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: 10153864
• 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 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10153864
• 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; risk prediction; 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 二叶式主动脉瓣（BAV）是最常见的先天性畸形，一般发生率为1-2%。 人口它与主动脉瓣（狭窄、返流）和主动脉瓣（狭窄、返流）的严重并发症有关。 （动脉瘤、夹层）。近端主动脉的任何或所有节段扩张，称为二尖瓣狭窄， 在约50%的先天性BAV患者中存在，严重动脉瘤的发生率为1/ 每年100例BAV患者。相关的脊椎病通常需要进行预防性手术以去除 逐渐扩大主动脉以防止致命的并发症然而，当代外科手术指南 干预依赖经验数据和专家意见，但缺乏明确证据。目前尚不清楚是否 BAV动脉病主要是主动脉壁的固有缺陷（即遗传易感性）的结果，或者 瓣膜介导的升主动脉血流变化诱导适应不良的主动脉壁重塑 下游（即获得性病因）。关怀公理以遗传假说为中心， 提示积极的手术切除策略（早期和广泛），以去除主动脉组织， 未来并发症的风险。相反，越来越多的证据表明，瓣膜相关的血液变化 血流也可能促进疾病进展。因此，临床实践在 临床医生和中心。对BAV中血流改变对主动脉壁影响的进一步认识 因此，迫切需要完整性和牙周病，以促进循证临床研究的发展。 指导方针与改进和有针对性的手术切除策略。 因此，本提案的目标是使用无创成像（4D flow MRI）直接评估影响 瓣膜介导的3D血流和壁切应力（WSS）对结构（组织病理学）和功能的影响 （蛋白表达，生物力学）BAV退行性病变中的组织变性。最终，我们的目标是测试 假设通过4D血流MRI评估的定量血流动力学生物标志物将与组织 通过以下活动评估糖尿病指标： (1)制定MRI方案，全面评估主动脉瓣形态、胸主动脉 几何形状和时间分辨的跨瓣3D血液流出模式。生理血流动力学生物标志物 将数值制成表格，以识别患者主动脉壁的异常血流动力学; (2)150枚BAV和150枚三叶主动脉瓣组织病变的表征和本构建模 (TAV)通过鉴定细胞外基质（ECM）分子进行主动脉切除术的患者 调节异常、中膜ECM结构的组织病理学和组织生物力学（强度和各向异性）; (3)组织主动脉病与血流动力学成像生物标志物的相关性分析。 这一建议将推进目前的知识关于血流动力学对主动脉组织功能的作用 在TAV和BAV存在的情况下，从而为未来确定最佳治疗方法提供信息 战略布局

项目成果

Aorta-specific DNA methylation patterns in cell-free DNA from patients with bicuspid aortic valve-associated aortopathy.

• DOI: 10.1186/s13148-021-01137-y
• 发表时间: 2021-07-28
• 期刊: Clinical epigenetics
• 影响因子: 5.7
• 作者: Maredia A;Guzzardi D;Aleinati M;Iqbal F;Khaira A;Madhu A;Wang X;Barker AJ;McCarthy PM;Fedak PWM;Greenway SC
• 通讯作者: Greenway SC

Aortic Valve Stenosis Alters Expression of Regional Aortic Wall Shear Stress: New Insights From a 4-Dimensional Flow Magnetic Resonance Imaging Study of 571 Subjects.

• DOI: 10.1161/jaha.117.005959
• 发表时间: 2017-09-13
• 期刊: Journal of the American Heart Association
• 影响因子: 5.4
• 作者: van Ooij P;Markl M;Collins JD;Carr JC;Rigsby C;Bonow RO;Malaisrie SC;McCarthy PM;Fedak PWM;Barker AJ
• 通讯作者: Barker AJ

Reply from authors: Toward physiologically meaningful biomechanical parameters from ex vivo biaxial testing.

作者回复：通过离体双轴测试获得具有生理意义的生物力学参数。

• DOI: 10.1016/j.xjon.2022.05.004
• 发表时间: 2022-06
• 期刊: JTCVS open
• 作者: Nightingale, Miriam;Sigaeva, Taisiya;Di Martino, Elena S
• 通讯作者: Di Martino, Elena S

The American Association for Thoracic Surgery consensus guidelines on bicuspid aortic valve-related aortopathy: Executive summary.

• DOI: 10.1016/j.jtcvs.2017.10.161
• 发表时间: 2018-08
• 期刊: The Journal of thoracic and cardiovascular surgery
• 作者: Borger MA;Fedak PWM;Stephens EH;Gleason TG;Girdauskas E;Ikonomidis JS;Khoynezhad A;Siu SC;Verma S;Hope MD;Cameron DE;Hammer DF;Coselli JS;Moon MR;Sundt TM;Barker AJ;Markl M;Della Corte A;Michelena HI;Elefteriades JA
• 通讯作者: Elefteriades JA

Seismocardiography and 4D flow MRI reveal impact of aortic valve replacement on chest acceleration and aortic hemodynamics.

地震心动图和 4D 血流 MRI 揭示了主动脉瓣置换术对胸部加速度和主动脉血流动力学的影响。

• DOI: 10.1111/jocs.14289
• 发表时间: 2020
• 期刊: Journal of cardiac surgery
• 影响因子: 1.6
• 作者: Johnson,EthanMI;Etemadi,Mozziyar;Malaisrie,SChris;McCarthy,PatrickM;Markl,Michael;Barker,AlexJ
• 通讯作者: Barker,AlexJ