A Definition of Initial, Fatty Streak, and Intermediate Lesions of Atherosclerosis

The compositions of lesion types that precede and that may initiate the development of advanced atherosclerotic lesions are described and the possible mechanisms of their development are reviewed. While advanced lesions involve disorganization of the intima and deformity of the artery, such changes are absent or minimal in their precursors. Advanced lesions are either overtly clinical or they predispose to the complications that cause ischemic episodes; precursors are silent and do not lead directly to complications. The precursors are arranged in a temporal sequence of three characteristic lesion types. Types I and II are generally the only lesion types found in children, although they may also occur in adults. Type I lesions represent the very initial changes and are In this report we characterize lesions that precede and may initiate the development of advanced atherosclerotic lesions. Advanced lesions are defined as those in which an accumulation of lipid in the intima is associated with intimal disorganization and thickening, deformity of the arterial wall, and often with complications such as fissure, hematoma, and thrombosis. Advanced lesions may produce symptoms, but the lesions that precede them are clinically silent. This report is the second in a series of three. The first provided a definition of the arterial intima and its atherosclerosis-prone regions. The third report will describe the different types of advanced atherosclerotic lesions and will provide a histological classification of all human atherosclerotic lesion types. The precursors of advanced lesions are divided into three morphologically characteristic types. Both type I and II lesions represent small lipid deposits in the arterial intima, and type II includes those lesions generally referred to as fatty streaks. Type III represents the stage that links type II to advanced lesions. The term "early lesions" is sometimes used for type I and II lesions. "Early" implies that these lesions are followed by "later" (advanced) lesions. It also implies that they are found early in life. Neither implication is necessarily "A Definition of Initial, Fatty Streak, and Intermediate Lesions of Atherosclerosis" was approved by the American Heart Association SAC/Steering Committee on October 20, 1992. Requests for reprints should be sent to the Office of Scientific Affairs, American Heart Association, 7272 Greenville Ave, Dallas, TX 75231-4596. recognized as an increase in the number of intimal macrophages and the appearance of macrophages filled with lipid droplets (foam cells). Type II lesions include the fatty streak lesion, the first grossly visible lesion, and are characterized by layers of macrophage foam cells and lipid droplets within intimal smooth muscle cells and minimal coarse-grained particles and heterogeneous droplets of extracellular lipid. Type III (intermediate) lesions are the morphological and chemical bridge between type II and advanced lesions. Type III lesions appear in some adaptive intimal thickenings (progressionprone locations) in young adults and are characterized by pools of extracellular lipid in addition to all the components of type II lesions. (Arterioscler Thromb. 1994;14:840-856.) true, although types I and II are generally the only lesions present in children, and there is evidence that certain type II lesions are prone to proceed to type III and more advanced lesions. The distinctions that separate individual lesion types are based on consistent morphological characteristics, which indicate that each type may stabilize temporarily or permanently and that progression to the next type may require an additional stimulus. The morphological features of each type of lesion and the time at which each tends to occur and predominate in the course of a human life are strong presumptive evidence that types I, II, and III are successive stages in the development of atherosclerosis. Each type is focal, relatively small, and contains abnormal accumulations of lipoproteins and cholesterol esters. Increased numbers of cells, mainly macrophages, and accumulations of lipid droplets, mainly within macrophages, can be demonstrated microscopically. Changes in the composition of the matrix and disruption of the intimal architecture are minimal or absent. The media adjacent to the lesions is not diseased, nor is the adventitia affected. In contrast, advanced lesions generally contain extracellular lipid deposits large enough to disrupt and deform the intima; in very advanced stages, these deposits may modify the underlying media and adventitia. In many lesions that have reached advanced stages, thrombotic mechanisms of progression become predominant, leading to accelerated progression and often clinically overt atherosclerosis. These subsequent mechanisms will be defined in the next report. by gest on O cber 3, 2017 http://atvajournals.org/ D ow nladed from AHA Scientific Council A Definition of Atherosclerotic Lesions 841 The clinical significance of lesion types I, II, and III lies in their role as the silent precursors of possible future disease. Recognition of the period of life in which type III lesions begin should lead to concentrated preventive measures at, or preferably before, that age. Similar lesions in laboratory animals regress completely when serum cholesterol is reduced. This report deals largely with lesions in the coronary arteries and aorta because information on initial and early lesions in other arteries is scant. Since the methods used in biological studies of arteries influence interpretation of the data obtained, technical problems are briefly discussed in the preceding report. The same problems apply to the studies reviewed here. Because it is impossible to determine the composition of an initial lesion and then to follow its behavior over a lifetime, the studies that provide evidence concerning the natural history of atherosclerosis use data from lesions of many persons of different ages. The general approach has been to characterize the intima and lesions in precisely defined locations of the arteries in children and then to study the same locations in adolescents and adults. The locations chosen for study are known for their predisposition to develop clinical lesions, the so-called progression-prone or advanced lesion-prone regions of arteries. In the following sections some mainly experimental data on the pathogenesis of atherosclerotic lesions and particularly on their initiation are summarized. Pathogenesis of Lesion Initiation Evidence That Atherogenic Lipoproteins