Development of a Non-Invasive Biomarker for Bleeding Risk Stratification of Gastroesophageal Varices

该应用的目的是开发一种非侵入性方法，用于预测终末期肝病（肝硬化）患者是否存在可治疗但可能致命的胃食管静脉曲张。2017年，肝硬化是德国过早死亡的第7大常见原因。肝硬化最严重的并发症之一是胃食管静脉曲张，可导致致命的内出血。为了识别和治疗高危患者，指南建议定期进行食管胃十二指肠镜检查和静脉曲张套扎，这可以将死亡率降低50- 70%。然而，内窥镜检查是侵入性的，并且在不需要治疗时通常是不必要的。由于这些原因，美国肝病研究协会已经确定开发“预测高危静脉曲张存在的非侵入性标志物”是一个主要的未满足的需求。这些标志物将有助于识别高危患者，同时减少不必要的侵入性程序。胃食管静脉曲张的发展的主要生物学机制是门静脉压力升高和胃左静脉血流逆转。这种反向血流的检测和定量是本申请提出检测有出血风险的胃食管静脉曲张的主要创新和基本生物学前提。本申请提出了新的基于定量4D Flow MRI的生物标志物的必要技术开发和临床前验证。4D Flow MRI是一种非侵入性MRI技术，可测量所有三维和随时间推移的流速。它可以量化复杂解剖结构中的血流，提供全面的解剖和血流动力学表征。令人信服的初步数据表明，4D Flow MRI可以通过量化胃左静脉的反向血流来检测高危胃食管静脉曲张。该应用的技术创新和临床前验证旨在为基于4D Flow MRI的高危静脉曲张检测的临床实施铺平道路。基本方面是一个快速的序列，具有高灵敏度的检测静脉曲张出血的风险。因此，通过利用门静脉血流的低脉动性和使用新的时间平均加速策略，今天12分钟的冗长采集将减少到3分钟。左胃静脉缓慢血流可视化的困难将通过包括深度学习算法在内的速度优化策略来解决。对拟议的MRI方法进行严格的临床前验证将包括患者特定的3D打印体模评估以及健康志愿者和低风险和高风险静脉曲张患者的体内测量。如果成功，拟议的速度优化，加速4D Flow MRI策略将为静脉曲张出血提供准确，精确和可重现的无创风险分层。它有可能从根本上改善临床管理和长期生存的疟疾患者。

The aim of this application is the development of a non-invasive method to predict the presence of treatable but potentially lethal gastroesophageal varices in patients with end-stage liver disease (cirrhosis).In 2017, cirrhosis was the 7th most common cause of premature deaths in Germany. One of the most critical complications of cirrhosis is the development of gastroesophageal varices that can cause fatal internal bleeding. To identify and treat at-risk patients, guidelines recommend regular esophagogastroduodenoscopy and variceal band ligation which can reduce mortality by 50-70%. However, endoscopy is invasive and often unnecessary when no treatment is required. For these reasons, the American Association for the Study of Liver Diseases has identified the development of “non-invasive markers that predict the presence of high-risk varices” as a major unmet need. Such markers would facilitate the identification of high-risk patients, while reducing unnecessary invasive procedures.The primary biological mechanism for the development of gastroesophageal varices is elevated portal pressure and reversal of flow in the left gastric vein. Detection and quantification of this reversed flow is the primary innovation and fundamental biological premise by which this application proposes to detect gastroesophageal varices at risk for bleeding.This application proposes the necessary technical development and preclinical validation of new quantitative 4D Flow MRI-based biomarkers. 4D Flow MRI is a non-invasive MRI technique that measures flow velocities in all 3 dimensions and over time. It can quantify blood flow in complex anatomy, providing comprehensive anatomic and hemodynamic characterization. Compelling preliminary data shows that 4D Flow MRI can detect high-risk gastroesophageal varices by quantifying reversed flow in the left gastric vein.This application’s technical innovations and preclinical validation aims to pave the way for clinical implementation of 4D Flow MRI-based detection of high-risk varices. Essential aspects are a fast sequence with high sensitivity for detection of varices at risk for bleeding. Therefore, today’s lengthy acquisitions of 12 min will be reduced to 3 min by exploiting the low pulsatility of portal venous flow and using novel time averaging acceleration strategies. Difficulty in visualizing slow flow in the left gastric vein will be addressed with velocity-optimized strategies including deep learning algorithms. Rigorous pre-clinical validation of the proposed MRI method will include patient specific 3D printed phantom evaluation and in vivo measurements in healthy volunteers and patients with low and high-risk varices.If successful, the proposed velocity-optimized, accelerated 4D Flow MRI strategy will provide accurate, precise and reproducible non-invasive risk stratification for variceal bleeding. It has the potential to fundamentally improve clinical management and long-term survival of cirrhotic patients.