Strain Controlled LVAD Unloading and Post MI Remodeling

描述（由申请人提供）：在美国，超过100万患者在心肌梗死（Ml）后发生左心室（LV）损伤。许多适应收缩功能丧失和心肌疤痕梗死扩张，整体左室扩张和收缩力降低。这个后Ml过程被称为重塑。该建议的总体目标是更好地了解Ml后区域应变的早期区域生物力学变化与分级重塑的关系。增加的应变可定义为尺寸变化或拉伸的结果，由左室几何形状的改变。它是梗死面积和心室负荷的产物。我们将验证这样一个假设，即在绵羊模型中，Ml后10周的重塑可以通过梗死后7天检测到的区域菌株的增加来预测。我们相信我们将能够检测到与自由壁舒张尺寸增加40%相关的面应变阈值。我们想知道应变如何影响心室肌细胞的兴奋收缩耦合（ECC）和Ca2+信号。由于肌细胞拉伸反应包括影响Ca2+处理和ECC的各种细胞内信号程序的机械转导，我们将研究选择蛋白质的协调变化，包括磷酸肌苷3'激酶（P13K）家族。我们将通过导管微心室辅助血泵将后Ml应变降低到重塑后Ml应变的阈值以下。应变的减小将使我们能够观察其对后Ml重塑和我们在非调节应变条件下确定的分子过程的影响。该提案汇集了完成目标所需的独特专业知识组合。区域菌株将通过嵌入式晶体阵列测量，ECC将通过区域单细胞分离得到的Ca2+处理进行评估，并在区域组织和单细胞上完成分子分析。区域细胞和组织样本的菌株历史将被知道。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。实验和方法的设计是为了转化为患者。我们需要知道什么时候心脏会在Ml之后重塑，需要深入了解关键的分子过程，以便未来可能的医学治疗。因此，我们将学习在介入应用微型VAD的大梗死后控制应变的影响。

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.