Imaging Macrophage and Hematopoietic Progenitor Proliferation in Atherosclerosis.

Rationale: Local plaque macrophage proliferation and monocyte production in hematopoietic organs promote progression of atherosclerosis. Therefore, noninvasive imaging of proliferation could serve as a biomarker and monitor therapeutic intervention.

Objective: To explore (18)F-FLT positron emission tomography-computed tomography imaging of cell proliferation in atherosclerosis.

Three-dimensional dynamic contrast-enhanced MRI for the accurate, extensive quantification of microvascular permeability in atherosclerotic plaques.

Atherosclerotic plaques that cause stroke and myocardial infarction are characterized by increased microvascular permeability and inflammation. Dynamic contrast-enhanced MRI (DCE-MRI) has been proposed as a method to quantify vessel wall microvascular permeability in vivo. Until now, most DCE-MRI studies of atherosclerosis have been limited to two-dimensional (2D) multi-slice imaging.

Inhibiting macrophage proliferation suppresses atherosclerotic plaque inflammation.

Inflammation drives atherosclerotic plaque progression and rupture, and is a compelling therapeutic target. Consequently, attenuating inflammation by reducing local macrophage accumulation is an appealing approach. This can potentially be accomplished by either blocking blood monocyte recruitment to the plaque or increasing macrophage apoptosis and emigration.

Feasibility of (18)F-Fluorodeoxyglucose radiotracer dose reduction in simultaneous carotid PET/MR imaging.

The purpose of this study was to develop and validate low dose (18)F-FDG-PET acquisition protocols for detection of inflamed carotid plaques specifically for simultaneous PET/MR imaging. The hypothesis was that increasing the duration of the PET acquisition to match that of the MR acquisition might allow for the use of lower levels of the radiotracer, while preserving quantification and image quality. Seven subjects were scanned twice at least one week apart on a simultaneous PET/MR scanner using either the standard clinical dose of (18)F-FDG (373 ± 63 MBq) for 8 minutes or a low dose (93 ± 17 MBq) for 75 minutes.

Labeling galectin-3 for the assessment of myocardial infarction in rats.

Background: Galectin-3 is a ß-galactoside-binding lectin expressed in most of tissues in normal conditions and overexpressed in myocardium from early stages of heart failure (HF). It is an established biomarker associated with extracellular matrix (ECM) turnover during myocardial remodeling. The aim of this study is to test the ability of (123)I-galectin-3 (IG3) to assess cardiac remodeling in a model of myocardial infarction (MI) using imaging techniques.

PET Imaging of Tumor-Associated Macrophages with 89Zr-Labeled High-Density Lipoprotein Nanoparticles.

Unlabelled: Tumor-associated macrophages (TAMs) are increasingly investigated in cancer immunology and are considered a promising target for better and tailored treatment of malignant growth. Although TAMs also have high diagnostic and prognostic value, TAM imaging still remains largely unexplored. Here, we describe the development of reconstituted high-density lipoprotein (rHDL)-facilitated TAM PET imaging in a breast cancer model.

Quantitative carotid PET/MR imaging: clinical evaluation of MR-Attenuation correction versus CT-Attenuation correction in (18)F-FDG PET/MR emission data and comparison to PET/CT.

Current PET/MR systems employ segmentation of MR images and subsequent assignment of empirical attenuation coefficients for quantitative PET reconstruction. In this study we examine the differences in the quantification of (18)F-FDG uptake in the carotid arteries between PET/MR and PET/CT scanners. Five comparisons were performed to asses differences in PET quantification: i) PET/MR MR-based AC (MRAC) versus PET/MR CTAC, ii) PET/MR MRAC versus PET/CT, iii) PET/MR MRAC with carotid coil versus PET/MR MRAC without coil, iv) PET/MR MRAC scan 2 versus PET/MR MRAC scan 1, and v) PET/MR CTAC versus PET/CT.

New Applications of Cardiac Computed Tomography: Dual-Energy, Spectral, and Molecular CT Imaging.

Computed tomography (CT) has evolved into a powerful diagnostic tool, and it is impossible to imagine current clinical practice without CT imaging. Because of its widespread availability, ease of clinical application, superb sensitivity for the detection of coronary artery disease, and noninvasive nature, CT has become a valuable tool within the armamentarium of cardiologists. In the past few years, numerous technological advances in CT have occurred, including dual-energy CT, spectral CT, and CT-based molecular imaging.

A Multicenter MRI Protocol for the Evaluation and Quantification of Deep Vein Thrombosis.

We evaluated a magnetic resonance venography (MRV) approach with gadofosveset to quantify total thrombus volume changes as the principal criterion for treatment efficacy in a multicenter randomized study comparing edoxaban monotherapy with a heparin/warfarin regimen for acute, symptomatic lower extremities deep vein thrombosis (DVT) treatment. We also used a direct thrombus imaging approach (DTHI, without the use of a contrast agent) to quantify fresh thrombus. We then sought to evaluate the reproducibility of the analysis methodology and applicability of using 3D magnetic resonance venography and direct thrombus imaging for the quantification of DVT in a multicenter trial setting.

Markerless attenuation correction for carotid MRI surface receiver coils in combined PET/MR imaging.

The purpose of the study was to evaluate the effect of attenuation of MR coils on quantitative carotid PET/MR exams. Additionally, an automated attenuation correction method for flexible carotid MR coils was developed and evaluated. The attenuation of the carotid coil was measured by imaging a uniform water phantom injected with 37 MBq of 18F-FDG in a combined PET/MR scanner for 24 min with and without the coil.

Impact of bariatric surgery on carotid artery inflammation and the metabolic activity in different adipose tissues.

In this study, we unravel a molecular imaging marker correlated with the known reduction of cardiovascular events (most commonly related to vulnerable plaques) in morbidly obese patients after bariatric surgery (BaS).We prospectively imaged 10 morbidly obese subjects with F-fluorodeoxyglucose (F-FDG) positron emission tomography/computed tomography before and 1 year after BaS. F-FDG uptake-which is enhanced in inflamed, atherosclerotic vessels and in metabolically active adipose tissues-was quantified in the carotids, pericardial adipose tissue (PAT), visceral adipose tissue (VAT), as well as brown adipose tissue (BAT).

The effect of BMS-582949, a P38 mitogen-activated protein kinase (P38 MAPK) inhibitor on arterial inflammation: a multicenter FDG-PET trial.

Objectives: This study evaluated the effect of p38 mitogen-activated protein kinase (p38MAPK) inhibitor, BMS-582949, on atherosclerotic plaque inflammation, using (18)FDG-PET imaging. p38MAPK is an important element of inflammatory pathways in atherothrombosis and its inhibition may lead to reduced inflammation within atherosclerotic plaques.

Methods: Subjects with documented atherosclerosis (n = 72) on stable low-dose statin therapy and having at least one lesion with active atherosclerotic plaque inflammation in either aorta or carotid arteries were randomized to BMS-582949 (100 mg once daily), placebo, or atorvastatin (80 mg once daily), for 12 weeks.

Simultaneous carotid PET/MR: feasibility and improvement of magnetic resonance-based attenuation correction.

Errors in quantification of carotid positron emission tomography (PET) in simultaneous PET/magnetic resonance (PET/MR) imaging when not incorporating bone in MR-based attenuation correction (MRAC) maps, and possible solutions, remain to be fully explored. In this study, we demonstrated techniques to improve carotid vascular PET/MR quantification by adding a bone tissue compartment to MRAC maps and deriving continuous Dixon-based MRAC (MRACCD) maps. We demonstrated the feasibility of applying ultrashort echo time-based bone segmentation and generation of continuous Dixon MRAC to improve PET quantification on five subjects.

HIF-1α and PFKFB3 Mediate a Tight Relationship Between Proinflammatory Activation and Anerobic Metabolism in Atherosclerotic Macrophages.

Objective: Although it is accepted that macrophage glycolysis is upregulated under hypoxic conditions, it is not known whether this is linked to a similar increase in macrophage proinflammatory activation and whether specific energy demands regulate cell viability in the atheromatous plaque.

Approach And Results: We studied the interplay between macrophage energy metabolism, polarization, and viability in the context of atherosclerosis. Cultured human and murine macrophages and an in vivo murine model of atherosclerosis were used to evaluate the mechanisms underlying metabolic and inflammatory activity of macrophages in the different atherosclerotic conditions analyzed.

Imaging systemic inflammatory networks in ischemic heart disease.

While acute myocardial infarction mortality declines, patients continue to face reinfarction and/or heart failure. The immune system, which intimately interacts with healthy and diseased tissues through resident and recruited leukocytes, is a central interface for a global host response to ischemia. Pathways that enhance the systemic leukocyte supply may be potential therapeutic targets.

Prednisolone-containing liposomes accumulate in human atherosclerotic macrophages upon intravenous administration.

Unlabelled: Drug delivery to atherosclerotic plaques via liposomal nanoparticles may improve therapeutic agents' risk-benefit ratios. Our paper details the first clinical studies of a liposomal nanoparticle encapsulating prednisolone (LN-PLP) in atherosclerosis. First, PLP's liposomal encapsulation improved its pharmacokinetic profile in humans (n=13) as attested by an increased plasma half-life of 63h (LN-PLP 1.

Pharmaceutical development and preclinical evaluation of a GMP-grade anti-inflammatory nanotherapy.

Unlabelled: The present study describes the development of a good manufacturing practice (GMP)-grade liposomal nanotherapy containing prednisolone phosphate for the treatment of inflammatory diseases. After formulation design, GMP production was commenced which yielded consistent, stable liposomes sized 100nm±10nm, with a prednisolone phosphate (PLP) incorporation efficiency of 3%-5%. Pharmacokinetics and toxicokinetics of GMP-grade liposomal nanoparticles were evaluated in healthy rats, which were compared to daily and weekly administration of free prednisolone phosphate, revealing a long circulatory half-life with minimal side effects.

A histological and functional description of the tissue causing chronic postthrombotic venous obstruction.

Background: Postthrombotic intraluminal tissue causing postthrombotic syndrome (PTS) has not been well described. This study defines its histological characteristics and assess whether tissue function evolves over time.

Methods: Specimens from 18 common femoral veins (CFV) from 16 patients obtained during CFV endovenectomy and iliocaval recanalization were examined.

A phase 2 randomized, double-blind, placebo-controlled study of the effect of VIA-2291, a 5-lipoxygenase inhibitor, on vascular inflammation in patients after an acute coronary syndrome.

Objective: Arachidonate 5-lipoxygenase (5-LO) is a key enzyme in the synthesis of leukotrienes. VIA-2291 is a potent 5-LO inhibitor, which has been shown to reduce hsCRP and noncalcified coronary plaque volume following an acute coronary syndrome (ACS). We aim to evaluate the effect of VIA-2291 on vascular inflammation compared to placebo using FDG-PET.

Elevated serum advanced glycation endproducts in obese indicate risk for the metabolic syndrome: a link between healthy and unhealthy obesity?

Context: Although obesity can predispose to the metabolic syndrome (MS), diabetes, and cardiovascular disease, not all obese subjects develop MS, hence the need for new indicators of risk for this syndrome. Advanced glycation end products (AGEs) correlate with factors involved in the MS, including inflammation and insulin resistance (IR). Because AGEs can be derived from food and are modifiable, it is important to determine whether they are a risk factor for MS.

Inflammation, Atherosclerosis, and Coronary Artery Disease: PET/CT for the Evaluation of Atherosclerosis and Inflammation.

Atherosclerosis is a prevalent cardiovascular disease marked by inflammation and the formation of plaque within arterial walls. As the disease progresses, there is an increased risk of major cardiovascular events. Owing to the nature of atherosclerosis, it is imperative to develop methods to further understand the physiological implications and progression of the disease.

HDL-mimetic PLGA nanoparticle to target atherosclerosis plaque macrophages.

High-density lipoprotein (HDL) is a natural nanoparticle that exhibits an intrinsic affinity for atherosclerotic plaque macrophages. Its natural targeting capability as well as the option to incorporate lipophilic payloads, e.g.

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.