Cardiovascular Disease (Non-traditional Risk Markers) - Risk Markers - CVD (Non-traditional)

  • Diagnosis
  • Screening
  • Monitoring
  • Background
  • Lab Tests
  • References
  • Related Topics

Indications for Testing

  • Known intermediate to high risk for CVD (referred to as atherosclerotic cardiovascular disease [ASCVD] in current ACC/AHA guidelines)

Laboratory Testing

  • Newest ACC/AHA guidelines (2013) deemphasize use of any markers other than cholesterol (LDL, HDL) except on occasional individualized basis in intermediate- to high-risk patients
  • hs-CRP assay
    • Order in patients with intermediate 10-year risk (10-year predicted risk ≥5%) as assessed by Framingham risk score (see Framingham Cardiac Risk calculator); otherwise, this test is not recommended
    • Combine with Lp-PLA2 to increase accuracy of risk prediction
    • hs-CRP results used to assign risk
      • <1.0 mg/L = low risk
      • 1.1-3.0 mg/L = average risk
      • 3.1-9.9 mg/L = high risk
      • ≥10 mg/L = very high risk
    • If initial value is >3.0 but <10 mg/L, repeat in 2 weeks
  • Lp-PLA2
    • Order in addition to hs-CRP in patients with intermediate to high 10-year risk (defined as borderline LDL-C 131 mg/dL or HDL-C 39 mg/dL) as assessed by Framingham risk score
  • Chronic kidney markers
    • No recommended testing if 10-year predicted risk as assessed by Framingham risk score is <5%
      • Estimated GFR and microalbumin testing in individuals with hypertension, diabetes mellitus (DM), CVD, and/or family history of CVD
      • Perform GFR and serum creatinine for all patients >65 years
  • APOE mutations
    • Consider for primary hypercholesterolemias/hyperlipidemias diagnosis
      • Most commonly type III hyperlipoproteinemia (HLP III)
    • Addition of APOE to existing risk models does not enhance predictive power of models; do not use routinely for assessment of cardiac risk
    • APOE genetic testing not recommended as a predictive test for Alzheimer disease (Choosing Wisely: 5 Things Physicians and Patients Should Question, 2015; American College of Medical Genetics and Genomics)
  • Apo A-1 and B
    • Addition of Apo A-1 and B to existing risk models does not enhance predictive power of models; do not use routinely for assessment of cardiac risk
      • May be used in addition to LDL-C monitoring as a non-HDL-C marker (LDL+IDL+VLDL) in patients with serum triglycerides ≥200 mg/dL
        • Apo B/Apo A-1 ratio may also be used as cholesterol/HDL-C ratio when used in scenario above
      • APOB mutation assessment is appropriate in inherited hypercholesterolemias
  • Homocysteine/MTFHR genotyping
    • Addition of homocysteine to existing risk models does not enhance predictive power of models; do not use routinely for assessment of cardiac risk
      • Homocysteine levels
        • ≤10 μmol/L – desirable
        • >10 μmol/L to <15 μmol/L – intermediate
        • ≥15 to 30 μmol/L – high
        • ≥30 μmol/L – very high
    • MTFHR genotyping – little indication for use of this test
  • Lp(a)
    • Addition of Lp(a) to existing risk models does not enhance predictive power of models; do not use routinely for assessment of cardiac risk
    • Possible clinical uses (in patients with intermediate risk category)
      • Established atherosclerotic disease with normal lipid profiles
      • Recurrent arterial stenosis
      • Hyperlipidemia refractory to therapy
  • NT-proBNP/BNP
    • Addition of NT-proBNP/BNP to existing risk models does not enhance the predictive power of models; do not use routinely for assessment of cardiac risk
  • Most biomarkers are not recommended for routine use or for risk stratification of CVD and should not be ordered prior to determining Framingham risk score
    • May be useful in patients with intermediate 10-year risk using Framingham risk score of 10-20% for further risk stratification
  • Insufficient data to recommend use of most current non-traditional markers for monitoring therapy
  • Apo B can be used as an alternative to non-HDL-C levels in monitoring
    • Goal is 80 mg/dL for patients with CVD or diabetes mellitus and one risk factor; 90 mg/dL if no CVD but 2 risk factors

Cardiovascular disease (CVD) (referred to as atherosclerotic cardiovascular disease [ASCVD] in current ACC/AHA guidelines) is a major cause of morbidity and mortality in U.S. Novel biomarkers can be valuable additions to standard risk factors for CVD.

For further clinical background information regarding cardiovascular disease, refer to cardiovascular disease (traditional risk markers).

Recent Focus in Research for Novel Markers of CVD

  • Other, less-well-defined markers are also being researched, including IL-6, TNF-α, MPO and CD40L

Tests generally appear in the order most useful for common clinical situations. Click on number for test-specific information in the ARUP Laboratory Test Directory.

C-Reactive Protein, High Sensitivity 0050182
Method: Quantitative Immunoturbidimetry

Limitations

Should not be performed during acute illness

Significantly decreased CRP values may result in specimens from patients treated with carboxypenicillins

Follow Up

If first result is >3.0 mg/L but <10.0 mg/L, recommend repeating test at least 2 weeks later when patient is in metabolically stable state free of infection or acute illness

The lower of the two results should be used to determine patient’s risk

Apolipoprotein A-1 0050030
Method: Quantitative Nephelometry

Apolipoprotein B/A Ratio 0050028
Method: Quantitative Nephelometry

Apolipoprotein B 0050029
Method: Quantitative Nephelometry

Apolipoprotein B (APOB) Mutation Detection 0055654
Method: Polymerase Chain Reaction/Fluorescence Monitoring

Limitations

Not recommended for asymptomatic patients <18 years

Mutations in other genes or other mutations in the APOB gene that may cause familial hypercholesterolemia or increased risk for CVD are not ruled out

Rare diagnostic errors may occur due to primer-site mutations

Apolipoprotein E (APOE) 2 Mutations, Cardiovascular Risk 0055566
Method: Polymerase Chain Reaction/Fluorescence Monitoring

Limitations

Addition of APOE to existing risk models does not enhance predictive power of models for most patients

Not recommended in individuals <18 years

Rare APOE isoforms and mutations in other genes that cause HLP III are not detected; if rare alleles are suspected, phenotyping by isoelectric focusing may be indicated

Diagnostic errors can occur due to rare sequence variations

Glomerular Filtration Rate, Estimated 0020725
Method: Quantitative Enzymatic

Microalbumin, Urine 0050203
Method: Quantitative Immunoturbidimetry

Creatinine, Serum or Plasma 0020025
Method: Quantitative Enzymatic

Lipoprotein-Associated Phospholipase A2 (PLAC) 0081055
Method: Quantitative Enzyme-Linked Immunosorbent Assay

Lipoprotein (a) 0099174
Method: Quantitative Immunoturbidimetry

Limitations

Addition to existing risk models does not enhance predictive power of models for most patients

Homocysteine, Total 0099869
Method: Quantitative Enzymatic

Limitations

Addition to existing risk models does not enhance predictive power of models for most patients

Related Tests

Guidelines

American College of Medical Genetics and Genomics. Choosing Wisely - Five Things Patients and Providers Should Question. An initiative of the ABIM Foundation. [Initial posting Jul 2015; Accessed: Nov 2015]

Buckley DI, Fu R, Freeman M, Rogers K, Helfand M. C-reactive protein as a risk factor for coronary heart disease: a systematic review and meta-analyses for the U.S. Preventive Services Task Force. Ann Intern Med. 2009; 151(7): 483-95. PubMed

Davidson MH, Corson MA, Alberts MJ, Anderson JL, Gorelick PB, Jones PH, Lerman A, McConnell JP, Weintraub HS. Consensus panel recommendation for incorporating lipoprotein-associated phospholipase A2 testing into cardiovascular disease risk assessment guidelines. Am J Cardiol. 2008; 101(12A): 51F-57F. PubMed

Emerging CV Risk Factors. American Association for Clinical Chemistry. Washington, DC [Accessed: Feb 2015]

Greenland P, Alpert JS, Beller GA, Benjamin EJ, Budoff MJ, Fayad ZA, Foster E, Hlatky MA, Hodgson JMcB, Kushner FG, Lauer MS, Shaw LJ, Smith SC, Taylor AJ, Weintraub WS, Wenger NK, Jacobs AK, Smith SC, Anderson JL, Albert N, Buller CE, Creager MA, Ettinger SM, Guyton RA, Halperin JL, Hochman JS, Kushner FG, Nishimura R, Ohman M, Page RL, Stevenson WG, Tarkington LG, Yancy CW, American College of Cardiology Foundation, American Heart Association. 2010 ACCF/AHA guideline for assessment of cardiovascular risk in asymptomatic adults: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2010; 56(25): e50-103. PubMed

Hickey SE, Curry CJ, Toriello HV. ACMG Practice Guideline: lack of evidence for MTHFR polymorphism testing. Genet Med. 2013; 15(2): 153-6. PubMed

Jellinger PS, Smith DA, Mehta AE, Ganda O, Handelsman Y, Rodbard HW, Shepherd MD, Seibel JA, AACE Task Force for Management of Dyslipidemia and Prevention of Atherosclerosis. American Association of Clinical Endocrinologists' Guidelines for Management of Dyslipidemia and Prevention of Atherosclerosis. Endocr Pract. 2012; 18 Suppl 1: 1-78. PubMed

NACB LMPG Committee Members, Myers GL, Christenson RH M, Cushman M, Ballantyne CM, Cooper GR, Pfeiffer CM, Grundy SM, Labarthe DR, Levy D, Rifai N, Wilson PW F. National Academy of Clinical Biochemistry Laboratory Medicine Practice guidelines: emerging biomarkers for primary prevention of cardiovascular disease. Clin Chem. 2009; 55(2): 378-84. PubMed

Perk J, De Backer G, Gohlke H, Graham I, Reiner Z, Verschuren M, Albus C, Benlian P, Boysen G, Cifkova R, Deaton C, Ebrahim S, Fisher M, Germano G, Hobbs R, Hoes A, Karadeniz S, Mezzani A, Prescott E, Ryden L, Scherer M, Syvänne M, Reimer WJ M Scholt, Vrints C, Wood D, Zamorano JLuis, Zannad F, European Association for Cardiovascular Prevention & Rehabilitation (EACPR), ESC Committee for Practice Guidelines (CPG). European Guidelines on cardiovascular disease prevention in clinical practice (version 2012). The Fifth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of nine societies and by invited experts). Eur Heart J. 2012; 33(13): 1635-701. PubMed

Stone NJ, Robinson JG, Lichtenstein AH, Goff DC, Lloyd-Jones DM, Smith SC, Blum C, Schwartz S, 2013 ACC/AHA Cholesterol Guideline Panel. Treatment of blood cholesterol to reduce atherosclerotic cardiovascular disease risk in adults: synopsis of the 2013 American College of Cardiology/American Heart Association cholesterol guideline. Ann Intern Med. 2014; 160(5): 339-43. PubMed

Stone NJ, Robinson JG, Lichtenstein AH, Merz NBairey, Blum CB, Eckel RH, Goldberg AC, Gordon D, Levy D, Lloyd-Jones DM, McBride P, Schwartz S, Shero ST, Smith SC, Watson K, Wilson PW F, American College of Cardiology/American Heart Association Task Force on Practice Guidelines. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2014; 63(25 Pt B): 2889-934. PubMed

U.S. Preventive Services Task Force. Using nontraditional risk factors in coronary heart disease risk assessment: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2009; 151(7): 474-82. PubMed

General References

Anderson JL. Lipoprotein-associated phospholipase A2: an independent predictor of coronary artery disease events in primary and secondary prevention. Am J Cardiol. 2008; 101(12A): 23F-33F. PubMed

Bhatti S, Hakeem A, Cilingiroglu M. Lp-PLA(2) as a marker of cardiovascular diseases. Curr Atheroscler Rep. 2010; 12(2): 140-4. PubMed

Corson MA, Jones PH, Davidson MH. Review of the evidence for the clinical utility of lipoprotein-associated phospholipase A2 as a cardiovascular risk marker. Am J Cardiol. 2008; 101(12A): 41F-50F. PubMed

Folsom AR. Classical and novel biomarkers for cardiovascular risk prediction in the United States. J Epidemiol. 2013; 23(3): 158-62. PubMed

Gilstrap LG, Wang TJ. Biomarkers and cardiovascular risk assessment for primary prevention: an update. Clin Chem. 2012; 58(1): 72-82. PubMed

Gooding HC, de Ferranti SD. Cardiovascular risk assessment and cholesterol management in adolescents: getting to the heart of the matter. Curr Opin Pediatr. 2010; 22(4): 398-404. PubMed

Harper CR, Jacobson TA. Using apolipoprotein B to manage dyslipidemic patients: time for a change? Mayo Clin Proc. 2010; 85(5): 440-5. PubMed

Humphrey LL, Fu R, Rogers K, Freeman M, Helfand M. Homocysteine level and coronary heart disease incidence: a systematic review and meta-analysis. Mayo Clin Proc. 2008; 83(11): 1203-12. PubMed

Lau JF, Smith DA. Advanced lipoprotein testing: recommendations based on current evidence. Endocrinol Metab Clin North Am. 2009; 38(1): 1-31. PubMed

Movva R, Rader DJ. Laboratory assessment of HDL heterogeneity and function. Clin Chem. 2008; 54(5): 788-800. PubMed

Patel AA, Budoff MJ. Screening for heart disease: C-reactive protein versus coronary artery calcium. Expert Rev Cardiovasc Ther. 2010; 8(1): 125-31. PubMed

Perkovic V, Verdon C, Ninomiya T, Barzi F, Cass A, Patel A, Jardine M, Gallagher M, Turnbull F, Chalmers J, Craig J, Huxley R. The relationship between proteinuria and coronary risk: a systematic review and meta-analysis. PLoS Med. 2008; 5(10): e207. PubMed

Psaty BM, Weiss NS. 2013 ACC/AHA guideline on the treatment of blood cholesterol: a fresh interpretation of old evidence. JAMA. 2014; 311(5): 461-2. PubMed

Rietzschel E, De Buyzere M. High-sensitive C-reactive protein: universal prognostic and causative biomarker in heart disease? Biomark Med. 2012; 6(1): 19-34. PubMed

Vavuranakis M, Kariori MG, Kalogeras KI, Vrachatis DA, Moldovan C, Tousoulis D, Stefanadis C. Biomarkers as a guide of medical treatment in cardiovascular diseases. Curr Med Chem. 2012; 19(16): 2485-96. PubMed

Vittos O, Toana B, Vittos A, Moldoveanu E. Lipoprotein-associated phospholipase A2 (Lp-PLA2): a review of its role and significance as a cardiovascular biomarker. Biomarkers. 2012; 17(4): 289-302. PubMed

References from the ARUP Institute for Clinical and Experimental Pathology

Anderson JL, Carlquist JF, Roberts WL, Horne BD, May HT, Schwarz EL, Pasquali M, Nielson R, Kushnir MM, Rockwood AL, Bair TL, Muhlestein JB, Intermountain Heart Collaborative Study Group. Asymmetric dimethylarginine, cortisol/cortisone ratio, and C-peptide: markers for diabetes and cardiovascular risk? Am Heart J. 2007; 153(1): 67-73. PubMed

Chittamma A, Roberts WL, Sritara P, Cheepudomwit S, Suriyawongpaisal P, Lolekha PH. Comparison of two homogeneous HDL cholesterol methods in a large population study. Clin Biochem. 2004; 37(9): 745-9. PubMed

Clarke JL, Anderson JL, Carlquist JF, Roberts RF, Horne BD, Bair TL, Kolek MJ, Mower CP, Crane AM, Roberts WL, Muhlestein JB, Intermountain Heart Collaborative Study Group. Comparison of differing C-reactive protein assay methods and their impact on cardiovascular risk assessment. Am J Cardiol. 2005; 95(1): 155-8. PubMed

Jasuja GKaur, Travison TG, Davda M, Murabito JM, Basaria S, Zhang A, Kushnir MM, Rockwood AL, Meikle W, Pencina MJ, Coviello A, Rose AJ, D'Agostino R, Vasan RS, Bhasin S. Age trends in estradiol and estrone levels measured using liquid chromatography tandem mass spectrometry in community-dwelling men of the Framingham Heart Study. J Gerontol A Biol Sci Med Sci. 2013; 68(6): 733-40. PubMed

La'ulu SL, Apple FS, Murakami MM, Ler R, Roberts WL, Straseski JA. Performance characteristics of the ARCHITECT Galectin-3 assay. Clin Biochem. 2013; 46(1-2): 119-22. PubMed

La'ulu SL, Rawlins ML, Pfeiffer CM, Zhang M, Roberts WL. Performance characteristics of six homocysteine assays. Am J Clin Pathol. 2008; 130(6): 969-75. PubMed

Lanman RB, Wolfert RL, Fleming JK, Jaffe AS, Roberts WL, Warnick R, McConnell JP. Lipoprotein-associated phospholipase A2: review and recommendation of a clinical cut point for adults. Prev Cardiol. 2006; 9(3): 138-43. PubMed

Lolekha PH, Chittamma A, Roberts WL, Sritara P, Cheepudomwit S, Suriyawongpaisal P. Comparative study of two automated high-sensitivity C-reactive protein methods in a large population. Clin Biochem. 2005; 38(1): 31-5. PubMed

Martins TB, Anderson JL, Muhlestein JB, Horne BD, Carlquist JF, Roberts WL, Carlquist JF. Risk factor analysis of plasma cytokines in patients with coronary artery disease by a multiplexed fluorescent immunoassay. Am J Clin Pathol. 2006; 125(6): 906-13. PubMed

Poulson MDean, Wittwer CT. Closed-tube genotyping of apolipoprotein E by isolated-probe PCR with multiple unlabeled probes and high-resolution DNA melting analysis. Biotechniques. 2007; 43(1): 87-91. PubMed

Seipp MT, Pattison D, Durtschi JD, Jama M, Voelkerding KV, Wittwer CT. Quadruplex genotyping of F5, F2, and MTHFR variants in a single closed tube by high-resolution amplicon melting. Clin Chem. 2008; 54(1): 108-15. PubMed

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Last Update: February 2016