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

Diagnosis

Indications for Testing

• Known intermediate to high risk for CVD

Laboratory Testing

• 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
  • Addition of APOE to existing risk models does not enhance predictive power of models; do not use routinely for assessment of cardiac risk
• 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
  • 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
• 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

Screening

Monitoring

Clinical Background

Cardiovascular disease (CVD) 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)
• Biomarkers of cardiovascular disease

  Cardiovascular Biomarkers for the Detection of Cardiovascular Disease
  Atheroscleroses	Traditional markers: Total cholesterol LDL-C/HDL-C Total cholesterol/HDL-C ratio Triglycerides Novel markers: Lp(a) Homocysteine Apolipoproteins (Apo A, B, E)
  Inflammation	Novel markers: Acute phase reactants hsCRP SAA Cytokines IL-6, IL-8, IL-18 TNF-α receptors 1&2 Leukocytes (neutrophils)/platelets, endothelium ICAM-1 VCAM-1 P-selectin, E-selectin Lp-PLA2 MPO CD40L MCP-2 Coagulation/fibrinolysis Factor VIII vWF PIGF PAPP-A
  Ischemia/Necrosis	Traditional markers: Troponins I & T CK-MB Novel markers: FABP GP-BB IMA FFAu WB-Chol Sphingomyosin MDA-LDL-C
  Myocardial Dysfunction	Traditional markers: NTproBNP/BNP Novel markers: ST2
  BNP = b-type natriuretic peptide; CD40L = CD40 ligand; CK-MB = creatine kinase-muscle and brain; CRP = C-reactive protein; hs-CRP = high-sensitivity CRP; FABP = fatty acid binding protein; FFAu = unbound free fatty acid; GP-BB = glycogen phosphorylase - brain; IL = interleukin; HDL-C = high-density lipoprotein-cholesterol; ICAM = inter-cellular adhesion molecule; IMA = ischemia-modified albumin; LD = lactate dehydrogenase; LDL-C = low-density lipoprotein-cholesterol; Lp(a) = lipoprotein a; Lp-PLA2 = lipoprotein-associated phospholipase A2; MCP-2 = monocyte chemoattractant protein-2; MDA-LDL-C = malondialdehyde-modified LDL-C; MPO = myeloperoxidase; NTproBNP = N-terminal proBNP; PAPP-A = pregnancy-associated plasma protein A; PIGF = placental-derived growth factor; SAA = serum amyloid A; ST2 = soluble member of the interleukin-1 receptor family; TNF-α = tumor necrosis factor alpha; VCAM = vascular cell adhesion molecule; vWF = von Willebrand Factor; WB-Chol = whole blood choline

Recent Focus in Research for Novel Markers of CVD

• hs-CRP

  hs-CRP

  CRP – most sensitive of the acute phase reactant proteins; elevated in the following Acute insults Elevates <2 hours in Myocardial infarction Trauma Surgery Infection Peaks and begins to decrease within 48 hours of acute insult if no other inflammatory event occurs Arterial disease hs-CRP is a marker of existing arterial disease and future risk Healthy individuals with hs-CRP results in highest quartile (upper 25%) have 2-fold greater risk of developing atherosclerotic disease as compared with results in the lowest quartile Basal CRP concentration remains stable over long periods of time

  Apolipoproteins

  Apolipoproteins
  Apo A1 Primarily found in HDL-C where it activates lecithin acyltransferase, resulting in the removal of free cholesterol from extrahepatic tissues Elevated Apo A1 levels may protect against CVD and peripheral vascular disease Reduced levels of Apo A1 are one of the most reliable predictors of CVD
  Apo B Main apolipoprotein of LDL-C and chylomicrons Apo B makes cholesterol soluble for transport, leading to arterial deposition Increased levels of LDL-C are associated with an increased risk of CVD Autosomal dominant familial hypercholesterolemia type B is caused by mutations in the APOB gene 40% of male and 20% of female APOB mutation heterozygotes develop CVD or hypercholesterolemia Homozygotes or compound heterozygotes for two APOB mutations are at highest risk for hypercholesterolemia and CVD Apo B is a surrogate marker for measuring non-LDL-C
  Apo E Present on plasma lipoproteins, including chylomicrons, very low density lipoprotein (VLDL), and HDL-C Serves as the ligand for lipoprotein receptors and plays an important role in lipoprotein metabolism Given their differing receptor affinities, the Apo E isoforms alter plasma lipoprotein concentrations to varying degrees APOE*E2 allele is associated with increased LDL-C and type III hyperlipoproteinemia   APOE*E4 allele is associated with increased total and LDL-C and may contribute to CHD Both E2 and E4 alleles are associated with increased plasma triglyceride concentrations

  Lp(a)

  Lp(a)
  Heterogenous family of lipoprotein molecules consisting of an Apo A molecule attached to an Apo B-100 and a lipid-rich, LDL-like core Concentrations that are generally very low are largely under genetic control Elevated concentrations associated with increased risk of myocardial infarction, stroke, and CVD

  Homocysteine

  Homocysteine

  Homocysteine is an amino acid that exists in the blood Moderately elevated homocysteine is an independent predictor for atherosclerosis, CVD and thromboembolism Risk of atherosclerosis increases progressively with increasing concentration of homocysteine 10% of total risk may be attributable to elevated plasma homocysteine Risk ratio of 1.18 for each 5 µmol/L homocysteine elevation (Humphrey 2008) Methylenetetrahydrofolate reductase (MTHFR) is the enzyme involved in homocysteine metabolism Enzyme inactivation causes an increase in plasma homocysteine Most common genetic risk factors for hyperhomocysteinemia are MTHFR mutations C677T and A1298C C677T homozygosity associated with 3-fold risk of early CVD Very high concentrations are associated with homocystinuria, a rare inborn error of metabolism Concentrations usually >50 μmol/L Associated with ocular, skeletal, central nervous system, and vascular abnormalities High risk for pulmonary embolism, stroke, and myocardial infarction

  Lp-PLA2

  Lp-PLA2

  Calcium independent enzyme located primarily on the surface of circulating LDL-C  Also known as platelet-activating factor acetylhydrolase High levels associated with ischemic stroke; may be useful in risk assessment Proatherogenic Lp-PLA2 hydrolyzes LDL-C with resulting formation of lysophosphatidylcholine Lysophosphatidylcholine is an attractant for macrophages, T-cells and vascular smooth muscle cells Antiatherogenic Functions to hydrolyze platelet activating factor Arterial disease Independent marker of moderate- and high-risk populations for CVD Use in combination with hs-CRP to increase risk prediction May be most useful in moderate- and high-risk groups with metabolic syndrome Has been found to be associated with ischemic stroke; may be useful in risk assessment

  ST2

  ST2
  Member of the interleukin-1 receptor family Secreted by myocytes under mechanical strain Elevated concentrations of soluble ST2 occur in patients with heart failure and are strongly predictive of mortality

  Kidney disease markers – serum creatinine, cystatin, urine microalbumin

  Chronic Kidney Disease (CKD)
  Independent kidney disease markers for CVD risk Serum creatinine – estimated glomerular filtration rate (GFR) Refer to GFR calculator <60 mL/min/1.73 m2 defined as CKD Urine microalbumin Used in WHO definition of metabolic syndrome; may be strong predictor of CVD risk Cystatin May be a more powerful predictor than GFR, but needs more evaluation

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

Indications for Laboratory Testing

• 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

Click the plus sign to expand the table of additional tests.

Test Name and Number	Comments
VAP Cholesterol 0095263 Method: Ultra Centrifugation
LDL Subclasses 0050021 Method: Quantitative Electrophoresis
Methylenetetrahydrofolate Reductase (MTHFR) 2 Mutations 0055655 Method: Polymerase Chain Reaction/Fluorescence Monitoring
C-Reactive Protein 0050180 Method: Quantitative Immunoturbidimetry	Should not be used for CVD risk assessment
LDL Cholesterol, Direct 0020257 Method: Quantitative Detergent Solubilization/ Enzymatic
HDL Cholesterol 0020053 Method: Detergent Solubilization/Enzymatic
Lipoprotein Electrophoresis 0080503 Method: Qualitative Electrophoresis/Quantitative Enzymatic/Detergent Solubilization
ST2, Soluble 2002270 Method: Quantitative Enzyme Immunoassay
NMR LipoProfile® Test 2002043 Method: Quantitative Nuclear Magnetic Resonance Spectroscopy
NMR LipoProfile®, Particle Analysis Only 2003323 Method: Quantitative Nuclear Magnetic Resonance Spectroscopy
proBrain Natriuretic Peptide, NT 0050083 Method: Quantitative Electrochemiluminescent Immunoassay
Cystatin C, Serum 0095229 Method: Quantitative Nephelometry