MECHANICAL REGULATION OF DILATED CARDIOMYOPATHY

描述：扩张型心肌病是一种心脏疾病，大多数 5例患者心功能下降，最终导致心脏充血。 失败了。力学因素，如应力和应变，被认为是 心脏肥厚等疾病的调节因子。整体而言 这一建议的假设是，机械因素起着重要作用 在扩张型心肌病和心脏疾病相关的组织重塑中 失败了。复杂的计算模型与实验相结合 对具有不同心力衰竭病因的啮齿动物的研究(包括遗传和 手术诱导的)将有助于阐明机械因素在 心脏扩张和衰竭的进展。以下假设将是 测试：(1)扩张型心肌病和最终的心力衰竭是由 心脏上的机械负荷，以及从代偿的过渡 从肥厚状态到心力衰竭取决于一个临界水平 压力或拉力。短暂性心功能变化前后的研究 阶段可以决定哪些力学因素是重要的。(2)改变 残余应力对心脏局部功能有重要影响， 这可能是心力衰竭时功能障碍的一种机制。我们会调查的 这种可能性是通过量化人体的几何形状和组织结构 从扩张期到舒张期的脑室无应力状态 故障，并使用数学模型来预测后续的 舒张期和收缩期壁应力。(3)我们预计这一变化将在。区域性 无论是在细胞水平还是在全球水平，肌细胞定向都是 心脏扩张和衰竭。为了验证这一假设，局部心肌细胞紊乱 和层流薄层取向的区域变化将在 向失败的过渡。我们会把这些措施纳入 心脏的计算模型，然后独立地改变心肌细胞 在模型中定位，并将功能结果与 是通过实验获得的。我们认为，这些地区性结构性变化 伴随着扩张性心力衰竭，是导致心脏收缩的机制 收缩时纤维缩短和壁增厚的能力。

DESCRIPTION: Dilated cardiomyopathy is a disease of the heart that in most cases leads to decreased cardiac function and eventually to congestive heart failure. Mechanical factors such as stress and strain have been implicated as regulatory factors in diseases such as cardiac hypertrophy. The overall hypothesis of this proposal is that mechanical factors play a significant role in the tissue remodeling associated with dilated cardiomyopathy and cardiac failure. Sophisticated computational models in conjunction with experimental studies in rodents with different etiologies of heart failure (both genetic and surgically-induced) will help elucidate the role of mechanical factors in the progression of cardiac dilation and failure. The following hypotheses will be tested: (1) Dilated cardiomyopathy and eventual heart failure are mediated by mechanical loads on the heart, and the transition from a compensated hypertrophic state to cardiac failure is dependent on a critical level of stress or strain. Studies of cardiac function before and after this transitory phase can determine which mechanical factors are important. (2) A change in residual stress has important consequences for regional function in the heart, and may be a mechanism of dysfunction in heart failure. We will investigate this possibility by quantifying geometry and tissue structure in the stress-free state of the ventricle during the transition from dilation to failure, and use mathematical models to predict subsequent abnormal changes in diastolic and systolic wall stresses. (3) We expect that changes in. regional myocyte orientation, both at the cellular and global levels, are mechanisms of cardiac dilatation and failure. To test this hypothesis, local myocyte disarray and regional variations in laminar sheet orientation will be measured during the transition to failure. We will incorporate these measures into computational models of the heart, and then independently alter the myocyte orientation in the model, and compare the functional results with those obtained experimentally. We propose that these regional structural changes accompanies dilatory heart failure, and are mechanisms behind the reduction in fiber shortening and the ability of the wall to thicken during systole.