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Terminology for high-risk and vulnerable coronary artery plaques

Johannes A Schaar, James E Muller, Erling Falk, Renu Virmani, Valentin Fuster, Patrick W Serruys, Antonio Colombo, Christodoulos Stefanadis, S Ward Casscells, Pedro R Moreno, Attilio Maseri, Anton F.W van der Steen
DOI: http://dx.doi.org/10.1016/j.ehj.2004.01.002 1077-1082 First published online: 2 June 2004

Abstract

A group of investigators met for two days in Santorini, Greece, to discuss progress in the field of identification and treatment of high risk/vulnerable atherosclerotic plaques and patients. Many differences in the manner in which terms are being utilized were noted. It was recognized that increased understanding of the pathophysiology of coronary thrombosis and onset of acute coronary syndromes has created the need for agreement on nomenclature. The participants spent considerable time discussing the topic and reached agreement on their own usage of the terms as described below. It is the hope that this usage might be of value to the larger community of scientists working in this field, and that widespread adoption of a common nomenclature would accelerate progress in the prevention of acute coronary events.

  • Vulnerable plaque
  • High-risk plaque
  • Acute coronary syndrome
  • Terminology

Report of a Meeting on the Vulnerable Plaque, June 17 and 18, 2003, Santorini, Greece

Introduction

A group of investigators met for two days in Santorini, Greece, to discuss progress in the field of identification and treatment of high risk/vulnerable atherosclerotic plaques and patients. Many differences in the manner in which terms are being utilized were noted. It was recognized that increased understanding of the pathophysiology of coronary thrombosis and onset of acute coronary syndromes has created the need for agreement on nomenclature.

The participants spent considerable time discussing the topic and reached agreement on their own usage of the terms as described below. It is the hope that this usage might be of value to the larger community of scientists working in this field, and that widespread adoption of a common nomenclature would accelerate progress in the prevention of acute coronary events.

Conceptual terms

Overview

The terms in Fig. 1 are proposed for use on a conceptual basis.

Fig. 1

Development of atherosclerosis and progression to thrombosis and clinical events.

The progression from asymptomatic atherosclerosis, to a high-risk/vulnerable plaque, to a thrombosed plaque, and to clinical events is presented. It is of note that the later stages of the progression may be repeated in a relatively short time interval as documented by the high short-term risk of a recurrent event in patients with acute coronary syndromes. This may be caused by rethrombosis of the lesion causing the index event, and/or the simultaneous occurrence of multiple high-risk/vulnerable plaques and/or thrombosed plaques, that have not previously caused symptoms. An acute coronary syndrome may be a clinical marker of widespread (multifocal) disease activity in the coronary arteries, possibly related to inflammation.1–8

The vulnerable patient

The primary clinical and preventive goal is to identify patients who are vulnerable to acute coronary thrombosis. Such patients are likely to have a high atherosclerotic burden, high-risk/vulnerable plaques, and/or thrombogenic blood.1 Traditional and newly identified risk factors 9 and imaging, both invasive and non-invasive, are likely to be of increasing utility in identifying such patients.10–15 It is well established that patients with the recent onset of an acute coronary syndrome remain at risk of suffering recurrent events in the weeks and months following their initial presentation.

There is an important need to improve diagnostic methods to identify vulnerable patients, and the plaques, which contribute to their increased risk.

High-risk/vulnerable plaques

Studies indicate that there are plaques at increased risk of thrombosis and rapid progression, which often lead to symptomatic disease. It is proposed that the terms “high-risk” or “vulnerable” be used as synonyms to describe a plaque that is at increased risk of thrombosis and rapid stenosis progression. The term “thrombosis-prone” may also be applied to such plaques.

At the present time, there is no widely accepted diagnostic method to prospectively identify such “high-risk”/“vulnerable” plaques. Until such information is provided, these terms should only be used to describe the concept and function of such plaques, and not their histologic basis.

In addition, the complicated thrombi that occur in non-disrupted predominantly fibrotic and severely stenotic plaques may well be dependent on a thrombogenic state which can be considered to be a condition of “high-risk blood”. Thus, an individual patient can be “high-risk” because of the presence of high-risk/vulnerable plaques and/or high-risk blood and/or an increased conventional risk factor profile.1

Histologic features of plaques causing coronary artery thrombosis

At present, the most detailed evidence concerning the plaques causing coronary thrombosis and rapid lesion progression, or symptomatic disease, is derived from autopsy studies.16–20 While this evidence is retrospective, the findings have established the nature of the lesions causing most clinical events. Such plaques are called “culprit lesions”. In most cases, culprit lesions can be identified by angiography combined with other clinical findings and/or at autopsy.

In the acute coronary syndromes, the culprit lesion is often a plaque complicated by thrombosis extending into the lumen.18–21 Such plaques are termed “thrombosed plaques”. In some cases, multiple thrombosed plaques may exist, only one of which is acting as the culprit lesion. A plaque may also develop thrombosis, which remains asymptomatic due to the presence of collaterals, or failure of the thrombus to significantly impede blood flow. However, such sub-clinical thrombosis may contribute to the rapid progression of stenosis.22,23 In cases of stable angina, the culprit lesion is often a non-thrombosed plaque.

The plaque, including its endothelium, is not the only determinant of thrombosis – the loss of the normal thrombotic–thrombolytic equilibrium in the circulating blood, and local flow conditions are also important contributors to thrombosis.

The following terms are proposed to describe the thrombosed plaques causing the coronary syndromes:

“A ruptured plaque”. A plaque with deep injury with a real defect or gap in the fibrous cap that had separated its lipid-rich atheromatous core from the flowing blood, thereby exposing the thrombogenic core of the plaque (Fig. 2). This is the most common cause of coronary thrombosis.17–19

Fig. 2

Ruptured plaque with thrombosis. (a) Cross-section of a coronary artery cut just distal to a bifurcation. The atherosclerotic plaque to the left (circumflex branch) is fibrotic and partly calcified whereas the plaque to the right (marginal branch) is lipid-rich with a non-occluding thrombus superimposed. (b) Higher magnification of the plaque–thrombus interface reveals that the fibrous cap over the lipid-rich core is extremely thin, inflamed and ruptured with a real defect – a gap – in the cap. Both arteries contain contrast medium injected postmortem. Trichrome stain, staining collagen blue and thrombus red.

“An eroded plaque”. A plaque with loss and/or dysfunction of the lumenal endothelial cells leading to thrombosis (Fig. 3). There is no structural defect (beyond endothelial injury) or gap in the plaque, which is often rich in smooth muscle cells and proteoglycans.20

Fig. 3

Eroded plaque with thrombosis. (a,b) Plaque erosion lesions from two different patients showing in (a) a lesion with lipid pool (Lp) and in (b) a necrotic core (Nc) with lumenal thrombi (Th). Note a thick fibrous cap above the necrotic core in (b) and a lack of communication between it and the lumenal. (c) A high power view of the lesion (shown in (a)), note that the lesion is rich in proteoglycan and smooth muscle cells beneath the thrombus.

“A plaque with a calcified nodule”. A heavily calcified plaque with the loss and/or dysfunction of endothelial cells over a calcified nodule (Fig. 4). This is the least common of the three causes of thrombosis described here.20

Fig. 4

Calcified nodule. (a) Section of the mid right coronary artery showing an eccentric lesion with extensive calcification (calcified plate) and surface calcified nodules with loss of fibrous cap and lumenal fibrin deposition (red). (b) High power view of the boxed area in (a) showing calcified nodules (*) intermingled, and on the surface of the nodules fibrin deposition can be observed.

Prospective identification of a high-risk/vulnerable plaque

There is considerable interest in the identification of plaques prior to the occurrence of thrombosis, since their early detection would lead to trials of novel preventive measures. As described above, it is proposed that such plaques be termed “high-risk”, “vulnerable” or “thrombosis-prone” plaques with the three terms used as synonyms.

On the basis of knowledge of the types of plaques identified as causes of thrombosis (ruptured, eroded and calcific nodule plaques), the following types of plaques are suspected to be high-risk/vulnerable plaques:

A plaque prone to rupture

Retrospective pathologic studies of plaque rupture with thrombosis suggest that prior to the event, the plaque was an inflamed, thin-cap fibroatheroma (TCFA) (Fig. 5).17–20,24–26

Fig. 5

Inflamed thin-cap fibroatheroma. (a) Coronary artery containing a large lipid-rich core that is covered by in thin fibrous cap. The lumen contains contrast medium injected postmortem. (b) Higher magnification reveals that the fibrous cap is severely inflamed, containing many macrophage foam cells, and extravasated erythrocytes are seen within the necrotic and avascular core just beneath the cap, indicating that the cap is ruptured nearby. Trichrome stain, rendering lipid colorless, collagen blue, and erythrocytes red.

The major components of such TCFA are:

  • A lipid-rich, atheromatous core.

  • A thin fibrous cap, with

    • macrophage and lymphocyte infiltration

    • decreased smooth muscle cell content

  • Expansive remodeling.

A plaque prone to erosion

Retrospective pathologic studies of plaque erosion with thrombosis suggest that, prior to the event, the plaque was often rich in proteoglycans, but, in most cases, lacked a distinguishing structure such as a lipid pool or necrotic core. If a lipid-rich core is present, the fibrous cap is usually thick and rich in smooth muscle cells.20 These plaques are often associated with constrictive remodeling.

A plaque with a calcified nodule

Retrospective pathologic studies of plaques with thrombosis covering a calcified nodule suggest that, prior to the event, the plaque appeared to be heavily calcified with a calcified nodule protruding into the lumen.20

While such plaques (an inflamed TCFA, a proteoglycan-rich plaque, and a plaque with a calcified nodule) are suspected to be high risk/vulnerable/thrombosis-prone plaques, they cannot be designated as such until prospective studies provide the necessary supporting data. Hence, an inflamed TCFA is best described as a “suspected” high risk/vulnerable plaque, since, while confirmatory data are lacking, its structure definitely resembles that of ruptured plaques.

Multiple new technologies to improve characterization of plaque in patients are under development.27–39 These techniques seek to identify the histologic features, discussed above, of plaques suspected to represent vulnerability, and provide additional information about plaques that has not heretofore been available (data on structure, composition, deformability, pathophysiology, metabolism, temperature, etc.). The novel information will expand the list of features suspected to represent high-risk/vulnerability.

All features suspected to represent high-risk/vulnerability require validation in longitudinal, prospective, clinical trials that will document the natural history of plaques with features suspected to make them high-risk and vulnerable.

If such trials are positive, it may then be possible to identify a high risk/vulnerable plaque prospectively in an individual patient.

It is also recognized that high-risk/vulnerability may vary over time. The use of systemic markers of inflammation may assist in assessment of the currently unknown time-course of risk.

It is hoped that the terminology defined above and summarized in Table 1 will diminish the need for the use of several other terms (plaque disruption, plaque fissuring and unstable plaque) that have been less specifically defined in previous usage.

View this table:
Table 1

Definitions

Culprit lesionA lesion in a coronary artery considered, on the basis of angiographic, autopsy or other findings, to be responsible for the clinical event. In unstable angina, myocardial infarction and sudden coronary death, the culprit lesion is often a plaque complicated by thrombosis extending into the lumen.
Eroded plaqueA plaque with loss and/or dysfunction of the lumenal endothelial cells leading to thrombosis. There is usually no additional defect or gap in the plaque, which is often rich in smooth muscle cells and proteoglycans.
High-risk, vulnerable and thrombosis-prone plaqueThese terms can be used as synonyms to describe a plaque that is at increased risk of thrombosis (or rethrombosis) and rapid stenosis progression.
Inflamed thin-cap fibroatheroma (TCFA)An inflamed plaque with a thin cap covering a lipid-rich, necrotic core. An inflamed TCFA is suspected to be a high-risk/vulnerable plaque.
Plaque with a calcified noduleA heavily calcified plaque with the loss and/or dysfunction of endothelial cells over a calcified nodule, resulting in loss of fibrous cap, that makes the plaque at high-risk/vulnerable. This is the least common of the three types of suspected high-risk/vulnerable plaques.
Ruptured plaqueA plaque with deep injury with a real defect or gap in the fibrous cap that had separated its lipid-rich atheromatous core from the flowing blood, thereby exposing the thrombogenic core of the plaque. This is the most common cause of thrombosis.
Thrombosed plaqueA plaque with an overlying thrombus extending into the lumen of the vessel. The thrombus may be occlusive or non-occlusive.
Vulnerable patientA patient at high-risk (vulnerable, prone) to experience a cardiovascular ischemic event due to a high atherosclerotic burden, high-risk/vulnerable plaques, and/or thrombogenic blood.

Treatment

Potential new treatments with systemic, regional, and local approaches have been proposed and also require evaluation in clinical trials.40,41 Improved identification and treatment of high-risk/vulnerable plaques is a goal of great importance since it would result in major decreases in coronary artery disease morbidity and mortality.

Participants in the meeting

The meeting was convened and directed by Drs. Patrick W. Serruys, Antonio Colombo, Christodoulos I. Stefanadis, and Johannes Schaar.

Drs. Erling Falk, Valentin Fuster, James Muller, and Renu Virmani served on the drafting committee for terminology.

The following participants contributed to the development of, and support the consensus terminology described above.

John A. Ambrose, Nico Bruining, George Dangas, Zahi A. Fayad, Pim J. de Feyter, Enrique P. Gurfinkel, Frank J.H. Gijsen, Antoinette ten Have, Victoria L.M. Herrera, Ik-Kyung Jang, Bob Jones, Dominique P. de Kleijn, Chris L. de Korte, Rob Krams, Richard T. Lee, Lars Lind, Frits Mastik, William McPheat, Gerard Pasterkamp, Sweder W.E. van de Poll, Evelyn Regar, Axel Schmermund, Bernward A. Schoelkens, Jean-Francois Tanguay, Shankar Vallabhajosula, Glenn Van Langenhove, Stefan Verheye, Jolanda J. Wentzel, Robert L. Wilensky, Andrew Zalewski.

References

  1. [1]
  2. [2]
  3. [3]
  4. [4]
  5. [5]
  6. [6]
  7. [7]
  8. [8]
  9. [9]
  10. [10]
  11. [11]
  12. [12]
  13. [13]
  14. [14]
  15. [15]
  16. [16]
  17. [17]
  18. [18]
  19. [19]
  20. [20]
  21. [21]
  22. [22]
  23. [23]
  24. [24]
  25. [25]
  26. [26]
  27. [27]
  28. [28]
  29. [29]
  30. [30]
  31. [31]
  32. [32]
  33. [33]
  34. [34]
  35. [35]
  36. [36]
  37. [37]
  38. [38]
  39. [39]
  40. [40]
  41. [41]
View Abstract