Atherosclerotic Cardiovascular Disease Risk Markers

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 is then focused 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), specifically, 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 of age 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

Traditional risk markers are often assessed usinga lipid panel. Fasting measurements of 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 to assess residual risk and guide 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 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 the evaluation of 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 can also be used to screen 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 for variants in the LDLR, APOB, PCSK9, or LDLRAP1 genes may be appropriate for individuals with familial hypercholesterolemia to identify the genetic cause. For more information, see the Familial Hypercholesterolemia Test Fact Sheet.

Screening

The AACE/ACE has issued 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 (ASCP) 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. The LDL-C targets for specific populations are as follow :

• Low-risk patients: <130 mg/dL
• High-risk patients: <100 mg/dL
• Very high-risk patients: <70 mg/dL
• Extreme-risk patients: <55 mg/dL