TY  - JOUR
A1  - Andelovic, Kristina
A1  - Winter, Patrick
A1  - Jakob, Peter Michael
A1  - Bauer, Wolfgang Rudolf
A1  - Herold, Volker
A1  - Zernecke, Alma
T1  - Evaluation of plaque characteristics and inflammation using magnetic resonance imaging
JF  - Biomedicines
N2  - Atherosclerosis is an inflammatory disease of large and medium-sized arteries, characterized by the growth of atherosclerotic lesions (plaques). These plaques often develop at inner curvatures of arteries, branchpoints, and bifurcations, where the endothelial wall shear stress is low and oscillatory. In conjunction with other processes such as lipid deposition, biomechanical factors lead to local vascular inflammation and plaque growth. There is also evidence that low and oscillatory shear stress contribute to arterial remodeling, entailing a loss in arterial elasticity and, therefore, an increased pulse-wave velocity. Although altered shear stress profiles, elasticity and inflammation are closely intertwined and critical for plaque growth, preclinical and clinical investigations for atherosclerosis mostly focus on the investigation of one of these parameters only due to the experimental limitations. However, cardiovascular magnetic resonance imaging (MRI) has been demonstrated to be a potent tool which can be used to provide insights into a large range of biological parameters in one experimental session. It enables the evaluation of the dynamic process of atherosclerotic lesion formation without the need for harmful radiation. Flow-sensitive MRI provides the assessment of hemodynamic parameters such as wall shear stress and pulse wave velocity which may replace invasive and radiation-based techniques for imaging of the vascular
function and the characterization of early plaque development. In combination with inflammation imaging, the analyses and correlations of these parameters could not only significantly advance basic preclinical investigations of atherosclerotic lesion formation and progression, but also the diagnostic clinical evaluation for early identification of high-risk plaques, which are prone to rupture. In this review, we summarize the key applications of magnetic resonance imaging for the evaluation of plaque characteristics through flow sensitive and morphological measurements. The simultaneous measurements of functional and structural parameters will further preclinical research on atherosclerosis and has the potential to fundamentally improve the detection of inflammation and vulnerable plaques in patients.
KW  - atherosclerosis
KW  - mouse models
KW  - wall shear stress
KW  - pulse wave velocity
KW  - arterial elasticity
KW  - inflammation
KW  - magnetic resonance imaging
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-228839
SN  - 2227-9059
VL  - 9
IS  - 2
ER  - 
TY  - JOUR
A1  - Andelovic, Kristina
A1  - Winter, Patrick
A1  - Kampf, Thomas
A1  - Xu, Anton
A1  - Jakob, Peter Michael
A1  - Herold, Volker
A1  - Bauer, Wolfgang Rudolf
A1  - Zernecke, Alma
T1  - 2D Projection Maps of WSS and OSI Reveal Distinct Spatiotemporal Changes in Hemodynamics in the Murine Aorta during Ageing and Atherosclerosis
JF  - Biomedicines
N2  - Growth, ageing and atherosclerotic plaque development alter the biomechanical forces acting on the vessel wall. However, monitoring the detailed local changes in wall shear stress (WSS) at distinct sites of the murine aortic arch over time has been challenging. Here, we studied the temporal and spatial changes in flow, WSS, oscillatory shear index (OSI) and elastic properties of healthy wildtype (WT, n = 5) and atherosclerotic apolipoprotein E-deficient (Apoe\(^{−/−}\), n = 6) mice during ageing and atherosclerosis using high-resolution 4D flow magnetic resonance imaging (MRI). Spatially resolved 2D projection maps of WSS and OSI of the complete aortic arch were generated, allowing the pixel-wise statistical analysis of inter- and intragroup hemodynamic changes over time and local correlations between WSS, pulse wave velocity (PWV), plaque and vessel wall characteristics. The study revealed converse differences of local hemodynamic profiles in healthy WT and atherosclerotic Apoe\(^{−/−}\) mice, and we identified the circumferential WSS as potential marker of plaque size and composition in advanced atherosclerosis and the radial strain as a potential marker for vascular elasticity. Two-dimensional (2D) projection maps of WSS and OSI, including statistical analysis provide a powerful tool to monitor local aortic hemodynamics during ageing and atherosclerosis. The correlation of spatially resolved hemodynamics and plaque characteristics could significantly improve our understanding of the impact of hemodynamics on atherosclerosis, which may be key to understand plaque progression towards vulnerability.
KW  - atherosclerosis
KW  - mouse
KW  - 4D flow MRI
KW  - aortic arch
KW  - flow dynamics
KW  - WSS
KW  - mapping
KW  - PWV
KW  - plaque characteristics
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-252164
SN  - 2227-9059
VL  - 9
IS  - 12
ER  - 
TY  - JOUR
A1  - Cochain, Clement
A1  - Chaudhari, Sweena M.
A1  - Koch, Miriam
A1  - Wiendl, Heinz
A1  - Eckstein, Hans-Henning
A1  - Zernecke, Alma
T1  - Programmed Cell Death-1 Deficiency Exacerbates T Cell Activation and Atherogenesis despite Expansion of Regulatory T Cells in Atherosclerosis-Prone Mice
JF  - PLoS ONE
N2  - T cell activation represents a double-edged sword in atherogenesis, as it promotes both pro-inflammatory T cell activation and atheroprotective Foxp3(+) regulatory T cell (Treg) responses. Here, we investigated the role of the co-inhibitory receptor programmed cell death-1 (PD-1) in T cell activation and CD4(+) T cell polarization towards pro-atherogenic or atheroprotective responses in mice. Mice deficient for both low density lipoprotein receptor and PD-1 (Ldlr(-/-)Pd1(-/-)) displayed striking increases in systemic CD4(+) and CD8(+) T cell activation after 9 weeks of high fat diet feeding, associated with an expansion of both pro-atherogenic IFNγ-secreting T helper 1 cells and atheroprotective Foxp3+ Tregs. Importantly, PD-1 deficiency did not affect Treg suppressive function in vitro. Notably, PD-1 deficiency exacerbated atherosclerotic lesion growth and entailed a massive infiltration of T cells in atherosclerotic lesions. In addition, aggravated hypercholesterolemia was observed in Ldlr(-/-)Pd1(-/-) mice. In conclusion, we here demonstrate that although disruption of PD-1 signaling enhances both pro- and anti-atherogenic T cell responses in Ldlr(-/-) mice, pro-inflammatory T cell activation prevails and enhances dyslipidemia, vascular inflammation and atherosclerosis.
KW  - nutritional deficiencies
KW  - atherosclerosis
KW  - spleen
KW  - aorta
KW  - diet
KW  - cytotoxic T cells
KW  - regulatory T cells
KW  - T cells
Y1  - 2014
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-119823
SN  - 1932-6203
VL  - 9
IS  - 4
ER  - 
TY  - JOUR
A1  - Gil-Pulido, Jesus
A1  - Cochain, Clement
A1  - Lippert, Malte A.
A1  - Schneider, Nicole
A1  - Butt, Elke
A1  - Amézaga, Núria
A1  - Zernecke, Alma
T1  - Deletion of Batf3-dependent antigen-presenting cells does not affect atherosclerotic lesion formation in mice
JF  - PLoS ONE
N2  - Atherosclerosis is the main underlying cause for cardiovascular events such as myocardial infarction and stroke and its development might be influenced by immune cells. Dendritic cells (DCs) bridge innate and adaptive immune responses by presenting antigens to T cells and releasing a variety of cytokines. Several subsets of DCs can be discriminated that engage specific transcriptional pathways for their development. Basic leucine zipper transcription factor ATF-like 3 (Batf3) is required for the development of classical CD8α\(^{+}\) and CD103\(^{+}\) DCs. By crossing mice deficient in Batf3 with atherosclerosis-prone low density lipoprotein receptor (Ldlr\(^{−/-}\))-deficient mice we here aimed to further address the contribution of Batf3-dependent CD8α\(^{+}\) and CD103\(^{+}\) antigen-presenting cells to atherosclerosis. We demonstrate that deficiency in Batf3 entailed mild effects on the immune response in the spleen but did not alter atherosclerotic lesion formation in the aorta or aortic root, nor affected plaque phenotype in low density lipoprotein receptor-deficient mice fed a high fat diet. We thus provide evidence that Batf3-dependent antigen-presenting cells do not have a prominent role in atherosclerosis.
KW  - atherosclerosis
KW  - dendritic cells
KW  - Batf3
KW  - deficiency
Y1  - 2017
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-170535
VL  - 12
IS  - 8
ER  - 
TY  - JOUR
A1  - Schäfer, Sarah
A1  - Zernecke, Alma
T1  - CD8\(^+\) T cells in atherosclerosis
JF  - Cells
N2  - Atherosclerotic lesions are populated by cells of the innate and adaptive immune system, including CD8\(^+\) T cells. The CD8\(^+\) T cell infiltrate has recently been characterized in mouse and human atherosclerosis and revealed activated, cytotoxic, and possibly dysfunctional and exhausted cell phenotypes. In mouse models of atherosclerosis, antibody-mediated depletion of CD8\(^+\) T cells ameliorates atherosclerosis. CD8\(^+\) T cells control monopoiesis and macrophage accumulation in early atherosclerosis. In addition, CD8\(^+\) T cells exert cytotoxic functions in atherosclerotic plaques and contribute to macrophage cell death and necrotic core formation. CD8\(^+\) T cell activation may be antigen-specific, and epitopes of atherosclerosis-relevant antigens may be targets of CD8\(^+\) T cells and their cytotoxic activity. CD8\(^+\) T cell functions are tightly controlled by costimulatory and coinhibitory immune checkpoints. Subsets of regulatory CD25\(^+\)CD8\(^+\) T cells with immunosuppressive functions can inhibit atherosclerosis. Importantly, local cytotoxic CD8\(^+\) T cell responses may trigger endothelial damage and plaque erosion in acute coronary syndromes. Understanding the complex role of CD8\(^+\) T cells in atherosclerosis may pave the way for defining novel treatment approaches in atherosclerosis. In this review article, we discuss these aspects, highlighting the emerging and critical role of CD8\(^+\) T cells in atherosclerosis.
KW  - atherosclerosis
KW  - CD8\(^+\) T cells
KW  - inflammation
KW  - cytotoxic T cells
KW  - single cell RNA sequencing
KW  - checkpoint inhibitors
KW  - immunotherapy
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-220170
SN  - 2073-4409
VL  - 10
IS  - 1
ER  - 
TY  - JOUR
A1  - Soehnlein, Oliver
A1  - Drechsler, Maik
A1  - Döring, Yvonne
A1  - Lievens, Dirk
A1  - Hartwig, Helene
A1  - Kemmerich, Klaus
A1  - Ortega-Gómez, Almudena
A1  - Mandl, Manuela
A1  - Vijayan, Santosh
A1  - Projahn, Delia
A1  - Garlichs, Christoph D.
A1  - Koenen, Rory R.
A1  - Hristov, Mihail
A1  - Lutgens, Esther
A1  - Zernecke, Alma
A1  - Weber, Christian
T1  - Distinct functions of chemokine receptor axes in the atherogenic mobilization and recruitment of classical monocytes
JF  - EMBO Molecular Medicine
N2  - We used a novel approach of cytostatically induced leucocyte depletion and subsequent reconstitution with leucocytes deprived of classical \((inflammatory/Gr1^{hi})\) or non-classical \((resident/Gr1^{lo})\) monocytes to dissect their differential role in atheroprogression under high-fat diet (HFD). Apolipoprotein E-deficient \((Apoe^{-/-})\) mice lacking classical but not non-classical monocytes displayed reduced lesion size and macrophage and apoptotic cell content. Conversely, HFD induced a selective expansion of classical monocytes in blood and bone marrow. Increased CXCL1 levels accompanied by higher expression of its receptor CXCR2 on classical monocytes and inhibition of monocytosis by CXCL1-neutralization indicated a preferential role for the CXCL1/CXCR2 axis in mobilizing classical monocytes during hypercholesterolemia. Studies correlating circulating and lesional classical monocytes in gene-deficient \(Apoe^{-/-}\) mice, adoptive transfer of gene-deficient cells and pharmacological modulation during intravital microscopy of the carotid artery revealed a crucial function of CCR1 and CCR5 but not CCR2 or \(CX_3CR1\) in classical monocyte recruitment to atherosclerotic vessels. Collectively, these data establish the impact of classical monocytes on atheroprogression, identify a sequential role of CXCL1 in their mobilization and CCR1/CCR5 in their recruitment.
KW  - hypercholeterolemia
KW  - CCR2
KW  - atherosclerosis
KW  - chemokine
KW  - accumulation
KW  - subsets
KW  - inflammatory sites
KW  - fractalkine
KW  - marcophages
KW  - mobilization
KW  - monocyte
KW  - recruitment
KW  - bone-marrow
KW  - atheriosclerotic lesions
KW  - hyperlipedemic mice
Y1  - 2013
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-122204
SN  - 1757-4676
VL  - 5
ER  - 
TY  - JOUR
A1  - Winter, Patrick M.
A1  - Andelovic, Kristina
A1  - Kampf, Thomas
A1  - Hansmann, Jan
A1  - Jakob, Peter Michael
A1  - Bauer, Wolfgang Rudolf
A1  - Zernecke, Alma
A1  - Herold, Volker
T1  - Simultaneous measurements of 3D wall shear stress and pulse wave velocity in the murine aortic arch
JF  - Journal of Cardiovascular Magnetic Resonance
N2  - Purpose

Wall shear stress (WSS) and pulse wave velocity (PWV) are important parameters to characterize blood flow in the vessel wall. Their quantification with flow-sensitive phase-contrast (PC) cardiovascular magnetic resonance (CMR), however, is time-consuming. Furthermore, the measurement of WSS requires high spatial resolution, whereas high temporal resolution is necessary for PWV measurements. For these reasons, PWV and WSS are challenging to measure in one CMR session, making it difficult to directly compare these parameters. By using a retrospective approach with a flexible reconstruction framework, we here aimed to simultaneously assess both PWV and WSS in the murine aortic arch from the same 4D flow measurement.

Methods

Flow was measured in the aortic arch of 18-week-old wildtype (n = 5) and ApoE\(^{−/−}\) mice (n = 5) with a self-navigated radial 4D-PC-CMR sequence. Retrospective data analysis was used to reconstruct the same dataset either at low spatial and high temporal resolution (PWV analysis) or high spatial and low temporal resolution (WSS analysis). To assess WSS, the aortic lumen was labeled by semi-automatically segmenting the reconstruction with high spatial resolution. WSS was determined from the spatial velocity gradients at the lumen surface. For calculation of the PWV, segmentation data was interpolated along the temporal dimension. Subsequently, PWV was quantified from the through-plane flow data using the multiple-points transit-time method. Reconstructions with varying frame rates and spatial resolutions were performed to investigate the influence of spatiotemporal resolution on the PWV and WSS quantification.

Results

4D flow measurements were conducted in an acquisition time of only 35 min. Increased peak flow and peak WSS values and lower errors in PWV estimation were observed in the reconstructions with high temporal resolution. Aortic PWV was significantly increased in ApoE\(^{−/−}\) mice compared to the control group (1.7 ± 0.2 versus 2.6 ± 0.2 m/s, p < 0.001). Mean WSS magnitude values averaged over the aortic arch were (1.17 ± 0.07) N/m\(^2\) in wildtype mice and (1.27 ± 0.10) N/m\(^2\) in ApoE\(^{−/−}\) mice.

Conclusion

The post processing algorithm using the flexible reconstruction framework developed in this study permitted quantification of global PWV and 3D-WSS in a single acquisition. The possibility to assess both parameters in only 35 min will markedly improve the analyses and information content of in vivo measurements.
KW  - 4D flow
KW  - pulse wave velocity
KW  - wall shear stress
KW  - radial
KW  - self-navigation
KW  - mouse
KW  - aortic arch
KW  - atherosclerosis
KW  - mice
KW  - flow
KW  - plaque
KW  - CMR
KW  - quantification
KW  - microscopy
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-259152
VL  - 23
IS  - 1
ER  -