International Task Force for Prevention of Coronary Heart Disease

International Task Force for Prevention of
Coronary Heart Disease

CORONARY HEART DISEASE: REDUCING THE RISK

It is likely that research currently under way in the areas of genetics, molecular biology, vascular physiology, and non-invasive imaging of arteries will improve our ability to assess risk of CHD in the future. Such areas include:

2.8.1 Genetic polymorphisms and abnormalities

Much information now exists on polymorphisms and abnormalities in genes affecting lipoprotein and glucose metabolism, and blood pressure. However, our knowledge of the impact of such polymorphisms on CHD, and on the efficacy of treatment in individuals with various polymorphisms, is still preliminary. The pace of technical advance makes it likely that clinical applications will be forthcoming within the next decade.

2.8.2 Endothelial function

In recent years, it has become clear that the endothelium has many important functions in maintaining the patency and integrity of the arterial system. The endothelium can reduce and so inactivate toxic super-oxides which may be present in diabetics and in smokers. The endothelium is a source of nitric oxide (NO), a local hormone that relaxes the adjacent smooth muscle cells in the media, and is one of the most powerful vasodilators known. Normal vessel tone therefore depends critically on an intact endothelium. In recent years, it has become clear that LDL, particularly if oxidized, may impair the production or release of NO by the endothelium. Under normal circumstances, acetylcholine causes the release of NO and widening of arteries. However, in atherosclerotic arteries, the endothelium is damaged and acetylcholine has the paradoxical effect of constricting the vessel. Endothelium also produces a peptide hormone, endothelin, that powerfully constricts arteries. In atherosclerosis, production of endothelin is increased. Overall, the result of endothelial damage in atherosclerosis is to narrow affected arteries.
Even before atherosclerosis develops, risk factors such as hypercholesterolaemia impair NO-mediated vasodilatation. Correction of elevated cholesterol levels rapidly restores the dilator response.
The arterial system is diffusely responsive to NO and to factors that modify its effects. Changes in the responsiveness of the brachial artery to NO can be measured by non invasive means and are predictive of the coronary arteries. In the future this test may be of clinical value.
Disorders of endothelial function occur early in atherosclerosis, but may be modified by several drugs:

Statins improve the abnormal paradoxical vasoconstrictor response to acetylcholine which is due to endothelial dysfunction in coronary artery disease.
Angiotensin converting enzyme inhibitors improve endothelial function in patients with coronary artery disease. These effects are more pronounced than the structural changes seen on angiography.
Calcium antagonists have been shown experimentally to improve impaired endothelial function, e.g. in hypercholesterolaemia.
Antioxidants such as probucol and vitamin C improve endothelium-dependent vasodilation in patients with hyperlipidaemia or diabetes and in smokers.

2.8.3 Further mechanisms currently under active investigation

2.8.3.1 Plaque instability and inflammation

The slowly-developing atherosclerotic plaque comprises a cholesterol-rich amorphous core, covered by a fibrous tissue cap. Acute coronary events (Q-wave myocardial infarction, unstable angina pectoris, sudden cardiac death) are believed to result from acute changes in which fissuring of the fibrous cap is followed by occulsive thrombosis. Plaque fissuring is increasingly regarded as the result of chronic inflammatory changes in the shoulder region of the fibrous cap. Recent work demonstrates that inflammation leads to decreased stability of the atheromatous plaque. Inflammatory mediators such as cytokines influence several biological processes in the plaque's fibrous cap lessening its resistance to rupture. For example, interferon-g, produced by activated T cells in the cap, inhibits the production of interstitial collagen by human vascular smooth muscle cells. Inflammatory cytokines in the atheromatous plaque, including interleukin 1, tumour necrosis factor a (TNF-a) and the cell surface homologue of TNF-a known as CD-40 ligand, lead to the production by macrophages and smooth muscle cells of enzymes that can weaken the extracellular matrix. Regions of the plaque that are prone to rupture contain few smooth muscle cells, the cells that normally elaborate and repair the vascular matrix. Inflammatory cytokines can also trigger programmed cell death (apoptosis) of human smooth muscle cells in culture. Thus, inflammatory mediators regulate several molecular processes that impair the stability of the plaque. According to one recent hypothesis, such inflammatory changes may be provoked by the presence of oxidised LDL (see Section 2.8.3.2, Oxidized LDL).

2.8.3.2 Oxidized LDL

Lipoproteins undergo minimal oxidation in the circulation but become progressively oxidized within the arterial wall. Results from many in vitro and in vivo studies have indicated the potential involvement of oxidized LDL in atherosclerosis. Oxidized LDL but not native LDL is taken up in an unregulated fashion by macrophages in the early stages of the atheromatous plaque. The oxidized LDL is degraded within these cells, releasing its lipid content. Cholesteryl esters in particular accumulate in the macrophages, which become foam cells. When these cells die, their lipid content forms the extracellular lipid pool of the plaque. Lipoproteins resembling LDL that has been oxidized in vitro have been isolated from atherosclerotic plaques. Patients with atherosclerosis, and laboratory animals in which this disease has been induced, frequently have circulating antibodies that react with oxidized LDL, and that react with material in atherosclerotic plaques; this is evidence for the presence of oxidized LDL in human atherosclerotic lesions.

Several indirect laboratory measures of oxidation are of value in research. These include measurement of the resistance of LDL to oxidation, measurement of conjugated dienes in isolated LDL, or detection of auto-antibodies against oxidized LDL. These tests are not suitable for routine laboratories and have not been evaluated in prospective studies.

The possible pathogenic role of oxidized LDL raises the possibility that antioxidant therapies may protect against atherosclerosis. Oxidation of lipids in LDL is enhanced by the presence of cholesterol and polyunsaturated fatty acids, both of which are invariable components of LDL (though in varying amounts). In the light of this it has been suggested that the proportion of polyunsaturated fatty acids in the diet should not be increased, while the intake of monounsaturated fatty acids should be supplemented; the latter have similar beneficial effects on plasma lipid levels but are much more resistant to oxidation. In the circulation, oxidation of LDL is inhibited by antioxidants, one of which is vitamin E (alpha-tocopherol). Trials on the effects of low dose vitamin E supplementation on coronary risk have produced varying results but one secondary prevention trial of 400 mg/day has provided evidence of substantial benefit in preventing non-fatal myocardial infarction; although total mortality was not significantly affected. The outcome of larger trials is awaited.
The antioxidant drug probucol inhibits oxidation of LDL in vitro. Probucol reduced progression of carotid atherosclerosis in one study, but in another study it failed to slow progression of peripheral vascular disease.

Consistent evidence of protection by antioxidants against cardiovascular disease from large clinical trials is not, as yet, available.

2.8.3.3 Alcohol and CHD risk

As noted above, an intake of more than 30 g ethanol per day is associated with an increased risk of CHD. However, much attention has been devoted to the observation in some studies that moderate alcohol intake is associated with lower than average risk of coronary heart disease. This has been used to explain the lower rate of coronary heart disease in France compared with other developed countries with comparable dietary intakes (the "French paradox"). In a study of alcohol, diet and mortality from 21 developed countries, an inverse correlation was found between wine alcohol consumption and CHD. The intake of wine ethanol, however, was unrelated to total mortality. This lack of an effect on total mortality may be due to the fact that the incidence of alcohol abuse, which sharply reduces life expectancy in populations, is correlated with the average alcohol consumption of those populations. In an important recent study of alcohol consumption among 490,000 men and women in the U.S. the rates of cardiovascular death were 30 to 40 percent lower in men and women reporting at least one drink (9 g alcohol) per day, compared with abstainers. In the same study, the overall mortality was lowest among men and women reporting about one drink daily, with rates 10 to 20% lower than in nondrinkers. However, mortality from all causes increased with heavy drinking. In particular, death rates from cirrhosis and from cancers of the mouth, esophagus, pharynx, larynx and liver were three to seven times higher among men and women who reported at least four drinks daily as among non-drinkers. Alcohol use correlates with cigarette smoking and it should be noted that the benefits of moderate alcohol consumption were much smaller than the hazards of smoking, which produced a two-fold increase in overall mortality. Thus, it appears inappropriate to recommend the use of more than one drink alcohol for cardioprotective purposes as a public health measure ¹⁸.