doi: 10.1161/01.CIR.0000025708.36290.05
(Circulation. 2002;106:760.)
© 2002 American Heart Association, Inc.
Editorial |
Plaque Vulnerability, Plaque Rupture, and Acute Coronary Syndromes
(Multi)-Focal Manifestation of a Systemic Disease Process
From the Department of Cardiovascular Medicine, The Cleveland Clinic Foundation, Cleveland, Ohio.
Correspondence to Stephen G. Ellis, MD, Sones Cardiac Catheterization Laboratories, Department of Cardiovascular Medicine, The Cleveland Clinic Foundation, 9500 Euclid Ave, F-24, Cleveland, Ohio, 44195. E-mail elliss{at}ccf.org
Key Words: Editorials • coronary disease • plaque • ultrasonics • imaging
In this issue of Circulation, Rioufol et al1 describe the presence of multiple ruptured atherosclerotic coronary plaques in patients presenting with an acute coronary syndrome (ACS). With the use of intravascular ultrasound (IVUS), the authors systematically examined proximal portions of the entire coronary tree in 24 patients. Ruptured plaques were found at the culprit lesion in 9 patients (37.5%) but, more importantly, distant from the culprit lesion in 19 patients (79%). These additional ruptured plaques were frequently multiple, located in a vessel different from the culprit vessel in 70% of patients and in 2 vessels not related to the acute event in 12% of patients. Both culprit lesions and additional ruptured plaques were characterized by positive remodeling. The authors proceeded with coronary stent placement at the culprit lesion site in 19 patients (86%) and, on the basis of angiographic and IVUS criteria (minimum luminal diameter <1.5 mm, minimum luminal cross-sectional-area <4 mm2), at additional sites in 16 patients (72%).
See p 804
It is important to consider these findings in the context of the recent literature. Traditional diagnostic criteria of lesion significance define focal, hemodynamically significant plaques that cause acute or chronic impairment of coronary blood flow. These lesions are identified by selective coronary angiography. However, it is well known from angiographic studies that most myocardial infarctions occur at sites that previously caused only mild-to-moderate luminal stenosis.2 In histological studies of patients with coronary artery disease who died suddenly, the plaque at the culprit lesion site shows evidence of rupture in 
70% of patients and superficial erosion in 30% of patients. 3 Acute superimposed thrombosis leads to luminal obstruction.
Similar to the findings of Rioufol et al, 1 other recent studies that used different clinical imaging modalities found evidence of ruptured plaques that were distant from the culprit lesion in patients with acute cardiovascular events. Goldstein et al4 reported the presence of additional complex angiographic lesions in 30% of patients presenting with ACS. Many of these lesions were found in vessels not related to the acute event. While these studies examined plaques that had already ruptured, coronary angioscopy can identify lesion characteristics presumably associated with a propensity to undergo rupture. In an angioscopic study, Asakura et al 5 reported the frequent presence of " vulnerable, yellow" coronary plaques distant from the culprit lesion in patients with ACS. Similarly, thermal heterogeneity within human atherosclerotic coronary arteries has been documented with the use of special thermography catheters.6 Areas with higher temperatures are thought to be associated with plaque instability. In subsequent studies, temperature heterogeneity has been found to be larger in patients presenting with ACS.7
These clinical findings support our present understanding of the pathophysiology of coronary artery disease.8 Rather than a simple mechanical problem, the development of coronary lesions is a complex biological process. The transition to an unstable atheroma is characterized by the accumulation of a large necrotic core, containing extracellular lipids, macrophages, and often microcalcifications. These unstable, vulnerable sites are frequently not highly stenotic before rupture because the accumulating plaque is accommodated by positive remodeling, alleviating the reduction of luminal size. 9,10 Both positive remodeling11 and eventual plaque rupture2 are related to an inflammatory response, supporting the role of systemic inflammation in patients with a high propensity for acute coronary events.12
Lesion stability appears to be a continuum with biologically inactive, but sometimes hemodynamically significant lesions on the one hand, and biologically active, vulnerable lesions that lead to ACS on the other. Importantly, although pathological studies have demonstrated that the sequence of plaque rupture and subsequent thrombus formation is the initiating event of most ACS,2,3 rupture of a coronary atheroma appears to be a frequent event that only occasionally leads to luminal obstruction. Therefore, many vulnerable plaques that rupture do not cause a clinical event. Presumably, patients presenting with ACS have an underlying (temporary?) biochemical milieu predisposing them to the development of widespread plaque degeneration and/or accelerated subsequent thrombus formation. The occluding thrombus at the culprit lesions determines the clinical presentation but is only the focal manifestation of an underlying systemic disease process. It is not clear why some plaques lead to clinical manifestations, whereas many others remain asymptomatic and heal with subsequent fibrosis, frequently associated with luminal narrowing.13
These findings are consistent with clinical observations. Sudden rupture of a previously hemodynamically insignificant lesion would explain why acute myocardial infarction and sudden cardiac death frequently occur in patients without prior symptoms of coronary artery disease. 3,13 The high incidence of recurrent events in patients with acute myocardial infarction, which correlates with systemic markers of inflammation,14 may be related in part to additional vulnerable lesions distant from the culprit lesion.
What are the clinical implications of these findings for the diagnostic and therapeutic approach to patients with ACS and those at risk for such events? The diagnosis of vulnerable lesions before rupture would have tremendous potential for event prevention. Several approaches are presently being explored: IVUS, along with other invasive and noninvasive imaging modalities, could allow the assessment of individual plaques and overall plaque burden.15,16 The tagging of markers specific to activated, vulnerable plaques could further enhance imaging techniques. Other diagnostic approaches could assess the biochemical activity by either measuring the local temperature heterogeneity 6,7 or biochemical markers, as exemplified by C-reactive protein.12 These present approaches have tremendously advanced our understanding of plaque vulnerability and rupture, but several questions remain unsolved:
- Will it be more important to identify individual vulnerable lesions or the number of vulnerable lesions at any one time?
- Is a plaque that has recently ruptured as dangerous as a plaque before rupture?
- When does a ruptured plaque lose its potential to form a superimposed thrombus?
An optimal diagnostic test would be noninvasive, safe, and easily repeatable. It would not only identify vulnerable and ruptured lesions but also differentiate plaques that are more likely to cause ACS. Such a test does not yet exist.
The treatment of hemodynamically insignificant lesions with characteristics of vulnerability or rupture is equally or more challenging. The diffuse distribution of these lesions may suggest that a systemic treatment would be most beneficial. It has been postulated that the success of common systemic treatments of patients with ACS (eg, platelet-receptor inhibitors and lipid-lowering medications)17,18 may in fact be related to their effect on additional lesions, rather than the culprit lesion alone. Preliminary results suggest that pharmacological approaches could prevent the transition of stable to unstable lesions (eg, by inhibiting matrix metalloproteinase–related pathways of plaque rupture and remodeling).19 However, systemic treatments entail the risk of systemic toxicity (eg, ticlopidine and neutropenia, matrix metalloproteinase inhibitors, and crippling joint pain).20
On the other hand, focal plaque stabilization with interventional intracoronary techniques has been proposed. Plaque sealing with coronary stents, which are known to cause a fibrotic response, might seem attractive, particularly with the expected low restenosis rate of drug-coated stents. However, there is no clinical experience in favor of such a treatment for either vulnerable or ruptured hemodynamically insignificant lesions, and major problems remain unsolved:
- There is presently no diagnostic tool that could guide the operator to those lesions that are at high risk to cause acute coronary events.
- Even if such a targeted approach would be safe and effective, it would leave many other sites unprotected, and the benefit from treating an individual lesion may be small.
With regard to the article by Rioufol et al,1 several aspects should be mentioned. A major limitation is the small size of the study population and the lack of a control group with stable coronary syndromes. As mentioned above, the presence of a plaque that has already ruptured does not necessarily imply that this site is still biologically active. The surprisingly low number of evident ruptures at the culprit lesion site is also noteworthy. As the authors point out, this could be caused by limitations of IVUS to differentiate between thrombus and atheroma. A superimposed thrombus at the culprit lesion site may mask the underlying rupture. This has important clinical consequences for patients presenting with ACS: In the presence of a ruptured plaque with superimposed acute thrombosis and additional lesions, the accurate identification of the culprit lesion may not always be possible.
The findings of Rioufol et al support the growing body of evidence that coronary artery disease is a systemic disease of the entire coronary tree. Further research is needed to illuminate the complex relation between focal manifestation and overall disease burden. In the meantime, the present approach to patients with ACS, which includes the focal treatment of the hemodynamically significant culprit lesion (including antiplatelet therapy)17 as well as systemic treatment (eg, statins, ß-blockers, and ACE inhibitors),18 remains the clinical standard and may already affect lesions distant from the culprit site.
Footnotes
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
References
1. Rioufol G, Finet G, Andre-Fouet X, et al. Multiple atherosclerotic plaque rupture in acute coronary syndrome: a three-vessel intravascular ultrasound study. Circulation. 2002; 106: 804–808.
2. Falk E, Shah PK, Fuster V. Coronary plaque disruption. Circulation. 1995; 92: 657–671.
3. 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.
4. 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.
5. Asakura M, Ueda Y, Yamaguchi O, et al. 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.
6. 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] [Order article via Infotrieve]
7. 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.
8. Libby P. Current concepts of the pathogenesis of the acute coronary syndromes. Circulation. 2001; 104: 365–372.
9. Glagov S, Weisenberg E, Zarins CK, et al. Compensatory enlargement of human atherosclerotic coronary arteries. N Engl J Med. 1987; 316: 1371–1353.[Abstract]
10. Schoenhagen P, Ziada KM, Kapadia SR, et al. Extent and direction of arterial remodeling in stable and unstable coronary syndromes. Circulation. 2000; 101: 598–603.
11. Varnava AM, Mills PG, Davies MJ. Relationship between coronary artery remodeling and plaque vulnerability. Circulation. 2002; 105: 939–943.
12. Ridker PM, Cushman M, Stampfer MJ, et al. Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med. 1997; 336: 973–979.
13. 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.
14. Ridker PM, Rifai N, Pfeffer M, et al. Elevation of tumor necrosis factor-
and increased risk of recurrent coronary events after myocardial infarction. Circulation. 2000; 101: 2149–2153.
15. Schroeder S, Kopp AF, Baumbach A, et al. Noninvasive characterization of coronary lesion morphology by multi-slice computed tomography: a promising new technology for risk stratification of patients with coronary artery disease. Heart. 2001; 85: 576–577.
16. Fayad ZA, Fuster V. Clinical imaging of the high-risk or vulnerable atherosclerotic plaque. Circ Res. 2001; 89: 305–316.
17. Newby LK, Ohman EM, Chritenson RH, et al. Benefit of glycoprotein IIb/IIIa inhibition in patients with acute coronary syndromes and troponin T-positive status. Circulation. 2001; 103: 2891–2896.
18. Aronow HD, Topol EJ, Roe MT, et al. Effect of lipid-lowering therapy on early mortality after acute coronary syndromes: an observational study. Lancet. 2001; 357: 9262:1063–1068.
19. Aikawa M, Rabkin E, Sugiyama S, et al. An HMG-CoA reductase inhibitor, Cerivastatin, suppresses growth of macrophages expressing matrix metalloproteinases and tissue factor in vivo and in vitro. Circulation. 2001; 103: 276–283.
20. Brinckerhoff CE, Matrisian LM. Matrix metalloproteinases: a tail of a frog became a prince. Nature Reviews Molecular Cell Biology. 2002; 3: 207–214.[CrossRef][Medline] [Order article via Infotrieve]
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