Microstructural Response of the Myocardium to Mechanical Load

摘要：主动脉瓣和二尖瓣狭窄和/或返流会对左侧造成过度负荷。 心室(LV)。LV可以通过经历肥厚和/或扩张来补偿这种负荷一段时间， 但最终失败了。众所周知，在显性瓣膜形成之前，瓣膜的更换或修复 心力衰竭会改善结局。最近，实验数据表明，早期干预之前 亚临床LV纤维化的发展，也可以改善预后。这一认识，加上不断增长的 使用基于导管的技术替换/修复主动脉和二尖瓣的能力，使得需要检测 早期纤维化等亚临床变化对左室微结构的影响更为迫切。在这里，我们建议两个- 左室扩散张量成像(DTI)和细胞外RNA测序的分叉式方法 血中有小泡。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、各向异性和无序的独特读数。在这里，我们将使用一本小说 我们小组最近开发的超高分辨率DTI技术，涉及使用定制的- 单元射频线圈，空间选择性2D激励脉冲，扩散编码梯度补偿 对于运动的第一个和第二个矩，以及使用低阶张量建模和 多任务框架。这种方法将体内DTI数据的空间分辨率提高了近一个数量级 并使我们能够探测到左心室中迄今未知的微结构模式。这部小说深深地-- 表型技术将与一种新的LV基因分型方法相结合，该方法涉及 对分泌到血液中的细胞外小泡中包含的mRNAs进行测序。我们假设 压力和体积超载将导致转录组和微结构的显著变化。 在出现明显的功能障碍之前很久就进行了左心室检查。我们进一步假设这些变化是可塑性的 可通过及时移除过量负载而可逆。在目标1中，我们将研究广泛的主题 主动脉瓣狭窄的表型谱。在目标2中，我们将研究主动脉瓣和二尖瓣关闭不全的受试者。在……里面 提案的目标3我们将描述瓣膜更换/修复对显微结构和 LV的转录组。这项研究的实施将为瓣膜的病理生理学提供重要的见解 并提供新的工具来评估风险和指导瓣膜更换/修复的时机。作为 基于导管的技术继续增长，这项建议解决了一个巨大的知识缺口 和未得到满足的临床需求，因此具有重大的医疗和公共卫生意义。

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.