Role of Valve-Mediated Hemodynamics on Bicuspid Aortopathy

瓣膜介导的血流动力学在二尖瓣主动脉病中的作用

• 批准号: 9918447
• 负责人: ALEX J. BARKER
• 金额: $ 52.63万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9918447
• 关键词: 3-Dimensional; 4D MRI; Age; Aneurysm; Anisotropy; Aorta; Aortic Aneurysm; Aortic Valve Stenosis; Architecture; Atlases; Bicuspid; Biological Markers; Biomechanics; Blood; Blood flow; Caring; Cell physiology; Clinical; Confidence Intervals; Data; Defect; Development; Diagnostic; Dilatation - action; Disease; Disease Progression; Dissection; Endothelial Cells; Etiology; Excision; Expert Opinion; Extracellular Matrix; Frequencies; Functional disorder; Future; Gender; General Population; Genetic; Genetic Predisposition to Disease; Geometry; Goals; Guidelines; Histopathology; Human; Image; Incidence; Individual; Knowledge; Location; Longitudinal Studies; Magnetic Resonance Imaging; Measurement; Medial; Mediating; Modeling; Molecular; Morphology; Operative Surgical Procedures; Patients; Pattern; Phenotype; Physiological; Pilot Projects; Prevention; Protocols documentation; Resected; Risk; Role; Severities; Specificity; Stimulus; Structure; Testing; Thoracic aorta; Time; Tissue Model; Tissues; Vascular remodeling; aortic valve; base; bicuspid aortic valve; biomarker development; clinical practice; congenital anomaly; evidence base; healthy volunteer; hemodynamics; imaging biomarker; improved; in vivo; individual patient; mechanical properties; mechanotransduction; molecular marker; non-invasive imaging; novel; patient biomarkers; prevent; prophylactic; protein expression; repaired; shear stress; tissue degeneration; tool; treatment strategy; two-arm study

PROJECT SUMMARY Bicuspid aortic valve (BAV) is the most common congenital anomaly with an incidence of 1-2% in the general population. It is associated with severe complications of both the aortic valve (stenosis, regurgitation) and aorta (aneurysm, dissection). Dilatation of any or all segments of the proximal aorta, known as bicuspid aortopathy, is present in ~50% of individuals with congenital BAV and severe aneurysms will develop at a frequency of 1 in 100 BAV patients per year. The associated aortopathy often requires prophylactic surgery to remove the progressively enlarging aorta to prevent lethal complications. However, contemporary guidelines for surgical intervention rely on empirical data and expert opinion but lack clear evidence. It remains unclear as to whether BAV aortopathy is primarily the result of an inherent defect in the aortic wall (i.e. genetic predisposition) or if valve-mediated changes in ascending aortic blood flow induces maladaptive aortic wall remodeling downstream (i.e. acquired etiology). The axiom of care is centered on the genetic hypothesis and has prompted aggressive surgical resection strategies (early and extensive) to remove aortic tissue considered at risk of future complications. Conversely, accumulating evidence indicates that valve-related changes in blood flow may also contribute to disease progression. As such, clinical practices are highly variable between clinicians and centers. A better understanding of the influence of altered blood flow in BAV on aortic wall integrity and aortopathy is thus urgently needed to enable the development of evidence-based clinical guidelines with improved and targeted surgical resection strategies. Therefore, the goal of this proposal is to use non-invasive imaging (4D flow MRI) to directly assess the impact of valve-mediated 3D blood flow and wall shear stress (WSS) on structural (histopathology) and functional (protein expression, biomechanics) tissue degeneration in BAV aortopathy. Ultimately, we aim to test the hypothesis that quantitative hemodynamic biomarkers as assessed by 4D-flow MRI will correlate with tissue metrics of aortopathy via the following activities: (1) development of an MRI protocol to comprehensively assess aortic valve morphology, thoracic aorta geometry, and time-resolved transvalvular 3D blood outflow patterns. Physiologic hemodynamic biomarker values will be tabulated to identify abnormal hemodynamics at the aorta wall in patients; (2) characterization and constitutive modeling of tissue aortopathy in 150 BAV and 150 trileaflet aortic valve (TAV) patients undergoing aortic resection via identification of extracellular matrix (ECM) molecular dysregulation, histopathology for medial ECM architecture, and tissue biomechanics (strength and anisotropy); (3) correlation analysis of tissue aortopathy with hemodynamic imaging biomarkers. This proposal will advance the current knowledge regarding the role of hemodynamics on aorta tissue function in the presence of the TAV and BAV, thereby informing future efforts to determine the best treatment strategies.

项目摘要 双质主动脉瓣（BAV）是最常见的先天性异常，发病率为1-2％ 人口。它与主动脉瓣（狭窄，反流）和主动脉的严重并发症有关 （动脉瘤，解剖）。近端主动脉的任何或所有段的扩张，称为双质主动脉病， 存在于约50％的先天性BAV患者中，严重动脉瘤的发生频率为1 每年100名BAV患者。相关的主动脉肿大通常需要预防手术才能去除 逐渐扩大主动脉以防止致命并发症。但是，现代手术指南 干预依赖于经验数据和专家意见，但缺乏明确的证据。尚不清楚是否 BAV主动脉肿大主要是主动脉壁（即遗传易感性）固有缺陷的结果 瓣膜介导的升高主动脉血流的变化会诱导不良适应性主动脉壁重塑 下游（即获得的病因）。护理的公理集中于遗传假设，并且具有 促使积极进取的手术切除策略（早期和广泛）去除考虑的主动脉组织 未来并发症的风险。相反，积累的证据表明血液相关的血液变化 流量也可能导致疾病进展。因此，临床实践之间是高度变化的 临床医生和中心。更好地理解BAV在主动脉壁上的血流改变的影响 因此，迫切需要完整性和主动脉疾病来发展基于证据的临床 具有改进和有针对性的手术切除策略的指南。 因此，该提案的目的是使用非侵入性成像（4D Flow MRI）直接评估影响 瓣膜介导的3D血流和壁剪应力（WSS）的结构（组织病理学）和功能 （蛋白质表达，生物力学）BAV主动脉病的组织变性。最终，我们旨在测试 假设由4D流MRI评估的定量血流动力学生物标志物将与组织相关 通过以下活动的主动脉病指标： （1）制定MRI协议以全面评估主动脉瓣形态，胸主动脉 几何形状和时间分辨的转瓣3D血液流出模式。生理血液动力学生物标志物 将列出值，以鉴定患者主动脉壁的异常血液动力学。 （2）150 BAV和150个三叶瓣主动脉瓣中组织主动脉病的表征和组成型建模 （TAV）通过鉴定细胞外基质（ECM）分子进行主动脉切除的患者 失调，内侧ECM结构的组织病理学和组织生物力学（强度和各向异性）； （3）组织主动脉病与血液动力学成像生物标志物的相关分析。 该建议将提高有关血流动力学在主动脉组织功能的作用的当前知识 在TAV和BAV的存在下，从而告知了未来确定最佳治疗的努力 策略。