Thrombus

MYOCARDIAL ► INFARCTION (Blood supply to heart muscle cut off)

Replacement of muscle by non-contractile tissue or death

Fig. 5.18 Possible processes involved in the development of ischaemic heart disease and myocardial infarction. Boxes indicate points at which lipids may be involved.

subject of considerable controversy. Now it is more widely accepted. A major reason for this acceptance has been that several major prospective clinical trials have shown that lowering LDL-cholesterol concentrations with the 'statin' drugs, inhibitors of HMG-CoA reductase (Section 5.3.1), leads to marked reductions in mortality from CHD, in proportion to the reduction in LDL-cholesterol achieved.

Despite widespread acceptance of the role of LDL-cholesterol, it remains true that many patients suffering an early myocardial infarction have relatively normal levels of LDL-cholesterol (Fig. 5.19). Increasingly, other abnormalities of lipid metabolism are being seen as associated with development of atherosclerosis. The clearest relationship is with the serum HDL-cholesterol concentration, which, in epidemiological studies, is strongly negatively related to CHD risk. This is understandable if we consider HDL-cholesterol concentrations to reflect activity of the reverse cholesterol transport pathway, removing excess cholesterol from peripheral tissues, such as macrophages, to the liver for ulti mate disposal. Again, epidemiological studies have now been reinforced by clinical trials. Fibrate drugs that raise HDL-cholesterol concentrations by acting as PPAR-a agonists (Section 5.3.2) reduce mortality from CHD.

Beyond the positive relationship of CHD with elevated LDL-cholesterol, and its negative relationship with HDL-cholesterol, there are other more subtle effects. Increasingly there is recognition of a phenotype that predisposes to CHD, known by a variety of names, including the atherogenic lipo-protein phenotype, the metabolic syndrome, syndrome X, or hyperapobetalipoproteinaemia (a high concentration of apoB in the circulation). The characteristics usually associated with the athero-genic lipoprotein phenotype are listed in Table 5.6. A brief description of its origin in terms of lipid metabolism may be given as follows. It appears to stem from a disturbance of the metabolism of the triacylglycerol-rich lipoproteins, with over-production of VLDL from the liver. That, in turn, may result from increased delivery of non-esterified fatty acids to the liver. An increased circulating con

3456789 10

Serum cholesterol (mmol/l)

Fig. 5.19 Distribution of serum cholesterol concentrations in 438 men who had a major coronary event and 7252 unaffected men. Note that there is considerable overlap between the distributions. An elevated serum cholesterol concentration is certainly a major risk factor for development of coronary heart disease, but nevertheless many people experiencing the disease have relatively normal cholesterol concentrations. Data from the British Regional Heart Study: redrawn by Wald, N.J. (1992) in Coronary Heart Disease Epidemiology (eds. M. Marmot & P. Elliott). Oxford University Press, Oxford. Reproduced with permission.

3456789 10

Serum cholesterol (mmol/l)

Fig. 5.19 Distribution of serum cholesterol concentrations in 438 men who had a major coronary event and 7252 unaffected men. Note that there is considerable overlap between the distributions. An elevated serum cholesterol concentration is certainly a major risk factor for development of coronary heart disease, but nevertheless many people experiencing the disease have relatively normal cholesterol concentrations. Data from the British Regional Heart Study: redrawn by Wald, N.J. (1992) in Coronary Heart Disease Epidemiology (eds. M. Marmot & P. Elliott). Oxford University Press, Oxford. Reproduced with permission.

centration of VLDL particles will compete for clearance by lipoprotein lipase when chylomicrons become enriched with triacylglycerol in the postprandial period. This will lead to a prolonged residence of partially lipolysed chylomicron and VLDL remnants in the circulation, something that has often been noted to be associated with increased CHD risk. If the circulating pool of triacylglycerol-rich lipoproteins is increased, there will be increased opportunity for the action of the cholesteryl ester transfer protein, a normal part of the reverse cholesterol transport pathway (Fig. 5.11), to exchange

Table 5.6 Features of the atherogenic lipoprotein phenotype triacylglycerol from VLDL and chylomicron remnants for cholesteryl esters from HDL and LDL particles. VLDL and chylomicron remnant particles therefore become enriched in cholesteryl esters. Some people believe that these become atherogenic particles - that is, they may themselves penetrate the arterial wall and become engulfed by macrophages. (There is some evidence for the presence of apoB48 in arterial lesions, although this is difficult to demonstrate as apoB48 is enormously outnumbered in the circulation by apoBlOO.) But in addition, LDL and HDL particles thereby lose cholesteryl esters.

Feature Comment

Hypertriglyceridaemia May be relatively mild, but usually is more marked after meals.

Low HDL-cholesterol concentration Reflects impairment of triacylglycerol-rich lipoprotein metabolism.

Small, dense LDL particles Total LDL-cholesterol concentration may be normal, hence number of particles must be increased.

Hyperapobetalipoproteinaemia Reflects increased number of LDL particles, as above.

(high concentration of apoBlOO in plasma)

Insulin resistance These features are often associated with impaired action of insulin on metabolic processes.

The triacylglycerol that they have gained in exchange can be hydrolysed by hepatic lipase, which acts preferentially on these smaller particles. Therefore the particles have lost both triacylglycerol and cholesterol. The result is a low HDL-cholesterol concentration (associated with increased risk of CHD as discussed above) and a predominance of small, relatively lipid-poor LDL particles. In the past few years these small, dense LDL particles have attracted much attention as the probable athero-genic particles of the atherogenic lipoprotein phe-notype. There is always a population of LDL particles of different sizes in the circulation, but some people tend to have a predominance of large, buoyant cholesterol-rich LDL particles (known as pattern A) and others a predominance of smaller, denser relatively lipid-poor LDL particles (pattern B). There is some evidence for a genetic component to this LDL phenotype, but it is clearly modifiable by diet and by other influences on the lipoprotein phenotype. Pattern B is associated with much higher risk of CHD than is pattern A, even though the total LDL-cholesterol concentration may be the same. The increased number of LDL particles that must be present in pattern B (to give the same total LDL-cholesterol concentration) accounts for the term hyperapobetalipoproteinaemia, which covers the same, or a closely related, phenotype. It is postulated that smaller LDL particles may more readily cross the endothelial wall and hence become substrates for macrophage uptake. In addition, there is considerable experimental evidence that small, dense LDL particles are more susceptible to peroxidation than are larger, more buoyant particles, and hence again more likely to be substrates for macrophage uptake.

Once the atherosclerotic plaques have developed, further events must follow to lead to myocardial infarction or ischaemic stroke. These are aggregation of platelets, probably at the site of rupture of the atherosclerotic lesion, and then the formation of a thrombus. These processes may be related to aspects of lipid metabolism. Platelet aggregation, an early step, is propagated by the formation of the eicosanoid, thromboxane A2, from arachidonic acid in platelets. Release of thromboxane A2 by activated platelets leads to a cascade effect on aggregation.

Formation of thromboxane A2 is inhibited by aspirin (an inhibitor of the cyclo-oxygenase pathway), and this is the reason that low doses of aspirin can markedly reduce the risk of re-infarction in people who have already suffered one myocardial infarction. Platelet aggregation is also inhibited by n-3 polyunsaturated fatty acids. This is probably mediated via the generation of eicosa-noids of the 3-series rather than the 2-series. The blood coagulation pathways are also related to lipid metabolism. High circulating concentrations of the activated form of coagulation factor VII, often known as Vila (or, if measured by assay of its coagulant activity, as VIIc), are associated with increased risk of CHD. Generation of factor Vila is now known to relate to triacylglycerol metabolism. There is a relationship between circulating concentrations of VIIa and of triacylglycerol, and the elevation of plasma triacylglycerol concentrations that occurs after a meal is associated with activation of factor VII.

Myocardial infarction may lead to death. If it does, this is not usually because of complete obstruction of blood flow to the myocardium, but because the electrical rhythm of the heart becomes grossly disturbed, leading to the critical conditions of ventricular fibrillation or cardiac arrest. Then blood supply to the rest of the body, including the brain, ceases. The stress reaction that sets in at the onset of myocardial infarction can lead to very high plasma concentrations of non-esterified fatty acids, and there is considerable evidence that these may themselves be a potent cause of ventricular dys-rhythmias. It has been postulated that the stresses associated with modern living lead to consistent elevations of the plasma non-esterified fatty acid concentration that are now inappropriate, and may lead to - or potentiate - ventricular dysrhythmias. The UK biochemist Eric Newsholme has put forward this view, and suggests that in earlier times we would have oxidized the excess fatty acids in muscular activity; hence the hazards of stressful, sedentary living. There is an interesting recent development in this story. The American nutritionist Alexander Leaf has shown that, amongst fatty acids, the n-3 polyunsaturated fatty acids appear to have a unique ability to stabilize the heart rhythm. In several studies in experimental animals he has shown that acute administration of n-3 polyunsaturated fatty acids can prevent death from coronary artery obstruction. There is convincing support now from human dietary trials. In the Diet and Reinfarction (DART) study, conducted in the UK, survivors of myocardial infarction were randomized into two groups, one of which was given advice to eat oily fish (and if this advice was not followed, they received supplementation with fish-oil capsules). Over the next two years, the fish-eating group suffered the same rate of new myo-cardial infarctions as did the control group; but their death rate was significantly reduced, by 29%. It has been proposed that this reflects protection against the fatal dysrhythmias that often accompany myocardial infarction. More recently, the Lyon Diet-Heart Study also investigated the effects of dietary modification in people who had suffered from a myocardial infarction. In this case the 'test' group was asked to follow a Mediterranean-style diet, which was particularly rich in a-linolenic acid (18:3n-3). The control group was given conventional dietary advice. The trial was stopped prematurely, after an average of 2.5 years on the diet, because the results were so clearly significant, with lower death rates in the Mediterranean-diet group. A four-year follow-up of the participants showed that even after the formal trial had finished, the subjects had largely kept to their diets, and the difference in all-cause mortality between the groups was marked (about half in the test group compared with the control group). For 'cardiac deaths' the ratio was 3:1.

5.4.2 Risk factors for CHD and the effects of diet

From the preceding description, it will be clear that the major lipid risk factors for CHD are: an elevated circulating LDL-cholesterol concentration; a low HDL-cholesterol concentration; a predominance of small, dense LDL particles; and elevated circulating triacylglycerol concentrations (particularly in the postprandial period). The total cholesterol concentration in serum is often listed as a risk factor, but this reflects the fact that LDL-cholesterol is the major component of total serum cholesterol. These risk factors are modified to a great extent by genetic and environmental factors, as described in more detail in Section 5.4.3, but they are also modulated to a considerable extent by dietary factors, which will be reviewed briefly here.

The realization of a connection between serum cholesterol concentrations and CHD risk began in the 1950s with the work of the celebrated American nutritionist, Ancel Keys. Keys had been travelling in the Mediterranean countries, investigating the apparently very low incidence of chronic diseases including CHD. He questioned whether this might be related to aspects of the diet in those areas. This led to the foundation of the Seven Countries Study, an international study of CHD and associated factors in a number of countries (it soon expanded beyond seven) with widely differing incidences of CHD. There were two major, early findings. Comparing average values in one country with another, there was a strong positive relationship between serum cholesterol concentration and incidence of CHD, and a strong positive relationship between consumption of saturated fat and serum cholesterol. This led to the recognition that the nature of the fatty acids in the diet is an important influence on the serum cholesterol concentration: saturated fatty acids tend to raise it, polyunsaturated fatty acids to lower it. For some years it was felt that monounsaturated fatty acids were neutral in this respect. However, the answer to any experimental trial is dependent upon how the experiment is conducted, and it is now realized that if mono-unsaturated fatty acids replace saturated fatty acids in the diet, they reduce serum cholesterol concentration. Amongst these fatty acid classes, not all fatty acids have the same effect. Of the saturated fatty acids, for instance, those with chain length below 12C seem to have no effect; 12C, 14C and 16C lengths raise cholesterol, whereas stearic acid, 18:0, may slightly reduce cholesterol (perhaps because of rapid desaturation to oleic acid). In contrast to the effects of dietary fatty acids, the effect of dietary cholesterol on serum cholesterol concentration is relatively weak over any reasonable range of intake. This can be understood if we remember the powerful systems that regulate cholesterol accumula tion in cells. The relative effects of fatty acids and cholesterol have been combined by many investigators to produce equations that predict the change in serum cholesterol in response to any dietary manipulation (Box 5.2). The mechanism for the effects of different dietary fatty acids on serum cholesterol concentration is not clearly understood. It appears to reflect a shift in the hepatic cholesterol pool between esterified and unesterified forms, with up-regulation of hepatic LDL-receptors (and a consequent reduction in serum LDL-cholesterol concentration) when polyunsaturated fatty acids predominate.

The n-3 polyunsaturated fatty acids have a special role. They are relatively neutral in terms of serum cholesterol, but they have a potent effect in reducing serum triacylglycerol concentrations. They also reduce platelet aggregation, and may stabilize the myocardial rhythm, as described above.

The double bonds in dietary unsaturated fatty acids are mostly of the cis geometrical configuration. However, some foods contain significant quantities of isomeric fatty acids in which the double bonds are in the trans configuration (Figs 1.1 and 4.1; Table 4.2 and Section 4.1.3.1). These are often produced as a result of hydrogenation of unsaturated fatty acids. This occurs in the reducing environment of the bovine rumen, so that dairy products and beef fat contain small proportions of the trans fatty acids. It also occurs during the hydrogenation of vegetable oils to produce 'harder' fats, e.g. in the production of margarine. A number of epidemiological studies have shown a relationship between trans fatty acid intake and cardiovascular disease, and controlled feeding studies suggest that dietary trans fatty acids raise serum cholesterol concentrations to a very similar extent to saturated fatty acids. Given the similarity of their molecular configurations, this is perhaps not

Box 5.2 Effects of dietary fatty acids on serum cholesterol concentrations

In many experiments in healthy subjects, the fatty acid composition of the diet has been manipulated to assess the effect on the serum cholesterol concentration. These studies have been summarized by a number of investigators to produce 'predictive equations'. Two examples are given here.

Hegsted etal. (1965) produced the equation

Aserum cholesterol = 0.026x

where Aserum cholesterol represents the change in serum cholesterol concentration (mmol l-1), ASFA and APUFA are changes in the percentage of dietary energy derived from saturated and polyunsaturated fatty acids, respectively, and AChol is the change in dietary cholesterol in lOOmgday"1. Note that the term for ASFA is positive (an increase in saturated fat intake raises serum cholesterol) whereas that for APUFA is negative (an increase in polyunsaturated fat intake reduces serum cholesterol).

Yu etal. (1995) collated data from 18 studies in the literature that gave information on individual fatty acids in the diet. Their predictive equation was:

Aserum cholesterol = 0.0522A(12:0 to 16:0)-0.0008A18:0 - 0.0124AMUFA - 0.0248APUFA

where AMUFA is the change in the percentage of dietary energy derived from monounsaturated fatty acids (other terminology as above). Note that most saturated fatty acids are shown as raising serum cholesterol, but stearic acid (18:0) as slightly lowering it.

References

Hegsted, D.M., McGandy R.B., Myers M.L. & Stare F.J. (1965) Quantitative effects of dietary fat on serum cholesterol in man. American Journal of Clinical Nutrition, 17, 281-295. Yu, S., Derr, J., Etherton, T.D., Kris-Etherton, P.M. (1995) Plasma cholesterol-predictive equations demonstrate that stearic acid is neutral and monounsaturated fatty acids are hypocholesterolemic. American Journal of Clinical Nutrition, 61, 1129-1139.

surprising. The content of trans fatty acids is being reduced by many food manufacturers as a result of this finding.

In most naturally occurring cis-polyunsaturated fatty acids, the double bonds are separated by a methylene bridge; e.g. the most common form of linoleic acid in nature is (cis-9,cis-12) 18:2. However, a large number of isomers of linoleic acid is found. Some of these have the double bonds between consecutive pairs of carbon atoms [the most common is (cis-9,trans-11) 18:2, also known as rumenic acid]. This arrangement of double bonds is similar to that seen in benzene, and is known as conjugated. The electrons become delocalized over conjugated double bonds, and this can confer unusual chemical properties. The group of isomers of linoleic acid with this configuration has become known (collectively) as conjugated linoleic acid (CLA). CLA is formed in the rumen of ruminant animals, and is found in milk fat, cheese and beef (Section 4.1.3). It has come to prominence because of claims from animal studies that CLA can protect against some forms of cancer. Dietary CLA has also been shown to alter body composition in mice, with a loss of body fat, and in cultured adipocytes to reduce the activity of lipoprotein lipase. More recently, it has been claimed that dietary CLA may protect against atherosclerosis. However, the evidence in this respect is not clear-cut: there have also been demonstrations that high levels of CLA fed to rodents can predispose to the formation of fatty streaks in the aorta (presumed to be the precursors of atherosclerotic lesions). Various mechanisms for the potential beneficial effects have been proposed, and may differ for the different isomers. For instance, some isomers are potent agonists of PPAR-a (Section 5.3.2).

The total quantity of dietary fat has an important influence on serum lipoprotein concentrations, beyond the nature of the fatty acids it contains. It is a common observation that a change to a diet containing a low proportion of energy from fat, and a correspondingly higher proportion from carbohydrate, is associated with a reduction in serum HDL-cholesterol concentration and an elevation of serum triacylglycerol concentration. The reduction in serum HDL-cholesterol concentration may reflect reduced flux of fat through the exogenous lipo-protein pathway, which involves the transfer of surface components from the chylomicrons, as they are lipolysed by lipoprotein lipase, to HDL particles. The elevation of serum triacylglycerol concentration is not clearly understood. It is thought to represent increased secretion of VLDL-triacylgly-cerol from the liver, perhaps because of a change in the metabolic partitioning of fatty acids in the liver between oxidation (favoured when fat levels in the diet are high) and esterification (favoured when carbohydrate is plentiful, and insulin levels are high). A recent study using isotopic methods to assess hepatic fatty acid metabolism has suggested, however, that the elevation of triacylglycerol concentration on a high-carbohydrate diet may reflect impaired removal of triacylglycerol from the circulation in peripheral tissues. These observations have led to questions about the safety of low-fat diets, since both these changes (depression of HDL-cholesterol, elevation of triacylglycerol concentrations) appear to be deleterious in terms of CHD risk. Such questioning is important, but many nutritionists feel that a shift towards lower fat diets may play an important role in reducing the incidence of obesity. The answers are not yet clear. We need to know: (1) Are the changes in lipoprotein particles that lead to elevation of triacylglycerol concentrations the same as those seen in subjects at increased risk of CHD? (2) Whether the changes in lipid concentrations are maintained long term (there is some evidence that they are not, but there are few long-term studies) (3) Whether the changes in lipid concentrations depend upon the nature of the dietary carbohydrate: in many short-term experimental studies, much of the dietary carbohydrate is in the form of simple sugars, which may have a particularly marked triacylglycerol-raising effect.

5.4.3 Hyperlipoproteinaemias

(elevated circulating lipoprotein concentrations) are often associated with increased incidence of cardiovascular disease

Diseases that involve elevation of circulating lipid concentrations (hyperlipoproteinaemias or hyper-lipidaemias) are often associated with increased incidence of atherosclerosis and myocardial infarction. They are often sub-divided into primary and secondary hyperlipoproteinaemias. Primary hyperlipoproteinaemias are considered to arise directly from a genetic cause, while the secondary condition arises from some other medical or environmental cause such as diabetes or obesity. If the diabetes or obesity is controlled or cured, the hyperlipoproteinaemia will disappear or lessen. However, the simplicity of this classification is now under question as we recognize increasingly that most diseases reflect interactions between genome and environment. For instance, even in familial hypercholesterolaemia, caused by a defect in the LDL-receptor, the degree of elevation of plasma cholesterol concentration is dependent upon other lifestyle and medical factors such as diet and thyroid hormone status.

A different classification is based upon the observed lipid phenotype. The classification normally used is that proposed in 1967 by the American clinician and biochemist, Donald Fredrickson (Table 5.7). Fredrickson believed this was a classification of familial (i.e. primary) hyperlipidaemias, but it is now recognized to include many conditions that we would regard as secondary.

There are a few well-described single-gene mutations that lead to 'classic' primary hyperlipo-proteinaemias, but for many conditions the background is polygenic, and the phenotype may be correspondingly more variable according to environmental factors. A given phenotype may result from different causes. For instance, amongst singlegene mutations, those that abolish activity of the LDL-receptor lead to familial hypercholester-olaemia, but an identical phenotype (Fredrickson Type IIa) is produced by rarer mutations in apoBlOO that affect its ability to bind to the LDL-receptor (the condition is known as familial defective apolipoprotein B1OO or FDB, but in most clinical situations would not be distinguished from familial hypercholesterolaemia). Complete lack of activity of lipoprotein lipase leads to familial chylomicronaemia syndrome or Fredrickson Type I hyperlipoproteinaemia, but again an identical phenotype is caused by mutations in apoCII that abolish its ability to activate lipoprotein lipase. For clinical purposes it may not be important to distinguish these causes, although genetic analysis is increasingly being applied to these conditions.

Secondary hyperlipoproteinaemias may be associated with many conditions, but amongst the most common are diabetes and obesity (see the following section), thyroid disease (low thyroid hormone concentrations lead to hypercholester-olaemia and hypertriglyceridaemia), over-consumption of alcohol (hypertriglyceridaemia), and liver and kidney diseases. Some drug treatments for other medical conditions may also lead to hyperli-poproteinaemias. A prominent example that is causing concern at present is a marked hyper-triglyceridaemia that is commonly observed in patients with human immunodeficiency virus (HIV) infection treated with viral protease inhibitors.

5.4.4 Obesity and diabetes are associated with increased risk of cardiovascular diseases

Mortality from cardiovascular disease (mainly coronary heart disease and ischaemic stroke) is considerably increased in obese compared to lean individuals. Almost all this increase can be accounted for by alterations in plasma lipid and lipoprotein concentrations. Statistically, it is sometimes claimed that obesity per se is not a significant risk factor for cardiovascular disease, but this merely implies that it has no residual effect beyond what would be expected from the alterations in lipid concentrations. The typical alterations in lipid concentrations in obesity are those described earlier as the atherogenic lipoprotein phenotype (Table 5.6). Because concentrations of some lipoprotein

Table 5.7 The classification of hyperlipidaemias according to phenotype

Type Plasma Plasma Particles Usual underlying defect Treatment cholesterol triacylglycerol accumulating

Table 5.7 The classification of hyperlipidaemias according to phenotype

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