Chapter 9 Atherosclerosis and dyslipidaemia
EPIDEMIOLOGY AND AETIOLOGY
The association between elevated serum cholesterol and coronary heart disease (CHD) was first reported in the 1930s, and subsequent large epidemiologic studies confirmed the strong relationship between serum cholesterol and CHD.1–3 Current predictions estimate that by the year 2020 cardiovascular diseases, notably atherosclerosis, will become the leading global cause of total disease burden.4 Lipoprotein disorders or dyslipidaemias are common and are an important risk factor for coronary artery disease and all types of atherosclerotic vascular disease.5 Cardiovascular risk was found to be positively associated with low-density lipoprotein (LDL-C) levels and inversely with high density lipoprotein (HDL-C) levels.6 The relationship between fasting serum triglyceride (TG) and cardiovascular risk has been confounded by the inverse association between TG and HDL-C, as well as by the association of TG with other risk factors such as diabetes mellitus and body mass (see Table 9.1).6 Triglycerides alone are now considered an important independent predictor of cardiovascular risk.1
Table 9.1 Common secondary causes of dyslipidaemia
| CAUSE | EFFECT ON LIPID PROFILE |
|---|---|
| Increased LDL-C | |
| Increased TG and/or decreased HDL-C | |
| Increased TG, HDL-C may increase rather than decrease; cardiovascular risk may not be increased |
Source: Therapeutic Guidelines (Cardiovascular).17
Atherosclerosis affects various regions of the circulation and will present with unique clinical symptoms depending on the particular vascular bed affected. In coronary arteries it causes myocardial infarction and angina, whereas stroke and transient cerebral ischaemia can occur when it is present in the arteries of the nervous system.2,7 In the peripheral circulation it can result in intermittent claudication and gangrene, which can jeopardise limb viability.4
Atherogenesis or the pathogenesis of atherosclerosis usually occurs over decades in a discontinuous fashion with relative periods of quiescence punctuated with periods of rapid evolution.3 The eventual clinical manifestation may be chronic, as is the case in angina, or acute, such as a heart attack or stroke or sudden death. Regardless, individuals may live with atherosclerosis and experience no symptoms or reduced life expectancy and morbidity.
The ‘fatty streak’ represents the initial lesion, usually due to focal increases in the density of lipoproteins within the region of the intima of a blood vessel; hence the reason for vigilance in maintaining low levels of these particles in the bloodstream.8 The lipoproteins often associate with glycosaminoglycans in the arterial extracellular matrix and become more ‘fixed’ in the vasculature. These lipoprotein macromolecules undergo oxidative modifications, giving rise to hydroperoxides, lysophospholipids, oxysterols and aldehydic breakdown products.4 Constituents of oxidatively modified LDL-C can augment expression of leukocyte adhesion molecules, recruiting leukocytes and macrophages into the area, which undergoes inflammation.9
Areas of inflammation produce altered laminar flow in the arteries affected, and reduce the production of nitric oxide, which is locally both vasodilatory and anti-inflammatory. The inflammatory process eventually penetrates or tears the endothelial layer with the products of lipoprotein oxidation, inducing cytokines and tumour necrosis factor alpha (TNF-α) released from the vascular cell walls.4 Once inside the walls of the artery mononuclear phagocytes mature into macrophages and become foam cells.
The cytokines and TNF-α produce growth factors that induce the smooth muscle to produce local growth factors such as platelet-derived growth factor and fibroblast growth factors.9 This fibro-fatty material recruits more smooth muscle cells into the intima from the tunica media layer of the vessel. At this point transforming growth factor beta (TGF-β), amongst other mediators, stimulates collagen production by the smooth muscle cells transforming the fatty streak into a more fibrous smooth-muscle cell and extracellular-rich lesion.4 In addition to this process products of blood coagulation and thrombosis contribute to atheroma evolution, which justifies the alternative term for the process, ‘atherothrombosis’ (see Figure 9.1).
Unfortunately the prevalence of traditional risk factors is almost as high in those without cardiovascular disease as in subsequently affected individuals.1 Recently, several novel key biomarkers have been implicated in the pathology of atherosclerosis. There are several, but the more commonly researched include C-reactive protein (CRP), homocysteine (Hcy) and indicators of oxidative stress.8,10
C-reactive protein (CRP)
CRP is a calcium-binding pentameric protein consisting of five identical, non-covalently linked 23-kDa subunits.1 It is present in trace amounts in humans and appears to have been highly conserved over hundreds of millions of years. It is synthesised primarily by hepatocytes in response to activation of several cytokines, such as interleukins 1 and 6, and TNF-α.1 In healthy people in the absence of active inflammatory states, CRP levels are usually below 1 mg/L. CRP is expressed in atherosclerotic plaque and may enhance expression of local adhesion molecules, increase expression of endothelial plasminogen activation inhibitor 1, reduce endothelial nitric oxide bioactivity and alter low-density lipoprotein (LDL) cholesterol by macrophages.10
Homocysteine (Hcy)
The homocysteine theory of arteriosclerosis attributes one of the underlying causes of vascular disease to elevation of blood homocysteine concentrations as the result of dietary, genetic, metabolic, hormonal or toxic factors.11 Dietary deficiency of vitamin B6 and folic acid and absorptive deficiency of vitamin B12, which result from traditional food processing or abnormal absorption of B vitamins, are important factors in causing elevations in blood homocysteine.11,10 It is believed that homocysteinylation of lipoproteins increases their atherogenicity and hence their cytotoxic effects on endothelial tissue.12 It is hypothesised that oxidative stress and methylative modification is the mechanism by which Hcy is pro-atherosclerotic.13
Oxidative stress
Endothelial dysfunction is the initial step in the pathogenesis of atherosclerosis.14,15 Nitric oxide (NO) plays an important role in the regulation of vascular tone and the suppression of smooth muscle cell proliferation. An increase in oxidative stress inactivates NO, impairing endothelium-dependent vasodilation and creating endothelial dysfunction.16 Dyslipidaemia may be primary or secondary. The secondary causes are shown in Table 9.1, and should be looked for in patients and treated appropriately. If secondary causes have been excluded, primary dyslipidaemia due to genetic and environmental (particularly dietary) factors is diagnosed.17
RISK FACTORS
The general risk factors applicable to atherosclerosis relate to lifestyle choices and genetics. Overall estimates of the heritability of myocardial infarction, one of the major clinical outcomes of atherosclerosis, have varied widely, ranging from very little to greater than 50%.18,19 It is important to note that heritability varies from population to population. In populations in which the environment is relatively homogeneous, for example in Iceland, genetics will tend to predominate, whereas in populations exhibiting large environmental differences, for example in Los Angeles, genetics are relatively less important.1 The known risk factors for atherosclerosis generally exhibit very significant heritability estimates as well (see Figure 9.2). Smoking and alcohol consumption as well as a diet rich in refined sugars and saturated fats will adversely influence the condition (see the box below).20 Hypertension, diabetes and obesity have a pronounced negative influence on the disease.1 Exercise is also a significant factor.3 In women the protective effects of oestrogen are greatly diminished in menopause.1 There are several medical conditions that drastically increase the risk associated with this condition, and all of these may cause altered blood fat profiles as secondary to their primary condition.
The influence of environmental factors on lipoprotein metabolism and cardiovascular disease has been dramatically revealed by comparisons of different populations.3 Studies have shown that intrauterine under-nutrition is associated with obesity and other detrimental metabolic characteristics in adulthood.1 In particular under-nutrition
GENETIC AND ENVIRONMENTAL RISK FACTORS FOR CARDIOVASCULAR DISEASE1
Risk factors with a significant genetic component (h2)
High-density-lipoprotein cholesterol (45–75%)
Systolic blood pressure (30–70%)
Diastolic blood pressure (30–65%)
Carotid intima-media thickness (~40%)
was associated with a premature onset of neonatal leptin surge, which appears to be involved in the formation of the energy-regulation circuits in the hypothalamus that affect metabolism in adults.1
CONVENTIONAL TREATMENT
The assessment of dyslipidaemia involves the measurement of fasting total cholesterol (TC), high density lipoprotein (HDL-C), low-density lipoprotein (LDL-C) and triglyceride (TG).10 Fasting usually takes place from midnight prior to the blood test.
Dyslipidaemia is treated in cases of:
| These target levels are adapted from the National Heart Foundation of Australia/Cardiac Society of Australia and New Zealand position statement on lipid management, 2005. |
Source: Therapeutic Guidelines (Cardiovascular).17
The question that needs to be addressed in relation to dyslipidaemia is: who should in fact be treated and when? Tables 9.3 and 9.4 list the current Australian medical protocols. The aim of treatment is to reduce the progression of atherosclerosis and improve survival rates of individuals. An even more important aim is to prevent myocardial infarct (heart attack) and stroke in patients with established cardiovascular disease. A reduction in triglyceride levels should prevent the occurrence of pancreatitis in susceptible individuals as well. Common pharmacological interventions are listed in Table 9.5.
Table 9.3 Patients at increased risk and warranting therapy, based on their fasting lipid levels
| PATIENT CHARACTERISTICS | LIPID LEVEL (FASTING) |
|---|---|
| Diabetes mellitus, but the patient is not in the ‘very high risk’ category (see below). | Total cholesterol > 5.5 mmol/L |
| Aboriginal or Torres Strait Islander Hypertension | |
| HDL cholesterol < 1 mmol/L | Total cholesterol > 6.5 mmol/L |
| Familial hypercholesterolaemia identified by: Family history of coronary heart disease: | If aged 18 years or less at treatment initiation: If aged more than 18 years at treatment initiation: |
| Patients not already identified who are: | Total cholesterol > 7.5 mmol/L or triglyceride > 4 mmol/L |
| Patients not already identified | Total cholesterol > 9 mmol/L or triglyceride > 8 mmol/L |
Source: Therapeutic Guidelines (Cardiovascular).17
Table 9.4 Patients in the ‘very high risk’ category warranting therapy regardless of their fasting lipid levels
| The following patients are in the ‘very high risk’ category, regardless of their fasting lipid levels: |
Source: Therapeutic Guidelines (Cardiovascular).17
Table 9.5 Pharmacological treatment of dyslipidaemia
| DRUG | BENEFIT | DISADVANTAGE |
|---|---|---|
| Statin | Reduces LDL-C by 30–50%. Best tolerated | Reduces coenzyme Q10 |
| Bile-acid binding resin | Reduces LDL-C by 15–25% | Poorly tolerated, may worsen hypertriglyceridaemia |
| Nicotinic acid | Reduces LDL-C by 15–30%, triglycerides by 25–40%. Increases HDL-C by 20–35% | Causes severe flushing, which limits use |
| Ezetimibe | Reduces LDL-C by 18%. Well tolerated | Generally not used alone |
| Fibrate | Reduces LDL-C by 18%,∗ and triglycerides by 40–80%. Increases HDL-C by 10–30% | ∗Can increase LDL-C in some instances. |
Source: Taken from Australian Medicines Handbook.45
KEY TREATMENT PROTOCOLS
Plasma total homocysteine (Hcy) has been associated with cardiovascular risk in multiple large-scale epidemiological studies, and it has been considered as an independent risk factor for atherosclerosis.21 Evidence indicates that although mild hyper-Hcy may be regarded as a minor risk factor for CHD in low-risk patients, it can play a role in triggering new events in patients with known CHD, also by interacting with the
‘classical’ CV risk factors.21 The administration of vitamins B6 (300 mg/day) and B12 (250 μg/day) and folic acid (10 mg/day) over a 120-day period reduced plasma Hcy levels by 24%; this in turn resulted in a 28.5% reduction in coronary risk.22 In a study of 23 patients with angiographically proven coronary artery disease, daily dosing with a multivitamin containing 0.65 mg folic acid, 150 mg alpha-tocopherol, 150 mg ascorbic acid, 12.5 mg beta-carotene and 0.4 mg B12 produced a 28% reduction in Hcy and a decrease in in vitro LDL oxidation of 39%.23 However, in patients with stable coronary artery disease, Hcy-lowering therapy with B vitamins does not affect levels of inflammatory markers (CRP and soluble CD4 ligands CD40L) associated with atherogenesis.24 After two months treatment with oral folic acid in 16 patients with insulin-dependent diabetes, plasma Hcy fell by 25%, however there was no difference in endothelial function or markers of oxidant stress.25 There was however both a reduction in Hcy levels and an increase in endothelial function in a study of 60 patients receiving either 5 mg of folic acid or 600 mg of N-acetylcysteine.26 Of interest is a small study in which 12 patients with coronary artery disease underwent therapy with high dose (10 mg daily) folic acid therapy. Whereas resting myocardial blood flow remained unchanged, stress myocardial blood flow and coronary flow reserve increased significantly along with reduction in Hcy.27 Phenolic compounds from extra virgin olive oil (hydroxytyrosol, homovanillyl alcohol, caffeic acid and ferulic acid) in vivo significantly reduced homocysteine-induced endothelial dysfunction.28
C-reactive protein (CRP)
C-reactive protein (CRP) is an inflammatory protein that may play a role in the pathogenesis of atherosclerosis. Evidence now suggests that a single nucleotide polymorphism that results in the CRP-757C allele may be responsible for an increase in the intima thickness in the carotid arteries of cardiovascular patients.29 Loss of body fat has a positive correlation with lower CRP levels. A study of 33 obese subjects over 20 weeks showed a 35% reduction in CRP levels only after significant loss of body fat; this reduction was maintained for the duration of the study.30 In epidemiological trials high fibre intakes have consistently been associated with reduction in cardiovascular disease risk and CRP levels. A data synthesis of seven clinical trials reported significantly lower CRP concentrations in six of them in the vicinity of 25–54% through increased dietary fibre consumption with dosages ranging between 3.3 and 7.8 g/MJ.31 Inflammatory reactions in coronary plaques play an important role in the pathogenesis of acute atherothrombotic events. The association of serum CRP with the incidence of first major coronary heart disease (CHD) event was studied in 936 men.32 The results indicated that there was a prognostic significance to raised CRP and CHD events.32 Antioxidants may play a role in reducing levels of CRP. Vitamin C supplementation at 515 mg daily reduced CRP levels by 24%.33 Alpha-tocopherol (vitamin E) supplementation (especially at higher doses) in human subjects and animal models has been shown to be both antioxidant and anti-inflammatory, decreasing C-reactive protein (CRP) and the release of pro-inflammatory cytokines such as chemokines IL-8 and PAI-1.34
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