We read the report by Makrygiannis et al regarding the prognostic usefulness of serial C-reactive protein (CRP) measurements in patients with ST-segment elevation acute myocardial infarction. The investigators recruited a total of 861 consecutive patients admitted for ST-segment elevation myocardial infarction and treated with intravenous thrombolysis, from whom blood samples to assess CRP were obtained at presentation and at 24, 48, and 72 hours. The investigators concluded that CRP levels at presentation represent an independent predictor for fatal and nonfatal events during long-term follow-up. In addition, CRP levels at 48 and 72 hours independently predicted only cardiac death. However, in their study, the investigators did not take into account the diurnal fluctuations in this marker.

In 1 of the largest cross-sectional studies published in the field, Rudnicka et al evaluated diurnal fluctuations in CRP in 9,377 men and women aged 45 years. After adjustment for standard cardiovascular risk factors, the amplitude of diurnal variation was 35% for CRP. Moreover, our group demonstrated that patients with acute coronary syndromes have daytime variations in serum CRP concentrations. Serum CRP values were significantly higher during the light phase (9 a.m ) compared with the dark phase (2 a.m ). Recently, Koc et al described measurements of CRP over a 24-hour cycle in 124 Turkish patients with and without coronary artery disease. They demonstrated variation of CRP in patients with stable coronary artery disease at 6-hour intervals over a 24-hour period. They also showed that the sampling time of CRR is important, because only midnight CRP measurements predicted severe coronary artery disease.

Circulating biomarkers are subject to variability arising from sampling procedures and biologic variation, and this variability must be determined and adjusted for in the interpretation of laboratory results. In summary, temporal variation is an important source of heterogeneity that may bias the analysis of epidemiologic studies and coronary artery disease risk prediction.