Strain Controlled LVAD Unloading and Post MI Remodeling

应变控制 LVAD 卸载和 MI 后重塑

• 批准号: 7100567
• 负责人: Bartley P GriffIth
• 金额: $ 70.2万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7100567
• 关键词: apoptosis; auxiliary heart prosthesis; biological signal transduction; biomechanics; calcium flux; cardiac myocytes; cardiovascular disorder therapy; cellular pathology; circulatory assist; disease /disorder model; heart contraction; heart imaging /visualization /scanning; heart ventricle; mechanical stress; mechanoreceptors; medical implant science; medical rehabilitation related tag; myocardial infarct sizing; myocardial infarction; myocardium disorder; phosphatidylinositol 3 kinase; protein isoforms; sheep; ventricular hypertrophy

DESCRIPTION (provided by applicant): In the U.S. more than one million patients sustain left ventricular (LV) injury after myocardial infarction (Ml). Many adapt to the loss of contractile function and the myocardial scar by infarct expansion, global LV dilatation and reduced contractility. This post Ml process is termed remodeling. The broad goal of this proposal is to better understand how early regional biomechanical changes in regional strain after Ml relate to graded remodeling. Increased strain that may be defined as dimensional changes or stretch results from alteration of LV geometry. It is the product of infarct size and ventricular load. We will test the hypothesis that remodeling at 10 weeks after Ml in an ovine model can be predicted by increases in regional strain detected at seven days following infarction. We believe we will be able to detect a threshold of areal strain that will be associated with a 40% increase in free wall diastolic dimension. We want to know how strain affects excitation contraction coupling (ECC) and Ca2+ signaling in ventricular myocytes. Because the myocyte stretch response includes mechanotransduction of various intracellular signaling programs that affect Ca2+ handling and ECC, we will study coordinate changes in select proteins, including the phosphoinositide 3' kinase (P13K) family. We uniquely will reduce post Ml strain below threshold for remodeling post Ml strain by catheter based micro ventricular assist blood pump. Reduction of strain will permit us to observe its effect on post Ml remodeling and the molecular processes we determined in the unregulated strain condition. This proposal brings together the unique combination of expertise required to complete the aims. Regional strain will be measured by embedded crystal array, ECC will be evaluated by Ca2+ handling derived from regional single cell isolates, and molecular analysis will be completed on regional tissue and single cells. The strain history of the regional cell and tissue samples will be known. New knowledge from this work will permit us to have a greater appreciation of the strain-stretch response on remodeling. The experiments and methods are designed to be translated to patients. We need to know when hearts will remodel after Ml and need to gain insight into critical molecular processes for possible future medical therapies. Accordingly, we will learn the impact of controlled strain after large infarction with an interventionally applied micro VAD.

描述（由申请人提供）：在美国，超过一百万患者在心肌梗塞（MI）后遭受左心室（LV）损伤。许多人适应因梗塞扩张、左心室整体扩张和收缩力降低而导致的收缩功能丧失和心肌疤痕。这个机器学习后的过程被称为重塑。该提案的总体目标是更好地理解 M1 后区域应变的早期区域生物力学变化如何与分级重塑相关。应变增加可定义为尺寸变化或因 LV 几何形状改变而导致的拉伸。它是梗塞面积和心室负荷的乘积。我们将测试这样的假设：在绵羊模型中，ML后10周的重塑可以通过梗塞后7天检测到的局部应变的增加来预测。我们相信我们将能够检测到与游离壁舒张尺寸增加 40% 相关的面积应变阈值。我们想知道应变如何影响心室肌细胞中的兴奋收缩耦合 (ECC) 和 Ca2+ 信号传导。由于肌细胞拉伸反应包括影响 Ca2+ 处理和 ECC 的各种细胞内信号传导程序的机械转导，因此我们将研究选定蛋白质的协调变化，包括磷酸肌醇 3' 激酶 (P13K) 家族。我们独特地通过基于导管的微心室辅助血泵将ML后应变降低到重塑ML后应变的阈值以下。应变的减少将使我们能够观察其对M1后重塑的影响以及我们在不受调节的应变条件下确定的分子过程。该提案汇集了完成目标所需的专业知识的独特组合。区域应变将通过嵌入式晶体阵列进行测量，ECC 将通过来自区域单细胞分离物的 Ca2+ 处理进行评估，并对区域组织和单细胞完成分子分析。区域细胞和组织样本的应变历史将是已知的。这项工作的新知识将使我们能够更好地理解重塑过程中的应变-拉伸反应。这些实验和方法旨在转化为患者。我们需要知道心肌梗死后心脏何时会重塑，并且需要深入了解未来可能的医学治疗的关键分子过程。因此，我们将了解大面积梗塞后通过介入应用微 VAD 控制应变的影响。