Transmural Deformation

描述（由申请人提供）：本研究的总体主题是跨壁细胞和结构异质性是正常和病理心功能的重要决定因素。我们将通过结合计算建模方法的狗体内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心脏壁功能的机械梯度。众所周知，这些功能上的机械梯度是正常心脏正常心功能的重要因素，并可能在衰竭心脏的机械功能障碍中发挥作用。在心力衰竭中，诸如增强心外膜钙动力学和优化外部起搏导联位置等技术将通过改变机械-电和细胞异质性来增强整体心室功能。具体目的将解决以下假设：(1)跨壁细胞异质性是左心室跨壁机械功能的决定因素。这将通过改变细胞特性（如钙处理和动作电位持续时间）来进行体内测试，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力学区域同步的作用。(2)层流板结构的跨壁和区域变化影响局部剪切应变和壁厚。新的研究结果表明，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力学功能中的作用。(3)结构和功能的异质性影响慢性心力衰竭的跨壁心室力学。在狗的心脏衰竭模型中，我们将改变局部细胞功能，并检查区域和整体力学的改善。我们将评估衰竭心脏组织结构的变化，以及这些变化的意义。心室起搏是用来增加衰竭心脏的心输出量。我们将验证最小化“预拉伸”组织面积可以作为一种算法来选择起搏点，从而改善衰竭心脏的整体和局部功能的假设。

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.