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J Br Heart 1993;69(Supplement):S 3-S 11 S 3 Atherosclerosis: what is it and why does it occur? Br Heart J: first published as 10.1136/hrt.69.1_Suppl.S3 on 1 January 1993. Downloaded from M J Davies, N Woolf The limits of what is encompassed by the luminal balloon injury or external compres- term atherosclerosis are fundamental to sion. A localised intimal smooth muscle pro- understanding the pathogenesis of the disease liferation occurs which simulates one and the ways in which clinical symptoms are component of the human atherosclerotic produced. plaque. Post angioplasty stenosis in humans is an example of such a response to injury by an atherosclerotic vessel but the lesion created is Basic definitions ofatherosclerosis different from a human plaque. Atherosclerosis is an intimal disease of arteries within a range of size from the aorta down to approximately 3 mm external diameter. The Clinical symptoms and atherosclerosis distribution of the disease is far from uniform; Plaque formation begins in early life, by the some arteries such as the internal mammary third decade advanced plaques are almost are largely spared while others such as the ubiquitous in Western populations. Therefore coronary arteries are at high risk. Similarly, in there is a long presymptomatic phase before the same individual the degree of coronary, the disease appears above the clinical horizon. cerebral, and carotid atherosclerosis is often The conversion from a person with athero- disparate. sclerosis, but no clinical symptoms, to a Atherosclerosis is a focal not a diffuse inti- patient with symptoms is an important break- mal disease. The focal nature can be appreci- point and may be largely determined by com- ated by examining the intimal surface of an plications most of which involve thrombosis opened artery, when discrete lesions or developing in association with plaques. Any plaques are visible. analysis of therapy should consider separately Lipid and the connective tissue matrix the prevention of plaque formation and the proteins are the two major components of reduction of plaque complications. plaques. The lipid may be extracellular or Clinical symptoms depend on four mecha- http://heart.bmj.com/ intracellular and both forms are usually found nisms. The primary process of atherogenesis in advanced plaques. Most lipid-containing (that is, lipid accumulation and connective foam cells are macrophages derived originally tissue matrix production by smooth muscle from circulating monocytes that have entered cells) may increase the volume of one or more the intima. Connective tissue matrix proteins key plaques so that they encroach on the are synthesised by smooth muscle cells. The lumen and become flow limiting. Second, a matrix protein is collagen. This is present plaque may enter an unstable phase and be in large amounts, conferring mechanical complicated by the formation of a thrombus. on September 25, 2021 by guest. Protected copyright. strength to the tissues and thereby holding the This thrombus may itself encroach on, or plaque together as a stable structure. occlude, the arterial lumen, or break away Some of the processes involved in athero- embolise and impact in smaller more distal sclerosis do occur in other vascular diseases, vessels. Third, though atherosclerosis is a and it is important that the definition of focal disease it is associated with a generalised atherosclerosis is not blurred or confused. abnormality of vascular tone in affected arter- The medial smooth muscle hypertrophy and ies that favours vasoconstriction often at in- British Heart subsequent fibrosis that occur in hypertension appropriate times such as on exercise. Finally, Foundation and affect smaller arteries are not athero- medial atrophy and destruction secondary to Cardiovascular Pathology Unit, St sclerosis. The medial calcification that occurs intimal atherosclerosis may lead to aneurysm George's Hospital with age in the lower limb arteries is not formation. Many patients suffer combinations Medical School, atherosclerosis. The use of the generic term of all these mechanisms. London often converted into the M J Davies "arteriosclerosis", lay term "hardening of the arteries", leads to University College and Middlesex Medical tremendous confusion by lumping all of these School ofMedicine, entities into one age-related arterial disease. Pathogenesis of atherosclerosis Histopathology Isolated intimal smooth muscle prolifera- Any consideration of what comprises human Department, London N Woolf tion is not atherosclerosis. Smooth muscle atherosclerosis raises the following salient is a to issues: Correspondence to proliferation general response injury by Professor M J Davies, the arterial wall and does occur in athero- (a) What is the origin of the intimal lipid? British Heart Foundation Cardiovascular Pathology sclerosis. But it is neither unique to nor (b) Why is there an intimal inflammatory Unit, St George's Hospital specific for atherosclerosis. Many animal response in which monocytes migrate into Medical School, Cranmer Terrace, London models of arterial disease have been created in and become permanently resident in the SW17 ORE. which vascular damage is induced by intra- intima? S 4 Davies, Woolf Figure 1 Diagram to Monocyte L ----SI show plasma low density MA LDL lipoprotein (LDL) entering the subendothelial space Br Heart J: first published as 10.1136/hrt.69.1_Suppl.S3 on 1 January 1993. Downloaded from and being oxidised, and the consequentformation of Endothelium a foam cell. iL _ _ Chemoattractant cz migration rzn C LOXIDISED LDL n o°°-,C:O J ----- 4) C C°~0? LIu 19 LI Activation N Division Phagocytosis 0 Foam cell formation 0 r-- EXTRACELLULAR 4 Cell death LIPID (c) How is smooth muscle proliferation and induces migration, initiates inflammatory collagen synthesis within the intima initi- responses, is toxic to monocytes, and is avidly ated and maintained? ingested by them via scavenger receptors.2 (d) What processes invoke thrombosis over Lipid uptake via this receptor is not down unstable plaques? regulated by intracellular lipid and the mono- Only when the answers to these questions, cyte becomes stuffed with lipid to become a all of which are discussed in this supplement, "foam cell". are known can truly rational therapy to con- Smooth muscle proliferation is controlled trol the progression of atherosclerosis be initi- by growth factors released from a wide range http://heart.bmj.com/ ated. of cells (fig 2) including platelets, endothelial In the broadest terms atherosclerosis is cells, macrophages, and other smooth muscle now recognised to be an immune/inflamma- cells. Inflammatory reactions readily induce tory response of the intima to injury.' It is growth factor production. All of these also being increasingly realised that the injury processes are considered in individual chap- is initiated by lipid. There is, however, a para- ters of this supplement. dox in that native plasma lipids, in particular Any consideration of human atherosclero- on September 25, 2021 by guest. Protected copyright. low density lipoproteins, though they freely sis cannot deny the role of lipid in intimal enter the intima, do not initiate an inflamma- injury. This lipid is largely plasma derived tory response, are not ingested by monocytes, and results from plasma concentrations that and do not damage tissue. Oxidation or alter- are greater than ideal for that individual. It is ation of low density lipoprotein will however important to remember that the plasma lipid radically alter this passive state (fig 1): oxi- profile of an individual is the result of interac- dised lipid is chemotactic for monocytes, tions between genetic and environmental fac- Figure 2 Influence of Platelets Endothelial cell growth factorproduction on smooth muscle proliferation. T Lymphocyte a 0 \>: oMacrophage Smooth muscle cells Atherosclerosis: what is it and why does it occur? S 5 tors the most important of the latter being FATTY STREAK containing: diet. Br Heart J: first published as 10.1136/hrt.69.1_Suppl.S3 on 1 January 1993. Downloaded from Foam cells 0 Intracellular lipid Progression ofplaques in humans An inherent drawback of any human necropsy study is that the state of the artery is seen at one moment only. Nevertheless, there are numerous morphological and histological descriptions of the different types of human plaque with speculation about how each is TRANSITIONAL PLAQUE related temporally. In reality the only safe containing: /~~~~~~~~~~ conclusion is that large plaques must evolve Foam cells 0 Intracellular lipid from smaller plaques but over what period of 1/I~~~~~~~/ Extracellular lipid time is unknown. The studies by Stary have provided many answers about plaque evolu- tion.' Detailed studies were made of the arteries in young subjects, from infancy to over 30 years of age, dying suddenly from non-cardiac disease. The cases were divided &z into cohorts by age. It was therefore possible ADVANCED FIBROLIPID PLAQUE to see the age at which lesions of any particu- containing: lar type first appeared, and the sequence of U~~ Extracellular lipid core plaque progression could be inferred. Smooth muscle cells The first observation was that in all human Foam cells 0 infants focal thickening of the intima develops due to smooth muscle proliferation. Stary has argued cogently that this is a ubiquitous adaptive response, and not early atherosclero- sis. Nevertheless, it does mean that the human coronary intima already contains smooth muscle cells, and is presensitised to COMPLICATED

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