Circulation, Vol 87, 1781-1791, Copyright © 1993 by American Heart Association
BG Brown, XQ Zhao, DE Sacco and JJ Albers
The consensus of evidence from angiographic trials demonstrates both
coronary artery and clinical benefits from lowering of lipids by a variety
of regimens. The findings of reduced arterial disease progression and
increased regression have been convincing but, at best, modest in their
magnitude. For example, among those treated intensively in FATS, the mean
improvement in proximal stenosis severity per patient was < 1% stenosis,
and only 12% of all lesions showed convincing regression. In view of these
modest arterial benefits, the associated reductions in cardiovascular
events have been surprisingly great. For example, coronary events were
reduced 75% in FATS; this was entirely a result of a 93% reduction in the
likelihood that a mildly or moderately diseased arterial segment would
experience substantial progression to a severe lesion at the time of a
clinical event. We believe that the magnitude of the clinical benefit is
best explained in terms of this observation, according to the following
lines of reasoning. Clinical events most commonly spring from lesions that
are initially of mild or moderate severity and then abruptly undergo a
disruptive transformation to a severe culprit lesion. The process of plaque
fissuring, leading to plaque disruption and thrombosis, triggers most
clinical coronary events. Fissuring is predicted by a large accumulation of
core lipid in the plaque and by a high density of lipid-laden macrophages
in its thinned fibrous cap. Lesions with these characteristics constitute
only 10-20% of the overall lesion population but account for 80-90% of the
acute clinical events. In the experimental setting, normalization of an
atherogenic lipid profile substantially decreases the number of lipid-
laden intimal macrophages (foam cells) and depletes cholesterol from the
core lipid pool. In the clinical setting, intensive lipid lowering
virtually halts the progression of mild and moderate lesions to clinical
events. Thus, the reduction in clinical events observed in these trials
appears to be best explained by the relation of the lipid and foam cell
content of the plaque to its likelihood of fissuring and by the effects of
lipid-lowering therapy on these "high-risk" features of plaque morphology.
The composite of data presented here supports the hypothesis that
lipid-lowering therapy selectively depletes (regresses) that relatively
small but dangerous subgroup of fatty lesions containing a large lipid core
and dense clusters of intimal macrophages. By doing so, these lesions are
effectively stabilized and clinical event rate is accordingly decreased.
ARTICLES
Lipid lowering and plaque regression. New insights into prevention of plaque disruption and clinical events in coronary disease
Department of Medicine, University of Washington School of Medicine, Seattle.
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