逆行散射資料分析 27
多保它命灌注方式 28
心臟超音波的執行與判讀 28
多保它命鉈-201心肌灌流掃描 29
病理學檢查 29
冠狀動脈攝影 29
統計方法 30
第四部分 30
斑馬魚心臟超音波觀察 30
斑馬魚 30
超音波檢查 30
由心室的灌流的杜卜勒面積衍生所得的參數 30
統計方法 31
建立心臟衰竭暨心律不整的斑馬魚模式 31
轉殖用質體(plasmid)的製備與構築 31
轉殖用質體的製備 31
轉殖用質體的構築 33
基因轉殖的操作: 顯微注射(Microinjection) 34
斑馬魚的飼育 34
顯微注射 34
基因轉殖魚種的檢測、篩選、觀察 34
檢測與篩選 34
遺傳 35
觀察 35
統計方法 36
結果 37
第一部份 37
Q波心肌梗塞病人之臨床資料 37
多保它命壓力超音波結果 37
多保它命鉈-201心肌灌流掃描之結果 37
第二部分 37
多保它命壓力超音波結果 38
細胞凋亡相關蛋白與TUNEL結果 38
細胞凋亡相關蛋白之表現與多保它命灌流下心肌收縮狀態之相關性 38
第三部分 38
加成性超音波逆行散射結果 39
多保它命超音波結果 39
多保它命鉈-201心肌灌流掃描檢查 39
病理學檢查 40
第四部分 40
斑馬魚之心臟超音波所見 40
杜普勒心臟超音波及動量血管攝影 40
由心室的灌流杜卜勒面積衍生所得的參數 40
溫度在由心室灌流杜卜勒面積所衍生之頻譜分析的效應 41
建立心臟衰竭暨心律不整的斑馬魚模式 41
綠螢光表現是否會影響斑馬魚心臟功能 41
cTnC抑制表現後心臟的變化 41
收縮異常 41
心律不整 42
討論 43
第一部份 43
第二部份 44
擴張性心肌病變的心肌細胞與細胞凋亡前期 44
擴張性心肌病變的心肌收縮潛力 44
第三部份 45
心臟移植後的血流不均現象 45
異常加成性超音波逆行散射與心肌灌流異常及病理變化之相關性 45
心肌細胞肥厚與間質性纖維原沉積 46
第四部分 46
斑馬魚心臟超音波觀察 46
與其他低等脊椎動物之比較 47
溫度對斑馬魚心臟的影響 47
心跳速度對心室舒張功能之影響 47
建立心臟衰竭暨心律不整的斑馬魚模式 48
綠螢光表現是否會影響斑馬魚心臟功能 48
四環黴素調控基因表現系統 48
cTnC抑制表現後心臟的變化 49
展望 50-52
論文英文簡述(summary) 53-58
參考文獻 59-72
圖表 73-103
表一、Q波心肌梗塞病人之臨床資料 73
表二、Q波心肌梗塞病人之多保它命壓力超音波所見 74
表三、給予多保它命下引起ST節段升高及T波偽正常化來預測超音波診斷心肌缺血及存活之敏感度、專一度及準確度 75
表四、給予多保它命下引起ST節段升高及T波偽正常化來預測鉈-201心肌灌流掃描診斷心肌缺血及存活之敏感度、專一度、陽性預測值、陰性預測值及準確度 76
表五、心肌梗塞對面部位(reciprocal area)的鉈-201灌流情況 77
表六、擴張性心肌病變患者其細胞凋亡相關蛋白之表現情形 78
表七、細胞凋亡相關蛋白之表現與多保它命灌注下心肌收縮力之相關 79
表八、換心人加成性超音波逆行散射異常(A群)及正常(B群)之臨床資料 80-81
表九、換心人病理變化正常與異常者之臨床資料 82-83
表十、溫度對斑馬魚心臟血流的效應 84-85
表十一、不同綠螢光的斑馬魚孵化4天後在2-phenoxyethanol 70ul/200ml 濃度下心臟大小及功能 86
圖一、在擴張性心肌病變心肌中偵測細胞凋亡 87
圖二、在擴張性心肌病變心肌中偵測細胞凋亡相關蛋白bcl2 88
圖三、在擴張性心肌病變心肌中偵測細胞凋亡相關蛋白bax 89
圖四、擷取加成性超音波逆行散射的方式 90
圖五、間質性纖維原沉積 91
圖六、斑馬魚彩色杜卜勒超音波心圖 92
圖七、斑馬魚動量血管攝影心圖 93
圖八、脈衝杜卜勒血流速度 94
圖九、心室舒張血流杜卜勒面積時間圖 95
圖十、心室舒張血流杜卜勒面積時間圖衍生參數 96
圖十一、心室舒張血流杜卜勒面積時間圖之頻譜分析 97
圖十二、不同亮度綠螢光斑馬魚心臟 98
圖十三、顯微鏡下操作斑馬魚心臟呈像 99
圖十四、綠螢光面積計算心臟收縮狀態 100
圖十五、cTnC表現正常之斑馬魚心臟 101
圖十六、cTnC表現抑制之斑馬魚心臟 102
圖十七、cTnC表現抑制之斑馬魚心臟出現完全性心房心室傳導阻滯 103
附錄 104
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Ho YL, Chen CL, Hsu RB, Lin LC, Huang PJ. The correlation between expression of apoptosis related proteins and myocardial functional reserve evaluated by dobutamine stress echocardiography in patients with dilated cardiomyopathy. J Am Sco Echgocardiogr 2003; 16: 931-936
Ho YL, Chen CL, Hsu RB, Lin LC, Yen RF, Lee CM, Chen MF, Huang PJ. Assessment of the Myocardial Changes in Heart Transplant Recipients Without Evident Acute Myocardial Rejection by Integrated Backscatter: Comparison with Simultaneous Dobutamine Stress Echocardiography and Thallium-201 SPECT. Ultrasound Med Biol 2001; 27:171-179
Ho YL, Shau YW, Tsai HJ, Lin LC, Huang PJ, Hsieh FC. Assessment of zebrafish cardiac performance using Doppler echocardiography and power angiography. Ultrasound Med Biol 2002; 28: 1137-1143

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