Carotid Plaque Inflammation Imaged by PET and Prediction of Recurrent Stroke at 5 Years

McCabe, John; Camps‐Renom, Pol; Giannotti, Nicola; McNulty, Jonathan P.; Coveney, Sarah; Murphy, Seán; Barry, Mary; Harbison, Joseph; Cronin, Simon; Williams, David J.; Horgan, Gillian; Cassidy, Tim; McDonnell, Ciarán; Kavanagh, Eoin; Foley, Shane; Collins, Seán; O’Connell, Martin; Fernández-León, Alejandro; Delgado‐Mederos, Raquel; Marnane, Michael; Martí‐Fàbregas, Joan; Kelly, Peter

doi:10.1212/wnl.0000000000012909

Cited by 25 publications

(40 citation statements)

References 28 publications

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“…161,162 An increasing number of studies show that increased uptake of 18 F-FDG in carotid PET imaging is associated with higher risk of future strokes. 156,163,164 Recently developed radiotracers may increase specificity. 165 Indeed, a radiotracer developed to specifically capture CCR2 expression ( 64 Cu-DOTA-ECL1i) shows high promise as a potentially specific biomarker for response to treatments interfering with the CCL2/CCR2 axis.…”

Section: Considerations For Clinical Translationmentioning

confidence: 99%

Targeting the CCL2–CCR2 axis for atheroprotection

Georgakis

Bernhagen

Heitman

et al. 2022

European Heart Journal

100

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Decades of research have established atherosclerosis as an inflammatory disease. Only recently though, clinical trials provided proof-of-concept evidence for the efficacy of anti-inflammatory strategies with respect to cardiovascular events, thus offering a new paradigm for lowering residual vascular risk. Efforts to target the inflammasome–interleukin-1β–interleukin-6 pathway have been highly successful, but inter-individual variations in drug response, a lack of reduction in all-cause mortality, and a higher rate of infections also highlight the need for a second generation of anti-inflammatory agents targeting atherosclerosis-specific immune mechanisms while minimizing systemic side effects. CC-motif chemokine ligand 2/monocyte-chemoattractant protein-1 (CCL2/MCP-1) orchestrates inflammatory monocyte trafficking between the bone marrow, circulation, and atherosclerotic plaques by binding to its cognate receptor CCR2. Adding to a strong body of data from experimental atherosclerosis models, a coherent series of recent large-scale genetic and observational epidemiological studies along with data from human atherosclerotic plaques highlight the relevance and therapeutic potential of the CCL2–CCR2 axis in human atherosclerosis. Here, we summarize experimental and human data pinpointing the CCL2–CCR2 pathway as an emerging drug target in cardiovascular disease. Furthermore, we contextualize previous efforts to interfere with this pathway, scrutinize approaches of ligand targeting vs. receptor targeting, and discuss possible pathway-intrinsic opportunities and challenges related to pharmacological targeting of the CCL2–CCR2 axis in human atherosclerotic disease.

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Section: Considerations For Clinical Translationmentioning

confidence: 99%

Targeting the CCL2–CCR2 axis for atheroprotection

Georgakis

Bernhagen

Heitman

et al. 2022

European Heart Journal

100

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“…Imaging methods currently under development, such as PET-based assessment of plaque inflammation could prove useful in this regard. 54 Third, pooling studies in a meta-analysis offered sufficient power to detect highly consistent effects for an effect of CCL2/CCR2 inhibition on plaque features beyond plaque size, which emphasizes the potential utility of this approach for patients with established atherosclerotic lesions. Fourth, our finding of a stronger effect on carotid and femoral lesions has implications for the selection of target populations that could benefited from such approaches.…”

Section: Discussionmentioning

confidence: 99%

Pharmacological Targeting of the CCL2/CCR2 Axis for Atheroprotection: A Meta-Analysis of Preclinical Studies

Živković¹,

Asare²,

Bernhagen

et al. 2022

ATVB

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Background: The CCL2 (CC-chemokine ligand 2)/CCR2 (CC-chemokine receptor 2) axis governs monocyte recruitment to atherosclerotic lesions. Genetic and epidemiological studies show strong associations of CCL2 levels with atherosclerotic disease. Still, experimental studies testing pharmacological inhibition of CCL2 or CCR2 in atheroprone mice apply widely different approaches and report variable results, thus halting clinical translation. Methods: We systematically searched the literature for studies employing pharmacological CCL2/CCR2 blockade in atheroprone mice and meta-analyzed their effects on lesion size and morphology. Results: In a meta-analysis of 14 studies testing 11 different agents, CCL2/CCR2 blockade attenuated atherosclerotic lesion size in the aortic root or arch ( g =−0.75 [−1.17 to −0.32], P =6×10 − 4 ; N=171/171 mice in experimental/control group), the carotid ( g =−2.39 [−4.23 to −0.55], P =0.01; N=24/25), and the femoral artery ( g =−2.38 [−3.50 to −1.26], P =3×10 − 5 ; N=10/10). Furthermore, CCL2/CCR2 inhibition reduced intralesional macrophage accumulation and increased smooth muscle cell content and collagen deposition. The effects of CCL2/CCR2 inhibition on lesion size correlated with reductions in plaque macrophage accumulation, in accord with a prominent role of CCL2/CCR2 signaling in monocyte recruitment. Subgroup analyses showed comparable efficacy of different CCL2- and CCR2-inhibitors in reducing lesion size and intralesional macrophages. The quality assessment revealed high risk of detection bias due to lack of blinding during outcome assessment, as well as evidence of attrition and reporting bias. Conclusions: Preclinical evidence suggests that pharmacological targeting of CCL2 or CCR2 might lower atherosclerotic lesion burden, but the majority of existing studies suffer major quality issues that highlight the need for additional high-quality research.

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“…43-45 Plaque rupture has been connected through increasing evidence to systemic and focal inflammation and might contribute to the association of hsCRP with pWMH and dWMH found in our study as well. 46-48…”

Section: Discussionmentioning

confidence: 99%

Association of Carotid Plaque and Flow Velocity With White Matter Integrity in a Middle-aged to Elderly Population

et al. 2022

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Background and Objectives:It is uncertain whether there is an association of carotid plaques (CP) and flow velocities with peak-width mean diffusivity (PSMD) and white matter hyperintensities (WMH) independent of shared risk factors. We aimed to study this association controlling for biomarkers of inflammation and cardiac dysfunction as well as typical cardiovascular risk factors and spatial distribution.Methods:We included participant from the population-based Hamburg City Health Study, recruiting citizens between 45 and 74 years of age. Medical history was obtained from structured interviews and extended laboratory tests, physical examinations, MRI of the head, echocardiography, abdominal and carotid ultrasound were performed. We performed multivariable regression analysis with PSMD, periventricular, deep, and total volume of WMH (pWMH, dWMH, tWMH) as dependent variables. PSMD was calculated as the difference between the 95th and 5th percentile of MD values on the white skeleton in standard space Volumes of WMH were determined by application of a manually trained k-nearest neighbor segmentation algorithm. WMH measured within a distance of 1 cm from the surface of the lateral ventricles were defined as pWMH, and above 1 cm as dWMH.Results:2623 participants were included. Median age was 65 years and 56% were women. Their median tWMH was 946 mm3(IQR:419, 2164), PSMD 2.24 mm2 /s x 10-4 (IQR: 2.04,2.47), peak systolic velocity (PSV) of internal carotid arteries 0.70m/sec (IQR:0.60, 0.81), and 35% had CP. Adjusted for age, sex, high-sensitive CRP, NT-proBNP, and commonly measured cardiovascular risk and systemic hemodynamic factors, both CP (B=0.15;CI:0.04, 0.26;p=0.006) and low PSV (B=-0.49; CI:-0.87,-0.11;p=0.012) were significantly associated with a higher tWMH and PSMD. Low PSV(B=-0.48;CI:-0.87,-0.1;p=0.013) was associated with pWMH, and presence of CP with pWMH (B=0.15; CI:0.04,0.26; p=0.008) and dWMH (B=0.42; CI:0.11,0.74; p<0.009).Conclusion:Low PSV and CP are associated with WMH and PSMD independent of cardiovascular risk factors and biomarkers of inflammation and cardiac dysfunction. This points towards pathophysiological pathways underlying both large and small vessel disease beyond the common cardiovascular risk profile.Trial Registration Information:The trial was submitted at www.clinicaltrials.gov, under NCT03934957 on January 4 2019. The first participant was enrolled in February 2016.

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Carotid Plaque Inflammation Imaged by PET and Prediction of Recurrent Stroke at 5 Years

Cited by 25 publications

References 28 publications

Targeting the CCL2–CCR2 axis for atheroprotection

Targeting the CCL2–CCR2 axis for atheroprotection

Pharmacological Targeting of the CCL2/CCR2 Axis for Atheroprotection: A Meta-Analysis of Preclinical Studies

Association of Carotid Plaque and Flow Velocity With White Matter Integrity in a Middle-aged to Elderly Population

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