Hajjar R J, Liao R, Young J B, Fuleihan F, Glass M G, Gwathmey J K
Cardiovascular Disease Laboratory, Harvard Medical School, Boston, MA 02115.
Cardiovasc Res. 1993 Dec;27(12):2212-21. doi: 10.1093/cvr/27.12.2212.
With the recent availability of human myocardium, many animal models have been shown to be unsuitable as models of human heart failure. The aim of this study was to describe the pathophysiological changes in a model of dilated cardiomyopathy in turkey poults and to compare them to results obtained from failing human hearts.
After receiving furazolidone for 2-3 weeks, animals developed cardiomyopathy (Fz-DCM) and were studied at the whole heart and isolated muscle level. Myofibrillar ATPase activity and noradrenaline turnover were determined in tissue homogenates in failing and non-failing control hearts.
Fz-DCM animals had greater heart weights, heart weight/body weight ratios, and end diastolic volumes. Fractional shortening of the left ventricle and systolic blood pressures were reduced (p < 0.01) in myopathic animals. Isolated perfused hearts had lower peak developed pressures (p < 0.01). Isolated muscle preparations showed no significant differences in peak twitch forces between control and Fz-DCM muscles at a 1 Hz stimulation rate. The relationship between force and frequency of stimulation was positive in control muscles up to 1.7 Hz, whereas in Fz-DCM muscles the relationship was sharply negative above 1 Hz. Time to 80% relaxation was markedly slower in the Fz-DCM muscles. Although [Ca2+]o responsiveness was similar for Fz-DCM and normal animals, responsiveness to isoprenaline was significantly reduced in Fz-DCM hearts. Cardiomyopathic animals displayed diminished noradrenaline content in the left ventricle. Fractional noradrenaline turnover was higher (p < 0.05) in the cardiomyopathic birds. In skinned fibre preparations from control and Fz-DCM hearts calcium activations were similar. Maximum myofibrillar ATPase activities were, however, significantly lower in myopathic animals and myofibrillar protein content was reduced by 25%.
In this model of dilated cardiomyopathy: (1) relaxation is markedly prolonged; (2) the response to beta adrenergic stimulation is diminished; (3) Mg-ATPase activities and myofibrillar protein content are reduced; and (4) sympathetic activity in the heart is markedly increased with depletion of noradrenaline stores. Furthermore, a reduction in tissue noradrenaline content per se is a misleading index of the dynamic state of cardiac noradrenaline stores. With its similarities to human cardiomyopathy, this model promises to provide new insights into the pathophysiology and progression of dilated cardiomyopathy.
随着近期人类心肌样本的可得性，许多动物模型已被证明不适用于人类心力衰竭模型。本研究的目的是描述火鸡雏鸡扩张型心肌病模型中的病理生理变化，并将其与人类衰竭心脏的研究结果进行比较。
在接受2 - 3周的呋喃唑酮后，动物发生心肌病（Fz - DCM），并在全心和离体肌肉水平进行研究。在衰竭和非衰竭对照心脏的组织匀浆中测定肌原纤维ATP酶活性和去甲肾上腺素周转率。
Fz - DCM动物的心脏重量、心脏重量/体重比和舒张末期容积更大。心肌病动物的左心室缩短分数和收缩压降低（p < 0.01）。离体灌注心脏的最大发育压力较低（p < 0.01）。在1Hz刺激频率下，离体肌肉制剂在对照和Fz - DCM肌肉之间的峰值抽搐力无显著差异。对照肌肉中，在1.7Hz以下，力与刺激频率的关系为正，而在Fz - DCM肌肉中，在1Hz以上该关系急剧为负。Fz - DCM肌肉中80%松弛时间明显更慢。尽管Fz - DCM动物和正常动物的[Ca2+]o反应性相似，但Fz - DCM心脏对异丙肾上腺素的反应性显著降低。心肌病动物左心室中的去甲肾上腺素含量减少。心肌病鸟类的去甲肾上腺素周转率分数更高（p < 0.05）。在对照和Fz - DCM心脏的脱膜纤维制剂中，钙激活相似。然而，心肌病动物的最大肌原纤维ATP酶活性显著更低，肌原纤维蛋白含量减少25%。
在这个扩张型心肌病模型中：（1）舒张明显延长；（2）对β肾上腺素能刺激的反应减弱；（3）Mg - ATP酶活性和肌原纤维蛋白含量降低；（4）心脏交感神经活性显著增加，同时去甲肾上腺素储备耗竭。此外，组织去甲肾上腺素含量本身的降低是心脏去甲肾上腺素储备动态状态的一个误导性指标。由于其与人类心肌病的相似性，该模型有望为扩张型心肌病的病理生理学和进展提供新的见解。
