Elevated Serum Levels of Soluble ST2 Are Associated With Plaque Vulnerability in Patients With Non-ST-Elevation Acute Coronary Syndrome

Guqing Luo, Yuxuan Qian, Xincheng Sheng, Jiateng Sun, Zhinan Wu, Fei Liao, Qi Feng, Yan Yin, Song Ding, Jun Pu, Guqing Luo, Yuxuan Qian, Xincheng Sheng, Jiateng Sun, Zhinan Wu, Fei Liao, Qi Feng, Yan Yin, Song Ding, Jun Pu

Abstract

Background: Recent studies have suggested that soluble suppression of tumorigenicity-2 (sST2), an inflammation-related protein receptor, is associated with atherosclerotic diseases. This study aimed to investigate the potential predictive value of sST2 on plaque vulnerability by assessing whether elevated serum levels of sST2 are associated with vulnerable plaque features in patients with non-ST-elevation acute coronary syndrome (ACS). Methods: A total of 120 patients with non-ST-elevation ACS (167 lesions) were prospectively enrolled and evaluated by standard coronary computed tomography angiography (CCTA) and coronary angiography in this study. Serum sST2 levels were measured by ELISA (Presage® ST2 Assay Kit, Critical Diagnostics), and semiautomated software (QAngioCT, Medis) was used to quantify coronary plaques. Results: The included patients were divided into 4 groups by serum sST2 level quartiles. Volumetric analysis of the whole lesion revealed that patients with higher sST2 levels had a larger absolute necrotic core (NC) volume (Quartile 4 vs. Quartile 1, 86.16 ± 59.71 vs. 45.10 ± 45.80 mm3, P = 0.001; Quartile 4 vs. Quartile 2, 86.16 ± 59.71 vs. 50.22 ± 42.56 mm3, P = 0.002) and a higher NC percentage (Quartile 4 vs. Quartile 1, 35.16 ± 9.82 vs. 23.21 ± 16.18%, P < 0.001; Quartile 4 vs. Quartile 2, 35.16 ± 9.82% vs. 22.50 ± 14.03%, P < 0.001; Quartile 4 vs. Quartile 3, 35.16 ± 9.82% vs. 25.04 ± 14.48%, P < 0.001). Correlation analysis revealed that serum sST2 levels were positively correlated with the NC (r = 0.323, P < 0.001) but negatively correlated with dense calcium (r = -0.208, P = 0.007). Furthermore, among those with plaque calcification, patients with spotty calcification exhibited higher serum sST2 levels than those with large calcification (26.06 ± 16.54 vs. 17.55 ± 7.65 ng/mL, P = 0.002). No significant differences in plaque components at the level of the minimal lumen area (MLA) were found among the groups. Conclusions: Serum sST2 levels were correlated with different coronary plaque components in patients with non-ST-elevation ACS. A higher serum level of sST2 was correlated with plaque vulnerability. Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT04797819.

Keywords: coronary computed tomography angiography; coronary plaque; non-ST elevation acute coronary syndromes; plaque vulnerability; soluble ST2.

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2021 Luo, Qian, Sheng, Sun, Wu, Liao, Feng, Yin, Ding and Pu.

Figures

Figure 1
Figure 1
Flowchart of patient enrollment. ACS, acute coronary syndrome; CCTA, coronary computed tomography angiography.
Figure 2
Figure 2
Example of the coronary plaque quantitative analysis of a lesion in the proximal LAD artery segment. (A) Longitudinal straightened multiplanar reconstruction, where “O” indicates the minimal lumen area. (B) Cross-sectional view of minimal lumen area. (C) Graph of the lumen and vessel area as a function of vessel length.
Figure 3
Figure 3
Analysis of the association between sST2 and plaque calcification. (A) No significant difference in serum sST2 levels was observed between the calcification and non-calcification groups. (B) Patients with spotty calcification had higher sST2 levels than those with large calcification.

References

    1. Boogers MJ, Schuijf JD, Kitslaar PH, van Werkhoven JM, de Graaf FR, Boersma E, et al. . Automated quantification of stenosis severity on 64-slice CT: a comparison with quantitative coronary angiography. JACC Cardiovasc Imaging. (2010) 3:699–709. 10.1016/j.jcmg.2010.01.010
    1. Boogers MJ, Broersen A, van Velzen JE, de Graaf FR, El-Naggar HM, Kitslaar PH, et al. . Automated quantification of coronary plaque with computed tomography: comparison with intravascular ultrasound using a dedicated registration algorithm for fusion-based quantification. Eur Heart J. (2012) 33:1007–16. 10.1093/eurheartj/ehr465
    1. Papadopoulou SL, Neefjes LA, Garcia-Garcia HM, Flu WJ, Rossi A, Dharampal AS, et al. . Natural history of coronary atherosclerosis by multislice computed tomography. JACC Cardiovasc Imaging. (2012) 5(3 Suppl):S28–37. 10.1016/j.jcmg.2012.01.009
    1. Zhang Y, Fan Z, Liu H, Ma J, Zhang M. Correlation of plasma soluble suppression of tumorigenicity-2 level with the severity and stability of coronary atherosclerosis. Coron Artery Dis. (2020) 31:628–35. 10.1097/MCA.0000000000000851
    1. Aimo A, Migliorini P, Vergaro G, Franzini M, Passino C, Maisel A, et al. . The IL-33/ST2 pathway, inflammation and atherosclerosis: trigger and target? Int J Cardiol. (2018) 267:188–92. 10.1016/j.ijcard.2018.05.056
    1. Aimo A, Vergaro G, Passino C, Ripoli A, Ky B, Miller WL, et al. . Prognostic value of soluble suppression of tumorigenicity-2 in chronic heart failure: a meta-analysis. JACC Heart Fail. (2017) 5:280–6. 10.1016/j.jchf.2016.09.010
    1. Aimo A, Vergaro G, Ripoli A, Bayes-Genis A, Pascual Figal DA, de Boer RA, et al. . Meta-Analysis of soluble suppression of tumorigenicity-2 and prognosis in acute heart failure. JACC Heart Fail. (2017) 5:287–96. 10.1016/j.jchf.2016.12.016
    1. Jenkins WS, Roger VL, Jaffe AS, Weston SA, AbouEzzeddine OF, Jiang R. Prognostic value of soluble ST2 after myocardial infarction: a community perspective. Am J Med. (2017) 130:1112.e9–.e15. 10.1016/j.amjmed.2017.02.034
    1. Miller AM, Xu D, Asquith DL, Denby L, Li Y, Sattar N, et al. . IL-33 reduces the development of atherosclerosis. J Exp Med. (2008) 205:339–46. 10.1084/jem.20071868
    1. Roffi M, Patrono C, Collet JP, Mueller C, Valgimigli M, Andreotti F, et al. . 2015 ESC guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: task force for the management of acute coronary syndromes in patients presenting without persistent ST-Segment Elevation of the European Society of Cardiology (ESC). Eur Heart J. (2016) 37:267–315. 10.1093/eurheartj/ehv320
    1. Fuchs S, Lavi I, Tzang O, Fuchs S, Brosh D, Bental T, et al. . Necrotic core and thin cap fibrous atheroma distribution in native coronary artery lesion-containing segments: a virtual histology intravascular ultrasound study. Coron Artery Dis. (2011) 22:339–44. 10.1097/MCA.0b013e3283467829
    1. Ito T, Terashima M, Kaneda H, Nasu K, Matsuo H, Ehara M, et al. . Comparison of in vivo assessment of vulnerable plaque by 64-slice multislice computed tomography versus optical coherence tomography. Am J Cardiol. (2011) 107:1270–7. 10.1016/j.amjcard.2010.12.036
    1. Deftereos S, Giannopoulos G, Kossyvakis C, Kaoukis A, Raisakis K, Panagopoulou V, et al. . Association of soluble tumour necrosis factor-related apoptosis-inducing ligand levels with coronary plaque burden and composition. Heart. (2012) 98:214–8. 10.1136/heartjnl-2011-300339
    1. de Graaf MA, Broersen A, Kitslaar PH, Roos CJ, Dijkstra J, Lelieveldt BP, et al. . Automatic quantification and characterization of coronary atherosclerosis with computed tomography coronary angiography: cross-correlation with intravascular ultrasound virtual histology. Int J Cardiovasc Imaging. (2013) 29:1177–90. 10.1007/s10554-013-0194-x
    1. Brodoefel H, Reimann A, Heuschmid M, Tsiflikas I, Kopp AF, Schroeder S, et al. . Characterization of coronary atherosclerosis by dual-source computed tomography and HU-based color mapping: a pilot study. Eur Radiol. (2008) 18:2466–74. 10.1007/s00330-008-1019-5
    1. Motoyama S, Sarai M, Harigaya H, Anno H, Inoue K, Hara T, et al. . Computed tomographic angiography characteristics of atherosclerotic plaques subsequently resulting in acute coronary syndrome. J Am Coll Cardiol. (2009) 54:49–57. 10.1016/j.jacc.2009.02.068
    1. Precht H, Kitslaar PH, Broersen A, Dijkstra J, Gerke O, Thygesen J, et al. . Influence of adaptive statistical iterative reconstruction on coronary plaque analysis in coronary computed tomography angiography. J Cardiovasc Comput Tomogr. (2016) 10:507–16. 10.1016/j.jcct.2016.09.006
    1. Mintz GS, Nissen SE, Anderson WD, Bailey SR, Erbel R, Fitzgerald PJ, et al. . American college of cardiology clinical expert consensus document on standards for acquisition, measurement and reporting of Intravascular Ultrasound Studies (IVUS). a report of the american college of cardiology task force on clinical expert consensus documents. J Am Coll Cardiol. (2001) 37:1478–92. 10.1016/s0735-1097(01)01175-5
    1. Higuma T, Soeda T, Abe N, Yamada M, Yokoyama H, Shibutani S, et al. . A combined optical coherence tomography and intravascular ultrasound study on plaque rupture, plaque erosion, and calcified nodule in patients with st-segment elevation myocardial infarction: incidence, morphologic characteristics, and outcomes after percutaneous coronary intervention. JACC Cardiovasc Interv. (2015) 8:1166–76. 10.1016/j.jcin.2015.02.026
    1. Kröner ES, van Velzen JE, Boogers MJ, Siebelink HM, Schalij MJ, Kroft LJ, et al. . Positive remodeling on coronary computed tomography as a marker for plaque vulnerability on virtual histology intravascular ultrasound. Am J Cardiol. (2011) 107:1725–9. 10.1016/j.amjcard.2011.02.337
    1. Ehara S, Kobayashi Y, Yoshiyama M, Shimada K, Shimada Y, Fukuda D, et al. . Spotty calcification typifies the culprit plaque in patients with acute myocardial infarction: an intravascular ultrasound study. Circulation. (2004) 110:3424–9. 10.1161/01.CIR.0000148131.41425.E9
    1. Motoyama S, Kondo T, Sarai M, Sugiura A, Harigaya H, Sato T, et al. . Multislice computed tomographic characteristics of coronary lesions in acute coronary syndromes. J Am Coll Cardiol. (2007) 50:319–26. 10.1016/j.jacc.2007.03.044
    1. Wolf D, Ley K. Immunity and inflammation in atherosclerosis. Circ Res. (2019) 124:315–27. 10.1161/CIRCRESAHA.118.313591
    1. Grootaert MOJ, Schrijvers DM, Van Spaendonk H, Breynaert A, Hermans N, Van Hoof VO, et al. . NecroX-7 reduces necrotic core formation in atherosclerotic plaques of Apoe knockout mice. Atherosclerosis. (2016) 252:166–74. 10.1016/j.atherosclerosis.2016.06.045
    1. Otsuka F, Yasuda S, Noguchi T, Ishibashi-Ueda H. Pathology of coronary atherosclerosis and thrombosis. Cardiovasc Diagn Ther. (2016) 6:396–408. 10.21037/cdt.2016.06.01
    1. Nasu K, Tsuchikane E, Katoh O, Vince DG, Virmani R, Surmely JF, et al. . Accuracy of in vivo coronary plaque morphology assessment: a validation study of in vivo virtual histology compared with in vitro histopathology. J Am Coll Cardiol. (2006) 47:2405–12. 10.1016/j.jacc.2006.02.044
    1. Pu J, Mintz GS, Brilakis ES, Banerjee S, Abdel-Karim AR, Maini B, et al. . In vivo characterization of coronary plaques: novel findings from comparing greyscale and virtual histology intravascular ultrasound and near-infrared spectroscopy. Eur Heart J. (2012) 33:372–83. 10.1093/eurheartj/ehr387
    1. Pu J, Mintz GS, Biro S, Lee JB, Sum ST, Madden SP, et al. . Insights into echo-attenuated plaques, echolucent plaques, and plaques with spotty calcification: novel findings from comparisons among intravascular ultrasound, near-infrared spectroscopy, and pathological histology in 2,294 human coronary artery segments. J Am Coll Cardiol. (2014) 63:2220–33. 10.1016/j.jacc.2014.02.576
    1. Ding S, Xu L, Yang F, Kong L, Zhao Y, Gao L, et al. . Association between tissue characteristics of coronary plaque and distal embolization after coronary intervention in acute coronary syndrome patients: insights from a meta-analysis of virtual histology-intravascular ultrasound studies. PLoS ONE. (2014) 9:e106583. 10.1371/journal.pone.0106583
    1. Shi X, Gao J, Lv Q, Cai H, Wang F, Ye R, et al. . Calcification in atherosclerotic plaque vulnerability: friend or foe? Front Physiol. (2020) 11:56. 10.3389/fphys.2020.00056
    1. Ono Y, Yoshino O, Hiraoka T, Akiyama I, Sato E, Ito M, et al. . IL-33 exacerbates endometriotic lesions via polarizing peritoneal macrophages to M2 subtype. Reprod Sci. (2020) 27:869–76. 10.1007/s43032-019-00090-9
    1. Shioi A, Ikari Y. Plaque calcification during atherosclerosis progression and regression. J Atheroscler Thromb. (2018) 25:294–303. 10.5551/jat.RV17020
    1. Willems S, Quax PH, de Borst GJ, de Vries JP, Moll FL, de Kleijn DP, et al. . Soluble ST2 levels are not associated with secondary cardiovascular events and vulnerable plaque phenotype in patients with carotid artery stenosis. Atherosclerosis. (2013) 231:48–53. 10.1016/j.atherosclerosis.2013.08.024
    1. Kohli P, Bonaca MP, Kakkar R, Kudinova AY, Scirica BM, Sabatine MS, et al. . Role of ST2 in non-ST-elevation acute coronary syndrome in the MERLIN-TIMI 36 trial. Clin Chem. (2012) 58:257–66. 10.1373/clinchem.2011.173369
    1. Xia S, Zhang X, Zheng S, Khanabdali R, Kalionis B, Wu J, et al. . An update on inflamm-aging: mechanisms, prevention, and treatment. J Immunol Res. (2016) 2016:8426874. 10.1155/2016/8426874
    1. Rea IM, Gibson DS, McGilligan V, McNerlan SE, Alexander HD, Ross OA. Age and age-related diseases: role of inflammation triggers and cytokines. Front Immunol. (2018) 9:586. 10.3389/fimmu.2018.00586
    1. Huang Y, Hu C, Ye H, Luo R, Fu X, Li X, et al. . Inflamm-aging: a new mechanism affecting premature ovarian insufficiency. J Immunol Res. (2019) 2019:8069898. 10.1155/2019/8069898
    1. Ding S, Lin N, Sheng X, Zhao Y, Su Y, Xu L, et al. . Melatonin stabilizes rupture-prone vulnerable plaques via regulating macrophage polarization in a nuclear circadian receptor RORα-dependent manner. J Pineal Res. (2019) 67:e12581. 10.1111/jpi.12581

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