It is well established that hypercholesterolemia is a risk factor for coronary heart disease (CHD), and routine screening is recommended for standard lipids and other major modifiable risk factors, including blood pressure, diabetes, obesity, and lifestyle habits.¹ Advances in our understanding of the pathophysiology of CHD have led to the discovery of several nonlipid risk factors that may enhance our ability to identify and manage patients who are most likely to have a future cardiovascular event. Information about a constellation of risk factors provides better predictive power than a single risk factor, but whether novel markers should be added to conventional risk factor screening is debated. Three candidate markers have potential use in practice to alter strategies for the prevention of CHD: C-reactive protein (CRP), homocysteine, and lipoprotein A.

There is increasing recognition that the underpinnings of atherosclerosis involve chronic inflammation and the deposition of cholesterol in the arterial wall.² CRP, a marker of systemic inflammation, predicts future risk of cardiovascular events in apparently healthy men and women, as well as among those with CHD.³ High-sensitivity tests for CRP (hsCRP) detect levels within a range that were previously considered normal but have subsequently been shown to be associated with increased CHD risk.³

Some studies have suggested that CRP provides additional prognostic information beyond traditional risk factors, but there is no consensus whether CRP levels should have an impact on the aggressiveness of risk factor management.⁴ Data from statin trials suggest that the efficacy of statin therapy may be partly related to a reduction in CRP levels and that persons without evidence of inflammation may not benefit from therapy.³ Prospective controlled trials to confirm the inflammation hypothesis and test whether treatment should be altered based on CRP are not yet available. For now, it may be helpful to measure hsCRP among those who fall into an intermediate risk group (i.e., more than two risk factors) where the information may be used to guide further evaluation or therapy. More data are needed before routine screening of CRP in all adults can be recommended.

Increased levels of homocysteine have been associated with an increased risk of CHD in many epidemiologic studies, but not all.⁵ The mechanisms by which hyperhomocystinemia is associated with atherosclerosis have not yet been established, but vascular inflammation and damage have been implicated. Homocysteine-lowering treatment (folic acid plus vitamin B₆) has been shown to decrease the progression of subclinical atherosclerosis, but no major randomized controlled trials with clinical outcomes have been published.⁶ Some clinicians argue that because folic acid is safe and inexpensive, cardiac patients with elevated homocysteine levels should be titrated to a homocysteine level less than 1.22 mg per L (9 μmol per L) with folic acid supplementation.⁷

Since the government has instituted folic acid fortification of certain food products, population levels of homocysteine have declined and widespread screening or treatment with folic acid supplements (except for women of childbearing age) may not be necessary. Dark green leafy vegetables, oranges, and beans are good sources of folic acid. Physicians should emphasize intake of these rather than supplements until more research is done, especially because most Americans do not eat enough fruits and vegetables.

Lipoprotein A is an atherogenic lipoprotein that resembles low-density lipoprotein (LDL) cholesterol and may have thrombotic properties caused by competitive inhibition of plasminogen binding.⁸ Approximately 20 percent of the population has elevated levels of lipoprotein A higher than 30 mg per dL, believed to be the threshold to increase the risk of CHD twofold.

Epidemiologic studies have demonstrated lipoprotein A to be an independent predictor of cardiovascular events, but no clinical trials have proven that lowering lipoprotein A levels lowers CHD risk.⁹ Widespread screening of lipoprotein A is therefore not recommended. Because lipoprotein A is a highly inherited risk factor and associated with premature CHD, it is reasonable to screen those with early CHD and their family members. Lipoprotein A tends to be unresponsive to lifestyle intervention, is not correlated with many traditional risk factors, and seems to be synergistic with LDL to increase CHD risk. Few therapies other than niacin lower lipoprotein A, so information about it in high-risk patients may influence the choice of therapy, in the hope that lowering lipoprotein A will decrease CHD risk.

Novel risk factors contribute to our understanding of the etiology of CHD and enhance our ability to identify persons at high risk of cardiovascular events in population-based studies. Despite this, routine screening is not recommended because information about how these markers should modify clinical practice is not established. Selective assessment of novel risk factors in intermediate-risk persons may be helpful in guiding therapeutic decisions that fall outside of the clinical scenarios where evidence-based approaches to prevention are available. Because there is widespread documentation of the lack of screening and optimal management of conventional risk factors, emphasis in clinical practice should be placed on more uniform application of prevention strategies that are proven to reduce incident and recurrent CHD.