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J Am Coll Cardiol, 2003; 42:1033-1036, doi:10.1016/S0735-1097(03)00904-5
© 2003 by the American College of Cardiology Foundation
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CLINICAL RESEARCH: CORONARY ARTERY DISEASE: EDITORIAL COMMENT

Acute coronary syndromes, plaque vulnerability,and carotid artery disease

The changing role ofatherosclerosis imaging*

E. Murat Tuzcu, MD, FACC{dagger},* and Paul Schoenhagen, MD{dagger}{ddagger}

{dagger} Department of Cardiovascular Medicine, The Cleveland Clinic Foundation, Cleveland, Ohio, USA
{ddagger} Department of Radiology, Cardiovascular Imaging, The Cleveland Clinic Foundation, Cleveland, Ohio, USA

* Reprint requests and correspondence: Dr. E. Murat Tuzcu, The Cleveland Clinic Foundation, F25, 9500 Euclid Avenue, Cleveland, Ohio 44195, USA.
tuzcue{at}ccf.org

The introduction of selective coronary angiography by Mason Sones in the late 1950s revolutionized clinical cardiology. Angiography, by allowing in vivo identification of focal coronary stenoses in patients presenting with stable and unstable coronary syndromes, has been the basis for the enormous success of surgical and percutaneous revascularization therapies. However, it was soon realized that the mechanical treatment of focal lesions did not affect the underlying systemic process of atherosclerosis (1). It was the identification of clinical risk factors, including diabetes, smoking, hyperlipidemia, and hypertension, that led to systemic therapeutic interventions that proved most effective in preventing ischemic cardiovascular events (2–4). Despite these important clinical advances, coronary artery disease remains the number one cause of mortality in Western societies (5). Obviously, current diagnostic and therapeutic tools are inadequate to predict or prevent a large number of acute cardiovascular events.

Atherosclerosis is a diffuse, systemic disease process that typically begins many years before symptoms occur (6,7). The dissociation between diffuse plaque accumulation and focal, angiographic lesion appearance is explained by a complex remodeling response of diseased arteries (8). Typically, the accumulating plaque burden is initially accommodated by an expansion of the vessel area with minimal changes in lumen size; a process called positive remodeling. It is now generally accepted that sudden rupture or erosion of such mildly stenotic but "vulnerable" lesions causes most acute coronary syndromes (9). Animal and human studies demonstrate that vulnerable plaques in coronary (10–13), peripheral, and carotid arteries (14–17) are associated with positive remodeling and intense inflammation. There is strong evidence that a systemic inflammatory response plays a central role in the destabilization of atherosclerotic lesions, initiating plaque rupture and subsequent thrombosis (18,19). Recent results in animal models and patients presenting with acute coronary syndromes consistently demonstrate simultaneous rupture of the culprit lesion and multiple additional plaques at distant locations in the coronary tree (20–24), supporting the existence of systemic triggers causing acute plaque destabilization. It is unclear why atherosclerotic lesions progress silently for extended periods of time and then suddenly undergo changes leading to rupture, thrombosis, and acute clinical syndromes. However, these acute changes are not limited to a single "culprit" site but are part of a more diffuse, multicentric inflammatory process involving the entire coronary tree, perhaps the arterial vasculature in general. It is conceivable that the combination of overall plaque burden and systemic triggers correlates with the risk to develop acute clinical syndromes.

These findings have initiated a paradigm shift in our approach to coronary atherosclerosis. Imaging of subclinical atherosclerosis is used for the detection and quantification of atherosclerotic plaque burden. However, the identification of plaque without knowledge about disease "activity" is not adequate for a comprehensive risk analysis because not all atherosclerotic plaques result in coronary events. Disease activity can be assessed by serologic markers that reflect the systemic inflammatory response. In particular, high-sensitivity C-reactive protein is increasingly incorporated in risk assessment algorithms and has recently been compared with traditional risk factors (19,25). A different approach is the local assessment of atheroma activity. Accurate methods identifying plaques with high-risk characteristics would open the way for more aggressive systemic treatments and potentially allow local mechanical treatments of the most dangerous nonobstructive plaques.

However, the clinical diagnosis of plaque vulnerability is a complex conundrum (26). Currently, neither invasive nor noninvasive imaging technology can reliably identify vulnerable plaques prospectively, that is, before rupture. Histologic studies describe characteristic findings of such lesions, which include a lipid-rich necrotic core with a thin fibrous cap, a prominent inflammatory response, and positive remodeling (9–11). Because of their limited resolution, even invasive imaging modalities cannot reliably identify minute plaque structures in vivo. However, recent technical advances in ultrasound imaging use radiofrequency analysis and elastography (27,28) and optical coherence tomography (29) to characterize more precisely the composition of atherosclerotic plaques. Yet another approach is the focal assessment of temperature differences with sensitive intravascular thermography catheters, presumably reflecting focal inflammatory changes of vulnerable lesions (30,31). Even if precise plaque characterization will be possible, the applicability of these intravascular tools would be limited because of their invasive nature. Thus, an accurate and easily applicable noninvasive tool that could characterize plaque vulnerability would be an important step forward.

Noninvasive coronary imaging modalities, including positron emission tomography (PET), magnetic resonance imaging (MRI), and computed tomography (CT), generally have a significantly lower resolution than invasive technologies, potentiating the limitations of tissue characterization (26,32). However, future developments in plaque-specific contrast media or fusion of, for example, CT and PET imaging could provide additional information about lesion vulnerability (33,34). Although in vivo tissue characterization of vulnerable coronary atheroma remains difficult, another feature consistently associated with vulnerability can be assessed with invasive and noninvasive imaging techniques. As stated in the preceding text, several histological studies describe a strong link between positive remodeling, inflammation, and acute coronary syndromes (10,11,14) This association has been confirmed in intravascular ultrasound studies in vivo (12,13,35) and more recently using the noninvasive imaging modalities, including CT and MRI (26,36). Data describing the relationship between remodeling and plaque vulnerability in vessels other than the coronary are limited (14–16). In carotid arteries, intima media thickness measurement has been extensively studied as a means for atherosclerosis risk assessment. Observational studies in large populations have demonstrated that the noninvasive assessment of carotid plaque burden is a marker for future coronary events (37,38). Other studies show a correlation between carotid plaque morphology and future events (39,40).

In this issue of the Journal, Kato et al. (41) explore this relationship further by correlating remodeling characteristics of carotid arteries with angiographically identified lesion complexity in the coronary arteries. Patients were divided into groups with single or multiple angiographically complex coronary lesions. Using B-mode ultrasound of the carotid arteries, the authors found a higher prevalence of calcified and noncalcified carotid plaque in the group with multiple complex coronary lesions. In addition, increased carotid plaque thickness and positive remodeling was significantly more frequent in patients with multiple versus single complex coronary plaques. An important limitation of this study is that the authors compare two groups of patients presenting with acute coronary syndromes without a control group of patients with stable coronary disease. The authors assume that a higher number of complex coronary plaques reflect a higher degree of vulnerability. Although plausible, there is no proof of that concept, and the demonstrated differences in carotid morphology may, for example, be secondary to the significantly higher frequency of multivessel disease in the multiple plaque group. Remodeling is defined in most clinical studies by a comparison of the lesion and adjacent reference site (42). The definition of remodeling used in the current study, which is based on absolute values of plaque and vessel diameter at the lesion site, is novel and will need to be validated and compared with more established definitions. Currently, the literature about remodeling of carotid arteries is limited (15,16), and it is not clear whether clinical evaluation of carotid remodeling has an incremental value to conventional risk assessment, high-sensitivity C-reactive protein, or intima media thickness (43).

Despite these limitations, the study by Kato et al. (41) contributes to the growing body of evidence demonstrating the diffuse nature of atherosclerosis. Plaque accumulation but also atheroma vulnerability are not confined to a single vascular bed. This pathophysiologic understanding creates clinical opportunities for early identification and treatment of atherosclerosis as well as challenges that come with the systemic nature of the disease.

Accurate and reproducible methods for detection and quantification of subclinical coronary atherosclerosis and plaque vulnerability could identify high-risk patients and allow serial monitoring during various therapeutic interventions. Several invasive and noninvasive imaging methods are already used to monitor plaque burden in atherosclerosis progression/regression studies. Serial intravascular ultrasound studies in native coronary arteries describe an attenuated increase in plaque volume and changes in plaque morphology during lipid-lowering treatment (44). Using noninvasive imaging, the effect of pharmacologic intervention on (calcified) coronary plaque burden has been observed in CT "calcium scoring" studies (45,46). Recent serial studies of the femoral artery, carotid artery, and aorta using B-mode ultrasound and MRI have also demonstrated regression of intimal thickness during lipid-lowering treatment (47–51). These emerging data demonstrate that invasive and noninvasive atherosclerosis imaging can identify regression of the plaque mass during pharmacologic intervention and, therefore, could be used as an end point in clinical studies. Methods that would in addition monitor changes in atheroma composition and vulnerability are still in their infancies. Whether arterial remodeling can be used for this purpose will require further study.

Integration of different invasive and noninvasive, morphologic, and functional imaging modalities is needed to compare the complex atherosclerotic disease patterns across vascular regions and to correlate the dynamic findings with clinical outcomes. In the context of a comprehensive clinical assessment, atherosclerosis imaging has the potential to improve preventive and therapeutic approaches to coronary, cerebrovascular, and peripheral atherosclerosis. It potentially could guide both systemic treatment as well as focal mechanical approaches intended to prevent ischemic cardiac events. However, a rigorous evaluation of these evolving modalities and their clinical impact will be necessary in the years ahead.


   Footnotes
 
Dr. Schoenhagen is supported by a grant from the Ohio Valley Affiliate of the American Heart Association.

* Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. Back


   References
Top
 References
 

  1. Topol EJ, Nissen SE. Our preoccupation with coronary luminology. The dissociation between clinical and angiographic findings in ischemic heart disease. Circulation. 1995;92:2333–2342[Medline]
  2. Schwartz GG, Olsson AG, Ezekowitz MD, et al. Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes: the MIRACL study. JAMA. 2001;285:1711–1718[Abstract/Free Full Text]
  3. Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G. Effects of an angiotensin-converting enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients: the Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med. 2000;342:145–153[Abstract/Free Full Text]
  4. Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK. The Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med. 2001;345:494–502[Abstract/Free Full Text]
  5. American Heart Association. 2000 Heart and Stroke Statistical Update. Dallas, TX: American Heart Association; 1999.
  6. Strong JP, Malcom GT, McMahan CA, et al. Prevalence and extent of atherosclerosis in adolescents and young adults: implications for prevention from pathobiological determinants of atherosclerosis in youth study. JAMA. 1999;281:727–735[Abstract/Free Full Text]
  7. Tuzcu EM, Kapadia SR, Tutar E, et al. High prevalence of coronary atherosclerosis in asymptomatic teenagers and young adults: evidence from intravascular ultrasound. Circulation. 2001;103:2705–2710[Medline]
  8. Glagov S, Weisenberg E, Zarins CK, Stankunavicius R, Kolettis GJ. Compensatory enlargement of human atherosclerotic coronary arteries. N Engl J Med. 1987;316:1353–1371[Abstract]
  9. Burke AP, Farb A, Malcom GT, Liang YH, Smialek J, Virmani R. Coronary risk factors and plaque morphology in men with coronary disease who died suddenly. N Engl J Med. 1997;336:1276–1282[Abstract/Free Full Text]
  10. Varnava AM, Mills PG, Davies MJ. Relationship between coronary artery remodeling and plaque vulnerability. Circulation. 2002;105:939–943[Abstract/Free Full Text]
  11. Burke AP, Kolodgie FD, Farb A, Weber D, Virmani R. Morphological predictors of arterial remodeling in coronary atherosclerosis. Circulation. 2002;105:297–303[Abstract/Free Full Text]
  12. Schoenhagen P, Ziada KM, Kapadia SR, Crowe TD, Nissen SE, Tuzcu EM. Extent and direction of arterial remodeling in stable and unstable coronary syndromes. Circulation. 2000;101:598–603[Medline]
  13. Schoenhagen P, Vince DG, Ziada KM, et al. Relation of matrix-metalloproteinase 3 found in coronary lesion samples retrieved by directional coronary atherectomy to intravascular ultrasound observations on coronary remodeling. Am J Cardiol. 2002;89:1354–1359[CrossRef][Medline]
  14. Pasterkamp G, Schoneveld AH, van der Wal AC, et al. Relation of arterial geometry to luminal narrowing and histologic markers for plaque vulnerability: the remodeling paradox. J Am Coll Cardiol. 1998;32:655–662[Abstract/Free Full Text]
  15. Godin D, Ivan E, Johnson C, Magid R, Galis ZS. Remodeling of carotid artery is associated with increased expression of matrix metalloproteinases in mouse blood flow cessation model. Circulation. 2002;102:2861–2866
  16. Ivan E, Khatri JJ, Johnson C, et al. Expansive arterial remodeling is associated with increased neointimal macrophage foam cell content: the murine model of macrophage-rich carotid artery lesions. Circulation. 2002;105:2686–2691[Abstract/Free Full Text]
  17. Hashimoto H, Kitagawa K, Hougaku H, et al. C-reactive protein is an independent predictor of the rate of increase in early carotid atherosclerosis. Circulation. 2002;104:63–67
  18. Libby P. Current concepts of the pathogenesis of the acute coronary syndromes. Circulation. 2001;104:365–372[Free Full Text]
  19. Ridker PM, Cushman M, Stampfer MJ, Tracy RP, Hennekens CH. Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med. 1997;336:973–979[Abstract/Free Full Text]
  20. Williams H, Johnson JL, Carson KGS, Jackson CL. Characteristics of intact and ruptured atherosclerotic plaques in brachiocephalic arteries of apolipoprotein E knockout mice. Arterioscler Thromb Vasc Biol. 2002;22:788–792[Abstract/Free Full Text]
  21. Buffon A, Biasucci LM, Liuzzo G, D'Onofrio G, Crea F, Maseri A. Widespread coronary inflammation in unstable angina. N Engl J Med. 2002;347:5–12[Abstract/Free Full Text]
  22. Rioufol G, Finet G, Ginon I, et al. Multiple atherosclerotic plaque rupture in acute coronary syndrome: a three-vessel intravascular ultrasound study. Circulation. 2002;106:804–808[CrossRef][Medline]
  23. Goldstein JA, Demetriou D, Grines CL, Pica M, Shoukfeh M, O'Neill WW. Multiple complex coronary plaques in patients with acute myocardial infarction. N Engl J Med. 2000;343:915–922[Abstract/Free Full Text]
  24. Asakura M, Ueda Y, Yamaguchi O, Adachi T, Hirayama A, Hori M, Kodama K. Extensive development of vulnerable plaques as a pan-coronary process in patients with myocardial infarction: an angioscopic study. J Am Coll Cardiol. 2001;37:1284–1288[Abstract/Free Full Text]
  25. Ridker PM, Rifai N, Rose L, Buring JE, Cook NR. Comparison of C-reactive protein and low-density lipoprotein cholesterol levels in the prediction of first cardiovascular events. N Engl J Med. 2002;347:1557–1565[Abstract/Free Full Text]
  26. Fayad ZA, Fuster V. Clinical imaging of the high-risk or vulnerable atherosclerotic plaque. Circ Res. 2001;89:305–316[Abstract/Free Full Text]
  27. Nair A, Kuban BD, Tuzcu EM, Schoenhagen P, Nissen SE, Vince DG. Coronary plaque classification with intravascular ultrasound radiofrequency data analysis. Circulation. 2002;106:2200–2206[CrossRef][Medline]
  28. de Korte CL, Pasterkamp G, van der Steen AF, Woutman HA, Bom N. Characterization of plaque components with intravascular ultrasound elastography in human femoral and coronary arteries in vitro. Circulation. 2000;102:617–623[Abstract/Free Full Text]
  29. Yabushita H, Bouma BE, Houser SL, et al. Characterization of human atherosclerosis by optical coherence tomography. Circulation. 2002;106:1640–1645[CrossRef][Medline]
  30. Casscells W, Hathorn B, David M, et al. Thermal detection of cellular infiltrates in living atherosclerotic plaques: possible implications for plaque rupture and thrombosis. Lancet. 1996;347:1447–1451[CrossRef][Medline]
  31. Stefanadis C, Diamantopoulos L, Vlachopoulos C, et al. Thermal heterogeneity within human atherosclerotic coronary arteries detected in vivo: a new method of detection by application of a special thermography catheter. Circulation. 1999;99:1965–1971[Medline]
  32. Cai JM, Hatsukami TS, Ferguson MS, Small R, Polissar NL, Yuan C. Classification of human carotid atherosclerotic lesions with in vivo multicontrast magnetic resonance imaging. Circulation. 2002;106:1368–1373[CrossRef][Medline]
  33. Rudd JHF, Warburton EA, Fryer TD, et al. Imaging atherosclerotic plaque inflammation with. Circulation. 2002;105:2708–2711 [18F]-fluorodeoxyglucose positron emission tomography[Abstract/Free Full Text]
  34. Fayad ZA, Fuster V, Nikolaou K, Becker C. Computed tomography and magnetic resonance imaging for noninvasive coronary angiography and plaque imaging: current and potential future concepts. Circulation. 2002;106:2026–2034[CrossRef][Medline]
  35. Yamagishi M, Terashima M, Awano K, et al. Morphology of vulnerable coronary plaque: insights from follow-up of patients examined by intravascular ultrasound before and acute coronary syndrome. J Am Coll Cardiol. 2000;35:106–111[Abstract/Free Full Text]
  36. Kim WY, Stuber M, Börnert P, Kissinger KV, Manning WJ, Botnar RM. Three-dimensional 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[CrossRef][Medline]
  37. O'Leary DH, Polak JF, Kronmal RA, Manolio TA, Burke GL, Wolfson SK. Carotid-artery intima and media thickness as a risk factor for myocardial infarction and stroke in older adults. N Engl J Med. 1999;340:14–22[Abstract/Free Full Text]
  38. Salonen JT, Salonen R. Ultrasonographically assessed carotid morphology and the risk of coronary heart disease. Arterioscler Thromb. 1991;11:1245–1249[Abstract]
  39. Grønholdt MLM, Nordestgaard BG, Schroeder TV, Vorstrup S, Sillesen H. Ultrasonic echolucent carotid plaques predict future strokes. Circulation. 2002;104:68–73[CrossRef]
  40. Mathiesen EB, Bønaa KH, Joakimsen O. Echolucent plaques are associated with high risk of ischemic cerebrovascular events in carotid stenosis: the Tromsø Study. Circulation. 2002;103:2171–2175
  41. Kato M, Dote K, Habara S, Takemoto H, Goto K, Nakaoka K. Clinical implications of carotid artery remodeling in acute coronary syndrome: ultrasonographic assessment of positive remodeling. J Am Coll Cardiol 2003;42:1026–32
  42. Schoenhagen P, Ziada KM, Vince DG, Nissen SE, Tuzcu EM. Arterial remodeling and coronary artery disease: the concept of "dilated" versus "obstructive" coronary atherosclerosis. J Am Coll Cardiol. 2001;38:297–306[Abstract/Free Full Text]
  43. Crouse JR, Tang R, Espeland MA, Terry JG, Morgan T, Mercuri M. Associations of extracranial carotid atherosclerosis progression with coronary status and risk factors in patients with and without coronary artery disease. Circulation. 2002;106:2061–2066[CrossRef][Medline]
  44. Schartl M, Bocksch W, Koschyk DH, et al. Use of intravascular ultrasound to compare effects of different strategies of lipid-lowering therapy on plaque volume and composition in patients with coronary artery disease. Circulation. 2001;104:387–392[Abstract/Free Full Text]
  45. Callister TQ, Raggi P, Cooil B, Lippolis NJ, Russo DJ. Effect of HMG-CoA reductase inhibitors on coronary artery disease by electron-beam computed tomography. N Engl J Med. 1998;339:1972–1978[Abstract/Free Full Text]
  46. Achenbach S, Ropers D, Pohle K, et al. Influence of lipid-lowering therapy on the progression of coronary artery calcification. Circulation. 2002;106:1077–1082[CrossRef][Medline]
  47. de Groot E, Jukema JW, Montauben van Swijndregt AD, et al. B-mode ultrasound assessment of pravastatin treatment effect on carotid and femoral artery walls and its correlation with coronary arteriographic findings: a report of the Regression Growth Evaluation Statin Study (REGRESS). J Am Coll Cardiol. 1998;31:1561–1567[Abstract/Free Full Text]
  48. Taylor AJ, Kent SM, Flaherty PJ, Coyle LC, Markwood TT, Vernalis MN. ARBITER: Arterial Biology for the Investigation of the Treatment Effects of Reducing cholesterol. A randomized trial comparing the effects of atorvastatin and pravastatin on carotid intima medial thickness. Circulation. 2002;106:2055–2060[CrossRef][Medline]
  49. MacMahon S, Sharpe N, Gamble G, et al. Effects of lowering average or below-average cholesterol levels on the progression of carotid atherosclerosis. Results of the LIPID Atherosclerosis Substudy. Circulation. 1998;97:1784–1790[Medline]
  50. Corti R, Fayad ZA, Fuster V, et al. Effects of lipid-lowering by simvastatin on human atherosclerotic lesions: a longitudinal study by high-resolution, noninvasive magnetic resonance imaging. Circulation. 2001;104:249–252[Abstract/Free Full Text]
  51. Zhao XQ, Yuan C, Hatsukami TS, et al. Effects of prolonged intensive lipid-lowering therapy on the characteristics of carotid atherosclerotic plaques in vivo by MRI. Arterioscler Thromb Vasc Biol. 2001;21:1623–1629[Abstract/Free Full Text]




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