Identifying Vulnerable Atherosclerotic Plaque in Rabbits Using DMSA-USPIO Enhanced Magnetic Resonance Imaging to Investigate the Effect of Atorvastatin

Abstract

BackgroundRupture of an atherosclerotic plaque is the primary cause of acute cardiovascular and cerebrovascular syndromes. Early and non-invasive detection of vulnerable atherosclerotic plaques (VP) would be significant in preventing some aspects of these syndromes. As a new contrast agent, dimercaptosuccinic acid (DMSA) modified ultra-small super paramagnetic iron oxide (USPIO) was synthesized and used to identify VP and rupture plaque by magnetic resonance imaging (MRI).MethodsAtherosclerosis was induced in male New Zealand White rabbits by feeding a high cholesterol diet (n = 30). Group A with atherosclerosis plaque (n = 10) were controls. VP was established in groups B (n = 10) and C (n = 10) using balloon-induced endothelial injury of the abdominal aorta. Adenovirus-carrying p53 genes were injected into the aortic segments rich in plaques after 8 weeks. Group C was treated with atorvastatin for 8 weeks. Sixteen weeks later, all rabbits underwent pharmacological triggering, and imaging were taken daily for 5 d after DMSA-USPIO infusion. At the first day and before being killed, serum MMP-9, sCD40L, and other lipid indicators were measured.ResultsDMSA-USPIO particles accumulated in VP and rupture plaques. Rupture plaques appeared as areas of hyper-intensity on DMSA-USPIO enhanced MRI, especially T2*-weighted sequences, with a signal strength peaking at 96 h. The group given atorvastatin showed few DMSA-USPIO particles and had lower levels of serum indicators. MMP-9 and sCD40L levels in group B were significantly higher than in the other 2 groups (P <0.05).ConclusionAfter successfully establishing a VP model in rabbits, DMSA-USPIO was used to enhance MRI for clear identification of plaque inflammation and rupture. Rupture plaques were detectable in this way probably due to an activating inflammatory process. Atorvastatin reduced the inflammatory response and stabilizing VP possibly by decreasing MMP-9 and sCD40L levels.

Iron Oxide Nanoparticles in Regenerative Medicine and Tissue Engineering

“…MPI, fluorescence imaging (FLI), and computed tomographic angiography (CTA) in an ApoE −/− mouse model confirmed high specificity and sensitivity of the particles and allowed quantitative assessment of the degree of inflammation. Finally, to identify vulnerable plaques and rupture plaques, dimercaptosuccinic acid (DMSA) was bound to ultra-small IONPs and showed high specificity and sensitivity for early detection of vulnerable plaques and ruptured plaques after injection into an atherosclerotic rabbit model [ 192 ].…”

Atherosclerosis Treatment with Stimuli‐Responsive Nanoagents: Recent Advances and Future Perspectives

“…In addition to MRI contrast agents, IONs can also be used to assess the effects of drug interventions. Two research groups have reported the use of USPIONs to evaluate the effects of atorvastatin on plaque stability of vulnerable atherosclerotic rabbits. The results showed that atorvastatin could prevent plaque instability by suppressing the synthesis of total cholesterol (TC) in hepatocytes, upregulating the density and activity of LDL‐C receptors on the surface of hepatocytes, and downregulating VCAM‐1 expressions and MMP‐9 concentrations …”

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“…For example, Cormode et al [9c] developed a gold‐conjugated‐high‐density lipoprotein NP (Au‐HDL) contrast agent for characterizing macrophage burden, calcification, and stenosis of plaques in apolipoprotein E knockout (ApoE −/− ) mice by using a spectral CT system. In 2015, Qi et al evaluated the anti‐atherosclerosis efficacy of atorvastatin by injecting iron oxide NPs into atorvastastin‐treated New Zealand white rabbits and imaging the reduction in plaque size by MRI. Next, bio‐nanomaterials allow for packaging of elevated amounts of therapeutic agents in a compact nanostructure and facilitate their delivery to the plaques.…”