Development of 4D Flow MRI for Risk Stratification of Variceal Bleeding in Cirrhosis

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PROJECT SUMMARY: The overarching goal of our research is to improve the management and health of an estimated 1 million Americans suffering from end-stage liver disease (cirrhosis) through non-invasive MRI-based blood flow measurements. In cirrhosis, increased resistance to blood flow leads to formation of collateral vessels that shunt blood away from the liver. Many forms of collaterals can develop, but gastroesophageal varices (GEV) are the most important to monitor - GEV are fragile submucosal vessels that can rupture without warning and cause fatal internal bleeding. Once bleeding starts, mortality is extraordinarily high: 1/3 of patients who bleed will die. Current clinical guidelines recommend esophagogastroduodenoscopy (EGD) surveillance every 1-3 years, to facilitate prophylactic treatment and avoid life-threatening bleeding. Unfortunately. EDG is invasive, expensive, and requires sedation. Importantly, most patients undergoing EGD do not have treatable varices, and compliance with surveillance is very poor. For these reasons, the AASLD has identified the development of non-invasive markers that predict the presence of high-risk varices as a major unmet need in the management of cirrhosis. We aim to address this need through development of non-invasive MRI-based markers of portal blood flow that leverage the primary biological mechanism for development and rupture of GEV: reversed flow from the portal circulation into GEV via the left gastric vein. Currently available markers include catheter-based hepatic venous pressure gradient measurements, and emerging non-invasive markers such as platelet-to-spleen ratio, and liver and spleen stiffness (using ultrasound or MRI). Unfortunately, these markers only provide a global assessment of liver disease, and do not have the specificity necessary to identify high-risk GEV. The investigative team at UW are pioneers in radial 4D flow MRI for comprehensive hemodynamic characterization of blood flow in the liver. Our pilot data demonstrates that radial 4D flow MRI can accurately identify high-risk GEV, by quantifying reversed flow in the LGV, with high sensitivity and specificity. We propose to translate advanced 4D flow MRI to address this unmet clinical need by overcoming remaining technical challenges, performing preclinical validation and optimization, and determining its diagnostic performance. Aim 1: Technical development of velocity-optimized, accelerated 4D flow MRI, to quantify flow in the portal circulation, in < 3 minutes. Aim 2: Rigorous validation of the proposed method in anatomically correct 3D-printed flow phantoms. Aim 3: Determine the diagnostic performance of the proposed method in cirrhotic adults undergoing EGD, to assess diagnostic accuracy and test-retest repeatability. Aim 4: evaluate the effects and added value of a meal challenge to assess for high-risk GEV. If successful, the proposed strategy would transform the management of cirrhosis, through: 1) prompt triage of patients to therapeutic EGD 2) reduction of unnecessary EGD procedures, and 3) increased compliance of GEV surveillance through access to a non-invasive method, ultimately improving the care and long-term survival of patients with cirrhosis.