CLINICAL RESEARCH: EDITORIAL COMMENT
Act Local, Act Global*
Inflammation and the Multiplicity of "Vulnerable" Coronary Plaques
Peter Libby, MD, FACC*
Donald W. Reynolds Cardiovascular Clinical Research Center, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts
* Reprint requests and correspondence: Dr. Peter Libby, Brigham and Women’s Hospital, 77 Avenue Louis Pasteur, NRB 741, Boston, Massachusetts 02115 (Email: plibby{at}rics.bwh.harvard.edu).
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A revolution in our thinking regarding the pathogenesis of acute coronary syndromes
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Contemporary clinical and laboratory data have challenged our classical concepts of the pathogenesis of the acute coronary syndromes. Indeed, several independent lines of clinical evidence have shown that critical stenoses cause only a fraction of acute coronary syndromes (1). Rather, disruptions due to fibrous cap fracture or superficial intimal erosion frequently trigger acute coronary thromboses at sites of non-critical narrowing of coronary arteries. This shift in our thinking has fostered the notion of the so-called "vulnerable" or "high-risk" plaque (2,3) and spawned manifold attempts to develop methods for detection of the "vulnerable" plaque (4), a quest predicated on the postulate that local intervention could preclude plaque thrombosis and possibly prevent acute coronary syndromes. Indeed, this approach may prove applicable to patients already targeted for invasive diagnosis or treatment in whom identification of nonstenotic lesions unseen by traditional angiography might guide a local intervention aimed at prophylaxis that may prevent a future coronary event. An acute coronary event marks a patient for a high short-term risk of recurrence and thus justifies such an aggressive stance. Moreover, individuals with stable coronary artery disease in drug intervention trials require many months or even years of treatment to achieve event reduction (5), hence the interest in an immediate invasive intervention that might "stabilize" potentially vulnerable plaques despite the challenge of designing a clinical trial to prove the benefit of such an approach.
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"Vulnerable plaques": single or multiple?
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Rapidly accumulating clinical data suggest that a search to identify a single vulnerable plaque to guide local therapy may seriously underestimate the complexity of the challenge. We traditionally view atherosclerosis as a segmental disease. Indeed, flow-limiting stenoses do occur focally, furnishing a foundation for the success of revascularization in relieving angina pectoris and other ischemic symptoms. However, the more we seek, the more we see that atherosclerosis most often extends beyond the segmental stenoses. Patients whose burden of disease includes flow-limiting stenoses usually harbor diffuse but angiographically unseen disease along the length of their arteries. Thus, the coronary tree may veritably teem with plaques at high risk of rupture and thrombosis (6).
Although well-suited to pinpoint stenoses, traditional contrast coronary arteriography affords only an indirect view of aspects of atheromata related to their propensity to trigger thromboses. For every culprit lesion, other potentially troublesome plaques may lurk undetected (6). Yet, even this relatively insensitive tool of angiography often shows a multiplicity of already disrupted or complex plaques in patients with acute coronary syndromes. Goldstein et al. (7) found angiographic features of instability of nonculprit plaques in nearly 40% of patients with acute coronary syndromes and further demonstrated a more dire prognosis in those with such findings. Others (8–12), including Tanaka et al. (12), as described in this issue of the Journal, have used intracoronary ultrasonography to seek more direct structural evidence of disruption remote from the angiographically apparent culprit lesions in a series of patients with acute coronary syndromes. Many such patients have more than one disrupted plaque detected echographically (Fig. 1). The autopsy study by Mauriello et al. (13), also reported in this issue of the Journal, provides pathoanatomical confirmation of this concept. They found plaques with characteristics of vulnerability in almost a quarter (22.3%) of non-infarct-related arteries in patients who succumbed to acute myocardial infarction (13).
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Figure 1 Prevalence of multiple coronary artery plaque ruptures detected by intravascular ultrasonography (IVUS) in five studies. Interrogation of coronary arteries of patients with acute coronary syndromes by IVUS reveals coincident ruptures of nonculprit lesions in 13% to 79% of cases. The differences in the prevalence of multiple plaque ruptures among studies may depend on technical issues (e.g., use of contrast), patient selection, timing of the investigation with relation to the index event, and other variables (8–12).
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Inflammation fans the flame of plaque vulnerability
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We now recognize inflammation as a common contributor to the acute thrombotic manifestations of atherosclerosis (14). As gauged by the robust biomarker C-reactive protein (CRP), inflammation predicts the prognosis of individuals with acute coronary syndromes and also those without manifest atherosclerosis (15). This predictive power of CRP seems independent of the overall plaque burden and of the palette of traditional risk factors encompassed by the Framingham algorithm. Pathophysiological studies have established many mechanistic links between inflammation and the thrombotic complications of atherosclerosis (Fig. 2). Inflammatory mediators not only elevate levels of biomarkers such as CRP but also unleash pathways that weaken the plaque’s fibrous cap, set the stage for superficial erosion of the intima, promote procoagulant production, and quench endogenous fibrinolysis (Fig. 2). Because of hepatic overproduction of acute-phase reactants such as fibrinogen, plasminogen activator inhibitor-1, and even CRP itself, the regulation of thrombosis by inflammatory mediators occurs not only in the local "solid state" of the plaque but in the fluid phase of blood as well. Both new studies on the multicentricity of vulnerable plaques reported within this issue of the Journal buttress the link between inflammation and plaque instability (12,13). C-reactive protein measured one month after an acute coronary syndrome correlates with the number of ruptured plaques observed by ultrasonography during the event (12). Although this relationship may reflect inflammation as a consequence rather than cause of plaque instability, it nonetheless strengthens the case that links inflammation and the vulnerability of atheromata.
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Figure 2 Mechanisms by which inflammation can promote plaque disruption and the acute coronary syndromes. The pathophysiology of the acute coronary syndromes depends on plaque disruption and the thrombotic/fibrinolytic balance of the plaque’s "solid state" and the blood’s "fluid phase." Inflammation regulates two major mechanisms of plaque disruption: a frank fracture of the fibrous cap and superficial erosion of the intimal surface. Inflammatory mediators also influence the thrombotic/fibrinolytic balance of both the plaque and the blood.
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Biomarker studies show that inflammation in the coronary tree of patients with acute coronary syndromes extends well beyond the site of the culprit lesion. The autopsy study by Mauriello et al. (13) underscores previous clinical findings in intact patients using myeloperoxidase as an index of inflammation (16). At autopsy, histopathologic hallmarks of inflammation characterize both culprit and non-infarct-related plaques in coronary arteries of those with fatal myocardial infarction. Coronary plaques in those who died noncoronary deaths tended to show lesser signs of inflammation (13).
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Clinical implications of the multicentricity of potentially unstable atheromata: act local, act global
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How should this snowballing evidence regarding inflammation and the multicentricity of potentially dangerous plaques inform our practice? Clearly, early invasive management, including local intervention on the culprit lesion in conjunction with contemporary pharmacologic "adjuvants," can improve outcomes of many with acute coronary syndromes. Still, recurrent cardiovascular events in this population remain unacceptably high. We must think not only locally, fixed by our traditional focus on the culprit lesion, but also consider globally the other vulnerable plaques in the coronary and other arteries of patients with acute coronary syndromes. The results of Tanaka et al. (12) and Mauriello et al. (13) add to the compelling case that beyond local therapy targeting today’s culprit lesion, all at-risk individuals also should have lifestyle and often pharmacologic intervention to "stabilize" plaques remote from the culprit lesion, thus curtailing recurrent events and improving long-term outcomes. Although reduction in coronary events in the statin "megatrials" of stable or apparently well populations requires many months or years of treatment, recent studies of aggressive statin administration to those with acute coronary syndromes have shown remarkably rapid reductions in recurrent event rates (17). Thus, acting "locally" with appropriate revascularization and "globally" with systemic treatments to address the multicentric plaques and their inflammatory basis may well afford an optimum approach to therapy of patients who present with acute coronary syndromes.
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Footnotes
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This work was funded in part by grants from the National Heart, Lung, and Blood Institute (Bethesda, Maryland) to Dr. Libby (HL-34636 and HL-56985) and the Fondation Leducq.
* 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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References
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2. Falk E, Shah P, Fuster V. Coronary plaque disruption Circulation 1995;92:657-671.[Free Full Text]
3. Davies MJ. Stability and instability: the two faces of coronary atherosclerosis. The Paul Dudley White Lecture, 1995 Circulation 1996;94:2013-2020.[Free Full Text]
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6. Nissen SE. Pathobiology, not angiography, should guide management in acute coronary syndrome/non-ST-segment elevation myocardial infarctionthe non-interventionist’s perspective. J Am Coll Cardiol 2003;41:103S-112S.[Abstract/Free Full Text]
7. 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]
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9. Kotani J, Mintz GS, Castagna MT, et al. Intravascular ultrasound analysis of infarct-related and non-infarct-related arteries in patients who presented with an acute myocardial infarction Circulation 2003;107:2889-2893.[Abstract/Free Full Text]
10. Schoenhagen P, Stone GW, Nissen SE, et al. Coronary plaque morphology and frequency of ulceration distant from culprit lesions in patients with unstable and stable presentation Arterioscler Thromb Vasc Biol 2003;23:1895-1900.[Abstract/Free Full Text]
11. Hong MK, Mintz GS, Lee CW, et al. Comparison of coronary plaque rupture between stable angina and acute myocardial infarctiona three-vessel intravascular ultrasound study in 235 patients. Circulation 2004;110:928-933.[Abstract/Free Full Text]
12. Tanaka A, Shimada K, Sano T, et al. Multiple plaque rupture and C-reactive protein in acute myocardial infarction J Am Coll Cardiol 2005;45:1594-1599.[Abstract/Free Full Text]
13. Mauriello A, Sangiorgi G, Fratoni S, et al. Diffuse and active inflammation occurs in both vulnerable and stable plaques of the entire coronary treea histopathologic study of patients dying of acute myocardial infarction. J Am Coll Cardiol 2005;45:1585-1593.[Abstract/Free Full Text]
14. Libby P. Inflammation in atherosclerosis Nature 2002;420:868-874.[CrossRef][Medline]
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16. 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]
17. Cannon CP, Braunwald E, McCabe CH, et al. Comparison of intensive and moderate lipid lowering with statins after acute coronary syndromes N Engl J Med 2004;344:1879-1887.
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A revolution in our...
"Vulnerable plaques": single or...