Utility of Atherosclerosis Imaging in the Evaluation of High-Density Lipoprotein–Raising Therapies

Decreased level of high density-lipoprotein cholesterol (HDL-C) is a rigorous predictor for future cardiovascular events. Much effort is being made to develop HDL-C–raising pharmacotherapies in the attempt to avert the pandemic of atherosclerotic disease. Important properties by which HDL-C–raising compounds are effective involve improvement of cholesterol uptake from macrophages in plaque for transport back to the liver, improvement of endothelial function, and anti-inflammatory effects. Vascular imaging can aid in the determination which HDL-C–raising compounds are effective. Ultrasound and MRI have proved suitable for assessment of structural changes of the vessel wall. Ultrasound can also be used or assessment of endothelial function. 18F-fluordeoxyglucose positron emission tomography has opened up the possibility to assess vessel wall inflammation. In this article we discuss these various imaging techniques and how they can assess efficacy as well as provide pathophysiologic information on the mechanism of action of novel HDL-C–raising drugs

Imaging plaques to predict and better manage patients with acute coronary events

Culprit lesions of patients, who have had an acute coronary syndrome commonly, are ruptured coronary plaques with superimposed thrombus. The precursor of such lesions is an inflamed thin-capped fibroatheroma. These plaques can be imaged by means of invasive techniques, such as intravascular ultrasound (and derived techniques), optical coherence tomography, and near-infrared spectroscopy. Often these patients exhibit similar (multiple) plaques beyond the culprit lesion. These remote plaques can be assessed noninvasively by computed tomographic angiography and MRI and also using invasive imaging. The detection of these remote plaques is not only feasible but also in natural history studies have been associated with clinical coronary events. Different systemic pharmacological treatments have been studied (mostly statins) with modest success and, therefore, newer approaches are being tested. Local treatment for such lesions is in its infancy and larger, prospective, and randomized trials are needed. This review will describe the pathological and imaging findings in culprit lesions of patients with acute coronary syndrome and the assessment of remote plaques. In addition, the pharmacological and local treatment options will be reviewed

Magnetic resonance venography to assess thrombus resolution with edoxaban monotherapy versus parenteral anticoagulation/warfarin for symptomatic deep vein thrombosis: A multicenter feasibility study

The feasibility of magnetic resonance venography (MRV) for measuring change in thrombus volume with a novel anticoagulation regimen versus standard anticoagulation in patients with symptomatic deep vein thrombosis (DVT) has not been assessed. Our aim was to study the feasibility of MRV to measure change in thrombus volume in patients with acute symptomatic objectively confirmed proximal DVT in an open-label multicenter trial (edoxaban Thrombus Reduction Imaging Study, eTRIS). We randomized patients in a 2:1 allocation ratio to edoxaban 90 mg/day for 10 days followed by 60 mg/day versus parenteral anticoagulation bridging to warfarin for 3 months. The primary efficacy outcome was a surrogate end point of the relative change in MRV-quantified thrombus volume from baseline to Day 14–21. A total of 85 eligible patients from 26 study sites were randomized to edoxaban monotherapy (n=56) versus parenteral anticoagulation as a ‘bridge’ to warfarin (n=29). The mean relative change in MRV-quantified thrombus volume from baseline to Day 14–21 was similar in patients treated with edoxaban and parenteral anticoagulation as a ‘bridge’ to warfarin (−50.1% vs −58.9%; 95% confidence interval of treatment difference, −12.7%, 30.2%). However, thrombus extension was observed in eight patients in the edoxaban monotherapy group and in none in the warfarin group. Rates of recurrent venous thromboembolism (3.6% vs 3.6%, p=0.45) and clinically relevant non-major bleeding (5.4% vs 7.1%, p=0.34) were also similar. No major bleeds occurred in either on-treatment group during the study period. In conclusion, MRV can assess change in thrombus volume in patients with acute DVT randomized to two different anticoagulant regimens. ClinicalTrials.gov Identifier: NCT01662908 Investigational New Drug (IND) Application: Edoxaban IND # 6326

Atherosclerotic plaque targeting mechanism of long-circulating nanoparticles established by multimodal imaging

Atherosclerosis is a major cause of global morbidity and mortality that could benefit from novel targeted therapeutics. Recent studies have shown efficient and local drug delivery with nanoparticles, although the nanoparticle targeting mechanism for atherosclerosis has not yet been fully elucidated. Here we used in vivo and ex vivo multimodal imaging to examine permeability of the vessel wall and atherosclerotic plaque accumulation of fluorescently labeled liposomal nanoparticles in a rabbit model. We found a strong correlation between permeability as established by in vivo dynamic contrast enhanced magnetic resonance imaging and nanoparticle plaque accumulation with subsequent nanoparticle distribution throughout the vessel wall. These key observations will enable the development of nanotherapeutic strategies for atherosclerosi

In vivo non-invasive serial monitoring of FDG-PET progression and regression in a rabbit model of atherosclerosis

We investigated the ability of fluorodeoxyglucose positron emission tomography (FDG PET) imaging to serially monitor macrophage content in a rabbit model of atherosclerosis. Atherosclerosis was induced in rabbits (n = 8) by a combination of atherogenic diet and balloon denudation of the aorta. At the end of nine months, the rabbits were randomized to a further six months of the same atherogenic diet (progression group) or normal diet (regression group). In vivo uptake of FDG by the thoracic aorta was measured using aortic uptake-to-blood radioactivity ratios at the start and end of the randomized period. A significant increase in FDG uptake of the progression group after continued cholesterol feeding (aortic uptake-to-blood radioactivity: 0.57 ± 0.02 to 0.68 ± 0.02, P = 0.001), and a corresponding fall in FDG uptake of the regression group after returning to a normal chow diet (aortic uptake-to-blood radioactivity ratios: 0.67 ± 0.02 to 0.53 ± 0.02, P < 0.0001). FDG PET can quantify in vivo macrophage content and serially monitor changes in FDG activity in this rabbit model.Stephen G. Worthley, Zhuang Y. Zhang, Josef Machac, Gérard Helft, Cheuk Tang, Gary Y. H. Liew, Azfar G. Zaman, Matthew I. Worthley, Zahi A. Fayad, Monte S. Buchsbaum, Valentin Fuster and Juan J. Badimo