Noninvasive assessment of portal hypertension and hepatic interstitial pressure with advanced magnetic resonance elastography

利用先进磁共振弹性成像无创评估门静脉高压和肝间质压

• 批准号: 10581864
• 负责人: Meng Yin
• 金额: $ 34.76万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10581864
• 关键词: 3-Dimensional; Alcoholic Liver Diseases; Animals; Architecture; Assessment tool; Biological; Biological Markers; Blood; Cause of Death; Choline Deficiency; Cirrhosis; Clinical; Clinical Research; Data; Development; Diagnosis; Diagnostic; Diet; Disease Progression; Disease regression; Early Intervention; Effectiveness; Elasticity; Endoscopy; Esophageal Varix; Esophagogastroduodenoscopy; Esophagus; Etiology; Evaluation; Evolution; Extracellular Matrix; Fibrosis; Frequencies; Goals; Hemorrhage; Hepatic; High Fat Diet; Histologic; Human; Hybrids; Image; Imaging Techniques; Inferior vena cava structure; Inflammation; Intercellular Fluid; Intervention; Knowledge; Laboratories; Life; Ligation; Liquid substance; Liver; Liver Fibrosis; Liver diseases; Longitudinal Studies; Magnetic Resonance Elastography; Magnetic Resonance Imaging; Measurement; Measures; Mechanics; Methods; Modeling; Monitor; Motion; Operative Surgical Procedures; Outcome; Pathologic Processes; Patients; Phase; Portal Hypertension; Portal Pressure; Prevalence; Protocols documentation; Radial; Rattus; Research; Research Personnel; Risk; Role; Severities; Solid; Sorting; Spleen; Steatohepatitis; Stress; Techniques; Technology; Test Result; Testing; Therapeutic Intervention; Tissues; Training; Variant; Varicosity; Venous Pressure level; Viscosity; Work; bile duct; chronic liver disease; clinical practice; clinical translation; clinically relevant; clinically significant; diagnostic accuracy; elastography; experience; hemodynamics; hepatocellular injury; high risk; human subject; imaging biomarker; in vivo; in vivo imaging; interstitial; liver biopsy; liver inflammation; liver stiffness; mechanical properties; neural network; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; preclinical study; predictive modeling; pressure; primary endpoint; reconstruction; response; screening; secondary endpoint; skills; soft tissue; success; vector; viscoelasticity

Chronic liver disease (CLD) is a highly common cause of death due to the development of cirrhosis and consequential life-threatening portal hypertension (PHTN). Hepatic venous pressure gradient (HVPG) measurement is the gold standard to evaluate PHTN but not readily available in routine clinical settings due to its invasiveness and requirement of adequate operator skill and experience. Thus, an urgent need for a safe, reliable, operator-independent noninvasive method exists for diagnosing and monitoring PHTN to allow early targeted interventions. Biological soft tissues usually have a biphasic architecture, including a solid matrix (cells, extracellular matrix) saturated with fluid (interstitial fluid and blood). MR elastography (MRE) can quantitatively assess multiple tissue mechanical properties. Within them, liver stiffness, which comprises solid stress and fluid pressure, is widely used clinically to assess hepatic fibrosis as a liver biopsy alternative. Our prior studies show that MRE-assessed viscoelasticity can distinguish solid-related fibrosis and fluid-related inflammation in early-stage CLD. Other hepatosplenic MRE parameters (compressibility and nonlinearity) are promising biomarkers for hemodynamics-associated fluid pressure but require systematic evaluation. The overall goal of this work is to develop an advanced multiparametric 3D vector MRE (3DV MRE) technique of the liver and spleen for fully characterizing PHTN in advanced CLD. • In Aim 1, a dual-frequency, self-navigating, and hybrid radial-Cartesian 3DV MRE method will be developed for characterizing multiple mechanical properties in both small animals and human subjects. We will develop a model-based iterative reconstruction and a 3D neural network inversion to calculate viscoelasticity, compressibility, and nonlinearity in the liver and spleen from the hybrid 3DV MRE data. • In Aim 2, we will use 3DV MRE imaging on three PHTN rat models (diet-induced nonalcoholic steatohepatitis (N=22), cirrhosis-induced PHTN after bile duct ligation surgery (N=22), and congestion-induced PHTN after partial inferior vena cava ligation surgery (N=22)). Technical integrity, scientific rigor, and diagnostic accuracy will be assessed by comparing multiple imaging biomarkers with in vivo interstitial fluid and portal pressure measurements, ex vivo dynamic mechanical analysis testing results, and histologic features. • Before the clinical translation, we will evaluate the repeatability of MRE biomarkers in 5 controls and 5 clinical patients using a test-retest strategy. Finally, a pilot clinical study in 10 controls and 50 clinical patients with endoscopy or HVPG will rigorously cross-validate the diagnostic accuracy of the PHTN predictors. Advanced 3DV MRE development enables other investigators and us to explore this promising technology for many other etiologies related to fluid pressure. This project’s success will also provide a valuable noninvasive assessment tool for emerging therapeutic interventions.

慢性肝病（CLD）是一种非常常见的死亡原因，由于肝硬化的发展和随之而来的危及生命的门静脉高压症（PHTN）。肝静脉压差（HVPG）测量是评价PHTN的金标准，但由于其侵入性和对操作者技能和经验的要求，在常规临床环境中不易获得。因此，迫切需要一种安全、可靠、不依赖于操作者的非侵入性方法来诊断和监测PHTN，以允许早期靶向干预。生物软组织通常具有双相结构，包括被流体（间质液和血液）饱和的固体基质（细胞、细胞外基质）。磁共振弹性成像（MRE）可以定量评估多种组织的力学性能。其中，包括固体应力和流体压力的肝硬度在临床上广泛用于评估肝纤维化作为肝活检的替代方案。 我们先前的研究表明，MRE评估的粘弹性可以区分早期CLD中的固体相关纤维化和液体相关炎症。其他肝脾MRE参数（可压缩性和非线性）是血流动力学相关液体压力的有希望的生物标志物，但需要系统评价。 这项工作的总体目标是开发一种先进的肝脏和脾脏的多参数三维矢量MRE（3DV MRE）技术，用于充分表征晚期CLD中的PHTN。 在目标1中，将开发一种双频、自导航和混合径向笛卡尔3DV MRE方法，用于表征小动物和人类受试者的多种机械性能。我们将开发基于模型的迭代重建和3D神经网络反演，以计算混合3DV MRE数据中肝脏和脾脏的粘弹性、可压缩性和非线性。 ·在目标2中，我们将对三种PHTN大鼠模型（饮食诱导的非酒精性脂肪性肝炎（N=22）、胆管结扎手术后水肿诱导的PHTN（N=22）和部分下腔静脉结扎手术后水肿诱导的PHTN（N=22））使用3DV MRE成像。将通过比较多种成像生物标志物与体内间质液和门静脉压力测量值、离体动态力学分析测试结果和组织学特征，评估技术完整性、科学严谨性和诊断准确性。 ·在临床转化之前，我们将使用测试-再测试策略评估5名对照和5名临床患者中MRE生物标志物的可重复性。最后，在10名对照组和50名临床患者中进行的一项试验性临床研究将严格交叉验证PHTN预测因子的诊断准确性。 先进的3DV MRE开发使其他研究人员和我们能够探索这种有前途的技术，用于与流体压力相关的许多其他病因。该项目的成功也将为新兴的治疗干预提供有价值的非侵入性评估工具。