Transmural Deformation

描述(申请人提供)：这项研究的总体主题是，跨壁细胞和结构的异质性是正常和病理心脏功能的重要决定因素。我们将结合计算建模方法，通过在犬体内的实验来研究跨壁异质性的意义。我们假设，细胞和结构的异质性有助于跨心壁功能的机械梯度。这些功能上的机械梯度被认为是正常心脏正常心功能的一个重要因素，并可能在衰竭心脏的机械功能障碍中发挥作用。在心力衰竭方面，增强心外膜钙动力学和优化体外起搏电极位置等技术将被用来通过改变机械力-电学和细胞异质性来提高整体心室性能。具体目标将解决以下假设：(1)跨室壁细胞的异质性是左心室跨壁机械功能的决定因素。这将在体内进行测试，通过改变细胞特性，如钙处理和跨壁不同的动作电位时程，并检查局部机械功能的变化。我们还将研究改变的激活序列对犬心脏局部力学同步性的作用。(2)层流板结构的跨壁和区域性变化影响局部剪切应变和壁厚。新的发现表明心内膜附近有不同的层状结构，模型和实验的结合将阐明这些异质性的作用，以及纤维弥散在局部机械功能中的作用。(3)结构和功能的异质性影响慢性心力衰竭患者的跨室壁心肌力学。在心力衰竭的狗模型中，我们将改变局部细胞功能，并检查局部和全球机制的改善。我们将评估衰竭心脏中组织结构的变化，以及这些变化的意义。心室起搏用于增加衰竭心脏的心输出量。我们将检验这样一种假设，即最小化“预拉伸”组织面积可以作为一种算法来选择起搏部位，从而改善衰竭心脏的整体和局部功能。

DESCRIPTION (provided by applicant): The overall theme of this research is that transmural cellular and structural heterogeneities are important determinants of normal and pathologic cardiac function. We will investigate the significance of transmural heterogeneity with in-vivo experiments in the dog in conjunction with computational modeling approaches. We hypothesize that cellular and structural heterogeneities contribute to mechanical gradients in function across the wall of the heart. These mechanical gradients in function are known to be an important factor for proper cardiac function in the normal heart, and may play a role in mechanical dysfunction in the failing heart. In heart failure, techniques such as enhancing epicardial calcium dynamics and optimizing external pacing lead location will be used to enhance global ventricular performance by altering mechano-electric and cellular heterogeneities. The specific aims will address the following hypotheses: (1) Transmural cellular heterogeneity is a determinant of transmural mechanical function in the left ventricle. This will be tested in-vivo by altering cellular properties such as calcium handling and action potential duration differentially across the wall, and examining the changes in local mechanical function. We will also examine the role of altered activation sequence on regional synchrony of mechanics in the canine heart. (2) Transmural and regional variations of laminar sheet structure influence local shear strains and wall thickening. Novel findings suggest a different laminar structure near the endocardium, and a combination of model and experiment will elucidate the role of these heterogeneities, as well as the role of fiber dispersion, in local mechanical function. (3) Heterogeneities in structure and function affect transmural ventricular mechanics in chronic heart failure. In a dog model of heart failure we will alter local cellular function and examine improvements in regional and global mechanics. We will assess changes in tissue structure in the failing heart, and the significance of the changes. Ventricular pacing is used to increase cardiac output in the failing heart. We will test the hypothesis that minimizing the 'prestretch' tissue area can be used as an algorithm to select pacing sites which improve global and regional function in the failing heart.