Cardiovascular disease (CVD) is a major cause of morbidity and mortality in the U.S. Novel biomarkers can be valuable additions to standard risk factors for cardiovascular disease (CVD).

• For clinical background information regarding cardiovascular disease see the topic, “Cardiovascular Disease (Traditional) Risk Markers”
• Multiple available biomarkers that detect CVD stages

Refer to www.arupconsult.com for the table of Cardiovascular Biomarkers for the Detection of Cardiovascular Disease

Recent focus in research regarding markers include:

• High sensitivity C-reactive protein
• Apolipoproteins A and B
• Apolipoprotein E
• Lipoprotein(a)
• Homocysteine
• Lipoprotein-associated phospholipase A2
• Kidney disease markers - serum creatinine, cystatin, urine microalbumin
• Other less well defined markers including IL-6, TNFalpha, myeloperoxidase, sCD40 ligand

High Sensitivity C-reactive Protein (hs-CRP)

• C-reactive protein (CRP) is the most sensitive of the acute phase reactant proteins
• CRP is elevated in acute insults
  • Elevates less than 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
  • The high sensitivity assay for CRP (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 times greater risk of developing atherosclerotic disease, compared with those in lowest quartile
  • Basal CRP concentration remains stable over long periods of time

Apolipoproteins

• Apolipoprotein A (Apo A1)
  • Primarily found in high density lipoprotein (HDL) where it activates lecithin acyltransferase resulting in the removal of free cholesterol from extrahepatic tissues
  • Elevated Apo A1 levels may protect against coronary artery disease (CAD) and peripheral vascular disease
  • Reduced levels of Apo A1 are one of the most reliable predictors of CAD
• Apolipoprotein B (Apo B)
  • Main apolipoprotein of low density lipoprotein (LDL) and chylomicrons
  • Apo B makes cholesterol soluble for transport leading to arterial deposition
  • Increased levels of LDL are associated with an increased risk of CAD
  • Familial hypercholesterolemia is an autosomal dominant disorder caused by mutations in the LDL-receptor (85%) or Apo B gene (15%)
  • 40% of male and 20% of female Apo B mutation heterozygotes develop CAD or hypercholesterolemia
  • Homozygotes or compound heterozygotes for two Apo B mutations are at highest risk for hypercholesterolemia and CAD
• Apolipoprotein E (Apo E)
  • Present on plasma lipoproteins, including chylomicrons, very low density lipoprotein (VLDL), and HDL serving as the ligand for lipoprotein receptors; thus, playing an important role in lipoprotein metabolism
  • Given their differing receptor affinities, the Apo E isoforms alter plasma lipoprotein concentrations to varying degrees
  • Apo E2 allele is associated with lower LDL cholesterol and type III hyperlipidemia
  • Apo E4 allele is associated with increased total and LDL cholesterol
  • Both Apo E2 and E4 alleles are associated with increased plasma triglyceride concentrations

Lipoprotein(a)

• Heterogenous family of lipoprotein molecules consisting of an apolipoprotein(a) molecule attached to an apolipoprotein B-100 and a lipid rich LDL-like core
• Concentrations are genetically determined
• Elevated concentrations associated with increased risk of myocardial infarction, stroke, and coronary artery disease

Homocysteine

• Homocysteine is an amino acid that exists in the blood
• Moderately elevated homocysteine is an independent predictor for atherosclerosis, CVD and thromboembolism
• The risk increases progressively with increasing concentration of homocysteine
  • 10% of total risk may be attributable to elevated plasma homocysteine
• 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 premature 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

Lipoprotein-associated phospholipase A2 (Lp-PLA2) enzyme

• Associated primarily with circulating low-density lipoprotein (LDL)  
• Functions to hydrolyze platelet activating factor
• Has been found to be associated with ischemic stroke; may be useful in risk assessment
• Proatherogenic
  • Lp-PLA2 hydrolyzes LDL 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 value in assessment of moderate and high risk populations for CVD
  • Use in combination with hsCRP to increase risk prediction
  • Has been found to be associated with ischemic stroke; may be useful in risk assessment

Chronic Kidney Disease Markers

• Independent marker of risk of CVD
• Serum creatinine - estimation of GFR
• Urine microalbumin
  • Used in WHO definition of metabolic syndrome
• Cystatin
  • May be a more powerful predictor, but needs more evaluation

Diagnosis

• Screening
  • Most markers are not recommended for routine use or risk stratification of CVD; however, they may be useful in patients at intermediate risk (10-20% 10-year risk) for further risk stratification
• Familial hypercholesterolemias/hyperlipidemias
  • Apo E testing may be considered
• Chronic kidney markers
  • Estimated GFR and Microalbumin testing in individuals with hypertension, diabetes mellitus, CVD and family history of CVD
• hs-CRP assay
  • Should be used for atherosclerotic risk assessment
    • Order in patients with intermediate 10-year risk as assessed by Framingham Risk Score
    • Combine with LpPLA2 to increase accuracy of risk prediction
  • Risks
    • <1 mg/L = low risk
    • 1-3 mg/L = average risk
    • >3 mg /L = high risk
• Homocysteine
  • The addition of homocysteine to existing risk models does not enhance predictive power of models; do not use routinely
• Lipoprotein(a)
  • The addition of lipoprotein(a) to existing risk models does not enhance predictive power of models so do not use routinely
• Lp-PLA2
  • Use for atherosclerotic risk assessment
  • Order along with hsCRP in patients with intermediate and high 10-year risk as assessed by Framingham Risk Score
• Apo E
  • The addition of Apo E to existing risk models does not enhance the predictive power of models; do not use routinely