Vol. 18 • Issue 7 • Page 22
Healthcare providers and patients alike are seeking biomarkers to identify arterial inflammation at all stages of the atherosclerotic disease process; the numbers of such markers are growing.
After all, heart attacks and strokes remain the largest cause of death and disability in the United States.1 At least half of the men and women who die suddenly of coronary artery disease (CAD) were asymptomatic immediately prior to their demise.2 The estimated direct and indirect cost of cardiovascular disease in the U.S. for 2008 was $448.5 billion.
It is now widely accepted that arterial inflammation is involved in the stages of atherosclerosis, from its inception all the way through the ultimate culmination, with an actual event such as heart attack and stroke.3 Individuals in a pro-atherogenic state can be targeted for medical management to halt the progression of disease.
In 2001, the annual growth rate for the world cardiac rapid assay market was projected to be 20 percent to 25 percent, with most growth driven by a host of new markers. Eight years later this market remains strong and continues to expand. The question remains: Which markers should diagnostic laboratories offer to clinicians? Current markers worthy of consideration are explored.
Microalbumin-creatinine Ratio (ACR)
ACR, a simple and inexpensive urine test, is a reflection of endothelial health and inflammation. ACR should be measured routinely to assess cardiovascular (CV) risk.4 The Framingham Study, a notable review of CV risk, measured numerous biomarkers. When an analysis was done to see which biomarkers independently predicted CV risk, only two measurements qualified. One was the ACR,5 the other was brain natriuretic peptide (BNP),5 a hormone largely produced in the heart in response to cardiac stress. This pre-cursor molecule is cleaved to generate both BNP and N-terminal pro-brain natriuretic peptide (NT-proBNP).
BNP is metabolically active but rapidly degraded. Though inactive, NT-proBNP circulates longer, accumulates to higher signal levels, is more stable and can be measured sensitively and reliably. NT-proBNP was FDA-approved in 2006 for event risk assessment in patients with known coronary heart disease.
Highly Sensitive C-reactive Protein (hs-CRP)
hs-CRP is elevated with inflammation. While hs-CRP is a good test to identify inflammation in the body, the measure frequently lacks the ability to identify inflammation that's specific to just the arteries. Factors such as periodontal (gum) disease, infection and arthritis will cause the level to be elevated.
In the Dallas Heart Study, higher hs-CRP levels failed to predict the prevalence of subclinical atherosclerosis independently of traditional cardiovascular risk factors.6 Despite this weakness, it is appropriate to check hs-CRP when assessing CV event risk in patients with no evident inflammation or infection. Results greater than 10 mg/L should not be considered; repeat levels should be checked at least two weeks later. If the level is <1.0 mg/L, a CV event is unlikely.7
Lipoprotein-associated Phospholipase A2 (Lp-PLA2)
Lp-PLA2 is a cardiovascular-specific inflammatory enzyme implicated in the formation of vulnerable, rupture-prone plaque. Lp-PLA2 associates in the blood primarily with low-density lipoprotein (LDL, the "bad" cholesterol). Lp-PLA2 is carried to the walls of coronary arteries by LDL, where the enzyme can activate an inflammatory response, making plaque more prone to rupture. When LDL becomes oxidized in the intima, Lp-PLA2 acts on the LDL to produce two pro-atherogenic and pro-inflammatory substances.8In more than 65 studies, Lp-PLA2 was associated with CV risk. It was FDA-approved for coronary heart disease risk assessment in 2003 and for ischemic stroke risk assessment in 2005. It is now the only blood test approved to assess stroke risk.
A recent study4 produced a strong signal that Lp-PLA2 is not just a marker, but a player in atherosclerotic disease. This enhances its value by making it a potential target for therapy.9
MPO is an evolving inflammatory marker that has recently gained FDA approval for clinical use in individuals experiencing acute chest pain. Substantial evidence shows that an elevated level of MPO in patients with chest pain is a strong indication of unstable CAD.5 When it's high, a much greater risk for heart attack exists immediately and throughout the next six months.10 Another study also shows association with MPO levels and risk of heart failure;11 it is an enzyme that can stimulate vascular inflammation and even death of endothelial cells.
Mounting evidence suggests that MPO may be involved in all stages of atherosclerosis.10 It may prove, for example, to be a valuable marker of CV risk beyond the acute circumstance. Further research is necessary to determine if it should be a therapeutic target.10
From the standpoint of reliable risk assessment, ACR and Lp-PLA2 fare well. The ACR has years of data demonstrating its association with CV risk and has been shown to be an independent predictor. Lp-PLA2 has similar data and also is known to be very specific for arterial inflammation.
Additionally, Lp-PLA2 appears to be directly involved in the evolution of atherosclerosis and may improve the prediction of an individual's cardiovascular health risk, potentially identifying hidden cardiovascular risk not revealed by traditional risk factors. This was signaled by a study in which a drug that blocks the activity of Lp-PLA2 in the wall of the artery was administered to patients with known CAD. Through sophisticated measurements it was demonstrated that blocking the activity prevented the enlargement of the necrotic core of atherosclerotic lesions. Advancement of the necrotic core is associated with increased risk of an event. The control group that received the placebo had significant advancement in necrotic core size, evidenced by the fact that Lp-PLA2 is involved in the atherosclerotic process and as such, a potential target for therapy.9 The tests discussed here can help detect individuals who harbor silent and potentially fatal atherosclerosis. Subjects found to be at higher CV risk can be targeted for more aggressive management to enhance their chance of avoiding the fatal or disabling consequences of a heart attack or stroke.
Dr. Bale is the founder of the Center for Heart Attack and Stroke Prevention in Spokane, WA; clinical assistant professor at Texas Tech School of Medicine and an adjunct professor at Texas Tech School of Nursing; and director of the Heart Health Program at the Grace Clinic in Lubbock, TX.