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  • Review Article
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Phenotyping atherosclerotic plaque and perivascular adipose tissue: signalling pathways and clinical biomarkers in atherosclerosis

Nature Reviews Cardiology volume 22, pages 443–455 (2025)Cite this article

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Abstract

Computed tomography coronary angiography provides a non-invasive evaluation of coronary artery disease that includes phenotyping of atherosclerotic plaques and the surrounding perivascular adipose tissue (PVAT). Image analysis techniques have been developed to quantify atherosclerotic plaque burden and morphology as well as the associated PVAT attenuation, and emerging radiomic approaches can add further contextual information. PVAT attenuation might provide a novel measure of vascular health that could be indicative of the pathogenetic processes implicated in atherosclerosis such as inflammation, fibrosis or increased vascularity. Bidirectional signalling between the coronary artery and adjacent PVAT has been hypothesized to contribute to coronary artery disease progression and provide a potential novel measure of the risk of future cardiovascular events. However, despite the development of more advanced radiomic and artificial intelligence-based algorithms, studies involving large datasets suggest that the measurement of PVAT attenuation contributes only modest additional predictive discrimination to standard cardiovascular risk scores. In this Review, we explore the pathobiology of coronary atherosclerotic plaques and PVAT, describe their phenotyping with computed tomography coronary angiography, and discuss potential future applications in clinical risk prediction and patient management.

Key points

  • Computed tomography coronary angiography (CTCA) provides a non-invasive method to evaluate coronary artery disease that allows the phenotyping of atherosclerotic plaques and surrounding perivascular adipose tissue (PVAT).

  • Bidirectional signalling between the coronary arteries and the adjacent PVAT might contribute to the progression of atherosclerosis.

  • Certain atherosclerotic plaque characteristics (such as positive remodelling, non-calcified plaque, spotty calcification and the napkin-ring sign) are indicative of an increased risk of adverse coronary events; quantitative plaque assessment might help to identify patients at high risk, beyond traditional assessments of stenosis severity.

  • Despite advances in radiomic and artificial intelligence-based algorithms, studies indicate that the use of PVAT signal attenuation on CTCA only modestly improves predictive discrimination beyond the use of standard cardiovascular risk scores.

  • Measuring PVAT attenuation by CTCA is affected by various technical factors (such as reconstruction algorithms, scanner variations and tube voltage), which can influence the consistency and accuracy of the measurements, complicating their use in clinical practice.

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Fig. 1: Anatomy and definitions of thoracic fat.
Fig. 2: The PVAT secretome: anti-inflammatory and pro-inflammatory profiles.
Fig. 3: Bidirectional interactions between PVAT and the vessel wall in atherosclerosis.
Fig. 4: Associations between 18F-NaF uptake and PVAT in coronary artery disease.
Fig. 5: Atherosclerotic plaque regression and stabilization.

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References

  1. Vaduganathan, M., Mensah, G. A., Turco, J. V., Fuster, V. & Roth, G. A. The global burden of cardiovascular diseases and risk. J. Am. Coll. Cardiol. 80, 2361–2371 (2022).

    Article  PubMed  Google Scholar 

  2. Ibanez, B. et al. Progression of early subclinical atherosclerosis (PESA) study. J. Am. Coll. Cardiol. 78, 156–179 (2021).

    Article  PubMed  Google Scholar 

  3. Libby, P. et al. Atherosclerosis. Nat. Rev. Dis. Prim. 5, 56 (2019).

    Article  PubMed  Google Scholar 

  4. Arbab-Zadeh, A., Nakano, M., Virmani, R. & Fuster, V. Acute coronary events. Circulation 125, 1147–1156 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  5. Falk, E., Shah, P. K. & Fuster, V. Coronary plaque disruption. Circulation 92, 657–671 (1995).

    Article  PubMed  CAS  Google Scholar 

  6. Wang, J. C., Normand, S. L., Mauri, L. & Kuntz, R. E. Coronary artery spatial distribution of acute myocardial infarction occlusions. Circulation 110, 278–284 (2004).

    Article  PubMed  Google Scholar 

  7. Stone, G. W. et al. A prospective natural-history study of coronary atherosclerosis. N. Engl. J. Med. 364, 226–235 (2011).

    Article  PubMed  CAS  Google Scholar 

  8. Puri, R., Nicholls, S. J., Ellis, S. G., Tuzcu, E. M. & Kapadia, S. R. High-risk coronary atheroma: the interplay between ischemia, plaque burden, and disease progression. J. Am. Coll. Cardiol. 63, 1134–1140 (2014).

    Article  PubMed  Google Scholar 

  9. Williams, M. C. et al. Low-attenuation noncalcified plaque on coronary computed tomography angiography predicts myocardial infarction: results from the Multicenter SCOT-HEART Trial (Scottish Computed Tomography of the HEART). Circulation 141, 1452–1462 (2020).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Narula, J. et al. Histopathologic characteristics of atherosclerotic coronary disease and implications of the findings for the invasive and noninvasive detection of vulnerable plaques. J. Am. Coll. Cardiol. 61, 1041–1051 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  11. Zhang, T. et al. Longitudinal assessment of coronary plaque regression related to sodium-glucose cotransporter-2 inhibitor using coronary computed tomography angiography. Cardiovasc. Diabetol. 23, 267 (2024).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. Liu, S. et al. Effect of PCSK9 antibodies on coronary plaque regression and stabilization derived from intravascular imaging in patients with coronary artery disease: a meta-analysis. Int. J. Cardiol. 392, 131330 (2023).

    Article  PubMed  Google Scholar 

  13. Vaidya, K. et al. Colchicine therapy and plaque stabilization in patients with acute coronary syndrome: a CT coronary angiography study. JACC Cardiovasc. Imaging 11, 305–316 (2018).

    Article  PubMed  Google Scholar 

  14. Goeller, M. et al. Pericoronary adipose tissue computed tomography attenuation and high-risk plaque characteristics in acute coronary syndrome compared with stable coronary artery disease. JAMA Cardiol. 3, 858–863 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  15. Kwiecinski, J. et al. Noninvasive coronary atherosclerotic plaque imaging. JACC Cardiovasc. Imaging 16, 1608–1622 (2023).

    Article  PubMed  Google Scholar 

  16. Qi, X.-Y. et al. Perivascular adipose tissue (PVAT) in atherosclerosis: a double-edged sword. Cardiovasc. Diabetol. 17, 134 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Tan, N., Dey, D., Marwick, T. H. & Nerlekar, N. Pericoronary adipose tissue as a marker of cardiovascular risk. J. Am. Coll. Cardiol. 81, 913–923 (2023).

    Article  PubMed  CAS  Google Scholar 

  18. Kotanidis, C. P. & Antoniades, C. Perivascular fat imaging by computed tomography (CT): a virtual guide. Br. J. Pharmacol. 178, 4270–4290 (2021).

    Article  PubMed  CAS  Google Scholar 

  19. Hillock-Watling, C. & Gotlieb, A. I. The pathobiology of perivascular adipose tissue (PVAT), the fourth layer of the blood vessel wall. Cardiovasc. Pathol. 61, 107459 (2022).

    Article  PubMed  CAS  Google Scholar 

  20. Oikonomou, E. K. & Antoniades, C. The role of adipose tissue in cardiovascular health and disease. Nat. Rev. Cardiol. 16, 83–99 (2019).

    Article  PubMed  Google Scholar 

  21. Brown, N. K. et al. Perivascular adipose tissue in vascular function and disease: a review of current research and animal models. Arterioscler. Thromb. Vasc. Biol. 34, 1621–1630 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Koenen, M., Hill, M. A., Cohen, P. & Sowers, J. R. Obesity, adipose tissue and vascular dysfunction. Circ. Res. 128, 951–968 (2021).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Frontini, A. & Cinti, S. Distribution and development of brown adipocytes in the murine and human adipose organ. Cell Metab. 11, 253–256 (2010).

    Article  PubMed  CAS  Google Scholar 

  24. Pérez-Martí, A. et al. A low-protein diet induces body weight loss and browning of subcutaneous white adipose tissue through enhanced expression of hepatic fibroblast growth factor 21 (FGF21). Mol. Nutr. Food Res. 61, 1600725 (2017).

    Article  Google Scholar 

  25. Otero-Díaz, B. et al. Exercise induces white adipose tissue browning across the weight spectrum in humans. Front. Physiol. 9, 1781 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  26. Lucchini, F. C. et al. ASK1 inhibits browning of white adipose tissue in obesity. Nat. Commun. 11, 1642 (2020).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Kalinovich, A. V., de Jong, J. M., Cannon, B. & Nedergaard, J. UCP1 in adipose tissues: two steps to full browning. Biochimie 134, 127–137 (2017).

    Article  PubMed  CAS  Google Scholar 

  28. Fischer, C. et al. A miR-327–FGF10–FGFR2-mediated autocrine signaling mechanism controls white fat browning. Nat. Commun. 8, 2079 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  29. Machado, S. A. et al. Browning of the white adipose tissue regulation: new insights into nutritional and metabolic relevance in health and diseases. Nutr. Metab. 19, 61 (2022).

    Article  CAS  Google Scholar 

  30. Britton, K. A. et al. Prevalence, distribution, and risk factor correlates of high thoracic periaortic fat in the Framingham Heart Study. J. Am. Heart Assoc. 1, e004200 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  31. El Khoudary, S. R. et al. Postmenopausal women with greater paracardial fat have more coronary artery calcification than premenopausal women: the Study of Women’s Health Across the Nation (SWAN) Cardiovascular Fat Ancillary Study. J. Am. Heart Assoc. 6, e004545 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  32. Ahmad, A. A., Randall, M. D. & Roberts, R. E. Sex differences in the role of phospholipase A(2) —dependent arachidonic acid pathway in the perivascular adipose tissue function in pigs. J. Physiol. 595, 6623–6634 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Wang, D. et al. Endothelial dysfunction and enhanced contractility in microvessels from ovariectomized rats. Hypertension 63, 1063–1069 (2014).

    Article  PubMed  CAS  Google Scholar 

  34. Yuvaraj, J. et al. Pericoronary adipose tissue attenuation on coronary computed tomography angiography associates with male sex and Indigenous Australian status. Sci. Rep. 13, 15509 (2023).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. van Rosendael, S. E. et al. Vessel and sex differences in pericoronary adipose tissue attenuation obtained with coronary CT in individuals without coronary atherosclerosis. Int. J. Cardiovasc. Imaging 38, 2781–2789 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  36. Kinoshita, D. et al. Sex-specific association between perivascular inflammation and plaque vulnerability. Circ. Cardiovasc. Imaging 17, e016178 (2024).

    Article  PubMed  Google Scholar 

  37. Matsuzawa, Y. & Lerman, A. Endothelial dysfunction and coronary artery disease: assessment, prognosis, and treatment. Coron. Artery Dis. 25, 713–724 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  38. Rajendran, P. et al. The vascular endothelium and human diseases. Int. J. Biol. Sci. 9, 1057–1069 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. Ross, R. Atherosclerosis — an inflammatory disease. N. Engl. J. Med. 340, 115–126 (1999).

    Article  PubMed  CAS  Google Scholar 

  40. Cheng, C. K., Bakar, H. A., Gollasch, M. & Huang, Y. Perivascular adipose tissue: the sixth man of the cardiovascular system. Cardiovasc. Drugs Ther. 32, 481–502 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  41. Akoumianakis, I. & Antoniades, C. The interplay between adipose tissue and the cardiovascular system: is fat always bad? Cardiovasc. Res. 113, 999–1008 (2017).

    Article  PubMed  CAS  Google Scholar 

  42. Akoumianakis, I., Tarun, A. & Antoniades, C. Perivascular adipose tissue as a regulator of vascular disease pathogenesis: identifying novel therapeutic targets. Br. J. Pharmacol. 174, 3411–3424 (2017).

    Article  PubMed  CAS  Google Scholar 

  43. Antonopoulos, A. S. et al. Adiponectin as a link between type 2 diabetes and vascular NADPH oxidase activity in the human arterial wall: the regulatory role of perivascular adipose tissue. Diabetes 64, 2207–2219 (2015).

    Article  PubMed  CAS  Google Scholar 

  44. Mani, S. et al. Decreased endogenous production of hydrogen sulfide accelerates atherosclerosis. Circulation 127, 2523–2534 (2013).

    Article  PubMed  CAS  Google Scholar 

  45. Kauser, K., da Cunha, V., Fitch, R., Mallari, C. & Rubanyi, G. M. Role of endogenous nitric oxide in progression of atherosclerosis in apolipoprotein E-deficient mice. Am. J. Physiol. Heart Circ. Physiol. 278, H1679–H1685 (2000).

    Article  PubMed  CAS  Google Scholar 

  46. Thomas, C., Mackey, M. M., Diaz, A. A. & Cox, D. P. Hydroxyl radical is produced via the Fenton reaction in submitochondrial particles under oxidative stress: implications for diseases associated with iron accumulation. Redox Rep. 14, 102–108 (2009).

    Article  PubMed  CAS  Google Scholar 

  47. Rippe, B., Rosengren, B. I., Carlsson, O. & Venturoli, D. Transendothelial transport: the vesicle controversy. J. Vasc. Res. 39, 375–390 (2002).

    Article  PubMed  CAS  Google Scholar 

  48. Jang, E., Robert, J., Rohrer, L., von Eckardstein, A. & Lee, W. L. Transendothelial transport of lipoproteins. Atherosclerosis 315, 111–125 (2020).

    Article  PubMed  CAS  Google Scholar 

  49. Sheedy, F. J. et al. CD36 coordinates NLRP3 inflammasome activation by facilitating intracellular nucleation of soluble ligands into particulate ligands in sterile inflammation. Nat. Immunol. 14, 812–820 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  50. Witztum, J. L. & Steinberg, D. The oxidative modification hypothesis of atherosclerosis: does it hold for humans? Trends Cardiovasc. Med. 11, 93–102 (2001).

    Article  PubMed  CAS  Google Scholar 

  51. Pober, J. S. & Sessa, W. C. Evolving functions of endothelial cells in inflammation. Nat. Rev. Immunol. 7, 803–815 (2007).

    Article  PubMed  CAS  Google Scholar 

  52. Ropraz, P., Imhof, B. A., Matthes, T., Wehrle-Haller, B. & Sidibé, A. Simultaneous study of the recruitment of monocyte subpopulations under flow in vitro. J. Vis. Exp. 141, e58509 (2018).

    Google Scholar 

  53. Gerhardt, T. & Ley, K. Monocyte trafficking across the vessel wall. Cardiovasc. Res. 107, 321–330 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  54. Choi, H. Y. et al. ATP-binding cassette transporter A1 expression and apolipoprotein A-I binding are impaired in intima-type arterial smooth muscle cells. Circulation 119, 3223–3231 (2009).

    Article  PubMed  CAS  Google Scholar 

  55. Allahverdian, S., Chehroudi, A. C., McManus, B. M., Abraham, T. & Francis, G. A. Contribution of intimal smooth muscle cells to cholesterol accumulation and macrophage-like cells in human atherosclerosis. Circulation 129, 1551–1559 (2014).

    Article  PubMed  CAS  Google Scholar 

  56. Chinetti-Gbaguidi, G. et al. Human atherosclerotic plaque alternative macrophages display low cholesterol handling but high phagocytosis because of distinct activities of the PPARγ and LXRα pathways. Circ. Res. 108, 985–995 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  57. Maitra, U., Parks, J. S. & Li, L. An innate immunity signaling process suppresses macrophage ABCA1 expression through IRAK-1-mediated downregulation of retinoic acid receptor alpha and NFATc2. Mol. Cell Biol. 29, 5989–5997 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  58. Fitzgibbons, T. P. & Czech, M. P. Epicardial and perivascular adipose tissues and their influence on cardiovascular disease: basic mechanisms and clinical associations. J. Am. Heart Assoc. 3, e000582 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  59. Verhagen, S. N., Vink, A., van der Graaf, Y. & Visseren, F. L. Coronary perivascular adipose tissue characteristics are related to atherosclerotic plaque size and composition. A post-mortem study. Atherosclerosis 225, 99–104 (2012).

    Article  PubMed  CAS  Google Scholar 

  60. Farias-Itao, D. S. et al. B lymphocytes and macrophages in the perivascular adipose tissue are associated with coronary atherosclerosis: an autopsy study. J. Am. Heart Assoc. 8, e013793 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  61. Oh, D. Y., Morinaga, H., Talukdar, S., Bae, E. J. & Olefsky, J. M. Increased macrophage migration into adipose tissue in obese mice. Diabetes 61, 346–354 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  62. Shirai, T., Hilhorst, M., Harrison, D. G., Goronzy, J. J. & Weyand, C. M. Macrophages in vascular inflammation — from atherosclerosis to vasculitis. Autoimmunity 48, 139–151 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  63. Moos, M. P. et al. The lamina adventitia is the major site of immune cell accumulation in standard chow-fed apolipoprotein E-deficient mice. Arterioscler. Thromb. Vasc. Biol. 25, 2386–2391 (2005).

    Article  PubMed  CAS  Google Scholar 

  64. Ketelhuth, D. F. & Hansson, G. K. Adaptive response of T and B cells in atherosclerosis. Circ. Res. 118, 668–678 (2016).

    Article  PubMed  CAS  Google Scholar 

  65. Tay, C. et al. B-cell-specific depletion of tumour necrosis factor alpha inhibits atherosclerosis development and plaque vulnerability to rupture by reducing cell death and inflammation. Cardiovasc. Res. 111, 385–397 (2016).

    Article  PubMed  CAS  Google Scholar 

  66. Du, X. et al. Insulin resistance reduces arterial prostacyclin synthase and eNOS activities by increasing endothelial fatty acid oxidation. J. Clin. Invest. 116, 1071–1080 (2006).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  67. Watson, M. G., Byrne, H. M., Macaskill, C. & Myerscough, M. R. A two-phase model of early fibrous cap formation in atherosclerosis. J. Theor. Biol. 456, 123–136 (2018).

    Article  PubMed  CAS  Google Scholar 

  68. Chamié, D., Wang, Z., Bezerra, H., Rollins, A. M. & Costa, M. A. Optical coherence tomography and fibrous cap characterization. Curr. Cardiovasc. Imaging Rep. 4, 276–283 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  69. Bennett, M. R., Sinha, S. & Owens, G. K. Vascular smooth muscle cells in atherosclerosis. Circ. Res. 118, 692–702 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  70. Manka, D. et al. Transplanted perivascular adipose tissue accelerates injury-induced neointimal hyperplasia: role of monocyte chemoattractant protein-1. Arterioscler. Thromb. Vasc. Biol. 34, 1723–1730 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  71. Miao, C. Y. & Li, Z. Y. The role of perivascular adipose tissue in vascular smooth muscle cell growth. Br. J. Pharmacol. 165, 643–658 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  72. Miyata, K. et al. Rho-kinase is involved in macrophage-mediated formation of coronary vascular lesions in pigs in vivo. Arterioscler. Thromb. Vasc. Biol. 20, 2351–2358 (2000).

    Article  PubMed  CAS  Google Scholar 

  73. Shimokawa, H. et al. Chronic treatment with interleukin-1 beta induces coronary intimal lesions and vasospastic responses in pigs in vivo. The role of platelet-derived growth factor. J. Clin. Invest. 97, 769–776 (1996).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  74. Johnson, J. L. et al. Relationship of MMP-14 and TIMP-3 expression with macrophage activation and human atherosclerotic plaque vulnerability. Mediators Inflamm. 2014, 276457 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  75. Giacco, F. & Brownlee, M. Oxidative stress and diabetic complications. Circ. Res. 107, 1058–1070 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  76. Creager, M. A., Lüscher, T. F., Cosentino, F. & Beckman, J. A. Diabetes and vascular disease: pathophysiology, clinical consequences, and medical therapy: part I. Circulation 108, 1527–1532 (2003).

    Article  PubMed  Google Scholar 

  77. Adkar, S. S. & Leeper, N. J. Efferocytosis in atherosclerosis. Nat. Rev. Cardiol. 21, 762–779 (2024).

    Article  PubMed  Google Scholar 

  78. Mulay, S. R. & Anders, H. J. Crystallopathies. N. Engl. J. Med. 374, 2465–2476 (2016).

    Article  PubMed  CAS  Google Scholar 

  79. Nishikawa, T. et al. Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage. Nature 404, 787–790 (2000).

    Article  PubMed  CAS  Google Scholar 

  80. García-García, H. M. et al. Relationship between cardiovascular risk factors and biomarkers with necrotic core and atheroma size: a serial intravascular ultrasound radiofrequency data analysis. Int. J. Cardiovasc. Imaging 28, 695–703 (2012).

    Article  PubMed  Google Scholar 

  81. Virmani, R., Burke, A. P., Farb, A. & Kolodgie, F. D. Pathology of the vulnerable plaque. J. Am. Coll. Cardiol. 47, C13–C18 (2006).

    Article  PubMed  CAS  Google Scholar 

  82. Lendon, C. L., Davies, M. J., Born, G. V. & Richardson, P. D. Atherosclerotic plaque caps are locally weakened when macrophages density is increased. Atherosclerosis 87, 87–90 (1991).

    Article  PubMed  CAS  Google Scholar 

  83. Xie, Z. et al. Adipose-derived exosomes exert proatherogenic effects by regulating macrophage foam cell formation and polarization. J. Am. Heart Assoc. 7, e007442 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  84. Itani, H. A. et al. Activation of human T cells in hypertension: studies of humanized mice and hypertensive humans. Hypertension 68, 123–132 (2016).

    Article  PubMed  CAS  Google Scholar 

  85. Wu, L. et al. Activation of invariant natural killer T cells by lipid excess promotes tissue inflammation, insulin resistance, and hepatic steatosis in obese mice. Proc. Natl Acad. Sci. USA 109, E1143–E1152 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  86. Wu, H. et al. T-cell accumulation and regulated on activation, normal T cell expressed and secreted upregulation in adipose tissue in obesity. Circulation 115, 1029–1038 (2007).

    Article  PubMed  CAS  Google Scholar 

  87. Amento, E. P., Ehsani, N., Palmer, H. & Libby, P. Cytokines and growth factors positively and negatively regulate interstitial collagen gene expression in human vascular smooth muscle cells. Arterioscler. Thromb. 11, 1223–1230 (1991).

    Article  PubMed  CAS  Google Scholar 

  88. Yamashita, A. et al. Medial and adventitial macrophages are associated with expansive atherosclerotic remodeling in rabbit femoral artery. Histol. Histopathol. 23, 127–136 (2008).

    PubMed  CAS  Google Scholar 

  89. Antonopoulos, A. S. et al. Detecting human coronary inflammation by imaging perivascular fat. Sci. Transl. Med. 9, eaal2658 (2017).

    Article  PubMed  Google Scholar 

  90. Antoniades, C. Dysfunctional’ adipose tissue in cardiovascular disease: a reprogrammable target or an innocent bystander? Cardiovasc. Res. 113, 997–998 (2017).

    Article  PubMed  CAS  Google Scholar 

  91. Mulligan-Kehoe, M. J. The vasa vasorum in diseased and nondiseased arteries. Am. J. Physiol. Heart Circ. Physiol. 298, H295–H305 (2010).

    Article  PubMed  CAS  Google Scholar 

  92. Greenstein, A. S. et al. Local inflammation and hypoxia abolish the protective anticontractile properties of perivascular fat in obese patients. Circulation 119, 1661–1670 (2009).

    Article  PubMed  CAS  Google Scholar 

  93. Aghamohammadzadeh, R. et al. Effects of bariatric surgery on human small artery function: evidence for reduction in perivascular adipocyte inflammation, and the restoration of normal anticontractile activity despite persistent obesity. J. Am. Coll. Cardiol. 62, 128–135 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  94. Calabro, P., Samudio, I., Willerson, J. T. & Yeh, E. T. Resistin promotes smooth muscle cell proliferation through activation of extracellular signal-regulated kinase 1/2 and phosphatidylinositol 3-kinase pathways. Circulation 110, 3335–3340 (2004).

    Article  PubMed  CAS  Google Scholar 

  95. Chen, C. et al. Resistin decreases expression of endothelial nitric oxide synthase through oxidative stress in human coronary artery endothelial cells. Am. J. Physiol. Heart Circ. Physiol. 299, H193–H201 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  96. Grant, R. W. & Stephens, J. M. Fat in flames: influence of cytokines and pattern recognition receptors on adipocyte lipolysis. Am. J. Physiol. Endocrinol. Metab. 309, E205–E213 (2015).

    Article  PubMed  CAS  Google Scholar 

  97. Kawanami, D. et al. Direct reciprocal effects of resistin and adiponectin on vascular endothelial cells: a new insight into adipocytokine-endothelial cell interactions. Biochem. Biophys. Res. Commun. 314, 415–419 (2004).

    Article  PubMed  CAS  Google Scholar 

  98. McLaughlin, T. et al. Relationship between coronary atheroma, epicardial adipose tissue inflammation, and adipocyte differentiation across the human myocardial bridge. J. Am. Heart Assoc. 10, e021003 (2021).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  99. Ohyama, K. et al. Association of coronary perivascular adipose tissue inflammation and drug-eluting stent-induced coronary hyperconstricting responses in pigs: 18F-fluorodeoxyglucose positron emission tomography imaging study. Arterioscler. Thromb. Vasc. Biol. 37, 1757–1764 (2017).

    Article  PubMed  CAS  Google Scholar 

  100. Takaoka, M. et al. Endovascular injury induces rapid phenotypic changes in perivascular adipose tissue. Arterioscler. Thromb. Vasc. Biol. 30, 1576–1582 (2010).

    Article  PubMed  CAS  Google Scholar 

  101. Kim, H. W., Shi, H., Winkler, M. A., Lee, R. & Weintraub, N. L. Perivascular adipose tissue and vascular perturbation/atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 40, 2569–2576 (2020).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  102. Matsumoto, H. et al. Standardized volumetric plaque quantification and characterization from coronary CT angiography: a head-to-head comparison with invasive intravascular ultrasound. Eur. Radiol. 29, 6129–6139 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  103. Cho, I. et al. Prognostic value of coronary computed tomographic angiography findings in asymptomatic individuals: a 6-year follow-up from the prospective multicentre international CONFIRM study. Eur. Heart J. 39, 934–941 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  104. Commandeur, F. et al. Machine learning to predict the long-term risk of myocardial infarction and cardiac death based on clinical risk, coronary calcium, and epicardial adipose tissue: a prospective study. Cardiovasc. Res. 116, 2216–2225 (2020).

    Article  PubMed  CAS  Google Scholar 

  105. Han, D. et al. Prognostic significance of subtle coronary calcification in patients with zero coronary artery calcium score: from the CONFIRM registry. Atherosclerosis 309, 33–38 (2020).

    Article  PubMed  CAS  Google Scholar 

  106. Osborne-Grinter, M. et al. Association of coronary artery calcium score with qualitatively and quantitatively assessed adverse plaque on coronary CT angiography in the SCOT-HEART trial. Eur. Heart J. Cardiovasc. Imaging 23, 1210–1221 (2022).

    Article  PubMed  Google Scholar 

  107. Kato, S., Azuma, M., Horita, N. & Utsunomiya, D. Prognostic significance of CAD-RADS for patients with suspected coronary artery disease: a systematic review and meta-analysis. Radiol. Adv. 1, umae007 (2024).

    Article  Google Scholar 

  108. Maclean, E., Cronshaw, R., Newby, D. E., Nicol, E. & Williams, M. C. Prognostic utility of semi-quantitative coronary computed tomography angiography scores in the SCOT-HEART trial. J. Cardiovasc. Comput. Tomogr. 17, 393–400 (2023).

    Article  PubMed  Google Scholar 

  109. Motoyama, S. et al. Multislice computed tomographic characteristics of coronary lesions in acute coronary syndromes. J. Am. Coll. Cardiol. 50, 319–326 (2007).

    Article  PubMed  Google Scholar 

  110. Williams, M. C. et al. Coronary artery plaque characteristics associated with adverse outcomes in the SCOT-HEART study. J. Am. Coll. Cardiol. 73, 291–301 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  111. Tanisawa, H. et al. Quantification of low-attenuation plaque burden from coronary CT angiography: a head-to-head comparison with near-infrared spectroscopy intravascular US. Radiol. Cardiothorac. Imaging 5, e230090 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  112. Chang, H. J. et al. Coronary atherosclerotic precursors of acute coronary syndromes. J. Am. Coll. Cardiol. 71, 2511–2522 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  113. Williams, M. C. et al. Sex-specific computed tomography coronary plaque characterization and risk of myocardial infarction. JACC Cardiovasc. Imaging 14, 1804–1814 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  114. Lin, A. et al. Deep learning-enabled coronary CT angiography for plaque and stenosis quantification and cardiac risk prediction: an international multicentre study. Lancet Digit. Health 4, e256–e265 (2022).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  115. Motoyama, S. et al. Plaque characterization by coronary computed tomography angiography and the likelihood of acute coronary events in mid-term follow-up. J. Am. Coll. Cardiol. 66, 337–346 (2015).

    Article  PubMed  Google Scholar 

  116. Tzolos, E. et al. Repeatability of quantitative pericoronary adipose tissue attenuation and coronary plaque burden from coronary CT angiography. J. Cardiovasc. Comput. Tomogr. 15, 81–84 (2021).

    Article  PubMed  Google Scholar 

  117. Chen, X. et al. Pericoronary adipose tissue attenuation assessed by dual-layer spectral detector computed tomography is a sensitive imaging marker of high-risk plaques. Quant. Imaging Med. Surg. 11, 2093–2103 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  118. Tan, N., Dey, D., Marwick, T. H. & Nerlekar, N. Pericoronary adipose tissue as a marker of cardiovascular risk: JACC review topic of the week. J. Am. Coll. Cardiol. 81, 913–923 (2023).

    Article  PubMed  CAS  Google Scholar 

  119. Ma, R. et al. Towards reference values of pericoronary adipose tissue attenuation: impact of coronary artery and tube voltage in coronary computed tomography angiography. Eur. Radiol. 30, 6838–6846 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  120. Oikonomou, E. K. et al. Non-invasive detection of coronary inflammation using computed tomography and prediction of residual cardiovascular risk (the CRISP CT study): a post-hoc analysis of prospective outcome data. Lancet 392, 929–939 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  121. Tzolos, E. et al. Pericoronary adipose tissue attenuation, low-attenuation plaque burden, and 5-year risk of myocardial infarction. JACC Cardiovasc. Imaging 15, 1078–1088 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  122. Chan, K. et al. Inflammatory risk and cardiovascular events in patients without obstructive coronary artery disease: the ORFAN multicentre, longitudinal cohort study. Lancet 403, 2606–2618 (2024).

    Article  PubMed  CAS  Google Scholar 

  123. Stuijfzand, W. J. et al. Value of hybrid imaging with PET/CT to guide percutaneous revascularization of chronic total coronary occlusion. Curr. Cardiovasc. Imaging Rep. 8, 26 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  124. Bao, W. et al. A preliminary coronary computed tomography angiography-based study of perivascular fat attenuation index: relation with epicardial adipose tissue and its distribution over the entire coronary vasculature. Eur. Radiol. 32, 6028–6036 (2022).

    Article  PubMed  Google Scholar 

  125. Goeller, M. et al. Relationship between changes in pericoronary adipose tissue attenuation and coronary plaque burden quantified from coronary computed tomography angiography. Eur. Heart J. Cardiovasc. Imaging 20, 636–643 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  126. Oikonomou, E. K. et al. A novel machine learning-derived radiotranscriptomic signature of perivascular fat improves cardiac risk prediction using coronary CT angiography. Eur. Heart J. 40, 3529–3543 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  127. Oikonomou, E. K. et al. Standardized measurement of coronary inflammation using cardiovascular computed tomography: integration in clinical care as a prognostic medical device. Cardiovasc. Res. 117, 2677–2690 (2021).

    PubMed  CAS  Google Scholar 

  128. Lin, A. et al. Myocardial infarction associates with a distinct pericoronary adipose tissue radiomic phenotype: a prospective case-control study. JACC Cardiovasc. Imaging 13, 2371–2383 (2020).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  129. Kotanidis, C. P. et al. Constructing custom-made radiotranscriptomic signatures of vascular inflammation from routine CT angiograms: a prospective outcomes validation study in COVID-19. Lancet Digit. Health 4, e705–e716 (2022).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  130. Buckler, A. J. et al. Virtual transcriptomics: noninvasive phenotyping of atherosclerosis by decoding plaque biology from computed tomography angiography imaging. Arterioscler. Thromb. Vasc. Biol. 41, 1738–1750 (2021).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  131. Lu, M. T. et al. Epicardial and paracardial adipose tissue volume and attenuation — association with high-risk coronary plaque on computed tomographic angiography in the ROMICAT II trial. Atherosclerosis 251, 47–54 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  132. Okubo, R. et al. Pericoronary adipose tissue ratio is a stronger associated factor of plaque vulnerability than epicardial adipose tissue on coronary computed tomography angiography. Heart Vessel. 32, 813–822 (2017).

    Article  Google Scholar 

  133. Kwiecinski, J. et al. Peri-coronary adipose tissue density is associated with 18F-sodium fluoride coronary uptake in stable patients with high-risk plaques. JACC Cardiovasc. Imaging 12, 2000–2010 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  134. Wall, C. et al. Pericoronary and periaortic adipose tissue density are associated with inflammatory disease activity in Takayasu arteritis and atherosclerosis. Eur. Heart J. Open 1, oeab019 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  135. Lin, A. et al. Pericoronary adipose tissue computed tomography attenuation distinguishes different stages of coronary artery disease: a cross-sectional study. Eur. Heart J. Cardiovasc. Imaging 22, 298–306 (2021).

    Article  PubMed  CAS  Google Scholar 

  136. Yuvaraj, J. et al. Pericoronary adipose tissue attenuation is associated with high-risk plaque and subsequent acute coronary syndrome in patients with stable coronary artery disease. Cells 10, 1143 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  137. Goeller, M. et al. Pericoronary adipose tissue CT attenuation and its association with serum levels of atherosclerosis-relevant inflammatory mediators, coronary calcification and major adverse cardiac events. J. Cardiovasc. Comput. Tomogr. 15, 449–454 (2021).

    Article  PubMed  Google Scholar 

  138. van Rosendael, S. E. et al. Pericoronary adipose tissue for predicting long-term outcome. Eur. Heart J. Cardiovasc. Imaging 25, 1351–1359 (2024).

    Article  PubMed  PubMed Central  Google Scholar 

  139. Mézquita, A. J. V. et al. Clinical quantitative coronary artery stenosis and coronary atherosclerosis imaging: a consensus statement from the Quantitative Cardiovascular Imaging Study Group. Nat. Rev. Cardiol. 20, 696–714 (2023).

    Article  PubMed  Google Scholar 

  140. Mori, H. et al. Coronary artery calcification and its progression: what does it really mean? JACC Cardiovasc. Imaging 11, 127–142 (2018).

    Article  PubMed  Google Scholar 

  141. van Rosendael, A. R. et al. Association of high-density calcified 1K plaque with risk of acute coronary syndrome. JAMA Cardiol. 5, 282–290 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  142. Aldana-Bitar, J., Bhatt, D. L. & Budoff, M. J. Regression and stabilization of atherogenic plaques. Trends Cardiovasc. Med. 34, 340–346 (2023).

    Article  PubMed  Google Scholar 

  143. Lee, S. E. et al. Effects of statins on coronary atherosclerotic plaques: the PARADIGM study. JACC Cardiovasc. Imaging 11, 1475–1484 (2018).

    Article  PubMed  Google Scholar 

  144. Andelius, L., Mortensen, M. B., Nørgaard, B. L. & Abdulla, J. Impact of statin therapy on coronary plaque burden and composition assessed by coronary computed tomographic angiography: a systematic review and meta-analysis. Eur. Heart J. Cardiovasc. Imaging 19, 850–858 (2018).

    Article  PubMed  Google Scholar 

  145. Shin, S. et al. Impact of intensive LDL cholesterol lowering on coronary artery atherosclerosis progression: a serial CT angiography study. JACC Cardiovasc. Imaging 10, 437–446 (2017).

    Article  PubMed  Google Scholar 

  146. Tsujita, K. et al. Impact of dual lipid-lowering strategy with ezetimibe and atorvastatin on coronary plaque regression in patients with percutaneous coronary intervention: the Multicenter Randomized Controlled PRECISE-IVUS trial. J. Am. Coll. Cardiol. 66, 495–507 (2015).

    Article  PubMed  Google Scholar 

  147. Pérez de Isla, L. et al. Alirocumab and coronary atherosclerosis in asymptomatic patients with familial hypercholesterolemia: the ARCHITECT study. Circulation 147, 1436–1443 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  148. Dai, X. et al. Serial change of perivascular fat attenuation index after statin treatment: insights from a coronary CT angiography follow-up study. Int. J. Cardiol. 319, 144–149 (2020).

    Article  PubMed  Google Scholar 

  149. Elnabawi, Y. A. et al. Association of biologic therapy with coronary inflammation in patients with psoriasis as assessed by perivascular fat attenuation index. JAMA Cardiol. 4, 885–891 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  150. Kavousi, M. et al. Evaluation of newer risk markers for coronary heart disease risk classification: a cohort study. Ann. Intern. Med. 156, 438–444 (2012).

    Article  PubMed  Google Scholar 

  151. Khan, S. S. et al. Development and validation of the American Heart Association’s PREVENT equations. Circulation 149, 430–449 (2024).

    Article  PubMed  Google Scholar 

  152. Fox, K. A. et al. Prediction of risk of death and myocardial infarction in the six months after presentation with acute coronary syndrome: prospective multinational observational study (GRACE). BMJ 333, 1091 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

  153. Yu, M.-M. et al. Evolocumab attenuate pericoronary adipose tissue density via reduction of lipoprotein(a) in type 2 diabetes mellitus: a serial follow-up CCTA study. Cardiovasc. Diabetol. 22, 121 (2023).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  154. Chatterjee, D. et al. Perivascular fat attenuation for predicting adverse cardiac events in stable patients undergoing invasive coronary angiography. J. Cardiovasc. Comput. Tomogr. 16, 483–490 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  155. Wen, D. et al. Lack of incremental prognostic value of pericoronary adipose tissue computed tomography attenuation beyond coronary artery disease reporting and data system for major adverse cardiovascular events in patients with acute chest pain. Circ. Cardiovasc. Imaging 16, 536–544 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  156. Chen, M. et al. Lesion-specific pericoronary adipose tissue CT attenuation improves risk prediction of major adverse cardiovascular events in coronary artery disease. Br. J. Radiol. 97, 258–266 (2024).

    Article  PubMed  Google Scholar 

  157. Yang, W. et al. Prognostic value of non-alcoholic fatty liver disease and RCA pericoronary adipose tissue CT attenuation in patients with acute chest pain. Acad. Radiol. 31, 1773–1783 (2024).

    Article  PubMed  Google Scholar 

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Acknowledgements

K.G. is supported by the Foundation for Polish Science and a Polish National Agency for Academic Exchange. J.G. is supported by the Research Foundation Flanders (FWO) grant for long stay abroad (V414524N, V428223N) and the European Association of Cardiovascular Imaging (EACVI) Research Grant 2022. N.N. is supported by the National Health and Medical Research Council of Australia (APP1197028). D.E.N. is supported by the British Heart Foundation (CH/09/002, RG/F/22/110093, RE/24/130012). K.G., J.G. and D.D. are supported by the National Institute of Health/National Heart, Lung, and Blood Institute grants (1R01HL148787-01A1, 1R01HL151266 and 1R01HL175875), and a grant from the Miriam and Sheldon G. Adelson Medical Research Foundation.

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Author notes

  1. These authors contributed equally: Kajetan Grodecki, Jolien Geers.

  2. These authors jointly supervised this work: David E. Newby, Damini Dey.

Authors and Affiliations

  1. Department of Biomedical Sciences, and Department of Medicine, Cedars-Sinai Medical Center, Biomedical Imaging Research Institute, Los Angeles, CA, USA

    Kajetan Grodecki, Jolien Geers, Piotr J. Slomka, Daniel Berman & Damini Dey

  2. 1st Department of Cardiology, Medical University of Warsaw, Warsaw, Poland

    Kajetan Grodecki

  3. Department of Cardiology, Centrum Voor Hart- en Vaatziekten (CHVZ), Universitair Ziekenhuis Brussel (UZ Brussel), Vrije Universiteit Brussel (VUB), Brussels, Belgium

    Jolien Geers

  4. Department of Interventional Cardiology and Angiology, National Institute of Cardiology, Warsaw, Poland

    Jacek Kwiecinski

  5. Monash Victorian Heart Institute and Monash Health Heart, Monash University, Victorian Heart Hospital, Melbourne, Victoria, Australia

    Andrew Lin & Nitesh Nerlekar

  6. Division of Cardiology, Montefiore Healthcare Network/Albert Einstein College of Medicine, New York, NY, USA

    Leandro Slipczuk

  7. British Heart Foundation Centre of Research Excellence, University of Edinburgh, Edinburgh, UK

    Marc R. Dweck, Michelle C. Williams & David E. Newby

  8. Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia

    Nitesh Nerlekar & Thomas Marwick

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K.G., J.G., D.E.N. and D.D. research data for the article. All the authors discussed its content, wrote the manuscript and reviewed/edited it before submission.

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Grodecki, K., Geers, J., Kwiecinski, J. et al. Phenotyping atherosclerotic plaque and perivascular adipose tissue: signalling pathways and clinical biomarkers in atherosclerosis. Nat Rev Cardiol 22, 443–455 (2025). https://doi.org/10.1038/s41569-024-01110-1

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