Cardiac MRI-Tractography In Vivo: Integrated Imaging of Structure and Function

描述(申请人提供)：左、右室压力超负荷最初会导致适应性肥厚。然而，随之而来的往往是适应不良的肥厚、心力衰竭和死亡。我们在此假设，3D心肌纤维结构的改变在从适应性肥厚到适应性不良肥厚和心力衰竭的有害转变中起着重要作用。我们进一步假设，体内扩散张量磁共振成像(DTI)将使心肌微结构的异常变化能够在明显转变为心力衰竭之前就被检测出来。DTI-Tractograph提供了一种独特的3D肌纤维结构读数，但在心脏方面，到目前为止还仅限于体外应用。在这里，我们 将在压力暴露期间对左心室(LV)进行连续的活体DTI-Tractograph 超载。体内的气管造影术数据将与(体内)左室质量、纤维化和应变的变化以及体外分离的心肌细胞的大小和功能相关。从而对心肌结构和功能之间的关系有了基本的认识。将野生型小鼠与高度抵抗左心室压力超负荷的转基因Gqi小鼠的左心室超负荷的微观结构变化进行比较。还将对超负荷的右室(RV)进行连续的纤维束成像，以确定为什么它与LV不同，它对压力超负荷的适应能力如此之差。在目标1中，我们将比较运动、主动脉缩窄和血管紧张素注射模型中生理性和病理性左心室肥厚的微结构变化。在目标2中，我们将确定右室纤维结构如何改变对肺动脉环扎的反应，以及这与左室对主动脉环扎的反应有何不同，特别是在Gqi小鼠中。在目标3中，我们将研究超载的LV/RV对高强度后负荷降低(去除压力超载)的微观结构响应。主动脉和肺动脉剥离将被用来确定当肥厚和/或衰竭的心室被卸载时，肌纤维结构如何变化。心肌纤维构筑的改变将与心功能、心肌纤维化和分离的心肌细胞功能的改变相关。在这项研究中使用小鼠模型将使MRI的结果与心肌的光学相干断层扫描相关联，并从转基因Gqi小鼠中获得基本的机制见解。该提议通过证明心脏的DTI-Tractograph可以在体内进行，并可以为常见问题提供重要的见解，如高血压性心脏病、舒张性左室衰竭和右室衰竭，从而推动了心脏成像的前沿。通过表征这些重要条件下的微结构变化，我们希望更好地理解并最终防止从适应性肥厚到心力衰竭和死亡的转变。在活体人体心脏的DTI-Tractograph是高度可行的，因此该建议具有重大的临床和公共卫生意义。

DESCRIPTION (provided by applicant): Pressure overload of the left and right ventricles initially leads to adaptive hypertrophy. This, however, is frequently followed by maladaptive hypertrophy, heart failure and death. We hypothesize here that changes in 3D myocardial fiber architecture play a significant role in the deleterious transition from adaptive to maladaptive hypertrophy and heart failure. We further hypothesize that in vivo diffusion tensor MRI (DTI) tractography will allow abnormal changes in myocardial microstructure to be detected well before the overt transition to heart failure. DTI-tractography provides a unique readout of 3D myofiber architecture but, in the heart, has been limited hitherto to ex vivo application. Here, we will perform serial in vivo DTI-tractography of the left ventricle (LV) during exposure to pressure overload. The in vivo tractography data will be correlated with changes in LV mass, fibrosis and strain (in vivo), and with isolated cardiomyocyte size and function ex vivo. Fundamental insights will thus be obtained into the relationship between myocardial structure and function. Microstructural changes in the overloaded LV of wildtype mice will be compared with those in transgenic Gqi mice, which are highly resistant to LV pressure overload. Serial tractography of the overloaded right ventricle (RV) will also be performed to determine why, unlike the LV, it adapts so poorly to pressure overload. In aim 1 we will compare the microstructural changes seen in physiological and pathological LV hypertrophy in models of exercise, aortic banding and angiotensin infusion. In aim 2 we will determine how RV fiber architecture changes in response to pulmonary artery banding, and how this differs from the response of the LV, particularly in Gqi mice, to aortic banding. In aim 3 we will examine the microstructural response of the overloaded LV/RV to intense afterload reduction (removal of the pressure overload). Aortic and pulmonary artery debanding will be used to determine how myofiber architecture changes when a hypertrophied and/or failing ventricle is unloaded. The changes in myofiber architecture will be correlated with changes in ventricular function, myocardial fibrosis and isolated cardiomyocyte function. The use of mouse models in this study will allow the MRI findings to be correlated with optical coherence tomography of the myocardium and fundamental mechanistic insights to be gained from the transgenic Gqi mice. The proposal advances the frontiers of cardiac imaging by demonstrating that DTI- tractography of the heart can be performed in vivo and can provide important insights into common problems such as hypertensive heart disease, diastolic LV failure and RV failure. By characterizing the microstructural changes in these important conditions we hope to better understand, and ultimately prevent, the transition from adaptive hypertrophy to heart failure and death. DTI-tractography of the human heart in vivo is highly feasible, and the proposal is thus of major clinical and public health significance.