International Task Force for Prevention of
Coronary Heart Disease

CORONARY HEART DISEASE: REDUCING THE RISK

2.3 Biochemical and laboratory risk factors<

2.3.1 Plasma lipids and lipoproteins

For comprehensive risk assessment, preferred measurements comprise plasma total cholesterol, LDL-cholesterol, HDL-cholesterol and triglyceride after a 14-hour fast (drinking water is allowed). If this is impracticable, a non-fasting cholesterol level should be obtained, as this will at least detect certain major familial hyperlipidaemias that confer very high risk and consequently require treatment. LDL-cholesterol is preferable to total cholesterol in monitoring therapy because it is more closely related to risk. For accurate assessment, two consistent lipid measurements are needed because of the considerable day-to-day variation in triglyceride levels. LDL-cholesterol levels are directly and causally related to CHD risk, while HDL-cholesterol is inversely related to risk. Triglyceride levels in the range of 150-400 mg/dL (1.7-4.5 mmol/L) are associated with increased risk of CHD, especially when accompanied by low HDL-cholesterol (< 35 mg/dL (0.9 mmol/L) in men, < 40 mg/dL (1.1 mmol/L) in women). A meta-analysis of epidemiological studies has confirmed that elevated plasma triglyceride levels are an independent risk factor for CHD, especially in women but also in men. No clinical trial designed to study the effect of lowering elevated triglyceride levels on CHD risk has yet been completed.
Hypertriglyceridemia is often associated with the presence of a particularly atherogenic form of LDL called small dense LDL. It is important that laboratories that measure lipids should take part in certified inter-laboratory quality control programmes in order to ensure comparability and accuracy of results.

Although CHD risk is continuously related to plasma lipid and lipoprotein levels the following limits are widely used and are helpful in clinical practice:

• Triglyceride 150-400 mg/dL (1.7-4.5 mmol/L) ¹¹
• Total cholesterol > 200 mg/dL (5.2 mmol/L) ¹².
• LDL-cholesterol > 135 mg/dL (3.5 mmol/L).
• HDL-cholesterol < 35 mg/dL (0.9 mmol/L) in men or << 40 mg/dl (1.0 mmol/L) in women
• A ratio of total cholesterol to HDL-cholesterol > 5 (Figure 4)
• Lp(a) levels > 30 mg/dL ¹³.

Figure 4: The risk of coronary heart disease increases with increases in the ratio of total to HDL-cholesterol and shows a sharp rise at ratios > 5.0.

In interpreting lipid results, four important items should be borne in mind:

1. THE LIPID FINDINGS SHOULD ALWAYS BE CONSIDERED IN THE CONTEXT OF THE PERSON'S GLOBAL RISK OF CORONARY HEART DISEASE.
2. The relationship between these levels and the risk of a CHD event is a continuous one; there is no threshold, i.e. no single value that separates "normal" from "abnormal" (Figure 5).
3. The relationship between plasma cholesterol or LDL-cholesterol and CHD risk is semi-logarithmic: a difference of e.g 40 mg/dL (1 mmol/L) predicts a far larger difference in risk at higher than at lower levels.
4. For a reliable estimate of risk, the mean of at least two consistent measurements should be used because of the considerable day-to-day variation in lipid levels. This variation can be lessened by using consistent technique for venesection i.e. avoiding prolonged venous stasis by minimal use of the tourniquet, and standardising posture i.e. always seated or always lying down. Since lipid and lipoprotein levels are often unrepresentatively low during acute illness or after injury, measurements should be deferred for 2 weeks after minor febrile illnesses, and for up to 3 months after major illness or surgery. A blood sample obtained within 24 hours of the onset of symptoms of a myocardial infarction provides reliable results. In general, however, lipid levels and HDL-cholesterol decrease soon after hospitalisation. Measurements taken during a hospital stay are therefore of limited value in calculating risk and deciding on treatment.

Figure5: Relationship between plasma LDL-cholesterol and CHD risk. The relationship is a continuous and semilogarithmic. The diagram shows curves derived from high risk and moderate risk groups of middle-aged men in the PROCAM study and illustrates the 8-year risk of a coronary event according to the LDL-cholesterol level. In addition, the theoretical benefit to be expected in an individual with 30% lower LDL-cholesterol is shown. Note that because of the semilogarithmic nature of the curves, the absolute benefit is greater at higher than at lower LDL-cholesterol levels. Also, high risk individuals may derive greater benefit from treatment than low risk individuals with the same LDL-cholesterol. Similar curves have been derived from the data of other large epidemiological investigations such as the Framingham study.

One recent advance in risk assessment is based on the recognition that asymptomatic atherosclerosis can be strongly predictive of increased risk. Using ultrasound imaging of both carotid arteries, the presence of stenoses predicts a 6-fold increase in risk of myocardial infarction compared with persons with normal arteries; the presence of plaque(s) predicts a 4-fold increase, and thickening of the intima and media without plaque or stenosis indicates a 2-fold increase in risk. In patients without symptomatic cardiovascular disease and without ischaemic ECG abnormalities, a quantitative Doppler ultrasound study of the carotid arteries is of value when risk status, and consequently choice of treatment, remain uncertain. Increased risk is also conferred by the presence of atherosclerosis of the peripheral arteries, as evidenced by a history of intermittent claudication, absent foot pulses, doppler sonographic studies or a subnormal ratio of ankle to brachial blood pressure. In one study, only 10% of patients with peripheral vascular disease were found to have normal coronary arteries, while 30% had advanced coronary atherosclerosis. Up to 50% of patients with intermittent claudication have atherosclerosis of the carotid arteries. ¹² In patients with peripheral vascular disease, the mortality rate is two to three times greater than in the general age- and sex-matched population; 10-20% of deaths in such patients are due to stroke and 40-60% due to coronary artery disease. ¹³

2.3.2 Blood glucose

2.3.2.1 Diabetes mellitus

• Both type 1 and type 2 diabetes mellitus are associated with a marked increase in risk of CHD, cerebrovascular, and peripheral vascular disease, and these disorders are major causes of morbidity and mortality in diabetics. In general, atherosclerosis and its complications occur earlier and are two to four times more frequent in diabetics than in non-diabetics. Progression of atherosclerosis is more rapid in diabetics and is often the cause of death.
• In most studies the excess risk of CHD caused by diabetes is relatively greater in diabetic women than in diabetic men. Diabetic women also have a greater risk of peripheral vascular disease than diabetic men.
• All type 2 diabetics pass through a phase of impaired glucose tolerance that precedes the onset of frank disease. Increased levels of cardiovascular risk factors, in particular high triglyceride, low HDL-cholesterol, a high proportion of the small, dense variety of LDL and hypertension may all occur in patients with impaired glucose tolerance.
• The increased risk of cardiovascular disease due to diabetes may result from many factors, including :
  • plasma lipid abnormalities (high triglyceride, low HDL-cholesterol, sometimes high LDL-cholesterol)
  • hypertension
  • nephropathy
  • insulin resistance
  • disorders of the clotting and fibrinolytic systems (hyperfibrinogenaemia, elevation of type 1 plasminogen activator inhibitor (PAI-I), impaired fibrinolysis).
  • the hyperglycaemia itself (due to formation of advanced glycosylation end-products)
• Lipid disorders are usually more pronounced in type 2 diabetes and impaired glucose tolerance than in type 1 diabetes.
• Lipid abnormalities are improved by good glycaemic control, especially if body weight is normalised, but may not be fully controlled. Thus, even in the presence of good glycaemic control, correction of lipid abnormalities is a necessary further goal. Lipid-lowering drugs including statins should therefore be prescribed as necessary in diabetic patients.

The diagnostic criteria for diabetes mellitus were revised in 1997 to take into account information accumulated over the past decade about the power of blood sugar levels to predict diabetic complications. The classification of diabetes has also been revised to reflect the disease's aetiology where possible.
The revised criteria for the diagnosis of diabetes are shown in Table 3. Three criteria are given, and each requires confirmation on a subsequent day. (For epidemiological studies, estimates of diabetes prevalence and incidence are based on a fasting plasma glucose ³ 126 mg/dL (7 mmol/L)).

Table 3:Criteria for diagnosis of diabetes mellitus.

1. Symptoms of diabetes (polyuria, polydipsia, unexplained weight loss), plus casual plasma glucose concentration ³ 200 mg/dl (11.1 mmol/L). "Casual" is defined as any time of the day without regard to time elapsed since last meal.

   OR

2. Fasting plasma glucose ³ 126 mg/dl (7.0 mmol/L). Fasting is defined as no caloric intake for at least eight hours.

   OR

3. Two-hour plasma glucose ³ 200 mg/dl (11.1 mmol/L) during an oral glucose tolerance test using a 75 g glucose load dissolved in water.

Some aspects of the revised classification of diabetes mellitus and other categories of glucose regulation should be referred to. The terms insulin-dependent diabetes mellitus (IDDM) and non-insulin-dependent diabetes mellitus (NIDDM) are no longer used, while the terms type 1 and type 2 diabetes are retained, (with Arabic numerals). Type 1 diabetes includes the vast majority of patients whose disease is primarily due to damage to pancreatic islet b-cells (usually by an autoimmune process), and who are prone to develop ketoacidosis. Type 2 diabetes, the most prevalent form of diabetes results from insulin resistance, although there is probably also impaired secretion of insulin. Obesity, which is highly prevalent in this type of diabetes, is a major cause of insulin resistance. Since hyperglycaemia and its symptoms develop gradually, this form of diabetes frequently goes undiagnosed for many years. Unfortunately even asymptomatic patients are at increased risk of developing macrovascular and micro-vascular complications. The diagnostic criteria of the prediabetic state were also revised in 1997 as shown in Table 4.

In patients with diabetes mellitus, annual screening for microalbuminuria will allow the identification of patients with diabetes nephropathy very early in its course. Improving glycaemic control, aggressive antihypertensive treatment, and the use of ACE-inhibitors will slow down the rate of progression of nephropathy. In addition, protein restriction and other treatments such as a low phosphate intake may benefit selected patients.

Table 4: Criteria for the diagnosis of the prediabetic state

1. Borderline fasting glucose
   Fasting plasma glucose ³ 110 mg/dl (6.1 mmol/L) but < 126 (7.0 mmol/L) mg/dl. "Fasting" is defined as no caloric intake for at least eight hours.

   OR

2. Impaired glucose tolerance (IGT)
   Two-hour plasma glucose ³ 140 mg/dl (7.8 mmol/L) but < 200 mg/dl (11.1 mmol/L) during an oral glucose tolerance test using a 75 g glucose load dissolved in water.

2.3.2.2 The "metabolic syndrome"

The term metabolic syndrome is one of the several used to describe a cluster of metabolic disturbances that strongly predispose to the development and progression of atherosclerosis. Other terms include "syndrome of central obesity", the "syndrome of insulin resistance" and "syndrome X". Visceral and central obesity and peripheral resistance to the action of insulin are thought by many to be at the heart of this metabolic syndrome, and many affected persons ultimately develop frank type 2 diabetes mellitus (Figure 6). The prevalence of insulin resistance varies according to ethnicity and is particularly high, for example, among native Americans, some Polynesian peoples and inhabitants of the Indian subcontinent. According to the World Health Organization, the prevalence of type 2 diabetes is expected to increase considerably within the next decade (Figure 7).

Figure 6: Insulin resistance and the metabolic syndrome. Under normal circumstances lipid metabolism is regulated by insulin, particularly in the postprandial period. Insulin, by its action on hormone sensitive lipase, inhibits the release of free fatty acids (FFA) from adipose tissue and the secretion of very low density lipoproteins (VLDL) by the liver. Insulin also accelerates the action of lipoprotein lipase (LPL), an enzyme localised in capillaries which hydrolyzes the triglycerides (TG) in VLDL and chylomicrons. All these effects lead to a reduction in circulating triglyceride-rich particles (VLDL and chylomicrons) and, secondarily, to a reduction in circulating low-density lipoproteins (LDL). Under circumstances of peripheral insulin sesistance, the release of FFA from adipose tissue and of VLDL from the liver is accelerated and the breakdown of these particles by LPL is reduced. This leads to an increase in circulating triglyceride-rich remnant lipoprotein particles which are thought to be particularly atherogenic. Secondarily, there is a reduction in HDL-cholesterol due to increased exchange of triglycerides in VLDL and chylomicrons for cholesteryl ester in HDL by action of cholesteryl ester (CE) transfer protein FC= free cholesterol

• Most experts agree that the metabolic syndrome comprises insulin resistance, central obesity (waist:hip ratio > 1.00 in men or > 0.85 in women), hyperinsulinism, and one or more of the following: impaired glucose tolerance, dyslipidaemia, hypertension, hyperuricaemia and gout, hypercoagulability, and fatty liver.
• The term impaired glucose tolerance refers to a stage intermediate between normal glucose homeostasis and diabetes and is defined in Table 4. Impaired glucose tolerance is not a disease entity but rather a risk factor for future diabetes and cardiovascular disease.
• The usual lipid abnormality in the metabolic syndrome is the so-called "lipid triad", with high plasma and LDL-cholesterol, high triglyceride, and low HDL-cholesterol levels.
• Treatment of the metabolic syndrome should focus in the first instance on the correction of overweight through diet and physical exercise. This often leads to improvement, even full correction of the other components of the disorder.

Figure 7: Worldwide prevalence of type 2 diabetes mellitus. The prevalence of type 2 diabetes mellitus is expected to increase throughout the world in the next years (The World Health Report 1997: conquering suffering, enriching humanity, World Health Organization, Geneva, 1997, p. 39).

2.3.3 Thrombogenic risk factors

Several studies have shown that high concentrations of fibrinogen, clotting factor VIIc and PAI-I an inhibitor of fibrinolysis, are associated with increased morbidity and mortality from coronary heart disease. High fibrinogen and LDL-cholesterol occurring together have a large effect in increasing the risk of coronary heart disease. In men with low fibrinogen concentrations the incidence of coronary heart disease is little affected by levels of LDL-cholesterol. These thrombogenic risk factors often accompany other risk factors: fibrinogen is strongly associated with smoking and age, factor VII with triglyceride and cholesterol, PAI-1 with the metabolic syndrome of insulin resistance and with obesity. There is a clear association between increased fibrinogen and coronary heart disease risk; but in the individual, a raised fibrinogen level must be interpreted with caution because transient elevation is common in intercurrent acute illness as part of the acute phase response. Problems with interlaboratory standardization have yet to be solved.

In many studies, anti-platelet drugs have been shown to reduce recurrence of myocardial infarction and mortality from cardiac causes in patients with preexisting CHD. They are also reduce the incidence of thrombosis in aorto-coronary bypass grafts.

Anti-platelet drugs should therefore be prescribed, unless contraindicated, for patients with:

• stable and unstable angina pectoris
• a history of recent myocardial infarction
• aorto-coronary bypass grafts or history of percutaneous transluminal coronary angioplasty
• transient ischaemic attacks
• thrombotic stroke and cerebral embolism
• · chronic occlusion of a peripheral artery

2.3.4 Homocysteine

Homocysteine is a sulfur-containing amino acid that is an intermediate product of the metabolism of methionine and cysteine. Rare homozygous defects of the key enzyme cystathione-beta-synthase cause homocystinuria, which is associated with up to tenfold elevations of plasma homocysteine levels and with premature atherosclerosis, recurrent thromboses of coronary, cerebral or peripheral arteries and venous thrombosis. Recent prospective studies and case control studies have shown that even moderately elevated levels of homocysteine also increase the risk of both atherosclerosis of the coronary, cerebral, and peripheral arteries and of cardiovascular death. A meta-analysis of 27 studies calculated that each 5 µmol/L increase in the homocysteine level increases the risk for coronary artery disease by 60% in men and by 80% in women, which is equivalent to the effect of an increase of 20 mg/dL in total plasma cholesterol. Homocysteine levels show a strong inverse correlation both with dietary intake and with plasma levels of the vitamins folate, B6 and B12; these are essential cofactors in homocysteine metabolism. A common polymorphism in the gene for methylene-tetrahydrofolate reductase appears to influence the sensitivity of homocysteine levels to folic acid deficiency.

At present, there is insufficient evidence to recommend measuring homocysteine levels in the general population. Homocysteine itself may not be an independent risk factor, since levels correlate with renal function, smoking, and levels of fibrinogen and C-reactive protein, which are known markers of increased risk for CHD. In addition, the risk threshold is unclear and recommended cut-off levels vary between 12 and 18 µmol/L. Treatment with folic acid, vitamin B6 and vitamin B12 lowers homocysteine levels, but no trial evidence exists that this treatment reduces cardiovascular event rates.

Homocysteine levels should be measured in patients with a history of premature coronary artery disease and/or stroke who do not have classical risk factors. It should also be determined in individuals with a history of venous thromboembolism and athero---sclerosis.

Individuals with homocysteine levels > 12 µmol/L should be encouraged to increase intake of foods rich in folic acid such as vegetables and fruit. Supplements of 400-800 µg folic acid + 2-4 mg vitamin B6 + 400 µg vitamin B12 per day may be given. If homocysteine level exceeds 30 µmol/L, vitamin supplements in this dosage should always be considered.