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(Circulation. 2000;101:1758.)
© 2000 American Heart Association, Inc.

Editorial

Circulating Markers of Inflammation for Vascular Risk Prediction

Are they Ready for Prime Time

Prediman K. Shah, MD

Key Words: Editorials • atherosclerosis • inflammation

Over the last several years, the idea that inflammation plays a key role in atherosclerosis and its complications has received considerable attention.¹ Inflammatory cell infiltration is observed in atherosclerotic plaques at virtually all stages, from the fatty streak to the advanced atheromatous lesions with plaque disruption and thrombosis.^{1 2} Atherosclerosis is substantially prevented when the biological effects of genes critical for the initiation or maintenance of inflammatory cell recruitment, survival, proliferation, and activation, such as monocyte chemotactic protein-1, interleukin-8, and macrophage colony stimulating factor, are eliminated by gene knockout in atherosclerosis-prone dyslipidemic mice.^{3 4 5} Similarly, the inhibition of inflammatory signaling pathways mediated by the ligation of CD-40 also results in reduced atherosclerosis in mice.⁶

Inflammatory cells may also play a key role in promoting plaque disruption by stimulating matrix degradation, inhibiting smooth muscle cell function or survival, and promoting thrombosis by producing tissue factor.² Similarly, the atheroprotective effects of a variety of interventions such as statins, apolipoprotein A-1/HDL, aspirin, and fibrates are often associated with the evidence of reduced inflammation, further bolstering the notion that inflammation and atherosclerosis are causally related.^{2 7 8} Although all of the potential triggers of inflammation are not fully known, cytokines, oxidized lipoproteins, and local (arterial) and distant infections (gingivitis, bronchitis) have been implicated.^{2 9} Early reports from small, randomized trials have shown a reduced clinical event rate with the use of macrolide antichlamydial antibiotics.² These preliminary observations support the notion that Chlamydia pneumoniae infection may be causally related to atherothrombosis, although a direct anti-inflammatory effect of macrolides, independent of antichlamydial action, cannot be excluded.

In view of the persuasive evidence implicating inflammation in atherothrombosis, several investigators have examined a variety of circulating markers of inflammation to predict either the presence of vascular disease or the risk of vascular events in a variety of clinical settings.¹⁰ These markers have included C-reactive protein (CRP), serum amyloid A protein (SAA), heat shock protein 65, interleukin-6 (IL-6), and a number of leukocyte adhesion molecules.

Of the variety of circulating markers, CRP, an acute phase reactant produced by the liver in response to IL-6 (a cytokine induced by interleukin-1 and tumor necrosis factor-) has been the best studied, with the most consistent relationship to future risk under diverse clinical settings (ie, asymptomatic, otherwise healthy subjects; patients with peripheral and stable coronary artery disease; and patients with unstable angina).¹⁰ Furthermore, the availability of a reliable, reproducible assay with a high sensitivity for CRP adds to its attractiveness as a circulating marker of risk. Because CRP gene transcription in the liver is stimulated by IL-6, a pleiotropic cytokine, CRP levels are generally well correlated with circulating levels of IL-6. Therefore, it is not surprising that like CRP, circulating IL-6 also provides prognostic information. This was first suggested by Biasucci et al¹¹ and is now further established by Ridker et al.¹²

Ridker et al¹² continue to take advantage of the Physician’s Health Study Database, which provides valuable prospective information on the predictive value of various markers in asymptomatic subjects. In the present study, they measured circulating IL-6 levels in 202 subjects who had suffered a myocardial infarction during a 6-year follow-up and compared them with those of 202 matched control subjects who had remained free of the intervening clinical events.¹² Although IL-6 and CRP levels were modestly correlated (r=0.4), multivariate analysis revealed a graded risk associated with increasing quartiles of IL-6 levels that was independent of CRP and many other traditional risk factors.¹² As with CRP levels in seemingly healthy subjects, the circulating IL-6 levels had prognostic value within the normal range for IL-6.

The results of this study are in general agreement with smaller studies reported previously and a recent prospective study in the geriatric population.¹³ As with CRP, it is unclear whether IL-6 is simply a messenger of risk or whether it is pathophysiologically involved in atherothrombosis. The potential causal role of IL-6 in atherothrombosis is suggested by its selective expression in macrophages in murine and human atheroma, its stimulatory effect on smooth muscle cell proliferation and tissue factor induction in macrophages, and its ability to accelerate early atherosclerosis in murine models.^{14 15 16} Furthermore, the IL-6–induced hepatic production of SAA may promote the incorporation of SAA with plasma HDL, rendering the HDL proinflammatory.¹⁷

Although this study and the body of data previously reported by Ridker et al¹⁰ have continued to enhance our knowledge of new risk factors for vascular disease, several limitations continue to preclude the routine use of these novel markers for risk stratification in clinical practice. First, many markers have been studied by various investigators, but comparative data regarding which ones are incremental and which ones are redundant are limited. It remains to be proven that any of the inflammatory markers provide incremental information over and above the traditional risk stratification algorithms developed by the Framingham Study Groups and the European Working Group.¹⁸

Ridker recently analyzed data from the Physician’s Health Study and demonstrated that circulating CRP levels provided significant incremental prognostic information over and above the total cholesterol to HDL ratio.¹⁹ It would have been of great interest to know whether circulating IL-6 also provides incremental prognostic data over and above that provided by a model that takes into account traditional risk factors and CRP levels. Unfortunately, the present report does not provide this critical piece of information. Given the ever-increasing list of inflammatory markers, their practical utility will likely remain uncertain until the issue of which marker is incrementally useful (instead of redundant) is resolved.

Another limitation of the routine use of these markers is the increasing use in clinical practice of several new, noninvasive imaging techniques for the detection of subclinical atherosclerosis. These techniques include electron beam computerized tomographic scanning and brachial artery reactivity for coronary atherosclerosis and ultrasound and MRI for carotid and aortic atherosclerosis. How will circulating inflammatory markers fare when stacked against these imaging tests? Answers to these questions can only be provided by properly designed prospective studies in which traditional risk factors and the novel inflammatory markers are measured along with imaging information to test both the incremental usefulness of the markers and the cost-effectiveness of various tests.

Despite the usefulness of inflammatory markers in predicting relative risks in populations, the prediction of absolute risk in individuals remains a challenging task, especially in low-risk populations in which event rates are low. Also, to be clinically useful, the assays must be precise, reproducible, relatively nontedious, easily standardizable, and inexpensive. Finally, new techniques to identify gene expression patterns should help decipher the complex nature of atherosclerosis at a molecular genetic level, providing insights about genetic modulations of susceptibility to disease and response to therapy.²⁰ Down the road, the incorporation of this information may add a whole new dimension to our ability to identify at-risk individuals for intervention. When that happens, it is quite possible that many of our more remote and indirect markers will end up relegated to history.

Not withstanding these limitations and although inflammatory markers such as IL-6 may not yet be ready for prime time, the evidence linking inflammation to atherothrombosis keeps piling up. The focus on inflammation as a critical player in atherothrombosis will likely lead to novel anti-inflammatory strategies against atherothrombotic vascular disease in the future. That may yet be the more important outcome of studies like that of Ridker and colleagues.

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