Comparative Study Of USPIO-enhanced And Gd-enhanced MRA In The Diagnosis Of Atherosclerotic Plaques In Rabbits

BackgoundNowadays, cardiovascular diseases, many of which has a direct link to atherosclerosis, have become the main threat to human health with its gradually increased morbidity and fatality rate in our modern society. The acknowledged theories, such as lipid infiltration theory, the one stressed on the formation of thrombus and the injury and inflammatory activation view, have only partly illustrated the occurrence and development of atherosclerosis. Modern perspectives have been put forward insisting that the genesis and progression of atherosclerosis has referred to a kind of chronic inflammation caused by the congenital and acquired adaptive immunologic mechanism. Thesevascular-inflammation-creating mechanisms conclude the direct one which emphasizes the central role of Vascular Endothelial Cells (VEC). It’s said that atherosclerosis results from an endovasculitis led by lipid deposition and stimulation from abnormal lipo-protein particles, bacteria and viruses. However, the indirect one claims that it is the cytokines and inflammatory factors released by some inflammatory activation that flow through our blood circulation intriguing a cross reaction between inflammatory cells and lipopmtein cholesterol to form auto-antibodies (AAbs) and give rise to a plaque. Under the following circumstances, a plague is more likely to be formed. For instance, some related immunologic diseases, smoking, respiratory tract infection, pollution, periodontal diseases and infection of stomach. In other words, they are all risk factors. The leading causes of Acute Coronary Syndrom are plaque rupture, plaque bleeding, or the formation of a thrombus because of the superficial ulcer of a plaque. These usually brings about myocardial infarction, heart failure, lethal arrhythmia and eventually death and for those cardiac-related deaths, almost half of them is emergent and unpredictable. Therefore, it’s vital to find out vulnerable plaques as soon as possible and take effective measures to make a timely intervention during our clinic work so as to stop fatal cardiovascular diseases from happening and decrease death rate. But the most awkward thing is that no such method is figured out to recognize unstable plaques at present. To seek out a non-invasive way to give an early warning of liable plaques seems to be an urgency in the face. The inflammatory factors can reflect the vulnerability of plaques in a way. Yet due to the circulation action of peripheral vessels, it’s really difficult to identify the precise place where the inflammation takes place. This tells us that it’s impractical to decide whether the plaque is stable or not merely through monitoring inflammatory factors in blood. The unstable plaques are characterized by its active inflammation, thin fibrous caps, lipid core, endothelial desquamation and platelet gathering on the surface, what’s more, cracked or impaired plaques, severe stenosis, superficial calcification nodules, yellow plaques(through a virtual endoscope), plaque bleeding, dysfunction of endothelium and positive reconstruction. The more macro-phagocytes get together, the less stabler the plaque is,the easier it is to rupture and the recent radiological technology has just provided a new way to help detect plaques taking advantage of this feature. In recent 10 years, detecting plaques by means of radiological technology has been a research hot spot for scientists from all over the world. In a whole, it can be divided into two categories according to whether it’s invasive. The former includes Coronary Angiography(CAG), Intra-vascular Ultrasound(IVUS), Intra-vascular Ultrasound Elastography(IVUSP), Intra-vascular Ultrasound touching Image, Optical Coherence Tomography(OCT), Raman Speetroscopy(RS), Coronary Angioscopy(CAS) etc. And the latter concludes Multi-slice Spiral Computed Tomography(MSCT), Electron Beam Computed Tomography(EBCT), Positron Emission Computed Tomography(PET), Magnetic Resonance Imaging(MRAI) etc. MRIA scanning can give arbitrary selection to any slices like Ultrasound and has the ability to reconstruct images like CT. Relying on its multi-sequencing and multi-parameter characteristics, MRIA becomes the most promising way to detect unstable plaques as well as to supply us with the so-called one-step service including checking the morphology and function of cardiac, to get to know myo-cardial perfusion, to perform vascular radiography, to find out arterial clots and to conduct molecular imaging. Particularly, the appearance of CE-MR has offered a bright future for one-step check service. There are two sorts of contrast agent for CE-MR. One is based on Gadolinium(Gd) as a para-magnetic contrast agent. The unpaired electrons from lots of Gd turn on its axis and produce a magnetic field that shorten the relaxation time of hydrogen proton contained in the near hydrone. T1 is mainly shortened and the signal sent by the contrast medium in the adjacent place is enhanced, promoting the contrast of the image and generating T1 positive signal contrast. The other is to utilize ferric oxide as a super-para-magnetic contrast agent as to provide a strong comparison with T2 negative signals. The Ultra-small Super-para-magnetic Iron Oxide (USPIO), is a tiny particle which can be recognized and absorbed by macro-phagocytes from reticuloendothelial system. The iron oxide with a diameter of 4-6nm as the core is surrounded by low molecular glucans. Once combined with a hydrone, its diameter gets to 18-30nm immediately. The super-para-magnetic effect arouses the nonuniform of local magnetic fields among organizations and when a hydrone crosses through the field, the speeding hydrogen proton loses phase resulting in the shortening of horizontal and longitudinal relaxation time(T1 and T2). Thus, we can see the corresponding change of T1,T2 with different signal intensity in MRA imaging. The traditional Gd series of contrast agent is less toxic but it can’t be injected in to human body in the form of ion. Instead, it needs to integrate with DTPA to reduce its toxicity. By shortening Ti, Gd-DTPA acquires increased signal intensity and has almost no impact on T2. After injection, Gd-DTPA swiftly diffuses through inter-cellular spaces and becomes kidney-expelled with worse bio-compatibility. Meanwhile, the Gd ion in the combined Gd-DTPA is a heavy metal ion, which does great harm to cells especially those in our kidney, leading to the occurrence of kidney-derived fibrosis. Nevertheless, USPIO has done the opposite. Iron is a necessary micro-element for our body and only when the content of it in our body badly exceeds normal standard does it become highly toxic. When the integrity of vascular endothelium is damaged by Gd and Gd gradually deposits in sub-endothelium via gaps to reinforce the signals emitting from contrast medium in near areas and to improve the contrast of imaging itself. The severer the endothelium is impaired, the stronger the signal will be. UAPIO can be engulfed by macro-phagocytes and the amount of it is in direct proportion to signal intension. This passage is about to research on New Zealand white rabbits to explore the role that enhanced MRA plays in detecting rabbit atherosclerosis by using two categories of contrast agent and to provide theoretical support to help give a non-invasive assessment on unstable plaques in our clinical practice.Part 1 Ultrasmall superparamagnetic iron oxide-enhanced magnetic resonance angiography combined with inflammatory factors for detecting atherosclerotic plaques in rabbitsObjective:To investigate the feasibility of Ultrasmall superparamagnetic iron oxide-enhanced magnetic resonance angiography (USPIO-MRA) combined with interleukin-6 (IL-6) and IL-10 detection for detecting atherosclerotic plaques inrabbits.Methods:Twnety-four normal male rabbits were randomly assigned (n=8) into group A with atherosclerosis induced by damaging the aortic tunica intima with Foley’s tube in combination with a high fat diet, group B with a high fat diet, and group C without any intervention. At week 12, plain and USPIO-MRA was performed in all the 24 rabbits and the results were compared with pathological examinations; blood samples were collected from the ear vein to examine blood lipids and levels of IL-6 and IL-10.Results:The rabbits in groups A and B showed significantly different IL-6 levels (167±21.3 vs 116±14.3pg/ml, P<0.05) but comparable blood lipids and IL-10 levels (P>0.05). The levels of IL-6, IL-10, TC, TG, and LDL, but not HDL, differed significantly between groups A and C and between groups B and C (P<0.01). Continuous MRA scan showed significantly different signal-to-noise ratios (SNR) between the 3 groups.Conclusion:USPIO-MRA combined with IL-6 and IL-10 detection is feasible in detecting atherosclerotic plaques in rabbits.Part2 Comparative study of USPIO-enhanced and Gd-enhanced MRA in the diagnosis of atherosclerotic plaques in rabbitsObjective:To investigate the imaging characteristics of USPIO-enhanced and Gd-enhanced MRA in atherosclerosis and to compare the detection rate of atherosclerotic plaque between them.Methods:Thirty-five healthy male rabbits were assigned to experimental group (n =30) to establish a model of atherosclerosis by damaging aortic tunica intima with Foley’s tube in combination with a high fat diet and 5 to control group without any intervention. At week 12, USPIO-enhanced and Gd-enhanced MRI scanning were conducted to compare the signal changes of atherosclerotic plaque before and after enhancement with the 2 contrast media. Ninety seven pictures were randomly selected respectively from the pictures enhanced by the 2 contrast media to compare the detection rate plaque between them.Pthology examination was used for detection standard.For the control group,pictures were randomly selected.Results:In the experimental group,7 rabbits died of Foley’s tube damaging,2 died of raising and 1 died of anesthesia.All 5 rabbits in control group survived. A total of 172 pathological sections were made with 134 plaques and 72 vulnerable plaques pathologically confirmed.In pictures enhanced by USPIO,84 plaques were confirmed by HE staining with a detection rate of 86.6%. In pictures enhanced by Gd,72 plaques were confirmed by HE staining with a detection rate of 74.2%.Detection rate of USPIO-enhanced MRI in atherosclerosis plaque was significantly higher than that of Gd-enhanced MRI (X2= 3.96, P= 0.046).Conclusion:USPIO shows its superiorityas a new contrast medium in detection of atherosclerosis plaque.