Biomarkers in Acute Coronary Syndromes: High IP-10 Levels Identify Plaques with a Vulnerable Phenotype
Jonathan Lipton1; Dolf Segers1; Caroline Cheng1; H Duckers1; Rob Krams1; Dennie Tempel1; Els Busser2; Dominique de Kleijn2; FL Moll2; Gerard Pasterkamp2.1Erasmus MC, Rotterdam, The Netherlands, 2 Univ Med Cntr, Utrecht, The Netherlands.
Introduction: Atherosclerosis is considered a Th1 cell driven disease, directed by the key cytokine interferon-gamma. Th1 cells are in part recruited by the chemokine interferon-gamma inducible protein-10 (IP-10). Our previous studies in an animal model of vulnerable plaque identified IP-10 as a possible biomarker for rupture. The aim of this study was to validate these findings in endartherectomy tissue and corresponding plasma.
Methods: IP-10 content of 109 human end-atherectomies and corresponding plasmas from the Athero-express database was analyzed.
Results: In high IP-10 quartiles, 69% of plaques were atheromatous, whereas the lowest quartile consisted of 68% fibrous plaques (p<0.001). CRP and ApoB failed to show such characteristics. Furthermore, higher IP-10 concentrations were associated with a gradual reduction in smooth muscle cell and collagen content, while macrophage numbers remained fairly constant. Consequently, IP-10 is dose dependently associated with a more vulnerable phenotype. Following, we selected high and low quartile serum levels of IP-10 (n=10, n=9 respectively) to predict tissue IP-10 levels. Despite this small sample size a clear trend was noted in plasma (126±69 vs. 214±208pg/ml, for low and high quartiles, respectively).
Conclusion: In animal studies we identified IP-10 as possible biomarker. This study confirmed these findings, by showing that IP-10 levels in human carotid plaques identifies plaques with a more vulnerable phenotype. Further studies may prove a similar role for plasma IP-10, which might be an interesting biomarker for vulnerable plaque diagnosis. link to abstract AHA2006
Atherosclerotic plaque stability is affected by the chemokine CXCL10 in both mice and humans
Dolf Segers, MD; Jonathan A. Lipton, MD; Pieter J. M. Leenen, PhD; Caroline Cheng, PhD; Dennie Tempel, Bsc; Henricus J. Duckers, MD, PhD; Gerard Pasterkamp, MD, PhD; Frans L. Moll, MD, PhD; Rini de Crom, PhD and Rob Krams, MD, PhD. Dept. of Cardiology (DS, JL, CH, DT, HD), Immunology (PL), and Cell Biology & Genetics (RdC) Erasmus University Medical Center, Rotterdam, The Netherlands. Dept. of Cardiology (GP) and Vascular Surgery (FM), University Medical Center Utrecht, The Netherlands. Dept. Bioengineering, Imperial College, London, United Kingdom (RK)
Background: We previously found the chemokine CXCL10 gene to be specifically upregulated early during experimental development of plaque with an unstable phenotype. In this study we evaluated the functional consequences of these findings in mice and subsequently whether these findings expressed importance for human vulnerable plaque development.
Methods and Results: In ApoE-/- mice, we induced unstable plaque with a flow-altering device around the carotid artery. From week 1-4, mice were injected with a bioactivity-neutralizing CXCL10 antibody. After 9 weeks, lesion compositions of plaques were evaluated. CXCL10 inhibition resulted in a more stable plaque phenotype: collagen increased by 58% (p=0.002), smooth muscle cell content increased 2-fold (p=0.03), while macrophage activation decreased by 50% (p=0.005). Also, the size of necrotic cores decreased by 41% (p=0.01). Next, in 106 human carotid endarterectomy specimens we measured concentrations of CXCL10 protein and tested for association with plaque morphology. We found that increasing concentrations of CXCL10 strongly associate with an increase in atheromatous plaque phenotype (ANOVA, p=0.003), with high macrophage, low smooth muscle cell and low collagen content.
Conclusions: In the present study we show that a causal relationship exists between local production of CXCL10 and development of vulnerable plaque. Inhibition of CXCL10 in a mouse model showed its functional involvement, while human endarterectomy analysis indicated an association between lesion morphology and the concentration of CXCL10. We conclude that CXCL10 might provide a new lead towards plaque stabilizing therapy.
This manuscript has been submitted to JACC