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，超过一百万的患者在心肌梗塞（ML）后承受左心室（LV）损伤。许多人通过梗塞扩张，全球LV扩张和降低收缩力来适应收缩功能的丧失和心肌疤痕。此帖子ML过程称为重塑。该提案的广泛目标是更好地了解ML后与分级重塑相关的区域应变的早期区域生物力学变化如何。增加的应变可能定义为尺寸变化或伸展而导致LV几何形状的改变。它是梗塞大小和心室负荷的产物。我们将检验以下假设：在卵子模型中ML后10周进行重塑，可以通过在梗塞后7天检测到的区域应变的增加来预测。我们相信，我们将能够检测到面积菌株的阈值，这将与自由壁舒张尺寸增加40％有关。我们想知道菌株如何影响心室心肌细胞中的激发收缩偶联（ECC）和Ca2+信号传导。由于心肌拉伸响应包括影响CA2+处理和ECC的各种细胞内信号传导程序的机械传导，因此我们将研究选定蛋白的坐标变化，包括磷酸肌醇3'激酶（P13K）家族。我们独特地将ML后菌株降低到阈值以下，用于通过导管基微心辅助血泵进行重塑后ML菌株。减少应变将使我们能够观察其对ML后重塑后的影响以及在不受管制的应变条件下确定的分子过程。该建议将完成目标所需的专业知识的独特组合汇集在一起​​。区域应变将通过嵌入式晶体阵列进行测量，ECC将通过从区域单细胞分离株中得出的Ca2+处理来评估，分子分析将在区域组织和单个细胞上完成。将知道区域细胞和组织样品的应变历史。这项工作的新知识将使我们对重塑的应变拉伸反应有更大的了解。实验和方法设计为转化为患者。我们需要知道心脏何时会在ML之后进行改造，并需要深入了解可能未来的医疗疗法的关键分子过程。因此，我们将通过介入介入的微VAD来学习受控菌株的影响。