Leakage and water exchange characterization of gadofosveset in the myocardium

Purpose: To determine the compartmentalization of the blood pool agent gadofosveset and the effect of its transient binding to albumin on the quantification of steady-state fractional myocardial blood volume (fMBV). Methods: Myocardial vascular fraction measurements were simulated assuming the limiting cases (slow or fast) of two-compartment water exchange for different contrast agent injection concentrations, binding fractions, bound and free relaxivities, and true cardiac vascular fractions. fMBV was measured in five healthy volunteers (4 males, 1 female, average age 33) at 1.5 T after administration of five injections of gadofosveset. The measurements in the volunteers were retrospectively compared to measurements of fMBV after three serial injections of the ultra-small, paramagnetic iron oxide (USPIO) blood pool agent ferumoxytol in an experimental animal. The true fMBV and exchange rate of water protons in both human and animal data sets was determined by chi square minimization. Results: Simulations showed an error in the measurement of fMBV due to partial binding of gadofosveset of less than 30%. Measured fMBV values over-estimate simulation predictions, and approach cardiac extracellular volume (22%), which suggests that the intravascular assumption may not be appropriate for the myocardium, although it may apply to more distal perfusion beds. In comparison, fMBV measured with ferumoxytol (5%, with slow water proton exchange across vascular wall) agree with published values of myocardial vascular fraction. Further comparison between myocardium relaxation rates induced by gadofosveset and by other extracellular and intravascular contrast agents showed that gadofosveset behaves like an extracellular contrast agent. Conclusions: The distribution of the volunteer data indicates that a three-compartment model, with slow water exchange of gadofosveset and water protons between the vascular and interstitial compartments, and fast water exchange between the interstitium and the myocytes, is appropriate. The ferumoxytol measurements indicate that this USPIO is an intravascular contrast agent that can be used to quantify myocardial blood volume, with the appropriate correction for water exchange using a two-compartment water exchange model. (C) 2014 Elsevier Inc. All rights reserved.