Inflammatory Markers in Coronary Artery Disease: Title and subTitle BreakLet Prevention Douse the Flames

Atherothrombosis is increasingly recognized as a dynamic chronic inflammatory process of the vessel wall, in which phases of inflammatory and thrombotic activity underlie the clinical presentations of acute coronary syndromes (ACS).¹ There is also evolving evidence that circulating monocytes and white blood cells may be involved in a proinflammatory or prothrombotic circulatory state.^{2 - 3} These 2 mechanisms—inflammatory involvement of the vessel wall and of the circulating blood—are not mutually exclusive, and both could occur within an individual patient. Two reports in this issue of THE JOURNAL draw attention to the inflammatory basis of coronary atherothrombotic disease.

Zhang et al⁴ examined the relationship between levels of myeloperoxidase (MPO), a leukocyte enzyme that promotes oxidation of lipoproteins in the atheroma, and the prevalence of coronary artery disease (CAD). In a carefully constructed case-control study performed among patients recruited from an outpatient clinic and a cardiac catheterization laboratory, the investigators found that MPO levels strongly correlate with prevalence of CAD (adjusted odds ratios of 11.9 and 20.4 for CAD prevalence between the highest vs lowest quartiles of leukocyte MPO levels and blood MPO levels, respectively). The authors speculate that these striking results may indicate that MPO plays a direct causal role in the development of atherosclerosis and may serve as a marker of inflammation.

Although other conventional markers of CAD risk were assessed in this study, these investigators did not compare MPO levels with other markers of inflammation such as C-reactive protein (CRP). The authors are appropriately cautious about recommending measurements of MPO levels in routine clinical practice on the basis of this report, particularly since the assay used to determine MPO levels does not appear to be available outside the context of research investigations. Perhaps the most intriguing implication of this observation about MPO, an enzyme principally associated with host defense mechanisms, is whether additional research ultimately may help elucidate the role of infectious agents such as Chlamydia pneumoniae in the pathogenesis of atherosclerosis.

In the second report, Lindmark et al⁵ measured circulating levels of interleukin 6 (IL-6) among patients enrolled in the prospective Fragmin and Fast Revascularisation During Instability in Coronary Artery Disease II (FRISC II) trial comparing invasive vs conservative management of patients with acute coronary syndromes. Elevated IL-6 levels were a strong and independent predictor of mortality for patients treated in both the invasive and conservative arms. Among patients with elevated IL-6 levels, assignment to the early invasive strategy strongly reduced mortality at 12 months (5.1% absolute risk reduction). Although IL-6 levels correlated with mortality, high levels of IL-6 were not predictive of the composite end point of both death and myocardial infarction at 6 to 12 months.

The automated assay used in this study may facilitate measurement of IL-6 levels in routine clinical practice. However, on the basis of this report, it would seem premature to recommend such a strategy until several additional practical questions are resolved: first, the authors used a single, crude cutoff of IL-6 levels higher than 5 ng/mL to denote elevated IL-6 concentration. Perhaps a more sophisticated assay would permit more accurate risk stratification by tertiles or quartiles of IL-6 levels. Additional trials may be necessary to establish the predictive value of IL-6 after adjustment for other risk factors. For example, increased weight is associated with higher IL-6^{6 - 7} and CRP⁸ levels. In the predominantly Scandinavian population enrolled in FRISC II, median body mass index (BMI) was approximately 26 kg/m² and was identical among those with normal and elevated IL-6 levels. Surveillance data continue to document the relentless progression of obesity in the United States: 56% of the population is overweight (BMI >25 kg/m²) and approximately 1 in 5 is obese (BMI >30 kg/m²).⁹ Precise definitions of elevated or abnormal marker levels must be validated for the heterogeneous real world of clinical practice before clinicians can base patient management decisions on such markers.

Second, the greatest potential role for IL-6 levels appeared to be in identifying patients with ACS who would benefit from an aggressive approach to revascularization. Thus the exclusion of patients older than 75 years from randomization into the invasive vs conservative arms of FRISC II is important since patients older than 75 years now make up more than one third of patients presenting with acute coronary disease.¹⁰ Furthermore, although Lindmark and colleagues described an age-related increase in IL-6 levels, other reports have shown that IL-6 levels increase, decrease, or remain unchanged with advancing age.¹¹

Third, since circadian variability has been reported with IL-6 levels,¹² the same value may be too high (false-positive), normal, or too low (false-negative), depending on the timing of sampling. Fourth, only 9% to 13% of patients in the FRISC II trial were receiving a statin at the time of IL-6 measurement. The significant absolute benefit of the invasive approach among patients with ACS with elevated IL-6 levels might have been blunted had these patients received chronic treatment with statins, particularly since data demonstrate that risk reduction achieved with statins is greater in patients with elevated markers of inflammation.¹³

Despite the interesting observations in the studies by Zhang et al and by Lindmark et al, 3 major questions need to be resolved before measurements of inflammation are incorporated into the routine assessment of patients with CAD.

1. Do measurements of inflammation identify patients at risk, and do such measurements independently predict risk beyond conventionally used stratification tools? Recent data suggest that measurements of markers of inflammation may extend the ability to identify high-risk groups of patients, particularly in the primary prevention setting.¹³ However, this approach has yet to be validated in a prospective trial. Moreover, it is unclear whether one marker of inflammation will prove superior to another (ie, CRP, IL-6, serum amyloid A, or others) and whether the same inflammatory marker should be used to predict risk in both the acute and chronic phases of coronary disease.

2. Are specific therapies available to reduce serum levels of markers of inflammation? Recently published data¹⁴ confirm previous reports that statins reduce CRP levels. However, the absolute reduction in CRP level achieved with statin therapy was relatively small (−0.02 mg/dL).¹⁴ The clinical implications of such modest changes in CRP levels remain unknown and need to be explored in rigorously designed prospective studies. For example, although aspirin is indisputably effective in both primary and secondary prevention of events in patients with atherosclerotic disease¹⁵ and aspirin therapy appears to have its greatest effect among men with CRP levels in the highest quartile,¹⁶ controversy exists as to whether aspirin therapy is associated with any detectable effect on CRP levels.^{17 - 19}

3. Most important, do therapies that lower serum levels of inflammatory markers reduce cardiovascular risk? The only drugs thus far demonstrated to reduce markers of inflammation are statins and possibly aspirin. These agents are already indicated for the majority of patients with CAD. Statins,²⁰ aspirin,¹⁵ and other classes of medications such as angiotensin-converting enzyme inhibitors,²¹ β-blockers,²² and antithrombotic drugs (fibrinolytics,²³ platelet glycoprotein IIb/IIIa inhibitors,²⁴ and clopidogrel²⁵ ) form the foundation of current medical therapy for patients with acute and chronic CAD. Ample evidence exists documenting the efficacy of these medications in reducing morbidity and mortality among patients with CAD. Unfortunately, considerable evidence also continues to reveal that significant proportions of patients at risk do not receive these effective therapies. For example, a recently published report from the National Registry of Myocardial Infarction 3 indicated that only 31.7% of patients who were hospitalized for acute myocardial infarction in the United States in 1998-1999 were prescribed lipid-lowering therapy at the time of discharge from the hospital.²⁶ Among the highest-risk patients (those with prior history of CAD, revascularization, or diabetes), less than one half were discharged with treatment. Such underuse of indicated therapy leads to significant measurable adverse outcomes.²⁷

New observations about the role of inflammation in the pathogenesis of atherosclerosis incrementally extend the current understanding of this disease. For now, such preliminary reports should not distract physicians or patients from treatments that have been unequivocally proven effective in treating CAD.