Atherosclerotic Cardiovascular Disease (ASCVD) Nontraditional Risk Markers - Cardiovascular Disease Risk Markers (Nontraditional)

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

Indications for Testing

Laboratory Testing

  • American College of Cardiology (ACC)/American Heart Association (AHA) guidelines (Stone, 2014), American Association of Clinical Endocrinologists (AACE)/American College of Endocrinology (ACE) guidelines (Jellinger, 2017), and Laboratory Medicine Best Practices (LMBP) systematic review (Sandhu, 2016) emphasize use of cholesterol markers (LDL, HDL) for routine screening
    • In select cases (eg, high-risk patients) other lipoprotein, genetic, chronic disease, or inflammatory markers have specific  recommendations for use ​
  • Lipoprotein testing
    • Apolipoprotein(Apo) B
      • Recommended to improve risk prediction in populations with multiple risk factors (Sandhu, 2016)
      • Considered an additional risk factor by AACE; may be useful in at-risk individuals for assessment of residual risk and guiding decision-making
      • May be useful to assess success of LDL therapy (Jellinger, 2017)
    • Apo A-I
      • Insufficient evidence to recommend (Sandhu, 2016)
    • Apo B/Apo A-1 ratio
      • Recommended to improve risk prediction in individuals with multiple risk factors (Sandhu, 2016; Jellinger, 2017)
    • LipoFit and LipoFit particle count only by quantitative nuclear magnetic resonance spectroscopy (emerging testing)
      • Appropriate for high-risk patients to monitor LDL particle number to guide therapy
      • Not recommended for cardiovascular disease risk assessment in most individuals
    • Lp(a)
      • No justification for screening general population (Piepoli, 2016)
      • High concentrations may support more aggressive control of other lipoprotein factors
      • May be considered for patients
        • At moderate risk to refine evaluation
        • With family history of early ASCVD
  • Genotyping
    • APOE genotyping
      • Variable significance for predicting the risk of vascular events
      • Associated with modulation of plasma lipids profile
    • APOB variant evaluation – appropriate in inherited hypercholesterolemias
    • MTFHR genotyping – little indication for use of this test
  • Inflammatory markers
    • High-sensitivity C-reactive protein (hs-CRP) assay
      • Guidelines for use (Stone, 2014)
        • Order in patients with intermediate 10-year risk as assessed by Framingham risk score (see Framingham Cardiac Risk calculator); otherwise, this test is not recommended
        • Combine with lipoprotein-associated phospholipase A2 (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 hs-CRP value is >3.0 but <10 mg/L, repeat in 2 weeks
      • Use to stratify ASCVD risk in (Jellinger,2017)
        • Borderline standard risk individuals or
        • Intermediate or higher risk with LDL <130 mg/dL
    • Lp-PLA2 (not offered at ARUP Laboratories)
      • Order in addition to hs-CRP in patients with intermediate to high 10-year risk (Stone, 2014)
  • Other markers
    • Chronic kidney markers
      • No recommended testing if 10-year predicted risk as assessed by Framingham risk score is <5%
        • Estimated glomerular filtration rate (GFR) and microalbumin testing recommended in individuals with hypertension, diabetes mellitus (DM), ASCVD, and/or family history of ASCVD
        • Perform GFR and serum creatinine for all patients >65 years for general risk
    • Heart failure/cardiac damage
      • 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
      • Homocysteine
        • Elevated by a diet high in red meat
        • 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
        • Addition of homocysteine to existing risk models does not enhance predictive power of models; do not use routinely for assessment of cardiac risk (Stone, 2014)
        • Routine measurement not recommended; no proven benefit (Jellinger, 2017)
  • Apolipoprotein B can be used as an alternative to non-HDL levels in monitoring response to therapy
  • LipoFit and LipoFit particle count only – evaluate or guide therapy based on LDL particle number
  • Insufficient data to recommend use of other nontraditional markers for monitoring 

Atherosclerotic cardiovascular disease (ASCVD) is a major cause of morbidity and mortality in U.S. Novel biomarkers are being investigated for their role in evaluating risk for ASCVD.

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

Recent Focus in Research for Novel Markers of ASCVD

  • 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

Glomerular Filtration Rate, Estimated 0020725
Method: Quantitative Enzymatic

Microalbumin, Urine 0050203
Method: Quantitative Immunoturbidimetry

Creatinine, Serum or Plasma 0020025
Method: Quantitative Enzymatic

Limitations 

Assay interference (negative) may be observed when high concentrations of N-acetylcysteine (NAC) are present

Negative interference has also been reported with NAPQI (an acetaminophen metabolite), but only when concentrations are at or above those expected during acetaminophen overdose

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

Limitations 

Other APOB gene variants will not be detected

Not recommended for asymptomatic patients <18 years

Variants in other genes that may cause familial hypercholesterolemia are not detected

Rare diagnostic errors may occur due to primer-site variants

Apolipoprotein A-1 0050030
Method: Quantitative Nephelometry

Apolipoprotein B/A Ratio 0050028
Method: Quantitative Nephelometry

Apolipoprotein B 0050029
Method: Quantitative Nephelometry

Apolipoprotein E (APOE) Genotyping, Cardiovascular Risk 2013337
Method: Polymerase Chain Reaction/Fluorescence Monitoring

Limitations 

NOT recommended for asymptomatic individuals <18 years

Clinical sensitivity – >90% for individuals with HLP III

Rare APOE isoforms and variants in other genes that cause HLP III are not detected

Diagnostic errors can occur due to rare sequence variations

APOE e2 homozygosity is neither sufficient nor necessary to cause HPL III

Follow-up 

If rare alleles are suspected, phenotyping by isoelectric focusing may be indicated

LipoFit by NMR 2013716
Method: Quantitative Nuclear Magnetic Resonance Spectroscopy/ Quantitative Enzymatic/ Detergent Solubilization

LipoFit by NMR, Particle Count Only 2013715
Method: Quantitative Nuclear Magnetic Resonance Spectroscopy

Guidelines

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

Choosing Wisely. An initiative of the ABIM Foundation. [Accessed: Sep 2017]

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: Dec 2016]

Greenland P, Alpert JS, Beller GA, Benjamin EJ, Budoff MJ, Fayad ZA, Foster E, Hlatky MA, Hodgson JM, 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, Handelsman Y, Rosenblit PD, Bloomgarden ZT, Fonseca VA, Garber AJ, Grunberger G, Guerin CK, Bell DS, Mechanick JI, Pessah-Pollack R, Wyne K, Smith D, Brinton EA, Fazio S, Davidson M, Zangeneh F, Bush MA. American Association of Clinical Endocrinologists and American College of Endocrinology Guidelines for Management of Dyslipidemia and Prevention of Cardiovascular Disease Endocr Pract. 2017; 23(4): 479-497. 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, Cushman M, Ballantyne CM, Cooper GR, Pfeiffer CM, Grundy SM, Labarthe DR, Levy D, Rifai N, Wilson PW. 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

Piepoli MF. 2016 European Guidelines on cardiovascular disease prevention in clinical practice : The Sixth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representat Int J Behav Med. 2017; 24(3): 321-419. 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 NB, 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, 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

Yeboah J, Polonsky TS, Young R, McClelland RL, Delaney JC, Dawood F, Blaha MJ, Miedema MD, Sibley CT, Carr J, Burke GL, Goff DC, Psaty BM, Greenland P, Herrington DM. Utility of Nontraditional Risk Markers in Individuals Ineligible for Statin Therapy According to the 2013 American College of Cardiology/American Heart Association Cholesterol Guidelines Circulation. 2015; 132(10): 916-22. PubMed

General References

Allaire J, Vors C, Couture P, Lamarche B. LDL particle number and size and cardiovascular risk: anything new under the sun? Curr Opin Lipidol. 2017; 28(3): 261-266. PubMed

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

El-Lebedy D, Raslan HM, Mohammed AM. Apolipoprotein E gene polymorphism and risk of type 2 diabetes and cardiovascular disease. Cardiovasc Diabetol. 2016; 15: 12. 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

Sandhu PK, Musaad SM, Remaley AT, Buehler SS, Strider S, Derzon JH, Vesper HW, Ranne A, Shaw CS, Christenson RH. Lipoprotein Biomarkers and Risk of Cardiovascular Disease: A Laboratory Medicine Best Practices (LMBP) Systematic Review. J Appl Lab Med. 2016; 1(2): 214-229. 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

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Medical Reviewers

Content Reviewed: 
May 2017

Last Update: October 2017