豬肥厚性心肌病心臟超音波診斷技術的建立與應用

Echocardiography in Pigs with Hypertrophic Cardiomyopathy: Establishment and Application

林志鴻(Jyh-Hung Lin)

指導教授 ： 朱瑞民

共同指導教授 ： 李文權(Wen-Chuan Lee)

國立臺灣大學/生物資源暨農學院/獸醫學研究所/博士(2006年)

https://doi.org/10.6342/NTU.2006.00220

摘要

在生物醫學研究中，動物模式佔有相當重要的地位，且提供了非常寶貴的實驗結果以應用於臨床醫學。哺乳動物中除了靈長類之外，豬的心臟血管系統在結構與功能方面與人類最為相似，所以豬模式在心臟血管疾病的研究上扮演著相當重要的角色。心臟血管疾病是人類死亡的重要原因，藉由豬模式來研究心臟血管疾病，將有助於醫學的進步和促進人類健康。肥厚性心肌病(hypertrophic cardiomyopathy, HCM)是人類的重要心臟血管疾病中的一種，典型病理變化包括有心肌肥厚、心肌纖維化、IMCAD及心肌排列不規則。本研究的目的為建立豬HCM的心臟超音波診斷技術，以篩選HCM豬進行育種，同時應用豬模式來探討人類的HCM中壁內冠狀動脈病變與心臟功能的關係。
利用心臟超音波檢查豬HCM，明顯地發現心室中隔的厚度變厚和左心室功能減低。嚴重時更出現二尖瓣收縮期前移動作(systolic anterior motion, SAM)，以及主動脈瓣狹窄造成血流速度變快。這些心臟超音波檢查的結果與人類臨床醫學的診斷結果相似。另外，在病理學檢查方面，我們發現豬HCM有三種典型病變包括心肌纖維排列不規則、壁內冠狀動脈異常及心肌纖維化病變，經過比較文獻上有關人類HCM的臨床與病理檢查分析的結果，證實以上豬HCM的心臟超音波及病理學檢查結果均與人類相似。
進一步以心臟超音波檢查試驗豬(N=84)心室中隔的厚度與腔室的直徑，並計算其左心室功能(left ventricular ejectional fraction, LVEF; fraction shortening, FS)，之後將豬隻送至屠宰場取回心臟進行病理學檢查。心臟超音波檢查則採用IVS-d的厚度> 15 mm來判定HCM，並依據病理學的準則來診斷HCM。在沒有高血壓的情況下，其病理學特徵包括；心肌細胞排列不規則、心肌纖維化及IMCAD。以病理學診斷HCM做為標準，計算心臟超音波檢查HCM的準確性得知陽性預測值(PPV)， 陰性預測值(NPV)， 敏感性、特異性及依序為：66.7 %，94.2 %，71.4 %，92.9 %，0.566。
探討豬HCM壁內冠狀動脈的病變發展過程，可讓我們研究各種病理病變結構與心臟功能之間的關係。在HCM的病變發展過程中，心肌壁內冠狀動脈病變發生的比率最高；此時左心室的功能仍在正常範圍，臨床上亦未出現明顯症狀，但是卻發現左心室的功能會隨著壁內冠狀動脈病變程度的增加而下降。另外，發現心中隔厚度增加時，心肌壁內冠狀動脈的管腔面積比例(%)會變小，左心室功能也下降，此種結果會產生心肌缺血，並增加臨床上出現猝死的機率。同時，我們發現心肌纖維化發生於嚴重壁內冠狀動脈病變的比率較多，此時左心室的功能則明顯減低。
再以心臟超音波來進行試驗豬群的HCM發生率的調查工作，發現在三個世代中HCM發生率由8.25 % (35/424)提高至14.16 % (96/678)，而對照豬群純種豬的HCM發生率為8.76 % (17/194)，雜交肉豬HCM的發生率則為7.83 % (18/230)。同時在不同的世代中的發生率雖有不同，但是其間的差異並不顯著(p>0.05)。此外，我們發現豬HCM的發生率隨年齡的增加而增多，而且至24月齡後發生率即不再增加，此與人類HCM的發生率亦有相似的情形。同時，經由系譜調查發現豬的HCM具有遺傳性，可能不是單一基因的突變所造成。
綜合以上結果，本研究的結論為：(1) 根據豬HCM的心臟超音波檢查結果，發現HCM豬的心室中隔厚度(心收縮期與舒張期)均顯著大於對照豬(p < 0.01)。另外，以心室中隔的厚度(心舒張期)大於15 mm為判定豬HCM的臨床標準，此時的陽性預測值可達66.7 %；(2) 在研究豬HCM的病變發展過程時，發現左心室功能隨著IMCAD病變程度增加而下降，因而建立了壁內冠狀動脈結構與左心室功能之間的關係; (3) 發現在三個世代的試驗豬群HCM發生率為14.16 %，明顯地高於對照豬群的8.25 % (p < 0.05)；在兩個代表性家族，其發生率分別為25.53 % (L977-6)與21.43 % (L1456-4)，皆顯著高於對照豬群與試驗豬群；(4) 利用心臟超音波檢查豬心臟，在7至8月齡時即可診斷出HCM，其發生率隨著年齡增加而上升，直到24月齡即不再增加；此時HCM豬發生非預期死亡的比率為27.27 %。

關鍵字

豬 ； 肥厚性心肌病 ； 心臟超音波

並列摘要

Animal models play important roles in biomedical researches, providing valuable experimental information for clinical applications. Apart from primates, the pig is the mammal most similar to humans in the terms of the structure and function of its cardiovascular system. Thus, pig models play vital roles in the research into cardiovascular diseases. Cardiovascular diseases are major causes of human death. Using pig models in cardiovascular disease research can facilitate the progress of human medicine and improve human health. Hypertrophic cardiomyopathy (HCM) is one of the most important human cardiovascular diseases. The typical pathological changes of HCM include hypertrophy of cardiac muscle, myocardial fibrosis, intramural coronary artery disease (IMCAD) and myocardial disorientation. This investigation establishes of echocardiography in diagnosing porcine HCM to screen HCM pigs for breeding, and ulilizes pig models tostudy the relationship between IMCAD lesion in HCM and cardiac functions.
The experimental results demonstrate that pigs with HCM show a significantly increase in the thickness of ventricular septum and a decrease in the left ventricular function. The systolic anterior motion and blood flow velocity increase caused by the obstraction of left ventricular outflow tract is observed in the severe cases of HCM. These echocardiographic results resemble the diagnostic results of human clinical medicine. Pathological examination also displays the symptoms of myocardial fibrosis, IMCAD and myocardial disorientation in pigs with HCM. A comparison of the clinical and pathological analysis of human HCM in the literature with the results of this study confirm that the results of clinical and pathological examinations of porcine HCM were similar those in humans.
Echocardiography was utilized to investigate the thickness of the ventricular septum and the diameter of ventricular chamber of 84 pigs. The parameters of the left ventricular function, especially left ventricular ejectional fraction (LVEF) and fraction shortening (FS), were obtained. The pigs were then sacrificed and their hearts were removed for pathological examination. The pathological criteria of myocardial disorientation, myocardial fibrosis and IMCAD excluding hypertension were adopted in HCM examination. The echocardiographic examination of IVS-d greater than 15 mm was set as the clinical threshold of porcine HCM. The PPV, NPV, sensitivity , specificity and kappa value of the clinical threshold, using the pathological examination as the golden standard for porcine HCM, were 66.7 %, 94.2 %, 71.4 %, 92.9 % and 0.566, respectively.
Exploring the pathogenesis of IMCAD is useful for clarifying the relationship between the pathological lesion and the cardiac function. The IMCAD is the most common lesion in HCM pathogenesis. This study found that the function of the left ventricular function remained normal, with no obvious clinical symptom. However, the left ventricular function decreased when the severity of IMCAD increased. The percentage of intramural coronary artery lumen and left ventricular funftion decresed when the thickness of ventricular septum increased. This condition uaually leads to ischemia, increasing the proximity of sudden death. Myocardial fibrosis was also found to have increased in the heart with severe IMCAD. Additionally, the left ventricular function was also significantly decreased.
Echocardiography was also used to survey the HCM incidence of the experimental population. The experimental results indicate that the incidence of HCM increased from 8.25% (35/424) in the first generation to 14.16% (96/678) in the third generation. The HCM incidence was 8.76 % (17/194) in the control purebred line and 7.83 % (18/230) in the hybrid line. Although the incidences differed among generations, the difference was not significant (P>0.05). The results also reveal that the incidence increased as the age of pigs increased, but did not increase further after 24 months of age. The incidence was similar to that of human HCM. Pedigree analysis showed that the porcine HCM may be inherited, and was not caused by a single gene mutation.
The following conclusions drawn from this study are: (1) echocardiography was established for porcine HCM examination, and pigs with HCM showed a significantly increase in the thickness of ventricular septum (end stage of diastolic), the criteria (IVS-d>15mm) for porcine HCM determination were confirmed using echocardiography and the PPV is 66.7 %, (2) the left ventricular function decreased when the severity of IMCAD increased, (3) the incidence of experimental pigs (14.16 %) after the breeding of three generations was higher than that of control pigs (8.25%), and (4) the porcine HCM could determinate by echocardiography at 7-8 months old, the incidence increased as the age of pigs increased, but did not increase further after 24 months of age; the mortality of HCM pigs due to unexpected death was 27.27%.

並列關鍵字

Pigs ； Hypertrophic cardiomyopathy ； Echocardiography

參考文獻

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