Metabolic remodeling precedes and triggers left ventricular remodeling in cardiac

心脏疾病中代谢重塑先于并触发左心室重塑

• 批准号: 7874107
• 负责人: Bijoy K Kundu
• 金额: $ 22.34万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-02 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7874107
• 关键词: Address; Adrenergic beta-Antagonists; Algorithms; Animals; Aortic Valve Stenosis; Arts; Blood specimen; Body Weight; Cardiac; Cardiovascular Diseases; Cause of Death; Clinical; Development; Discipline of Nuclear Medicine; Disease; Disease Progression; EFRAC; Evaluation; Exhibits; Genes; Glucose; Goals; Grant; Heart; Heart Hypertrophy; Heart failure; Hypertension; Hypertrophy; Image; Image Analysis; Imaging Techniques; Individual; Intervention; Kinetics; Lead; Left Ventricular Hypertrophy; Left Ventricular Remodeling; Magnetic Resonance Imaging; Maps; Measurement; Metabolic; Metabolism; Modeling; Morbidity - disease rate; Mortality Determinants; Mus; Myocardial; Operative Surgical Procedures; Outcome; Patients; Play; Positron-Emission Tomography; Prevention; Production; Protocols documentation; Pump; Role; Saline; Sample Size; Stress; Structure; Techniques; Technology; Testing; Therapeutic Intervention; Thick; Time; Tracer; United States; Weight; attenuation; base; clinically relevant; constriction; fetal; glucose metabolism; glucose uptake; heart metabolism; improved; in vivo; inhibitor/antagonist; innovation; male; metabolic abnormality assessment; mouse model; novel strategies; pressure; prevent; programs; public health relevance; response; standard of care; tool; treatment strategy; uptake

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.

背景：全身性高血压和主动脉瓣狭窄可导致左心室肥厚（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。随着持续的压力，肥厚变得不适应。Taegtmeyer等人在2004年提出了一个假设，即压力过载LVH的代谢重塑先于左室重塑，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。由于使用专用小动物扫描仪对小鼠心脏进行无创成像的最新技术进步，确定压力过载导致LVH心力衰竭进展过程中发生的代谢机制现在成为可能。因此，我们将利用左室压力过载心肌肥厚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：目的1：开发和优化体内定量PET成像技术，以评估代谢变化导致左室重构的假设。在疾病进展早期进行定量PET-MR测量将有助于评估体内压力过载LVH的代谢重塑先于结构和功能变化的假设。连续成像超过8周的过程将能够确定在LVH的适应性反应变得不适应的时间。目的2：评估药物干预对LVH中葡萄糖代谢和结构功能的影响：将在LVH中评估ace抑制剂（AI）和β受体阻滞剂（BB）或AI+BB联合治疗等标准护理治疗对心脏代谢和结构功能的影响。本研究的目的是评估心肌代谢的无创成像是否可以提供治疗有益效果的早期指示，从而可能用于针对个体的治疗以改善结果。样本量和统计考虑：PET-MRI成像方案将在每个时间点使用每组约10只小鼠（未经治疗的TAC，假的和治疗的TAC），基于样本量计算，组间差异为25%，功率为0.8，置信水平为95%。图像分析：葡萄糖SUV测量，在室模型方法中的示踪动力学和逐像素的葡萄糖内流图将用于PET研究代谢改变。射血分数、心脏重量与体重比、壁厚测量和PCr/ATP比将使用MRI-MRS用于功能、结构和代谢变化。目的：最终，我们的目标是通过开发和优化有效的体内成像策略来验证代谢重塑先于、触发和维持LVH中左室重塑的假设。时间线：前12-14个月的假设检验，未来10-12个月的AI和BB效果。