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Editorials |
1 From the Departments of Radiology (T.C.M., J.F.E) and Surgery (J.F.E.), University of Arkansas for Medical Sciences, 4301 West Markham St, Mail Slot 556, Little Rock, AR 72205. Received January 31, 2003; accepted February 3. Address correspondence to T.C.M. (e-mail: mccowantimothyc@uams.edu).
Index terms: Arteries, restenosis, 92.454, 92.458, 92.721 • Arteries, transluminal angioplasty, 92.1282, 92.454, 92.721 • Arteritis, 92.29, 92.454, 92.458 • Editorials
For more than a decade, mounting evidence has identified inflammation as an important, if not key, factor in the pathogenesis of atherosclerotic vascular disease (1,2). This discovery has implications not just for the understanding of the development of disease but also for the guidance and prediction of the outcome of treatment options. In this issue of Radiology, Schillinger et al (3) investigate the role of C-reactive protein, a marker and perhaps critical component of the vascular inflammatory process, as an indicator of the risk of restenosis following angioplasty in arteries below the knee.
The acute-phase reaction refers to systemic biologic responses to both acute and chronic inflammatory stimuli, such as infection, trauma, tissue infarction, surgery, and some neoplasms (4,5). These biologic changes can involve multiple organ systems, which include the blood vessel wall. Among the myriad biochemical alterations that occur, concentrations of a number of plasma proteins, known as the acute-phase proteins, increase (positive acute-phase proteins) or decrease (negative acute-phase proteins). Examples of acute-phase proteins include complement system components, fibrinogen, tissue plasminogen activator, antiproteases, C-reactive protein, haptoglobin, angiotensinogen, serum amyloid A, and albumin. Cytokines, intercellular signaling polypeptides synthesized predominantly by activated cells such as monocytes and macrophages at inflammatory sites, stimulate the production, mainly by the liver, of acute-phase proteins that operate synergistically and competitively in a complex network of cascading and self-regulating biochemical reactions that ultimately manifest as physiologic, nutritional, and behavioral alterations.
Investigators discovered C-reactive protein, named for its reaction to pneumococcal C-polysaccharide, in 1930 (6). Synthesized primarily by hepatocytes (but also probably by some endothelial cells) in response to interleukin 6 and possibly other cytokines, C-reactive protein has many roles in the inflammatory process (4,5,7). C-reactive protein activates complement, binds to membrane molecules of cells and possibly targets them for elimination, and induces production of inflammatory cytokines and expression of cellular adhesion molecules, including those in the endothelial cell. Some functions of C-reactive protein may actually be antiinflammatory, which is indicative of the complicated nature of the acute-phase response. Most healthy subjects have a plasma C-reactive protein level of 0.2 mg/dL (2.0 mg/L) or less (4). Although plasma levels may increase 1,000-fold in certain inflammatory processes, adverse cardiovascular events occur at C-reactive protein levels far below those seen with systemic infections. Unlike the cytokines, C-reactive protein has a long half-life and can be easily measured at most commercial laboratories by using standard assays. The erythrocyte sedimentation rate, an indirect assessment of plasma acute-phase proteins, can now be regarded as an imprecise, less reliable, and less responsive measurement of the inflammatory response.
Baseline levels of C-reactive protein can be used to strongly predict risk of myocardial infarction, peripheral vascular disease, and stroke. This correlation holds for individuals both with and without known vascular disease (8). In one study, the relative risk of future stroke for patients who have the highest quartile of C-reactive protein levels compared with those who have the lowest quartile was 2.0 for men and 2.7 for women (9). Patients with unstable angina and increased C-reactive protein levels (>0.3 mg/dL [3.0 mg/L]) have higher rates of myocardial infarction, revascularization procedures, and death than have their matched cohorts (10). Increased C-reactive protein levels may be used to more powerfully predict vascular disease than undesirable lipid profiles (11). Although imaging techniques, such as electron-beam and multi–detector row computed tomography, can help to assess atherosclerotic plaque burden by means of quantification of calcium content, these techniques may compare less favorably with use of the C-reactive protein level in the prediction of actual adverse cardiovascular events (12). Convincing data exist for higher restenosis rates following angioplasty and stent insertion in the coronary and femoral arterial systems in patients with increased C-reactive protein levels (13,14).
In the prospective study by Schillinger et al (3), 89 patients underwent percutaneous transluminal angioplasty of arteries below the knee. In most cases, this procedure was performed in the distal popliteal artery. The authors measured C-reactive protein levels immediately before and after intervention and correlated the levels with 6-month patency rates determined with follow-up ankle-brachial index and findings at duplex ultrasonography. Follow-up also included a substantial number of corroborative arteriograms obtained in each patient. At a statistically significant level, C-reactive protein, both before and after intervention, negatively correlated with the ankle-brachial index at 6 months. When stratified according to range, the C-reactive protein level, with ranges of 0.23–0.92 mg/dL (2.3–9.2 mg/L), 0.92–2.42 mg/dL (9.2–24.2 mg/L), and greater than 2.42 mg/dL (24.2 mg/L), was used to predict a 3.7-, 4.7-, and 10.7-fold increase, respectively, in the risk for restenosis. A suboptimal angioplasty result achieved with 30%-40% residual stenosis at the treatment site also correlated with restenosis.
Findings in the article by Schillinger et al well complement a growing body of evidence that indicates the value of the C-reactive protein level in the prediction of restenosis rates in different vascular territories following vascular intervention. Two issues may possibly weaken the results of their study with presentation of possible confounding factors: the high rate of suboptimal angioplasty (56%) that could in itself lead to restenosis and the lack of correlation with patient medications that could alter the inflammatory response. Patients with peripheral vascular disease commonly receive antiplatelet and lipid-lowering statin medications, among others. All patients in the study of Schillinger et al (3) received a standard 100-mg dose of acetylsalicylic acid before and after endovascular intervention. The authors did not analyze this or other possible drug interactions. Acetylsalicylic acid may reduce C-reactive protein levels. The benefit of acetylsalicylic acid in prevention of myocardial infarction was related directly to baseline levels of C-reactive protein in one large randomized trial (15). In that study, the risk reduction for acetylsalicylic acid was 56% in men in the highest quartile of C-reactive protein levels. Statin therapy lowers C-reactive protein levels independent of its lipid-altering properties. Findings of a large prospective study (16) of coronary atherosclerosis demonstrated benefits of statin therapy in individuals with increased C-reactive protein levels and no overt hyperlipidemia. In that investigation, individuals with decreased low-density lipoprotein levels (ie, < 149 mg/dL [3.85 mmol/L]) but increased C-reactive protein levels (
0.16 mg/dL [1.6 mg/L]) had a more than twofold increased risk for future cardiovascular events compared with those with decreased low-density lipoprotein levels and decreased C-reactive protein levels. These researchers determined that despite the lack of hyperlipidemia in this risk category, lovastatin (Mevacor; Merck, West Point, Pa) therapy resulted in a risk reduction similar to that in the group with hyperlipidemia. Findings in a recently published article (17) showed the benefit (decreased clinical events and restenosis rates) of oral steroid therapy after coronary angioplasty and stent placement in patients with C-reactive protein levels greater than 0.5 mg/dL (5.0 mg/L). Exercise may have a beneficial effect on atherosclerosis because it helps to reduce inflammation, as indicated by decreased circulating C-reactive protein levels in patients who engage in vigorous physical activities (18).
Overwhelming evidence implicates inflammation as a component in vascular disease and in failures of percutaneous transluminal angioplasty. We now need more studies that include not only documentation of the role of inflammation in this process but also delineate pathophysiologic mechanisms and effective treatment options in patients we can now define as high risk.
FOOTNOTES
See also the article by Schillinger et al (pp 419–425 ) in this issue.
REFERENCES
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