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Total Cholesterol

This is the amount of cholesterol contained in all lipoprotein components present in one deciliter of plasma, including chylomicrons, very-low-density lipoproteins (VLDL), intermediate-density lipoproteins (IDL), LDL, lipoprotein(a) [Lp(a)], and high-density lipoproteins (HDL). Cholesterol is a crucial component of all cell membranes within the body and is necessary for the manufacture of important hormones and vitamins. However, a high level of total cholesterol is a contributing factor to the initiation and progression of atherosclerosis. While decisions about cholesterol-lowering therapies are no longer focused on LDL-C targets, but based on the 10-year risk of atherosclerotic cardiovascular disease (ASCVD) and other factors, controversy surrounds the use of the updated risk calculator and guidelines. 1 Many physicians still follow the American College of Cardiology (ACC)/American Heart Association (AHA) guidelines for treatment of blood cholesterol or the National Lipid Association (NLA) recommendations for management of dyslipidemias to reduce ASCVD risk.2 Guidelines include strategies for lifestyle changes and/or cholesterol-lowering drugs such as statins.

1. Stone NJ, et al. Circulation 2014;129[Suppl 2]:S1–S45.
2. Waite LH, et al. J Am Pharm Assoc 2016;56:284–292.


LDL-C reflects the cholesterol transported within the LDL particles and is a well-established risk factor for ASCVD. 3 LDL-C represents about 65% of the total circulating cholesterol but can vary according to insulin sensitivity, leading to discordance between LDL-C and measures of LDL particle concentration (LDL-P or apoB).4 Guidelines include strategies for implementing lifestyle changes and/or cholesterol-lowering drugs such as statins.1,2

1. Stone NJ, et al. Circulation 2014;129[Suppl 2]:S1–S45.
2. Waite LH, et al. J Am Pharm Assoc 2016;56:284–292.

3. Shah S, et al. Circ Cardiovasc Genet 2013;6(1):63–72.
4. Otvos JD, et al. J Clin Lipidol 2011;5(2):105–113.


HDL particles are produced mainly in the liver from apoA-I, cholesterol, and phospholipids. They capture and assimilate excess cholesterol from around the body (including that deposited in macrophages in the vasculature which can fuel atherogenesis), returning it to the liver in a process called “reverse cholesterol transport” and/or donating it to TG-rich lipoproteins (VLDL, IDL, and LDL) during their maturation. HDL particles are complex molecules with antioxidative, anti-inflammatory, antithrombotic, and vasodilatory properties, and may protect LDL from oxidation. 1 HDL-C reflects the cholesterol transported within the HDL particles and has been linked in multiple studies to a reduced risk of CVD.1,2 Low HDL-C may indicate the presence of metabolic syndrome, especially if TG are also elevated.41 However, studies have not shown a clear preventive effect of increasing HDL-C on risk of CVD.3

1. Toth PP, et al. J Clin Lipidol 2013;7:484–525.
2. Toth PP, et al. Atherosclerosis 2014;235:585–591.
3. Ali KM, et al. Br J Pharmacol 2012;167:1177–1194.


Non-HDL-C represents the concentration of cholesterol in all atherogenic lipoproteins including chylomicrons, VLDL, IDL, LDL, and lipoprotein(a) [Lp(a)], and is calculated as total cholesterol minus HDL-C.  Studies have demonstrated that non-HDL-C is a superior predictor of risk for CVD events than is LDL-C.1 The use of non-HDL-C for CVD risk prediction has been emphasized in several recent guidelines and consensus papers.1,3 The NLA recommends treatment goals for non-HDL-C.3

  1. Verbeek R, et al. Curr Opin Lipidol 2015;26:502–510.
  2. Waite LH, et al. J Am Pharm Assoc 2016;56:284–292.
  3. Perk J, et al. Eur Heart J 2012;33:1635–1701.


This test measures the TG in all the lipoprotein particles; most is in the VLDL. Increased TG levels are associated with insulin resistance, metabolic syndrome, and diabetes but may also be due to secondary causes such as thyroid disease, high alcohol intake, or certain medications.1,2 Recent insights strongly suggest that elevated TG-rich lipoproteins represent causal risk factors for inflammation, ASCVD, and all-cause mortality.3,4 Severely elevated TG also increase the risk of acute pancreatitis. Lifestyle changes including regular exercise, decreased consumption of simple sugars and refined carbohydrates, and increased intake of omega-3 fatty acids may effectively decrease blood TG level.5 Marked high levels (> 500 mg/dL) may indicate inherited TG-rich lipoproteinemias (e.g., familial hypertriglyceridemia, lipoprotein lipase deficiency).

  1. Lee J-E, et al. Int J Cardiol 2016;225:327–331.
  2. Tenenbaum A, et al. Cardiovasc Diabetol 2014;13:159.
  3. Nordestgaard BG. Circ Res 2016;118:547–563.
  4. Miller M, et al. Circulation 2011;123:2292–2333.
  5. Bays HE, et al. J Clin Lipidol 2013;7:304–383.

Triglycerides, Blanked

Most TG assays presently used in clinical laboratories hydrolyze the fatty acids from the TG backbone, to produce free glycerol. The second step of the reaction measures all the free glycerol in the sample and produces a signal that is proportional to the TG concentration. In some conditions (especially glycerol kinase deficiency, GKD), a patient’s sample can contain an excess of endogenous free glycerol that leads to aberrantly elevated TG, significantly higher than the actual value. Elevated endogenous free glycerol by itself is a relatively benign condition, but these patients are resistant to all means of lowering their factitiously elevated TG and may undergo unnecessary follow-up testing and inappropriate treatment.

For that reason, Salveo Diagnostics also analyzes all samples with TG >400 mg/dL with a blanked method and then looks for any discrepancy in the two results. There are three possible outcomes and the report commenting will reflect one of those options.

1.The blanked and non-blanked TG results were comparable with no apparent excess free glycerol present in the sample.

2.Minimal free glycerol interference was present, reflective of increased lipolysis. However, levels were significantly lower than seen in GKD.

3.The TG results were suggestive of GKD. If other sources of free glycerol cannot be ruled out (e.g., parenteral nutrition containing glycerol), GKD should be considered. In adults, this is generally a benign condition known as pseudohypertriglyceridemia. However, in severe infantile forms, vomiting, failure to thrive, and metabolic decompensation acidosis can have severe consequences.

Triglycerides/HDL-C Ratio

The TG/HDL-C ratio provides a simple approach to identify individuals at heightened cardiovascular risk associated with an increased prevalence of insulin resistance, independent of BMI.2  In fact, subjects with insulin resistance (as measured by the TG/HDL-C ratio) but healthier-than-average lipid measures have been shown to have worse cardiovascular outcomes than those who are insulin sensitive but with unhealthier lipid measures.1  An elevated TG/HDL-C ratio thus supports more aggressive efforts to enhance insulin sensitivity. Improvement in the TG/HDL-C ratio may be achieved by weight loss, exercise, dietary supplementation with omega-3 fatty acids, and reducing intake of alcohol, simple sugars, and refined carbohydrates.

  1. Bertsch RA, et al. Perm J 2015;19(4):4–10.
  2. Armato J, et al. Endocr Pract 2015;21(5):495–500.


Lipoprotein Particles


LDL particles are captured via specific receptors in the liver or by peripheral tissues, where their cholesterol is normally recycled or used in hormone and cell membrane production. This test measures the concentration of LDL particles in the circulation (LDL-P), which data suggests may more accurately reflect LDL atherogenicity and heart disease risk than traditional cholesterol measures.2 Indeed, elevated LDL-P is associated with increased risk for CHD, even in the presence of optimal LDL-C values. LDL-P is also an important goal of therapy. When LDL-P and LDL-C are discordant, the LDL-P value is the one most consistent with clinical status and outcomes.1 LDL-P is often higher in patients with insulin resistance and type 2 diabetes mellitus (T2DM),3 and may be decreased by regular exercise and reduced intake of refined carbohydrates and simple sugars. Pharmacological treatments include statins, niacin, ezetimibe, fibrates, and combination therapy (statin + niacin or statin + fibrate).

Salveo Diagnostics measures LDL-P using agarose gel electrophoresis to separate LDL from other lipoproteins, followed by immunostaining [quantitative lipoprotein immunofixation electrophoresis (Lipo-IFE)].4 Although there is no “gold-standard” method for determination of LDL-P, ultracentrifugation relies most directly on the density-based definition of LDL particles. In comparison to nuclear magnetic resonance (NMR) spectroscopy (another method of measuring lipoprotein particle concentration) Lipo-IFE shows closer agreement to ultracentrifugation, is more direct, has significantly greater precision and higher throughput, is less expensive, and can resolve lipoprotein subfractions [i.e., Lp(a) and IDL] that NMR cannot.5

  1. Shah S, et al. Circ Cardiovasc Genet 2013;6(1):63–72.
  2. Toth PP, et al.. J Clin Lipidol 2013;7:484–525.
  3. Armato J, et al. Endocr Pract 2015;21(5):495–500.
  4. Guadagno PA, et al. Clin Chim Acta2015;439:219–224.
  5. Hopkins PN, et al. Atherosclerosis 2015;243:99–106.


Lipoprotein(a) [Lp(a)] particles consist of an LDL particle with an apo(a) molecule covalently linked to the apoB moiety and are the most atherogenic particles in the circulation, with thrombogenic potential due to their structural similarity to plasminogen. The Salveo Diagnostics method of measuring Lp(a) particle concentration [Lp(a)-P], lipoprotein immunofixation electrophoresis (Lipo-IFE), is not affected by apo(a) isoform size (unlike commercially available methods measuring Lp(a) mass) and thus provides the most accurate assessment of circulating Lp(a).1 Elevated Lp(a) levels are linked to atherogenesis, thrombosis, and increased risk of cardiovascular events.2-5 In women, Lp(a) levels rise significantly after menopause, due to loss of estrogen.6

Because Lp(a)-P is an inherited trait, it is especially important to measure in those with a family history of premature CHD, venous thrombosis, and/or spontaneous abortion. Evidence supports aggressive treatment of other CVD risk factors when Lp(a)-P is elevated. Although reduction of Lp(a)-P has not been proven to reduce CVD risk (agents tested to date also affect other risk factors), lowering Lp(a)-P may have beneficial effects. Substances demonstrated to lower Lp(a)-P include aspirin, niacin, and PCSK9 inhibitors.3,7 As Lp(a) is an inflammatory lipoprotein, an anti-inflammatory diet and lifestyle may be particularly helpful in patients with elevated Lp(a)-P.

  1. Guadagno PA, et al. Clin Chim Acta 2015;439:219–224.
  2. Kiechl S, Willeit J. J Am Coll Cardiol 2010;55(19):2168–2170.
  3. Tsimikas S, Hall JL. J Am Coll Cardiol 2012;60(8):716–721.
  4. Nordestgaard BG, et al. Eur Heart J 2010;31:2844–2853.
  5. Hopewell JC, et al. J Intern Med 2014;276:260–268.
  6. Derby CA, et al. Am J Epidemiol 2009;169(11):1352–1361.
  7. Jacobson, TA, et al. Mayo Clin Proc 2013;88(11):1294–1311.


Very-low-density lipoprotein (VLDL) particles are TG-rich lipoproteins that are synthesized in the liver and excreted into the bloodsteam in response to the body’s energy needs. VLDL particles are rapidly metabolized to IDL particles which are cleared from the blood by the liver or converted to LDL particles. Increased VLDL particle concentration (VLDL-P) may result from familial hypertriglyceridemia or familial combined lipoproteinemia, or may be seen in patients with mild lipoprotein lipase or apolipoprotein CII deficiencies.1 Increased VLDL-P may also be triggered by conditions such as insulin resistance, metabolic syndrome, and diabetes, or by agents such as estrogens, glucocorticoids, excessive alcohol, or anabolic steroids.2,3-5 Measurement of VLDL-P can help explain differences in CVD risk in the prediabetic state. Lifestyle changes (e.g., increased exercise and Mediterranean diet with reduced intake of refined carbohydrates), treatment of the underlying condition, or removal of a triggering agent may effectively reduce VLDL-P.1

  1. Armato J, et al. Endocr Pract 2015;21(5):495–500.
  2. Sniderman AD, et al. J Am Heart Assoc 2016;5(10). pii: e003665.
  3. Jiang ZG, et al. Metabolism 2016;65(3):92–99.
  4. Lorenzo C, et al. J Clin Endocrinol Metab 2013;98(4):1622–1630.
  5. Mackey RH, et al. Diabetes Care 2015;38(4):628-636.


Intermediate-density lipoprotein (IDL) particles are remnant lipoproteins resulting from the breakdown of VLDL particles. They contain less TG than VLDL: some will continue to lose TG and ultimately become LDL particles (containing about 50% cholesterol), while others will be taken up in the liver and excreted in the bile. In a fasting blood sample, IDL particle concentration (IDL-P) is typically low or undetectable. IDL is an atherogenic lipoprotein.1 Elevated fasting IDL-P may be observed in patients with type III hyperlipoproteinemia (dysbetalipoproteinemia) or secondary to conditions which adversely affect normal metabolism of lipoproteins including diabetes, metabolic syndrome, hypothyroidism, and fatty liver disease [or non-alcoholic steatohepatitis (NASH)].1 If such conditions exist, treatment should focus on the specific underlying disease or condition.  Lifestyle change is often the first approach to therapy, including increased exercise and a Mediterranean diet with reduced refined carbohydrate intake, which can improve IDL-P as well as associated conditions.1

  1. Armato J, et al. Endocr Pract 2015;21(5):495–500.

Apolipoprotein B

A measure of the number of potentially atherogenic lipoproteins (VLDL, IDL, and LDL) in the blood, the majority of which are LDL particles that can deposit cholesterol into the artery wall. Multiple studies have shown that apoB concentrations are more predictive of atherosclerotic risk and CVD events than LDL-C, especially in younger adults.2,3,4 Elevated apoB concentration is associated with increased risk for CHD even in the presence of optimal LDL-C values. The NLA recommends that apoB be used as a secondary target of treatment for dyslipidemia.1 In most individuals, apoB levels are an effective surrogate for LDL-P, and are highly predictive of CHD and cardiovascular events.5 Discordance of apoB and LDL-P is especially common among individuals with insulin resistance or metabolic syndrome, and with patients taking medications that reduce LDL-C more effectively than they do LDL-P.6 Elevated apoB levels have also been linked to declining cognitive abilities, dementia, and Alzheimer disease.7 ApoB concentration may be decreased by regular exercise and reduced intake of refined carbohydrates and simple sugars. Pharmacological treatments include statins, niacin, ezetimibe, fibrates, and combination therapy (statin + niacin or statin + fibrate). Combination therapy (statin + niacin) may be particularly effective in lowering apoB, especially when small dense LDL particles are present.8

  1. Shah S, et al. Circ Cardiovasc Genet 2013;6(1):63–72.
  2. Wang J, et al. J Intern Med 2012;272(6):562–572.
  3. Guadagno PA, et al. Clin Chim Acta 2015;439:219–224.
  4. Pencina MJ, et al. Eur J Prev Cardiol 2015;22(10):1321–1327.
  5. Cole TG, et al. Clin Chem 2013;59(5):752–770.
  6. Varvel SA, et al. J Clin Lipidol 2015;9(2):247–255.
  7. Reynolds CA, et al. J Am Geriatr Soc 2010;58(3):501–509.
  8. Bays H, et al. Prev Cardiol 2003;6(4):179–188.

Apolipoprotein A-I

Apolipoprotein A-I (apoA-I) is the major protein component of HDL particles and may be used as a surrogate measure of HDL particle concentration (HDL-P). ApoA-I is important for cholesterol transport, and possesses potent antioxidant and anti-inflammatory properties. Low apoA-I levels are independently associated with insulin resistance, metabolic syndrome, and risk for cardiovascular events, including myocardial infarction and stroke.1,2 If apoA-1 is decreased in the setting of normal HDL-C, this suggests that the HDL present may not be cardioprotective.3 ApoA-I concentration may be increased by regular exercise and dietary supplementation with omega-3 fatty acids; pharmacological treatments include niacin, fibrates, and combination therapy (statin + niacin).

  1. Fizelova M, et al. Atherosclerosis 2015;240(1):272–277.
  2. Holme I, et al. Atherosclerosis 2010;213:299–305.
  3. Rached F, et al. J Lipid Res 2014;55(12):2509–2520.

ApoB/ApoA-I Ratio

A high apoB/apoA-I ratio has been shown to be an excellent baseline predictor of cardiovascular event risk and is associated with the severity of coronary stenosis in patients with CHD.1-4 A high apoB/apoA-I ratio is also associated with insulin resistance.5Therapeutic lifestyle strategies to reduce circulating apoB and increase apoA-I include increasing regular exercise, reducing intake of simple sugars and refined carbohydrates, and dietary supplementation with omega-3 fatty acids. Medications include statins, fibrates, and niacin, or combination therapy.

  1. Schmidt C, Bergstrom G. Angiology 2014;65(10):901–905.
  2. Liting P, et al. Herz 2015;40:1–7.
  3. Song Y, et al. Lipids Health Dis 2015;14:150.
  4. Ying X, et al. Acta Diabetol 2012;49(6):465–472.


Small dense LDL cholesterol (sdLDL-C) is a measure of the cholesterol trafficked within the smaller LDL species and is a strong predictor of incident CHD.1,2 Plasma sdLDL-C levels are strongly correlated with an atherogenic lipid profile and are higher in patients with diabetes than those without diabetes.1,2 Because sdLDL particles are typically elevated in the presence of excess TG levels, they may be used as a marker of insulin resistance. Several mechanisms have been proposed to explain the enhanced atherogenicity of sdLDL over LDL, including (1) a lower affinity for the LDL receptor, (2) easier entry into the arterial wall, (3) greater arterial retention due to increased binding to proteoglycans, and (4) greater susceptibility to oxidation.

As sdLDL particles contain less cholesterol than large buoyant ones, increased levels of sdLDL-C also represent a greater number of atherogenic particles, which may not be reflected by levels of LDL-C. Larger LDL subclasses are predominant in centenarians, suggesting that low sdLDL levels are compatible with extreme longevity. Observational studies and clinical practice reports have found that sdLDL-C can be reduced by decreasing consumption of simple sugars and refined carbohydrates.3

  1. Hoogeveen RC, et al. Arterioscler Thromb Vasc Biol 2014;34:1069–1077.
  2. Ai M, et al. Clin Chem 2010;56:967–976.
  3. Faghihnia N, et al. J Lipid Res 2010;51(11):3324–3330.

Apolipoprotein E Genotype

Apolipoprotein E (apoE) genotype testing can help with cardiovascular risk assessment and individualizing therapeutic recommendations. ApoE is a key regulator of plasma lipids and helps identify how people respond to dietary fat. The APOE gene is polymorphic, that is, it can exist in three different forms, with alleles ε2, ε3, and ε4 coding for apoprotein isoforms apoE2, apoE3, and apoE4 that differentially affect lipoprotein metabolism.1 The apoE4 isoform (and ε4 allele) has been associated with higher plasma levels of total cholesterol and LDL-C and a greater risk of CAD when compared with the most common isoform, apoE3 (and ε3 allele).1-3 Individuals with the apoE4 isoform often show hyperabsorption of cholesterol and decreased absorption of omega-3 fatty acids (hence reduced omega-3 index).4 Although not diagnostic, there is an association between apoE4 and Alzheimer disease.5 The apoE2 isoform is associated with lower plasma levels of LDL-C and lower risk of CAD but susceptibility to familial dysbetalipoproteinemia, which confers increased cardiovascular risk and may be induced by TG elevations due to metabolic disturbances (e.g., hypothyroidism and insulin resistance).2,6

In general, patients with the E4 allele respond less favorably to high-dose statin therapy and may respond better to dietary change (reduced fat intake) or combination drug therapy as a means to lower lipid levels. Patients with the ε2 and/or ε3 alleles generally respond well to statin therapy, depending on their cholesterol absorption/synthesis status. Omega-3 fatty acid supplementation has been shown to benefit patients with the ε2 and/or ε3 alleles.7 As patients carrying apoE4 tend to have reduced omega-3 indexes and an increased risk for CHD, this genotype may be the most in need of supplemental omega-3 fatty acids.6 If the patient also has insulin resistance, a low-carbohydrate or Mediterranean diet may be appropriate.

Type III hyperlipoproteinemia is a familial dyslipidemia characterized by the combination of elevated serum cholesterol and TG and the presence of the apoE genotype ε2/ ε2.1 Approximately 1% of the general population has the ε2/ ε2 genotype, but development of the frank lipid disorder occurs in about 5-10% of these predisposed individuals, triggered by secondary causes (genetic, hormonal, or environmental).8 The most effective drugs for type III hyperlipoproteinemia are fibrates or nicotinic acid that decrease production of VLDL and can substantially lower both cholesterol and TG levels. Family members of affected individuals may consider being tested for the apoE ε2/ ε2 genotype and screened for hyperlipidemia.

  1. Phillips MC. IUBMB Life 2014;66(9):616–623.
  2. El-Lebedy D, et al. Cardiovasc Diabetol 2016;15:12.
  3. Song Y, et al. Ann Intern Med 2004;141:137–147.
  4. Dayspring T, et al. J Clin Lipidol 2015;9:807–816.
  5. Lopez MR, et al. Expert Rev Proteomics 2014;11(3):371–381.
  6. Harris WS, et al. J Cardiovasc Transl Res 2014;7(5):526–532.
  7. Thifault E, et al. Nutrigenomics 2013;6:73–82.
  8. Schaefer JR. Eur J Hum Genet 2009;17:541–542.

Why Gut Health?

Poor gut health is at the heart of many chronic conditions. A healthy gastrointestinal (GI) tract is vital to overall well-being and even survival. A recent explosion of scientific research worldwide, including the Human Microbiome Project (HMP), is providing new insights into the importance of the gut as the “gateway to good health” and giving new meaning to the phrase “you are what you eat.”

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