Early in vivo discrimination of vulnerable atherosclerotic plaques that disrupt: A serial MRI study

Background Current drug therapy of atherosclerosis is focused on treatment of major risk factors, e.g. hypercholesterolemia while in the future direct disease modification might provide additional benefits. However, development of medicines targeting vascular wall disease is complicated by the lack of reliable biomarkers. In this study, we took a novel approach to identify circulating biomarkers indicative of drug efficacy by reducing the complexity of the in vivo system to the level where neither disease progression nor drug treatment was associated with the changes in plasma cholesterol. Results ApoE-/- mice were treated with an ACE inhibitor ramipril and HMG-CoA reductase inhibitor simvastatin. Ramipril significantly reduced the size of atherosclerotic plaques in brachiocephalic arteries, however simvastatin paradoxically stimulated atherogenesis. Both effects occurred without changes in plasma cholesterol. Blood and vascular samples were obtained from the same animals. In the whole blood RNA samples, expression of MMP9, CD14 and IL-1RN reflected pro-and anti-atherogenic drug effects. In the plasma, several proteins, e.g. IL-1β, IL-18 and MMP9 followed similar trends while protein readout was less sensitive than RNA analysis. Conclusion In this study, we have identified inflammation-related whole blood RNA and plasma protein markers reflecting anti-atherogenic effects of ramipril and pro-atherogenic effects of simwastatin in a mouse model of atherosclerosis. This opens an opportunity for early, non-invasive detection of direct drug effects on atherosclerotic plaques in complex in vivo systems.

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Silencing of junctional adhesion molecule-like protein attenuates atherogenesis and enhances plaque stability in ApoE−/− mice

Clinical Science ◽

10.1042/cs20180561 ◽

2019 ◽

Vol 133 (11) ◽

pp. 1215-1228 ◽

Cited By ~ 1

Author(s):

Yu Sun ◽

Juan Guan ◽

Yunfeng Hou ◽

Fei Xue ◽

Wei Huang ◽

...

Keyword(s):

Adhesion Molecule ◽

Wound Repair ◽

Inflammatory Responses ◽

Atherosclerotic Lesion ◽

Atherosclerotic Plaques ◽

Plaque Stability ◽

Fibrous Cap ◽

Enhanced Expression

Abstract Background: Although junctional adhesion molecule-like protein (JAML) has recently been implicated in leukocyte recruitment during inflammation and wound repair, its role in atherosclerosis remains to be elucidated. Methods and results: First, we showed that JAML was strongly expressed in atherosclerotic plaques of cardiovascular patients. Similar results were obtained with atherosclerotic plaques of ApoE−/− mice. Co-immunofluorescence staining showed that JAML was mainly expressed in macrophages. Enhanced expression of JAML in cultured macrophages was observed following exposure of the cells to oxLDL. The functional role of JAML in atherosclerosis and macrophages function was assessed by interference of JAML with shRNA in vivo and siRNA in vitro. Silencing of JAML in mice significantly attenuated atherosclerotic lesion formation, reduced necrotic core area, increased plaque fibrous cap thickness, decreased macrophages content and inflammation. In addition, histological staining showed that JAML deficiency promoted plaques to stable phenotype. In vitro, JAML siRNA treatment lowered the expression of inflammatory cytokines in macrophages treated with oxLDL. The mechanism by which JAML mediated the inflammatory responses may be related to the ERK/NF-κB activation. Conclusions: Our results demonstrated that therapeutic drugs which antagonize the function of JAML may be a potentially effective approach to attenuate atherogenesis and enhance plaque stability.

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Assessment of Albumin ECM Accumulation and Inflammation as Novel In Vivo Diagnostic Targets for Multi-Target MR Imaging

Biology ◽

10.3390/biology10100964 ◽

2021 ◽

Vol 10 (10) ◽

pp. 964

Author(s):

Jana Möckel ◽

Julia Brangsch ◽

Carolin Reimann ◽

Jan O. Kaufmann ◽

Ingolf Sack ◽

...

Keyword(s):

Inductively Coupled Plasma ◽

Endothelial Damage ◽

Plaque Burden ◽

Signal Loss ◽

Inductively Coupled ◽

Before And After ◽

Plasma Mass Spectrometry ◽

Magnetic Resonance Imaging Mri ◽

Mri Study

Atherosclerosis is a progressive inflammatory vascular disease characterized by endothelial dysfunction and plaque burden. Extracellular matrix (ECM)-associated plasma proteins play an important role in disease development. Our magnetic resonance imaging (MRI) study investigates the feasibility of using two different molecular MRI probes for the simultaneous assessment of ECM-associated intraplaque albumin deposits caused by endothelial damage and progressive inflammation in atherosclerosis. Male apolipoprotein E-deficient (ApoE-/-)-mice were fed a high-fat diet (HFD) for 2 or 4 months. Another ApoE-/--group was treated with pravastatin and received a HFD for 4 months. T1- and T2*-weighted MRI was performed before and after albumin-specific MRI probe (gadofosveset) administration and a macrophage-specific contrast agent (ferumoxytol). Thereafter, laser ablation inductively coupled plasma mass spectrometry and histology were performed. With advancing atherosclerosis, albumin-based MRI signal enhancement and ferumoxytol-induced signal loss areas in T2*-weighted MRI increased. Significant correlations between contrast-to-noise-ratio (CNR) post-gadofosveset and albumin stain (R2 = 0.78, p < 0.05), and signal loss areas in T2*-weighted MRI with Perls’ Prussian blue stain (R2 = 0.83, p < 0.05) were observed. No interference of ferumoxytol with gadofosveset enhancement was detectable. Pravastatin led to decreased inflammation and intraplaque albumin. Multi-target MRI combining ferumoxytol and gadofosveset is a promising method to improve diagnosis and treatment monitoring in atherosclerosis.

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Exploring the Relationships Between Hemodynamic Stresses in the Carotid Arteries

Frontiers in Cardiovascular Medicine ◽

10.3389/fcvm.2020.617755 ◽

2021 ◽

Vol 7 ◽

Author(s):

Magnus Ziegler ◽

Jesper Alfraeus ◽

Elin Good ◽

Jan Engvall ◽

Ebo de Muinck ◽

...

Keyword(s):

Vessel Wall ◽

Carotid Arteries ◽

Carotid Bifurcation ◽

Vessel Diameter ◽

Atherosclerotic Plaques ◽

Shear Stresses ◽

Strongly Correlated ◽

4D Flow ◽

Bifurcation Angle

Background: Atherosclerosis manifests as a focal disease, often affecting areas with complex hemodynamics such as the carotid bifurcation. The magnitude and regularity of the hemodynamic shear stresses acting on the vessel wall are thought to generate risk patterns unique to each patient and play a role in the pathogenesis of atherosclerosis. The involvement of different expressions of shear stress in the pathogenesis of carotid atherosclerosis highlights the need to characterize and compare the differential impact of the various expressions of shear stress in the atherosclerotic carotid bifurcation. Therefore, the aim of this study is to characterize and compare hemodynamic wall shear stresses (WSS) in the carotid arteries of subjects with asymptomatic atherosclerotic plaques. Shear stresses were also compared against vessel diameter and bifurcation angle to examine the relationships with the geometry of the carotid bifurcation.Methods: 4D Flow MRI and contrast-enhanced MRA data were acquired for 245 subjects with atherosclerotic plaques of at least 2.7 mm in conjunction with the Swedish CArdioPulmonary bioImage Study (SCAPIS). Following automatic segmentation and geometric analysis, time-resolved WSS and near-wall turbulent kinetic energy (nwTKE) were derived from the 4D Flow data. Whole-cycle parameters including time-averaged WSS and nwTKE, and the oscillatory shear index (OSI) were calculated. Pairwise Spearman rank-correlation analyses were used to investigate relationships among the hemodynamic as well as geometric parameters.Results: One hundred and seventy nine subjects were successfully segmented using automated tools and subsequently geometric and hemodynamic analyses were performed. Temporally resolved WSS and nwTKE were strongly correlated, ρ = 0.64. Cycle-averaged WSS and nwTKE were moderately correlated, ρ = 0.57. Cycle-average nwTKE was weakly correlated to OSI (ρ = −0.273), revealing that nwTKE provides information about disturbed flow on the vessel wall that OSI does not. In this cohort, there was large inter-individual variation for both WSS and nwTKE. Both WSS and nwTKE varied most within the external carotid artery. WSS, nwTKE, and OSI were weakly correlated to vessel diameter and bifurcation angle.Conclusion: The turbulent and mean component of WSS were examined together in vivo for the first time, and a strong correlation was found between them. nwTKE presents the opportunity to quantify turbulent wall stresses in vivo and gain insight into the effects of disturbed flow on the vessel wall. Neither vessel diameter nor bifurcation angle were found to be strongly correlated to the turbulent or mean component of WSS in this cohort.

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