has in the pathogenesis of the acute ischaemic syndromes of CHD, a predisposition to arterial thrombosis may exist as a risk factor for the different stages leading to the clinical expression of CHD. That is, thrombogenic risk factors may be important in the pathogenesis of atherosclerotic plaque formation as well as obstructive thrombo sis.
1.5.1 Coronary Thrombosis
As discussed above, thrombus superimposed on a fissured atherosclerotic plaque is usually present in the coronary artery supplying infarcted myocardium, 1,3,13 and
other acute coronary artery syndromes.208'210
1.5.2 Progression of CAD
The formation of severe atherosclerotic lesions may develop following recurrent episodes of localised thrombus formation, 10,11 with concomitant fragmentation of
thrombus. 115 Support for this concept arises from a number of pathological studies.
Microemboli and/or microinfarcts found in the myocardium distal to evolving coro nary thrombi, indicate the dynamic aspect of intravascular thrombosis.3,25,211 Fibrin
appears to be a major component of atherosclerotic lesions,212 which is compatible
with the incorporation of fibrin into the lesion following recurrent mural thrombosis. Alternatively, this fibrin may be formed from fibrinogen found within the intima. 34
In addition, intimal haemorrhage, a well known complication of atherosclerosis,213"
215 may cause rapid progression of atherosclerotic lesions. These haemorrhages may
be due to intimal dissection from the lumen, 2,11,216 or arise as a sequelae to neo-
vascularisation of the intima.213,214,217,218
In an autopsy study of the evolution of atherosclerotic lesions in young individuals, fibrous caps were found to form slowly.9 When platelets and fibrin accumulated on
the endothelial surface, the caps thickened and reduced the arterial lumen quickly. The deposition of platelets and fibrin on the surface of atherosclerotic lesions was thought to be the cause of the collagenous caps and the main cause of the rapid progression to lumen stenosis. This was found to be an uncommon process up to the third decade when most caps were thinner with little collagenous thickening when compared with cases having thrombotic deposits.9 The latter were observed in the
third decade of life in some subjects and were episodic in their occurrence.9 This
autopsy study provides evidence of lesion progression consistent with angiographic studies showing rapid lesion development in areas of minimal disease. On the other hand, lipid cores often begin to develop soon after puberty and increase linearly over time.9 Proliferation of smooth muscle cells and synthesis of collagen forming the cap
develops after a lipid core evolves.9
1.5.3 Extent and Severity of CAD
The concept that coronary thrombosis and CHD may not be the simple and direct result of the presence of atherosclerosis alone, has been previously considered on the basis of results from historical and epidemiological necropsy studies. 11,34' 37 The
suggestion that "ischaemic heart disease is not a simple, proportional function of coronary atherosclerosis"37 is an important concept in understanding the aetiology of
CHD. There are a significant number of individuals who have AMI and are subse quently shown to have angiographically near normal, or normal, coronary arteries, particularly younger patients.219"222 Younger patients also have less extensive coro nary atheroma.207 Furthermore, in necropsy studies, substantial differences in the frequency of myocardial fibrosis have been observed which correspond only mod erately to the frequency of coronary occlusions, and which do not relate at all to the frequency of lesser narrowing of the coronary lumen.35 If plaque fissuring, subse quent coronary thrombosis, and hence coronary occlusion were related to the arterial burden of atherosclerosis alone, it would be reasonable to assume some quantitative association between the extent of myocardial fibrosis due to Mis and coronary ather osclerosis. When the prevalence of coronary atherosclerosis recorded in postmor tems in the United Kingdom for the years 1908-13 was compared with that for the years 1944-49, there appeared to be some reduction in the amount of mural atheros clerosis in the population, while at the same time there was a tenfold increase in deaths from ischaemic heart disease.37 Obviously there must be other factors operat ing to produce CHD, other than simply the presence of atherosclerosis, albeit an important prerequisite.
1.5.4 Circadian Variation of Coagulation and Myocardial Ischeamia
Evidence now exists that AMI is not entirely or necessarily a random event occur ring at any time of the day. The circadian variation in the occurrence of AMI is well documented,223,224 the peak onset being between 6.00am and 12.00am.223 The au thors of these publications have documented an extensive number of older studies from throughout the world showing a remarkable similarity in the time of onset of rest angina and AMI. In addition to the circadian variation in clinically apparent and also asymptomatic CHD, there is increasing support for the presence of a circadian rhythm of the some of the components of thrombus formation, predisposing to a hypercoaguable state during the peak period for the onset of AMI. Numerous chang es occur during this period. A decrease in fibrinolytic activity of blood,225 increased
in vitro platelet aggregation,226 increased in vivo platelet activation in patients with atherosclerotic vascular disease,227 increased metabolism of pharmacological doses of heparin,228 and also increased blood fibrinogen levels in normal subjects226 have all been demonstrated. Thus, an increase in coagulability may be sufficient to coin cidentally sustain thrombus formation on the random occurrence of plaque rupture. Alternatively, an environmental and/or heritable factor may be required to create a sufficiently hypercoaguable state.
1.5.5 Age and CAD
The distribution of coronary atherosclerosis in the elderly is similar to that in young er age g ro u p s,229 although there are d ifferen ces in the p ath o lo g ical composition.230,231 Increased calcification and fibrosis, and atrophy of the media occur with aging.229 The incidence of CAD increases from approximately 46% in the 6th decade, to 84% in the 9th decade.232 Not surprisingly, the Framingham Study demonstrated a continuing increase in the frequency of the clinical events of CHD with age in women. However, in men the incidence of clinical events declined in the 7th and 8th decades, but subsequently rose in the 9th and 10th decades.205 The increased risk of CHD in males occurred in the 6th decade in the Framingham
Study, but in the 7th decade in eastern Finland.233 If the acute occlusive syndromes of clinical CAD were a random event related to the chance occurrence of plaque rupture, then there should be a progressive, unabated rise in the incidence of CHD with age since the occurrence of coronary atherosclerosis increases with age. The prevalence, however, may decline due to attrition from premature deaths.
In the very elderly, the incidence of clinical CAD is approximately equal in men and women.205,234 Indeed, age is the strongest cardiovascular risk factor.202,235 Further more, in patients who die suddenly of ischaemic heart disease, coronary thrombosis in the presence of significant CAD was found more frequently in a younger age group, despite a tendency for the older group to have more extensive disease.36 Although, more than 60% of sudden deaths in the elderly are associated with severe CAD,229 thrombus formation may play less of a role in the older patient with CHD manifestations.36 Nevertheless, the relative contributions of stenosis, thrombosis and arterial spasm in the development of acute ischaemic syndromes in the elderly are unknown.229