Atherosclerotic Cardiovascular Disease Risk Markers

Atherosclerotic cardiovascular disease (ASCVD) involves the buildup of cholesterol plaque in arteries and includes acute coronary syndrome, peripheral arterial disease, and events such as myocardial infarction and stroke. ASCVD is a major cause of morbidity and mortality in the United States. Risk factors such as dyslipidemia, diabetes mellitus (DM), obesity, inactive lifestyle, hypertension, smoking, and family history inform ASCVD risk assessments. Understanding a patient’s 10-year ASCVD risk is fundamental in establishing appropriate medical management (eg, cholesterol-lowering medication). Traditional lipid tests for markers such as total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides are recommended for the evaluation of ASCVD risk; such testing is also used for screening and monitoring. Nontraditional, novel markers like apolipoproteins, lipoprotein particles, and high-sensitivity C-reactive protein (hsCRP) are gaining recognition for their role in the evaluation of high-risk patients.

Quick Answers for Clinicians

Which atherosclerotic cardiovascular disease markers are considered traditional and which are considered nontraditional?

Traditional markers of atherosclerotic cardiovascular disease (ASCVD) are those included in a lipid panel: total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides. These markers have generally well-established guidelines for their use in ASCVD risk determination. Newer, nontraditional disease markers include apolipoproteins, high-sensitivity C-reactive protein (hsCRP), lipoprotein(a), and lipoprotein particles. Genotyping is also considered a nontraditional method in ASCVD risk evaluation. These markers and methods are not yet universally accepted for risk evaluation in the general population. However, they may be useful in assessment and risk stratification, especially for high-risk individuals.

Does the use of nontraditional markers and methods improve performance of risk score or clinical outcomes?

Although research is ongoing, there is insufficient evidence to recommend or discourage the use of certain nontraditional markers (eg, high-sensitivity C-reactive protein [hsCRP]) in asymptomatic adults.  However, the American Association of Clinical Endocrinologists (AACE) and American College of Endocrinology (ACE)  guidelines support the use of apolipoprotein B (apoB), hsCRP, and  low-density lipoprotein (LDL) particle concentration to guide effective therapy and decision-making.  Nontraditional markers may be beneficial, especially for select, higher-risk groups.

Who should be screened for dyslipidemia?

General population screening for dyslipidemia can begin for individuals at 20 years of age.  However, because the U.S. Preventive Services Task Force (USPSTF) found insufficient evidence to support screening for individuals 20-39 years, clinicians should use clinical judgment for this age group.  Individuals with type 1 or type 2 diabetes mellitus (DM) should be screened.  See Screening for age-related frequency recommendations.

What are the criteria for statin treatment?

Statin treatment is recommended for individuals :

  • With clinical atherosclerotic cardiovascular disease (ASCVD)
  • With primary low-density lipoprotein cholesterol (LDL-C) levels ≥190 mg/dL
  • 40-75 years of age with diabetes mellitus (DM) and an LDL-C measurement of 70-189 mg/dL without clinical ASCVD
  • 40-75 years of age without clinical ASCVD or DM but with an LDL-C measurement of 70-189 mg/dL and an estimated 10-year ASCVD risk ≥7.5% (clinician-patient discussion is required for this population)

Risk Assessment

Several tools have been developed to determine a patient’s 10-year risk of an ASCVD event. These calculators should be used to establish appropriate treatment.

The American College of Cardiology/American Heart Association (ACC/AHA) guidelines   recommend incorporating the Pooled Cohort Equations  into clinical practice. This calculator is specific to age and sex and helps predict 10-year and lifetime risks for hard ASCVD in patients with or without DM. The risk percentage helps determine the need for and intensity of treatment. Treatment then focuses on reducing the risk rather than on treating cholesterol levels.

The American Association of Clinical Endocrinologists (AACE) and American College of Endocrinology (ACE) guidelines  recommend using at least one of the following four risk calculators for dyslipidemia screening:

  • The Framingham Risk Score (Adult Treatment Panel III [ATP-III]) is an algorithm to help predict risk specifically for coronary heart disease (CHD) in a white population and tends to be more accurate for women. 
  • The Multi-Ethnic Study of Atherosclerosis (MESA) is a study of risk factors that predicts progression to clinically overt CVD or progression of subclinical disease; it is more appropriate for patients 45-85 years old and of select racial/ethnic groups. 
  • The Reynolds Risk Score is a risk calculator that includes hsCRP results and family history of premature ASCVD in addition to other factors. 
  • The United Kingdom Prospective Diabetes Study (UKPDS) risk engine calculates ASCVD risk specifically in individuals with type 2 DM. 

Laboratory Testing

Traditional Risk Markers

Fasting Lipid Panel

A fasting lipid panel that includes total cholesterol, LDL-C, HDL-C, and triglycerides provides the most precise lipid assessment.  Nonfasting measurements can be used if fasting is impractical.

Total Cholesterol

A total cholesterol test provides one measurement for the total amount of cholesterol in the blood, whether it be LDL-C, HDL-C, or triglycerides.

Low-Density Lipoprotein Cholesterol

An LDL-C level can be derived using an equation with other lipid measurements, but an LDL-C measurement should be obtained directly in patients with DM, known vascular disease, or a fasting triglyceride level >250 mg/dL. 

High-Density Lipoprotein Cholesterol

HDL-C measurements should be part of dyslipidemia screening tests.  Non-HDL-C measurements can be derived by subtracting HDL-C from total cholesterol. A non-HDL-C level is helpful in determining risk in patients with DM, established ASCVD, or elevated triglycerides; it can also provide information on a patient’s total atherogenic lipoprotein burden. 

Triglycerides

Triglyceride testing can help identify patients with insulin resistance syndrome or those at increased risk for ASCVD; it should be included in routine screening. 

Nontraditional Risk Markers

Apolipoproteins

In at-risk individuals, apolipoprotein evaluation, namely apoB and the apoB/apoA1 ratio, may be helpful in assessing residual risk and guiding decision-making. Both measurements are recommended to improve risk prediction ; however, the usefulness of apoB in assessing risk for a first ASCVD event is uncertain.  ApoB measurements that reflect LDL particle concentration and other atherogenic lipoprotein levels may be useful for determining therapy success.  Evidence is insufficient to conclude that the apoA1 marker improves the risk prediction for cardiovascular events in at-risk populations. 

High-Sensitivity C-Reactive Protein

An hsCRP measurement can help stratify risk in individuals with a borderline risk assessment or with intermediate or high risk and an LDL-C measurement of <130 mg/dL.   The U.S. Preventive Services Task Force (USPSTF) determined that there is insufficient evidence to recommend or discourage hsCRP measurement as part of the risk assessment for ASCVD in asymptomatic adults.  An hsCRP test should not be performed in patients with current acute illness.

Lipoprotein(a)

Although there is no justification for screening the general population for lipoprotein(a) [Lp(a)] concentration, Lp(a) testing may be considered for patients with a family history of early ASCVD or to refine evaluation for patients at moderate risk; high concentrations may support more aggressive control of other lipoprotein factors. 

Lipoprotein Particle Count

Lipoprotein particle number evaluation (eg, with the LipoFit test) may be appropriate for high-risk patients, such as those with type 2 DM, to guide and refine therapy; it is not recommended for routine CVD risk assessment in most individuals.

Lipoprotein-Associated Phospholipase A2

Lipoprotein-associated phospholipase A2 (Lp-PLA2) is an indicator specifically of vascular inflammation, independent of obesity.  Measurements can provide additional information for risk stratification and can be especially useful in the presence of hsCRP elevations.  Studies have shown that Lp-PLA2 has greater specificity than hsCRP. Individuals with elevated Lp-PLA2 and hsCRP are at substantial risk, even with low or moderately elevated LDL-C. 

Genotyping

The apolipoprotein E (APOE) gene is associated with modulation of the plasma lipids profile. APOE genotyping can provide supporting evidence for a diagnosis of premature coronary heart disease; it may also be used in the screening of individuals with a family history of type III hyperlipoproteinemia. It should be used for CVD risk assessment only and has variable significance in prediction. Evaluation of apolipoprotein B (APOB) gene variants may be appropriate for individuals with inherited hypercholesterolemia to identify genetic cause.

Screening

The AACE/ACE has made the following screening recommendations :

  • Individuals with a family history of premature ASCVD or high cholesterol levels should be screened for familial hypercholesterolemia.
  • Children at risk for familial hypercholesterolemia should be screened for dyslipidemia at 3 years, between 9 and 11 years, and at 18 years.
  • Adolescents older than 16 years who have ASCVD risk factors, are overweight or obese, or have other symptoms of insulin resistance should be screened for dyslipidemia every 5 years or more frequently.
  • Adults with type 1 or type 2 DM should be screened annually for dyslipidemia.
  • Men 20-45 years or women 20-55 years without ASCVD risk factors should be screened for dyslipidemia every 5 years.
  • Men 45-65 years and women 55-65 years without ASCVD risk factors should be screened for dyslipidemia at least every 1-2 years. Clinical judgment should be used to modify testing intervals as appropriate.
  • Adults older than 65 years with one or no risk factor should be screened for dyslipidemia annually; those with two or more ASCVD risk factors should have a lipid assessment performed.

The USPSTF found insufficient evidence to recommend or discourage screening for dyslipidemia in adults 20-39 years or in children and adolescents; clinicians should use their judgment. 

Nontraditional markers are not recommended for routine screening or risk assessment in asymptomatic adults, and routine testing of children for nontraditional risk factors/biomarkers is also not recommended, due to a lack of convincing data.  The American Society for Clinical Pathology recommends not ordering expanded lipid panels (eg, particle sizing, nuclear magnetic resonance) as screening tests for CVD. 

Additionally, patients on statin therapy should be screened for new-onset DM according to current DM guidelines. 

Monitoring

Lipid testing is recommended to assess medication and lifestyle adherence. A baseline fasting lipid panel should be repeated 1-3 months after statin initiation, after which monitoring with a lipid panel should be performed every 3-12 months.  The ACC/AHA guideline de-emphasizes fixed goals for LDL and HDL and instead supports a percentage decrease in LDL-C of 30-49% for moderate-intensity therapy and >50% for high-intensity therapy.  AACE/ACE guidelines recommend treating to achieve lipid targets based on risk category; LDL-C targets are <130 mg/dL for low-risk patients, <100 mg/dL for high-risk patients, <70 mg/dL for very high-risk patients, and <55 mg/dL for extreme-risk patients. 

ARUP Lab Tests

Traditional Tests

Lipid Panels

Assess CVD risk and guide therapy

Individual Lipid Tests

Assess CVD risk and guide therapy

Nontraditional Tests

Apolipoproteins

Acceptable secondary CVD risk screen for specific populations

Not recommended for ASCVD risk assessment

Use to detect Tangier disease

High-Sensitivity C-Reactive Protein

May aid in ASCVD risk stratification in specific populations

Not recommended for ASCVD risk assessment in asymptomatic adults

Lipoprotein(a)

May aid in ASCVD risk stratification in specific populations

Not recommended for ASCVD risk assessment in asymptomatic adults

Lipoprotein Particle Assessments

Appropriate for high-risk patients to guide therapy

Not recommended for CVD risk assessment in most individuals

Differentiates LDL particles with respect to size

Lipoprotein-Associated Phospholipase A2

May aid in ASCVD risk stratification, especially in individuals with elevated hsCRP

Genotyping

Identify genetic cause for inherited hypercholesterolemia

Provides supporting evidence for a diagnosis of type III hyperlipoproteinemia for evaluation of premature coronary heart disease

Medical Experts

Contributor

Genzen

Jonathan R. Genzen, MD, PhD
Associate Professor of Clinical Pathology, University of Utah
Chief Operations Officer, Medical Director of Automated Core Laboratory and Farmington Health Center Clinical Laboratory, ARUP Laboratories

References

  1. 24239923

    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 PWF

    American College of Cardiology/American Heart Association Task Force on Practice Guidelines

    J Am Coll Cardiol

    2014
    63
    25 Pt B
    2889-934
    PubMed
  2. 24222018

    Goff DC

    Lloyd-Jones DM

    Bennett G

    Coady S

    D'Agostino RB

    Gibbons R

    Greenland P

    Lackland DT

    Levy D

    O'Donnell CJ

    Robinson JG

    Schwartz S

    Shero ST

    Smith SC

    Sorlie P

    Stone NJ

    Wilson PWF

    Jordan HS

    Nevo L

    Wnek J

    Anderson JL

    Halperin JL

    Albert NM

    Bozkurt B

    Brindis RG

    Curtis LH

    DeMets D

    Hochman JS

    Kovacs RJ

    Ohman M

    Pressler SJ

    Sellke FW

    Shen WK

    Smith SC

    Tomaselli GF

    American College of Cardiology/American Heart Association Task Force on Practice Guidelines

    Circulation

    2014
    129
    25 Suppl 2
    S49-73
    PubMed
Additional Resources
Resources from the ARUP Institute for Clinical and Experimental Pathology®