Evaluation of ultrasmall superparamagnetic iron-oxide (USPIO) enhanced MRI with ferumoxytol to quantify arterial wall inflammation.

BACKGROUND AND AIMS: Inflammation in atherosclerotic plaques is an important determinant of plaque vulnerability, and can be detected non-invasively using ultra-small superparamagnetic iron-oxide (USPIO) enhanced MRI. The aims of the current study were: 1) to determine whether ferumoxytol can be used for USPIO-MRI of atherosclerotic plaques, 2) to establish a protocol for quantitative USPIO-MRI of carotid artery plaques using ferumoxytol, and 3) to study the relation between USPIO uptake and plaque burden and 18F-fluorodeoxyglucose (FDG) uptake (measured by 18F-FDG PET/CT scan) in atherosclerotic plaques. METHODS: In 9 patients with carotid artery stenosis >30% and 4 healthy controls, quantitative R2* MRI scans of the carotid arteries were performed before and 72 h after USPIO administration (4 mg/kg ferumoxytol). USPIO uptake was assessed by quantifying the difference in R2* (ΔR2*) between baseline and post-USPIO scans. In addition to MRI, 18F-FDG PET/CT was performed on both carotid arteries. MR and PET/CT images were co-registered, and 18F-FDG uptake was quantified in all slices containing atherosclerotic plaque. RESULTS: Infusion of ferumoxytol resulted in higher R2* values after 72 h in atherosclerotic plaques (ΔR2* 24.6 ± 19.8 s-1; p = 0.0003), but not in the healthy control vessel wall (ΔR2* 2.6 ± 5.6 s-1, p = 0.23). USPIO uptake in patients was higher in atherosclerotic plaques compared to the patient non-plaque vessel wall (ΔR2* of 24.6 ± 19.8 vs. 7.5 ± 9.3 s-1, p = 0.004). No correlation was found between USPIO uptake and 18F-FDG uptake in atherosclerotic plaques (R2 = 0.03, p = 0.55). CONCLUSIONS: Ferumoxytol is selectively taken up by atherosclerotic plaques and can thus be used for carotid USPIO-MRI. As USPIO and 18F-FDG uptake in atherosclerotic plaque do not correlate in this cohort, these agents may visualize different pathophysiological aspects of plaque inflammation.

HDL mimetic CER-001 targets atherosclerotic plaques in patients.

BACKGROUND AND AIMS: Infusion of high-density lipoprotein (HDL) mimetics aimed at reducing atherosclerotic burden has led to equivocal results, which may relate in part to the inability of HDL mimetics to adequately reach atherosclerotic lesions in humans. This study evaluated delivery of recombinant human apolipoprotein A-I (apoA-I) containing HDL mimetic CER-001 in carotid plaques in patients. METHODS: CER-001 was radiolabeled with the long-lived positron emitter zirconium-89 ((89)Zr) to enable positron emission tomography with computed tomography (PET/CT) imaging. Eight patients with atherosclerotic carotid artery disease (>50% stenosis) received a single infusion of unlabeled CER-001 (3 mg/kg), co-administered with 10 mg of (89)Zr-labeled CER-001 (18 MBq). Serial PET/CT imaging and contrast enhanced-magnetic resonance imaging (CE-MRI) were performed to evaluate targeted delivery of CER-001. RESULTS: One hour after infusion, mean plasma apoA-I levels increased by 9.9 mg/dL (p = 0.026), with a concomitant relative increase in the plasma cholesterol efflux capacity of 13.8% (p < 0.001). Using serial PET/CT imaging, we showed that arterial uptake of CER-001 expressed as target-to-background ratio (TBRmax) increased significantly 24 h after infusion, and remained increased up to 48 h (TBRmax t = 10 min: 0.98; t = 24 h: 1.14 (p = 0.001); t = 48 h: 1.12 (p = 0.007)). TBRmax was higher in plaque compared with non-plaque segments (1.18 vs. 1.05; p < 0.001). Plaque TBRmax correlated with local plaque contrast enhancement (r = 0.56; p = 0.019) as assessed by CE-MRI. CONCLUSIONS: Infusion of HDL mimetic CER-001 increases plasma apoA-I concentration and plasma cholesterol efflux capacity. Our data support the concept that CER-001 targets plaque regions in patients, which correlates with plaque contrast enhancement. These clinical findings may also guide future nanomedicine development using HDL particles for drug delivery in atherosclerosis. CLINICAL TRIAL REGISTRATION: Netherlands Trial Registry - NTR5178. http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=5178.

Multiple pathway assessment to predict anti-atherogenic efficacy of drugs targeting macrophages in atherosclerotic plaques.

BACKGROUND: Macrophages play a central role in atherosclerosis development and progression, hence, targeting macrophage activity is considered an attractive therapeutic. Recently, we documented nanomedicinal delivery of the anti-inflammatory compound prednisolone to atherosclerotic plaque macrophages in patients, which did however not translate into therapeutic efficacy. This unanticipated finding calls for in-depth screening of drugs intended for targeting plaque macrophages. METHODS AND RESULTS: We evaluated the effect of several candidate drugs on macrophage activity, rating overall performance with respect to changes in cytokine release, oxidative stress, lipid handling, endoplasmic reticulum (ER) stress, and proliferation of macrophages. Using this in vitro approach, we observed that the anti-inflammatory effect of prednisolone was counterbalanced by multiple adverse effects on other key pathways. Conversely, pterostilbene, T0901317 and simvastatin had an overall anti-atherogenic effect on multiple pathways, suggesting their potential for liposomal delivery. CONCLUSION: This dedicated assay setup provides a framework for high-throughput assessment. Further in vivo studies are warranted to determine the predictive value of this macrophage-based screening approach and its potential value in nanomedicinal drug development for cardiovascular patients.

Liposomal prednisolone promotes macrophage lipotoxicity in experimental atherosclerosis.

Atherosclerosis is a lipid-driven inflammatory disease, for which nanomedicinal interventions are under evaluation. Previously, we showed that liposomal nanoparticles loaded with prednisolone (LN-PLP) accumulated in plaque macrophages, however, induced proatherogenic effects in patients. Here, we confirmed in low-density lipoprotein receptor knockout (LDLr(-/-)) mice that LN-PLP accumulates in plaque macrophages. Next, we found that LN-PLP infusions at 10mg/kg for 2weeks enhanced monocyte recruitment to plaques. In follow up, after 6weeks of LN-PLP exposure we observed (i) increased macrophage content, (ii) more advanced plaque stages, and (iii) larger necrotic core sizes. Finally, in vitro studies showed that macrophages become lipotoxic after LN-PLP exposure, exemplified by enhanced lipid loading, ER stress and apoptosis. These findings indicate that liposomal prednisolone may paradoxically accelerate atherosclerosis by promoting macrophage lipotoxicity. Hence, future (nanomedicinal) drug development studies are challenged by the multifactorial nature of atherosclerotic inflammation.

Four-Corner Arthrodesis Versus Proximal Row Carpectomy: A Retrospective Study With a Mean Follow-Up of 17 Years.

PURPOSE: To compare the long-term outcomes of proximal row carpectomy (PRC) and 4-corner arthrodesis (FCA) in a consecutive series of patients surgically treated between 1989 and 1998 in a single teaching hospital. METHODS: We included 12 patients (14 wrists) in the PRC group and 8 patients (8 wrists) in the FCA group. Mean follow-up time was 17 years. We compared functional outcome measures (range of motion and grip strength) and patient-reported outcome measures (visual analog score for pain, Mayo Wrist Score, and Michigan Hand Questionnaire). Radiographic evaluation of joint degeneration using the Culp and Jebson scoring system and postoperative complications were assessed for both groups. RESULTS: Active range of motion was slightly better after PRC. There were no differences in grip strength and patient-reported outcomes between groups. Severity of degenerative changes did not differ between groups and was not correlated with pain scores. The FCA group showed more postoperative complications. CONCLUSIONS: Considering the objective and patient-reported outcomes of this study, both types of surgery perform well in the long run. Proximal row carpectomy seems to result in slightly better movement of the wrist with fewer surgical complications and no need for hardware removal. Moreover, postoperative immobilization time was much shorter. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic III.