NEWS & EVENTS

NEWS ARCHIVE | EDUCATIONAL RESOURCES

LIPID AND CARDIAC RISK PROFILES

Over the last several decades, abundant evidence has accumulated relating the concentrations of lipids (chiefly cholesterol and triglycerides) and their associated blood transporting lipoproteins (e.g., high density lipoproteins [HDL], low density lipoproteins [LDL], very low density lipoproteins [VLDL]) with the occurrence of atherosclerosis in general, and coronary artery disease (CAD), in particular. There has been success in moderating the incidence of CAD and its sequela by altering activities of daily living (diet, weight control/exercise, smoking cessation, stress reduction, etc.) and, more recently, by the introduction of the “statin” drugs (medications which inhibit the liver enzyme hydroxymethyl coenzyme A reductase [HMGCoA reductase], which controls the production of lipids in the liver).

However, it is a disquieting fact that approximately one-half of first-time myocardial infarctions (heart attacks) are experienced by people who have no apparent lipid abnormalities. This fact has led to the search for other demonstrable markers (cardiac risk factors) through which we may identify those at risk earlier. Desirable characteristics of these additional cardiac risk factors would be: (1) they should be independent of other risk factors in origin or predictive value, and (2), they should be modifiable such that the excess risk the patient experiences is also reduced.

Over the last decade, considerable effort has been expended in identifying cardiac risk factors, with very encouraging results. Current research is focusing on further defining the efficacy of these (and other) apparently independent risk factors for CAD and this new information has reinvigorated the investigations of the fundamental causes of atherosclerotic plaque formation in our arteries. Though still very early, there is accumulating evidence that: (1) the excess risk of CAD attributable to each of the independent risk factors appears to be additive, and (2), amelioration of these risk factors, in some cases, does appear to decrease the risk for a future coronary event.

We at Physicians Reference Laboratory (PRL) have reviewed the current diagnostic laboratory options for cardiac risk assessment and have established the following approach:

LEVEL I - LIPID PROFILE
This group of blood tests includes total cholesterol, HDL cholesterol, triglycerides, calculated LDL cholesterol, VLDL cholesterol and total cholesterol/HDL cholesterol ratio. If abnormalities are identified, if other risk factors are present, or if there is a family history of atherosclerosis or CAD, proceed to Level II.

LEVEL II - CARDIAC RISK PROFILE
This group of blood tests includes measurement of hs-C-reactive protein (hs-CRP), homocysteine, fibrinogen, total blood cholesterol (TC), triglycerides, and lipoprotein electrophoretic fractionation (in percentages and mg/dL), including HDL, LDL, VLDL, along with calculated LDL/HDL and TC/HDL ratios. Also included is the quantitation of the lipoprotein Lp(a).

In certain circumstances, as in a patient with normal blood lipids but with a family history of atherosclerosis/CAD or early mortality, the physician may find the assessment of LDL particle size to be helpful and PRL can provide this by request. Diagnostic notes are also included in the report.

INTERPRETIVE NOTES FOR PROFILE ELEMENTS
ATP III Guidelines for LDL, Total Cholesterol, HDL Cholesterol, and Triglycerides (in mg/dL)*

LDL CHOLESTEROL		TRIGLYCERIDES
<100	Optimal	<150	Normal
100 - 129	Near optimal/above optimal	150 - 199	Borderline high
130 - 159	Borderline high	200 - 499	High
160 - 189	High	>500	Very high
>190	Very high

TOTAL CHOLESTEROL		HDL CHOLESTEROL
<200	Desirable	<40	Low
200 - 239	Borderline high	>60	High (Desirable)
>240	High

*National Cholesterol Education Program, ATP III Guidelines, May, 2001

TOTAL CHOLESTEROL/HDL-CHOLESTEROL (TC/HDL-C) AND LDL-CHOLESTEROL/HDL-CHOLESTEROL RATIOS

Though somewhat crude, these ratios have been shown to be predictive of risk potential for future CAD. As the ratios rise, so does the risk for CAD. Correlation of the TC/HDL-C ratio and hs-CRP level is also a powerful CAD risk predictor (see below).

HS-CRP

This is one of the "acute-phase reactant" blood proteins and can be elevated in a wide variety of conditions (in infections, inflammation, trauma, diabetes, post-menopausal women on hormone replacement therapy, etc.). However, in the absence of these, the blood concentration is relatively stable and has been found to be quite predictive of future CAD/myocardial infarction, particularly when considered in concert with the TC/HDL-C ratio. Note that aspirin, the "statin" drug pravastatin and anti-inflammatory agents have been shown to lower the hs-CRP level.

Relative risk estimates for future coronary events in men and women associated with quintiles of hs-CRP and TC:HDL-C ratio.
			Quintiles of hs-CRP, mg/L
Quintile of TC:HDL-C ratio	Men	Women	1 (< 0.7)	2 (0.7 - 1.1)	3 (1.2 - 1.9)	4 (2.0 - 3.8)	5 (3.9 - 15.0)
1	< 3.4	< 3.4	1	1.2	1.4	1.7	2.2
2	3.4 - 4.0	3.4 - 4.1	1.4	1.7	2.1	2.5	3
3	4.1 - 4.7	4.2 - 4.7	2	2.5	2.9	3.5	4.2
4	4.8 - 5.5	4.8 - 5.8	2.9	3.5	4.2	5.1	6
5	> 5.5	> 5.8	4.2	5	6	7.2	8.7

Source: Rafai and Ridker, Clin Chem. 2001; 47: 407

HOMOCYSTEINE

Studies have shown that increased levels of blood homocysteine represents an independent risk factor for acute coronary thrombosis, is a predictor of premature coronary disease/atherosclerosis, and is associated with deep vein thrombosis and thromboembolism. It should be remembered that vitamin deficiencies (B-12, folate), smoking, and many drugs may increase the blood concentration of homocysteine.

FIBRINOGEN

A significant positive relationship exists between fibrinogen levels and the severity of CAD and its sequela. There is also some evidence that low fibrinogen levels reflect a low risk for coronary events even in the presence of elevated cholesterol levels [Thompson, NEJM 1995 March 9;332(10);635-541].

LIPOPROTEIN (a) [Lp(a)]

A number of studies have demonstrated elevated levels of the lipoprotein Lp(a) in patients with angiographic evidence of coronary artery stenosis. As the blood Lp(a) level rises above normal, the odds ratio for progression of CAD also rises, such that at greater than or equal to 30 mg/dL, the risk is more than doubled [Matsumoto, J Atheroscler Thromb, 1998;5(2):47-53]. Another study has related Lp(a) levels to total cholesterol/HDL-cholesterol (TC/HDL-C) ratios such that when Lp(a) is greater than 50 mg/dL and the plasma TC/HDL-C ratio is greater than 5.8, the relative odds for CAD is 8.0-9.6 [Hopkins, Atherosclerosis 1998 Dec;141(2):333-45].

LDL PARTICLE SIZE DETERMINATION

Monitoring and manipulation of blood LDL-cholesterol have been the principle focus of prevention and control of atherosclerosis/CAD, as reflected above in the NCEP ATP III Guidelines. Beyond LDL-cholesterol proper is research beginning in the early 1990s that suggests that the determination of the size of the LDL particles may have some benefit in some patients [Lamarche, Quebec Cardiovascular Study, Circulation 1996; 94:2146-2153]. Fundamentally, LDL particles may be separated by several different methods (polyacrylamide gel electrophoresis being the “gold standard”) into a group of larger, less-dense particles (type A) and a group of smaller, more-dense particles (type B). The presence of more of the type B (small, dense particle) has been related to an increased risk of CAD and is also seen in type II diabetes mellitus and a syndrome termed the insulin resistance syndrome (or metabolic syndrome). For the exceptional patient with normal lipid studies as above, but with a family history of CAD or early mortality, or some combination of risk factors as previously described, LDL particle size determination may offer some clinical benefit. Additionally, there is some suggestion that this determination may be helpful in monitoring drug therapy. Until further research clarifies and rationalizes its use, LDL particle size determination will continue to be available for the exceptional clinical circumstance and is not considered an appropriate screening test.

Kenneth C. Cummings, MD
Chief, Clinical Pathology
March, 2003