Magnetic resonance imaging of atherosclerosis by targeting extracellular matrix deposition with Gadofluorine M

As previously reported, Gadofluorine M-enhanced magnetic resonance imaging clearly demarcates atherosclerotic plaques from the normal vessel wall. To date, the underlying mechanism has remained unknown. Gadofluorine M is a gadolinium-containing macrocyclic contrast agent containing hydrophilic and hydrophobic moieties. To elucidate the mechanism of accumulation, fluorescently labeled and radioactively labeled derivates of Gadofluorine M were used to determine affinity and specificity of Gadofluorine M binding to blood serum and plaque components in vitro and for the distribution within the plaque of WHHL rabbits in vivo. Gadofluorine M binds to serum albumin, leading to a breakdown of micelles after intravenous injection. The affinity of Gadofluorine M to serum albumin is k_D = 2 μmol/l. Gadofluorine then penetrates the atherosclerotic plaque while bound to albumin and then accumulates within the extracellular, fibrous parts of the plaque by binding to collagens, proteoglycans and tenascin, having the same affinity to these plaque constituents as to albumin. In contrast, weak binding was determined to LDL (k_D = 2 mmol/1) and even no binding to hyaluronic acid. The driving force of binding and accumulation is the hydrophobic moiety of the molecules interacting with hydrophobic plaque materials. Thus, Gadofluorine M accumulates within the fibrous plaque or in the fibrous cap of a plaque containing high amounts of extracellular matrix components, but not in the lipid-rich areas. In combination with high-resolution MRI, Gadofluorine M might enable the detection of thin-cap fibroatheromas, also named the vulnerable plaque.