Strain Controlled LVAD Unloading and Post MI Remodeling

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。 许多适应收缩功能的丧失和心肌梗死扩大的心肌瘢痕， 扩张和收缩性降低。这种MI后过程被称为重塑。这个广泛的目标 建议是更好地了解MI后早期局部生物力学变化与局部应变的关系 到分级重塑增加的应变可被定义为尺寸变化或拉伸， LV几何结构改变。它是梗死面积和心室负荷的产物。 我们将检验这一假设，即在绵羊模型中，MI后10周的重构可以通过以下方式预测： 在梗塞后7天检测到局部应变增加。我们相信我们能够探测到 一个区域的门槛！与游离壁舒张期尺寸增加40%相关的应变。我们 我想知道应变如何影响心室肌兴奋收缩偶联（ECC）和Ca 2+信号转导， 肌细胞由于肌细胞牵张反应包括各种细胞内的机械传导， 影响Ca 2+处理和ECC的信号程序，我们将研究选择蛋白质的协调变化， 包括磷酸肌醇3'激酶（P13 K）家族。我们独特地将Ml后应变降低到以下 基于导管的微型心室辅助血泵在Ml应变后重塑的阈值。减少 菌株将允许我们观察其对Ml后重塑的影响以及我们确定的分子过程 在不受控制的应变条件下。这项提案汇集了独特的专业知识， 必须完成目标。区域应变将通过嵌入式晶体阵列测量，ECC将 通过来自区域单细胞分离株的Ca 2+处理进行评价，并将进行分子分析。 在局部组织和单细胞上完成。区域细胞和组织样品的菌株历史将 被人所知从这项工作中获得的新知识将使我们能够更好地理解应变拉伸 对重塑的回应这些实验和方法旨在转化为患者。我们需要 了解心肌梗死后心脏何时重塑，需要深入了解关键的分子过程， 未来可能的治疗方法因此，我们将了解控制应变的影响后，大 介入应用微型VAD的梗死。

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 10weeks 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 area! 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 analysiswill 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.