Our study shows significant temporal variation in hs-CRP levels over 24 hours, whether patients had CAD or normal coronary arteries. Morning hs-CRP was markedly higher than at other sampling times in all 3 groups. Moreover, different cutoff hs-CRP values for samples taken at different times had similar sensitivities and specificities for predicting severe CAD.
In our study, patients with stable CAD had significantly elevated hs-CRP levels regardless of the sampling time, which is in accordance with previous studies that reported high hs-CRP levels in stable and unstable patients alike.4,6,9,11,12
Our investigation of sampling time of hs-CRP revealed high hs-CRP at all measurement times in patients with mild and severe CAD.
To the best of our knowledge, temporal hs-CRP variation in patients with CAD had not previously been investigated over a time frame such as ours. The available data on diurnal variations of hs-CRP levels in healthy subjects are few and controversial. A recent study13
of hs-CRP, D-dimer, tissue plasminogen activator, and von Willebrand factor in a middle-aged population showed diurnal variation as high as 34% in hs-CRP, with maximum hs-CRP levels observed at 3 PM. However, that study was limited in that hs-CRP was measured between 9 AM and 10 PM. In our study, we measured hs-CRP 4 times over 24 hours at 6-hour intervals, and we observed the highest levels of hs-CRP in the morning, with a variation of 86%. These results also held true for our 30 patients who had normal coronary arteries. Previously, Meier-Ewert and colleagues14
found no diurnal variation in hs-CRP samples that were taken hourly from 13 healthy subjects. The variation in our study could be due to cardiovascular factors in all patients—even in those with normal coronary arteries—because such risk factors as obesity, hypertension, diabetes mellitus, and smoking have been shown to induce hs-CRP secretion.6
A high baseline level of hs-CRP has been associated with the severity and prognosis of coronary atherosclerosis in patients who have stable CAD.5–8
To indicate a high risk of CAD in adults without known cardiovascular disease, the AHA/CDC recommended a CRP cutoff value of 3 mg/L.9
Likewise, Sabatine and associates6
showed that an hs-CRP cutoff value of more than 3 mg/L predicted a 78% increased risk of adverse cardiovascular events in patients with stable CAD. Another study17
showed that hs-CRP is an independent predictor of CAD in patients with diabetes, and the cutoff value was determined to be 5.2 mg/L. In our study, our respective cutoff values of 5.5 mg/L, 3 mg/L, 3.5 mg/L, and 4.5 mg/L for morning, midday, evening, and midnight samplings strongly predicted severe CAD.
The number of angiographically detected critical coronary artery stenoses is a predictor of unfavorable events in patients with CAD.18
In previous studies,11,19
no significant association was reported between baseline serum CRP levels and CAD severity or the extent of disease in patients with unstable CAD. This may be related to lesion morphology and vulnerability. Conversely, in a large study of patients with stable CAD, Zebrack and colleagues5
reported a weak but significant correlation between hs-CRP and CAD severity. Our results similarly showed an independent relationship between midnight hs-CRP levels and severe CAD. Furthermore, all cutoff values of our temporal hs-CRP measurements predicted severe CAD with similar sensitivity and specificity.
Limitations of the Study
Our study is limited in several ways. The sample population was relatively small, considering the prevalence of CAD in any community. Whereas we measured hs-CRP 4 times during a 24-hour period, hourly measurements may more precisely disclose round-the-clock variations in hs-CRP levels. (Of note, hourly or more frequent sampling would be more costly, and arguably unethical because of frequent venipunctures.) In support of our quadripartite testing over 1 day, almost all of our patients had consistent hs-CRP measurements during a particular sampling time, so we conclude that our approach was sufficient and not of major concern. All of our patients were in stable overall condition, and all were on optimal medical regimens for their cardiovascular conditions. The individualized therapy involved different medications and dosages, which may have influenced hs-CRP levels,6
and we did not consider medications in our analyses. Furthermore, our CAD-severity groups differed greatly regarding age, sex, and treatment. Although these factors were adjusted in the analyses, it is a major concern that the severity groups were unmatched for these variables. Finally, because stable CAD and acute coronary syndromes have different pathogeneses, it remains to be determined whether our results would apply to patients with unstable angina pectoris and acute myocardial infarction.
This is the 1st study to show variation of hs-CRP levels in patients with stable CAD at 6-hour intervals over a 24-hour period. We have shown that the sampling time of hs-CRP is important, because only midnight hs-CRP measurements predicted severe CAD in our study population. This aside, when different cutoff values were applied to particular sampling times, severe CAD was predicted with similar sensitivity and specificity. Whether our results apply to other forms of CAD needs to be confirmed in future study populations.