Metabolic remodeling precedes and triggers left ventricular remodeling in cardiac

描述（由申请人提供）： 背景资料：全身性高血压和主动脉瓣狭窄可导致左心室肥大（LVH），这是美国死亡和发病的主要原因。心肌肥大最初是对应激的适应性反应。随着压力的持续，肥大变得不适应。Taegtmeyer等在2004年提出了一个假说，即在压力超负荷LVH中代谢重构先于LV重构，并诱导胎儿基因程序。然而，由于现有技术有限，这一假设尚未得到完全验证。由于最近使用专用小动物扫描仪对小鼠心脏进行非侵入性成像的技术进步，现在可以确定压力超负荷导致LVH心力衰竭进展过程中发生的代谢机制。因此，我们将利用LV压力超负荷心肌肥大的小鼠模型和最先进的正电子发射断层扫描（PET）和磁共振成像（MRI）来解决以下目标：目标1：开发和优化体内定量PET成像技术，以评估代谢变化导致LVH中LV重构的假设：在疾病进展的早期进行定量PET-MR测量将能够评估代谢重构先于体内压力超负荷LVH的结构和功能变化的假设。在8周的过程中连续成像将能够确定LVH中适应性反应变得适应不良的时间。目标二：评价药物干预对LVH中葡萄糖代谢以及结构和功能的影响：将在LVH中体内评价标准治疗（如ACE抑制剂（AI）和β受体阻滞剂（BB）或AI+BB组合）对心脏代谢以及结构和功能的影响。该目的将评估心肌代谢的非侵入性成像是否可以提供治疗有益效果的早期指示，这可能用于为个体定制治疗以改善结果。样本量和统计学考虑：PET-MRI成像方案将在每个时间点在每组（未处理的TAC、假手术和处理的TAC）中使用约10只小鼠，基于样本量计算，组间差异为25%，功效为0.8和95%置信水平。图像分析：葡萄糖SUV测量、隔室模型方法中的示踪剂动力学和逐像素葡萄糖内流图将用于使用PET研究代谢改变。射血分数，心脏重量体重比，壁厚测量和PCr/ATP比值将用于功能，结构和代谢变化，使用MRI-MRS. End-point：最终，目标是测试的假设，即代谢重塑先于，触发和维持左心室重塑LVH通过开发和优化有效的成像策略在体内。时间线：前12-14个月的假设检验，以及未来10-12个月AI和BB的效果。 公共卫生相关性： 在美国，患有压力超负荷性疾病（如全身性高血压和主动脉瓣狭窄）的患者表现出左心室肥大（LVH），这是心血管疾病死亡率和发病率的主要决定因素。本项目将定量评价和检验葡萄糖代谢的改变先于压力超负荷LVH的结构和功能变化这一假设。这是非常重要的，因为它可能导致早期针对代谢的治疗策略的发展，以防止不良的结构和功能变化，从而改善患者的预后。LVH的适应性反应随着持续的压力而变得不适应的临床相关问题也可能得到回答。通过改进的非侵入性核医学和磁共振成像技术在该提案中进行的研究可能有助于开发用于预防和治疗心肌肥大的新策略和工具，这是一个重要的临床问题。

DESCRIPTION (provided by applicant): Background: Systemic hypertension and aortic valve stenosis can lead to left ventricular hypertrophy (LVH), which is a leading cause of death and morbidity in the US. Myocardial hypertrophy is initially an adaptive response to stress. Hypertrophy becomes maladaptive with ongoing stress. A hypothesis was proposed by Taegtmeyer et al in 2004, that metabolic remodeling precede LV remodeling in pressure overload LVH and induces the fetal gene program. However, this hypothesis has not been completely tested due to the limited available technologies. Identifying metabolic mechanisms that occur during the progression to heart failure with LVH from pressure overload is now possible due to recent technological advances in non-invasive imaging of the mouse heart using dedicated small animal scanners. Accordingly, we will utilize a mouse model of LV pressure-overload myocardial hypertrophy and state-of-the-art Positron Emission Tomography (PET) and Magnetic Resonance Imaging (MRI) to address the following aims: Aim 1: Develop and optimize quantitative PET imaging techniques in-vivo to evaluate the hypothesis that metabolic changes lead to LV remodeling in LVH: Quantitative PET-MR measurements early on in the disease progression will enable evaluation of the hypothesis, that metabolic remodeling precedes structural and functional changes in pressure overload LVH in-vivo. Serial imaging over a course of 8 weeks will enable determination of the time at which the adaptive response becomes maladaptive in LVH. Aim 2: Evaluate the effect of pharmacologic interventions on glucose metabolism and structure and function in LVH: The effect of standard of care treatments such as Ace-inhibitors (AI) and beta-blockers (BB) or a combination of AI+BB on cardiac metabolism and structure and function will be evaluated in-vivo in LVH. This aim will evaluate whether noninvasive imaging of myocardial metabolism can provide an early indication of the beneficial effect of therapy, which could possibly be used to tailor therapy to the individual to improve outcome. Sample size and statistical considerations: The PET-MRI imaging protocols will utilize approximately 10 mice in each group (untreated TAC, shams and treated TAC) at each time point based on a sample size calculation of 25% difference between the groups with a power of 0.8 and 95% confidence level. Image analysis: Glucose SUV measurements, tracer kinetics in a compartment model approach and pixel-by- pixel glucose influx map will be used to study metabolic alterations using PET. Ejection fractions, heart weight to body weight ratios, wall thickness measurements and PCr/ATP ratios will be used for functional, structural and metabolic changes using MRI-MRS. End-point: Ultimately, the goal is to test the hypothesis that metabolic remodeling precedes, triggers and sustains LV remodeling in LVH by developing and optimizing effective imaging strategies in-vivo. Time line: Hypothesis testing in the first 12-14 months and the effect of AI and BB in the next 10-12 months. PUBLIC HEALTH RELEVANCE: Patients with pressure-overload diseases such as systemic hypertension and aortic valve stenosis exhibit left ventricular hypertrophy (LVH), a major determinant of mortality and morbidity in cardiovascular diseases in the United States. This project would quantitatively evaluate and test the hypothesis that alterations in glucose metabolism precede structural and functional changes in pressure overload LVH. This is very important as it may lead to the development of treatment strategies targeting metabolism early on to prevent adverse structural and functional changes and thereby improve patient outcomes. Also the clinically relevant question of the adaptive response in LVH becoming maladaptive with ongoing stress may be answered. The studies to be carried out in this proposal by improved non-invasive nuclear medicine and magnetic resonance imaging techniques may contribute to the development of novel strategies and tools for the prevention and treatment of myocardial hypertrophy, which is a significant clinical problem.