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

慢性肝病(CLD)是一种非常常见的死亡原因，由肝硬变和由此导致的危及生命的门静脉高压症(PHTN)引起。肝静脉压力梯度(HVPG)测量是评估PHTN的金标准，但由于其侵袭性和对操作员技能和经验的要求，在常规临床环境下不易获得。因此，迫切需要一种安全、可靠、不依赖于操作员的非侵入性方法来诊断和监测PHTN，以便能够早期进行有针对性的干预。生物软组织通常具有双相结构，包括充满液体(间质性液体和血液)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特性。其中，肝硬度，包括固体应力和液体压力，被广泛用于临床评估肝纤维化作为肝活检的替代方法。 我们先前的研究表明，MRE评估的粘弹性可以区分早期CLD中固体相关的纤维化和流体相关的炎症。其他肝脾MRE参数(可压缩性和非线性度)是血流动力学相关流体压力的有前景的生物标志物，但需要系统评估。 本研究的总体目标是发展一种先进的肝脾多参数3D矢量MRE(3DV MRE)技术，以全面描述晚期CLD的PHTN。 ·在目标1中，将开发一种双频率、自导航和径向-笛卡尔混合3DV MRE方法，用于表征小动物和人类受试者的多种力学特性。我们将开发基于模型的迭代重建和3D神经网络反演，以从混合3DV MRE数据计算肝和脾的粘弹性、可压缩性和非线性。 在目标2中，我们将在三种PHTN大鼠模型(饮食诱导的非酒精性脂肪性肝炎(N=22)、胆管结扎术后肝硬变诱导的PHTN(N=22)和部分下腔静脉结扎术后充血诱导的PHTN(N=22))上应用3DV MRE成像。技术完整性、科学严谨性和诊断准确性将通过将多种成像生物标志物与体内间质液体和门静脉压力测量、体外动态机械分析测试结果和组织学特征进行比较来评估。 ·在临床翻译之前，我们将使用测试-重测策略评估5名对照和5名临床患者MRE生物标记物的重复性。最后，在10名对照和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预测指标的诊断准确性。 先进的3DV MRE开发使其他研究人员和我们能够探索这项充满希望的技术，以治疗与流体压力相关的许多其他病因。该项目的成功还将为新出现的治疗干预提供有价值的非侵入性评估工具。

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.