Microstructural Response of the Myocardium to Mechanical Load

翻译后摘要：狭窄和/或主动脉瓣和二尖瓣返流强加了一个多余的负荷在左边 心室（LV）。LV可以通过经历肥大和/或扩张来补偿这种负荷一段时间， 但最终还是失败了众所周知，在发生显性心脏瓣膜病之前， 心力衰竭改善预后。最近，实验数据表明，早期干预， 亚临床LV纤维化的发展，也可以改善结局。这种认识，加上日益增长的 用基于导管的技术置换/修复主动脉瓣和二尖瓣的能力使得需要检测 早期纤维化和其他亚临床改变对LV微结构的影响更为迫切。在这里，我们提出了两个- 包括LV扩散张量MRI（DTI）和细胞外 血液中的囊泡我们的团队在心脏DTI的发展中发挥了重要作用，并表明， 它可以提供心肌细胞取向、各向异性和紊乱独特读数。在这里我们将使用一本小说 超高分辨率DTI技术，最近在我们的小组，涉及使用定制的64- 元件射频线圈，空间选择性2D激励脉冲，扩散编码梯度补偿 对于运动的第一和第二时刻，以及使用低秩张量建模和 多任务框架这种方法使活体DTI数据的空间分辨率提高了近一个数量级 的大小，并允许我们检测到迄今未知的微观结构模式的LV。这部小说深- 表型分型技术将与LV基因分型的新方法相结合，该方法涉及 对分泌到血液中的细胞外囊泡中所含的mRNA进行测序。我们假设 压力和容量过载将在转录组和微结构中产生显著变化， 在明显的功能障碍出现之前就对左心室进行了检查。我们进一步假设这些变化是可塑性的， 可以通过及时去除过量负荷而可逆。在aim 1中，我们将学习广泛的主题 主动脉瓣狭窄的表型谱。在目标2中，我们将研究患有主动脉瓣和二尖瓣返流的受试者。在 我们将描述瓣膜置换/修复对微结构的影响， LV的转录组。该研究的执行将为瓣膜病的病理生理学提供重要见解。 心脏病，并提供新的工具来评估风险和指导瓣膜置换/修复的时机。为 随着导管技术的不断发展，该提案解决了一个很大的知识缺口 和未满足的临床需求，因此具有重大的医学和公共卫生意义。

Abstract: Stenosis and/or regurgitation of the aortic and mitral valves imposes an excess load on the left ventricle (LV). The LV can compensate for this load for some time by undergoing hypertrophy and/or dilation, but ultimately fails. It is well recognized that replacement or repair of the valve before the development of overt heart failure improves outcome. More recently, experimental data have suggested that early intervention, before the development of subclinical LV fibrosis, can also improve outcome. This realization, coupled with the growing ability to replace/repair the aortic and mitral valves with catheter-based techniques, has made the need to detect early fibrosis and other subclinical changes in LV microstructure even more pressing. Here we propose a two- pronged approach involving diffusion tensor MRI (DTI) of the LV and RNA-sequencing of the extracellular vesicles in blood. Our group has played a major role in the development of DTI in the heart and has shown that it can provide unique readouts of cardiomyocyte orientation, anisotropy and disorder. Here we will use a novel ultra-high resolution DTI technique, recently developed in our group, that involves the use of a tailored 64- element radiofrequency coil, a spatially-selective 2D excitation pulse, diffusion-encoding gradients compensated for the first and second moments of motion, and a reconstruction scheme using low-rank tensor modeling and a multitasking framework. This approach has improved the spatial resolution of in vivo DTI data by almost an order of magnitude and has allowed us to detect hitherto unknown microstructural patterns in the LV. This novel deep- phenotyping technique will be integrated with a novel approach for genotyping the LV, which involves the sequencing of mRNAs contained in the extracellular vesicles secreted into the blood. We hypothesize that pressure and volume overload will produce significant changes in both the transcriptome and microstructure of the LV well before the onset of overt dysfunction. We further hypothesize that these changes are plastic and may be reversible with timely removal of the excess load. In aim 1, we will study subjects across the broad phenotypic spectrum of aortic stenosis. In aim 2, we will study subjects with aortic and mitral regurgitation. In aim 3 of the proposal we will characterize the impact of valve replacement/repair on the microstructure and transcriptome of the LV. Execution of the study will provide important insights into the pathophysiology of valvular heart disease and provide new tools to assess risk and guide the timing of valve replacement/repair. As the armamentarium of catheter-based techniques continues to grow, this proposal addresses a large knowledge gap and an unmet clinical need and, therefore, is of major medical and public health significance.