CARDIOVASCULAR DISEASES

8.2 CARDIOVASCULAR DISEASES

Myocardial infarction, angina, and stroke are major cardiovascular diseases. The diseases are caused by atherosclerotic plaques developed in the blood vessels, making the vessels narrower and stiffer. It is uncertain how this process starts, but one important factor is low-density lipoprotein (LDL). LDL is rich in cholesterol, and if there is no need of cholesterol supply in the cells, its uptake is low and it continues to circulate in the blood. It can also enter the endothelium of the blood vessels and be converted to oxidized LDL (LDLox), which can start an inflam- matory process. Briefly, macrophages engulf the LDLox, leading to the formation of the first stage of atherosclerosis — a fatty streak (Figure 8.1). The inflammation can become permanent, and later smooth muscle cells and fibrous tissues will proliferate and surround the lipids (the second stage). The third stage is represented by the development of unstable plaques that are prone to rupture and lead to the formation of luminal thrombosis. Plaque rupture is responsible for most acute coronary syndromes.

Many different factors influence the development of atherosclerosis. The factors are normally divided into those possible to modify and nonmodifiable ones (Table 8.1). The atherosclerotic process outlined above takes many years to develop, and most of the CVDs occur in middle-aged or older subjects. Women that have not entered menopause are somewhat protected from atherosclerosis. Thus, the incidence of CHD is three to four times higher in men than in women during middle age, but

only two times higher in the elderly. 3 It is also well documented that a sedentary lifestyle increases the risk for CVD. Data from the Framingham study indicate that active subjects were only one half to one third as likely to develop CHD as sedentary

subjects. 4 In men, physical exercise reduces CVD and also the overall mortality. Cardiovascular events occur more frequently in smokers than in nonsmokers, and myocardial infarctions are more likely to be fatal in smokers. 3 The relationship of smoking to CVD risk is dose dependent and observed in both women and men. 5 Patients with diabetes mellitus have a 2.5-fold increase in cardiovascular disease risk for males and a 6-fold increase for women. Other examples of risk factors are

Carbohydrates and the Risk of Cardiovascular Disease

A normal artery

Tunica intima

Blood

Tunica media Tunica adventitia

An atherosclerotic artery

Rupture

Thrombus

Narrowed lumen

A cellular (‘necrotic’) core: lipids, rests of dead cells, exidation products

FIGURE 8.1 Development of atherosclerosis.

TABLE 8.1 Factors Linked to the Development of Atherosclerosis

Modifiable Nonmodifiable

Diet Genetic disposition Alcohol Negative stress Physical activity Diabetes

obesity (upper-body location), family history of CVD, high consumption of alcohol, and negative stress.

8.2.1 B LOOD L IPIDS ,A POLIPOPROTEINS ,B LOOD P RESSURE , AND H EMOSTATIC F ACTORS

Chylomicrons transport lipids absorbed after a meal to different tissues and the chylomicron remnants are taken up in the liver. Very low density lipoprotein (VLDL) also mainly transports triglycerides. It is produced in the liver when there is a need for lipids in other tissues. Triglycerides are delivered to the cells and VLDL is transformed to another lipoprotein — LDL. LDL has a longer half-life and binds to

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LDL receptors in cells, and its uptake increases when the cells need cholesterol. High-density lipoprotein (HDL) instead mainly transports cholesterol from periph- eral tissues to the liver, where the cholesterol is channeled to the bile or used for the production of bile acids. The liver is also the major organ for cholesterol biosynthesis, and its synthesis is subject to feedback inhibition if HDL delivers cholesterol to the liver.

Many observational studies have shown a relationship between serum cholesterol levels and the incidence of CVD. The Framingham Heart Study, the Multiple Risk Factor Intervention Trial, and the Lipid Research Clinics trials found a direct asso- ciation between total cholesterol levels and the rate of new-onset cardiovascular heart disease in both men and women that were initially free of CVD, and also in

subjects with established cardiovascular heart disease. 5 Moreover, in the Seven Country Study, median cholesterol values were highly correlated with mortality in cardiovascular heart disease. Elevated cholesterol levels play a role in the develop- ment of mature coronary plaque. No other blood constituent varies so much between different populations as cholesterol. From south Japan to east Finland, the mean

serum cholesterol value ranges from 2.6 to 7.0 mmol/l. 2 Cholesterol levels above

5.2 mmol/l are considered elevated, between 5.2 and 6.2 mmol/l are borderline high and levels above 6.2 mmol/l are high (Table 8.2). A prolonged reduction in serum cholesterol with 0.6 mmol/l was associated with an almost 30% reduction in the risk of coronary heart disease. 6

The strong relationship between blood cholesterol and risk of CVD is due to elevations of LDL cholesterol. Several lines of evidence support the link between LDL cholesterol and CVD. 7 The level of LDL cholesterol correlates with cross- cultural variance in CVD risk, and prospective cohort studies show a positive relation between serum LDL cholesterol and CHD mortality. Furthermore, oxidatively mod- ified forms of LDL have been isolated from plaques in postmortem samples in amounts directly proportional to the concentration of LDL. Recent evidence indicates that elevated LDL cholesterol levels contribute to plaque instability, and thus low- ering of the LDL cholesterol stabilizes the plaques and reduces the risk for CVD. 5 There is another rationale for long-term lowering of the LDL cholesterol since it also slows development of the atherosclerotic plaques. In five studies, treatment with LDL cholesterol-lowering drugs like statins led to a 28% reduction in the LDL

cholesterol level and a 30% decrease in cardiovascular heart incidence. 8 Observa- tional and clinical trials suggest that each 0.026 mmol/l increment in LDL cholesterol

TABLE 8.2 Relation between Blood Lipid Levels and an

Increased Risk for Cardiovascular Diseases 5

Level

Increased Risk

Cholesterol >5.2 mmol/l LDL cholesterol

>3.4 mmol/l HDL cholesterol

<1.0 mmol/l Triglycerides

>2.3 mmol/l

Carbohydrates and the Risk of Cardiovascular Disease

causes a 1% increase in coronary risk. 9 LDL cholesterol is one of the best markers for risk of CVD, and it is easily measured in health control programs. It is thus also the main target of lipid-lowering therapy, and a decrease to a value below 3.4 mmol/l of LDL cholesterol reduces the risk for CVD (Table 8.2).

A high level of HDL cholesterol is related to a decreased risk of CVD. Data from the Framingham study indicate that every 0.26 mmol/l increase in HDL cho- lesterol results in a 33 to 50% reduction in risk for cardiovascular heart disease. 10 HDL transports cholesterol from the artery wall and other organs to the liver and in that way reduces the size of the atherosclerotic plaque.

The mean HDL levels are higher in women than in men, and other factors that influence the HDL levels are weight loss (increase), physical activity (increase),

weight gain (reduce), and smoking (reduce). An HDL cholesterol level below 1.0 mmol/l leads to an increased risk of CVD. At a low HDL concentration the HDL particles become smaller and denser, and this type of particles is more strongly

associated with increased risk for CHD. 11 In the elderly, low concentrations of HDL are more predictive of vascular disease risk than elevated LDL cholesterol levels. 12 Another parameter often calculated is the total cholesterol/HDL cholesterol ratio. It has been shown to be a powerful predictor of coronary heart disease risk, but usually not as good as the LDL cholesterol level. 5

Elevated triglyceride levels in the blood are associated with a substantial increase in risk for CVD. If the triglyceride level is higher than 1.5 mmol/l, it can lead to an increased formation of small, dense LDL particles and a low HDL cholesterol level. 13 Small, dense LDL particles can more easily infiltrate the intima than larger ones, and thus increase the risk for development of atherosclerosis. The triglyceride level has been recommended to be used as a predictor for CVD, especially in women,

based on results in the Framingham study. 14 A meta-analysis by Hokanson and Austin 15 showed that raised triglyceride levels were positively associated with the risk of CHD. Triglyceride levels are influenced by many factors, like alcohol intake, diet, weight changes, and physical activity. The independent impact of elevated

triglyceride levels on CVD risk has earlier been questioned, 3 except in the presence of diabetes. There is increasing consensus on triglyceride levels being a valuable predictor for CVD according to a recent review. 7 A triglyceride concentration over

2.3 mmol/l is regarded as supernormal, but lower triglyceride levels also negatively influence the pattern of LDL and HDL particles.

Apolipoproteins in lipoproteins are important for receptor recognition and enzyme regulation. The apolipoproteins are categorized into A, B, C, D, and E classes, with additional subclasses. The dominating apolipoprotein in LDL is B, as it is also in chylomicrons and VLDL. The level of apolipoprotein B is positively related to CVD since it is in these potentially atherogenic lipoproteins. It is also raised in subjects with increased triglyceride levels. Different apolipoproteins A are the major proteins in HDL, and a low level of apolipoprotein A-I is associated with an increased risk for coronary heart disease. This marker is naturally dependent of the HDL level . In the AMORIS study, a high apolipoprotein B and a low apolipo- protein A-I level were shown to be good predictive factors for fatal myocardial

infarction. 16 Apolipoprotein E is important for the cholesterol clearance in the blood, and its level is higher in subjects that have had a myocardial infarction than in

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controls. There are also different genetic variants (polymorphism) of apolipoprotein

E containing ε4, ε3, or ε2 alleles. Subjects with the ε4 allele have higher total and LDL cholesterol levels, and some studies have shown that these subjects are more responsive to dietary changes than those without an ε4-allele. 17 More research is needed to relate different polymorphic forms of apolipoproteins to the response to diet changes.

One important risk factor of CVD is hypertension. It is defined as a systolic blood pressure of 140 mmHg or a diastolic blood pressure of 90 mmHg. An increased

blood pressure affects the artery wall, and this can lead to smooth muscle cell proliferation and a narrower vessel lumen. This contributes to an increased risk for myocardial infarction, stroke, and peripheral vascular disease. Systolic blood pres- sure is a good predictor of CHD in subjects older than 60 years, and therapy to decrease the blood pressure in subjects with hypertension reduces cardiovascular morbidity and mortality. 7,18

High levels of plasma fibrinogen are positively correlated with CVD and are identified as a major independent risk marker for CVD. Fibrinogen increases the platelet aggregation and fibrin formation and influences plasma viscosity. Other hemostatic parameters that have been investigated in relation to CVD risk are platelet functions and the level of plasminogen activator inhibitor-1 as a marker of fibrinol- ysis. However, all these hemostatic factors are relatively unaffected by the diet, and thus not very suitable markers for the effects of diet. 7