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The laboratory's role in identifying lipid and lipoprotein risk factors for CHD.

Periodic physical exams are part of a program of good health habits, and clinical laboratory tests are usually part of any periodic physical exam. Among the laboratory tests under these circumstances are those that screen for the long-term risk of coronary heart disease coronary heart disease: see coronary artery disease.
coronary heart disease
 or ischemic heart disease

Progressive reduction of blood supply to the heart muscle due to narrowing or blocking of a coronary artery (see atherosclerosis).
 (CHD CHD coronary heart disease.

Latin Chirurgiae Doctor (Doctor of Surgery)

CHD, See disease, coronary heart.


canine hip dysplasia.
), which can often be prevented if physicians and patients work together when necessary in response to the laboratory results. CHD is a complex phenomenon with multiple risk factors that are either modifiable or nonmodifiable. Age, gender, and genetic predisposition genetic predisposition Molecular medicine The tendency to suffer from certain genetic diseases–eg, Huntington's disease, or inherit certain skills–eg, musical talent  are nonmodifiable risk factors. Other established risk factors, such as smoking, hypertension, obesity, and dyslipoproteinemias are generally considered to be within one's control to normalize normalize

to convert a set of data by, for example, converting them to logarithms or reciprocals so that their previous non-normal distribution is converted to a normal one.
. Abnormalities in hemostatic hemostatic /he·mo·stat·ic/ (he?mo-stat´ik)
1. causing hemostasis, or an agent that so acts.

2. due to or characterized by stasis of the blood.

, oxidative, or inflammatory factors might also increase the long-term risk for CHD but are not discussed here.

CHD develops slowly and asymptomatically for many years, and the first stage of the disease is often evident at a surprisingly early age. Coronary fatty streaks can present even in the late teens and twenties, as observed in a high proportion of postmortem postmortem /post·mor·tem/ (post-mort´im) performed or occurring after death.

Relating to or occurring during the period after death.

See autopsy.
 exams of individuals who suffered traumatic, non-CHD fatalities.[1-3] At the present time, approximately 30% of CHD-related deaths occur in individuals with no prior symptomatic manifestations of the disease, partially because more than 65% of myocardial infarctions occur in vessels with less than 50% stenosis.[4]

Despite significant declines over the past 20 years, CHD is the number one cause of death in the United States, outranking all cancers combined by approximately 2:1. Declines in CHD-related mortality can be credited to a combination of factors, including (1) increased public awareness through campaigns that focus on smoking prevention and cessation; (2) increased understanding of the contribution of hypertension, diet, exercise, and cholesterol levels to disease; and (3) increased effectiveness of various therapies. However, substantial progress is still required, and new risk factors continue to be proposed and evaluated. If shown to add significantly to the risk profile, assays for these risks may become part of future laboratory test menus, in addition to the established risk factors that already involve clinical laboratory testing.

Traditional lipoprotein lipoprotein (lĭp'əprō`tēn), any organic compound that is composed of both protein and the various fatty substances classed as lipids, including fatty acids and steroids such as cholesterol.  profile

Approximately 30 years ago, a cholesterol level was considered high risk when it exceeded 7.8 mmol/L (300 mg/dL). Low density lipoprotein Low density lipoprotein (LDL)
A fraction of total serum lipids, the so called "bad" cholesterol.

Mentioned in: Hypercholesterolemia
 (LDL LDL - ["LDL: A Logic-Based Data-Language", S. Tsur et al, Proc VLDB 1986, Kyoto Japan, Aug 1986, pp.33-41]. ) and high density lipoprotein High density lipoprotein (HDL)
A fraction of total serum lipids, the so called "good" cholesterol.

Mentioned in: Hypercholesterolemia
 (HDL (Hardware Description Language) A language used to describe the functions of an electronic circuit for documentation, simulation or logic synthesis (or all three). Although many proprietary HDLs have been developed, Verilog and VHDL are the major standards. ) cholesterol were not determined clinically, and triglycerides Triglycerides
Fatty compounds synthesized from carbohydrates during the process of digestion and stored in the body's adipose (fat) tissues. High levels of triglycerides in the blood are associated with insulin resistance.
 were rarely measured. Since the late 1970s, however, the standard lipoprotein profile has included measurements for total cholesterol, triglycerides, HDL cholesterol HDL cholesterol
See high-density lipoprotein.

HDL Cholesterol
About one-third or one-fourth of all cholesterol is high-density lipoprotein cholesterol.
, and a calculated estimate of LDL cholesterol LDL cholesterol
See low-density lipoprotein.

LDL Cholesterol
Low-density lipoprotein cholesterol is the primary cholesterol molecule. High levels of LDL increase the risk of coronary heart disease.
 based on the equation by Friedewald et al.[5] This profile is still an important diagnostic tool for lipoprotein disorders.

It became increasingly clear over time that an elevated cholesterol level was associated with increased risk of CHD.[6-8] In 1988, the Adult Treatment Panel of the National Cholesterol Education Program The National Cholesterol Education Program is a program managed by the National Heart, Lung and Blood Institute, a division of the National Institutes of Health. Its goal is to reduce increased cardiovascular disease rates due to hypercholesterolemia (elevated cholesterol  (NCEP NCEP National Cholesterol Education Program ) set the cutoff for high-risk total serum cholesterol at [greater than or equal to] 6.2 mmol/L (240 mg/dL) by using data from Multiple Risk Factor Intervention Trial (MRFIT MRFIT Multiple Risk Factor Intervention Trial Cardiology A long-term prospective study designed to analyze the effects of modifying the risk factors for heart disease ).[8] A value of [greater than or equal to]4.1 mmol/L (160 mg/dL) was selected for LDL cholesterol because it corresponds to this total cholesterol level, and both values approximate the 75th percentile for adults. In addition, patients with LDL cholesterol levels of [greater than or equal to] 4.1 mmol/L (160 mg/dL) in the Lipid Research Center Coronary Primary Prevention Trial (LRC/CPPT) benefited by lowering their LDL cholesterol values.[7] Total cholesterol of 5.2-6.2 mmol/L (200-239 mg/dL) was in the borderline category. For HDL cholesterol, a value of [less than] 0.9 mmol/L (35 mg/dL) is the NCEP low cutoff for high risk based on Framingham data, and approximates the 20th percentile in men. NCEP considered triglyceride levels of [less than] 2.25 mmol/L (200 mg/dL) to be optimal, 2.25-4.50 mmol/L (200-359 mg/dL) to be borderline, and [greater than or equal to] 4.50 mmol/L (400 mg/dL) to be a high value. However, there was a lack of consensus in these studies on the value of using triglyceride as a CHD risk factor.

Total and HDL cholesterol results are used to screen and monitor patients; triglyceride results are often used to calculate an estimate of LDL cholesterol concentration, using the formula developed by Friedewald et al: LDL cholesterol = total cholesterol HDL cholesterol - (triglycerides/5).[5]

Triglyceride measurements are also important for diagnosing and monitoring individuals with severe hypertriglyceridemia. Borderline hypertriglyceridemia (2.25-4.50 mmol/L; 200-400 mg/dL) is associated with decreased HDL cholesterol levels and is commonly found in diabetics and CHD patients. Although not associated with CHD, severe hypertriglyceridemia ([greater than] 11 mmol/L; [greater than] 1000 mg/dL) is important to diagnose and treat because it can produce pancreatitis, which is a life-threatening condition.

In the late 1980s, the NCEP Laboratory Standardization Panel first established precision (coefficient of variation Coefficient of Variation

A measure of investment risk that defines risk as the standard deviation per unit of expected return.
) and accuracy (bias) limits at [less than or equal to] 5% for total cholesterol and later tightened them to the current limits of [less than or equal to] 3 % for each.9 Precision and accuracy limits were later set at [less than or equal to] 5% for triglycerides.[10]

Preanalytical considerations. There are additional factors separate from the actual analyses that can affect the reliability of individual lipid results. Sources of biological variation and other preanalytical variables are often difficult to control but must be minimized to whatever extent possible.[11] Although capillary blood is often used for screening purposes, results are potentially more variable than those from venous blood venous blood
n. Abbr. v
Blood that has passed through the capillaries of various tissues other than the lungs, is found in the veins, in the right chambers of the heart, and in pulmonary arteries, and is usually dark red as a result of a
. However, fingerstick specimens collected from a puncture that allows an adequate blood flow without excessively squeezing the finger can provide results that are as reliable as those from venous blood.[12]

In addition to proper technique for specimen collection, the position of an individual during collection is also important because lipid values vary depending on whether the person is standing, sitting, or prone.[13,14] When standing and prone positions are compared, cholesterol concentrations are approximately 10% higher when the patient stands versus when the patient is prone; triglycerides are approximately 12% higher; and HDL cholesterol is approximately 7% higher.[14] Although complete equilibration equilibration /equi·li·bra·tion/ (e-kwil?i-bra´shun) the achievement of a balance between opposing elements or forces.

occlusal equilibration
 takes about 30 minutes when changing position, sitting quietly for 5 minutes before specimen collection accounts for most of the hemodynamic he·mo·dy·nam·ics  
n. (used with a sing. verb)
The study of the forces involved in the circulation of blood.

 changes.[14] Consequently, this time for sitting has been incorporated into "standard procedure" for specimen collection. These changes are considered in the general population but will necessarily affect results obtained from hospitalized patients who cannot sit up for blood collection. Therefore, it is generally advisable to defer lipid testing until the patient is ambulatory and preferably free living.

Patient stress during hospitalization also affects lipid concentrations. Types of stress include both physiological (e.g., during hospitalization) and psychological. Total and HDL cholesterol concentrations can be markedly reduced under these conditions.[15,16] Viral infections for both inpatients and outpatients can also substantially reduce total and HDL cholesterol concentrations. If possible, specimen collection should be postponed until after a vital infection has resolved. It is rarely necessary to determine lipid/lipoprotein concentrations for inpatients; these analytes are better determined on an outpatient basis whenever possible.

Patient fasting is essential for accurate results from lipoprotein profiles; however, fasting is a relative term and can affect the accuracy of results and increase the variability among serial results. The time required to return to a true fasting state after eating depends on the amount and the type of food ingested and each individual's metabolic efficiency, which varies with body type, age, level of exercise, and lipid status. The triglyceride levels for young, fit individuals with low fasting values will often return to baseline within 8 hours, even after a high-fat, high-calorie meal. However, triglyceride levels for individuals with high fasting values and less efficient metabolism may require as many as 14 hours to return to baseline.[17,18] NCEP recommends a 9-hour fast. Based on our studies,[17,18] we recommend a 12- to 14-hour fast after a low-fat, low-calorie meal, with no intake of alcohol for 24 hours Adv. 1. for 24 hours - without stopping; "she worked around the clock"
around the clock, round the clock
. Our recommendations differ from those of the NCEP for several reasons, one of which is that our data are based on a high-fat meal (worst case scenario
This article is about the television show. For other uses, see worst-case scenario.

Worst Case Scenario is a reality show aired on TBS in 2002 in the U.S..
), whereas NCEP recommends a low-fat meal. Most lipid labs use 12 hours.

LDL cholesterol

Listed behind only smoking and hypertension, LDL and HDL cholesterol are currently considered to be the most important modifiable risk factors indicative of CHD. Therefore, laboratory assessment of these analytes must be precise and accurate. The NCEP Adult Treatment Panel uses LDL and HDL cholesterol concentrations as the basis for national guidelines to diagnose and treat CHD.[19] Consequently, the NCEP Laboratory Standardization panels have set national guidelines for laboratory precision and accuracy when measuring lipid analytes.[9,10,20,21]

Indirect measurement. Historically, LDL cholesterol has been measured after separation of lipoprotein classes by ultracentrifugation ultracentrifugation /ul·tra·cen·trif·u·ga·tion/ (ul?trah-sen-trif?u-ga´shun) subjection of material to an exceedingly high centrifugal force, which will separate and sediment the molecules of a substance. [22,23] or estimated using a formula.[5,24] As performed at the Centers for Disease Control and Prevention Centers for Disease Control and Prevention (CDC), agency of the U.S. Public Health Service since 1973, with headquarters in Atlanta; it was established in 1946 as the Communicable Disease Center. , the ultracentrifugation method, also known as beta quantification, has become the reference method, even though it does not directly measure LDL cholesterol. Rather, this method determines LDL cholesterol by subtracting HDL cholesterol from the cholesterol in the 1.006 kg/L infranate. In addition to LDL and HDL, the 1.006 kg/L infranate also includes intermediate density lipoproteins (IDL (1) (Interface Definition Language) A language used to describe the interface to a routine or function. For example, objects in the CORBA distributed object environment are defined by an IDL, which describes the services performed by the object and how the data ) and lipoprotein(a) [Lp(a)]. After subtracting the HDL cholesterol concentration, LDL cholesterol equals the sum of the cholesterol in LDL plus IDL plus Lp(a).

For most individuals, the impact on LDL cholesterol from IDL and Lp(a) is negligible. However, for the few patients with increased levels of either IDL or Lp(a), the impact on the total LDL cholesterol concentration can be significant. Generally, IDL are considered to represent a subspecies subspecies, also called race, a genetically distinct geographical subunit of a species. See also classification.  of triglyceride-rich lipoprotein (TRL TRL

In currencies, this is the abbreviation for the Turkish Lira.

The currency market, also known as the Foreign Exchange market, is the largest financial market in the world, with a daily average volume of over US $1 trillion.
) remnants. Compared with very low-density lipoproteins very low-density lipoproteins (VLDLs), lipoproteins containing approximately 9% protein that transport triglycerides from the liver to tissues throughout the body.
 (VLDL VLDL very-low-density lipoprotein.

ß-VLDL , beta VLDL a mixture of lipoproteins with diffuse electrophoretic mobility approximately that of ß-lipoproteins but having lower density; they are remnants derived from
), IDL are relatively cholesterol-enriched and their accumulation is associated with type III hyperlipoproteinemia. In some studies, increased Lp(a) has been associated with increased CHD risk, and this is covered in more detail in a later section.

While measurement of LDL cholesterol based on beta quantification is indirect and influenced by "contamination" with other lipoproteins Lipoproteins
The packages in which cholesterol and triglycerides travel throughout the body.

Mentioned in: Lipoproteins Test

 [IDL and Lp(a)], beta quantification is considered the reference procedure because it has been used to determine LDL cholesterol concentrations in many of the large studies,[23] whose results were used by the NCEP Adult Treatment Panel to determine the national guidelines. Also, beta quantification results are not subject to interference from high triglycerides or from nonfasting status. However, beta quantification is unsuitable for use in most clinical laboratories because of its many disadvantages, including expensive equipment, slow throughput, high labor intensity, and large sample volume requirements.

Most clinical laboratories have relied instead on a mathematical formula developed from beta quantification data derived from studies performed at the National Institutes of Health by Friedewald et al.[5] For accurate estimation of LDL cholesterol concentration, the Friedewald formula requires accurate measurement of total cholesterol, HDL cholesterol, and triglycerides from fasting samples. This formula is useful when (1) samples are truly fasting, (2) the 3 measured analytes are determined with very little bias, and (3) triglyceride concentrations are [less than] 2.8 mmol/L (250 mg/dL). However, reliability of the formula decreases markedly when any one of these criteria is not met, including a fasting triglyceride in the range of 2.8-4.5 mmol/L (250-400 mg/dL).[25]

Use of triglyceride/5 as an estimate of VLDL in the Friedewald equation involves 2 assumptions: (1) all serum triglyceride resides in VLDL, and (2) all VLDL contain 20% of their mass as cholesterol. While not totally correct, the first assumption is reasonable because most serum triglyceride is found in VLDL when samples have relatively normal triglyceride values and are obtained in the truly fasting state (ideally, 12-14 hours after a low-fat meal with no alcoholic intake for 24 hours). Only small amounts of triglyceride are carried in LDL and HDL. However, substantial quantities of triglyceride are carried in chylomicrons chylomicrons (kī´lōmī´kronz) the tiny lipoproteins of approximately 2% protein that convey dietary fat throughout the body.
 in postprandial postprandial /post·pran·di·al/ (-pran´de-al) occurring after a meal.

Following a meal, especially dinner.
 and severely hypertriglyceridemic samples and in IDL in samples from patients with type III hyperhpoproteinemia.

The second assumption is also reliable when triglycerides are fasting and relatively low ([less than] 2.8 mmol/L or 250 mg/dL). However, when triglycerides are elevated, the presence of particles with abnormal composition is more likely. These particles have either (1) a much higher proportion of cholesterol as found in individuals with type III hyperlipoproteinemia (more than 30% of mass as cholesterol), or (2) a much lower proportion of cholesterol, as in the case of nonfasting samples where chylomicrons are present (less than 10% of mass as cholesterol). Consequently, when the composition of particles is abnormal, the Friedewald formula doesn't provide accurate results. In our opinion, a reasonable solution is to use the Friedewald equation when samples are from fasting subjects and triglycerides are below 2.8 mmol/L (250 mg/dL) but to reflexively use one of the direct LDL cholesterol assays when either of those 2 criteria are not met.

Direct measurement. Even within the confines of precision and accuracy limits set by the NCEP Laboratory Standardization Panel[9] and the Working Group on Lipoprotein Measurement[10,20,21] for total, LDL, and HDL cholesterol and triglyceride, it is possible for LDL cholesterol concentrations to be outside recommended limits when estimated by the Friedewald formula. Consequently, the NCEP Working Group on Lipoprotein Measurement recommended the development of methods for direct measurement of LDL cholesterol that would be suitable for use in clinical laboratories and would not require ultracentrifugation.[20] Subsequent methods have been developed and are commercially available.[26-29]

Manufacturers have retained Lp(a) in LDL supernates to mimic the beta quantification LDL. However, depending on their formulation, manufacturers differ in inclusion of IDL among the different direct LDL cholesterol methods. For example, immunoseparation methods that employ anti-apo E necessarily remove IDL along with VLDL because both species contain apo E. Other methods that use detergents to isolate specific lipoprotein classes have slightly different separation characteristics. Indeed, whenever methodological or environmental differences (such as density, charge, immunology, size, carbohydrate content, pH, and temperature) are the basis for isolation, the specific particles isolated will differ slightly. For certain individuals whose particles have unique properties, separation will be quite different according to the method used.

Manufacturers of total and LDL cholesterol reagents and analytical systems have access to the Cholesterol Reference Method Laboratory Network (CRMLN) certification program established by the CDC See Control Data, century date change and Back Orifice.

CDC - Control Data Corporation
 to evaluate assays and calibration, using fresh samples compared with the reference method. However, incorporating these LDL methods into clinical laboratory test menus has been slow, partly due to their limited use in large studies to date, but primarily due to reagent costs, which are not associated with a mathematical formula. Consequently, the perceived cost associated with the direct LDL cholesterol reagents is relatively high.

The NCEP Adult Treatment Panel has made LDL cholesterol the primary determinant of therapy in relation to lipoprotein risk factors. Despite these high costs, therefore, laboratories must provide physicians with the most accurate LDL cholesterol levels possible so that physicians can then provide the patient with the most accurate estimates of risk. Neither over- nor undertreatment is in the best interest of the individual patient or the healthcare industry as a whole. Laboratories must have the appropriate tests in place that can help diagnose patients and monitor therapy.

One major advantage of both reference and direct assays that measure LDL cholesterol is the ability to assay nonfasting samples[26,28] because LDL cholesterol testing can then be included in random screening panels. However, regardless of the method used, LDL and HDL cholesterol concentrations measured in the postprandial state will, on average, be slightly lower than their fasting counterparts because of actual physiological changes rather than a miscalculation mis·cal·cu·late  
tr. & intr.v. mis·cal·cu·lat·ed, mis·cal·cu·lat·ing, mis·cal·cu·lates
To count or estimate incorrectly.

.[17] The decreased concentration for both LDL cholesterol and HDL cholesterol content is due to transfer of cholesterol out of these particles and into newly synthesized chylomicrons and VLDL. The decreases in LDL cholesterol are moderate, generally [less than] 3-5% but as high as approximately 8%, when postprandial triglyceridemia peaks after a very high-fat meal. The level of decrease varies with the meal's size and fat content and with the length of time between the meal and specimen collection. While the concentration decreases are relatively small, they should be considered when interpreting borderline results.

HDL cholesterol

HDL cholesterol is another well established CHD risk factor,[30-32] and the NCEP Adult Treatment Panel recommends that HDL cholesterol be assayed along with total cholesterol as part of a screening program to assess a patient's risk for CHD.[19] Concentrations [less than] 0.90 mmol/L (3 5 mg/dL) are considered to confer increased risk, and concentrations [greater than] 1.55 mmol/L (60 mg/dL) are generally considered protective.[19] These tests can be performed in the nonfasting state, although HDL cholesterol levels will be slightly lower postprandially, as discussed earlier.[17] Individuals whose HDL cholesterol concentrations are [less than] 0.90 mmol/L (35 mg/dL) at screening should then have the test repeated in the fasting state for a complete lipoprotein profile.

While high levels of HDL cholesterol are known to be protective against CHD, until recently it was not known if patients with low HDL cholesterol levels could decrease their risk for CHD by raising their HDL cholesterol levels. The 7-year Veterans Administration HDL Intervention Trial (VA-HIT), a secondary prevention study of 2,500 men,[33] found that when compared to men taking a placebo, men who raised their HDL cholesterol concentrations while taking gem-fibrozil experienced a significant reduction in primary (combined incidence of and nonfatal MI and CHD death) and secondary (stroke, transient ischemia, death by any cause, revascularization, carotid carotid /ca·rot·id/ (kah-rot´id) pertaining to the carotid artery, the principal artery of the neck.

 endoarterectomy, and hospitalization for unstable angina un·sta·ble angina
Angina pectoris characterized by pain of coronary origin that occurs in response to less exercise or other stimuli than usually required to produce pain.
 or congestive heart failure congestive heart failure, inability of the heart to expel sufficient blood to keep pace with the metabolic demands of the body. In the healthy individual the heart can tolerate large increases of workload for a considerable length of time. ) endpoints.[34] This study enrolled men with previously diagnosed coronary disease who had relatively normal LDL cholesterol and triglyceride levels, i.e., LDL cholesterol [less than] 3.6 mmol/L (140 mg/dL) and triglycerides [less than] 3.4 mmol/L (300 mg/dL) but who had low HDL cholesterol levels ([less than] 40 mg/dL). It is difficult to raise HDL cholesterol levels, and in the HIT study, the magnitude of change associated with benefit was small but significant; a 22% decrease in coronary events was associated with a 7.5% increase in HDL cholesterol and a 24.5% decrease in triglycerides. These changes were not related to changes in LDL cholesterol, which were not different between placebo and gemfibrozil groups.

The precision and accuracy of HDL cholesterol assays are very important because both the range of HDL cholesterol concentration in the population and the therapeutic changes associated with therapy are small and individuals at greatest CHD risk have the lowest HDL cholesterol concentrations. Manufacturers can evaluate the calibration of their HDL cholesterol assay systems through the CRMLN HDL cholesterol certification program. Laboratories should monitor precision closely and check accuracy through enrollment in an approved proficiency testing program. In 1998, NCEP recommended that acceptable limits for bias and precision be tightened.[21] The bias limit was changed to [+ or -] 5 % or less and precision limits were [less than or equal to] 4% coefficient of variation (CV) for concentrations [greater than or equal to] 1.09 mmol/L (42 mg/dL) and [greater than or equal to] 0.04 mmol/L (1.7 mg/dL) standard deviation In statistics, the average amount a number varies from the average number in a series of numbers.

(statistics) standard deviation - (SD) A measure of the range of values in a set of numbers.
 for concentrations [less than] 1.09 mmol/L (42 mg/dL).

For clinical analysis of HDL cholesterol, interference from high levels of triglyceride in the sample is a problem, particularly in nonfasting and previously frozen samples, where the interference is generally more evident at lower triglyceride levels than in fasting samples. The CDC developed and uses the reference method for HDL cholesterol, which consists of a heparin-manganese precipitation from a 1.006 kg/L infranate. By using the 1.006 kg/L infranate, any interference from triglyceride is eliminated, but all the other disadvantages of ultracentrifugation are still present. Unfortunately, triglyceride interference has not been totally eliminated by the newer direct nonprecipitation-based assays for HDL cholesterol.[35] Dilution, filtration, and (for frozen samples) a modification of the dextran dextran /dex·tran/ (dek´stran) a high-molecular-weight polymer of d-glucose, produced by enzymes on the cell surface of certain lactic acid bacteria.  sulfate-magnesium method[36] can each be used to eliminate triglyceride-rich particles from supernates when using precipitation methods. For the direct nonprecipitation-based assays, dilution is probably the option. However, precision data reported for the assays have been tighter than those typically obtained using precipitation methods.[35,37]

Research assays for possible future use in the clinical laboratory

Lipoprotein (a). Based primarily on case-control studies, elevated serum levels of Lp(a) are thought to confer increased risk of CHD,[38-43] but prospective studies have been inconsistent in confirming the association.[41,44,45] Lp(a) particles are synthesized in the liver and consist of LDL particles with an extra apolipoprotein apolipoprotein /apo·lipo·pro·tein/ (ap?o-lip?o-pro´ten) any of the protein constituents of lipoproteins, grouped by function in four classes, A, B, C, and E.

 [apo(a)] linked to apo B-100 by 2 disulfide bonds.[46] The length of apo(a) is heterogeneous because of varying numbers of repeating peptide sequences called kringles. Molecular weights range from approximately 185 kda to 650 kda, and protein length is genetically determined.

Lp(a) by electrophoresis. The plasma concentration of Lp(a) is inversely related to the apo(a) isoform length, that is, the longer the peptide chain, the lower the plasma concentration. Lp(a) has a density range of approximately 1.05-1.15 kg/L, which overlaps the LDL and HDL density ranges. On agarose gel electrophoresis Agarose gel electrophoresis is a method used in biochemistry and molecular biology to separate DNA, RNA, or protein molecules by size. This is achieved by moving negatively charged nucleic acid molecules through an agarose matrix with an electric field (electrophoresis). , Lp(a) migrate in the pre-beta range and were once called sinking pre-beta lipoprotein.[47,48] If whole plasma is applied to the gel, visualization of Lp(a) is obscured by the presence of VLDL, which also has pre-beta mobility. Consequently, to observe Lp(a) by agarose agarose

more highly purified form of agar with similar uses to agar and widely used in the separation of nucleic acid fragments.
 electrophoresis, ultracentrifugation must first be performed to isolate the 1.006 kg/L infranate. Apo(a) also has more than 75% homology with plasminogen,[49] and is thought to compete with plasminogen for fibrin fibrin: see blood clotting.  binding sites, thereby interfering with fibrinolysis fibrinolysis /fi·bri·nol·y·sis/ (fi?brin-ol´i-sis) dissolution of fibrin by enzymatic action.fibrinolyt´ic

n. pl.

Quantitative assays. Lp(a) can be measured either (1) by determining apo(a) protein concentration, which is then converted to an estimate of total Lp(a) particle mass (sum of the molar concentrations of the protein, cholesterol, triglyceride, and phospholipid phospholipid (fŏs'fōlĭp`ĭd), lipid that in its simplest form is composed of glycerol bonded to two fatty acids and a phosphate group.  that comprise the particles)[53] or (2) by measuring Lp(a) cholesterol concentration,[43,54] as is done to assay LDL and HDL concentration. Protein and cholesterol each account for approximately 30% of Lp(a) mass. Mass assays involving immunologic separation of apo(a) must use specific epitopes to avoid regions homologous to plasminogen and regions subject to kringle IV, type 2 sequences, which are the peptides that account for size heterogeneity. The protein is then quantitated by ELISA ELISA (e-li´sah) Enzyme-Linked Immuno-Sorbent Assay; any enzyme immunoassay using an enzyme-labeled immunoreactant and an immunosorbent.

, EIA (Electronic Industries Alliance, Arlington, VA, A membership organization founded in 1924 as the Radio Manufacturing Association. It sets standards for consumer products and electronic components. , or nephelometric or turbidometric assays. For the Lp(a) cholesterol assay, Lp(a) are bound to lectin lectin /lec·tin/ (lek´tin) any of a group of hemagglutinating proteins found primarily in plant seeds, which bind specifically to the branching sugar molecules of glycoproteins and glycolipids on the surface of cells. , taking advantage of the high degree of glycosylation found in Lp(a). After eluting Lp(a) off the column, the cholesterol is measured. Standardization procedures and materials are currently being evaluated through the International Federation of Clinical Chemistry and the National Institutes of Health. Reference materials selected by the IFCC IFCC International Federation of Clinical Chemistry and Laboratory Medicine
IFCC Internet Fraud Complaint Center (US FBI)
IFCC Interface Control Check
IFCC International Federation of Christian Churches
 committee will be used by manufacturers to set calibrator calibrator

an instrument for dilating a tubular structure or for determining the caliber of such a structure.
 concentrations in the same way that reference materials developed for apos A-I A-I General Audiences (Catholic movie rating)  and B are used. Evaluation of assays with respect to isoform size, currently being conducted under an NIH "Not invented here." See digispeak.

NIH - The United States National Institutes of Health.
 contract, will help assure that the antibodies employed identify all peptides equally.

Genetic distribution. Lp(a) concentrations are unevenly distributed in Caucasian populations, with most individuals having very low concentrations. For example, in the third offspring exam of the Framingham Heart Study The Framingham Heart Study is a cardiovascular study based in Framingham, Massachusetts. The study began in 1948 with 5,209 adult subjects from Framingham, and is now on its third generation of participants. , the mean total mass concentration was approximately 15 mg/dL, whereas the median value was only 8 mg/dL.[55] Concentrations in some individuals can exceed 100 mg/dL and can occasionally be as high as 200-300 mg/dL. African-Americans demonstrate a more Gaussian distribution of Lp(a) values than Caucasians but with a more elevated median level. In the CARDIA study, the median value for African-Americans was 3 times higher than that for Caucasians.[56] It is not yet clear whether the more elevated levels observed in the African-American population confer greater CHD risk.[57-59] However, regardless of race, an Lp(a) total mass concentration [greater than] 30 mg/dL is considered to be elevated; the corresponding Lp(a) cholesterol cutpoint is 10 mg/dL.[40]

Despite the similarity between Lp(a) and LDL, most LDL-lowering drugs have little or no effect on Lp(a) concentrations. Only niacin niacin: see coenzyme; vitamin.
 or nicotinic acid or vitamin B3

Water-soluble vitamin of the vitamin B complex, essential to growth and health in animals, including humans.
 and the estrogen replacement preparations for postmenopausal post·men·o·paus·al
Of or occurring in the time following menopause.

postmenopausal Change of life Gynecology adjective Referring to the time in ♀ when menstrual periods stop for ≥ 1 yr
 women have substantially decreased Lp(a) levels. Prospective studies generally confirm Lp(a)'s atherogenicity.[41,44,45] Treatment with niacin in such patients with CHD can be recommended because niacin has been shown to reduce secondary CHD events in unselected CHD patients.[61] An elevated Lp(a) level can also indicate the need to be assertive in normalizing other modifiable CHD risk factors.

TRL remnants

Triglyceride-rich lipoproteins (TRLs) include chylomicrons, chylomicron chylomicron /chy·lo·mi·cron/ (-mi´kron) a class of lipoproteins that transport exogenous (dietary) cholesterol and triglycerides after meals from the small intestine to tissues for degradation to chylomicron remnants.  remnants, VLDL, and VLDL remnants. Both chylomicron and VLDL remnants may be atherogenic ath·er·o·gen·ic
Initiating, increasing, or accelerating atherogenesis.

atherogenic adjective Referring to the ability to initiate or accelerate atherogenesis—the deposition of atheromas, lipids, and
.[62-66] Chylomicrons synthesized in the intestine after a meal rapidly undergo lipolysis lipolysis /li·pol·y·sis/ (li-pol´i-sis) the splitting up or decomposition of fat.lipolyt´ic

n. pl. li·pol·y·ses
The hydrolysis of lipids.
 via the action of the enzyme, lipoprotein lipase lipoprotein lipase /lipo·pro·tein li·pase/ (li´pas) an enzyme that catalyzes the hydrolytic cleavage of fatty acids from triglycerides (or di- or monoglycerides) in chylomicrons, very-low-density lipoproteins, and low-density  (LPL LPL - List Programming Language. LISP-like language with ALGOL-like syntax, for IBM 360. "LPL - LISP Programming Language", F.W. Blair et al, RC 3062, IBM TJWRC, Sep 1970. ), causing a loss of triglyceride from the core, which is partially replaced by a transfer of cholesteryl esters from LDL and HDL. Importantly, these remnant particles are now relatively enriched in apo E. Chylomicron remnants[62] are eventually removed by the liver through a receptor-mediated process.

VLDL constitute another species of TRL but are synthesized in the liver rather than the intestine. As with chylomicrons, VLDLs have a hydrated hy·drat·ed  
Chemically combined with water, especially existing in the form of a hydrate.

Adj. 1. hydrated - containing combined water (especially water of crystallization as in a hydrate)
 density of [less than] 1.006 kg/L and are heterogeneous in size. The main compositional difference between VLDL remnants and chylomicron remnants is the presence of apo B 100 as the major protein of VLDL remnants, rather than apo B48, and the lower relative triglyceride concentration. VLDL remnants can be removed from circulation directly by the liver or can undergo further degradation to become IDL (density 1.006-1.019 kg/L) and then LDL (density 1.019-1.063 kg/L). IDL are another species of TRL remnants that are even more cholesterol- and apo E-enriched and triglyceride-poor.

While many patients with CHD present with moderately elevated triglycerides, independent associations between triglycerides and CHD have been inconsistent.[67-70] Lack of association in many studies is probably related to biologic variability and to the compositional heterogeneity within TRL that also causes difficulty with the Friedewald calculation. Proposed mechanisms of action of TRL remnants include interference with vasorelaxation[63,71] and subendothelial accumulation of chylomicron remnants.[64]

Separation of remnant lipoproteins has always been difficult because of overlapping size, density, and composition among the native and remnant forms of TRL. Traditionally, remnants have been separated using ultracentrifugation and column separation techniques, but these are not suitable for large-scale studies. Nonetheless, the ability to separate remnants could possibly allow direct quantitation of the specific atherogenic subspecies within TRL without analyzing newly formed native TRL, which may not be atherogenic. Studies have shown that remnants can circulate for extended periods of time postprandially, even in individuals with normal fasting triglyceride concentrations.[17,18,64,72-74]

A recently developed immunologic assay isolates a subset of TRL that are enriched in apo E and display classic remnant-like characteristics.[75-77] These unbound unbound

said of electrolytes, e.g. iron and calcium, and other substances which are circulating in the bloodstream and are not bound to plasma proteins so that they are available immediately for metabolic processes. See also calcium, iron.
 remnants remain in the supernate and have been identified as remnant-like particles (RLP RLP Rheinland-Pfalz (state in Germany)
RLP Resource Location Protocol (Cisco)
RLP Radio Link Protocol
RLP Remote Line Printer
RLP Revolving Loan Program
RLP Rotatable Log Periodic
). Reference ranges have been generated in 2 populations,[78,79] and initial case control and prevalence studies examining the relationship between RLP and CHD indicate an association,[80-82] and the first prospective study has yet to be completed.

The RLP assay may also eventually be used in clinical laboratories to assess risk in diabetes[84] and to diagnose individuals with type III hyperlipoproteinemia or dysbetalipoproteinemia[85,86] who are also at high risk for developing CHD. Diagnosis of type III hyperlipoproteinemia currently requires (1) ultracentifugation to calculate the ratio of VLDL cholesterol to total triglyceride ([greater than] 0.3 in type III patients) and to document the presence of beta VLDLs on agarose electrophoresis and (2) apo E pheno-typing or genotyping to document an apo E 2/2 phenotype. Sophisticated techniques are used to fulfill these requirements, and consequently, many type III patients are not identified and are categorized as having combined hypeflipoproteinemia. Use of the ratio for RLP cholesterol RLP cholesterol Remnant-like particle cholesterol Cardiology A form of cholesterol that is ↑ in Pts who have had acute MIs and have otherwise normal LDL-C and HDL-C; remnant lipoproteins result from metabolism of VLDLs; RLP cholesterol occurs in Pts with type  to total triglyceride could replace the ratio to VLDL cholesterol to triglyceride, thereby eliminating the need for ultracentrifugation. Type III patients generally have elevated RLP cholesterol concentrations (at or above the 75th percentile of the population) and RLP cholesterol to triglyceride ratios of more than 0.10.[85,87] In our view, elevated RLP cholesterol concentrations can be effectively lowered with some inhibitors of 3-hydroxy 3-methylglutaryl coenzyme A coenzyme A
n. Abbr. CoA
A coenzyme present in all living cells that functions as an acyl group carrier and is necessary for fatty acid synthesis and oxidation, pyruvate oxidation, and other acetylation.
 (HMG hMG menotropins (human menopausal gonadotropin).

human menopausal gonadotropin
 CoA) reductase reductase /re·duc·tase/ (-tas) a term used in the names of some of the oxidoreductases, usually specifically those catalyzing reactions important solely for reduction of a metabolite.  such as atorvastatin atorvastatin /ator·va·stat·in/ (ah-tor?vah-stat´in) an antihyperlipidemic agent that acts by inhibiting cholesterol synthesis, used as the calcium salt in the treatment of hypercholesterolemia and other forms of dyslipidemia. .[87,88]

Homocysteine Homocysteine Definition

Homocysteine is a naturally occurring amino acid found in blood plasma. High levels of homocysteine in the blood are believed to increase the chance of heart disease, stroke, Alzheimer's disease, and osteoporosis.

Homocysteinurias are a class of inborn inborn /in·born/ (in´born?)
1. genetically determined, and present at birth.

2. congenital.

1. Possessed by an organism at birth.

 errors of metabolism that affect metabolism of sulfur-containing amino acids and result in extremely elevated plasma and urinary levels of homocysteine. When untreated, individuals with this defect frequently develop CHD by their teens and as early as infancy. It was thus hypothesized that individuals with more moderate increases in plasma homocysteine levels might also be at some increased risk for CHD, and most studies have confirmed this hypothesis.[89-96] The metabolic pathway involved in the synthesis and catabolism catabolism (kətăb`əlĭz'əm), subdivision of metabolism involving all degradative chemical reactions in the living cell.  of homocysteine contains several enzymes that, if defective or inactive, can interfere with homocysteine metabolism and result in its elevation. These enzymes include cystathionine beta-synthase, methylenetetrahydrofolate reductase, and N-5-methylenetetrahydrofolate:homocysteine methyltransferase.[97] Elevated plasma homocysteine levels have been associated with oxidative cell damage, vasoconstriction vasoconstriction /vaso·con·stric·tion/ (-kon-strik´shun) decrease in the caliber of blood vessels.vasoconstric´tive

, vascular smooth muscle Vascular smooth muscle refers to the particular type of smooth muscle found within, and composing the majority of the wall of blood vessels.

Vascular smooth muscle contracts or relaxes to both change the volume of blood vessels and the local blood pressure, a mechanism that
 proliferation, and hypercoagulability,[98-100] all of which are potential mechanisms for homocysteine's positive association with CHD risk.

Distribution of homocysteine levels in the population varies by age, gender, and ethnicity.[101,102] The elderly tend to have a lower dietary intake of B vitamins B vitamins
This family of vitamins consists of thiamine (B1), riboflavin (B2), niacin (B3), pantothenic acid (B5), pyridoxine (B6), biotin, folic acid (B9), and cobalamin (B12).
 and thus have higher homocysteine concentrations.[103-105] Other populations at increased risk of having hyperhomocysteinemia are diabetics[93,106] and patients with renal disease Renal disease
Kidney disease.

Mentioned in: Glycogen Storage Diseases

hypertension High blood pressure Cardiovascular disease An abnormal ↑ systemic arterial pressure, corresponding to a systolic BP of > 160 mm Hg
 because the kidney is the site of transsulfuration enzymes.[107,108]

Many individuals with increased concentrations of homocysteine are easily treated with supplementary intake of folate folate /fo·late/ (fo´lat)
1. the anionic form of folic acid.

2. more generally, any of a group of substances containing a form of pteroic acid conjugated with l-glutamic acid and having a variety of substitutions.
 and vitamins [B.sub.6] and [B.sub.12].[106,109] Recently, the U.S. grain supply has been fortified fortified (fôrt´fīd),
adj containing additives more potent than the principal ingredient.
 with folate to reduce the incidence of neural tube defect neural tube defect

Congenital defect of the brain or spinal cord from abnormal growth of their precursor, the neural tube (see embryology), usually with spine or skull defects.
 in fetuses. This fortification fortification, system of defense structures for protection from enemy attacks. Fortification developed along two general lines: permanent sites built in peacetime, and emplacements and obstacles hastily constructed in the field in time of war.  will secondarily reduce homocysteine levels in the general population.[106] Whether this reduction will translate into a reduction in cardiac and vascular events awaits future evaluation. Existing evidence gained from studies where homocysteine levels have been reduced would lead to the prediction that there will be a reduction in CHD events.[94]

Generally, laboratory analysis of homocysteine has been conducted using HPLC HPLC high-performance liquid chromatography.


high performance liquid chromatography.

HPLC High-performance liquid chromatography Lab instrumentation A highly sensitive analytic method in which analytes are placed
 methodology, which is not performed in most clinical laboratories. However, with the positive association found in studies evaluating homocysteine as a CHD risk factor, new methods such as immunoassays have been developed that are more useful in a routine clinical chemistry laboratory,[110,111] Regardless of the method, a fasting specimen fasting specimen Lab medicine A blood specimen drawn from a Pt who has not eaten for 12 hrs; fasting is an absolute requirement for a limited number of tests–eg, GTT; prolonged fasting causes a marked–240% ↑ in bilirubin, ↑ plasma TGs,  should be collected in EDTA EDTA: see chelating agents.  or heparin, and the plasma should be removed and analyzed immediately or stored at -70 [degrees] C, where it is stable for extended periods of time.

However, issues important to clinical laboratory measurement of homocysteine involve more than just assay technology. For example, assays aren't standardized, making it potentially difficult to compare results among methods,[112] While no standardization currently exists, a homocysteine proficiency testing program has recently been initiated through the Wadsworth Center of the New York New York, state, United States
New York, Middle Atlantic state of the United States. It is bordered by Vermont, Massachusetts, Connecticut, and the Atlantic Ocean (E), New Jersey and Pennsylvania (S), Lakes Erie and Ontario and the Canadian province of
 State Department of Health to assess the variability among methods and laboratories. Initial comparisons showed substantial variability, indicating the need for such a program. Regular proficiency testing for homocysteine is now being offered by the New York program.

Laboratorians also question whether homocysteine levels will be requested frequently enough to add a homocysteine assay to the test menu. Because vitamin supplementation easily decreases homocysteine levels in most individuals, many physicians may elect to begin supplementation without assaying homocysteine. However, 2 problems with that approach include (1) that supplementation with folate alone will mask, but not resolve, symptoms of pernicious anemia pernicious anemia: see anemia.
pernicious anemia

Slow-developing disease in which vitamin B12 (see vitamin B complex) deficiency impairs red-blood-cell production.
[105] and (2) that defects in the thermolabile thermolabile /ther·mo·la·bile/ (-la´bil) easily affected by heat.

Subject to destruction, decomposition, or great change by moderate heating.
 methylenetetrahydrofolate reductase enzyme will require greater levels of folate supplementation than would be required to normalize most increases in homocysteine.[113] This defect is a common mutation found in individuals with elevated homocysteine concentrations, indicating that both initial and follow-up homocysteine concentrations should be measured.

Early detection of risk factors for CHD is essential to reduce the incidence of this number-one killer, and detection of many of these risk factors involves laboratory determinations. Although specific assays and assay parameters have changed and improved in the last 30 years, the lipoprotein profile is still essential to help determine a patient's risk level for CHD. Prevention is essential because only 50% of myocardial infarctions occur in people who have already been diagnosed with CHD. As the prevalence of CHD remains high, identification of new risk factors will also be important. Current data indicate that CHD events can be reduced by approximately 30% when LDL cholesterol levels are reduced with diet and medication. Identification and treatment of individuals with decreased levels of HDL cholesterol levels and increased levels of Lp(a) cholesterol or particle mass, RLP cholesterol, and homocysteine should further reduce CHD risk. In addition, identification, validation, and incorporation of other new risk factors into new clinical laboratory assays should eventually reduce the risk even further.


Preanalytical variables that can affect results for lipoprotein profiles

Proper specimen collection, especially for fingerstick specimens

Patient position during specimen collection

* standing

* sitting

* recumbent recumbent /re·cum·bent/ (re-kum´bent) lying down.

Lying down, especially in a position of comfort; reclining.

Patient stress during hospitalization

* physiological (from interventional procedures and/or illness)

* psychological (from worries about health status, impending im·pend  
intr.v. im·pend·ed, im·pend·ing, im·pends
1. To be about to occur: Her retirement is impending.

 procedures, and/or pain)

Viral infections

Compliance with a true fasting status

* duration of the fast

* limitation of alcohol

* amount and the type of food ingested

* metabolic efficiency of each individual


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Sudden cardiac death (SCD) is an unexpected death due to heart problems, which occurs within one hour from the start of any cardiac-related symptoms. SCD is sometimes called cardiac arrest.
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Any of a class of drugs that inhibit a key enzyme involved in the synthesis of cholesterol and promote receptor binding of LDL cholesterol, resulting in decreased levels of serum cholesterol.
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1. Occluding or tending to occlude.

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104. Stehouwer CD, Weijenberg MP, van den Berg Van den Berg is the surname of:
  • Rudolf van den Berg (born 1949), Dutch director
  • Albert van den Berg (born 1976), South African rugby player
  • Jan Hendrik van den Berg (born 1914), Dutch psychologist
  • Janwillem van den Berg (1920-1985), Dutch speech scientist
 M, et al. Serum homocysteine and risk of coronary heart disease and cerebrovascular disease in elderly men: A 10-year follow-up. Arterioscler Thromb Vasc Biol. 1998;18:1895-1901.

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106. Chico A, Perez A, Cordoba cor·do·ba  
See Table at currency.

[American Spanish córdoba, after Francisco Fernández de Córdoba (1475?-1526?), Spanish explorer.]

Noun 1.
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108. Hong SY, Yang DH, Chang SK. The relationship between plasma homocysteine and amino acid concentrations in patients with end-stage renal disease End-stage renal disease (ESRD)
Total kidney failure; chronic kidney failure is diagnosed as ESRD when kidney function falls to 5-10% of capacity.

Mentioned in: Chronic Kidney Failure

end-stage renal disease 
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111. Frantzen F, Faaren AL, Alfheim I, Nordhei AK. Enzyme conversion immunoassay Immunoassay

An assay that quantifies antigen or antibody by immunochemical means. The antigen can be a relatively simple substance such as a drug, or a complex one such as a protein or a virus.
 for determining total homocysteine in plasma or serum. Clin Chem. 1998;44:311-316.

112. Ubbink JB, Delport R, Riezler R, Vermaak WJ. Comparison of three different plasma homocysteine assays with gas chromatography-mass spectrometry. Clin Chem. 1999;45:670-675.

113. Jacques PF, Bostom AG, Williams RR, et al. Relation between folate status, a common mutation in methylenetetrahydrofolate reductase, and plasma homoeysteine concentrations. Circulation. 1996;93:7-9.

Judith R. McNamara is supervisor, Leo Leo, in astronomy
Leo [Lat.,=the lion], northern constellation lying S of Ursa Major and on the ecliptic (apparent path of the sun through the heavens) between Cancer and Virgo; it is one of the constellations of the zodiac.
 J. Seman is research scientist, and Ernst J. Schaefer is chief at the Lipid Metabolism Laboratory, Jean Mayer USDA USDA, See United States Department of Agriculture.
 Human Nutrition Research Center on Aging, Tufts University, Boston, MA. The authors are also affiliated with the Lipid Research Laboratory, Division of Endocrinology, Diabetes, Metabolism, & Molecular Medicine, at the New England Medical Center, Boston, MA.
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No portion of this article can be reproduced without the express written permission from the copyright holder.
Copyright 1999 Gale, Cengage Learning. All rights reserved.

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Title Annotation:coronary heart disease
Author:McNamara, Judith R.; Seman, Leo J.; Schaefer, Ernst J.
Publication:Medical Laboratory Observer
Date:Oct 1, 1999
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