these patients results in reduced heart rates and improved cardiovascular efficiency during usual daily
activities.
This is only the second report providing a systematic evaluation of the effects of programmed training
on aerobic capacity after the Fontan operation. Minamisawa et al20 reported on a 2- to 3-month exercise
training program (walking or jogging) held 2 or 3
times a week for 20 to 30 minutes in 19 teens and
young adults after the Fontan operation. The exercise
training in these patients resulted in an increase in
maximal oxygen consumption (7%) and exercise time
(4%). They also observed that heart rate tended to
decrease during small workloads after training and
oxygen pulse tended to increase. Our findings are
similar but of greater magnitude, probably because the
training period was longer. Further, we found definite
improvement in cardiovascular efficiency at small
workloads. In addition to the longer training program,
these differences may be due to the personalized prescription of the exercise program, including a specific
target heart rate range.
Acknowledgment: We gratefully acknowledge
Francesca Forner, Francesca Gasbarro, and Professor
Giorgio Andreaggi for their excellent assistance during the exercise training session and Cecilia Giron,
MD, for the statistical analysis.
1. Driscoll DJ, Danielson GK, Puga FJ, Schaff HV, Heise CT, Staats BA.
Exercise tolerance and cardiorespiratory response to exercise after the Fontan
operation for tricuspid atresia or functional single ventricle. J Am Coll Cardiol
1986;7:1087–1094.
2. Goldberg B, Fripp RR, Lister G, Loke J, Nicholas JA, Talner NS. Effect of
physical training on exercise performance of children following surgical repair of
congenital heart disease. Pediatrics 1981;68:691– 699.
3. Gewelling MH, Lundstrom UR, Bull C, Wyse RKH, Deanfield JE. Exercise
response in patients with congenital heart disease after Fontan repair: patterns and
determinants of performance. J Am Coll Cardiol 1990;15:1424 –1432.
4. Troutman WB, Barstow TJ, Galindo AJ, Cooper DM. Abnormal dynamic
cardiorespiratory responses to exercise in pediatric patients after Fontan procedure. J Am Coll Cardiol 1998;31:668 – 673.
5. Picchio FM, Colonna PL, Daliento L, Ginnico S, Pelliccia S, Vergari B,
Vignati G. Linee guida: criteri di valutazione della capacità lavorativa, idoneità al
lavoro specifico, attitudine ed attività fisica e sportiva ed assicurabilità nel
cardiopatico congenito. Ital Heart J Suppl 2001;2:46 –77.
6. Miyairi T, Kawauchi M, Takamoto S, Morizuki O, Furuse A. Oxygen utilization and hemodynamic response during exercise in children after Fontan
procedure. Jpn Heart J 1998;39:659 – 669.
7. Ruttemberg HD, Adams TD, Orsmond GS, Conlee RK, Fisher AG. Effects of
exercise training on aerobic fitness in children after open heart surgery. Ped
Cardiol 1983;4:19 –24.
8. Balfour IC, Drimmer AM, Nouri S, Pennington DG, Hemkens CL, Harvey LL.
Pediatric cardiac rehabilitation. Am J Dis Child 1991;145:627– 630.
9. de Leval MR. The Fontan circulation: what have we learned? What to expect?
Pediatr Cardiol 1998;19:316 –320.
10. Rosenthal M, Bush A, Deanfield J, Redington A. Comparison of cardiopulmonary adaptation during exercise in children after the atriopulmonary and total
cavopulmonary connection Fontan procedures. Circulation 1995;91:372–378.
11. Driscoll DJ, Offord KP, Feldt RH, Schaff HV, Puga FJ, Danielson GK. Fiveto fifteen-year follow-up after Fontan operation. Circulation 1992;85:469 – 496.
12. Adamopolulos S, Parissis JT, Kremastinos DT. New aspects for the role of
physical training in the management of patients with chronic heart failure. Int
J Cardiol 2003;90:1–14.
13. Sullivian MJ, Higginbotham MB, Cobb FR. Exercise training in patients with
severe left ventricular dysfunction. Hemodynamic and metabolic effects. Circulation 1988;78:506 –515.
14. Sullivian MJ, Higginbotham MB, Cobb FR. Exercise training in patients with
chronic heart failure delays ventilatory anaerobic threshold and improves submaximal exercise performance. Circulation 1989;79:324 –329.
15. Coats ATS, Adamopolulos S, Meyer TE, Conway J, Sleight P. Effects of
physical training in chronic heart failure. Lancet 1990;335:63– 66.
16. Coats AJ. Exercise and heart failure. Cardiol Clin 2001;19:517–524.
17. Belardinelli R, Georgiou D, Cianci G, Purcaro A. Randomized, controlled
trial of long-term moderate exercise training in chronic heart failure, effects on
functional capacity, quality of life and clinical outcome. Circulation 1999;99:
1173–1182.
18. Belardinelli R, Georgiou D, Scocco V, Barstow TJ, Purcaro A. Low intensity
exercise training in patients with chronic heart failure. J Am Coll Cardiol
1995;26:975–982.
19. Durongpisitkul K, Driscoll DJ, Mahoney DW, Wollan PC, Mottran CD,
Puga FJ, Danielson GK. Cardiorespiratory response to exercise after modified
Fontan operation: determinants of performance. J Am Coll Cardiol 1997;29:
785–790.
20. Minamisawa S, Nakazawa M, Momma K, Imai Y, Satomi G. Effect of
aerobic training on exercise performance in patients after the Fontan operation.
Am J Cardiol 2001;88:695– 698.
Values of High-Sensitivity C-Reactive Protein in Each
Month of the Year in Apparently Healthy Individuals
Ori Rogowski, MD, Sharon Toker, MSc, Itzhak Shapira, MD, Samuel Melamed,
Arie Shirom, PhD, David Zeltser, MD, MPH, and Shlomo Berliner, MD, PhD
The serum levels of high-sensitivity C-reactive protein
were determined during a 12-month period. No seasonal variation was found in a group of 1,677 apparently healthy patients in whom the presence of
clinically evident infection or inflammation was exFrom the Department of Medicine “D” and Institute for Special Medical
Examinations (MALRAM), Tel Aviv Sourasky Medical Center, Tel Aviv;
and the National Institute of Occupational & Environmental Health,
Raanana, Israel. Dr. Berliner’s address is: Department of Internal
Medicine “D,” Tel-Aviv Sourasky Medical Center, 6 Weizman Street,
Tel Aviv 64239, Israel. E-mail: [email protected]. Manuscript received April 14, 2004; revised manuscript received and
accepted August 16, 2004.
152
©2005 by Excerpta Medica Inc. All rights reserved.
The American Journal of Cardiology Vol. 95 January 1, 2005
PhD,
cluded by an appropriate questionnaire. 䊚2005 by
Excerpta Medica Inc.
(Am J Cardiol 2005;95:152–155)
t has been repeatedly shown that high-sensitivity Creactive protein (hs-CRP) is a useful marker for the
Ipresence
of low-grade inflammation in apparently
healthy patients.1 The determination of hs-CRP in these
patients has been shown to have significant prognostic
implications in terms of future cardiovascular events.2 In
this regard, it is important to determine whether the
concentration of this protein changes during the winter
season, when respiratory tract infections are more prevalent
and could have an influence on the results of hs-CRP.
0002-9149/05/$–see front matter
doi:10.1016/j.amjcard.2004.08.086
FIGURE 1. Mean hs-CRP of each day during the year in women.
FIGURE 2. Mean hs-CRP of each day during the year in men.
TABLE 1 Mean ⫾ SD (median) of hs-CRP in Each Month in
Men and Women
Month
January
February
March
April
May
June
July
August
September
October
November
December
Women
1.91
2.08
1.74
1.37
1.82
1.42
1.49
1.46
1.96
1.66
1.84
1.73
⫾
⫾
⫾
⫾
⫾
⫾
⫾
⫾
⫾
⫾
⫾
⫾
3.02
3.40
3.30
3.90
3.34
3.14
3.02
3.48
3.49
2.90
3.03
3.11
Men
(1.71)
(1.67)
(1.79)
(1.16)
(2.21)
(1.50)
(1.53)
(1.41)
(2.29)
(1.52)
(1.75)
(1.90)
1.43
1.49
1.31
1.72
1.31
1.53
1.25
1.55
1.34
1.48
1.46
1.53
⫾
⫾
⫾
⫾
⫾
⫾
⫾
⫾
⫾
⫾
⫾
⫾
2.34
2.75
3.00
2.51
2.70
2.85
2.76
2.84
2.71
2.55
2.75
2.85
(1.46)
(1.43)
(1.27)
(1.84)
(1.25)
(1.51)
(1.23)
(1.22)
(1.22)
(1.49)
(1.36)
(1.46)
•••
We used information obtained from the Tel Aviv
Medical Center Inflammation Survey,3 a relatively
large cohort of apparently healthy patients who are
evaluated during their annual checkups. The main
advantage of this cohort is that we excluded any
patient who had an infective or inflammatory condition during a 6-month period before his or her recruitment. This approach enabled us to examine the even-
tual changes in the concentration of
this protein, not necessarily at the
prevalence of intercurrent infections
in the population.
Patients attending the Tel Aviv
Sourasky Medical Center for routine
health examination from December 1,
2002, to November 31, 2003 were included. A total of 2,053 subjects
agreed (1,195 men, 858 women),
yielding a compliance rate of 88%.
Systematic examination of the reasons
for participation yielded no effect of
sociodemographic or biomedical variables. An additional 376 subjects were
later excluded from the analysis because of known inflammatory diseases
(arthritis, inflammatory bowel disease,
etc.), pregnancy, steroidal or nonsteroidal treatment (except aspirin at a
dose of ⱕ325 mg/dl), acute infection,
or invasive procedures (surgery, catheterization, etc.) during the previous 6
months, or missing data for 1 of the
study parameters. The study was approved by the local ethics committee.
We determined hs-CRP using the
Behring BN II (Dade Behring Holding
GmbH, Marburg, Germany) nephelometer and a method described by
Rifai et al.4
Statistical analysis was performed
separately for men and women. The
hs-CRP levels had a non-normal distribution, so we used a logarithmic
transformation, and all the results expressed as hs-CRP are back-transformed as geometric means, SDs, SEMs, and medians.
All data were summarized and are displayed as mean ⫾
SD or mean ⫾ SE of the mean for hs-CRP. Participants
were divided first into groups on the basis of the months
of the year. A 1-way analysis of variance was performed
to compare log(hs-CRP) among the months of the year
for the 2 genders. The Ryan-Einot-Gabriel-Welsch multiple range test was used for pairwise comparison among
months. Participants were later grouped on the basis of
the 4 seasons of the year to evaluate whether there was a
difference among the seasons. Again, 1-way analysis of
variance and the Ryan-Einot-Gabriel-Welsch multiple
range test were used. In addition, we used the locally
weighted scatterplot smoothing procedure with a
smoothing parameter of 0.5 for the data divided by
month, and finally, we used a rhythm analysis in which
we found the best match between the hs-CRP data points
and the sinus curve using the least-squares method to
find the maximum and minimum dates. The level of
significance used for all analyses was a 2-tailed p value
⬍0.05. The SPSS statistical package (SSPS, Inc., Chicago, Illinois) and the SAS system (SAS Institute Inc.,
Cary, North Carolina) for Windows were used to perform all statistical evaluations.
We included a cohort of 1,677 patients (mean age
BRIEF REPORTS
153
onstrated that there was a significant
difference between men and women.
In women, the maximum point of the
fitted sinus curve was at the end of
December (winter) and the minimum
point at the end of June (summer),
whereas in men, the maximum was in
mid-April and the minimum in midOctober. Because there was no significant difference among the months of
the year, the maximum and minimum
points of the fitted sinus curves could
be a matter of chance.
•••
hs-CRP is an established cardiovascular risk factor and a useful
marker for future events.5,6 Moreover,
FIGURE 3. Mean ⴞ SE of mean of hs-CRP in men and women grouped by month of
recent studies have suggested that it
the year. All significance between the months in each gender are not significant.
might be not only a biomarker but
can also affect the process of atherothrombosis.7–15 Thus, the question of
whether hs-CRP concentration is enhanced during periods of prevalent infections in the population is relevant
for epidemiologic studies in which
high-risk patients are singled out by
this biomarker.
The question of seasonal variation
in hs-CRP concentrations has been addressed in the past by several investigators. Fröhlich et al16 found no
strong, consistent evidence for intraand interpatient seasonal variation of
CRP, except for men in the third Monitoring Cardiovascular Disease study,
for whom a seasonal difference was
found, with the largest CRP values
observed in May. However, the invesFIGURE 4. Mean ⴞ SE of mean of hs-CRP in men and women grouped by season of
tigators found a statistically significant
the year. All significance between the seasons in each gender are not significant.
lack of fit of the data, which could
indicate that their model was not ap47.1 ⫾ 11.2 years; 1,067 men, 610 women). The mean propriate, and suggested that their data be interpreted
daily hs-CRP concentration for women is reported in with caution. In addition, participants in the Monitoring
Figure 1, and that for men is reported in Figure 2. The Cardiovascular Disease studies were observed for a pemean ⫾ SD and the median of hs-CRP in each month in riod that covered 8 to 10 months, with a lack of data in
men and women are listed in Table 1, and the graphic August and September. In contrast, Woodhouse et al17
representation of these results (mean ⫾ SE of the mean) reported greater CRP concentrations in winter, with a
is shown in Figure 3. The results of the 1-way analysis of peak in March, and Crawford et al18 found a significant
variance to reveal potential differences between hs-CRP seasonal variation of CRP, with a peak in late February.
concentrations divided by month were negative, con- Thus, it is not completely clear from the data that are
firming the lack of differences among the different currently available whether a lack of seasonal variation is
months of the year. The locally weighted scatterplot a consistent finding.
smoothing procedure was used with a smoothing paramAlthough it has been determined that 2 or even 3
eter of 0.5 and did not demonstrate a significant seasonal tests are needed before firm conclusions are drawn as
variation among the months for men and women (data to whether a certain patient has enhanced cardiovasnot represented). We also grouped the results of hs-CRP cular risk,19 most patients obtain a single test during
on the basis of the 4 seasons, and the results are dis- their annual checkups. In addition, it has been sugplayed in Figure 4. Again, there was no significant dif- gested that cut-off points of up to 1, from 2 to 3, and
ference among the seasons using 1-way analysis of vari- ⬎3 mg/L be used to categorized patients into groups
ance and the Ryan-Einot-Gabriel-Welsch multiple range of low, intermediate, and relatively high risk.6 Thus,
test in men and women. Finally, we found the best fit changes of hs-CRP that relate to seasonal variation
between the hs-CRP data and the sinus curve and dem- due to subclinical infections during the winter might
154 THE AMERICAN JOURNAL OF CARDIOLOGY姞
VOL. 95
JANUARY 1, 2005
have an impact on this classification. Our study is
therefore significant, in that it shows a lack of seasonal
variation in hs-CRP concentrations. This is, of course,
when recent infection or inflammation has been excluded by an appropriate questionnaire.
1. Ridker PM. On evolutionary biology, inflammation, infection, and the causes
of atherosclerosis. Circulation 2002;105:2– 4.
2. Yeh ET, Willerson JT. Coming of age of C-reactive protein: using inflammation markers in cardiology. Circulation 2003;107:370 –371.
3. Cohen S, Tolshinsky T, Rogowski O, Shapira I, Lachmi K, Hirsch M, Ben
Assayag E, Burke M, Deutch V, Berliner S, et al. Real time, control adjusted
evaluation of intensity of the inflammatory response. J Inform Technol Healthcare 2003;1:195–207.
4. Rifai N, Tracy RP, Ridker PM. Clinical efficacy of an automated highsensitivity C-reactive protein assay. Clin Chem 1999;45:2136 –2141.
5. Ridker PM, Buring JE, Cook NR, Rifai N. C-reactive protein, the metabolic
syndrome, and risk of incident cardiovascular events: an 8-year follow-up of 14
719 initially healthy American women. Circulation 2003;107:391–397.
6. Ridker PM. C-reactive protein: a simple test to help predict risk of heart attack
and stroke. Circulation 2003;108:e81– e85.
7. Devaraj S, Xu DY, Jialal I. C-reactive protein increases plasminogen activator
inhibitor-1 expression and activity in human aortic endothelial cells: implications for
the metabolic syndrome and atherothrombosis. Circulation 2003;107:398 – 404.
8. Pasceri V, Willerson JT, Yeh ETH. Direct proinflammatory effect of C-reactive protein on human endothelial cells. Circulation 2000;102:2165–2171.
9. Wang CH, Li SH, Weisel RD, Fedak PWM, Dumont AS, Szmitko P, Li RK,
Mickle DAG, Verma S. C-reactive protein upregulates angiotensin type 1 receptors in vascular smooth muscle. Circulation 2003;107:1783–1790.
10. Torzewski M, Rist C, Mortensen RF, Zwaka TP, Bienek M, Waltenberger J,
Koenig W, Schmitz G, Hombach V, Torzewski J. C-reactive protein in the arterial
intima: role of C-reactive protein receptor-dependent monocyte recruitment in
atherogenesis. Arterioscler Thromb Vasc Biol 2000;20:2094 –2099.
11. Cermak J, Key NS, Bach RR, Balla J, Jacob HS, Vercellotti GM. C-reactive
protein induces human peripheral blood monocytes to synthesis tissue factor.
Thromb Haemost 2000;84:730 –731.
12. Pasceri V, Cheng JS, Willerson JT, Yeh ET, Chang J. Modulation of C-reactive
protein-mediated monocyte chemoattractant protein-1 induction in human endothelial
cells by anti-atherosclerosis drugs. Circulation 2001;103:2531–2534.
13. Venugopal SK, Devaraj S, Yuhanna I, Shaul P, Jialal I. Demonstration that
C-reactive protein decreases eNOS expression and bioactivity in human aortic
endothelial cells. Circulation 2002;106:1439 –1441.
14. Venugopal SK, Devaraj S, Jialal I. C-reactive protein decreases prostacyclin
release from human aortic endothelial cells. Circulation 2003;108:1676 –1678.
15. Paul A, Ko KWS, Li L, Yechoor V, McCrory MA, Szalai AJ, Chan L.
C-reactive protein accelerates the progression of atherosclerosis in apolipoprotein
E-deficient mice. Circulation 2004;109:647– 655.
16. Fröhlich M, Sund M, Thorand B, Hutchinson WL, Pepys MB, Koenig W.
Lack of seasonal variation in C-reactive protein. Clin Chem 2002;48:575–577.
17. Woodhouse PR, Khaw KT, Plummer M, Foley A, Meade TW. Seasonal
variations of plasma fibrinogen and factor VII activity in the elderly: winter
infections and death from cardiovascular disease. Lancet 1994;343:435– 439.
18. Crawford VL, Sweeney O, Coyle PV, Halliday IM, Stout RW. The relationship between elevated fibrinogen and markers of infection: a comparison of
seasonal cycles. Quart J Med 2000;93:745–750.
19. Hackam DG, Anand SS. Emerging risk factors for atherosclerotic vascular
disease: a critical review of the evidence. JAMA 2003;290:932–940.
Comparison of Differing C-Reactive Protein Assay
Methods and Their Impact on Cardiovascular
Risk Assessment
Jessica L. Clarke, Jeffrey L. Anderson, MD, John F. Carlquist, PhD,
Richard F. Roberts, MS, Benjamin D. Horne, MStat, MPH, Tami L. Bair, BS,
Matthew J. Kolek, BS, Chrissa P. Mower, Ashle M. Crane, William L. Roberts, MD, PhD,
and Joseph B. Muhlestein, MD, for the Intermountain Heart Collaborative (IHC)
Study Group
A medium-sensitivity assay for C-reactive protein
(CRP) was compared with a high-sensitivity, enhanced immunoturbidimetric assay in 803 angiographically studied patients. Different absolute CRP
values were found by the assays, but there was a
high correlation by quartile rank and similar predictive values for death and myocardial infarction. This
suggests that the conclusions of previous studies performed using the medium-sensitivity assay are still
valid but that cross-study comparisons should use
percentile rank. 䊚2005 by Excerpta Medica Inc.
(Am J Cardiol 2005;95:155–158)
From the Cardiovascular Department, LDS Hospital; the Cardiology
Division and Pathology Division, University of Utah; and ARUP Institute
for Clinical and Experimental Pathology, Salt Lake City, Utah. This
study was supported by the Deseret Foundation, Salt Lake City, Utah.
Dr. Anderson’s address is: LDS Hospital, Cardiovascular Department,
8th Avenue & C Street, Salt Lake City, Utah 84143. E-mail:
[email protected]. Manuscript received August 5, 2004; revised manuscript received and accepted August 24, 2004.
©2005 by Excerpta Medica Inc. All rights reserved.
The American Journal of Cardiology Vol. 95 January 1, 2005
oronary artery disease (CAD) remains the leading
cause of serious morbidity and mortality in adults.
C
Standard risk factors explain much of population-level
risk, but they provide incomplete and suboptimal assessment of risk in patients. During the past decade,
the inflammatory basis of atherogenesis has been recognized.1,2 C-reactive protein (CRP) has emerged as
the prototypic inflammatory predictor of primary and
secondary risk in men and women and is the only
inflammatory marker currently recommended for clinical application.1– 4 Despite a wealth of data,3,5–7 controversy still surrounds CRP as a risk marker.8 Part of
the controversy relates to questions about the comparability of CRP assays used in these studies. In our
own and others’ experience with CAD risk prediction,
medium- and high-sensitivity CRP (hs-CRP) assays
have become variously available and used over several years.5–17 More recently, higher sensitivity assays
have become more widely available and recommended as preferred for risk assessment.3–5 Despite
this, few studies have actually addressed the comparability or differences in these assays and their predictive value, especially in diseased populations. In0002-9149/05/$–see front matter
doi:10.1016/j.amjcard.2004.08.087
155