Do Cholesterol Numbers Really Assess Cardiovascular Risk?

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1 of people at risk for HEART DISEASE are not identified by routine testing. Visit us at Do Cholesterol Numbers Really Assess Cardiovascular Risk? Lipoprotein Particle numbers tell the story.

2 Lipoprotein Particle Profile Testing LPP testing is the most advanced cardiovascular risk assessment Approximately 50 percent of people suffering from heart attacks have normal cholesterol levels (NIH National Heart, Lung and Blood Institute, 2001). How can the large discrepancy between accurate diagnosis and standard cholesterol testing be prevented? Simply by testing lipoprotein VLDL, LDL and HDL particle numbers using the Lipoprotein Particle Profile (LPP ) from SpectraCell Laboratories. Overview of lipoprotein particles and cholesterol Cholesterol testing has historically been used as the standard indicator for cardiovascular disease by measuring HDL (good) or LDL (bad) cholesterol. However, it is actually the lipoprotein particles that carry the cholesterol throughout the body and not the cholesterol within them that is responsible for key steps in plaque production and the resulting development of cardiovascular disease. Now there is an advanced cholesterol testing technology which accurately measures both the density and number of lipoprotein particles. This test is known as the Lipoprotein Particle Profile, or LPP, from SpectraCell Laboratories. Measuring the lipoprotein subgroups is the only way to evaluate the new NCEP risk factors, which is crucial for an accurate assessment of cardiovascular risk according to the National Cholesterol Education Program (NCEP). Measuring cholesterol alone does not provide the complete picture and can be misleading. SpectraCell s LPP is the only panel that detects ALL the new NCEP risk factors which include: Small, dense LDL: these atherogenic particles easily penetrate the arterial endothelium and cause plaque formation. Lp(a): a small, dense LDL builds plaque, is easily oxidized and can prevent clots from dissolving. RLP (Remnant Lipoprotein): is very atherogenic and is believed to be a building block of plaque since it does not need to be oxidized like the rest of LDL. HDL2b: is correlated with heart health because it is an indicator of how well excess lipids are removed.

3 Knowing the precise information about a patient s lipoproteins is a critical step in establishing an effective treatment program. Why is it important to know lipoprotein numbers? Cardiovascular risk increases with a higher LDL particle count. With a higher non-hdl lipoprotein count the probability of particle penetration of the arterial wall rises regardless of the total amount of cholesterol contained in each particle. On average, the typical LDL particles contains 50 percent cholesterol. Lipoprotein Particle More than 20 percent of the population has cholesterol-depleted LDL, a condition in which a patient s cholesterol may be normal but their lipoprotein particle number, and hence their actual risk, could be much higher than expected. This is especially common in persons whose triglycerides are high and HDL is low. In the population with a cholesterol-depleted LDL, there can be up to a 40 percent error in risk assessment. The LPP test from SpectraCell Laboratories provides physicians with the actual LDL particle count, allowing healthcare providers to accurately determine and diagnose cardiovascular risk in their practice. Each patient shown below has the same LDL cholesterol of 125 mg/dl, but particles differ. (normal) (depleted) (enriched) (depleted)

4 Lipoprotein Particle Profile (LPP ) Providing a complete look at lipoprotein subgroups SpectraCell s LPP test is a proprietary technology developed from research started at Texas A&M University that separates the lipoproteins in blood serum by density using analytical ultracentrifugation, the CDC gold standard for lipoprotein testing. High numbers of small dense LDL particles could ultimately cause cardiovascular disease. Use LPP in your practice for accurate atherogenic risk assessments Traditionally, the standard lipid panel calculates LDL from measurements of the other lipoproteins. In contrast, the LPP method presents values for all of the lipoproteins from direct measurement. SpectraCell s LPP technology aids the physician in assessing a patient s cardiovascular risk. With LPP, a physician can diagnose patients with atherogenic lipoprotein profiles before overt dyslipidemia becomes apparent. Lipoprotein Particle Profile

5 Atherosclerotic Plaque Formation SpectraCell s Lipoprotein Particle Profile (LPP ) identifies all the National Cholesterol Education Program s (NCEP) Lipoprotein Risk Factors. PLAQUE RUPTURES DUE TO INFLAMMATION 3 Lp(a) 2 RLP HDL2b 4 HDL3 ARTERIAL LUMEN LDL MONOCYTE CELL Foam Cells Build Plaque Foam Cell DENSE LDL 1 DAMAGED ENDOTHELIUM CELL ARTERIAL INTIMA 5 OXIDIZED LDL MACROPHAGE CELL 1 2 Small, Dense LDL is three times more atherogenic than buoyant LDL due to the additional number of LDL particles per cholesterol equivalent and the rapid penetration of small LDL particles through the arterial endothelium. RLP (Remnant Lipoprotein) is readily scavenged by macrophage cells without having to be oxidized (like other LDL) and becomes a major component of plaque. 4 5 HDL Removes Excess Lipids HDL2b is formed from HDL3 as it removes excess lipids. High HDL2b is an indicator of functional reverse cholesterol transport. LDL Oxidation is when LDL is oxidized in the intima of the vessel wall and is scavenged by macrophage cells to form foam cells. The foam cells are the building blocks of plaque. Antioxidants, measured by Spectrox, can retard LDL oxidation. 3 Lp(a) are small, dense LDL s and that are easily oxidized. Lp(a) is prothrombotic in many of the genetic variations.

6 LPP Features and Benefits Advanced Testing for Cardiovascular Risk Why is LPP Testing The Most Comprehensive Risk Assessment? u Provides much more accurate cardiovascular risk assessment and treatment guidelines than conventional cholesterol testing u Detects all new NCEP risk factors, including Lp(a), RLP, HDL2b and small, dense LDL u Accurately measures the lipoprotein subgroups of VLDL, LDL and HDL u Helps identify the 50% of patients that are at risk for cardiovascular disease but have normal cholesterol levels Measures Particle Density & Number u Directly measures lipoprotein particles both number and density (which directly correlates to size) u Takes into account cholesterol-depleted and cholesterol-enriched patients which can mislead risk assessment u Enables clinician to treat atherogenic lipoprotein profiles before overt dyslipidemia becomes apparent Superior Technology u Separates lipoproteins by analytical ultracentrifugation, which is considered the CDC gold standard u Counts lipoprotein particles using proprietary technology u Uses a continuous gradient through the entire lipoprotein density range u Low end of gradient is g/ml for accurate VLDL results u Separation by analytical ultracentrifugation at 120,000 rpm Additional Risk Factor Measurements u Independent chemical assay of Lp(a) u Gives clinician overall cardiovascular lipoprotein particle profile with subgroups and inflammation risk assessment Easy-To-Understand Reporting u Lists all lipid-related metabolic syndrome traits u Graphical results are included with every report u Clinical suggestions with treatment recommendations on each report u Cumulative reporting available Easy Sample Collection u Complete test kit and transportation provided u Small sample size (less than 4 ml serum) u Quick turnaround (less than one week) u LPP is very cost effective and is covered by most insurances and medicare.

7 LPP Sample Test Report Page 1 Page Town Park Dr. Tel: Houston, TX CLIA ID 45D Fax: Laboratory Director: John F. Crawford, Ph.D. Lipid Science Director: Jan M. Troup, Ph.D. Name: Doe, John DOB: February 23, 1946 Physician: Dr. Joe E. Lewis Reference: j:\lab\lpp\data\b32.2\k rpt Batch: B4452 Accession No: K10133 Draw Date: October 16, 2010 Report Date: March 14, 2011 VLDL Particles Lipoprotein Particle Numbers Green - Normal Yellow - Borderline Red - Abnormal Reference Value Patient Results Values in (nmol/l) 112 Total LDL Particles Non - HDL Particles #REF! RLP (Remnant Lipoprotein) Small - Dense LDL III Small - Dense LDL IV Total HDL Particles Large - Buoyant HDL 2b Apo B-100 (mg/dl) Lp(a) (mg/dl) 1 Biomarkers and Risk Factors SAMPLE Metabolic Syndrome Traits #REF! Lp-PLA2 (ng/ml) C-Reactive Protein-hs (mg/l) Patient Results Insulin Homocysteine (µlu/ml) (µmol/l) Total Cholesterol LDL - Cholesterol Lipid Panel Values in (mg/dl) HDL - Cholesterol Triglycerides Non - HDL - Cholesterol HDL Comments: 1. Reference Value for Blacks is 50.0 mg/dl SpectraCell Laboratories, Inc. 2007, 2008, 2009, 2010, 2011 All rights reserved Form Rev 32.0

8 Clinical Interpretation Guide to the LPP Test Step 1. Primary Risk Assessment Lipoprotein non-hdl particle numbers and other lipid and non-lipid risk factors may show a greater patient risk than a standard lipid panel and therefore, a greater LDL reduction than indicated by a standard lipid panel. Non-HDL lipoprotein particle numbers and/or Apo B-100 are measures of the number of atherogenic lipoprotein particles and are compliant with the recent consensus statement from the American Diabetes Association and the American College of Cardiology1 stating that lipoprotein particle numbers are more predictive of CVD risk than cholesterol. Moderate to elevated triglycerides can cause the lipoproteins to be cholesterol depleted or triglyceride enriched and these patients will show a greater CVD risk from non-hdl particle numbers or Apo B-100 than from a standard lipid panel. This occurs in about 30% of the population. Step 2. Modify Risk Using Metabolic Syndrome Traits, Lp(a) and Inflammation Risk Markers Evaluate possible Metabolic Syndrome by combining the lipid traits from the LPPTM test with possible hypertension, obesity and high glucose. Three total traits is a diagnosis of Metabolic Syndrome and raises the CVD risk to the next level. Also check for insulin resistance using the LPP fasting insulin value. Take into account additional risk from elevated Lp(a) or inflammation markers such as hs-crp or Lp-PLA2 if ordered, in determining the final treatment goals. Also consider non-lipid risk factors such as hypertension, obesity, high glucose, smoking, family history and other medical history. The risk assessment and treatment goal from Step 1 should be adjusted in light of the presence of these additional Biomarkers and Risk Factors. A standard directly measured cholesterol Lipid Panel is presented at the bottom of the report for comparison to previously determined lipid results. Step 3. Determine Therapeutic Approach Based On the Lipid Subgroup Distribution, Lp(a) and Therapeutic Guidelines Using the risk level established in Step 2 and treatment goals from the NCEP guidelines, determine if VLDL, LDL subgroups, HDL subgroups and/or Lp(a) should be therapeutic targets. The LPP particle numbers by subgroup and Lp(a) each have a specific therapeutic approach that is most effective. Often, combination therapy is needed to address the different risk areas. A special HDL species enriched in Apo C-1 is atherogenic but displays health attributes2. It is generally identified by high HDL>70mg/dL, high HDL 2b > 4000 nmol/l with a high HDL peak or hump extending into LDL IV region and low TG s < 70 mg/dl. Check for CVD development with a CIMT, a Coronary Calcium Score or other method to confirm. Refer to the LPP Therapeutic Guidelines for lipoprotein subgroup specific information. 1. Diabetes Care, Volume 31, Number 4, April Kwiterovich P., et al. JAMA 2005; 293(15): SpectraCell Laboratories, Inc. All rights reserved. LPP DOC 418

9 LPP Sample Test Report Page 2 Page Town Park Dr. Tel: Houston, TX CLIA ID 45D Fax: Laboratory Director: John F. Crawford, Ph.D. Lipid Science Director: Jan M. Troup, Ph.D. Name: DOB: Physician: Reference: Doe, John February 23, 1946 Dr. Joe E. Lewis j:\lab\lpp\data\b32.2\k Batch: Accession No: Draw Date: B4452 K10133 October 16, Report Date: March 14, 2011 Particle Numbers, nmol/l RLP Large LDL Lipoprotein Particle Profile TM Small LDL Large HDL Small HDL 1300 Risk Factor Approximate LDL Approximate HDL Borderline 1400 Normal VLDL l IDL RLP l l l l l Lipoprotein Density g/ml LDL I & II LDL III LDL IV HDL2b Lipoprotein Particle Numbers (nmol/l) HDL2a HDL 3 Value Reference Value Alert (Notes Page 3) VLDL Particles 112 <85 Borderline High (12) Total LDL Particles 1031 <900 High (13) Non - HDL Particles 1143 <1000 High (19) SAMPLE RLP (Remnant Lipoprotein) 230 <150 High (14) Small - Dense LDL III 339 <300 Borderline High (15) Small - Dense LDL IV 126 <100 High (16) Total HDL Particles 7148 >7000 Borderline-M, Low-F (17) Large - Buoyant HDL 2b 1268 >1400 Low (18) l l Biomarkers and Risk Factors Value Reference Value Alert (Notes Page 3) Apo B-100 (mg/dl) 115 <100 High (20) Lp(a) (mg/dl) 42.5 < High (6) Metabolic Syndrome Traits 1 0 Possible (8) Lp-PLA2 (ng/ml) 225 <200 Borderline (7) C-Reactive Protein-hs (mg/l) 3.2 <3.0 High (9) Insulin (ulu/ml) 15.5 <35.0 Homocysteine (umol/l) 10.2 <11.0 Lipid Panel (mg/dl) Value Reference Value Alert (Notes Page 3) Total Cholesterol 193 <200 LDL - Cholesterol 121 <130 Borderline High (2) HDL - Cholesterol 40 >40 Borderline (3) Triglycerides 217 <150 High (4) Non - HDL- Cholesterol 153 <160 Borderline (5) 1. Reference Value for Blacks is 50.0 mg/dl SpectraCell Laboratories, Inc. 2006, 2007, 2008, 2009, 2010, 2011 All rights reserved Form Rev 32.0

10 Lipoprotein Particle Profile Testing - Therapeutic Guidelines Lipoprotein Abnormality Lifestyle Changes (diet & exercise) Statins Niacin Fibrates Oral Estrogens Resins Absorption Inhibitors Omega-3 s EPA & DHA Alcohol (moderate) LDL I & II Buoyant LDL III - Dense HDL 2b - Buoyant Therapeutic Beneficial Little or No Effect Negative Effect

11 Why Cholesterol Measurements May be Misleading about Lipoprotein Levels and Cardiovascular Risk Technical Summary: J Lab Med 2002; 26 (11/12): pages This article demonstrates how the cholesterol content of lipoproteins, specifically low density lipoprotein (LDL), will vary significantly from person to person. It also emphasizes why lipoprotein particles (both their number as well as their size and density) are atherogenic, not the cholesterol inside them. So for people with cholesterol-depleted LDL, which is common in our population, the standard measure of cholesterol will be falsely low and will not effectively identify accurately their true cardiovascular risk. This is especially true in patients with even moderately elevated plasma triglyceride levels or low HDL cholesterol. KEY POINTS Lipoproteins vs. Cholesterol The fact that lipoproteins (vs. the cholesterol they contain) are what actually cause atherosclerosis has been well established decades ago. But cardiovascular disease (CVD) has been framed a cholesterol issue simply because there was no commercial technology for measuring lipoprotein particles until recently. Technology for measuring cholesterol has been widely available for years, so cholesterol became synonymous with CVD, when really it is only a surrogate marker. LDL cholesterol values for many individuals do not accurately reflect the number of circulating LDL particles and the cardiovascular risk these particles represent. Origins of LDL cholesterol content variability There are two independent sources of variability in LDL cholesterol content: 1. Variability in core lipid composition this occurs when plasma triglycerides are exchanged for cholesterol ester molecules inside an LDL particle. The LDL particle then becomes triglyceride-enriched and cholesterol-depleted. 2. Variability in particle size when an LDL particle becomes cholesterol-depleted, it may undergo structural changes that transform it into a smaller, denser LDL particle, which can eventually become cholesterol-depleted as well. As a result of the reactions referenced above, four types of LDL particles can exist: These reactions are fully reversible. For this reason, when a patient undergoes successful triglyceride lowering therapy, it is possible for the LDL particle number to decrease (which is good) while the LDL cholesterol measurement actually increases. Clinical implications of low HDL cholesterol data suggests that much of the cardiovascular risk associated with low HDL cholesterol (as measured by routine cholesterol tests) actually stems from an unrecognized excess number of LDL particles that are cholesterol-depleted. In other words, the low HDL cholesterol may be both a marker of CVD, as well as an actual cause.

12 Abstract Small dense low-density lipoprotein cholesterol concentration and carotid atherosclerosis Atherosclerosis Feb;202(2): Small dense low-density lipoprotein cholesterol concentration and carotid atherosclerosis. Shoji T, Hatsuda S, Tsuchikura S, Shinohara K, Kimoto E, Koyama H, Emoto M, Nishizawa Y. Department of Metabolism, Endocrinology and Molecular Medicine, Osaka City University Graduate School of Medicine, 1-4-3, Asahi-machi, Abeno-ku, Osaka , Japan. t- BACKGROUND: Low-density lipoprotein cholesterol (LDL-C) and the small dense LDL (SdLDL) phenotype are both predictors for ischemic heart disease. OBJECTIVE: We examined whether cholesterol of SdLDL (SdLDL-C) is more closely associated with carotid artery intima-media thickness (CA-IMT), a surrogate measure of atherosclerosis, than LDL-C and other lipid parameters. DESIGN AND METHODS: The subjects were 326 consecutive participants including those with dyslipidemia, diabetes mellitus, hypertension, chronic kidney disease, and smokers. SdLDL-C was quantified by a newly developed precipitation method, and CA-IMT by highresolution B-mode ultrasound. RESULTS: In univariate analysis, CA-IMT was most strongly correlated with SdLDL-C (Spearman's r=0.441, P<0.001), followed by apolipoprotein (apo) B, LDL-C, non-high-density lipoprotein cholesterol (Non-HDL-C), and plasma triglycerides (TG). HDL-C and apo A-I correlated inversely with CA-IMT. Non-lipid variables that were associated with CA-IMT were age, sex, presence of diabetes mellitus, presence of hypertension, estimate glomerular filtration rate (egfr), and C-reactive protein (CRP). Even after adjustment for age, sex, diabetes mellitus, hypertension, smoking, egfr and CRP, the positive association of CA-IMT with SdLDL-C remained significant, and again stronger than the associations with others lipid parameters. Further analyses revealed that the level of SdLDL-C was elevated in subgroups of the subjects including men, older subjects, smokers, those with higher CRP levels, those with diabetes mellitus, and hypertensive patients. CONCLUSION: These results indicate that SdLDL-C was the best marker of carotid atherosclerosis among the lipid parameters tested, and suggest that quantitative measurement of SdLDL-C gives useful information in the risk assessment for atherosclerotic disease. PMID:

13 HS-Omega-3 Index & ApoE Genotyping Complements to the LPP SpectraCell offers two additional tests recommended for cardiovascular risk reduction and the management and treatment of lipoprotein disorders. This test determines the patient's risk for sudden cardiac death (SCD). Half of all fatal heart attacks are due to SCD which is defined as death within one hour of the event. Most sudden cardiac deaths are due to cardiac arrhythmia. An adequate level of the omega-3's EPA and especially DHA can reduce this risk by 90%. The HS-Omega-3 Index measures the percentage of EPA and DHA levels in red blood cell membranes (RBC's) which are highly correlated to myocardial membrane omega-3 levels. Most Americans have a 4% RBC omega-3 fatty acid percentage which represents normal risk; however an 8 % RBC level may reduce the risk of SCD by 90%. This test determines an individual's genetic risk associated with the Apolipoprotein E gene. ApoE is involved in the metabolism of cholesterol and triglycerides, and variants in this gene can have clinically relevant implications for disease risk as well as one's response to statin therapy, dietary fat and other risk factors (e.g., smoking and alcohol consumption). Approximately 45% of individuals carry one or more of the high risk variants within the ApoE gene. The results of the genotyping of Apolipoprotein E have important implications in the treatment strategies for individual patients in reducing cardiovascular disease risk. Six possible ApoE genotypes exist: e2/e2, e2/e3, e2/e4, e3/e3, e3/e4 and e4/e4. ApoE Genotype Percent of Population Associated Risk Factors e2 / e2 1% Lower LDL e2 / e3 12% Increased triglycerides e2 / e4 2% None e3 / e3 62% None Normal e3 / e4 21% Increased LDL e4 / e4 2% Increased triglycerides Treatment Recommendation Tend to respond well to statin therapy May not respond well to low fat diet Moderate alcohol beneficial May not respond well to statin therapy Tend to respond well to low fat diet. Alcohol increases risk

14 PANELS/TESTS Patient Payment Options (non-medicare) STANDARD BILLING 1 INSURED PATIENTS PREFERRED UNINSURED/ PAY 2 CASH PRICE PAYMENT REQUIRED WITH SPECIMEN Nutritional COMPREHENSIVE NUTRITIONAL PANEL (WBC) $0 $170 3 $370 CHEMISTRY PANEL (SERUM) $0 $40 $80 LIPOPROTEIN PARTICLE COMPREHENSIVE PANEL LPP PLUS (SERUM) $0 $80 $160 Cardiovascular LIPOPROTEIN PARTICLE BASIC PANEL LPP (SERUM) $0 $40 $80 STANDARD LIPID PANEL (SERUM) $0 $25 $50 ASPIRIN RESPONSE TEST (URINE) $0 $25 $50 APOLIPOPROTEIN E GENOTYPING (WHOLE BLOOD) $0 NA $150 Specialty MTHFR GENOTYPING (WHOLE BLOOD) $0 NA $150 TELOMERE TEST (WHOLE BLOOD) $0 NA $290 HS-OMEGA-3 INDEX (WHOLE BLOOD) NA NA $ Patient is responsible for charges not paid by insurance, and will be billed for balance due, if any. 2. Patients choosing this option will receive no further bills for uncovered or disallowed tests, or other charges. 3. Not available for Blue Cross Blue Shield patients drawn in TX, IL, NM, OK and SC, or Cigna patients. 4. Only available with advance payment. (Not covered by insurance).

15 Client Payment Options PANELS/TESTS CLIENT PRICE CREDIT CARD ON FILE CLIENT PRICE BILLED MONTHLY Nutritional COMPREHENSIVE NUTRITIONAL PANEL (WBC) $290 $370 CHEMISTRY PANEL (SERUM) $60 $80 LIPOPROTEIN PARTICLE COMPREHENSIVE PANEL LPP PLUS (SERUM) $140 $160 Cardiovascular LIPOPROTEIN PARTICLE BASIC PANEL LPP (SERUM) $50 $80 STANDARD LIPID PANEL (SERUM) $40 $50 ASPIRIN RESPONSE TEST (URINE) $40 $50 APOLIPOPROTEIN E GENOTYPING (WHOLE BLOOD) $120 $150 Specialty MTHFR GENOTYPING (WHOLE BLOOD) $120 $150 TELOMERE TEST (WHOLE BLOOD) $250 $290 HS-OMEGA-3 INDEX (WHOLE BLOOD) $125 $150

16 REFERENCES & RESOURCES 1. Chandra R, Macfarlane R. Remnant Lipoprotein Density Profiling by CsBiEDTA Density Gradient Ultracentrifugation. Analytical Chemistry. 2006;78: Espinosa L, Macfarlane R, McNeal C. Method for Lipoprotein(a) Density Profiling by BiEDTA Differential Density Lipoprotein Ultracentrifugation. Analytical Chemistry. 2006; 78: Nakajima K, Nakano T, Tanaka A. The oxidative modification hypothesis of atherosclerosis: the comparison of atherogenic effects on oxidized LDL and remant lipoproteins in plasma. Clin Chim Acta. 2006;367(1-2): Packard CJ. Small dense low-density lipoprotein and its role as an independent predictor of cardiovascular disease. Curr Opin Lipidol. 2006;17(4): Watanabe H, et al. Decreased high-density lipoprotein (HDL) particle size, prebeta-, and large HDL subspecies concentration in Finnish low-hdl families: relationships with intima-media thickness. Aterioscler Thromb Vasc Biol. 2006;26(4): Bell N, Johnson J, Donahoe E, Macfarlane R. Metal Ion Complexes of EDTA as Solutes for Density Gradient Ultracentrifugation: Influence of Metal Ions. Analytical Chemistry. 2005;77: Capuzzi D, Carey C, Lincoff A, Morgan J. High-density Lipoprotein Subfractions and Risk of Coronary Artery Disease. Current Atherosclerosis Reports. 2004;6: Marcovina SM, Koschinsky ML. Evaluation of lipoprotein(a) as a prothrombotic factor: progress from bench to bedside. Curr Opin Lipidol. 2003;14(4): Otvos J. Why Cholesterol Measurements May be Misleading about Lipoprotein Levels and Cardiovascular Disease Risk Clinical Implications of Lipoprotein Quantification Using NMR Spectroscopy. J Lab Med. 2002;26(11/12): Cupples A, McNamara J, Nakajima K, Ordovas J, Schaefer E, Shah P, Wilson P. Remnant-like particle (RLP) cholesterol is an independent cardiovascular disease risk factor in women: results from the Framingham Heart Study. Atherosclerosis. 2001;154(1): Handbook of Lipoprotein Testing, 2nd Edition, American Association for Clinical Chemistry, Inc., Washington DC, Masuoka H, et al. Association of Remnant-Like Particle Cholesterol with Coronary Artery Disease in Patients with Normal Total Cholesterol Levels. Am Heart J. 2000;139(2): Seman L, et al. Lipoprotein(a)-cholesterol and coronary heart disease in the Framingham Heart Study. Clinical Chemistry. 1999;45: Cantin B, Dagenais G, Després J, Lamarche B, Moorjani S, Lupien P. Associations of HDL2 and HDL3 subfractions with ischemic heart disease in men. Prospective results from the Quebec Cardiovascular Study. Arterioscler Thromb Vasc Biol. 1997;17(6): Fortmann S, Gardner C, Krauss R. Association of small low-density lipoprotein particles with the incidence of coronary artery disease in men and women. JAMA. 1996; 276(11); pages Dahlen G. Lp(a) lipoprotein in cardiovascular disease. Atherosclerosis. 1994;108: Town Park Drive Houston, Texas Tel LABS (5227) Fax