The Diagnosis And Treatment Of Vulnerable Atherosclerotic Plaques Based On High-resolution Magnetic Resonance Imaging:A Clinical And Experimental Analysis

Part 1 Clinical evaluation study on the recurrence and outcome ofischemic stroke patients with intracranial atherosclerotic disease usinghigh-resolution vessel wall magnetic resonance imagingChapter 1 Characteristics of intracranial atherosclerotic plaquepredicting the recurrent stroke: a prospective studyPurpose: Patients with intracranial atherosclerotic disease(ICAD)have a high frequency of stroke recurrence.However,there has been little investigation into the prognostic value of higher-resolution vessel wall magnetic resonance imaging(hr-VW-MRI).This study aims to investigate the use of intracranial atherosclerotic plaques features in predicting risk of recurrent cerebrovascular ischemic events using hr-VW-MRI.Materials and methods: 58 acute/subacute stroke patients(age,57.7±11.5 years;45males)were imaged using hr-VW-MRI of the intracranial vessels twice following the initial event with imaging sessions at >3 month intervals.Patients were also followed clinically for recurrent ischemic events or transient ischemic attack(TIA)for up to 48 months or until a subsequent event occurred.The degree of stenosis,plaque burden(PB),minimal lumen area(MLA),contrast enhancement ratio,and changes over time of those metrics were recorded.PB was defined as(1 – MLA/outer area(maximal stenosis)×100%).Univariate and multivariate Cox regression analyses were used to calculate the hazard ratio(HR)for predicting recurrent events.Results: The mean time interval between baseline and follow-up MRI scans was 6.2± 4.1 months.After the second MRI scan,20.7% of patients(n=12)had experienced ipsilateral recurrent TIA/stroke within 10.9 ± 9.2 months.Univariable analyses showed that baseline triglyceride,percentage change of PB,and progression of PB were significantly associated with recurrent events(all P < 0.05).Multivariable Cox regression indicated that progression of PB(HR,6.293;95% CI,1.620–24.444;P = 0.001)was a significant independent imaging feature for recurrent ischemic events.Conclusion: Progression of PB was independently associated with recurrent ischemic cerebrovascular events.hr-VW-MRI may help risk stratification of patients at risk of recurrent stroke.Chapter 2 A prospective analysis on prediction of recurrent stroke and evaluation of neurological functional outcome after intensive medical managementPurpose: It is demonstrated in our previous study that high-resolution magnetic resonance imaging(hr-VW-MRI)may predict the risk of recurrent stroke due to intracranial atherosclerotic disease(ICAD).However,the 2D&non-whole brain scan and the lack of the clinical management on the patients' follow-up and the outcome evaluation were the significant limitation.On this chapter,we aims to investigate the change of the clinical and imaging features during the intensive medical management and further assess the independent high-risk factors in predicting the recurrent cerebrovascular ischemic events and neurological functional outcome in both short and long time of following up using hr-VW-MRI.Materials and methods: The patients with acute ischemic stroke were prospectively analyzed and imaged using 3D neck and head combining hr-VW-MRI.And all of the patients underwent hr-VW-MRI after aggressive medical management at 3 month intervals.The clinical characteristics including physical activity,the clinical symptom and blood testing associated with ICAD were also followed.The evaluation on the recurrence and outcome of ischemic stroke were performed by telephone interview before March 1,2021.The unfavorable outcome [modified Rankin scale(m RS)?2] and neurological functional disability(m RS?1)were assessed by the neurologist.Univariate and multivariate Cox regression and Logistic regression analysis were used to calculate the hazard ratio(HR)for predicting recurrent events and the odds ratio(OR)for the clinical outcome,respectively.Results: Eighty patients were recruited in the final study(age,59.64±12.03 years).The mean time interval of short time follow-up was 92.4±15.9 days while the time interval of the long time follow-up were 583.4±130.8 days.After the intensive medical management,the plaque activity had a significant decreasing(with enhancement ratio decreasing,P <0.001;and median of histogram increasing,P=0.012).Multivariable Cox regression indicated that plaque like gibbous moon(HR,7.137;95%CI,1.531-33.277;P =0.047)was a significant high-risk predictor for recurrent ischemic events in short time follow-up and the presence of physical activity or not(HR=0.104;95%CI,0.018-0.591;P =0.010)was significantly associated with recurrence.Multivariable logistic regression showed that none of high-risk control(OR=4.544;95%CI,1.238-24.761;P=0.045),total metabolic equivalent(OR=0.678;95%CI,0.465-0.990;P=0.044)and entropy(OR=0.073;95%CI,0.011-0.473;P=0.006)were strong predictors of the unfavorable outcome after intensive medical management and the plaque location(OR=9.617;95%,2.0159-44.911;P=0.004),regular medication(OR=0.135;95%,0.030-0.610;P=0.009)and none of high-risk control(OR=6.234;95%,1.723-22.553;P=0.005)were significantly associated with neurological functional disability.Conclusion: hr-VW-MRI could provide visualization of the change on plaque features during the intensive medical management,and may help predicting the patients with ICAD at risk of recurrent stroke and evaluating the neurological functional disability.Part 2 Diagnosis and therapy for vulnerable atherosclerosis plaques using multifunctional lipid nanoparticles for imaging and targeted to inflammatory macrophagesPurpose: The rupture of unstable atherosclerosis(AS)plaques is a leading cause of death worldwide.However,the M1–M2 polarization of macrophages could induce stability in unstable AS plaques.Herein,we construct multifunctional lipid nanoparticles for hybrid nuclear medicine imaging/magnetic resonance imaging,targeted delivery of curcumin,improvement of AS plaque stability and the comprehensive evaluation of AS plaque vulnerability with high sensitivity and resolution.Materials and methods: First,cholesteryl-9-carboxynonanoate(9-CCN)(¹²⁵I-iron oxide nanoparticle(ION)/Cur)lipid-coated nanoparticles(LNPs)were developed using hybrid imaging agents ¹²⁵I-ION with lipids containing “eat-me” phagocytic signals for targeting inflammatory M1 macrophages in vulnerable AS plaques.The in vivo accumulation of 9-CCN(¹²⁵I-ION/Cur)-LNPs were reflected by single photon emission tomography(SPECT)and magnetic resonance imaging(MRI)accurately highlighted lesions.Targeted distribution of unstable plaque in the aorta was further confirmed by ex vivo planar images of nuclide and Prussian blue staining for ION.Furthermore,9-CCN(¹²⁵I-ION/Cur)-LNPs could specifically and effectively bind to the proinflammatory M1 macrophages in the AS plaque.Results: The transmission electron microscopy images revealed that 9-CCN(125 I-ION/Cur)-LNPs was moderately uniform.It could specifically target RAW264.7 cells and readily delivered ¹²⁵I-ION and curcumin to macrophages,resulting in radiography,MRI,and M1-M2 polarization.Due to the M1–M2 polarization,unstable AS plaques became stable,resulting in notably less nanoparticle uptake,decreased radioactivity,and MRI T2 WI imaging signals.Conclusion: 9-CCN(¹²⁵I-ION/Cur)-LNPs achieved simultaneous detection and improvement of vulnerable AS plaque stability,and its therapeutic efficacy was reflected by radiography and MRI imaging.