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Cardiovascular Risk Panel

Myocardial infarction often occurs among individuals without traditional risk factors such as hyperlipidemia, hypertension, diabetes mellitus, and smoking. Many epidemiological studies have reported an association between coronary heart disease (CHD) and various “inflammatory” factors, including plasma levels of fibrinogen, C-reactive protein, albumin, and white blood cell (WBC) count. Other factors such as homocysteine and Lp(a) can also play a significant role.

Fibrinogen

Fibrinogen is an acute phase reactant and the fibrinogen level may be elevated as a consequence of the inflammation that accompanies atherosclerosis. Several studies indicate that fibrinogen is an important risk factor for atherosclerotic vascular disease. A meta-analysis confirmed the association of increased fibrinogen levels with subsequent MI or stroke. Eighteen prospective studies involving 4018 cases of CHD were analyzed (JAMA 1998; 279:1477-82). Persons with fibrinogen concentrations in the upper tertile had a relative risk of future cardiovascular disease that was 1.8 times higher than the risk in persons in the lowest tertile.

Tertile

Fibrinogen (mg/dL)

Risk Ratio

1

<250

1.0

2

250 – 350

NA

3

>350

1.8

For men, fibrinogen risk was greatest for stroke, intermediate for MI and smallest for peripheral vascular disease. For women, fibrinogen risk was greatest for CHD. Fibrinogen levels are, in part, genetically determined. Men tend to have higher levels than women and black persons tend to have higher levels than white persons. Several environmental factors also affect fibrinogen levels. Fibrinogen levels are 10% higher in smokers. Smoking cessation, exercise, alcohol intake and estrogens can reduce fibrinogen levels.

High Sensitivity CRP (hs-CRP)

All prospective studies reported to date have indicated that basal CRP values in the highest tertile of data are associated with a 2.3 to 4.8-fold increased relative risk of developing cardiovascular disease (JAMA 2001; 285:2481-85).

Interpretation

CRP (mg/L)

Low cardiac risk

<1.0

Average cardiac risk

1.0 – 3.0

High cardiac risk

>3.0

Infection or Inflammation

>10

CRP is a risk factor for future myocardial infarction, ischemic stroke, peripheral arterial disease and CHD mortality in apparently healthy men and women. In addition, elevated CRP is predictive of cardiac complications in patients with unstable angina or myocardial infarction. CRP should only be ordered for cardiovascular risk assessment. It should not be ordered if a patient has had recent inflammation, infection or trauma, in which case a period of 2 weeks is usually adequate for CRP concentrations to return to basal levels. The predictive value of CRP is greatly improved if two measurements are made approximately 1 month apart and the lowest of these values is used to determine the appropriate quintile for cardiovascular risk assessment. It is especially important to repeat CRP values >5 mg/L to avoid misclassification because of clinically silent infection.

Homocysteine

A meta-analysis of 27 studies indicated that increased homocysteine (Hcy) levels are associated with an increased risk of CHD, peripheral arterial disease, stroke and venous thromboembolism (Ann Intern Med 1999;131:363-375). The European Collaborative Study concluded that homocysteine was an independent risk factor for atherosclerotic vascular disease and calculated that a 5 uM/L increment in fasting Hcy was associated with a relative risk of 1.35 in men and 1.42 in women. This is the same degree of risk that is conferred by a 20 mg/dL increase in total cholesterol.

Hcy Level uM/L

Interpretation

Risk Ratio

<12

Optimal

1.0

12-15

Borderline

1.9

16-30

Moderate elevation

2.2

>30

Significant elevation

5.7

Lipoprotein (a)

A meta-analysis of 27 prospective studies involving 5436 CHD cases observed during a mean interval of 10 years provides the most reliable assessment so far of the association of Lp(a) levels and CHD (Circulation 2000;102:1082-85). Comparison of individuals with baseline Lp(a) levels in the highest tertile with those in the lowest tertile yielded a risk ratio of 1.6 for all studies. When the analysis was restricted to the 18 studies involving general populations the combined risk ratio was still 1.7. The risk ratio was lower (1.3) in the 9 studies of patients with preexisting disease.

The Heart and Estrogen/Progestin Replacement Study (HERS) determined the relationships among treatment with estrogen and progestin, plasma Lp(a) levels and subsequent CHD in 2763 post-menopausal women (JAMA 2000;283:1845-52). Women in the third and fourth quartiles had an increased relative risk of subsequent coronary heart disease, death or nonfatal myocardial infarction compared to women in the lowest quartile.

Quartile

Lp(a) mg/dL

Relative Risk

1

0 – 7.0

1.00

2

7.1 – 25.3

1.01

3

25.4 – 54.9

1.31

4

55 - 236

1.54

Estrogen and progestin therapy reduced mean Lp(a) levels by 15 mg/dL for women in the third and fourth quartiles and reduced the risk of secondary coronary events by 15 to 20%. Estrogen and progestin therapy had a more favorable effect in women with high initial Lp(a) levels than in women with low levels.

Hemoglobin A1c

Macrovascular disease is the most important cause of mortality and morbidity in individuals with type 2 diabetes. Even when adjusted for conventional risk factors, diabetic individuals still exhibit a two to four fold increased risk in comparison to nondiabetic people. Therefore, hyperglycemia is strongly suspected of promoting atherogenesis. Excess glucose is transformed into advanced glycation endproducts (AGEs) that not only make blood vessels inelastic and stenotic but also activate chronic inflammation.

Hemoglobin A1c concentration is an indicator of average blood glucose concentration over the previous three months and is the most widely used test to monitor diabetes. Recent studies have demonstrated that HbA1c is also a predictor of all-cause, cardiovascular and ischemic heart disease mortality even at concentrations below the accepted threshold for diabetes (British Med J 2001; 322:15-18). The following table lists the relative risk of cardiovascular disease for each quartile of HbA1c concentration.

HbA1c (%)

Relative Risk

<5

1.0

5.0 – 5.4

2.5

5.5 – 6.9

2.5

7 or >

5.0

Individuals with HbA1c concentrations above 5% had greater risk than individuals with concentrations below 5%. Approximately 25% of the population had HbA1c levels below 5% and 70% of the population had levels between 5 and 6.9%. HbA1c appears to resemble blood pressure and cholesterol in terms of its continuous relationship with cardiovascular risk.

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