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

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

 

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

Click here for chart of Cardiovascular Biomarkers for the Detection of Cardiovascular Disease

Recent focus in research regarding markers include:

  • High sensitivity C-reactive protein (hs-CRP)
  • Apolipoproteins A and B
  • Apo E mutation
  • Lipoprotein(a)
  • Homocysteine
  • Lipoprotein-associated phospholipase A2 (Lp-PLA2)
  • Kidney disease markers – serum creatinine, cystatin, urine microalbumin
  • Other less well defined markers including IL-6, TNFα, myeloperoxidase, sCD40 ligand

Unfortunately, no concise evidence exists to suggest any of the above markers singly or in combination significantly improve risk-stratification scoring

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.

High Sensitivity C-reactive Protein (hs-CRP)

  • C-reactive protein 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 2-4 times greater risk of developing atherosclerotic disease, compared with those in lowest quartile
    • Basal CRP concentration remains stable over long periods of time
    • Recommendations
      • hs-CRP assay should be used for atherosclerotic risk assessment
      • Order in patients with intermediate 10 year risk as assessed by Framingham Risk Score (10-20%  risk)
      • Risks
        • <1 mg/L = low risk
        • 1-3 mg/L = average risk
        • >3 mg /L = high risk

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
    • Apo E4 allele is associated with increased total and LDL cholesterol
    • Both Apo E2 and E4 alleles are associated with increased plasma triglyceride concentrations
    • Recommendation – the addition of (Apo E) to existing risk models does not enhance predictive power of models; do not use routinely

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
  • Recommendation – the addition of lipoprotein(a) to existing risk models does not enhance predictive power of models so do not use routinely

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
    • Recommendation – the addition of homocysteine to existing risk models does not enhance predictive power of models; do not use routinely

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
    • Recommendation – the addition of Lp-PLA2 to existing risk models does not enhance predictive power of models; do not use routinely

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
  • Recommendation – estimated GFR and Microalbumin testing in individuals with hypertension, diabetes mellitus, CVD and family history of CVD

See Also