BlueCross BlueShield of Tennessee Medical Policy Manual

Novel Biomarkers in Risk Assessment and Management of Cardiovascular Disease


A standard lipid panel calculates LDL, HDL, triglycerides and total cholesterol. New laboratory tests have been developed to address non-standard lipid and non-lipid markers either individually or as part of a panel.  These novel biomarkers include:

Some cardiovascular risk panels are relatively limited, including a few markers in addition to standard lipids.  Others include both genetic and nongenetic risk factors while some are composed entirely of genetic markers.  Some examples of commercially available cardiovascular risk panels are as follows:

Health Diagnostics Cardiac Risk Panel: MTHFR gene analysis, common variants; vitamin D, 1,25 dihydroxy; B-type natriuretic peptide; lipoprotein-associated phospholipase A2 (Lp-PLA2); myeloperoxidase; apolipoprotein; immune complex assay; lipoprotein, blood; electrophoretic separation and quantitation; very long chain fatty acids; total cholesterol; HDL; LDL; triglycerides; hs-CRP; Lp(a); insulin, total; fibrinogen; apolipoprotein analysis; multiple SNPs associated with coronary artery disease (CAD).

Genova Diagnostics CV Health Plus Genomics™ Panel: apo E; prothrombin; factor V Leiden; fibrinogen; HDL; HDL size; HDL particle number; homocysteine; LDL; LDL size; LDL particle number; Lp(a); Lp-PLA2; MTHFR gene; triglycerides; very-low-density lipoprotein (VLDL); VLDL size; vitamin D; hs-CRP.

Genova Diagnostics CV Health Plus™ Panel: fibrinogen; HDL; HDL size; HDL particle number; homocysteine; LDL; LDL size; LDL particle number; lipid panel; Lp(a); Lp-PLA2; triglycerides; VLDL; VLDL size; vitamin D; hs-CRP.

Cleveland Heartlab CVD Inflammatory Profile: hs-CRP, urinary microalbumin, myeloperoxidase, Lp-PLA2, F2 isoprostanes.

Applied Genetics Cardiac Panel: genetic mutations associated with CAD: cytochrome p450 mutations associated with metabolism of clopidogrel, ticagrelor, warfarin, beta-blockers, rivaroxaban, prasugrel (2C19, 2C9/VKORC1, 2D6, 3A4/3A5), factor V Leiden, prothrombin gene, MTHFR gene, APOE gene.

Genetiks Genetic Diagnosis and Research Center Cardiovascular Risk Panel: factor V Leiden, factor V R2, prothrombin gene, factor XIII, fibrinogen-455, PAI-1, GPIIIs (HPA-1), MTHFR, ACE I/D, apo B, apo E.

Singulex® Cardiac-Related Test Panels:  Several panels of markers related to cardiac dysfunction, vascular inflammation and dysfunction, dyslipidemia, and cardiometabolic status are offered by Singulex (Alameda, CA). Some of these panels are offered in conjunction with a CV disease testing and wellness management service. The test panels use an immunoassay method referred to as “Proprietary high-precision Single Molecule Counting [SMC] technology.”


When a standardized test is billed alone (e.g., BNP test, LDL, HDL), and is not part of a novel biomarker risk assessment, this policy should not be used to deny that test.



Published data are inadequate to determine how novel biomarker measurements should guide treatment decisions and whether these treatment decisions result in beneficial outcomes.


American Association of Clinical Endocrinologists. American College of Endocrinology. (2017). American Association of Clinical Endocrinologists and American College of Endocrinology guidelines for management of dyslipidemia and prevention of cardiovascular disease. Retrieved March 9, 2017 from

American Heart Association. Scientific Statement. (2011) Nontraditional risk factors and biomarkers for cardiovascular disease: mechanistic, research, and clinical considerations for youth. Retrieved March 9, 2017 from

BlueCross BlueShield Association. Evidence Positioning System. (12:2018). Novel biomarkers in risk assessment and management of cardiovascular disease (2.04.65). Retrieved October 18, 2018 from (126 articles and/or guidelines reviewed)

BlueCross BlueShield Association. Medical Policy Reference Manual. (12:2017). Cardiovascular Risk Panels (2.04.100) Retrieved October 18, 2018 from (25 articles and/or guidelines reviewed)

Boekholdt, S. M., Arsenault, B. J., Mora, S., Pedersen, T. R., LaRosa, J. C., Nestel, P. J., et al. (2012). Association of LDL cholesterol, non-HDL cholesterol, and apolipoprotein B levels with risk of cardiovascular events among patients treated with statins. A meta-analysis. JAMA, 307 (12), 1302-1309. (Level 1 evidence) Center for Medicare & Medicaid Services. Palmetto, GBA. (2018, October)  MolDX: Biomarkers in Cardiovascular Risk Assessment (LCD ID L36129). Retrieved October 18, 2018 from 

Di Angelantonio, E., Gao, P., Pennells, L., Kaptoge, S., Caslake, M., Thompson, A., et al. (2012). Lipid-related markers and cardiovascular disease prediction. JAMA, 307 (23), 2499-2506. (Level 2 evidence)

National Institute for Health and Care Excellence. (2014; last update search September, 2016). Cardiovascular disease: risk assessment and reduction, including lipid modification. Retrieved March 9, 2017 from

Wang, J., Tan, G., Han, L., Bai, Y., He, M., & Liu, H. (2017). Novel biomarkers for cardiovascular risk prediction. Journal of geriatric Cardiology, 14, 135-150. (Level 2 evidence)




Policies included in the Medical Policy Manual are not intended to certify coverage availability. They are medical determinations about a particular technology, service, drug, etc. While a policy or technology may be medically necessary, it could be excluded in a member's benefit plan. Please check with the appropriate claims department to determine if the service in question is a covered service under a particular benefit plan. Use of the Medical Policy Manual is not intended to replace independent medical judgment for treatment of individuals. The content on this Web site is not intended to be a substitute for professional medical advice in any way. Always seek the advice of your physician or other qualified health care provider if you have questions regarding a medical condition or treatment.

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