Assessing the role of circulating, genetic, and imaging biomarkers in cardiovascular risk prediction.

The use of biomarkers to augment traditional cardiovascular risk prediction has attracted considerable attention in the past decade. This interest has been fueled by the realization that traditional risk factors do not identify everyone who will eventually develop cardiovascular disease.1 This has been accompanied by the emergence of potential screening tests such as high-sensitivity C-reactive protein (CRP), single-nucleotide polymorphism arrays, and coronary calcium scanning. Nonetheless, whether these biomarkers are ready for routine clinical use, to be measured alongside existing tests such as cholesterol, is controversial. Recently, the US Preventive Services Task Force concluded that “current evidence is insufficient to assess the balance of benefits and harms of using the nontraditional risk factors.”2 This conclusion underscores gaps in the current literature, as well as the inherent challenge of predicting the occurrence of future cardiovascular events in generally healthy adults. However, the use of newer screening tests for cardiovascular risk assessment has been endorsed in some quarters. For instance, the state of Texas passed legislation in 2009 mandating the coverage of screening coronary calcium scans in older adults. Furthermore, the Food and Drug Administration recently expanded the labeling of a statin drug, rosuvastatin, to include older individuals with elevated CRP levels in addition to conventional risk factors. The present article reviews the case for and against the use of newer biomarkers for cardiovascular risk prediction. There are literally hundreds of circulating, genetic, and imaging biomarkers that have been proposed or evaluated in the cardiovascular literature. Several comprehensive reviews exist on the topic.3,4 Rather than attempting to provide a systematic overview, this article focuses on a few of the most illustrative biomarkers. Particular emphasis will be given to placing these biomarkers in a pathophysiological context (what stage of disease is represented?), addressing the utility of a multimarker approach (does it help to combine biomarkers?), and proposing priorities for future research in this area (where do we go from here?). Why Do We Need Biomarkers? Cardiovascular disease remains the leading cause of death in the United States, a fact that underscores the importance of primary prevention. The success of preventive measures depends in part on the accurate identification of individuals who are at risk for future cardiovascular events (risk prediction). Traditionally, risk prediction has relied on assessment of risk factors such as hypertension, diabetes mellitus, hyperlipidemia, and smoking. Indeed, the approach to risk prediction has changed relatively little since Dr William Kannel coined the phrase factors of risk in 1961 to describe these predisposing conditions.5 Despite the value of traditional risk factors, as many as half of individuals who develop coronary heart disease have only 1 or none of these risk factors.1,6 Indeed, individuals with few clinical risk factors are the least likely to be targeted for preventive therapies, but as a group they experience the largest number of cardiovascular events. Thus, there is an important need for new ways to improve on the information obtained from traditional risk assessment so that preventive measures can be applied to those who are the most likely to experience events. Efforts to address the problem of identification have largely focused on the use of new measurements, or biomarkers, that could be added to traditional ones such as blood pressure and cholesterol. In 2001, a National Institutes of Health working group proposed a definition of a biomarker as “a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacological responses to a therapeutic intervention.”7 This definition highlights the fact that biomarkers are not limited to blood tests, although that is the context in which the term is most frequently used in the cardiology literature. Thus, a biomarker could include any representation of a biological process, including circulating molecules, genetic markers, cellular markers, results of imaging, or findings on physical examination. Furthermore, which of these biomarkers is most informative is partly a function of the phase in the disease process (Figure 1). It is now recognized that overt cardiovascular disease is typically preceded by a long period of subclinical cardiovascular disease. For instance, subclinical atheroscle-