Hemodynamics and Vascular Wall Biology Determine Arteriovenous Fistula Maturation

描述（由申请方提供）：功能性动静脉内瘘（AVF）是长期血液透析血管通路的首选形式。然而，高达60%的AVF从未成熟，即，实现足够的管腔扩张，以允许足够的血液流速用于长期透析。NIDDK最近成立了血液透析瘘管成熟（HFM）联盟，通过在6个临床中心、数据协调中心（DCC）和核心实验室进行的600例患者队列研究来调查这一问题。HFM队列研究将确定AVF成熟失败的预测因素，并收集有关机制假设的间接证据。然而，其广泛的范围不可避免地限制了对具体机制进行更直接和更广泛的调查。我们建议在三个HFM临床中心和DCC进行一项HFM辅助研究，以检查异常血流动力学在AVF成熟失败发病机制中的作用。虽然已知血流动力学壁切应力（WSS）的改变可调节血管重塑和新生内膜增生形成，但目前尚不清楚WSS在AVF发展中的空间分布特征以及WSS特征与AVF成熟之间的关系。此外，WSS对AVF管腔的影响可能受到AVF创建前血管壁的既存属性的调节。以前关于AVF中WSS的研究很少，并且没有检查WSS、既存血管壁特性和AVF结局之间的关系。这项辅助研究将使用最先进的磁共振成像（MRI）和计算流体动力学（CFD）建模技术收集随着时间推移开发AVF的WSS数据，并将该信息与母HFM研究中收集的血管壁属性数据联系起来。通过这种联系，我们将能够检查WSS，血管壁特性和AVF成熟之间的相互作用。在特定目标1中，我们将在三个临床中心各入组40例患者，总计120例患者，这些患者已入组母HFM队列研究。我们将在AVF创建后2天、6周、6个月和18个月通过MRI获得AVF中的管腔几何形状和血流数据，并使用CFD建模从MRI数据中获得WSS轮廓。在特定目标2中，我们将分析AVF创建后2天和6周的局部WSS与6个月和18个月时AVF管腔横截面积和血流速度的后续变化之间的关系。在具体目标3中，我们将评估预先存在的内皮功能、静脉生物力学和静脉壁形态测定是否是具体目标2中描述的关系的额外预测因素、混杂因素或特别是修饰因素。阐明血流动力学和预先存在的血管壁特性与AVF结局的相互作用应导致AVF成熟的新预测因子，阐明AVF失败的关键途径，并指出通过靶向这些途径支持成功成熟的创新疗法。

DESCRIPTION (provided by applicant): A functional rteriovenous fistula (AVF) is the preferred form of vascular access for chronic hemodialysis. However, up to 60% of AVFs never mature, i.e., achieve sufficient lumen dilation to allow adequate blood flow rate for chronic dialysis. The NIDDK has recently established the Hemodialysis Fistula Maturation (HFM) Consortium to investigate this problem through a 600-patient cohort study at six Clinical Centers, a Data Coordinating Center (DCC) and Core Laboratories. The HFM cohort study will identify predictors of AVF maturation failure, and collect indirect evidence about mechanistic hypotheses. However, its broad scope inevitably limits more direct and extensive investigations of specific mechanisms. We propose an HFM ancillary study, at three HFM Clinical Centers and the DCC, to examine the role of aberrant hemodynamics in the pathogenesis of AVF maturation failure. While alterations in hemodynamic wall shear stress (WSS) are known to modulate vascular remodeling and neointimal hyperplasia formation, the spatial distribution profile of WSS in the developing AVF, and the relationship between this WSS profile and AVF maturation, are currently unclear. In addition, the impact of WSS on the AVF lumen is likely modulated by the pre-existing properties of the vascular wall before AVF creation. Previous studies on WSS in AVF have been small, and have not examined the relationships among WSS, pre-existing vascular wall properties, and AVF outcomes. This ancillary study will collect WSS data in developing AVFs over time using state-of-the art magnetic resonance imaging (MRI) and computational fluid dynamic (CFD) modeling techniques, and link this information with vascular wall property data collected in the parent HFM study. Through this linkage, we will be able to examine the interplay among WSS, vascular wall properties, and AVF maturation over time. In Specific Aim 1, we will enroll 40 patients in each of the three Clinical Centers, for a total of 120 patients, who are already enrolled in the parent HFM cohort study. We will obtain luminal geometry and blood flow data in the AVF by MRI at 2 days, 6 weeks, 6 months and 18 months after AVF creation, and derive WSS profiles from the MRI data using CFD modeling. In Specific Aim 2, we will analyze the relationships between local WSS at 2 days and 6 weeks after AVF creation with subsequent changes in AVF lumen cross-sectional area and blood flow rate at 6 and 18 months. In Specific Aim 3, we will assess whether pre-existing endothelial functionality, venous biomechanics and vein wall morphometry are additional predictors, confounders, or especially modifiers, of the relationships described under Specific Aim 2. Illuminating the interplay of hemodynamics and pre-existing vascular wall properties with the AVF outcomes should lead to novel predictors of AVF maturation, elucidate critical pathways to AVF failure, and point towards innovative therapies supporting successful maturation by targeting these pathways.