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

描述（由申请人提供）：左心室和右心室的压力超负荷最初导致适应性肥大。然而，这通常伴随着适应不良肥大、心力衰竭和死亡。我们在这里假设，三维心肌纤维结构的变化在从适应性肥大到适应不良肥大和心力衰竭的有害转变中起着重要作用。我们进一步假设，在体内的扩散张量MRI（DTI）纤维束成像将允许心肌微结构的异常变化，以检测之前，明显过渡到心力衰竭。DTI纤维束成像提供了一个独特的3D肌纤维结构的读出，但在心脏，迄今为止，已被限制到离体应用。这里我们 将在暴露于压力期间对左心室（LV）进行连续体内DTI纤维束成像 超载。体内纤维束成像数据将与LV质量、纤维化和应变（体内）的变化以及离体分离的心肌细胞大小和功能相关。因此，对心肌结构和功能之间的关系将有基本的了解。将野生型小鼠的超负荷LV中的微结构变化与转基因Gqi小鼠中的微结构变化进行比较，转基因Gqi小鼠对LV压力超负荷具有高度抗性。还将对超负荷的右心室（RV）进行连续纤维束造影，以确定为什么与LV不同，它对压力超负荷的适应性如此差。在目标1中，我们将比较运动、主动脉缩窄和血管紧张素输注模型中生理性和病理性左心室肥大的显微结构变化。在目标2中，我们将确定RV纤维结构如何响应于肺动脉束带而改变，以及这与LV（特别是Gqi小鼠中的LV）对主动脉束带的响应如何不同。在目标3中，我们将检查过载LV/RV对强烈后负荷减少（压力过载消除）的微观结构响应。主动脉和肺动脉去带将用于确定当肥大和/或衰竭心室卸载时肌纤维结构如何变化。肌纤维结构的变化与心室功能、心肌纤维化和离体心肌细胞功能的变化相关。在本研究中使用小鼠模型将使MRI结果与心肌的光学相干断层扫描和从转基因Gqi小鼠获得的基本机制见解相关。该提案通过证明心脏的DTI纤维束成像可以在体内进行，并可以提供对高血压性心脏病、舒张期LV衰竭和RV衰竭等常见问题的重要见解，从而推进了心脏成像的前沿。通过表征这些重要条件下的微结构变化，我们希望更好地了解并最终预防从适应性肥大到心力衰竭和死亡的转变。人体心脏在体内的DTI纤维束成像是高度可行的，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.