When Is Atherosclerosis Not Atherosclerosis?
To the Editor:
When is atherosclerosis not atherosclerosis? In the last decade, there have been 2 revolutions in the study of atherosclerosis. On the one hand, a more sophisticated appreciation of the relationship between the morphology and fate of human atherosclerotic plaques and clinical outcomes has been developed. On the other hand, the blossoming of mouse genetics has allowed us the possibility of exploring prospectively the mechanisms that lead to various types of atherosclerotic lesions. These advances, in the view of the author, should compel us as experimentalists, mainly using murine models, to fashion a more nuanced view and description of experimental atherosclerosis.
The last issue of Arteriosclerosis, Thrombosis, and Vascular Biology contained a review on a comprehensive morphologic classification scheme for atherosclerotic lesions, which was derived by studies of lesions from autopsy examinations of sudden coronary deaths.1 There was also a commentary by Dr H. Stary2 updating the natural history and histological classification of human atherosclerotic lesions. This follows several prior publications by the lesions committee of the Arteriosclerosis Council of the American Heart Association. The update of the histological classification by Stary2 refers to the early stages I, II, and III of lesions, which are made up mostly of macrophage foam cells, with perhaps some extracellular lipid as well. He points out that these stages can regress to normal and thus are not necessarily evolving to mature atherosclerotic lesions. The morphological classification discussed by Dr Virmani and colleagues,1 refers to these early foam cell lesions as “nonatherosclerotic intimal lesions.” These are foam cell lesions without a necrotic core or fibrous cap. These are the classical fatty streaks for which they have suggested the term “intimal xanthoma.” Such lesions (Virmani et al, Table 2B) “usually regress.” What distinguishes these lesions from progressive atherosclerotic lesions is the presence of necrotic core, fibrous cap, luminal thrombosis, and smooth muscle cells in a proteoglycan rich matrix. Because the fatty streaks or “intimal xanthomata” often regress and may not progress to mature atherosclerotic lesions, one may ask whether it is now reasonable to refer to these early lesions as atherosclerosis. Not only do they not bear the hallmarks of mature atherosclerosis, but they also are not associated with any significant clinical sequelae.
It is the goal of the experimentalists using rabbits or mice to learn about the evolution of the clinically significant atherosclerotic plaque. Yet for reasons of ease of study and rapidity of read out, a great proportion of the murine studies purported to be of atherosclerosis actually examine fatty streaks or intimal xanthomata. These are also very often studied in the proximal aorta or aortic root, where foam cell–rich lesions predominate, especially if the study time is less than 12 to 16 weeks in the mouse, depending upon the model. These lesions may be examined histologically, but often investigators assess lesion extent by en face staining of the whole aorta with lipid soluble dyes. Alternatively, lesion extent may be measured by enrichment of the aorta with cholesterol or steryl ester. These are perfectly reasonable measures of lipid deposition in the aorta but do not necessarily portend mature atherosclerosis. The nature of the lesions usually found in the various commonly used genetic and nutritional models or “atherosclerosis” are quite different, even though they are designated similarly, eg, the apoE−/− mice fed on chow or Western diet versus the lesions in LDL receptor negative mice fed a Western diet. The animal models of atherosclerosis generally involve manipulation of the plasma cholesterol and lipoprotein metabolism and levels. In these cases, the pathogenesis of atherosclerosis probably depends on the initial formation of macrophage foam cells. There is good reason to expect that most fatty streaks in the apoE-deficient mouse will progress to more complex plaques, although this is not necessarily the case with all models, nor is the time frame of such progression, if it occurs, likely to be the same. Furthermore, as yet more subtle models of vascular lesions are developed, the distinctions between fatty streaks (intimal xanthomata) and atherosclerosis will probably become more cogent.
Given the regressibility of predominantly fatty lesions, the fact that such lesions are not per se pathophysiologically significant, and the need to understand the evolution of fatty streaks or “intimal xanthomata” to more mature progressive atherosclerotic lesions that are clinically and pathophysiologically significant, I wish to suggest to the editor that the use of the term “atherosclerosis” in the title or abstract of published papers in the Journal be reserved for those studies demonstrating the presence of at least some of the hallmarks of the progressive atherosclerotic lesions. These terminological distinctions would enhance the precision of our thinking about the pathogenesis, evolution, and significance of the mature atherosclerotic lesion.
Virmani R, Kolodgie F-D, Burke AP, Farb A, Schwartz SM. Lesions from sudden coronary death: a comprehensive morphologic classification scheme for atherosclerotic lesions. Arterioscler Thromb Vasc Biol.. 2000;20:1262–1275.
Stary HC. Natural history and histological classification of atherosclerotic lesions: an update. Arterioscler Thromb Vasc Biol.. 2000;20:1177–1178.