Common complications of portal hypertension include gastroesophageal varices, ascites, and portasystemic encephalopathy. Patients with cirrhosis have a 5-10% yearly incidence of variceal formation, and a 4-15% yearly incidence of bleeding. Each bleeding episode carries up to a 20% risk of death. Consequently, the development of an accurate and noninvasive technique for measurement of portal venous pressure would represent a major advance in the diagnosis and management of portal hypertension. Currently, clinicians evaluate portal hypertension invasively through the hepatic venous pressure gradient (HVPG) determined by the gradient in pressure readings between wedged and free hepatic vein catheter positions via a transjugular approach. Our group developed the fundamental concept of contrast-enhanced subharmonic-aided pressure estimation (SHAPE). We conducted a first-in-humans pilot study of this technique’s ability to estimate portal pressures in 45 adult patients with HVPG measurements supported by an NIDDK Challenge Grant (RC1 DK087365), which showed significantly higher SHAPE gradients between the portal and hepatic veins in subjects with clinically significant portal hypertension (CSPH; HVPG>10 mmHg) than in those with lower HVPGs (1.37±0.59 dB vs. - 1.68±0.27 dB, p<0.001). Recently, we expanded on the concept of using SHAPE for portal pressure estimation in a larger multi-center trial (supported by this grant i.e., R01 DK098526). Results from 178 subjects across two sites using modified GE Logic 9 systems were very encouraging with an accuracy for diagnosing CSPH of 95% (with a 95% confidence interval (CI): 89%-99%, p<0.001) and achieving a sensitivity of 91% (95% CI: 88%-93%) and a specificity of 82% (95% CI: 75%-85%). The development of SHAPE as an accurate noninvasive technique for measurement of portal venous pressure represents a major advance in the diagnosis and management of portal hypertension. This has encouraged us to bring together researchers and clinicians from Thomas Jefferson University (TJU), the Hospital of the University of Pennsylvania (HUP) and University of Bern (UB) with a premier manufacturer of ultrasound scanners (GE) in order to expand on the clinical utility of SHAPE for the management of portal hypertension. We will conduct large-scale clinical trials of SHAPE in patients with compensated cirrhosis undergoing routine hepatocellular carcinoma surveillance (N=210) as well as in patients (N=276) treated for portal hypertension (in particular with non-selective beta blockers) and (as a secondary aim) in patients (N=96) that may need to undergo screening of varices using a state-of-the-art ultrasound scanner (Logiq E10, GE Healthcare, Waukesha, WI). Finally, we will study 78 subjects with CSPH scheduled for transjugular HVPG measurements using two different ultrasound contrast agents in the same subjects to determine the reproducibility of SHAPE. Hence, this renewal study aims to further develop a novel, shareable and ...