OPERACIONES PARA EL ANÁLISIS DE ORO

It is now generally accepted that there are two main elements in the aetiology of ischaemic heart disease - atherogenesis and thrombogenesis, and there is evidence that coagulation factors are of importance in both these processes. Atherogenesis in its early stages can be explained as a protective mechanism associated with inflammation and repair. However, should these responses becom e excessive or prolonged, due to continued injury from w hatever cause, then they can both destroy sufficient tissue and induce such a chronic, inflammatory and proliferative response that they cause a pathological lesion, the atherosclerotic plaque. The ‘response to injury' hypothesis as a cause of

atherosclerosis has been modified over the past few years in the light of increasing observation and knowledge of the clinico-pathological consequences of the disease (Ross, 1986; Ross, 1993 ). Before this unifying hypothesis, there were two main hypotheses, not mutually exclusive, as to the pathogenesis of atherosclerosis; the ‘encrustation’ hypothesis and the ‘lipid’ hypothesis. Duguid, while examining recanalized thrombosed coronary arteries, noticed that the thrombosis extended along the vessel in the form of a thick inner lining which had organized and had the appearance of an intimai overgrowth. He concluded that mural thrombi had become incorporated into the atherosclerotic plaque (Duguid, 1946). A further study on mural thrombi in the aorta confirmed his findings but he also described a ‘variety of fine, fibrinous encrustations’ often not visible macroscopically which he also concluded becam e organized and w ere a source of intimai thickening (Duguid, 1948). In both studies he reasoned that the organized thrombus undenwent fatty change producing an appearance identical to atherosclerosis. The lipid hypothesis, put fonvard by Virchow, stressed the importance of infiltration of blood lipid into the arterial wall. It was argued that this formed complexes with acid mucopolysaccharides and that there was an imbalance between deposition and removal which resulted in accumulation of the lipid (reviewed by Fuster et al,1992).

The earliest recognisable lesion of atherosclerosis is the ‘fatty-streak’ which is an aggregation of lipid-rich macrophages and T lymphocytes within the intima. Stary showed that these lesions can be found in the coronary arteries of 4 5 % of infants

in the first 8 months of life (Stary 1989). There is then a decrease in the number of lesions but a further, steady increase from puberty, so that 65% of 12-14 year olds had lesions which included foam cells, lipid droplets in smooth muscle cells and extracellular lipid. 8% of children in this age group had preatheromatous lesions and there was a steady increase to 34% of 29 year olds who possessed these lesions (Stary, 1989). A recent report investigating atherosclerosis in youth has shown more extensive fatty streaks and raised lesions in both coronary arteries and aorta in those between 15-35 years with a prediabetic or early diabetic state as indicated by elevated glycohaemoglobin levels, and with obesity (McGill et al, 1995). Injury caused to the endothelium, especially at branch points in the arterial tree (Sadoshima,1979; Stary, 1989), result in a degree of dysfunction of the endothelium which leads to increased trapping of lipoprotein in the artery and the appearance of adhesive proteins on the surfaces of the endothelial cells. Monocytes and T lymphocytes attach to these proteins and migrate between the endothelial cells in response to cytokines and growth factors released by the altered endothelium, the adherent white cells and possibly underlying smooth muscle cells (Ross, 1993). As the monocytes and lymphocytes reach deeper beneath the endothelial surface, the monocytes become macrophages and accumulate lipid thus becoming foam cells and, together with the lymphocytes, form the ‘fatty-streak'. If injury, in its broadest sense, persists, then more advanced lesions can form and lead to the atherosclerotic plaque. Thus it can be seen that platelet-endothelial interactions are unlikely to be the initiating factors for the development of a plaque (Davies, 1990; Ross, 1993) but, as described below, they

have an important role in the advancement of plaques and the formation of thrombi.

The fundamental lesion of atherosclerosis is the intimai raised plaque which leads ultimately to both chronic stenosis of coronary arteries and episodic coronary thrombosis. The progression of atherosclerosis is through two main pathways, primary growth of the fatty streak and thrombosis, both major and minor. Primary growth of the fatty streak occurs in response to continued injury such as that resulting from exposure to oxidized low density lipoprotein or due to cigarette smoking or hypertension, by smooth muscle proliferation and lipid accumulation which form alternating layers and result in an intermediate lesion, the fibrofatty plaque (Ross, 1993). As the lesions accumulate more cells and the macrophages scavange the lipid, some of the lipid-laden macrophages may migrate back into the blood stream by pushing apart the endothelial cells (Ross, 1993). Exposure of the underlying lipid-filled macrophages, particulary at sites such as arterial branches and bifurcations where blood flow is turbulent, may produce thrombogenic areas that lead to the formation of platelet mural thrombi. These mural thrombi can then become incorporated into the plaque and lead to further growth of the lesion. In addition, such thrombi can release cytokines and growth factors. Platelet derived growth factor (PDGF) may be one of the principal growth regulatory hormones responsible for the migration of smooth muscle cells into the intima and for proliferation of existing collections of smooth muscle cells. There is evidence that one of the sources of PDGF is the macrophage (Ross et al, 1990)

and thus macrophages provide not only a site for platelet interactions but also a potent chemotactic and growth-stimulatory molecule to the intimai smooth muscle cells. Smooth muscle cells form new connective tissue matrix as well as proliferate and therefore play an important role in the progression of the plaque. Major thrombosis can also occur, often in association with plaque fissuring (Fuster et al,

1990; Davies, 1990), and this can lead to an acute clinical event.

The advanced plaque is m ade up of a lipid core and a collagenous cap separating the lipid from the lumen of the vessel. In the plaque is tissue factor, crystalline cholesterol and fragmented collagen with variable amounts of elastin and proteoglycans (Davies, 1990). The lipid core which is predominantly cholesterol, is either intracellular in foam cells, or extracellular as a pool of lipid. The margins of the lipid core also contain monocytes/macrophages concentrated at the shoulder area of the plaque. The normal cap consists of inten^/oven collagen strands with lacunae in which lie the smooth muscle cells, making it a strong structure. The smooth muscle cells produce and maintain the collagenous matrix which is important both for the integrity of the plaque and for that structural integrity to be maintained (Davies, 1990; Davies, verbal communication, 1994). The plaques can be either concentric in the artery which will produce a fixed degree of obstruction, or eccentric, where a crescent of normal vessel wall is retained allowing changes in the tone of medial smooth muscle which in turn will vary the degree of stenosis. From the study of necropsy specimens of men with stable angina, more than 50% of patients had at least one high-grade (>50% occlusion), eccentric and potentially

variable stenotic lesion (Hangartner et al, 1986). Examination of high-grade stenoses shows that 4 8 % were caused by fibrous, concentric plaques, which is higher than that found at lesser degrees of stenosis (Hangartner et al, 1986). This suggests that fibrous lesions may represent a progression of an earlier lipid-rich lesion that has undergone an episode of thrombosis and organisation (Hangartner et al, 1986).