Thromb Haemost 2009; 102(02): 231-239
DOI: 10.1160/TH09-01-0030
Theme Issue Article
Schattauer GmbH

The vulnerable patient: Refocusing on the plaque?

Wouter J. Eijgelaar
,
Sylvia Heeneman
1   Experimental Vascular Pathology (EVP) Division, Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), University of Maastricht, Maastricht, The Netherlands
,
Mat J. A. P. Daemen
1   Experimental Vascular Pathology (EVP) Division, Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), University of Maastricht, Maastricht, The Netherlands
› Author Affiliations
Further Information

Publication History

Received: 13 January 2009

Accepted after major revision: 01 June 2009

Publication Date:
22 November 2017 (online)

Summary

The term ‘vulnerable plaque’ is used to refer to the lesions that are prone to rupture and may cause life-threatening events like acute coronary syndrome or stroke.The study of the vulnerable plaque phenotype and its detection has attracted increasing interest over the past decades. During this time, there have been some remarkable transitions in the paradigm on methods to identify patients at risk or patients to treat.Whereas formerly, the key factors used to determine an individual’s risk were primarily population-based traditional risk factors such as age, sex, body mass index, hypertension etc., new approaches are based on conditional risk factors that represent an individual’s current risk of suffering a cardiovascular event.These population based risk factors fall short in predicting near-future events in a high-risk individual. In the early 2000s, the focus of research into surrogate markers for cardiovascular event prediction shifted from the vulnerable plaque to the identification of the vulnerable patient.This new paradigm stimulated a number of new initiatives that aimed to identify vulnerable patients by testing systemic biomarkers that could identify patients at high risk for cardiovascular events. A second research paradigm is refocusing on the plaque by searching for plaque-derived biomarkers and non-invasive imaging modalities to assess characteristics of a plaque that determine its vulnerability.Although both concepts are attractive, they still need proper validation in large multicenter cohorts, while cost-effectiveness arguments also need to be assessed.

 
  • References

  • 1 Falk E. Pathogenesis of atherosclerosis. J Am Coll Cardiol 2006; 47: C7-12.
  • 2 Naghavi M, Libby P, Falk E. et al. From vulnerable plaque to vulnerable patient: a call for new definitions and risk assessment strategies: Part II. Circulation 2003; 108: 1772-1778.
  • 3 Naghavi M, Libby P, Falk E. et al. From vulnerable plaque to vulnerable patient: a call for new definitions and risk assessment strategies: Part I. Circulation 2003; 108: 1664-1672.
  • 4 Thim T, Hagensen MK, Bentzon JF. et al. From vulnerable plaque to atherothrombosis. J Intern Med 2008; 263: 506-516.
  • 5 Rosamond W, Flegal K, Furie K. et al. Heart disease and stroke statistics--2008 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation 2008; 117: e25-146.
  • 6 Lloyd-Jones D, Adams R, Carnethon M. et al. Heart Disease and Stroke Statistics--2009 Update. A Report From the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation. 2008
  • 7 Naghavi M, Falk E, Hecht HS. et al. From vulnerable plaque to vulnerable patient--Part III: Executive summary of the Screening for Heart Attack Prevention and Education (SHAPE) Task Force report. Am J Cardiol 2006; 98: 2H-15H.
  • 8 Hellings WE, Peeters W, Moll FL. et al. From vulnerable plaque to vulnerable patient: the search for biomarkers of plaque destabilization. Trends Cardiovasc Med 2007; 17: 162-171.
  • 9 Weintraub HS. Identifying the vulnerable patient with rupture-prone plaque. Am J Cardiol 2008; 101: 3F-10F.
  • 10 Mallat Z, Tedgui A. Cytokines as regulators of atherosclerosis in murine models. Curr Drug Targets 2007; 08: 1264-1272.
  • 11 Tedgui A, Mallat Z. Cytokines in atherosclerosis: pathogenic and regulatory pathways. Physiol Rev 2006; 86: 515-581.
  • 12 Ross R. Atherosclerosis--an inflammatory disease. N Engl J Med 1999; 340: 115-126.
  • 13 Packard RR, Libby P. Inflammation in atherosclerosis: from vascular biology to biomarker discovery and risk prediction. Clin Chem 2008; 54: 24-38.
  • 14 Kannel WB, Dawber TR, Kagan A. et al. Factors of risk in the development of coronary heart disease--six year follow-up experience. The Framingham Study. Ann Intern Med 1961; 55: 33-50.
  • 15 Assmann G, Cullen P, Schulte H. The Munster Heart Study (PROCAM). Results of follow-up at 8 years. Eur Heart J 1998; 19 (Suppl A) A2-11.
  • 16 Akosah KO, Schaper A, Cogbill C. et al. Preventing myocardial infarction in the young adult in the first place: how do the National Cholesterol Education Panel III guidelines perform?. J Am Coll Cardiol 2003; 41: 1475-1479.
  • 17 Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). J Am Med Assoc. 2001 285. 2486-2497.
  • 18 Sheridan S, Pignone M, Mulrow C. Framinghambased tools to calculate the global risk of coronary heart disease: a systematic review of tools for clinicians. J Gen Intern Med 2003; 18: 1039-1052.
  • 19 Assmann G, Cullen P, Schulte H. Simple scoring scheme for calculating the risk of acute coronary events based on the 10-year follow-up of the prospective cardiovascular Munster (PROCAM) study. Circulation 2002; 105: 310-315.
  • 20 Buffon A, Biasucci LM, Liuzzo G. et al. Widespread coronary inflammation in unstable angina. N Engl J Med 2002; 347: 5-12.
  • 21 Burke AP, Farb A, Malcom GT. et al. Coronary risk factors and plaque morphology in men with coronary disease who died suddenly. N Engl J Med 1997; 336: 1276-1282.
  • 22 Mann J, Davies MJ. Mechanisms of progression in native coronary artery disease: role of healed plaque disruption. Heart 1999; 82: 265-268.
  • 23 Goldstein JA, Demetriou D, Grines CL. et al. Multiple complex coronary plaques in patients with acute myocardial infarction. N Engl J Med 2000; 343: 915-922.
  • 24 Nissen SE. Who is at risk for atherosclerotic disease? Lessons from intravascular ultrasound. Am J Med 2002; 112 (Suppl 8A) 27S-33S.
  • 25 Berk BC, Weintraub WS, Alexander RW. Elevation of C-reactive protein in “active” coronary artery disease. Am J Cardiol 1990; 65: 168-172.
  • 26 Liuzzo G, Biasucci LM, Gallimore JR. et al. The prognostic value of C-reactive protein and serum amyloid a protein in severe unstable angina. N Engl J Med 1994; 331: 417-424.
  • 27 Lowe GD, Pepys MB. C-reactive protein and cardiovascular disease: weighing the evidence. Curr Atheroscler Rep 2006; 08: 421-428.
  • 28 Danesh J, Erqou S, Walker M. et al. The Emerging Risk Factors Collaboration: analysis of individual data on lipid, inflammatory and other markers in over 1.1 million participants in 104 prospective studies of cardiovascular diseases. Eur J Epidemiol 2007; 22: 839-869.
  • 29 Tracy RP, Lemaitre RN, Psaty BM. et al. Relationship of C-reactive protein to risk of cardiovascular disease in the elderly. Results from the Cardiovascular Health Study and the Rural Health Promotion Project. Arterioscler Thromb Vasc Biol 1997; 17: 1121-1127.
  • 30 Ridker PM, Buring JE, Shih J. et al. Prospective study of C-reactive protein and the risk of future cardiovascular events among apparently healthy women. Circulation 1998; 98: 731-733.
  • 31 Jager A, van Hinsbergh VW, Kostense PJ. et al. von Willebrand factor, C-reactive protein, and 5-year mortality in diabetic and nondiabetic subjects: the Hoorn Study. Arterioscler Thromb Vasc Biol 1999; 19: 3071-3078.
  • 32 Mendall MA, Strachan DP, Butland BK. et al. C-reactive protein: relation to total mortality, cardiovascular mortality and cardiovascular risk factors in men. Eur Heart J 2000; 21: 1584-1590.
  • 33 Casas JP, Shah T, Hingorani AD. et al. C-reactive protein and coronary heart disease: a critical review. J Intern Med 2008; 264: 295-314.
  • 34 Hanriot D, Bello G, Ropars A. et al. C-reactive protein induces pro- and anti-inflammatory effects, including activation of the liver X receptor alpha, on human monocytes. Thromb Haemost 2008; 99: 558-569.
  • 35 Danesh J, Wheeler JG, Hirschfield GM. et al. C-reactive protein and other circulating markers of inflammation in the prediction of coronary heart disease. N Engl J Med 2004; 350: 1387-1397.
  • 36 Ridker PM, Rifai N, Stampfer MJ. et al. Plasma concentration of interleukin-6 and the risk of future myocardial infarction among apparently healthy men. Circulation 2000; 101: 1767-1772.
  • 37 Ikonomidis I, Stamatelopoulos K, Lekakis J. et al. Inflammatory and non-invasive vascular markers: the multimarker approach for risk stratification in coronary artery disease. Atherosclerosis 2008; 199: 3-11.
  • 38 Tan J, Hua Q, Gao J. et al. Clinical implications of elevated serum interleukin-6, soluble CD40 ligand, metalloproteinase-9, and tissue inhibitor of metalloproteinase-1 in patients with acute ST-segment elevation myocardial infarction. Clin Cardiol 2008; 31: 413-418.
  • 39 Oren H, Erbay AR, Balci M. et al. Role of novel biomarkers of inflammation in patients with stable coronary heart disease. Angiology 2007; 58: 148-155.
  • 40 Inoue T, Komoda H, Nonaka M. et al. Interleukin-8 as an independent predictor of long-term clinical out-come in patients with coronary artery disease. Int J Cardiol 2008; 124: 319-325.
  • 41 Ikonomidis I, Andreotti F, Economou E. et al. Increased proinflammatory cytokines in patients with chronic stable angina and their reduction by aspirin. Circulation 1999; 100: 793-798.
  • 42 Saremi A, Anderson RJ, Luo P. et al. Association between IL-6 and the extent of coronary atherosclerosis in the veterans affairs diabetes trial (VADT). Atherosclerosis 2009; 203: 610-614.
  • 43 Gotsman I, Stabholz A, Planer D. et al. Serum cytokine tumor necrosis factor-alpha and interleukin-6 associated with the severity of coronary artery disease: indicators of an active inflammatory burden?. Isr Med Assoc J 2008; 10: 494-498.
  • 44 Wang TJ, Gona P, Larson MG. et al. Multiple biomarkers for the prediction of first major cardiovascular events and death. N Engl J Med 2006; 355: 2631-2639.
  • 45 Braunwald E. Biomarkers in heart failure. N Engl J Med 2008; 358: 2148-2159.
  • 46 Pasterkamp G, Daemen M. Circulating cells: the biofactory for markers of atherosclerotic disease. Eur Heart J 2008; 29: 2701-2702.
  • 47 Schirmer SH, Fledderus JO, van der Laan AM. et al. Suppression of inflammatory signaling in monocytes from patients with coronary artery disease. J Mol Cell Cardiol 2009; 46: 177-185.
  • 48 Ganesh SK, Skelding KA, Mehta L. et al. Rationale and study design of the CardioGene Study: genomics of in-stent restenosis. Pharmacogenomics 2004; 05: 952-1004.
  • 49 Patino WD, Kang JG, Matoba S. et al. Atherosclerotic plaque macrophage transcriptional regulators are expressed in blood and modulated by tristetraprolin. Circ Res 2006; 98: 1282-1289.
  • 50 Hurks R, Peeters W, Derksen WJ. et al. Biobanks and the search for predictive biomarkers of local and systemic outcome in atherosclerotic disease. Thromb Haemost 2009; 101: 48-54.
  • 51 Cleutjens KB, Faber BC, Rousch M. et al. Noninvasive diagnosis of ruptured peripheral atherosclerotic lesions and myocardial infarction by antibody profiling. J Clin Invest 2008; 118: 2979-2985.
  • 52 Narula J, Garg P, Achenbach S. et al. Arithmetic of vulnerable plaques for noninvasive imaging. Nat Clin Pract Cardiovasc Med 2008; 05 (Suppl. 02) S2-10.
  • 53 Naghavi M, Falk E, Hecht HS. et al. The First SHAPE (Screening for Heart Attack Prevention and Education) Guideline. Crit Pathw Cardiol 2006; 05: 187-190.
  • 54 Sitzer M. Atherosclerotic carotid stenosis and occlusion. Front Neurol Neurosci 2006; 21: 36-56.
  • 55 Little WC, Constantinescu M, Applegate RJ. et al. Can coronary angiography predict the site of a subsequent myocardial infarction in patients with mild-tomoderate coronary artery disease?. Circulation 1988; 78: 1157-1166.
  • 56 Ambrose JA, Tannenbaum MA, Alexopoulos D. et al. Angiographic progression of coronary artery disease and the development of myocardial infarction. J Am Coll Cardiol 1988; 12: 56-62.
  • 57 Beneficial effect of carotid endarterectomy in symptomatic patients with high-grade carotid stenosis. North American Symptomatic Carotid Endarterectomy Trial Collaborators. N Engl J Med 1991; 325: 445-453.
  • 58 andomised trial of endarterectomy for recently symptomatic carotid stenosis: final results of the MRC European Carotid Surgery Trial (ECST). Lancet. 1998 351. 1379-1387.
  • 59 Budoff MJ, Achenbach S, Blumenthal RS. et al. Assessment of coronary artery disease by cardiac computed tomography: a scientific statement from the American Heart Association Committee on Cardiovascular Imaging and Intervention, Council on Cardiovas-cular Radiology and Intervention, and Committee on Cardiac Imaging, Council on Clinical Cardiology. Circulation 2006; 114: 1761-1791.
  • 60 Mitsutake R, Niimura H, Miura S. et al. Clinical significance of the coronary calcification score by multidetector row computed tomography for the evaluation of coronary stenosis in Japanese patients. Circ J 2006; 70: 1122-1127.
  • 61 Schroeder S, Kuettner A, Leitritz M. et al. Reliability of differentiating human coronary plaque morphology using contrast-enhanced multislice spiral computed tomography: a comparison with histology. J Comput Assist Tomogr 2004; 28: 449-454.
  • 62 Inoue F, Sato Y, Matsumoto N. et al. Evaluation of plaque texture by means of multislice computed tomography in patients with acute coronary syndrome and stable angina. Circ J 2004; 68: 840-844.
  • 63 Miller JM, Rochitte CE, Dewey M. et al. Diagnostic performance of coronary angiography by 64-row CT. N Engl J Med 2008; 359: 2324-2336.
  • 64 Ropers D, Rixe J, Anders K. et al. Usefulness of multidetector row spiral computed tomography with 64– x 0.6-mm collimation and 330-ms rotation for the noninvasive detection of significant coronary artery stenoses. Am J Cardiol 2006; 97: 343-348.
  • 65 Fine JJ, Hopkins CB, Ruff N. et al. Comparison of accuracy of 64-slice cardiovascular computed tomography with coronary angiography in patients with suspected coronary artery disease. Am J Cardiol 2006; 97: 173-174.
  • 66 Dodd JD, Rieber J, Pomerantsev E. et al. Quantification of nonculprit coronary lesions: comparison of cardiac 64-MDCT and invasive coronary angiography. AJR Am J Roentgenol 2008; 191: 432-438.
  • 67 Brenner DJ, Hall EJ. Computed tomography--an increasing source of radiation exposure. N Engl J Med 2007; 357: 2277-2284.
  • 68 Yuan C, Mitsumori LM, Beach KW. et al. Carotid atherosclerotic plaque: noninvasive MR characterization and identification of vulnerable lesions. Radiology 2001; 221: 285-299.
  • 69 Kwong RY, Chan AK, Brown KA. et al. Impact of unrecognized myocardial scar detected by cardiac magnetic resonance imaging on event-free survival in patients presenting with signs or symptoms of coronary artery disease. Circulation 2006; 113: 2733-2743.
  • 70 Trivedi RA, Mallawarachi C, JM UK-I. et al. Identifying inflamed carotid plaques using in vivo USPIOenhanced MR imaging to label plaque macrophages. Arterioscler Thromb Vasc Biol 2006; 26: 1601-1606.
  • 71 Tang T, Howarth SP, Miller SR. et al. Assessment of inflammatory burden contralateral to the symptomatic carotid stenosis using high-resolution ultrasmall, superparamagnetic iron oxide-enhanced MRI. Stroke 2006; 37: 2266-2270.
  • 72 Okane K, Ibaraki M, Toyoshima H. et al. 18F-FDG accumulation in atherosclerosis: use of CT and MR coregistration of thoracic and carotid arteries. Eur J Nucl Med Mol Imaging 2006; 33: 589-594.
  • 73 Nahrendorf M, Zhang H, Hembrador S. et al. Nanoparticle PET-CT imaging of macrophages in inflammatory atherosclerosis. Circulation 2008; 117: 379-387.
  • 74 Raylman RR, Wahl RL. Evaluation of ion-implanted-silicon detectors for use in intraoperative positron-sensitive probes. Med Phys 1996; 23: 1889-1895.
  • 75 Nabi HA, Zubeldia JM. Clinical applications of (18)F-FDG in oncology. J Nucl Med Technol 2002; 30: 3-9 quiz 10–1..
  • 76 Ogawa M, Ishino S, Mukai T. et al. (18)F-FDG accumulation in atherosclerotic plaques: immunohistochemical and PET imaging study. J Nucl Med 2004; 45: 1245-1250.
  • 77 Chen W, Bural GG, Torigian DA. et al. Emerging role of FDG-PET/CT in assessing atherosclerosis in large arteries. Eur J Nucl Med Mol Imaging 2009; 36: 144-151.
  • 78 Groen HC, Gijsen FJ, van der Lugt A. et al. High shear stress influences plaque vulnerability Part of the data presented in this paper were published in Stroke 2007;38:2379–81. Neth Heart J 2008; 16: 280-283.
  • 79 Huang X, Yang C, Yuan C. et al. Patient-Specific Artery Shrinkage and 3D Zero-Stress State in Multi-Component 3D FSI Models for Carotid Atherosclerotic Plaques Based on In Vivo MRI Data. Mol Cell Biomech 2009; 06: 121-134.
  • 80 Kerwin WS, Liu F, Yarnykh V. et al. Signal features of the atherosclerotic plaque at 3.0 Tesla versus 1.5 Tesla: impact on automatic classification. J Magn Reson Imaging 2008; 28: 987-995.
  • 81 Tang D, Yang C, Mondal S. et al. A negative correlation between human carotid atherosclerotic plaque progression and plaque wall stress: in vivo MRI-based 2D/3D FSI models. J Biomech 2008; 41: 727-736.
  • 82 Yuan C, Oikawa M, Miller Z. et al. MRI of carotid atherosclerosis. J Nucl Cardiol 2008; 15: 266-275.
  • 83 Zhao X, Miller ZE, Yuan C. Atherosclerotic plaque imaging by carotid MRI. Curr Cardiol Rep 2009; 11: 70-77.
  • 84 Davies MJ. The contribution of thrombosis to the clinical expression of coronary atherosclerosis. Thromb Res 1996; 82: 1-32.
  • 85 Spuentrup E, Buecker A, Katoh M. et al. Molecular magnetic resonance imaging of coronary thrombosis and pulmonary emboli with a novel fibrin-targeted contrast agent. Circulation 2005; 111: 1377-1382.
  • 86 Botnar RM, Buecker A, Wiethoff AJ. et al. In vivo magnetic resonance imaging of coronary thrombosis using a fibrin-binding molecular magnetic resonance contrast agent. Circulation 2004; 110: 1463-1466.
  • 87 Overoye-Chan K, Koerner S, Looby RJ. et al. EP-2104R: a fibrin-specific gadolinium-Based MRI contrast agent for detection of thrombus. J Am Chem Soc 2008; 130: 6025-6039.
  • 88 Spuentrup E, Botnar RM, Wiethoff AJ. et al. MR imaging of thrombi using EP-2104R, a fibrin-specific contrast agent: initial results in patients. Eur Radiol 2008; 18: 1995-2005.
  • 89 von zur Muhlen C, von Elverfeldt D, Moeller JA. et al. Magnetic resonance imaging contrast agent targeted toward activated platelets allows in vivo detection of thrombosis and monitoring of thrombolysis. Circulation 2008; 118: 258-267.
  • 90 Kolodgie FD, Gold HK, Burke AP. et al. Intraplaque hemorrhage and progression of coronary atheroma. N Engl J Med 2003; 349: 2316-2325.
  • 91 Sluimer JC, Gasc JM, van Wanroij JL. et al. Hypoxia, hypoxia-inducible transcription factor, and macrophages in human atherosclerotic plaques are correlated with intraplaque angiogenesis. J Am Coll Cardiol 2008; 51: 1258-1265.
  • 92 Virmani R, Kolodgie FD, Burke AP. et al. Atherosclerotic plaque progression and vulnerability to rupture: angiogenesis as a source of intraplaque hemorrhage. Arterioscler Thromb Vasc Biol 2005; 25: 2054-2061.
  • 93 O’Malley SM, Vavuranakis M, Naghavi M. et al. Intravascular ultrasound-based imaging of vasa vasorum for the detection of vulnerable atherosclerotic plaque. Med Image Comput Comput Assist Interv Int Conf Med Image Comput Comput Assist Interv 2005; 08: 343-351.
  • 94 Kerwin W, Hooker A, Spilker M. et al. Quantitative magnetic resonance imaging analysis of neovasculature volume in carotid atherosclerotic plaque. Circulation 2003; 107: 851-856.
  • 95 Burtea C, Laurent S, Murariu O. et al. Molecular imaging of alpha v beta3 integrin expression in atherosclerotic plaques with a mimetic of RGD peptide grafted to Gd-DTPA. Cardiovasc Res 2008; 78: 148-157.