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  • Review Article
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Evolving concepts of the vulnerable atherosclerotic plaque and the vulnerable patient: implications for patient care and future research

Nature Reviews Cardiology volume 20, pages 181–196 (2023)Cite this article

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Abstract

Understanding the natural history of coronary artery atherosclerosis is necessary to determine prognosis and prescribe effective therapies. Traditional management of coronary artery disease has focused on the treatment of flow-limiting anatomical obstructions that lead to ischaemia. In most scenarios, revascularization of these atherosclerotic plaques has not substantially improved freedom from death or myocardial infarction, questioning the utility of contemporary revascularization strategies to improve prognosis. Advances in non-invasive and invasive imaging techniques have helped to identify the characteristics of obstructive and non-obstructive plaques that are precursors for plaque progression and future acute coronary syndromes as well as cardiac death. These ‘vulnerable plaques’ develop as a consequence of systemic inflammation and are prone to inducing thrombosis. Vulnerable plaques most commonly have a large plaque burden with a well-formed necrotic core and thin fibrous cap and are metabolically active. Perivascular adipose tissue might, in some patients, be used as a surrogate for coronary inflammation and predict future risk of adverse cardiac events. Vulnerable plaques can be identified in their quiescent state, offering the potential for therapeutic passivation. In this Review, we describe the biological and compositional features of vulnerable plaques, the non-invasive and invasive diagnostic modalities to characterize vulnerable plaques, the prognostic utility of identifying vulnerable plaques, and the future studies needed to explore the value of intensified pharmacological and focal treatments of vulnerable plaques.

Key points

  • Vulnerable plaques are atherosclerotic coronary lesions prone to thrombosis owing to their specific structure and biological and chemical features.

  • Non-invasive and invasive diagnostic modalities, including CT angiography and catheter-based imaging techniques, have been developed to detect these lesions before they cause adverse cardiovascular events.

  • Pharmacological and interventional treatments of vulnerable plaques have been shown to favourably alter the mechanical structure and composition of vulnerable plaques, which might lead to plaque stabilization and improve clinical outcomes.

  • Future large-scale, randomized, controlled clinical trials are needed to explore the value of intensified pharmacological and focal treatments of high-risk vulnerable plaques in vulnerable patients, that is, those patients who have an increased risk of cardiac events.

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Fig. 1: Major coronary atherosclerotic lesion types prone to thrombosis.
Fig. 2: Mechanisms of vulnerable atherosclerotic plaque formation and progression.
Fig. 3: Potential role of adipose tissue in cardiovascular inflammation and atherosclerosis.
Fig. 4: Features of high-risk vulnerable plaques on coronary CT angiography.
Fig. 5: Detection of high-risk vulnerable plaques on coronary MRI.
Fig. 6: Features of high-risk vulnerable plaques on coronary PET.
Fig. 7: Atherosclerotic plaque classification on intravascular ultrasonography.
Fig. 8: Vulnerable plaque features are associated with an increased risk of cardiac events.
Fig. 9: Algorithm for vulnerable plaque screening and treatment for primary prevention.

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References

  1. Khan, M. A. et al. Global epidemiology of ischemic heart disease: results from the global burden of disease study. Cureus 12, e9349 (2020).

    PubMed  PubMed Central  Google Scholar 

  2. Alderman, E. L. et al. Five-year angiographic follow-up of factors associated with progression of coronary artery disease in the Coronary Artery Surgery Study (CASS). J. Am. Coll. Cardiol. 22, 1141–1154 (1993).

    Article  CAS  PubMed  Google Scholar 

  3. Maddox, T. M. et al. Nonobstructive coronary artery disease and risk of myocardial infarction. JAMA 312, 1754–1763 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. The BARI 2D Study Group. A randomized trial of therapies for type 2 diabetes and coronary artery disease. N. Engl. J. Med. 360, 2503–2515 (2009).

    Article  PubMed Central  Google Scholar 

  5. Boden, W. E. et al. Optimal medical therapy with or without PCI for stable coronary disease. N. Engl. J. Med. 356, 1503–1516 (2007).

    Article  CAS  PubMed  Google Scholar 

  6. Maron, D. J. et al. Initial invasive or conservative strategy for stable coronary disease. N. Engl. J. Med. 382, 1395–1407 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  7. Bangalore, S., Maron, D. J., Stone, G. W. & Hochman, J. S. Routine revascularization versus initial medical therapy for stable ischemic heart disease. Circulation 142, 841–857 (2020).

    Article  PubMed  Google Scholar 

  8. Sorbets, E. et al. Long-term outcomes of chronic coronary syndrome worldwide: insights from the international CLARIFY registry. Eur. Heart J. 41, 347–356 (2020).

    Article  PubMed  Google Scholar 

  9. Kedhi, E. et al. Thin-cap fibroatheroma predicts clinical events in diabetic patients with normal fractional flow reserve: the COMBINE OCT-FFR trial. Eur. Heart J. 42, 4671–4679 (2021).

    Article  CAS  PubMed  Google Scholar 

  10. Lee, J. M. et al. Prognostic implications of plaque characteristics and stenosis severity in patients with coronary artery disease. J. Am. Coll. Cardiol. 73, 2413–2424 (2019).

    Article  PubMed  Google Scholar 

  11. Muller, J. E., Tofler, G. H. & Stone, P. H. Circadian variation and triggers of onset of acute cardiovascular disease. Circulation 79, 733–743 (1989).

    Article  CAS  PubMed  Google Scholar 

  12. Liang, M., Puri, A. & Devlin, G. The vulnerable plaque: the real villain in acute coronary syndromes. Open. Cardiovasc. Med. J. 5, 123–129 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  13. Arnold, S. V. et al. Adherence to guideline medication recommendations to prevent atherosclerotic cardiovascular disease progression among adults with prior myocardial infarction. JAMA Netw. Open 3, e203032 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  14. Knuuti, J. et al. 2019 ESC Guidelines for the Diagnosis and Management of Chronic Coronary Syndromes. Eur. Heart J. 41, 407–477 (2020).

    Article  PubMed  Google Scholar 

  15. Arnett, D. K. et al. 2019 ACC/AHA guideline on the primary prevention of cardiovascular disease: a report of the American College of Cardiology/American Heart Association task force on clinical practice guidelines. Circulation https://doi.org/10.1161/CIR.0000000000000678 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  16. Emond, M. et al. Long-term survival of medically treated patients in the coronary artery surgery study (CASS) registry. Circulation 90, 2645–2657 (1994).

    Article  CAS  PubMed  Google Scholar 

  17. Bergmark, B. A. & Morrow, D. A. Beyond the ISCHEMIA trial: revascularization for stable ischemic heart disease in patients with high-risk coronary anatomical features. J. Am. Heart Assoc. 10, e019974 (2021).

    Article  PubMed  Google Scholar 

  18. Bainey, K. R. et al. Long-term clinical outcomes following revascularization in high-risk coronary anatomy patients with stable ischemic heart disease. J. Am. Heart Assoc. 10, e018104 (2021).

    Article  PubMed  Google Scholar 

  19. Yusuf, S. et al. Effect of coronary artery bypass graft surgery on survival: overview of 10-year results from randomised trials by the Coronary Artery Bypass Graft Surgery Trialists Collaboration. Lancet 344, 563–570 (1994).

    Article  CAS  PubMed  Google Scholar 

  20. Cortigiani, L. et al. Prediction of mortality by stress echocardiography in 2835 diabetic and 11305 nondiabetic patients. Circ. Cardiovasc. Imaging 8, e002757 (2015).

    Article  PubMed  Google Scholar 

  21. Dorbala, S. et al. Prognostic value of stress myocardial perfusion positron emission tomography: results from a multicenter observational registry. J. Am. Coll. Cardiol. 61, 176–184 (2013).

    Article  PubMed  Google Scholar 

  22. Patel, K. K. et al. Myocardial blood flow reserve assessed by positron emission tomography myocardial perfusion imaging identifies patients with a survival benefit from early revascularization. Eur. Heart J. 41, 759–768 (2020).

    Article  CAS  PubMed  Google Scholar 

  23. Hachamovitch, R., Hayes, S. W., Friedman, J. D., Cohen, I. & Berman, D. S. Comparison of the short-term survival benefit associated with revascularization compared with medical therapy in patients with no prior coronary artery disease undergoing stress myocardial perfusion single photon emission computed tomography. Circulation 107, 2900–2907 (2003).

    Article  PubMed  Google Scholar 

  24. Zimmermann, F. M. et al. Deferral vs. performance of percutaneous coronary intervention of functionally non-significant coronary stenosis: 15-year follow-up of the DEFER trial. Eur. Heart J. 36, 3182–3188 (2015).

    Article  PubMed  Google Scholar 

  25. Gersh, B. J. et al. To stent or not to stent? Treating angina after ISCHEMIA-introduction. Eur. Heart J. 42, 1387–1388 (2021).

    Article  PubMed  Google Scholar 

  26. Reynolds, H. R. et al. Outcomes in the ISCHEMIA trial based on coronary artery disease and ischemia severity. Circulation 144, 1024–1038 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Lopes, R. D. et al. Initial invasive versus conservative management of stable ischemic heart disease in patients with a history of heart failure or left ventricular dysfunction. Circulation 142, 1725–1735 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  28. Gersh, B. J. & Bhatt, D. L. To stent or not to stent? Treating angina after ISCHEMIA-the impact of the ISCHEMIA trial on the indications for angiography and revascularization in patients with stable coronary artery disease. Eur. Heart J. 42, 1389–1393 (2021).

    Article  PubMed  Google Scholar 

  29. Head, S. J. et al. Mortality after coronary artery bypass grafting versus percutaneous coronary intervention with stenting for coronary artery disease: a pooled analysis of individual patient data. Lancet 391, 939–948 (2018).

    Article  PubMed  Google Scholar 

  30. Lee, C. W. et al. Coronary artery bypass surgery versus drug-eluting stent implantation for left main or multivessel coronary artery disease: a meta-analysis of individual patient data. JACC Cardiovasc. Interv. 9, 2481–2489 (2016).

    Article  PubMed  Google Scholar 

  31. Sabatine, M. S. et al. Percutaneous coronary intervention with drug-eluting stents versus coronary artery bypass grafting in left main coronary artery disease: an individual patient data meta-analysis. Lancet 398, 2247–2257 (2021).

    Article  CAS  PubMed  Google Scholar 

  32. Taqueti, V. R. et al. Global coronary flow reserve is associated with adverse cardiovascular events independently of luminal angiographic severity and modifies the effect of early revascularization. Circulation 131, 19–27 (2015).

    Article  PubMed  Google Scholar 

  33. Finn, A. V., Nakano, M., Narula, J., Kolodgie, F. D. & Virmani, R. Concept of vulnerable/unstable plaque. Arterioscler. Thromb. Vasc. Biol. 30, 1282–1292 (2010).

    Article  CAS  PubMed  Google Scholar 

  34. Virmani, R., Burke, A. P., Farb, A. & Kolodgie, F. D. Pathology of the vulnerable plaque. J. Am. Coll. Cardiol. 47 (Suppl. 8), C13–C18 (2006).

    Article  CAS  PubMed  Google Scholar 

  35. Arbab-Zadeh, A. & Fuster, V. From detecting the vulnerable plaque to managing the vulnerable patient: JACC state-of-the-art review. J. Am. Coll. Cardiol. 74, 1582–1593 (2019).

    Article  PubMed  Google Scholar 

  36. Burke, A. P. et al. Healed plaque ruptures and sudden coronary death: evidence that subclinical rupture has a role in plaque progression. Circulation 103, 934–940 (2001).

    Article  CAS  PubMed  Google Scholar 

  37. Burke, A. P. et al. Coronary risk factors and plaque morphology in men with coronary disease who died suddenly. N. Engl. J. Med. 336, 1276–1282 (1997).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  39. Calvert, P. A. et al. Association between IVUS findings and adverse outcomes in patients with coronary artery disease: the VIVA (VH-IVUS in vulnerable atherosclerosis) study. JACC Cardiovasc. Imaging 4, 894–901 (2011).

    Article  PubMed  Google Scholar 

  40. Fleg, J. L. et al. Detection of high-risk atherosclerotic plaque. JACC Cardiovasc. Imaging 5, 941–955 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  41. Wentzel, J. J. et al. Endothelial shear stress in the evolution of coronary atherosclerotic plaque and vascular remodelling: current understanding and remaining questions. Cardiovasc. Res. 96, 234–243 (2012).

    Article  CAS  PubMed  Google Scholar 

  42. Stone, P. H. et al. Prediction of progression of coronary artery disease and clinical outcomes using vascular profiling of endothelial shear stress and arterial plaque characteristics. Circulation 126, 172–181 (2012).

    Article  PubMed  Google Scholar 

  43. Libby, P. Lipoprotein (a): a frustrating final frontier in lipid management? JACC Basic. Transl. Sci. 1, 428–431 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  44. Deb, A. & Caplice, N. M. Lipoprotein(a): new insights into mechanisms of atherogenesis and thrombosis. Clin. Cardiol. 27, 258–264 (2004).

    Article  PubMed  Google Scholar 

  45. 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  CAS  PubMed  PubMed Central  Google Scholar 

  46. Antoniades, C., Antonopoulos, A. S. & Deanfield, J. Imaging residual inflammatory cardiovascular risk. Eur. Heart J. 41, 748–758 (2020).

    Article  CAS  PubMed  Google Scholar 

  47. Libby, P. & Lee, R. T. Matrix matters. Circulation 102, 1874–1876 (2000).

    Article  CAS  PubMed  Google Scholar 

  48. Deguchi, J. O. et al. Inflammation in atherosclerosis. Circulation 114, 55–62 (2006).

    Article  PubMed  Google Scholar 

  49. Sukhova, G. K. et al. Evidence for increased collagenolysis by interstitial collagenases-1 and -3 in vulnerable human atheromatous plaques. Circulation 99, 2503–2509 (1999).

    Article  CAS  PubMed  Google Scholar 

  50. Wang, J. et al. High fluid shear stress prevents atherosclerotic plaque formation by promoting endothelium denudation and synthetic phenotype of vascular smooth muscle cells. Mol. Med. Rep. 24, 577 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Ambrose, J. A. et al. Angiographic progression of coronary artery disease and the development of myocardial infarction. J. Am. Coll. Cardiol. 12, 56–62 (1988).

    Article  CAS  PubMed  Google Scholar 

  52. Glaser, R. et al. Clinical progression of incidental, asymptomatic lesions discovered during culprit vessel coronary intervention. Circulation 111, 143–149 (2005).

    Article  PubMed  Google Scholar 

  53. Aguirre, A. D., Arbab-Zadeh, A., Soeda, T., Fuster, V. & Jang, I. K. Optical coherence tomography of plaque vulnerability and rupture. J. Am. Coll. Cardiol. 78, 1257–1265 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  54. 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 

  55. Shmilovich, H. et al. Vulnerable plaque features on coronary CT angiography as markers of inducible regional myocardial hypoperfusion from severe coronary artery stenoses. Atherosclerosis 219, 588–595 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Puchner, S. B. et al. High-risk plaque detected on coronary CT angiography predicts acute coronary syndromes independent of significant stenosis in acute chest pain: results from the ROMICAT-II trial. J. Am. Coll. Cardiol. 64, 684–692 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  57. Kröner, E. S. J. et al. Positive remodeling on coronary computed tomography as a marker for plaque vulnerability on virtual histology intravascular ultrasound. Am. J. Cardiol. 107, 1725–1729 (2011).

    Article  PubMed  Google Scholar 

  58. Maehara, A. & Stone, G. W. High-risk coronary atherosclerosis. Circ. Cardiovasc. Imaging 10, e007116 (2017).

    Article  PubMed  Google Scholar 

  59. 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 

  60. Otsuka, K. et al. Prognosis of vulnerable plaque on computed tomographic coronary angiography with normal myocardial perfusion image. Eur. Heart J. Cardiovasc. Imaging 15, 332–340 (2014).

    Article  PubMed  Google Scholar 

  61. Lee, S. E. et al. Differences in progression to obstructive lesions per high-risk plaque features and plaque volumes with CCTA. JACC Cardiovasc. Imaging 13, 1409–1417 (2020).

    Article  PubMed  Google Scholar 

  62. Williams, M. C. et al. Low-attenuation noncalcified plaque on coronary computed tomography angiography predicts myocardial infarction. Circulation 141, 1452–1462 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Xie, J. X. et al. Prognostic significance of nonobstructive left main coronary artery disease in women versus men: long-term outcomes from the CONFIRM registry. Circ. Cardiovasc. Imaging 10, e006246 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  64. Kotanidis, C. P. et al. Pericoronary fat radiomic profile (FRP) predicts long-term cardiac risk in individuals with calcium score below 100 on coronary computed tomography angiography. Eur. Heart J. 41 (Suppl. 2), ehaa946.0181 (2020).

    Article  Google Scholar 

  65. Oikonomou, E. K. et al. Perivascular fat attenuation index stratifies cardiac risk associated with high-risk plaques in the CRISP-CT study. J. Am. Coll. Cardiol. 76, 755–757 (2020).

    Article  PubMed  Google Scholar 

  66. 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 

  67. Channon, K. M., Newby, D. E., Nicol, E. D. & Deanfield, J. Cardiovascular computed tomography imaging for coronary artery disease risk: plaque, flow and fat. Heart https://doi.org/10.1136/heartjnl-2021-320265 (2022).

    Article  PubMed  Google Scholar 

  68. Takaya, N. et al. Association between carotid plaque characteristics and subsequent ischemic cerebrovascular events: a prospective assessment with MRI-initial results. Stroke 37, 818–823 (2006).

    Article  PubMed  Google Scholar 

  69. Phinikaridou, A. et al. In vivo detection of vulnerable atherosclerotic plaque by MRI in a rabbit model. Circ. Cardiovasc. Imaging 3, 323–332 (2010).

    Article  PubMed  Google Scholar 

  70. Vancraeynest, D., Pasquet, A., Roelants, V., Gerber, B. L. & Vanoverschelde, J. L. J. Imaging the vulnerable plaque. J. Am. Coll. Cardiol. 57, 1961–1979 (2011).

    Article  PubMed  Google Scholar 

  71. Asaumi, Y. et al. High-intensity plaques on noncontrast T1-weighted imaging as a predictor of periprocedural myocardial injury. JACC Cardiovasc. Imaging 8, 741–743 (2015).

    Article  PubMed  Google Scholar 

  72. Noguchi, T. et al. High-intensity signals in coronary plaques on noncontrast T1-weighted magnetic resonance imaging as a novel determinant of coronary events. J. Am. Coll. Cardiol. 63, 989–999 (2014).

    Article  PubMed  Google Scholar 

  73. Liu, W. et al. Relationship between coronary hyper-intensive plaques identified by cardiovascular magnetic resonance and clinical severity of acute coronary syndrome. J. Cardiovasc. Magn. Reson. 23, 12 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  74. Matsumoto, K., Ehara, S., Hasegawa, T., Nishimura, S. & Shimada, K. The signal intensity of coronary culprit lesions on T1-weighted magnetic resonance imaging is directly correlated with the accumulation of vulnerable morphologies. Int. J. Cardiol. 231, 284–286 (2017).

    Article  PubMed  Google Scholar 

  75. Engel, L. C. et al. Novel approach for in vivo detection of vulnerable coronary plaques using molecular 3-T CMR imaging with an albumin-binding probe. JACC Cardiovasc. Imaging 12, 297–306 (2019).

    Article  PubMed  Google Scholar 

  76. González Ballester, M. A., Zisserman, A. P. & Brady, M. Estimation of the partial volume effect in MRI. Med. Image Anal. 6, 389–405 (2002).

    Article  PubMed  Google Scholar 

  77. Noguchi, T. et al. Noninvasive coronary plaque imaging. J. Atheroscler. Thromb. 25, 281–293 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Lairez, O. & Hyafil, F. A clinical role of PET in atherosclerosis and vulnerable plaques? Semin. Nucl. Med. 50, 311–318 (2020).

    Article  PubMed  Google Scholar 

  79. Strauss, H. W. & Narula, J. Imaging vulnerable plaque. J. Am. Coll. Cardiol. 69, 1792–1794 (2017).

    Article  PubMed  Google Scholar 

  80. Tarkin, J. M. et al. Detection of atherosclerotic inflammation by 68Ga-DOTATATE PET compared to [18F]FDG PET imaging. J. Am. Coll. Cardiol. 69, 1774–1791 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Marnane, M. et al. Carotid plaque inflammation on 18F-fluorodeoxyglucose positron emission tomography predicts early stroke recurrence. Ann. Neurol. 71, 709–718 (2012).

    Article  PubMed  Google Scholar 

  82. Kwiecinski, J. et al. Coronary 18F-sodium fluoride uptake predicts outcomes in patients with coronary artery disease. J. Am. Coll. Cardiol. 75, 3061–3074 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Bourassa, M. G. The history of cardiac catheterization. Can. J. Cardiol. 21, 1011–1014 (2005).

    PubMed  Google Scholar 

  84. Tonino, P. A. L. et al. Fractional flow reserve versus angiography for guiding percutaneous coronary intervention. N. Engl. J. Med. 360, 213–224 (2009).

    Article  CAS  PubMed  Google Scholar 

  85. Götberg, M. et al. Instantaneous wave-free ratio versus fractional flow reserve to guide PCI. N. Engl. J. Med. 376, 1813–1823 (2017).

    Article  PubMed  Google Scholar 

  86. Fearon, W. F. et al. Fractional flow reserve–guided PCI as compared with coronary bypass surgery. N. Engl. J. Med. 386, 128–137 (2022).

    Article  PubMed  Google Scholar 

  87. Glagov, S., Weisenberg, E., Zarins, C. K., Stankunavicius, R. & Kolettis, G. J. Compensatory enlargement of human atherosclerotic coronary arteries. N. Engl. J. Med. 316, 1371–1375 (1987).

    Article  CAS  PubMed  Google Scholar 

  88. Schoenhagen, P. et al. Extent and direction of arterial remodeling in stable versus unstable coronary syndromes. Circulation 101, 598–603 (2000).

    Article  CAS  PubMed  Google Scholar 

  89. Darmoch, F. et al. Intravascular ultrasound imaging–guided versus coronary angiography-guided percutaneous coronary intervention: a systematic review and meta-analysis. J. Am. Heart Assoc. 9, e013678 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  90. Zheng, B. et al. Predictors of plaque rupture within nonculprit fibroatheromas in patients with acute coronary syndromes: the PROSPECT study. JACC Cardiovasc. Imaging 8, 1180–1187 (2015).

    Article  PubMed  Google Scholar 

  91. Kotani, J. I. et al. Intravascular ultrasound analysis of infarct-related and non-infarct-related arteries in patients who presented with an acute myocardial infarction. Circulation 107, 2889–2893 (2003).

    Article  PubMed  Google Scholar 

  92. Suh, W. M., Seto, A. H., Margey, R. J. P., Cruz-Gonzalez, I. & Jang, I. K. Intravascular detection of the vulnerable plaque. Circ. Cardiovasc. Imaging 4, 169–178 (2011).

    Article  PubMed  Google Scholar 

  93. Bourantas, C. V. et al. Clinical and angiographic characteristics of patients likely to have vulnerable plaques: analysis from the PROSPECT study. JACC Cardiovasc. Imaging 6, 1263–1272 (2013).

    Article  PubMed  Google Scholar 

  94. McPherson, J. A. et al. Residual plaque burden in patients with acute coronary syndromes after successful percutaneous coronary intervention. JACC Cardiovasc. Imaging 5, S76–S85 (2012).

    Article  PubMed  Google Scholar 

  95. Inaba, S. et al. Impact of positive and negative lesion site remodeling on clinical outcomes: insights from PROSPECT. JACC Cardiovasc. Imaging 7, 70–78 (2014).

    Article  PubMed  Google Scholar 

  96. Jang, I. K. et al. Visualization of coronary atherosclerotic plaques in patients using optical coherence tomography: comparison with intravascular ultrasound. J. Am. Coll. Cardiol. 39, 604–609 (2002).

    Article  PubMed  Google Scholar 

  97. Kubo, T. et al. Optical frequency domain imaging vs. intravascular ultrasound in percutaneous coronary intervention (OPINION trial): one-year angiographic and clinical results. Eur. Heart J. 38, 3139–3147 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  98. Tearney, G. J. et al. Consensus standards for acquisition, measurement, and reporting of intravascular optical coherence tomography studies: a report from the International Working Group for intravascular optical coherence tomography standardization and validation. J. Am. Coll. Cardiol. 59, 1058–1072 (2012).

    Article  PubMed  Google Scholar 

  99. Romagnoli, E., Gatto, L. & Prati, F. The CLIMA study: assessing the risk of myocardial infarction with a new anatomical score. Eur. Heart J. Suppl. 21 (Suppl. B), B80–B83 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  100. Prati, F. et al. Relationship between coronary plaque morphology of the left anterior descending artery and 12 months clinical outcome: the CLIMA study. Eur. Heart J. 41, 383–391 (2020).

    Article  PubMed  Google Scholar 

  101. Kedhi, E. et al. Thin-cap fibroatheroma predicts clinical events in diabetic patients with normal fractional flow reserve: the COMBINE OCT–FFR trial. Eur. Heart J. 42, 4671–4679 (2021).

    Article  CAS  PubMed  Google Scholar 

  102. Xing, L. et al. Clinical significance of lipid-rich plaque detected by optical coherence tomography: a 4-year follow-up study. J. Am. Coll. Cardiol. 69, 2502–2513 (2017).

    Article  PubMed  Google Scholar 

  103. Kubo, T. et al. Optical coherence tomography detection of vulnerable plaques at high risk of developing acute coronary syndrome. Eur. Heart J. Cardiovasc. Imaging https://doi.org/10.1093/ehjci/jeab028 (2021).

    Article  PubMed  Google Scholar 

  104. Jinnouchi, H. et al. Micro–computed tomography demonstration of multiple plaque ruptures in a single individual presenting with sudden cardiac death. Circ. Cardiovasc. Imaging 11, e008331 (2018).

    Article  PubMed  Google Scholar 

  105. Stefanadis, C., Antoniou, C., Tsiachris, D. & Pietri, P. Coronary atherosclerotic vulnerable plaque: current perspectives. J. Am. Heart Assoc. 6, e005543 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  106. Gardner, C. M. et al. Detection of lipid core coronary plaques in autopsy specimens with a novel catheter-based near-infrared spectroscopy system. JACC Cardiovasc. Imaging 1, 638–648 (2008).

    Article  PubMed  Google Scholar 

  107. Muller, J. & Madder, R. OCT-NIRS imaging for detection of coronary plaque structure and vulnerability. Front. Cardiovasc. Med. 7, 90 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  108. Patel, D. et al. Subsequent development of fibroatheromas with inflamed fibrous caps can be predicted by intracoronary near infrared spectroscopy. Arterioscler. Thromb. Vasc. Biol. 33, 347–353 (2013).

    Article  CAS  PubMed  Google Scholar 

  109. Schuurman, A. S. et al. Near-infrared spectroscopy-derived lipid core burden index predicts adverse cardiovascular outcome in patients with coronary artery disease during long-term follow-up. Eur. Heart J. 39, 295–302 (2018).

    Article  PubMed  Google Scholar 

  110. Waksman, R. et al. Identification of patients and plaques vulnerable to future coronary events with near-infrared spectroscopy intravascular ultrasound imaging: a prospective, cohort study. Lancet 394, 1629–1637 (2019).

    Article  CAS  PubMed  Google Scholar 

  111. Waksman, R. et al. The Lipid-Rich Plaque Study of vulnerable plaques and vulnerable patients: study design and rationale. Am. Heart J. 192, 98–104 (2017).

    Article  PubMed  Google Scholar 

  112. Erlinge, D. et al. Identification of vulnerable plaques and patients by intracoronary near-infrared spectroscopy and ultrasound (PROSPECT II): a prospective natural history study. Lancet 397, 985–995 (2021).

    Article  CAS  PubMed  Google Scholar 

  113. Khraishah, H. & Jaffer, F. A. Intravascular molecular imaging: near-infrared fluorescence as a new frontier. Front. Cardiovasc. Med. 7, 587100 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Costopoulos, C. et al. Heterogeneity of plaque structural stress is increased in plaques leading to MACE: insights from the PROSPECT study. JACC Cardiovasc. Imaging 13, 1206–1218 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  115. Samady, H. et al. Coronary artery wall shear stress is associated with progression and transformation of atherosclerotic plaque and arterial remodeling in patients with coronary artery disease. Circulation 124, 779–788 (2011).

    Article  CAS  PubMed  Google Scholar 

  116. Braunwald, E. Epilogue: what do clinicians expect from imagers. J. Am. Coll. Cardiol. 47, C101–C103 (2006).

    Article  PubMed  Google Scholar 

  117. Braunwald, E. Noninvasive detection of vulnerable coronary plaques. J. Am. Coll. Cardiol. 54, 58–59 (2009).

    Article  PubMed  Google Scholar 

  118. Stone, G. W. et al. Percutaneous coronary intervention for vulnerable coronary atherosclerotic plaque. J. Am. Coll. Cardiol. 76, 2289–2301 (2020).

    Article  CAS  PubMed  Google Scholar 

  119. Cannon, C. P. et al. Ezetimibe added to statin therapy after acute coronary syndromes. N. Engl. J. Med. 372, 2387–2397 (2015).

    Article  CAS  PubMed  Google Scholar 

  120. Bhatt, D. L. et al. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N. Engl. J. Med. 380, 11–22 (2019).

    Article  CAS  PubMed  Google Scholar 

  121. Sabatine, M. S. et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N. Engl. J. Med. 376, 1713–1722 (2017).

    Article  CAS  PubMed  Google Scholar 

  122. Ridker, P. M. et al. Low-dose methotrexate for the prevention of atherosclerotic events. N. Engl. J. Med. 380, 752–762 (2019).

    Article  CAS  PubMed  Google Scholar 

  123. Tardif, J. C. et al. Efficacy and safety of low-dose colchicine after myocardial infarction. N. Engl. J. Med. 381, 2497–2505 (2019).

    Article  CAS  PubMed  Google Scholar 

  124. Ridker, P. M. et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N. Engl. J. Med. 377, 1119–1131 (2017).

    Article  CAS  PubMed  Google Scholar 

  125. Navarese, E. P. et al. Cardiac mortality in patients randomised to elective coronary revascularisation plus medical therapy or medical therapy alone: a systematic review and meta-analysis. Eur. Heart J. 42, 4638–4651 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  126. Mehta, S. R. et al. Complete revascularization with multivessel PCI for myocardial infarction. N. Engl. J. Med. 381, 1411–1421 (2019).

    Article  PubMed  Google Scholar 

  127. Puymirat, E. et al. Multivessel PCI guided by FFR or angiography for myocardial infarction. N. Engl. J. Med. 385, 297–308 (2021).

    Article  PubMed  Google Scholar 

  128. Pinilla-Echeverri, N. et al. Nonculprit lesion plaque morphology in patients with ST-segment-elevation myocardial infarction: results from the COMPLETE trial optical coherence tomography substudys. Circ. Cardiovasc. Interv. 13, e008768 (2020).

    Article  CAS  PubMed  Google Scholar 

  129. Komukai, K. et al. Effect of atorvastatin therapy on fibrous cap thickness in coronary atherosclerotic plaque as assessed by optical coherence tomography: the EASY-FIT study. J. Am. Coll. Cardiol. 64, 2207–2217 (2014).

    Article  CAS  PubMed  Google Scholar 

  130. Kini, A. S. et al. Changes in plaque lipid content after short-term intensive versus standard statin therapy: the YELLOW trial (reduction in yellow plaque by aggressive lipid-lowering therapy). J. Am. Coll. Cardiol. 62, 21–29 (2013).

    Article  CAS  PubMed  Google Scholar 

  131. Nicholls, S. J. et al. Effect of evolocumab on coronary plaque phenotype and burden in statin-treated patients following myocardial infarction. JACC Cardiovasc. Imaging 15, 1308–1321 (2022).

    Article  PubMed  Google Scholar 

  132. Räber, L. et al. Effect of alirocumab added to high-intensity statin therapy on coronary atherosclerosis in patients with acute myocardial infarction: the PACMAN-AMI randomized clinical trial. JAMA 327, 1771–1781 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  133. Moreno, P. R. Vulnerable plaque: definition, diagnosis, and treatment. Cardiol. Clin. 28, 1–30 (2010).

    Article  PubMed  Google Scholar 

  134. Verheye, S. et al. Cryotherapy increases features of plaque stability in atherosclerotic rabbits. EuroIntervention 12, 748–756 (2016).

    Article  PubMed  Google Scholar 

  135. Wykrzykowska, J. J. et al. Plaque sealing and passivation with a mechanical self-expanding low outward force nitinol vShield device for the treatment of IVUS and OCT-derived thin cap fibroatheromas (TCFAs) in native coronary arteries: report of the pilot study vShield Evaluated at Cardiac hospital in Rotterdam for Investigation and Treatment of TCFA (SECRITT). EuroIntervention 8, 945–954 (2012).

    Article  PubMed  Google Scholar 

  136. Brugaletta, S. et al. Circumferential evaluation of the neointima by optical coherence tomography after ABSORB bioresorbable vascular scaffold implantation: can the scaffold cap the plaque. Atherosclerosis 221, 106–112 (2012).

    Article  CAS  PubMed  Google Scholar 

  137. Chen, H. Y. et al. Effects of stent sizing on endothelial and vessel wall stress: potential mechanisms for in-stent restenosis. J. Appl. Physiol. 106, 1686–1691 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  138. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT05027984 (2021).

  139. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02316886 (2021).

  140. Meier, B. Plaque sealing by coronary angioplasty. Heart 90, 1395–1398 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Falk, E., Nakano, M., Bentzon, J. F., Finn, A. V. & Virmani, R. Update on acute coronary syndromes: the pathologists’ view. Eur. Heart J. 34, 719–728 (2013).

    Article  CAS  PubMed  Google Scholar 

  142. Yahagi, K. et al. Pathophysiology of native coronary, vein graft, and in-stent atherosclerosis. Nat. Rev. Cardiol. 13, 79–98 (2016).

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Division of Cardiovascular Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA

    Prakriti Gaba & James Muller

  2. Department of Cardiovascular Medicine, Mayo Clinic College of Medicine and Science, Rochester, MN, USA

    Bernard J. Gersh

  3. The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Jagat Narula & Gregg W. Stone

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P.G. and G.W.S. researched data for the article. All the authors contributed substantially to the discussion of content, wrote the manuscript, and reviewed and/or edited the manuscript before submission.

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Correspondence to Gregg W. Stone.

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Competing interests

J.M. cofounded Spectrawave. G.W.S. has received speaker honoraria from Infraredx, Medtronic and Pulnovo; has served as a consultant to Abiomed, Ablative Solutions, Amgen, Ancora, Apollo Therapeutics, Cardiomech, CorFlow, Elucid Bio, Gore, HeartFlow, Impulse Dynamics, Miracor, Neovasc, Occlutech, Robocath, Shockwave, TherOx, Valfix, Vascular Dynamics, Vectorious and V-Wave; and has equity/options from Ancora, Applied Therapeutics, Aria, Biostar family of funds, Cagent, Cardiac Success, Orchestra Biomed, Spectrawave, Valfix and Xenter. G.W.S.’s daughter is an employee at Medtronic. G.W.S.’s employer, Mount Sinai Hospital, receives research support from Abbott, Abiomed, Biosense-Webster, Bioventrix, Cardiovascular Systems, Phillips, Shockwave, Vascular Dynamics and V-wave. The other authors declare no competing interests.

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Gaba, P., Gersh, B.J., Muller, J. et al. Evolving concepts of the vulnerable atherosclerotic plaque and the vulnerable patient: implications for patient care and future research. Nat Rev Cardiol 20, 181–196 (2023). https://doi.org/10.1038/s41569-022-00769-8

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