As described in the 2009 Canadian Cardiovascular Society Guidelines for the Diagnosis and Treatment of Dyslipidemia and Prevention of Cardiovascular Disease in the Adult, the inflammatory biomarker high-sensitivity C-reactive protein (hs-CRP) is now recognized as a major cardiovascular risk factor and as a secondary target for statin therapy.1 This important change in prevention guidelines reflects data from the recent JUPITER trial of apparently healthy men and women with hs-CRP levels greater than 2 mg/L who did not otherwise qualify for statin therapy because of “low” absolute risk, as calculated by traditional risk algorithms and native low-density-lipoprotein cholesterol levels below 130 mg/dL. Nonetheless, in comparison with the administration of a placebo, the JUPITER investigators' allocation of such patients to 20 mg of rosuvastatin resulted in a 44% reduction in the primary trial endpoint of major vascular events (P <0.00001), a 54% reduction in myocardial infarction (P=0.0002), a 48% reduction in stroke (P=0.002), a 46% reduction in the need for angioplasty or bypass surgery (P <0.0001), and a 20% reduction in all-cause death (P=0.02).2 These risk reductions were observed at all levels of Framingham Risk—among 6,091 persons in JUPITER with elevated hs-CRP but Framingham Risk Scores of 5% to 10%, a 45% reduction in major vascular events was observed (hazard ratio, 0.55; 95% confidence interval, 0.36–0.84; P=0.005), whereas among 7,340 persons with elevated hs-CRP but Framingham Risk Scores of 11% to 20%, a 49% reduction in major vascular events was observed (hazard ratio, 0.51; 95% confidence interval, 0.39–0.68; P=0.0001). On the basis of these and other data, the 2009 National Academy of Clinical Biochemistry Laboratory Medicine Practice Guidelines included and endorsed the use of hs-CRP as a novel means by which to identify individuals who are at high risk for vascular disease.3
Two papers in this issue of the Texas Heart Institute Journal deal with clinical issues that relate to the use of hs-CRP in cardiovascular practice. In the first,4 Koc and colleagues describe measurements of hs-CRP over a 24-hour cycle in 124 Turkish patients with and without coronary artery disease. Whereas prior reports have shown no evidence of diurnal variation in hs-CRP in healthy men and women, a modest variation was observed in the Turkish participants with atherosclerosis, particularly in those who had increasingly more severe forms of coronary disease. Because hs-CRP levels are known to increase with acute ischemia, one explanation for this potential difference between healthy persons and those with severe stenosis is that the individuals with stenosis may be experiencing silent ischemia as they perform their usual daily activities. Consistent with prior work that describes a circadian variation in the time of onset of acute myocardial infarction that is maximal early in the morning, Koc and colleagues report highest levels of hs-CRP in the morning. This issue is of potential pathophysiologic interest, because aspirin—an agent that is known to moderate inflammation—is also most effective in the early morning.5 Koc and co-authors acknowledge that these small differences are unlikely to have substantive clinical impact, because most patients are screened in the morning while fasting, and levels of hs-CRP are consistently high in patients who have mild or severe coronary artery disease, regardless of the time of day when sampling occurs. This finding is consistent with multiple reports that the day-to-day, month-to-month, and year-to-year variation in hs-CRP is similar to that of cholesterol and blood pressure.6
In the second paper,7 Li and associates provide a meta--analysis that evaluates the impact of preprocedural hs-CRP levels on in-stent restenosis (ISR) after stenting in patients who have unstable coronary artery disease. Upon analysis of 9 studies that comprised more than 1,000 patients, these investigators found that hs-CRP levels were significantly higher in patients who subsequently developed ISR than in those who did not, an effect that was even larger when 2 studies with heterogeneity were excluded. The data from Li and co-authors are consistent with prior work that showed the relation of elevated hs-CRP and poor outcomes in the setting of acute coronary syndrome and bypass surgery, and therefore their meta-analysis provides corroborative data that describe the importance of inflammation in multiple vascular situations. With specific regard to ISR, the data are also of interest, because the 2 major approaches to reducing ISR after angioplasty have been the application of localized radiation therapy and the use of sirolimus-coated stents. Radiation and sirolimus are both potent anti-inflammatory interventions that inhibit neointimal proliferation and slow late vascular remodeling.
Whether targeted anti-inflammatory therapy can or cannot reduce vascular-event rates remains a matter of controversy. Multiple interventions to directly test the inflammatory hypothesis of atherosclerosis have been proposed, including novel agents that inhibit CRP directly, agents that inhibit upstream inflammatory cytokines and chemokines, and vaccination strategies. An approach now being considered by the Cardiovascular Inflammation Reduction Trial (CIRT) investigators is to use very low-dosage methotrexate (10 mg weekly). Methotrexate at this dosage, which is widely used to treat rheumatoid arthritis and psoriasis, has a well-known toxicity profile and is a highly effective anti-inflammatory agent.8 Trials such as CIRT will be crucial toward moving the inflammatory hypothesis of atherosclerosis forward. If CIRT results in the anticipated outcome, it will lead to broad pharmaceutical interest in the development of novel therapies that directly inhibit inflammation and atherosclerosis at the level of the vascular endothelium.