Response to Kholeif et al.
We appreciate the comments of Dr. Kholeif (1) regarding the utility of C-reactive protein (CRP) measurement in stratifying cardiovascular disease (CVD) risk as it relates to our report of patients with the metabolic syndrome (2). While our data must be interpreted cautiously because they are of a cross-sectional nature, our findings are consistent with those of Ridker et al. (3) showing metabolic syndrome patients with elevated CRP levels to have a less optimistic prognosis than those with normal CRP levels.
We agree with Dr. Kholeif that a single CRP measurement, given its intraindividual biological variability, is not suitable and that the use of multiple measures would establish the certainty of a given level. Our study relied on the single measurement provided by the National Health and Nutrition Examination Survey (NHANES) study and thus did not have duplicate measures over time. Recently, the Centers for Disease Control (CDC)/American Heart Association (AHA) workshop on markers of inflammation and cardiovascular disease did recommend that the mean of only two measures taken 2 weeks apart could be averaged to provide a clinically useful value (4). We also agree that high-sensitivity CRP assays are critical for examining the range over which CHD risk varies; our NHANES report did utilize high-sensitivity CRP measures as recommended by the CDC/AHA statement on the use of CRP in cardiovascular risk stratification (5).
We agree with Dr. Kholeif that more accurate risk assessment might be possible if CRP were regarded as a continuum and included within Framingham risk or other global risk algorithms modeling 10-year risk of coronary heart disease, for example, as Ridker et al. (5) have recommended. Until this is done, however, we feel that the CDC/AHA cut points (6) for categorizing CRP into normal (<1 mg/l), borderline (1–3 mg/l), and high-risk (>3 mg/l) levels are appropriate for stratifying patient risk in combination with Framingham risk estimates or other risk factor information such as LDL cholesterol levels.
We also agree with the CDC/AHA statement regarding the appropriateness of screening those at intermediate global risk for CRP. Given this, many such persons with metabolic syndrome would be indicated for possible screening by CRP to better identify their CVD risk where Framingham or other global risk algorithms may fail to fully address risk given their exclusion of abdominal obesity, elevated triglycerides, and glucose intolerance. Of note is that we have also shown that many with metabolic syndrome have subclinical atherosclerosis (defined by having significant levels of coronary calcium) regardless of estimated Framingham risk. While ∼20% of such patients have >20% 10-year CHD risk, ∼40% have significant calcium and/or >20% 10-year risk (7), indicating the need to better identify those at significant CVD risk beyond what global risk assessment provides. Nonetheless, we agree that more work from clinical trials is needed to establish whether intervention targeting “high-risk” metabolic syndrome patients, identified either on the basis of elevated CRP or other screening tests, effectively lowers CVD risk.