The overall goal of this research is the development of a comprehensive, non-invasive MRI based method to quantify blood flow in the hepatic vasculature of patients with portal hypertension. Portal hypertension is the most common and lethal complication of end-stage chronic liver disease and leads to the development of portosystemic collaterals (varices) that shunt blood from the liver, renal dysfunction (hepatorenal syndrome), accumulation of ascites, among other complications. Portal hypertension is currently assessed using invasive catheter-based measurements of hepatic venous pressure gradient (HVPG). HVPG is the best-validated biomarker of portal hypertension, but only provides a global measure of disease. Most therapies reduce portal pressure through reductions in the flow to the liver (eg. beta-blockers) or shunting flow from the portal circulation (TIPS procedure). There is need for accurate biomarkers of blood flow to the liver that would complement and augment HVPG measurements. However, there are currently no available methods to provide such hemodynamic information. This proposal seeks to develop a velocity sensitive "4D flow" MRI method that simultaneously images the hepatic vascular anatomy and quantifies blood flow within all vascular territories of the liver. This approach is based on established and validated radially undersampled k-space trajectories (PC VIPR) and will provide a rapid image acquisition with advanced velocity encoding to improve velocity sensitivity, matching the range of flow velocities encountered in the liver. This acquisition will be coupled with non-Cartesian parallel imaging to further reduce scan time to approximately 10 min of free breathing while maintaining high spatial (<1.3 mm isotropic), and high temporal resolution (<50 ms) over a large imaging volume with good image quality and accurate flow quantification. The accuracy of this approach will be evaluated in the hepatic vasculature of swine using perivascular ultrasonic flow probes as the reference standard. The precision (repeatability) of the flow measurements will be determined in patients with portal hypertension and in normal subjects while also quantifying factors that impact precision (meals, diurnal variation). Finally, the clinical utility of the apprach will be determined with non-invasive flow measurements in the liver as part of a pilot study that uses a well- validated beta-blocker test-dose paradigm in patients with portal hypertension. The decrease in hepatic venous pressure gradient (HVPG) will be correlated with decreases in portal blood flow achieved using test dose of propranolol, a non-selective beta-blocker. This study will demonstrate the potential clinical utility of 4D flow MRI as a non-invasive surrogate biomarker of HVPG. If successful, 4D flow MRI would provide a comprehensive tool to quantify and characterize blood flow in portal hypertension, improving risk stratification for variceal hemorrhage and providing non- invasive surrogate biomarkers to evaluate the response of portal flow to pharmacological challenges.

Public Health Relevance

The overall goal of this research is the development of a non-invasive method to measure blood flow to the liver, particularly in patients with liver disease for improving treatment strategy and providing a non-invasive method to measure changes in liver flow in response to treatment with drugs. The liver is the largest solid organ in the body and as a result of several technical challenges there are currently no adequate methods to measure blood flow to this important organ. In this work we will optimize and validate new magnetic resonance imaging (MRI) methods to measure regional blood flow to the liver accurately, inexpensively and non- invasively, without the need for ionizing radiation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK096169-02
Application #
8511624
Study Section
Medical Imaging Study Section (MEDI)
Program Officer
Serrano, Jose
Project Start
2012-07-20
Project End
2015-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
2
Fiscal Year
2013
Total Cost
$309,235
Indirect Cost
$99,256
Name
University of Wisconsin Madison
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Landgraf, Benjamin R; Johnson, Kevin M; Roldán-Alzate, Alejandro et al. (2014) Effect of temporal resolution on 4D flow MRI in the portal circulation. J Magn Reson Imaging 39:819-26
Bultman, Eric M; Klaers, Jessica; Johnson, Kevin M et al. (2014) Non-contrast enhanced 3D SSFP MRA of the renal allograft vasculature: a comparison between radial linear combination and Cartesian inflow-weighted acquisitions. Magn Reson Imaging 32:190-5
Beatty, Philip J; Chang, Shaorong; Holmes, James H et al. (2014) Design of k-space channel combination kernels and integration with parallel imaging. Magn Reson Med 71:2139-54
Hernando, Diego; Levin, Yakir S; Sirlin, Claude B et al. (2014) Quantification of liver iron with MRI: state of the art and remaining challenges. J Magn Reson Imaging 40:1003-21
Bultman, Eric M; Brodsky, Ethan K; Horng, Debra E et al. (2014) Quantitative hepatic perfusion modeling using DCE-MRI with sequential breathholds. J Magn Reson Imaging 39:853-65
Hernando, Diego; Cook, Rachel J; Diamond, Carol et al. (2013) Magnetic susceptibility as a B0 field strength independent MRI biomarker of liver iron overload. Magn Reson Med 70:648-56
Hernando, Diego; Kramer, J Harald; Reeder, Scott B (2013) Multipeak fat-corrected complex R2* relaxometry: theory, optimization, and clinical validation. Magn Reson Med 70:1319-31
Horng, Debra E; Hernando, Diego; Hines, Catherine D G et al. (2013) Comparison of R2* correction methods for accurate fat quantification in fatty liver. J Magn Reson Imaging 37:414-22
Hansmann, Jan; Hernando, Diego; Reeder, Scott B (2013) Fat confounds the observed apparent diffusion coefficient in patients with hepatic steatosis. Magn Reson Med 69:545-52
Brodsky, Ethan K; Bultman, Eric M; Johnson, Kevin M et al. (2013) High-spatial and high-temporal resolution dynamic contrast-enhanced perfusion imaging of the liver with time-resolved three-dimensional radial MRI. Magn Reson Med :

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