Test descriptions for CVD

Cardio IQ® Advanced Cardiovascular Tests

Lipid Panel/ASCVD (Atherosclerotic Cardiovascular Disease) Risk Panel

Lipid Panel with Direct LDL Reflex 92061(X) and without Direct LDL Reflex 91716(X) is a panel of blood tests that serves as an initial broad medical assessment tool for abnormalities in total cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides, low-density lipoprotein (LDL) cholesterol (calculated), and cholesterol/HDL ratio (calculated). A lipid panel is used to identify hyperlipidemia, which may indicate an increased risk for cardiovascular disease. If the triglycerides level is greater than 400 mg/dL, LDL will be directly measured, and not calculated, if direct LDL reflex was chosen.

Lipid Panel/ASCVD Risk Panel Assessment 92052(X) is a lipid panel with a reflex to direct LDL cholesterol (when triglycerides are greater than 400 mg/dL) and a calculation of a 10-year risk of a first ASCVD event—defined as coronary death or nonfatal myocardial infarction (MI), or fatal or nonfatal stroke—using race- and sex-specific pooled cohort evaluations, and as recommended by the 2013 ACC/AHA Guidelines on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults. Patient information is provided by the ordering physician.

Lipid panel components may be ordered separately: Cholesterol, Total 91717(X)/334 (CPT 82465); Triglycerides 91718(X)/896 (CPT84478); HDL Cholesterol 91719(X)/608 (CPT 83718). If triglyceride results are >400 mg/dL, Direct LDL Cholesterol will be performed at an additional charge (CPT 83721).

Lipoprotein subfractionation

Ion Mobility 91604(X) is a proprietary test methodology for lipoprotein subfractionation. Individual lipoprotein subclasses are separated with high resolution, and direct quantification of lipoproteins provides precise particle counts for each lipoprotein type and subclass. Measurements of LDL or HDL determined as part of the conventional lipid panel may be optimal, while LDL and HDL subclass analysis may indicate increased cardiovascular disease (CVD) risk.

Ion Mobility identifies small- and medium-LDL subclasses, which are highly atherogenic. There is a 1.3x increased CVD risk associated with the small LDL trait and a 1.4x increased risk for the medium LDL trait.1-3 The large HDL subclass is the most efficient cholesterol reabsorbing HDL particle, and best reflects the efficacy of the reverse cholesterol transport system and cholesterol clearance by the liver. Low levels of large HDL are correlated with a 1.8x increased CVD risk.1

HDL2b 36405(X) consists of the largest and most buoyant particles of the HDL subclasses. A low level of large HDL particles may reduce the efficacy of the reverse cholesterol transport process and increase CVD risk.

sdLDL 36406(X), or small dense LDL, particles are particularly atherogenic due to their increased affinity for vessel walls, increased susceptibility to oxidation, and reduced ability to be cleared by the liver, increasing the length of time in which these particles remain in circulation.

Apolipoproteins

ApoB 91726(X), or apolipoprotein B, is the predominant apoprotein attached to LDL, intermediate-density lipoproteins (IDL), and very-low-density lipoproteins (VLDL). Several decades of scientific literature support the measurement of ApoB for monitoring response to statin therapy. Elevated ApoB is associated with a 2.0–2.5x increased CVD risk.4

Lp(a) 91729(X), or lipoprotein(a), consists of an inherited protein attached to an LDL particle. Elevated Lp(a) is associated with increased coagulation and a 1.5–5.3x increased incidence of CVD.5 Lp(a) has been linked to the promotion of both early- and advanced-stage atherosclerosis. When the measurement of Lp(a) is combined with other abnormal CVD risk markers, the associated risk increases further.

Inflammation

F2-IsoPs 92771(X), or F2-Isoprostanes, are prostaglandin-like compounds formed from free radical-mediated oxidation of arachidonic acid. F2-IsoPs measure oxidative stress induced by lifestyle risk factors for CVD, which includes smoking, poor diet, high red meat intake, and a sedentary lifestyle. F2-IsoPs contribute to CVD progression through increased vasoconstriction via thromboxane production, platelet aggregation, and thrombus formation. Elevated levels of F2-IsoPs indicate a 2.6x increased risk for CAD and a 1.8x increased risk of CVD mortality.6

OxLDL 92769(X), or oxidized LDL, measures damage of the ApoB protein subunit on the surface of LDL due to oxidative modification. Oxidation of ApoB is an initiating factor in macrophage recruitment, foam cell formation, and vascular inflammation within the arterial wall. Elevated OxLDL levels indicate a 4.3x increased risk of having a coronary heart disease (CHD) event and a 3.5x increased risk of developing metabolic syndrome (MetS).7,8

ADMA/SDMA 94153(X), or asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA), are derivatives of the amino acid L-arginine and are produced via protein degradation. ADMA is a competitive inhibitor of nitric oxide synthase and can reduce the production of nitric oxide. Nitric oxide deficiency is an early manifestation of endothelial dysfunction and atherosclerotic disease. Elevated ADMA indicates a 1.4x increased risk of CVD and CHD and a 1.6x increased risk of stroke. SDMA is primarily excreted in the urine and strongly correlates with reduced renal function.9

Fibrinogen 91743(X) is a plasma glycoprotein that can be transformed into a fibrin clot in response to vascular or tissue injury. The combination of elevated fibrinogen with other CVD risk factors produces an additive risk and may substantially increase disease potential.10

hs-CRP 91737(X) is a highly sensitive measurement of C-reactive protein, an acute-phase reactant protein that increases in response to inflammation. In large epidemiologic studies, elevated levels of CRP have been shown to be a strong indicator of CVD. Patients with high CRP have a 1.5–2.0x increased risk of developing subsequent atherosclerotic disease compared with patients with low CRP levels. It’s also been demonstrated that lowering hs- CRP, independent of lipid levels, results in a 15% risk reduction of recurrent cardiovascular events.11-13

Lp-PLA2 94218(X), or lipoprotein-associated phospholipase A2, is an enzyme produced by macrophages and foam cells within the necrotic core of arterial plaque. Lp-PLA2 measures the disease activity within the arterial wall under the calcified cap of the plaque. Elevated Lp- PLA2 has been associated with a 2.0x increased risk for developing CHD independent of non- HDL cholesterol levels. Also, elevated Lp-PLA2 levels indicate a 2.0x risk of having a CHD event (MI, coronary revascularization or CHD-related death).14

MPO 92814(X), or myeloperoxidase, is an inflammatory enzyme released within the vascular lumen during white blood cell activation in response to fissures, erosions, or degradation of the fibrous cap. MPO is a specific marker of vascular inflammation and is a measure of vulnerable plaque. Elevated levels of MPO independently predict 2.0–2.4x increased risk of future cardiovascular events (MI, coronary revascularization, or CVD-related death).15,16

Metabolic markers

Cardio IQ® Insulin Resistance Panel with Score 96509(X) combines fasting insulin and Cpeptide measurements to evaluate the likelihood that an individual has insulin resistance. Both analytes are simultaneously quantified by liquid chromatography-tandem mass spectrometry (LC/MS/MS).

Diabetes Risk Panel with Score 92026(X) measures glucose, hemoglobin A1c (HbA1c), and lipids. It also estimates the 8-year risk of developing diabetes using laboratory test results, anthropomorphic data, and family history. The risk algorithm is based on the analysis of 3,453 individuals (ages 30–79) within the Framingham cohort. It is intended to aid in the identification of patients at risk for developing diabetes mellitus, permitting lifestyle or pharmacologic interventions.

Diabetes panel components may be ordered separately: Glucose 91947/483 (CPT 82947); Hemoglobin A1c 91732/496 (CPT 83036); Cholesterol, Total 91717(X)/334 (CPT 82465); HDL Cholesterol 91719(X)/608 (CPT 83718); Triglycerides 91718(X)/896 (CPT 84478). Available with and without score.

Glucose 91947(X) measures serum glucose levels under fasting conditions. Elevated serum glucose (hyperglycemia) is associated with diabetes and insulin resistance. Low levels indicate hypoglycemia.

Cholesterol, Total 91717(X) is useful in the diagnosis of hyperlipoproteinemia, atherosclerosis, hepatic, and thyroid diseases.

Hemoglobin A1c 91732(X) reflects average blood sugar levels over the preceding 90-day period. Elevated levels are associated with prediabetes and diabetes. HbA1c measurement requires no fasting or glucose loading requirement, is less sensitive than glucose to stress and illness, and is more specific for identifying individuals at increased risk for diabetes. Lowering HbA1c levels by 1% reduces the risk of microvascular complications by approximately 40%.17

Insulin 91731(X) is associated with the characterization of an atherogenic lipid profile and metabolic syndrome. Abnormal fasting insulin, especially when combined with other risk factors, identifies patients at significantly higher risk for the development of CVD.

Homocysteine 91733(X) is a metabolic by-product of methionine metabolism. Progressively elevated blood levels of homocysteine are a documented risk marker for CVD events.

Omega-3 and -6 Fatty Acids (FAs) 91734(X)—a diet rich in omega-3 fatty acids is associated with a decreased risk of cardiovascular events, including sudden cardiac death (SCD). The three major omega-3 fatty acids are eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and alpha-linolenic acid. Omega-6 fatty acids are proinflammatory and prothrombotic. The major omega-6 fatty acid is arachidonic acid (AA). The omega-3 index—EPA and DHA expressed as a percentage of phospholipid FAs—is an indicator of risk for SCD and nonfatal cardiovascular events and is used as a therapeutic target. The EPA/AA ratio is a marker of cardiovascular risk, with higher ratios being associated with lower cardiac risk. This test measures omega-3 and -6 fatty acid levels free in serum.

OmegaCheck 92701(X) measures the long-chain omega-3 fatty acids: EPA, docosapentaenoic acid (DPA), DHA, and the most abundant forms of omega-6 fatty acids: AA and linoleic acid (LA). Omega-3 fatty acids have anti-oxidant, anti-inflammatory, and antithrombotic effects, and may help reduce triglycerides. Increased levels of omega-3 fatty acids are associated with a lower risk of sudden cardiac death. High ratios of AA/EPA or omega-6/omega-3 are associated with increased CVD and mortality risk. The OmegaCheck test measures omega-3 and -6 fatty acid levels in whole blood.

TMAO 94154(X), or trimethylamine-N-oxide, is a metabolite produced by the gut microbiome following consumption of food products containing the precursors L-carnitine, choline, and phosphatidylcholine (lecithin), which are abundant in various animal-derived products (dairy, egg yolk, and red meat) as well as dietary supplements and energy drinks. TMAO impacts physiological processes that may increase risk of atherosclerosis, enhance platelet hyperreactivity, and increase thrombosis. Elevated TMAO is associated with a 2.5x increased risk of incident major adverse cardiovascular events (MACE). A meta-analysis also demonstrated a 7.6% increase in relative risk for CVD mortality for every 10μmol/L increase in TMAO.18

Vitamin D, 25 Hydroxy, LC/MS/MS 91735(X) at low levels are associated with increased risk of CVD events and death due to heart failure, sudden cardiac death, and stroke. The cardiovascular impact of low vitamin D is via activation of the renin-angiotensin-aldosterone system, as well as via increased parathyroid hormone levels (which predispose individuals to increased insulin resistance associated with diabetes, hypertension, inflammation, and increased cardiovascular risk).

LC/MS/MS=liquid chromatography/tandem mass spectrometry.

Heart failure (HF)

NT-proBNP 91739(X), or N-terminal pro b-type natriuretic peptide, is an endogenously produced neurohormone secreted from the cardiac ventricular myocytes in response to cardiac stress. Elevated levels indicate the presence of ongoing myocardial stress and potentially an underlying cardiac disorder. As a highly sensitive marker for cardiac dysfunction, elevated NT-proBNP levels are prognostic of future cardiovascular events, even in the setting of undiagnosed, subclinical CVD.

ST2, Soluble (sST2) 91823(X) can be used in risk assessment of patients with acute and chronic heart failure. The sST2 biomarker binds and removes Interleukin-33 from the circulation, thus eliminating the protective effect the IL-33 provides to the cardiac muscle. Patients with HF and elevated sST2 levels are at increased risk for progression, heart transplantation, and possibly death. sST2 is not affected by confounding factors as is BNP/ NT-proBNP. Using sST2 alongside BNP/NT-proBNP may help improve the risk stratification of patients with chronic HF. High levels of both sST2 and BNP/NT-proBNP, compared with high levels of only one, better predict HF progression.

Galectin-3 92768(X) is a carbohydrate-binding lectin that increases collagen production and cardiac fibroblast proliferation. Elevated levels of galectin-3 have been associated with macrophage infiltration, cardiac fibrosis, and cardiac hypertrophy, which contribute to progression of heart failure and poor cardiovascular outcomes. Measuring galectin-3 in conjunction with BNP/NT-proBNP and ST2 may further enhance risk stratification to monitor and treat HF and CVD.

Genetic cardiovascular markers

4q25 AF Risk Genotype Test 90948(X) may help predict risk of atrial fibrillation (AF) and cardioembolic (CE) stroke. 4q25 AF Risk carriers may have up to a 1.7x19 increased risk of AF and up to a 1.5x20 increased risk of CE stroke related to AF.* Physicians may benefit from knowledge of their patients’ increased AF risk, and therefore consider additional clinical follow-up for these patients.

Apolipoprotein E (ApoE) Genotype Test 90649(X) may help predict risk of CVD and response to different diets.

9p21 Genotype Test 90648(X) may help predict risk of early onset MI, abdominal aortic aneurysm (AAA), and MI/CHD.† Identification of 9p21 carriers may allow clinicians to take steps to characterize and reduce risk factors that may contribute to the development or progression of disease.

CYP2C19 Genotype Test 90668(X) may help predict response to Plavix® (clopidogrel).‡ Patients carrying one or two copies of nonfunctional alleles may not receive the full benefits of Plavix, and therefore may benefit from alternative dosing strategies or an anti-platelet agent other than Plavix.

Familial Hypercholesterolemia (FH) Panel 94877(X) tests for variants in the genes LDLR, APOB, and PCSK9 to help diagnose FH.

KIF6 Genotype Test 90645(X) may help predict risk of a CHD event and response to Lipitor® (atorvastatin) or Pravachol® (pravastatin).§ In certain studies, atorvastatin and pravastatin therapy was found to reduce CHD event risk more effectively in KIF6 carriers compared with noncarriers.

LPA Aspirin Genotype Test 90553(X) may help predict risk of CVD and response to aspirin therapy.ll In the Women’s Health Study (WHS), low-dose aspirin therapy resulted in a greater reduction of CVD events in LPA Aspirin carriers than in noncarriers.

LPA Intron 25 Genotype Test 90655(X) may help predict risk of CHD, providing additional insight into a patient’s risk for CHD beyond traditional risk factors.#

This information is provided for informational purposes only and is not intended as medical advice. A physician’s test selection and interpretation, diagnosis, and patient management decisions should be based on his/her education, clinical expertise, and assessment of the patient.

 

*Being a carrier of this genetic risk factor does not mean that patients will develop AF or CE stroke. Similarly, patients who are noncarriers of this genetic risk factor are not immune to these heart disorders.

Being a carrier of this genetic risk factor does not mean that patients will develop early MI or AAA. The 9p21 genetic variant has been found to be associated with risk of AAA, but not with rate of aneurysmal expansion or risk of rupture.

The clinical impact of the CYP2C19 genotype on the metabolism of specific drugs will vary based on nongenetic factors, such as hepatic and renal status, other medications used (including over-the-counter medications, herbals, and other supplements), alcohol or illegal drug use, race, age, weight, diet, and diseases present in an individual patient.

§The benefit of statin therapy has only been observed with atorvastatin and pravastatin therapy. Other studies of simvastatin and rosuvastatin indicate that this benefit is not generalizable to all statins. The treating healthcare professional should refer to the manufacturer’s approved labeling for prescribing, warnings, side effects, and other important information.

llAspirin therapy has only been studied with low-dose (100 mg) aspirin taken orally on alternate days.

#Study populations predominantly consisted of Caucasian men and women in Europe. LPA-Intron 25- associated risk has not been studied in African-American, Mexican-American, or East Asian populations. However, carrier frequencies in these ethnic groups are approximately 2% in African-American and Mexican-American populations, and <1% in East Asian populations.

Current supporting data for relevance of specific genetic tests may be limited to certain patient populations. Physicians should request and review the relevant product sheets before recommending a particular test as part of a patient’s risk reduction plan.

The KIF6 Genotype Test, LPA Aspirin Genotype Test, LPA-Intron 25 Genotype Test, 4q25 AF Risk Genotype Test, 9p21 Genotype Test, and CYP2C19 Genotype Test were developed and their performance characteristics determined by Quest Diagnostics, a CLIA-certified and CAP-accredited laboratory. These tests have not been cleared or approved by the US FDA.

Plavix is a registered trademark of Bristol-Myers Squibb.

Lipitor is a registered trademark of Pfizer.

Pravachol is a registered trademark of Bristol-Myers Squibb.

 

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References

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2. Melander O, Shiffman D, Caulfield MP, et al. Low-density lipoprotein particle number is associated with cardiovascular events among those not classified into statin benefit groups. J Am Coll Cardiol. 2015;65(23): 2571-2573.

3. Mora S, Caulfield MP, Wohlgemuth J, et al. Atherogenic lipoprotein subfractions determined by ion mobility and first cardiovascular events after random allocation to high-intensity statin or placebo: the justification for the use of statins in prevention: an intervention trial evaluating rosuvastatin (JUPITER) trial. Circulation. 2015;132:2220-2229.

4. Sniderman AD, Williams K, Contois JH, et al. A meta-analysis of low density lipoprotein cholesterol, nonhigh- density lipoprotein cholesterol, and apolipoprotein b as markers of cardiovascular risk. Circ Cardiovasc Qual Outcomes. 2011;4:337-345.

5. Nordesgaard B, Chapman MJ, Ray K, et al. Lipoprotein(a) as a cardiovascular risk factor: current status. Eur Heart J. 2010;31:2844-2853.

6. Roest M, Voorbij HAM, Van der Schouw YT, et al. High levels of urinary F2-isoprostanes predict cardiovascular mortality in postmenopausal women. J Clin Lipidol. 2008;2:298-303.

7. Meisinger C, Baumert J, Khuseyinova N, et al. Plasma oxidized low-density lipoprotein, a strong predictor for acute coronary heart disease events in apparently healthy, middle-aged men from the general population. Circulation. 2005;112:651-657.

8. Holvoet P, De Keyzer D, Jacobs DR. Oxidized LDL and the metabolic syndrome. Future Lipidol. 2008;3(6):637-649.

9. Willeit P, Freitag DF, Laukkanen JA, et al. Asymmetric dimethylarginine and cardiovascular risk: systematic review and meta-analysis of 22 prospective studies. J Am Heart Assoc. 2015;4e001833.

10. Kannel WB. Influence of fibrinogen on cardiovascular disease. Drugs. 1997;54 Suppl 3:32-40.

11. Ridker PM, Danielson E, Fonseca FA, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008;359:2195-2207.

12. Ridker PM, Cushman M, Stampfer MJ, et al. Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med. 1997;336:973-979.

13. Ridker PM, Rifai N, Rose L, et al. Comparison of C-reactive protein and low-density lipoprotein cholesterol levels in the prediction of first cardiovascular events. N Engl J Med. 2002;347:1557-1565.

14. Cushman M, Judd S, Kissela, et al. Lipoprotein-associated phospholipase A2 (Lp-PLA2) activity and coronary heart disease risk in a biracial cohort: the reasons for geographic and racial differences in stroke (REGARDS) Cohort. Atherosclerosis. 2015;241:e1-e31. [Abstract].

15. Wong ND, Gransar H, Narula J, et al. Myeloperxoidase, subclinical atherosclerosis, and cardiovascular disease events. J Am Coll Cardiol. 2009;2(9):1093-1099.

16. Heslop CL, Frohlich JJ, Hill JS. Myeloperoxidase and C-reactive protein have combined utility for longterm prediction of cardiovascular mortality after coronary angiography. J Am Coll Cardiol. 2010;55:1102-1109.

17. Centers for Disease Control and Prevention. National diabetes fact sheet, 2011. Available at www.cdc.gov/diabetes/pubs/pdf/ndfs_2011.pdf. Accessed May 31, 2018.

18. Tang WHW, Wang Z, Levison BS, et al. Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk. N Engl J Med. 2013;368(17):1575-1584.

19. Parvez B, Shoemaker MB, Muhammad R, et al. Common genetic polymorphism at 4q25 locus predicts atrial fibrillation recurrence after successful cardioversion. Heart Rhythm. 2013;10(6):849-855.

20. Gretarsdottir S, Thorleifsson G, Manolescu A, et al. Risk variants for atrial fibrillation on chromosome 4q25 associate with ischemic stroke. Ann Neurol. 2008;64(4):402-409.