Evaluating Novel Cardiovascular Risk Factors: Can We Better Predict Heart Attacks?

Hyperlipidemia has proven to be an important modifiable cardiovascular risk factor for myocardial infarction, but many myocardial infarctions occur among persons with normal lipid values who otherwise appear to be at low clinical risk. In an attempt to better predict future myocardial infarction, epidemiologic studies have explored a series of novel risk factors for coronary disease, many of which are important for specific individuals (1). Of these factors, lipoprotein(a) levels; total plasma homocysteine levels; fibrinolytic function, as assessed by levels of tissue-type plasminogen activator and plasminogen activator inhibitor antigens; and inflammatory markers, such as fibrinogen and high-sensitivity C-reactive protein, have received the most attention (Table 1). However, when considering the clinical utility of any new marker for cardiovascular disease in currently healthy persons, three important issues must be considered. Table 1. Potential Markers of Risk for Vascular Occlusion First, there must be consensus among clinical chemists and research scientists on a sensitive and specific diagnostic test for the marker of interest. If assay characteristics are unacceptable or if controversy over the best way to measure a given marker is ongoing, it is unlikely that a clinically useful recommendation for screening to detect high risk can be made. For example, despite many years of research, there is no consensus on the appropriate method for lipoprotein(a) evaluation, and standardization of lipoprotein(a) testing in several commercially available kits remains inadequate (2). Efforts to standardize clinical assays for fibrinogen are improving, but intra-assay and interassay coefficients of variation for this marker remain high when different measurement methods are compared. By contrast, World Health Organization standards have been set for high-sensitivity assessment of C-reactive protein, and testing for high-sensitivity C-reactive protein seems to provide consistent and reproducible results (3, 4). Accurate assessment of fibrinolytic function requires standardized phlebotomy conditions, an issue that limits the utility of this approach. Furthermore, fibrinolytic markers have wide diurnal and seasonal variations (5, 6). With regard to total plasma homocysteine, the labor and expertise required for high-pressure liquid chromatography reduce the application of this technique for general screening. Second, there must be a consistent series of prospective epidemiologic studies indicating that the novel marker of interest can be detected in apparently healthy persons before the onset of clinical disease. Prospective studies (in which exposure is ascertained before the onset of thrombosis) are critical in determining the validity of any proposed relation between a novel risk factor and subsequent myocardial infarction or stroke. Several markers, including lipoprotein(a) and total plasma homocysteine levels, may increase after acute myocardial infarction (7-10), whereas fibrinogen and C-reactive protein are part of the acute phase response. Thus, caution should be used when interpreting data from retrospective studies (in which exposure is ascertained after the onset of thrombosis). It is important to recognize that retrospective evaluations of novel markers cannot exclude the possibility that the marker of interest is a result rather than a cause of acute vascular occlusion. Meta-analyses of retrospective studies, even when carefully performed, do not reduce the possibility of such bias (11, 12). To date, consistent prospective data are available for fibrinogen (13-17), high-sensitivity C-reactive protein (16, 18-24), and the fibrinolytic markers tissue-type plasminogen activator and plasminogen activator inhibitor (16, 25-29). For each of these substances, several large-scale studies have been completed in diverse patient populations, indicating both consistency and generalizability. In contrast, prospective studies for lipoprotein(a) and total plasma homocysteine are inconsistentboth positive and negative results have been reported in high-quality prospective studies. For example, several prospective studies of total plasma homocysteine have reported modest positive associations (30-34), but results of other studies have been null (35-38). Furthermore, one prospective study of homocysteine provided evidence of association with short-term (30) but not long-term (39) follow-up. Similarly, although several prospective studies of lipoprotein(a) have provided evidence of a positive association (40-44), other large-scale studies have not (45-47). Thus, the clinical utility of population-based assessment of lipoprotein(a) and homocysteine remains controversial. Third, there must be evidence that assessment of a novel marker adds to our ability to predict risk over and above that already achievable through the use of established cardiovascular risk factors. The demonstration that a given marker has predictive value in univariate analysis is not sufficient to recommend clinical use because the observed association may be the result of confounding by other, traditional risk factors. Thus, fibrinolytic markers, such as tissue-type plasminogen activator and plasminogen activator inhibitor, both of which predict future cardiovascular disease in univariate analysis, may be of limited clinical utility for screening because the predictive value in multivariate analysis appears marginal (1). Of perhaps greater importance is the demonstration that the novel marker is at least additive in terms of risk prediction to that of established coronary risk factors (48). In particular, the clear clinical demonstration that a given marker improves the predictive value of total and high-density lipoprotein (HDL) cholesterol levels is critical because assessment of these markers is unlikely to be replaced by any new marker. To date, data demonstrating the additive value of lipoprotein(a) and homocysteine measurement are inconsistent. By contrast, measurement of fibrinogen (16, 17) or high-sensitivity C-reactive protein (22, 49) in addition to lipid measurement has been shown to cause significant improvement in clinical prediction models based on lipids alone in both men and women. An example of this additive effect for high-sensitivity C-reactive protein, a sensitive marker of chronic low-grade vascular inflammation, is shown in Figure 1. Figure 1. Relative risk for future myocardial infarction on the basis of simultaneous assessment of high-sensitivity C-reactive protein and the lipid profile. HDL Although it is not critical for risk prediction per se, an additional issue to consider is whether a given marker is modifiable and whether such modification reduces cardiovascular risk. No completed randomized trials indicate that specific therapies designed to reduce levels of any novel marker lead to reduced cardiovascular event rates. Several studies indicate, however, that folate replacement reduces homocysteine levels (50, 51), and ongoing trials of folate therapy will help to determine the clinical utility of homocysteine screening. Recently, the U.S. supply of cereals and grains was fortified with folic acid to reduce the risk for neural tube defects. Although the impact of such fortification on cardiovascular risk is unknown, preliminary data indicate that the overall population distribution of homocysteine has been significantly reduced. Thus, food fortification may have further reduced the utility of generalized screening for mild to moderate hyperhomocystinemia. Such agents as niacin and bezafibrate are reported to have some efficacy in reducing lipoprotein(a) and fibrinogen levels, respectively, but the magnitude and specificity of these effects are uncertain. No currently available therapies specifically reduce high-sensitivity C-reactive protein levels, although it is of interest that baseline concentrations of high-sensitivity C-reactive protein seem to modulate the efficacy of two preventive therapies, low-dose aspirin and 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibition. For example, data from double-blind, randomized clinical trials suggest that the relative efficacy of these two commonly used therapies may be greater in persons with evidence of underlying inflammation as assessed by high-sensitivity C-reactive protein (19, 52). Moreover, preliminary data suggest that long-term 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibition reduces high-sensitivity C-reactive protein levels in a manner that is relatively independent of low-density lipoprotein cholesterol levels. Taken together, these data raise the possibility that novel markers may also have a role in monitoring preventive therapies. As shown in Table 2, the criteria outlined above for assay characteristics, consistency of prospective epidemiologic studies, and the ability of a given marker to add to the predictive value of total and HDL cholesterol can assist clinicians in deciding whether a novel marker of risk deserves clinical consideration in general outpatient settings. For specific patients who have known metabolic disorders or have a personal or family history of unexplained premature atherothrombosis, a more aggressive approach to evaluation of novel risk markers may be warranted. In addition, markers that help with disease prognostication may not necessarily be the most relevant markers for understanding disease pathophysiology. For example, recent prospective data concerning specific cytokines and cellular adhesion molecules help explain the inflammatory processes underlying atherosclerosis (53, 54), but the prognostic value of these markers in clinical settings is uncertain compared with more easily measured markers of inflammation, such as high-sensitivity C-reactive protein. Table 2. Assessment of the Clinical Utility of Novel Markers of Cardiovascular Risk Few studies have systematically evaluated the relative efficacy of different novel ri