An imbalance between the supply of oxygen (and other essential myocardial nutrients) and the myocardial demand for these substances results in myocardial ischaemia. The causes are as follows: .
1) The coronary blood flow to a region of the myocardium may be reduced by an obstruction due to:
(e) Coronary ostial stenosis (e.g. syphilis)
(f) Coronary arteritis (e.g. ‘polyarteritis)
2 There can be a decrease in the flow of oxygenated blood to the myocardium due to:
(c) Hypotension causing decreased coronary perfusion pressure
3 An increased demand for oxygen may occur owing to an increase in cardiac output (e.g. during exercise or in thyrotoxicosis) or myocardial hypertrophy (e.g. from aortic stenosis or hypertension).
In types 2 and 3, ischaemia may occur despite normal coronary arteries. In a small number of cases, ischaemia develops despite norma,Lcoronarv arteries and a normal ~ for oxygen. This condition is known drome X and is possibly caused by an abnormality of small coronary vessels, resulting in a reduction of coronary are flow reserve.
The most common cause of ischaemic heart disease is coronary atheroma, which causes a fixed obstruction to coronary blood flow. Variations in the tone of smooth muscle in the wall of a coronary artery may add an important element of dynamic or variable obstruction. Sometimes an extreme increase in coronary tone may produce coronary spasm and severely reduced coronary blood flow in the absence of any underlying coronary atheroma.
This condition, which affects medium-sized arteries, is characterized by the development of atherosclerotic plaques. Such a plaque consists of a necrotic core, rich in cholesterol and other lipids, surrounded by smooth muscle cells and fibrous tissue.
The pathogenesis of atherosclerosis is complex. The two major hypotheses of the nineteenth century (the ‘incrustation’ and ‘lipid’ hypotheses) Qa”,e been combined to form the ‘response to injury’ hypothesis. Experimentally, this divides the formation of atheroma into three stages.
Stage I consists of functional alteration of endothelial cells without substantial morphological changes. In stage II there is endothelial denudation and intimal damage with intact internal elastic lamina and in stage III there is endothelial damage to both intima and media.
Stage I injury may occur at branching points of vessels and can be caused by a high circulating cholesterol, vasoactive amines, immunocornplexes, infection and chemical irritants in tobacco smoke. This leads to an accumulation of lipids and macrophages at these sites of injury. Toxic products released by the latter lead to stage II damage with adhesion of platelets. There is a proliferation of smooth muscle cells, disruption of the endothelium and thrombus formation. This thrombus becomes organized and leads to the development of an atherosclerotic plaque. Cholesterol-rich material accumulates within the plaque and this becomes surrounded by a fibrotic cap which narrows the lumen of the vessel. The rate of development of these lesions is variable and depends on risk factors (see below). Fissuring and disruption of the plaque triggers the release of mediators, e.g. serotonin, ADP, and the formation of a thrombus leading to total occlusion of the vessel. These thrombotic occlusions can resolve spontaneously or can be treated with thrombolytic therapy.
RISK FACTORS FOR CORONARY ARTERY DISEASE
A number of ‘risk’ factors are known to predispose to coronary artery disease. Some of these, such as age, sex and family history, cannot be modified, whereas other major risk factors, such as serum cholesterol, smoking habits and hypertension, can be changed.
Age Atherosclerosis develops progressively as age advances. It is rarely present in early childhood, except in familial hyperlipidaernia, but it is often detectable in post-mortem specimens of young men between 20 and 30 years. It is almost universal in the elderly in the Western World.
Men are more affected than premenopausal women. However, after the menopause the incidence of atheroma in women becomes similar to that in men. The cause of this difference in incidence is not clearly understood.
Coronary artery disease is often found in several members of the same family. Because the disease is so prevalent and because other risk factors are familial, it is uncertain whether family history is an independent risk factor.
Atherosclerotic plaques contain cholesterol. A high serum cholesterol, especially when associated with low values of high-density lipoproteins (HDLs), is strongly associated with coronary atheroma. High triglyceride levels are less definitely linked with coronary atheroma. Familial hypercholesterolaernia, familial combined hyperlipidaernia and remnant hyperlipidaemia are associated with an increased risk of coronary atherosclerosis. Measurement of total cholesterol, HDL cholesterol with calculation of low-density lipoprotein (LDL) cholesterol and HDL ratio as well as triglycerides should be performed on all patients. Lowering the serum cholesterol has been shown to decrease the incidence of coronary artery disease and slow the progression of coronary atheroma.
In men, the risk of developing coronary artery disease is directly related to the number of cigarettes smoked. This relationship is less certain, but still important, in women, and in cigar and pipe smokers. The risk from smoking declines to almost normal after 10 years of abstention.
Both systolic and diastolic hypertension are associated with an increased risk of coronary artery disease. The risk is the same for men and women. Reduction of blood pressure with hypotensive therapy reduces the risks of a cerebrovascular accident but does not affect the risk of cardiac events such as myocardial infarction. Other factors Lack of exercise increases the risk of coronary artery disease, and regular exercise probably protects against its development. Diabetes mellitus, or even just an abnormal glucose tolerance test, is associated with vascular disease. Obesity is certainly associated with coronary artery disease, but it is not certain whether obesity itself is independently linked with the condition.
Recently it has been shown that possession of an ACE gene polymorphic marker (D) (deletion of a 287 base pair Alu repeat sequence) has been shown to be a risk factor for coronary artery disease. DD genotype, which is associated with higher concentrations of circulating ACE, is significantly more frequent in people who have had a myocardial infarction than in age-matched controls. This is seen particularly in young people assumed to be at low risk by standard criteria.
A certain kind of personality type known as ‘type A’, which is characterized by unsuccessful aggression, ambition, compulsion and competitiveness, is said to be associated twice as frequently with coronary artery disease than is ‘type B’ (the converse of type A). Gout, oral contraceptives, alcohol and soft water have also been suggested as risk factors for coronary atheroma. It is clear that many factors influence the development of coronary atheroma. It is not certain that modification of any of these can substantially reverse the established atherosclerotic process.