A Definition of Advanced Types of Atherosclerotic Lesions and a Histological Classification of Atherosclerosis

Abstract

This report is the continuation of two earlier reports that defined human arterial intima and precursors of advanced atherosclerotic lesions in humans. This report describes the characteristic components and pathogenic mechanisms of the various advanced atherosclerotic lesions. These, with the earlier definitions of precursor lesions, led to the histological classification of human atherosclerotic lesions found in the second part of this report. The Committee on Vascular Lesions also attempted to correlate the appearance of lesions noted in clinical imaging studies with histological lesion types and corresponding clinical syndromes. In the histological classification, lesions are designated by Roman numerals, which indicate the usual sequence of lesions progression. The initial (type I) lesion contains enough atherogenic lipoprotein to elicit an increase in macrophages and formation of scattered macrophage foam cells. As in subsequent lesion types, the changes are more marked in locations of arteries with adaptive intimal thickening. (Adaptive thickenings, which are present at constant locations in everyone from birth, do not obstruct the lumen and represent adaptations to local mechanical forces). Type II lesions consist primarily of layers of macrophage foam cells and lipid-laden smooth muscle cells and include lesions grossly designated as fatty streaks. Type III is the intermediate stage between type II and type IV (atheroma, a lesion that is potentially symptom-producing). In addition to the lipid-laden cells of type II, type III lesions contain scattered collections of extracellular lipid droplets and particles that disrupt the coherence of some intimal smooth muscle cells. This extracellular lipid is the immediate precursor of the larger, confluent, and more disruptive core of extracellular lipid that characterizes type IV lesions. Beginning around the fourth decade of life, lesions that usually have a lipid core may also contain thick layers of fibrous connective tissue (type V lesion) and/or fissure, hematoma, and thrombus (type VI lesion). Some type V lesions are largely calcified (type Vb), and some consist mainly of fibrous connective tissue and little or no accumulated lipid or calcium (type Vc).

Atherogenic Lipids Induce Adhesion of Human Coronary Artery Smooth Muscle Cells to Macrophages by Up-regulating Chemokine CX3CL1 on Smooth Muscle Cells in a TNFα-NFκB-dependent Manner

“…They also suggest an explanation for organization and retention of foam cells in plaque involving heterotypic adhesive interactions with smooth muscle cells. Consistent with this, electron microscopy of atherosclerotic lesions has shown that many SMC are in fact in contact with foamy macrophages (19,20), and CX3CL1 and CX3CR1 have been shown to be expressed and to co-localize in plaque (17,18). Thus, our study provides new insight into potential cellular and molecular mechanisms underlying the genetic link established previously between the CX3CL1-CX3CR1 axis and atherosclerosis.…”

“…However, it is important to emphasize that the hallmark of the atherosclerotic microenvironment is the presence of oxLDL and its bioactive derivatives (3), which trigger monocyte differentiation to foamy macrophages (46,47). In human atherosclerotic plaque, foamy macrophages are the major cell type of the monocyte-macrophage lineage that are in direct contact with SMC (19,20). Moreover, our adhesion studies demonstrate that CX3CR1 ϩ monocytes adhere very poorly to CX3CL1…”

“…Moreover, CX3CL1 on smooth muscle cells (SMCs) was found to co-localize with macrophage CX3CR1 (18), consistent with close proximity of these cells in human plaque (19,20). In atherosclerosis, both cell types are exposed to atherogenic lipids (3) that could affect gene expression and function.…”

Development of Human‐Like Advanced Coronary Plaques in Low‐Density Lipoprotein Receptor Knockout Pigs and Justification for Statin Treatment Before Formation of Atherosclerotic Plaques

“…To evaluate the extent of atherosclerosis, we classified all lesions into 6 types according to the Stary criteria but with some modification 22. In short, type I to III lesions were considered early‐stage atherosclerotic lesions (type I: seen as intimal thickening; type II: consisting primarily of layers of macrophage foam cells and lipid‐laden smooth muscle cells; type III: seen as scattered collections of extracellular lipid droplets), and type IV to VI lesions were considered advanced lesions with a lipid core (type IV: atheroma; type V: fibroatheroma; type VI: a type IV or type V lesion with fissure, hemorrhage, thrombus, or calcification).…”

Ratiometric Activatable Cell‐Penetrating Peptides Provide Rapid In Vivo Readout of Thrombin Activation

“…[21,[26][27] The non-ratiometric thrombin ACPPs also showed a correlation between thrombin activity and the severity and spatial extent of damage in the ischemic core of stroke. [22] The ratiometric ACPPs should be even better for such studies on disease etiology, because they signal thrombin activity more quickly and more reliably.…”