EDITORIAL COMMENT
Toward understanding the evolution of plaque rupture
Correlating vascular pathology with clinical outcomes*
James S. Forrester, MD, FACC*,*
* Division of Cardiology, Cedars–Sinai Medical Center, UCLA School of Medicine, Los Angeles, California, USA
* Reprint requests and correspondence: Dr. James S. Forrester, Division of Cardiology, Cedars–Sinai Medical Center, UCLA School of Medicine, Los Angeles, California 90048, USA.
James.Forrester{at}cshs.org
Acute coronary syndromes are initiated by plaque rupture (i.e., by the interaction between flowing blood and the intimal surface). This interface is in continual flux over a period of months. The blood vessel surface, very poorly assessed by angiography (1,2), is best visualized by angioscopy, which provides images most analogous to postmortem gross anatomy. Unlike the postmortem, angioscopy can be repeated over months and can be performed in symptomatic living man. Thus, angioscopy first allowed us to discover that patients with unstable angina have a disrupted intimal surface (3,4). Now, serial angioscopic studies, such as that by Sakai et al. (5) in this issue of the Journal, provide an unparalleled opportunity to construct a framework for understanding the natural temporal evolution of plaque rupture and how it is modified by therapy, thereby to better understand and interpret both therapeutic alternatives and clinical trial results.
To begin to construct this framework, we can define the initial presentation of myocardial infarction (MI). In contrast to angiography, angioscopy demonstrates thrombus in essentially 100% of patients with atherosclerotic acute MI (4,6). In contrast, unstable angina is more heterogeneous. About 75% of patients have plaque rupture, and the thrombus is much more platelet-rich (seen angioscopically as white thrombus) than the fibrin-rich with trapped red cells (red thrombus) (6,7). This difference in clot composition may explain the failure of thrombolytic therapy in unstable angina (8).
The vascular pathology of plaque rupture is modified by revascularization therapy. Even after restoration of Thrombolysis In Myocardial Infarction (TIMI) trial III angiographic flow by successful thrombolysis in acute MI, however, the thrombus persists over at least a month after therapy (9). Thus, in 56 patients studied between 24 h and four weeks after MI, Van Belle et al. (10) found that thrombolytic therapy reduced thrombus size, but that, remarkably, there was no reduction in the number of plaques containing thrombi. These data provide a potential basis for understanding the 15% to 25% rate of reocclusion following successful thrombolytic therapy. Conversely, angioscopy has shown that thrombosis may be clinically and angiographically silent. For instance, in 52 patients with angiographically normal coronary artery segments, Alfonso et al. (11) found plaque in 23 patients, flaps in 2, and thrombus in 5.
In contrast to thrombolysis, percutaneous coronary intervention (PCI) clearly has the potential to even more powerfully alter the acutely ruptured plaque. We need first to understand how angioplasty affects stable lesions. Balloon angioplasty frequently induces angioscopically large surface dissections that are undetected by angiography (12). For instance, after percutaneous transluminal coronary angioplasty (PTCA), Kanamasa et al. (13) found disruptions in 17/35 and thrombi in 24/35 patients. The clinical relevance of this observation is that post-PTCA abrupt closure is predominantly due to dissection. Thus, in 17 patients with acute postangioplasty occlusion, White et al. (14) found that the primary cause of postangioplasty abrupt closure was dissection in 14 patients (82%) and intracoronary thrombi in 3 others (18%). Angiography correctly identified the cause of vessel occlusion in only 5 (29%) of these patients (14). The lesions that are most prone to postprocedure cardiac events most commonly have a thin fibrous cap and a large lipid core (yellow plaques). Because these types of plaques are also most prone to spontaneous rupture, they presumably have a greater propensity to rupture and become thrombogenic during angioplasty (15,16). In contrast to its important role in abrupt closure, dissection does not correlate with restenosis, whereas postprocedure thrombus correlates strongly (17).
With this background we can analyze the effect of angioplasty in acute MI. Ueda et al. (18) found that, although the frequency of thrombus persistence is less than that observed after thrombolysis, the percentage remains strikingly high, 64%, at one month. Thus, even with restoration of apparently normal flow, there remains a potent stimulus to rethrombosis, providing a biologic rationale for ongoing antiplatelet therapy.
By six months' postangioplasty, however, thrombus is detected in only 5% of patients, and the yellow color typical of ruptured plaques evolves to the white surface that is characteristic of stable lesions. From these observations we may infer that intimal proliferation is active in the first six months following angioplasty. On the clinical level, these data provide a logical basis for assuming that both thrombogenic potential and the need for antithrombotic therapy to prevent rethrombosis of the culprit lesion is low beyond this point in time.
To evaluate the impact of stenting in acute MI, we must again understand its effect on stable lesions. Sakatani et al. (19) found that the rate of thrombus formation after stenting was comparable to that following balloon angioplasty. Although some experimental results in animals have shown completion of neointimal coverage of stents in a few weeks, this does not occur in human atherosclerotic lesions. Thus, Ueda et al. (20) found that at 8 to 18 days after stenting, no stent was covered by neointima. Later, at two to four months, all stents were covered by neointima (20). Although we might infer that the completion of neointimal coverage of stents in human coronary arteries requires approximately three months, others found only about 80% of stents were covered at three months and that incomplete neointimal coverage persisted at beyond six months in about 10% of patients (19). This percentage is likely to increase with the latest generation of stents, because radiation and drugs eluted from the stent surface may substantially inhibit and delay stent re-endothelialization.
With this background we can now analyze what happens when a lesion disrupted by plaque rupture is modified by percutaneous intervention. Sakai et al. (5) recorded angioscopic images before and after balloon angioplasty and then again after stent placement. Consistent with both prior natural history and thrombolytic studies, all of the culprit lesions had a protruding thrombus on a yellow plaque. Balloon angioplasty reduced the mass of thrombus in about two-thirds of the cases, but an intimal flap remained in approximately 90%. Thus, although the vessel patency and TIMI flow rate is markedly improved, the immediate effect of balloon angioplasty on the blood vessel surface is not much different from that of thrombolysis. The most striking insight from the study by Sakai et al. (5) is the change in vascular surface morphology after stenting. The stent compressed the thrombus and covered the dissected surface, eliminating both visually detectable thrombus and dissection in all cases. This initial difference provides a logical basis for the findings of the widely quoted CADILLAC trial in which patients treated by a stent plus abciximab had a lower rate of combined death, reinfarction, disabling stroke, and less repeat revascularization than did patients treated by PTCA alone or by PTCA plus abciximab (21).
Conversely, it is clear that placement of a bare metallic stent in a flowing blood stream clearly increases the risk of thrombosis until it is re-endothelialized. From this study we now know that, at one month, the stents are only partially endothelialized and are covered with a thin lining of thrombus. The lack of re-endothelialization of the stented surface after MI, therefore, is similar to that seen in stable lesions. The combination of lack of re-endothelialization and the thin layer of thrombus also explains the high risk of reocclusion in the first month following stenting in patients not treated with antiplatelet agents, and fully justifies use of these agents for the first few months after stenting (22).
By six months, however, about 95% of the stents were covered with smooth white neointima. From these data we can infer a second striking insight. At six months both the rate of healing and the post-stent appearance does not seem to be different from the previously reported observation of stented stable plaques, which we know are often disrupted by the angioplasty procedure itself. By six months, stented stable and unstable lesions are essentially indistinguishable. This result, then, explains why reinfarction at a site of prior angioplasty is quite rare.
The return of 95% of stented culprit lesions to stability at six months, however, also creates a clinical conundrum. Clearly antiplatelet therapy for prevention of reocclusion at the stented site might have little therapeutic role beyond six months for the majority of patients. The parallel event curves in clopidogrel-treated and -untreated patients in the CURE trial after three to six months of therapy are consistent with these data (23). In contrast, if we accept the logical premise that failure to completely re-endothelialize represents an ongoing prothrombotic risk, a small subgroup of the stented infarct population remains at increased risk at six months. Ironically, we have no method, other than repeat angioscopy, to identify them. Thus, the question of long duration of clopidogrel therapy post-stenting will remain difficult, unless the drug is more clearly shown to have a beneficial effect on atherosclerosis.
From these studies, we can construct a framework upon which management of plaque rupture can be conceptualized (Fig. 1). In atherosclerotic acute MI, a fibrin-rich thrombus on a disrupted plaque is present, whether or not it is clearly visualized by angiography. The lesion beneath the thrombus is typically lipid-rich, with a thin fibrous cap. In contrast, although unstable angina most commonly begins with plaque rupture, the thrombus is nonocclusive and platelet-rich. Following thrombolytic therapy in acute MI, the natural history of thrombus evolution is slow, such that a layer of thrombus persists on the healing surface at one month. Beyond one month there is a gradual evolution toward plaque stability. At three months the culprit lesion is not fully healed: the culprit lesion remains ragged and discolored. By six months, the lesion becomes smooth-surfaced and has the appearance of a stable atheroma. This natural history is modified by interventional procedures. Although balloon angioplasty alone commonly restores TIMI III flow, it does so by increasing lumen diameter and reducing thrombus mass. Possibly because the torn surface and thrombus remain, balloon angioplasty parallels thrombolytic therapy in plaque evolution. Thrombus is present at one month, and the lesion becomes stable by six months.
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Figure 1 Evolution of the ruptured plaque after revascularization. PTCA = percutaneous transluminal coronary angioplasty.
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In contrast, balloon angioplasty followed by stenting has a different effect. The stent eliminates visible thrombus and dissection. At one month, however, the stent is not endothelialized, and it is often covered with a thin layer of thrombus. As with the natural history of plaque evolution, however, the stent surface gradually endothelializes. By six months, 95% of the stents have a smooth intimal surface characteristic of stable plaques. Perhaps 5% of stents retain patchy areas that are not re-endothelialized. This framework may prove useful in clinical trial design and interpretation. Clearly, similar angioscopic studies will be of substantial value in understanding the local vascular response after radiation therapy and implantation of the new generation of drug-eluting stents.
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Footnotes
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* 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. 
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