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

基本信息

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
项目类别：
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

项目摘要

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）是由于肝硬化和随之而来的威胁生命的门户高血压（PHTN）而导致的高度普遍死亡原因。肝静脉压力梯度（HVPG）测量是评估PHTN但在常规临床环境中不容易获得的金标准，这是由于其具有足够的操作员技能和经验的要求，因此在常规临床环境中不易获得。这是迫切需要一种安全，可靠，独立的非侵入性方法来诊断和监测PHTN以允许早期有针对性的干预措施。生物软组织通常具有双相结构，包括固体基质（细胞，细胞外基质），充满了液体（间质液和血液）。 MR弹性图（MRE）可以定量评估多个组织机械性能。在其中，包括固体应力和液压的肝僵硬在临床上被广泛用于评估肝炎纤维化作为肝活检替代方案。我们先前的研究表明，MRE评估的粘弹性可以区分与固体相关的纤维化和早期CLD中与流体相关的炎症。其他肝苯丙胺MRE参数（可压缩性和非线性）是与血液动力学相关的液压的承诺生物标志物，但需要系统评估。这项工作的总体目标是开发肝脏和脾脏的高级多参数3D矢量MRE（3DV MRE）技术，以使高级CLD中的PHTN充分表征。 •在AIM 1中，将开发双频，自动化和杂交radial-cartesian 3DV MRE方法，以表征小动物和人类受试者的多种机械性能。我们将开发一种基于模型的迭代重建和3D神经网络倒置，以计算肝脏和脾脏中混合3DV MRE数据的粘弹性，可压缩性和非线性。 • 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将多个成像生物标志物与体内间质流体和门户压力测量，离体动态机械分析测试结果以及组织学特征进行比较。 •在临床翻译之前，我们将使用重测策略评估5个对照和5名临床患者中MRE生物标志物的可重复性。最后，对10例对照和50例内窥镜检查或HVPG的50例临床患者进行了试点临床研究，将严格跨越验证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针对与流体压力有关的许多其他病因探索这项承诺技术。该项目的成功还将为新兴的治疗干预提供宝贵的无创评估工具。