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Articles |
1
Department of Cardiology, Lahey Clinic Medical Center, 41 Mall Rd., Burlington, MA 01805.
2
Center for Cardiovascular Disease Prevention, Harvard
Medical School and Brigham and Women’s Hospital, Boston, MA 02115.
3
Departments of Pathology and Laboratory Medicine,
Harvard Medical School and Children’s Hospital, Boston, MA 02115.
4
Department of Psychiatry, University of Pennsylvania
School of Medicine, Philadelphia, PA 19104.
5
Department of Neurology, Harvard Medical School and Beth
Israel Deaconess Medical Center, Boston, MA 02215.
6
Leducq Center for Molecular and Genetic Epidemiology of
Cardiovascular Disorders, Boston, MA 02115.
a Author for correspondence. Fax 781-744-5261; e-mail
hans.k.meierewert{at}lahey.org.
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Methods: To examine the existence of a time-of-day effect for baseline CRP values, we determined CRP concentrations in hourly blood samples drawn from healthy subjects (10 males, 3 females; age range, 21–35 years) during a baseline day in a controlled environment (8 h of nighttime sleep).
Results: Overall CRP concentrations were low, with only three subjects having CRP concentrations >2 mg/L. Comparison of raw data showed stability of CRP concentrations throughout the 24 h studied. When compared with cutoff values of CRP quintile derived from population-based studies, misclassification of greater than one quintile did not occur as a result of diurnal variation in any of the subjects studied. Nonparametric ANOVA comparing different time points showed no significant differences for both raw and z-transformed data. Analysis for rhythmic diurnal variation using a method fitting a cosine curve to the group data was negative.
Conclusions: Our data show that baseline CRP concentrations are not subject to time-of-day variation and thus help to explain why CRP concentrations are a better predictor of vascular risk than interleukin-6. Determination of CRP for cardiovascular risk prediction may be performed without concern for diurnal variation.
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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CRP is synthesized and secreted by the liver in response to cytokines, predominantly interleukin-6 (IL-6) (12)(13). Studies of inflammatory markers in healthy subjects have shown that the concentration of cytokines in plasma follows a diurnal variation (14)(15). The concentration of IL-6 has consistently been shown to be low in the morning and high just before bedtime when measured both in vivo (16)(17) or in stimulated blood samples ex vivo (18)(19)(20). This variation in the IL-6 concentration may reflect feedback inhibition of cytokine concentrations by endogenous cortisol, which is subject to circadian variation (21), although others have challenged this view (12)(22)(23).
The present study was designed to look for the presence of a diurnal variation in the concentrations of hs-CRP in healthy subjects using a newly available assay (7). Such variations may have important implications for the timing of blood sampling when measuring hs-CRP for the assessment of cardiovascular risk stratification.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The data presented in this report were taken from baseline nights from two different experimental protocols where, after the baseline period, subjects remained in the GCRC for 14–16 days participating in studies on the effects of shortened sleep duration. The baseline sleep periods were either 8.2 or 8 h/night. Throughout the 24 h of these test days, wakefulness was monitored polygraphically to ensure that subjects did not sleep outside of the scheduled nocturnal sleep period. Nutritionally balanced meals were provided at appropriate times for breakfast, lunch, and dinner (caffeine and alcohol were prohibited). Meals were prepared in the GCRC metabolic kitchen for the subjects and served at regular meal times. None of the subjects was permitted to have visitors during the portion of the protocol included in this report.
specimen sampling and processing
Blood was drawn via an indwelling forearm catheter at intervals of
15 or 30 min, depending on the protocol. Subjects remained in bed for
the collection period and were permitted out of bed only for bathroom
breaks.
Vacutainer Tubes with EDTA were used to collect the blood samples, and the samples were subsequently centrifuged immediately at 2600g for 7 min at 4 °C. After centrifugation, plasma was pipetted into polypropylene tubes and frozen to -70 °C for later assay. Hourly samples were used for the determination of CRP by an ultrasensitive latex-enhanced immunoassay (Dade Behring) (7). The day-to-day imprecision (CV) for the hs-CRP assay at concentrations of 0.6 and 12.6 mg/L was 8.8% and 4.3%, respectively.
data analysis
Missing values made up 5.8% of the total number of hs-CRP data
points, or 1.5 missing values per subject. Each individual time series
was displayed in a chronogram to inspect data for patterns, trends, and
outliers. Data points below the detection limit of the hs-CRP assay
(<0.2 mg/L) were converted to values of 0.1 mg/L (this was done for
only one subject). Outliers, defined as points more than 3 SD from the
subject’s mean score, were removed from analysis. Kruskal–Wallis
one-way ANOVA of ranks was performed to detect significant differences
for different time points in raw data and after transformation into
normalized scores.
For the analysis of a rhythmic diurnal variation, individual as well as combined raw data and normalized scores were submitted to a computer program (Chronolab 3.0) (24), which fit a single cosine curve to the data using linear regression techniques. The analysis yielded a value for "percent rhythm", explained by the fitted curve, and a P value for the "goodness-of-fit" statistic. The midline estimating statistic of rhythm (MESOR) is the value midway between the highest and the lowest values of the fitted cosine curve. Amplitude is the measure of one-half of the extent of the rhythmic change estimated by the fitted cosine curve. Acrophase represents the crest-time of the fitted cosine curve relative to a defined reference time point (e.g., the beginning of the sampling period), expressed in degrees (360 degrees = 24 h).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, and averaged data are shown in Fig. 2
.Only three subjects had hs-CRP concentrations >2 mg/L, and only one
subject had values >10 mg/L, probably reflecting the good general
health of the study population. On the other extreme, four subjects had
values consistently <0.5 mg/L, including one subject with all values
below the detection limit of the assay (<0.2 mg/L).
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The dashed lines in Fig. 1
represent cutoffs for the quintiles of
baseline hs-CRP concentrations derived from population studies
(25). Inspection of raw and combined data suggested that
overall there is little variation of hs-CRP concentrations from the
mean values over time, suggesting an absence of systematic variation in
hs-CRP over the course of a single 24-h day. Nonparametric
Kruskal–Wallis one-way ANOVA for detection of significant differences
between individual time points confirmed this observation. Testing was
negative for raw data and z-scores (H =
23.0, 23 degrees of freedom; P = 0.461).
Analysis for presence of a circadian rhythm in the data was performed
by submitting raw data and standardized scores to a program fitting a
cosine curve and testing for the likelihood that variation in the data
could be explained by this curve. Two subjects for whom removal of
outliers produced constant values throughout the 24-h period were
excluded from this analysis. Results for the group-averaged data are
displayed as rhythmograms in Fig. 2
. Statistical testing for
goodness of fit of the fitted cosine curve yielded nonsignificant
P values for raw (P = 0.492) and
standardized data (P = 0.897), failing to determine a
significant circadian pattern of variation in these data. When the
cosine-fitting function was applied to individual data series, the
goodness-of-fit statistic was significant (P <0.05) in 7 of
11 subjects. However, the amplitudes of the detected variations were
low (median amplitude, 0.2 mg/L), and acrophases of the detected
variations were distributed evenly across the nyclthemeron,
with five acrophase peaks occurring during the day (0900–2100) and six
at night (2100–0900).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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), significant misclassification is unlikely to occur. These data
demonstrate that hs-CRP testing in clinical situations can be performed
without regard to time of day. These findings, therefore, extend prior
studies that have demonstrated stable hs-CRP concentrations, not
considering time-of-day effects, over a 5-year follow-up period
(26). CRP measured in healthy subjects has been validated as a powerful predictor of future risk of myocardial infarction or stroke (25). This effect appears to be present even among very young populations (27). The current data demonstrating a lack of circadian variation for hs-CRP also help to explain why hs-CRP concentrations appear to be a better predictor of vascular risk than IL-6, an inflammatory marker with a shorter half-life and a well-documented circadian variation (16)(17).
Prior studies evaluating diurnal variation of CRP concentrations have been limited to patients with active rheumatoid arthritis and markedly increased CRP concentrations. Results of these studies have been conflicting (28)(29). Until recently, technology has not permitted measurement of the very low concentrations of CRP seen in healthy individuals (29). To our knowledge this is the first study to investigate the presence of variability in hs-CRP concentrations in healthy subjects.
The absence of a diurnal variation in hs-CRP concentrations across the
24-h sleep-wake cycle may have several explanations. Studies of the
appearance of CRP in plasma have shown that increased concentrations in
response to exogenous IL-6 administration occur 
6–12 h after IL-6
challenge (30)(31). This is consistent with data
on the increase of CRP after acute myocardial infarction
(32). A single study has examined the half-life of the
disappearance of allogeneic CRP in humans and found it to be
15–19 h, independent of underlying disease or degree of CRP
increase (33), whereas the measured decline of CRP
concentrations after acute myocardial infarction in an earlier
publication suggests an even longer plasma half-life (32).
The combined effects of delayed production and prolonged half-life
would thus dampen any variability in CRP concentrations attributable to
variation in IL-6.
The fact that cosine fitting detected a significant variation in some
subjects should not be construed as evidence for an underlying
significant diurnal rhythm. The detected variations were evenly
distributed in phase across the 24-h period, and the detected
amplitudes were low. Thus, when data for the group were averaged, all
systematic variability was lost (Fig. 2
).
In conclusion, no diurnal variation of hs-CRP concentrations was detected in hourly samples of 13 healthy subjects under baseline conditions in the course of 24 h. Thus, determination of hs-CRP for cardiovascular risk prediction can be performed without concern for time of day.
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Acknowledgments |
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Footnotes |
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References |
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, and granulocyte-macrophage colony-stimulating factor in adult men. Chronobiol Int 1995;12:19-27.[Web of Science][Medline]
[Order article via Infotrieve]
(TNF ) production in humans: high sensitivity of TNF and resistance to IL-6. J Clin Endocrinol Metab 1997;82:2182-2191.The following articles in journals at HighWire Press have cited this article:
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  J. A Alvarez, P. B Higgins, R. A Oster, J. R Fernandez, B. E Darnell, and B. A Gower Fasting and postprandial markers of inflammation in lean and overweight children Am. J. Clinical Nutrition, April 1, 2009; 89(4): 1138 - 1144. [Abstract] [Full Text] [PDF]
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 S. S. Boekhoorn, J. R. Vingerling, J. C. M. Witteman, A. Hofman, and P. T. V. M. de Jong C-reactive Protein Level and Risk of Aging Macula Disorder: The Rotterdam Study Arch Ophthalmol, October 1, 2007; 125(10): 1396 - 1401. [Abstract] [Full Text] [PDF]
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 I. Barutcu, A. T. Sezgin, N. Sezgin, H. Gullu, A. M. Esen, E. Topal, R. Ozdemir, F. Kosar, and S. Cehreli Increased High Sensitive CRP Level and Its Significance in Pathogenesis of Slow Coronary Flow Angiology, September 1, 2007; 58(4): 401 - 407. [Abstract] [PDF]
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 S. M. Zhang, J. Lin, N. R. Cook, I-M. Lee, J. E. Manson, J. E. Buring, and P. M. Ridker C-Reactive Protein and Risk of Breast Cancer J Natl Cancer Inst, June 6, 2007; 99(11): 890 - 894. [Abstract] [Full Text] [PDF]
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D. A. Schaumberg, W. G. Christen, J. E. Buring, R. J. Glynn, N. Rifai, and P. M. Ridker High-Sensitivity C-Reactive Protein, Other Markers of Inflammation, and the Incidence of Macular Degeneration in Women Arch Ophthalmol, March 1, 2007; 125(3): 300 - 305. [Abstract] [Full Text] [PDF]
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 A. R. Rudnicka, A. Rumley, G. D.O. Lowe, and D. P. Strachan Diurnal, Seasonal, and Blood-Processing Patterns in Levels of Circulating Fibrinogen, Fibrin D-Dimer, C-Reactive Protein, Tissue Plasminogen Activator, and von Willebrand Factor in a 45-Year-Old Population Circulation, February 27, 2007; 115(8): 996 - 1003. [Abstract] [Full Text] [PDF]
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 T. A. Lakka, T. Rankinen, T. Rice, A. S. Leon, D. C. Rao, J. S. Skinner, and C. Bouchard Quantitative trait locus on chromosome 20q13 for plasma levels of C-reactive protein in healthy whites: the HERITAGE Family Study Physiol Genomics, October 11, 2006; 27(2): 103 - 107. [Abstract] [Full Text] [PDF]
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 M. Soinio, J. Marniemi, M. Laakso, S. Lehto, and T. Ronnemaa High-Sensitivity C-Reactive Protein and Coronary Heart Disease Mortality in Patients With Type 2 Diabetes: A 7-year follow-up study Diabetes Care, February 1, 2006; 29(2): 329 - 333. [Abstract] [Full Text] [PDF]
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 T Sturmer, E Raum, M Buchner, K Gebhardt, M Schiltenwolf, W Richter, and H Brenner Pain and high sensitivity C reactive protein in patients with chronic low back pain and acute sciatic pain Ann Rheum Dis, June 1, 2005; 64(6): 921 - 925. [Abstract] [Full Text] [PDF]
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 M. Di Napoli, M. Schwaninger, R. Cappelli, E. Ceccarelli, G. Di Gianfilippo, C. Donati, H. C.A. Emsley, S. Forconi, S. J. Hopkins, L. Masotti, et al. Evaluation of C-Reactive Protein Measurement for Assessing the Risk and Prognosis in Ischemic Stroke: A Statement for Health Care Professionals From the CRP Pooling Project Members Stroke, June 1, 2005; 36(6): 1316 - 1329. [Abstract] [Full Text] [PDF]
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E. K. Larkin, C. L. Rosen, H. L. Kirchner, A. Storfer-Isser, J. L. Emancipator, N. L. Johnson, A. M. V. Zambito, R. P. Tracy, N. S. Jenny, and S. Redline Variation of C-Reactive Protein Levels in Adolescents: Association With Sleep-Disordered Breathing and Sleep Duration Circulation, April 19, 2005; 111(15): 1978 - 1984. [Abstract] [Full Text] [PDF]
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G. L. Myers, N. Rifai, R. P. Tracy, W. L. Roberts, R. W. Alexander, L. M. Biasucci, J. D. Catravas, T. G. Cole, G. R. Cooper, B. V. Khan, et al. CDC/AHA Workshop on Markers of Inflammation and Cardiovascular Disease: Application to Clinical and Public Health Practice: Report From the Laboratory Science Discussion Group Circulation, December 21, 2004; 110(25): e545 - e549. [Full Text] [PDF]
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P Z Hrycaj, T Sturmer, H Brenner, W Koenig, and K P Gunther Systemic inflammation in osteoarthritis * Authors' reply Ann Rheum Dis, June 1, 2004; 63(6): 750 - 751. [Full Text]
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 R. Orvieto, R. Chen, J. Ashkenazi, A. Ben-Harush, J. Bar, and B. Fisch C-reactive protein levels in patients undergoing controlled ovarian hyperstimulation for IVF cycle Hum. Reprod., February 1, 2004; 19(2): 357 - 359. [Abstract] [Full Text] [PDF]
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T Sturmer, H Brenner, W Koenig, and K-P Gunther Severity and extent of osteoarthritis and low grade systemic inflammation as assessed by high sensitivity C reactive protein Ann Rheum Dis, February 1, 2004; 63(2): 200 - 205. [Abstract] [Full Text] [PDF]
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K. C.B. Tan, W.-S. Chow, S. Tam, R. Bucala, and J. Betteridge Association Between Acute-Phase Reactants and Advanced Glycation End Products in Type 2 Diabetes Diabetes Care, January 1, 2004; 27(1): 223 - 228. [Abstract] [Full Text] [PDF]
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S. Kinlay, G. G. Schwartz, A. G. Olsson, N. Rifai, S. J. Leslie, W. J. Sasiela, M. Szarek, P. Libby, P. Ganz, and for the Myocardial Ischemia Reduction with Aggress High-Dose Atorvastatin Enhances the Decline in Inflammatory Markers in Patients With Acute Coronary Syndromes in the MIRACL Study Circulation, September 30, 2003; 108(13): 1560 - 1566. [Abstract] [Full Text] [PDF]
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T. B. Ledue and N. Rifai Preanalytic and Analytic Sources of Variations in C-reactive Protein Measurement: Implications for Cardiovascular Disease Risk Assessment Clin. Chem., August 1, 2003; 49(8): 1258 - 1271. [Abstract] [Full Text] [PDF]
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M. F. Carroll and D. S. Schade Timing of Antioxidant Vitamin Ingestion Alters Postprandial Proatherogenic Serum Markers Circulation, July 8, 2003; 108(1): 24 - 31. [Abstract] [Full Text] [PDF]
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E. T.H. Yeh and J. T. Willerson Coming of Age of C-Reactive Protein: Using Inflammation Markers in Cardiology Circulation, January 28, 2003; 107(3): 370 - 371. [Full Text] [PDF]
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T. A. Pearson, G. A. Mensah, R. W. Alexander, J. L. Anderson, R. O. Cannon III, M. Criqui, Y. Y. Fadl, S. P. Fortmann, Y. Hong, G. L. Myers, et al. Markers of Inflammation and Cardiovascular Disease: Application to Clinical and Public Health Practice: A Statement for Healthcare Professionals From the Centers for Disease Control and Prevention and the American Heart Association Circulation, January 28, 2003; 107(3): 499 - 511. [Full Text] [PDF]
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 P. M. Ridker, N. Rifai, L. Rose, J. E. Buring, and N. R. Cook Comparison of C-Reactive Protein and Low-Density Lipoprotein Cholesterol Levels in the Prediction of First Cardiovascular Events N. Engl. J. Med., November 14, 2002; 347(20): 1557 - 1565. [Abstract] [Full Text] [PDF]
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D. L. Bhatt and E. J. Topol Need to Test the Arterial Inflammation Hypothesis Circulation, July 2, 2002; 106(1): 136 - 140. [Full Text] [PDF]
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A. S.M. Shamsuzzaman, M. Winnicki, P. Lanfranchi, R. Wolk, T. Kara, V. Accurso, and V. K. Somers Elevated C-Reactive Protein in Patients With Obstructive Sleep Apnea Circulation, May 28, 2002; 105(21): 2462 - 2464. [Abstract] [Full Text] [PDF]
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P. Libby, P. M. Ridker, and A. Maseri Inflammation and Atherosclerosis Circulation, March 5, 2002; 105(9): 1135 - 1143. [Abstract] [Full Text] [PDF]
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M. Frohlich, M. Sund, B. Thorand, W. L. Hutchinson, M. B. Pepys, and W. Koenig Lack of Seasonal Variation in C-Reactive Protein Clin. Chem., March 1, 2002; 48(3): 575 - 577. [Full Text] [PDF]
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 M. A Vickers, F. R Green, C. Terry, B. M Mayosi, C. Julier, M. Lathrop, P. J Ratcliffe, H. C Watkins, and B. Keavney Genotype at a promoter polymorphism of the interleukin-6 gene is associated with baseline levels of plasma C-reactive protein Cardiovasc Res, March 1, 2002; 53(4): 1029 - 1034. [Abstract] [Full Text] [PDF]
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P. M. Ridker High-Sensitivity C-Reactive Protein : Potential Adjunct for Global Risk Assessment in the Primary Prevention of Cardiovascular Disease Circulation, April 3, 2001; 103(13): 1813 - 1818. [Abstract] [Full Text] [PDF]
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