Clinical perspectives in assessment of high-risk atherosclerotic plaques
Clinical perspectives in assessment of high-risk atherosclerotic plaques
This short review discusses the implications of findings from recent clinical studies on the use of invasive and noninvasive imaging modalities in the detection of high-risk coronary lesions. Based on findings from autopsy studies, a short summary of the morphological features of coronary plaques responsible for acute coronary events is provided, and the concept of the “vulnerable plaque” is outlined. With regard to invasive imaging of the coronary vasculature, a focus is given to intravascular ultrasound, with discussion of recent prospective data on the morphology and progression of coronary plaques and their correlation with plaque rupture. Advances in optical coherence tomography are also illustrated in relation to defining the features of unstable plaques. Among the noninvasive imaging modalities, a focus is placed on computed tomography coronary angiography for identification of the morphological characteristics of coronary plaques that correlate with future coronary events. In addition, the prospects for magnetic resonance imaging and molecular hybrid imaging are outlined. Among the latter, combined positron emission tomography/computed tomography angiography is emerging as a prominent modality that enables characterization of both the morphology and biology of coronary plaques in patients. Finally, the place of imaging modalities alongside the currently available clinical risk scores and biomarkers for identification of individuals at risk for future coronary events is discussed, in addition to how these may guide therapeutic management.
Plaque rupture or erosion (or more rarely, calcific nodules) with ensuing atherothrombosis constitutes the underlying pathophysiology of acute coronary syndromes (ACS). The pathomorphological features of ruptured plaques comprise a thin fibrous cap, a large lipid core, outward (positive) remodeling, angiogenesis, and an abundance of inflammatory cells.1 Thin-cap fibroatheroma (TCFA) by definition comprises a large necrotic core covered by a thin fibrous cap of <65 μm. It is typically found in the proximal segments of coronary arteries with less than 50% diameter stenosis, and represents the most frequent type of lesion found in patients dying of coronary plaque rupture.2
By inference, when plaque composition is characteristic of a ruptured plaque, but there is an intact fibrous cap remaining, it is considered to predispose the “vulnerable plaque” to rupture.1 The natural course of coronary plaques with features of vulnerable plaque is not unidirectional, and it does not always involve a move toward plaque rupture manifesting as ACS, but rather it often remains asymptomatic, with ruptured plaques healing.3 The advent of novel imaging modalities has enabled detailed analysis of the natural course of vulnerable plaques and its correlation with clinical events.
Invasive imaging modalities for assessment of high-risk coronary laques
For decades, coronary angiography constituted the primary invasive imaging modality for assessment of the presence and degree of luminal stenosis (quantitative coronary angiography; QCA). Particularly when combined with pressure wire measurements, the modality enables quantitative evaluation of the functional relevance of myocardial perfusion and the risk for future cardiovascular events.4,5 Although QCA improved the quantification of coronary lesions, the fact that it is based on only 2 projections of a 3-dimensional structure means that it nevertheless has limitations. On the other hand, the assessment of fractional flow reserve has made it possible to precisely quantify the hemodynamic relevance of coronary lesions (for a review see reference 6).
Grayscale intravascular ultrasound (IVUS) enables visualization of vessel size, plaque burden, and morphology at a resolution of 100 μm to 120 μm by means of amplitude analysis of backscattered sound waves.7 In contrast to IVUS, coronary angiography grossly underestimates the extent of plaque burden and outward expansion of the atheromatous arterial wall (positive remodeling).8 Radiofrequency IVUS (RF-IVUS, virtual histology) allows for enhanced assessment of plaque composition, and results correlate well with histology findings.9 The prospective multicenter PROSPECT study (Providing Regional Observations to Study Predictors of Events in the Coronary Tree), an imaging study in patients with unstable atherosclerotic lesions, evaluated the morphological characteristics of nonculprit lesions and their progression over time, as well as their association with future cardiovascular events, using grayscale IVUS and RF-IVUS versus coronary angiography. After 3 years, cardiovascular events were reported in 20.4% of patients, and were associated in equal measure with nonculprit lesions and culprit lesions that had previously been treated by percutaneous coronary intervention (PCI) at the time of ACS.10 Nonculprit lesions associated with cardiovascular events were characterized by a plaque burden of ≥70%, a minimal lumen area of ≤4 mm2, and TCFA, the latter defined by RF-IVUS. Interestingly, nonculprit lesions associated with future events were classified angiographically at baseline as mild stenotic lesions, indicating that identification of patients at risk for future events using coronary angiography alone is limited. In turn, nonculprit lesions with angiographically mild stenosis, but a high plaque burden (≥70%), were found in one-third of patients and were more frequent in patients with diffuse coronary artery disease (CAD) (3-vessel disease) and a prior history of PCI,11 demonstrating the systemic nature of atherosclerosis as the underlying disease. However, it should be noted that of the 74 events that occurred in nonculprit vessels, 67 were related to revascularization procedures for progressive or unstable angina. There were no deaths or cardiac arrests and only 6 myocardial infarctions in nonculprit vessels during follow- up, highlighting the overall low event rates achieved with current medical prevention strategies. Grayscale IVUS has consistently been used to demonstrate slowing of coronary plaque progression, and even regression following statin therapy.12-15 Thus, IVUS is a useful tool to assess the effects of pharmacotherapy on plaque stabilization. Recently, a pooled analysis was carried out of 7 trials involving performance of serial IVUS measurements at baseline and after 21 months to assess the effects of various pharmacotherapies. The analysis identified smaller minimal lumen area, greater plaque burden at baseline, and greater progression of atheroma volume and constrictive arterial remodeling in the left main coronary artery (LMCA) as predictors of cardiovascular events.16 Interestingly, the response to treatment in the LMCA was opposite that in other vascular territories of the coronary tree, and it remains unclear as to how this impacts on risk prediction for future events. Furthermore, in a recent prospective multicenter trial, IVUS-based identification of a minimum lumen area of 6 mm2 as a cutoff value to guide revascularization of intermediate LMCA plaques did not translate into a difference in the rate of future events within 2 years.17
Figure 1. Intravascular imaging modalities for the assessment of coronary plaque.
After reference 18: Klingenberg et al. Clinical manifestations of atherosclerosis. In: Wick G, Grundtman C, eds. Inflammation and Atherosclerosis, Vol I. New York: Springer Wien New York; 2012:69-58. © 2012, Springer Science and Business Media.
Optical coherence tomography (OCT) is based on infrared light emitted from a catheter-based light source, and has better resolution (10 μm to 15 μm), but less penetration than IVUS (Figure 1),18 enabling clear visualization of the intima and differentiation of the intima/media.19 Frequency domain (FD) OCT constitutes a refinement of the time-domain technology of OCT, enabling a faster pull-back during imaging, reducing the time needed for flushing of blood from the lumen and thus providing better image quality and improved handling of this technique.20 Due to its excellent imaging quality in the near field, the main application of this technique is currently visualization of stent coverage and assessment of stent apposition and intimal dissection in the evaluation of the vascular response to stent implantation in interventional cardiology.21 Furthermore, FD OCT can be used to visualize plaque morphology such as fibrous cap thickness, the lipid core, calcium, plaque rupture, and thrombus apposition (including atherosclerotic plaques in bypass grafts, as shown in Figure 2),19 and even macrophage density22 and collagen composition of fibrous caps.23 Early reports indicate that OCT provides better detection of plaque rupture and thrombus in patients with ACS than IVUS and coronary angiography, in addition to defining TCFAs.24 The ability to detect TCFA was found to be better in patients with acute myocardial infarction/ACS than in those with symptomatic stable CAD.25 Unlike IVUS, OCT is a rather novel technique, and standards for characterization of plaque composition and useful data interpretation need to be defined.26,27 In this respect, a recent study involving a systematic comparison of computed tomography (CT) angiography, IVUS, and OCT against histopathological examination ex vivo may set the stage for future studies. For discriminating between early and advanced coronary plaques, diagnostic accuracy was found to be best with OCT, followed by CT angiography and IVUS.28 Furthermore, by using both OCT (high spatial resolution) and IVUS (high penetration), thus combining the strengths of both methods, it was recently demonstrated that statin therapy increased fibrous cap thickness and decreased plaque and lipid volume indices in patients with CAD.29
Figure 3. Coronary plaque assessment in a 68-year-old asymptomatic patient prior to liver transplant.
Noninvasive imaging modalities for assessment of high-risk coronary laques
Multidetector CT technology enables determination of the coronary artery calcium (CAC) score, which is a measure of total plaque burden in the coronary vasculature. The CAC score is a powerful tool for risk prediction in asymptomatic individuals.30,31 However, a high CAC score does not rule out significant coronary stenosis and does not exclude the presence of noncalcified plaques. CT coronary angiography (CTCA) permits delineation of coronary plaque morphology, plaque volume, eccentric remodeling, and the presence of calcifications, and allows a crude assessment of plaque composition based on increasing amounts of calcium (noncalcified, mixed, and calcified plaques).32 A large plaque area, a high remodeling index, and a relatively large proportion of noncalcified and mixed plaque components on CTCA is found more often in culprit plaques of ACS patients than in patients with stable angina.33-36 Moreover, in 1 study, patients who had plaques with signs of positive remodeling and lower CT density had a higher likelihood of developing an ACS during a 2-year follow-up period.33 Furthermore, addition of plaque composition (≥2 segments with noncalcified plaque) to stenosis severity (≥50%) provided incremental prognostic information to reduced myocardial perfusion in patients with suspected CAD who were evaluated prospectively by CTCA and single-photon emission CT myocardial perfusion imaging.37 In addition, CTCA enables assessment of the progression of coronary plaques38 and statin-induced changes in plaque morphology.39 However, current CTCA analysis of coronary plaques is still limited by the spatial resolution of CTCA, which precludes depiction of TCFA (<65 μm cap thickness), the presumable precursor to plaque rupture. Furthermore, subclassification of noncalcified plaques into predominantly lipid-rich/necrotic versus fibrous plaque based on CT density is still unreliable.40 A “napkin- ring”–like enhancement of the plaque border surrounding the hypodense core seen on intravascular imaging with OCT and on histopathology examination41 was recently found to be associated with TCFAs (Figure 3) and is thought to represent a sign of plaque vulnerability.
Magnetic resonance imaging (MRI) of the coronary vasculature is an emerging modality driven forward by technological advances that have translated into better temporal resolution, improved signal-to-noise ratio, and reduced scan times.42 Recent MRI studies have demonstrated positive remodeling of the vascular wall in patients with CAD,43 and a positive correlation between coronary wall thickness and cardiovascular risk factors and intima-media thickness, but not CAC score.44 Combining MRI with use of ultra-small superparamagnetic iron oxide particles allows for visualization of macrophage-rich areas, and thus plaque inflammation, in carotid arteries. A recent study using ultrasmall superparamagnetic iron oxide particles showed that administration of statin therapy was associated with a significant reduction in carotid plaque inflammation.45 Several additional contrast agents have been developed, and multimodality positron emission tomography (PET) and MRI hold great promise for visualization of plaque morphology and biology, although they are not yet ready for clinical use.46,47
Molecular imaging combines imaging modalities to assess plaque morphology, perfusion, and metabolism/inflammation. From a clinical standpoint, the combination of PET, which uses a radiolabeled tracer capable of visualizing molecular targets in the picomolar range, and CT angiography, which has excellent spatial and temporal resolution, figures prominently among the current most advanced modalities.47,48 Promising tracers for detecting macrophage-driven inflammation in atherosclerotic plaque comprise 18F-NaF fluorodeoxyglucose (FDG),49-51 11C-PK11195,52 and 68Ga-DOTATATE.53 Two recent FDG-PET/CT angiography studies demonstrated the feasibility of the tracer approach, with a markedly higher FDG uptake found in culprit lesions from patients with an ACS compared with target lesions in patients with stable angina.50,51
The place of imaging in the diagnostic work-up of individuals at risk for future adverse events
In primary prevention, risk calculators such as the Framingham Risk Score54 or the Systematic COronary Risk Evaluation (SCORE) model55 are widely used. These scores integrate established cardiovascular risk factors to identify high-risk individuals, defined as those with a >20% absolute risk of experiencing a fatal coronary event or a nonfatal myocardial infarction within a 10-year period (Framingham Risk Score) or those with a ≥5% risk of death within a 10-year period (SCORE).
The challenge for the clinician concerning whether to initiate lifestyle changes and/or therapy lies in the identification of individuals in the intermediate-risk group. A recent analysis of a large cohort of asymptomatic individuals identified CAC as an independent predictor of future cardiovascular events in intermediate- risk individuals, as measured by CT. CAC provided superior discrimination and risk reclassification compared with other risk markers, including C-reactive protein.30 At present, it is unclear whether imaging of plaque morphology and biology that goes beyond the determination of CAC can translate into even better discrimination of individuals at risk and, most importantly, help guide the decision as to when to initiate therapy in asymptomatic individuals.
In the setting of ACS, commonly-used risk scores are the Thrombolysis in Myocardial Infarction (TIMI) risk score for patients with unstable angina/non–ST-segment elevation myocardial infarction (NSTEMI)56 and ST-segment elevation myocardial infarction (STEMI),57 and the Global Registry of Acute Coronary Events (GRACE) risk score, which covers the whole spectrum of ACS.58 Compared with the clinical TIMI risk score alone, addition of a highly sensitive troponin test to the TIMI risk score resulted in improved risk stratification of patients with NSTEMI.59
Despite the impact of PROSPECT in defining with the use of RF-IVUS morphological characteristics of coronary plaques that are associated with future cardiovascular events, the study did not provide any answers concerning lesions that are not TCFAs, but that also cause ACS in the absence of plaque rupture, ie, in the presence of plaque erosion and calcific nodules. Future studies are needed to address whether RF-IVUS–based identification of nonculprit lesions in patients with ACS can guide interventional/pharmacological strategies to prevent future events. Furthermore, prospective studies assessing the morphological characteristics and progression over time of nonculprit lesions and their association with future cardiovascular events with the use of OCT versus coronary angiography are lacking. Moreover, studies that address the impact of interventions on outcome after OCT identification of vulnerable plaques are clearly needed. Among the noninvasive imaging modalities, CT angiography appears the most clinically advanced, but identification of the most appropriate population to screen for coronary plaque morphology in order to prevent future ACS remains to be addressed in future studies. Similarly, following successful proof-of-concept studies using FDGPET/ CT angiography, prospective studies are needed to evaluate whether vulnerable plaques can therefore be identified prior to any clinical manifestation, and there is also a need to minimize radiation exposure with these modalities.
In summary, despite having a prominent place in the identification of coronary plaques that show characteristics of vulnerability, prospective data are only now beginning to emerge regarding the value of these imaging modalities in helping to guide therapies. ■
1. Ylä-Herttuala S, Bentzon JF, Daemen M, et al. Stabilisation of atherosclerotic plaques. Position paper of the European Society of Cardiology (ESC) Working Group on atherosclerosis and vascular biology. Thromb Haemost. 2011;106: 1-19.
2. Virmani R, Burke AP, Farb A, Kolodgie FD. Pathology of the vulnerable plaque. J Am Coll Cardiol. 2006;47:C13-C18.
3. Burke AP, Kolodgie FD, Farb A, et al. Healed plaque ruptures and sudden coronary death: evidence that subclinical rupture has a role in plaque progression. Circulation. 2001;103:934-940.
4. Tonino PA, De Bruyne B, Pijls NH, et al. Fractional flow reserve versus angiography for guiding percutaneous coronary intervention. N Engl J Med. 2009;360: 213-224.
5. De Bruyne B, Pijls NH, Kalesan B, et al. Fractional flow reserve-guided PCI versus medical therapy in stable coronary disease. N Engl J Med. 2012;367:991-1001.
6. Pijls NH, Tanaka N, Fearon WF. Functional assessment of coronary stenoses: can we live without it? Eur Heart J. 2013;34:1335-1344.
7. Mintz GS, Nissen SE, Anderson WD, 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;37:1478-1492.
8. Schoenhagen P, Ziada KM, Kapadia SR, Crowe TD, Nissen SE, Tuzcu EM. Extent and direction of arterial remodeling in stable versus unstable coronary syndromes: an intravascular ultrasound study. Circulation. 2000;101:598- 603.
9. Garcia-Garcia HM, Mintz GS, Lerman A, et al. Tissue characterisation using intravascular radiofrequency data analysis: recommendations for acquisition, analysis, interpretation and reporting. EuroIntervention. 2009;5:177-189.
10. Stone GW, Maehara A, Lansky AJ, et al. A prospective natural-history study of coronary atherosclerosis. N Engl J Med. 2011;364:226-235.
11. McPherson JA, Maehara A, Weisz G, et al. Residual plaque burden in patients with acute coronary syndromes after successful percutaneous coronary intervention. JACC Cardiovasc Imaging. 2012;5:S76-S85.
12. Nissen SE, Tuzcu EM, Schoenhagen P, et al. Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis: a randomized controlled trial. JAMA. 2004;291:1071-1080.
13. Okazaki S, Yokoyama T, Miyauchi K, et al. Early statin treatment in patients with acute coronary syndrome: demonstration of the beneficial effect on atherosclerotic lesions by serial volumetric intravascular ultrasound analysis during half a year after coronary event: the ESTABLISH Study. Circulation. 2004;110: 1061-1068.
14. Nissen SE, Nicholls SJ, Sipahi I, et al. Effect of very high-intensity statin therapy on regression of coronary atherosclerosis: the ASTEROID trial. JAMA. 2006;295: 1556-1565.
15. Nicholls SJ, Ballantyne CM, Barter PJ, et al. Effect of two intensive statin regimens on progression of coronary disease. N Engl J Med. 2011;365:2078-2087.
16. Puri R, Wolski K, Uno K, et al. Left main coronary atherosclerosis progression, constrictive remodeling, and clinical events. JACC Cardiovasc Interv. 2013;6: 29-35.
17. de la Torre Hernandez JM, Hernández Hernandez F, Alfonso F, et al. Prospective application of pre-defined intravascular ultrasound criteria for assessment of intermediate left main coronary artery lesions results from the multicenter LITRO study. J Am Coll Cardiol. 2011;58:351-358.
18. Klingenberg R, Hasun M, Corti R, Lüscher TF. Clinical manifestations of atherosclerosis. In: Wick G, Grundtman C, eds. Inflammation and Atherosclerosis, Vol I. New York: Springer Wien; 2012:69-58.
19. Tearney GJ, Regar E, Akasaka T, 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. 2012;59:1058-1072.
20. Prati F, Guagliumi G, Mintz GS, et al. Expert review document part 2: methodology, terminology and clinical applications of optical coherence tomography for the assessment of interventional procedures. Eur Heart J. 2012;33:2513- 2520.
21. Puri R, Tuzcu EM, Nissen SE, Nicholls SJ. Exploring coronary atherosclerosis with intravascular imaging. Int J Cardiol. 2013;168(2):670-679.
22. Tearney GJ, Yabushita H, Houser SL, et al. Quantification of macrophage content in atherosclerotic plaques by optical coherence tomography. Circulation. 2003;107:113-119.
23. Nadkarni SK, Pierce MC, Park BH, et al. Measurement of collagen and smooth muscle cell content in atherosclerotic plaques using polarization-sensitive optical coherence tomography. J Am Coll Cardiol. 2007;49:1474-1481.
24. Kubo T, Imanishi T, Takarada S, et al. Assessment of culprit lesion morphology in acute myocardial infarction: ability of optical coherence tomography compared with intravascular ultrasound and coronary angioscopy. J Am Coll Cardiol. 2007;50:933-939.
25. Jang IK, Tearney GJ, MacNeill B, et al. In vivo characterization of coronary atherosclerotic plaque by use of optical coherence tomography. Circulation. 2005; 111:1551-1555.
26. van Soest G, Regar E, Goderie TP, et al. Pitfalls in plaque characterization by OCT: image artifacts in native coronary arteries. JACC Cardiovasc Imaging. 2011;4:810-813.
27. Radu MD, Falk E. In search of vulnerable features of coronary plaques with optical coherence tomography: is it time to rethink the current methodological concepts? Eur Heart J. 2012;33:9-12.
28. Maurovich-Horvat P, Schlett CL, Alkadhi H, et al. Differentiation of early from advanced coronary atherosclerotic lesions: systematic comparison of CT, intravascular US, and optical frequency domain imaging with histopathologic examination in ex vivo human hearts. Radiology. 2012;265:393-401.
29. Hattori K, Ozaki Y, Ismail TF, et al. Impact of statin therapy on plaque characteristics as assessed by serial OCT, grayscale and integrated backscatter-IVUS. JACC Cardiovasc Imaging. 2012;5:169-177.
30. Yeboah J, McClelland RL, Polonsky TS, et al. Comparison of novel risk markers for improvement in cardiovascular risk assessment in intermediate-risk individuals. JAMA. 2012;308:788-795.
31. Budoff MJ, Shaw LJ, Liu ST, et al. Long-term prognosis associated with coronary calcification: observations from a registry of 25,253 patients. J Am Coll Cardiol. 2007;49:1860-1870.
32. Voros S, Rinehart S, Qian Z, et al. Coronary atherosclerosis imaging by coronary CT angiography: current status, correlation with intravascular interrogation and meta-analysis. JACC Cardiovasc Imaging. 2011;4:537-548.
33. Motoyama S, Sarai M, Harigaya H, et al. Computed tomographic angiography characteristics of atherosclerotic plaques subsequently resulting in acute coronary syndrome. J Am Coll Cardiol. 2009;54:49-57.
34. Kitagawa T, Yamamoto H, Horiguchi J, et al. Characterization of noncalcified coronary plaques and identification of culprit lesions in patients with acute coronary syndrome by 64-slice computed tomography. JACC Cardiovasc Imaging. 2009;2:153-160.
35. Hoffmann U, Moselewski F, Nieman K, et al. Noninvasive assessment of plaque morphology and composition in culprit and stable lesions in acute coronary syndrome and stable lesions in stable angina by multidetector computed tomography. J Am Coll Cardiol. 2006;47:1655-1662.
36. Pundziute G, Schuijf JD, Jukema JW, et al. Head-to-head comparison of coronary plaque evaluation between multislice computed tomography and intravascular ultrasound radiofrequency data analysis. JACC Cardiovasc Interv. 2008;1:176-182.
37. van Werkhoven JM, Schuijf JD, Gaemperli O, et al. Prognostic value of multislice computed tomography and gated single-photon emission computed tomography in patients with suspected coronary artery disease. J Am Coll Cardiol. 2009;53:623-632.
38. Papadopoulou SL, Neefjes LA, Garcia-Garcia HM, et al. Natural history of coronary atherosclerosis by multislice computed tomography. JACC Cardiovasc Imaging. 2012;5:S28-S37.
39. Inoue K, Motoyama S, Sarai M, et al. Serial coronary CT angiography-verified changes in plaque characteristics as an end point: evaluation of effect of statin intervention. JACC Cardiovasc Imaging. 2010;3:691-698.
40. Leber AW, Knez A, Becker A, et al. Accuracy of multidetector spiral computed tomography in identifying and differentiating the composition of coronary atherosclerotic plaques: a comparative study with intracoronary ultrasound. J Am Coll Cardiol. 2004;43:1241-1247.
41. Kashiwagi M, Tanaka A, Kitabata H, et al. Feasibility of noninvasive assessment of thin-cap fibroatheroma by multidetector computed tomography. JACC Cardiovasc Imaging. 2009;2:1412-1419.
42. Corti R, Fuster V. Imaging of atherosclerosis: magnetic resonance imaging. Eur Heart J. 2011;32:1709-1719b.
43. Kim WY, Stuber M, Bornert P, Kissinger KV, Manning WJ, Botnar RM. Threedimensional black-blood cardiac magnetic resonance coronary vessel wall imaging detects positive arterial remodeling in patients with nonsignificant coronary artery disease. Circulation. 2002;106:296-299.
44. Macedo R, Chen S, Lai S, et al. MRI detects increased coronary wall thickness in asymptomatic individuals: the multi-ethnic study of atherosclerosis (MESA). J Magn Reson Imaging. 2008;28:1108-1115.
45. Tang TY, Howarth SP, Miller SR, et al. The ATHEROMA (Atorvastatin Therapy: Effects on Reduction of Macrophage Activity) Study. Evaluation using ultrasmall superparamagnetic iron oxide-enhanced magnetic resonance imaging in carotid disease. J Am Coll Cardiol. 2009;53:2039-2050.
46. van der Hoeven BL, Schalij MJ, Delgado V. Multimodality imaging in interventional cardiology. Nat Rev Cardiol. 2012;9:333-346.
47. Fleg JL, Stone GW, Fayad ZA, et al. Detection of high-risk atherosclerotic plaque: report of the NHLBI Working Group on current status and future directions. JACC Cardiovasc Imaging. 2012;5:941-955.
48. Camici PG, Rimoldi OE, Gaemperli O, Libby P. Non-invasive anatomic and functional imaging of vascular inflammation and unstable plaque. Eur Heart J. 2012;33:1309-1317.
49. Dweck MR, Chow MW, Joshi NV, et al. Coronary arterial 18F-sodium fluoride uptake: a novel marker of plaque biology. J Am Coll Cardiol. 2012;59:1539- 1548.
50. Rogers IS, Nasir K, Figueroa AL, et al. Feasibility of FDG imaging of the coronary arteries: comparison between acute coronary syndrome and stable angina. JACC Cardiovasc Imaging. 2010;3:388-397.
51. Cheng VY, Slomka PJ, Le Meunier L, et al. Coronary arterial 18F-FDG uptake by fusion of PET and coronary CT angiography at sites of percutaneous stenting for acute myocardial infarction and stable coronary artery disease. J Nucl Med. 2012;53:575-583.
52. Gaemperli O, Shalhoub J, Owen DR, et al. Imaging intraplaque inflammation in carotid atherosclerosis with 11C-PK11195 positron emission tomography/ computed tomography. Eur Heart J. 2012;33:1902-1910.
53. Rominger A, Saam T, Vogl E, et al. In vivo imaging of macrophage activity in the coronary arteries using 68Ga-DOTATATE PET/CT: correlation with coronary calcium burden and risk factors. J Nucl Med. 2010;51:193-197.
54. Wilson PW, D’Agostino RB, Levy D, Belanger AM, Silbershatz H, Kannel WB. Prediction of coronary heart disease using risk factor categories. Circulation. 1998;97:1837-1847.
55. Conroy RM, Pyorala K, Fitzgerald AP, et al. Estimation of ten-year risk of fatal cardiovascular disease in Europe: the SCORE project. Eur Heart J. 2003;24: 987-1003.
56. Antman EM, Cohen M, Bernink PJ, et al. The TIMI risk score for unstable angina/ non-ST elevation MI: a method for prognostication and therapeutic decision making. JAMA. 2000;284:835-842.
57. Morrow DA, Antman EM, Charlesworth A, et al. TIMI risk score for ST-elevation myocardial infarction: A convenient, bedside, clinical score for risk assessment at presentation: an intravenous nPA for treatment of infarcting myocardium early II trial substudy. Circulation. 2000;102:2031-2037.
58. Eagle KA, Lim MJ, Dabbous OH, et al. A validated prediction model for all forms of acute coronary syndrome: estimating the risk of 6-month postdischarge death in an international registry. JAMA. 2004;291:2727-2733.
59. Scirica BM, Sabatine MS, Jarolim P, et al. Assessment of multiple cardiac biomarkers in non-ST-segment elevation acute coronary syndromes: observations from the MERLIN-TIMI 36 trial. Eur Heart J. 2011;32:697-705.
Keywords: coronary artery disease; high-risk coronary lesion; invasive imaging; noninvasive imaging; risk stratification