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The American Journal of Medicine (2007) 120, 616-622
CLINICAL RESEARCH STUDY
AJM Theme Issue: Diabetes/Metabolism
C-Reactive Protein and Heart Failure after Myocardial
Infarction in the Community
Francesca Bursi, MD, MSc,a Susan A. Weston, MS,b Jill M. Killian, BS,b Sherine E. Gabriel, MD, MSc,b
Steven J. Jacobsen, MD, PhD,b Véronique L. Roger, MD, MPHa,b
a
Division of Cardiovascular Diseases, Department of Internal Medicine, bDepartment of Health Sciences Research, Mayo Clinic and
Foundation, Rochester, Minn.
ABSTRACT
BACKGROUND: There is a paucity of data on the prognostic role of C-reactive protein (CRP) measured
after myocardial infarction. We prospectively examined the association of CRP with heart failure and death
among patients with myocardial infarction in the community.
METHODS AND RESULTS: All Olmsted County residents who had a myocardial infarction meeting
standardized criteria were prospectively enrolled to measure CRP on admission and followed for heart
failure and death. A total of 329 consecutive patients (mean age 69 ⫾ 16 years, 52% men) were enrolled.
At 1 year, 28% of patients experienced heart failure and 20% died. There was a strong positive graded
association between CRP and the risk of developing heart failure, as well as dying over the period of
follow-up (P ⬍ .001). Compared with patients in the first tertile, patients in the third tertile of the CRP
distribution had a markedly increased risk of heart failure and death independently of age, sex, troponin
T, Q wave, comorbidity, previous myocardial infarction, and recurrent ischemic events (adjusted hazard
ratio 2.47 [95% confidence interval, 1.27-4.82] for heart failure and 3.96 [95% confidence interval,
1.78-8.83] for death).
CONCLUSIONS: These prospective data indicate that among contemporary community subjects with
myocardial infarction, heart failure and death remain frequent complications. CRP is associated with a
large increase in the risk of heart failure and death, independently of age, sex, myocardial infarction
severity, comorbidity, previous myocardial infarction, and recurrent ischemic events. These data suggest
that inflammatory processes may play a role in the development of heart failure and death after myocardial
infarction independently of other conventional prognostic indicators. © 2007 Elsevier Inc. All rights
reserved.
KEYWORDS: C-reactive protein; Community; Death; Heart failure; Myocardial infarction; Prognosis
Despite studies reporting temporal declines in the incidence
of heart failure and death after myocardial infarction, these
complications remain frequent1-4 and have not decreased in
ways commensurate to the large declines in short-term case
Supported in part by grants from the Public Health Service and the
National Institutes of Health (AR30582, R01 HL 59205, R01 HL 72435)
and by an American Heart Association Postdoctoral Greater Midwest
Fellowship Award to Dr Bursi. Dr Roger is an Established Investigator of
the American Heart Association.
Requests for reprints should be addressed to Véronique L. Roger, MD,
MPH, Division of Cardiovascular Diseases, Mayo Clinic, 200 First Street
SW, Rochester, MN 55901.
E-mail address: [email protected]
0002-9343/$ -see front matter © 2007 Elsevier Inc. All rights reserved.
doi:10.1016/j.amjmed.2006.07.039
fatality rates observed in clinical trials.5,6 This scenario
underscores the relevance of risk stratification in the
community.
There is intense interest in the use of C-reactive protein
(CRP) for risk assessment. Since the introduction of highsensitivity techniques, CRP has been studied in acute coronary syndromes as a marker of a proinflammatory state and
plaque instability.7 However, few studies examined the association between CRP and death and cardiac mortality
after myocardial infarction.8-13
The association between CRP and heart failure after
myocardial infarction seldom has been investigated,12,14
despite the emerging evidence of the role of inflammation in
Bursi et al
CRP After Myocardial Infarction
617
heart failure.15,16 Finally, most studies published on CRP
Time to presentation was defined as the interval from the
after myocardial infarction evaluated only early outcomes14
self-reported onset of symptoms to the first electrocardioor consisted of case series12,13,17,18 or post hoc analyses of
gram in hours. Killip class was assessed within 24 hours of
clinical trials,8-11,19 with their inherent selection biases and
admission. Comorbidity was measured by the Charlson inthe inconsistent control they have over important characterdex.24 Clinical diagnoses were used to ascertain hypertenistics such as comorbidity.
sion, diabetes, hyperlipidemia,
We prospectively addressed
family history of coronary disease
these gaps in knowledge among
(defined as coronary disease in
CLINICAL SIGNIFICANCE
all consecutive patients presenting
first-line male descendants aged ⬍
with myocardial infarction from a
55 years and in first-line female
● Our research revealed a strong, graded
geographically defined commudescendants aged ⬍ 65 years), and
association between CRP and the develnity by examining whether CRP
smoking.
The extent of angioopment of heart failure after myocardial
was associated with an increased
graphic coronary disease was
infarction.
risk of heart failure and death after
measured as the number of vessels
myocardial infarction, indepenwith stenosis greater than 50%;
● Patients with the highest levels of CRP
dently of other predictors of these
multivessel disease was defined as
had a 4-fold increase in risk of death
outcomes.
at least 2 vessels with greater than
after myocardial infarction.
50% stenosis. Recurrent ischemic
events included recurrent myocarMETHODS
dial infarction or unstable angina
and
were
defined
by
physicians’
diagnoses.
Study Population
Olmsted County, Minnesota, is relatively isolated from
other urban centers, and nearly all medical care in virtually
every specialty is delivered to residents by a few providers,20 which include the Mayo Clinic and its affiliated hospitals; the Olmsted Medical Center and its affiliated community hospital; local nursing homes; and a few private
practitioners. Each provider in the community uses 1 medical record, whereby all medical information for each individual is in a single file. Through the Rochester Epidemiology Project, medical diagnoses, surgical interventions,
and other key information from the dossier are abstracted
and coded, thereby allowing the linkage of medical records
from all sources of care. This provides a unique infrastructure to analyze disease outcomes. The county population
was 106,479 in 199020 and increased to 124,277 in 2000
while becoming ethnically more diverse.
Patient Enrollment
All Olmsted County residents hospitalized between November 2002 and December 2004 and presenting with a troponin T value greater than or equal to 0.03 ng/mL (upper limit
of normal defined using the value at which the coefficient of
variation is ⬍10%) were prospectively identified within 12
hours of the blood draw through the electronic files of the
Department of Laboratory Medicine. Consent was sought
from patients (or the next of kin) to measure CRP in unused
serum initially stored for additional clinical need. Three
patients did not have serum available in which to measure
CRP; thus, they were not included in the analyses.
Of the approached patients, 82% consented for the study.
Cases were classified using published recommendations,21
and definite or probable myocardial infarction was included
as defined by the combination of cardiac pain, biomarkers,
and Minnesota coding of electrocardiograms.22 The reliability of this methodology is excellent.1,23
Biomarkers
Patients who undergo a clinically indicated blood draw have
blood stored to allow for tests without additional phlebotomy. These samples are stored at ⫺70°C and held for 6
days. All patients potentially experiencing a myocardial
infarction or next of kin were contacted for permission to
use these samples for measurement of CRP.
CRP was measured on serum from the first draw after
symptom onset using a latex-enhanced immunoturbidimetric assay on a Hitachi 912 automated analyzer (Hitachi Ltd,
Fukushima, Japan) and reagents from Diasorin (Stillwater,
Minn). The reference interval for the assay was 0.20 to 0.8
mg/L. The interassay and intra-assay coefficients of variation of the high-sensitivity CRP method were less than 10%
for the lower limit and less than 5% for the upper limit;
interassay precision was 8.5% at a mean CRP of 1.0 mg/L,
4.6% at a mean CRP of 2.3 mg/L, and 3.4% at a mean CRP
of 52.0 mg/L.
Venous samples for troponin T were obtained at the time
of admission and 6 to 9 hours after the symptom onset.
Serum stored from clinically indicated draws was used to
measure creatine kinase-MB (CKMB) with the Elecsys
2010 automated immunochemistry analyzer (Roche Diagnostic, Indianapolis, Ind). Peak troponin T and CKMB values were used in the analyses. Biomarkers were measured in
the Immunochemical Core Laboratory of Mayo Medical
Laboratories, where all quality control and quality assurance procedures are in place.
Follow-up
The complete (inpatient and outpatient) medical record for
each participant was reviewed by abstractors who were
unaware of the CRP value. This process yields information
that is complete, because more than 90% of the population
618
The American Journal of Medicine, Vol 120, No 7, July 2007
Table 1
Baseline Characteristics According to Tertiles of C-Reactive Protein
Baseline characteristics
Age, mean ⫾ SD
Male sex, %
Hypertension, %
Diabetes, %
Current smoking, %
Hyperlipidemia, %
BMI, mean ⫾ SD
Familial history of CAD, %
Previous myocardial infarction, %
Comorbidity index
0, %
1-2, %
ⱖ3, %
Myocardial infarction characteristics
Q wave, %
ST segment elevation, %
Killip class ⬎1, %
Time from symptoms to CRP measurement,
median (25th-75th percentile)
Peak troponin T, median (25th-75th percentile)
Peak CKMB, median (25th-75th percentile)
Tertile 1
CRP ⬍ 3 mg/L
N ⫽ 112
Tertile 2
CRP ⫽ 3-15 mg/L
N ⫽ 109
Tertile 3
CRP ⬎ 15 mg/L
N ⫽ 108
68 ⫾ 14
59.8
70.5
10.7
17.0
59.8
27.2 ⫾ 4.4
21.8
2.7
67 ⫾ 16
46.8
71.6
31.2
24.8
71.6
29.7 ⫾ 6.5
13.3
4.6
72 ⫾ 17
49.1
75.9
38.0
15.7
54.6
27.3 ⫾ 6.3
10.4
9.3
47.3
34.8
17.9
27.5
39.5
33.0
13.0
25.9
61.1
52.9
23.2
15.2
7.2 (3.1-10.2)
56.7
22.9
31.2
6.3 (1.9-26.6)
54.6
12.0
39.8
3.0 (0.6-9.7)
.81
.04
⬍.01
⬍.01
0.91 (0.19-2.54)
17.2 (7.1-90.8)
0.75 (0.23-2.91)
17.7 (8.3-114.4)
0.40 (0.13-1.38)
9.9 (4.5-23.1)
⬍.01
⬍.01
P value
.07
.11
.37
⬍.01
.83
.44
.84
.02
.03
⬍.01
SD ⫽ standard deviation; BMI ⫽ body mass index; CAD ⫽ coronary artery disease; CRP ⫽ C-reactive protein; CKMB ⫽ creatine kinase-MB.
receives care at Mayo Clinic or Olmsted Medical Center,
and residents are seen on average every 3 years at Mayo
Clinic.20 Heart failure, including both inpatient and outpatient events, was validated using the Framingham criteria,25
the reliability of which has been published for Olmsted
County studies.2 Outpatient events included all episodes of
heart failure that were not diagnosed in the hospital (ie,
outpatient diagnoses made by primary care physicians or
cardiologists during clinic or nursing home visits). The
ascertainment of death incorporated death certificates filed
in Olmsted County, autopsy reports, obituary notices, and
death certificates obtained from the State of Minnesota
Department of Vital and Health Statistics.1,23 The 10th
version of the International Classification of Diseases was
used to classify the underlying cause of death. Coronary
deaths were defined with codes I20 to I25, including inhospital and out-of-hospital deaths.26
Statistical Analysis
Data are presented as frequencies for categoric variables,
mean ⫾ standard deviation for continuous variables, or
median (25th-75th percentile) for skewed variables.
Trends in variables across tertiles of CRP were tested using
the Mantel-Haenszel chi-square test for categoric variables and
analysis of variance for continuous variables treating the tertiles of CRP as a 3-level variable. Trends in skewed variables
were analyzed after logarithmic transformation.
Correlations between CRP and troponin T and CKMB
were assessed with the Pearson correlation coefficient (r)
after logarithmic transformation.
Kaplan-Meier curves estimated survival according to
CRP tertiles and were compared using the log-rank test. For
survival free from heart failure, the analysis was repeated
treating death as a competing risk.27 Cox proportional hazards regression estimated the hazard ratio (HR) and 95%
confidence interval (CI) for death and heart failure. Recurrent ischemic events were analyzed as a time-dependent
covariate. Analyses were performed using SAS statistical
software, version 8 (SAS Institute Inc, Cary, NC). The
institutional review board approved the study.
RESULTS
We included 329 subjects with a mean age of 69 ⫾ 16
years; 52% were men, 269 patients had definite myocardial
infarction, and 60 patients had probable myocardial infarction. CRP was measured a median of 6.1 hours (25th-75th
percentile 1.2-11.0 hours) after symptom onset. The median
CRP was 5.7 mg/L (25th-75th percentile 2.0-31.0 mg/L).
The baseline characteristics were examined according to the
tertiles of the distribution of CRP (Table 1). Tertile 1 includes patients with CRP less than 3 (n ⫽ 112), tertile 2
includes patients with CRP between 3 and 15 (n ⫽ 109), and
tertile 3 includes patients with CRP greater than 15 mg/L
(n ⫽ 108). The CRP value that identifies patients in the
second tertile (CRP ⬎ 3 mg/L) matches the published cutoff
for intermediate risk, whereas the CRP value identifying the
third tertile (CRP ⬎ 15 mg/L) is only slightly higher than
the published cutoff for high risk.28 Patients with higher
CRP were more likely to be diabetic and less likely to have
Bursi et al
Figure 1
protein.
CRP After Myocardial Infarction
619
Survival free of heart failure (top) and overall survival (bottom) according to CRP tertiles. Hs-CRP ⫽ high sensitivity C-reactive
familial coronary disease, but no association was found
between CRP and other cardiovascular risk factors. Elevated CRP was positively associated with greater comorbidity (P ⬍ .001).
Ninety-four patients (29%) were in Killip class greater
than I at presentation, and greater Killip class was associated with increased CRP.
There was no association between CRP and Q waves on
the electrocardiogram and no positive association between
CRP and the presence of ST elevation or other biomarkers.
Indeed, there was no association between CRP and troponin
T at the time of hospitalization (r ⫽ ⫺0.02, P ⫽ .74) and
only a weak inverse correlation with peak troponin T (r ⫽
⫺0.177, P ⬍ .01) and peak CKMB (r ⫽ ⫺0.291, P ⬍ .01).
C-Reactive Protein, Heart Failure, and Death
After Myocardial Infarction
The mean follow-up was 1.0 ⫾ 0.6 years. At 1 year, 63
patients had died and 182 were still alive, whereas 84 had
less than 1 year of follow-up. On the basis of Kaplan-Meier
estimates, at 1 year 28% of patients (95% CI, 23%-33%)
had experienced heart failure and 20% of patients (95% CI,
15%-24%) had died; 103 recurrent ischemic events occurred.
There was a strong positive graded association between
CRP and the long-term development of heart failure. Oneyear survival free from heart failure was 88% (95% CI,
81%-94%) in the first tertile of CRP, 72% (95% CI, 64%81%) in the second tertile, and 52% (95% CI, 43%-64%) in
the third tertile (P ⬍ .01) (Figure 1). These estimates were
unchanged after death was analyzed as a competing risk.
Compared with patients in the first tertile, patients in the
second and third tertiles had a markedly increased risk of
heart failure independently of age, sex, and comorbidity.
Further adjustment for peak troponin, Q wave, Killip class
on admission, previous myocardial infarction, and recurrent
ischemic events as a time-dependent covariate did not modify this association (Table 2), nor did further adjustments for
cardiovascular risk factors and history of heart failure (data
not shown).
During follow-up, 75 deaths occurred. There was a
strong positive association between CRP and 1-year survivals. One-year survivals were 93% (95% CI, 88%-98%)
among patients in the first CRP tertile, 84% (95% CI,
77%-91%) in the second tertile, and 62% (95% CI, 54%-72%)
in the third tertile (P ⬍ .01) (Figure 1). Patients in the third
tertile had an 8-fold increase in the unadjusted risk of death
compared with patients in the first tertile (HR 7.92, 95%
CI, 3.75-16.73; P ⬍ .01). After further adjustment for
age, sex, and comorbidity, patients in the third tertile had
a 4-fold increase in the risk of death (adjusted HR 4.28,
95% CI, 1.95-9.38; P ⬍ .01) (Table 2). Further adjustment for peak troponin T, Q wave, Killip class, previous
myocardial infarction, and recurrent ischemic events as a
time-dependent covariate did not modify this association
(Table 2). Adjustment for cardiovascular risk factors and
history of heart failure did not modify this association
(data not shown).
DISCUSSION
Heart failure and death remain frequent after myocardial
infarction, as shown in this contemporary, geographically
defined cohort of patients with rigorously ascertained myocardial infarction. CRP measured on hospital admission for
myocardial infarction is associated with a strong, positive
620
Table 2
The American Journal of Medicine, Vol 120, No 7, July 2007
Hazard Ratios for Heart Failure and Death According to the Tertiles of C-Reactive Protein
HR (95% CI)
Heart failure
CRP tertile
CRP tertile
CRP tertile
P value
Death
CRP tertile
CRP tertile
CRP tertile
P value
Unadjusted
Adjusted*
Adjusted†
1 (referent)
2
3
1
2.45 (1.30-4.62)
4.59 (2.53-8.36)
⬍.01
1
2.16 (1.14-4.10)
2.83 (1.50-5.36)
⬍.01
1
1.92 (1.01-3.67)
2.47 (1.27-4.92)
.019
1 (referent)
2
3
1
2.39 (1.04-5.50)
7.92 (3.75-16.73)
⬍.01
1
2.10 (0.91-4.84)
4.28 (1.95-9.38)
⬍.01
1
1.73 (0.72-4.15)
3.96 (1.78-8.83)
⬍.01
HR ⫽ hazard ratio; CI ⫽ confidence interval; CRP ⫽ C-reactive protein.
*Adjusted for age, sex, comorbidity.
†Adjusted for age, sex, comorbidity, peak troponin T, Q wave, Killip class, previous myocardial infarction, and recurrent ischemic events as
time-dependent covariate.
graded increase in the risk of heart failure and death independently of known prognostic factors. Because CRP was
not associated with conventional measures of myocardial
infarction size (Q waves, ST elevation, troponin T, or peak
CKMB), its effect is likely not mediated by these indicators.
C-Reactive Protein, Heart Failure, and Death
After Myocardial Infarction
Heart failure and death remain frequent during the first year
after an acute myocardial infarction, reaffirming data from
earlier studies.2-4
After myocardial infarction, studies on CRP focused on
all-cause and cardiac deaths, which were evaluated mainly
in case series13,17 and subgroup analysis of data from clinical trials.8-12 Yet, studies of patients referred to tertiary
centers do not represent the entire spectrum of patients with
myocardial infarction, and secondary analyses of clinical
trials8,9,11,19 pertain to selected patients who often have
fewer comorbidities.29 Few studies have investigated the
association of postmyocardial infarction heart failure with
CRP.12,14,30,31 Although suggesting a positive association,
the studies focused chiefly on short-term risk,14,30 used
low-sensitivity assays,12 or considered only patients referred to intensive coronary care units and heart failure
episodes that required hospitalization.31
The present study pertains to all patients with myocardial
infarction within a geographically defined community,
which enhances its generalizability. It indicates that elevated CRP is associated with a large increase in the risk of
heart failure and death during the first year after myocardial
infarction independently of known risk indicators, including
other biomarkers, comorbidity, and recurrent ischemic
events. To this end, although CRP was higher among subjects with higher Killip class, its predictive value for heart
failure during follow-up is independent of Killip class, thus
providing incremental information. The graded positive as-
sociation between CRP and heart failure and death is consistent with a dose-response pattern.
Because few studies have investigated the association of
CRP and heart failure, the mechanism for this association is
unknown. It is unlikely related to recurrent ischemia because the associations between CRP and heart failure and
death were not altered by adjusting for recurrent ischemic
events. Alternative explanations include an exaggerated immune response to myocardial injury,32-34 as demonstrated
by the association of inflammatory cytokines with ventricular remodeling after myocardial infarction, ejection fraction, and heart failure progression.33,35,36 Finally, experimental animal studies showed that CRP may have direct
harmful effects on the ischemic myocardium. Griselli et al37
demonstrated that after coronary ligation, injection of CRP
increased infarct size. Barrett et al38 demonstrated that elevated endogenous CRP is associated with an increase in
ischemia/reperfusion injury. All these explanations remain
hypothetical and addressing them directly is beyond the
scope of this study, which, however, underscores the need
of doing so.
A recent study reported that CRP measured at discharge
was not associated with the combined end point of death,
myocardial infarction, unstable angina, urgent revascularization, and stroke.39 Heart failure was not examined as an
outcome such that these findings further support our hypothesis that the association between CRP and death is not
mediated by ischemia, but rather that heart failure plays an
important role.
Previous studies reported conflicting results on whether
CRP was associated with myocardial infarction size as assessed by cardiac biomarkers.18,19,30 In acute coronary syndromes, a significant although weak association of CRP
with CKMB40 and troponin was reported.8,9,11 Among community cases that met rigorous criteria for acute myocardial
infarction,21,41 CRP was not associated with higher troponin, CKMB, or Q waves. Thus, when measured early after
Bursi et al
CRP After Myocardial Infarction
myocardial infarction, CRP does not seem to be related to
myocardial injury.7,14,42 This is consistent with the fact that
CRP provides incremental information over troponin and
CKMB to predict death and heart failure, as documented in
this article.
These findings provide indirect evidence against the hypothesis that ischemia is the mechanism whereby CRP relates to heart failure and death, an observation further supported by the fact that greater CRP is associated with these
outcomes independently of recurrent ischemic events. Indeed, our results resonate with data14,43 suggesting that CRP
elevation does not reflect plaque inflammation but rather the
response of the “downstream myocardium” to the necrosis,
and with the report that, compared with other cardiovascular
risk predictors, CRP is only a modest predictor of recurrent
ischemic events in patients with coronary disease.44
Several predictors of heart failure after myocardial infarction have been examined, such as age, female sex,
diabetes, hypertension,45,46 brain natriuretic peptide, ejection fraction,47 and wall motion score index.47,48 Although
no study has directly compared CRP with other predictors
of heart failure after myocardial infarction, our finding of an
almost 4-fold increase in the risk of heart failure was independent of several other known risk markers.
Some potential limitations should be acknowledged to
interpret the data. Imaging to quantify myocardial infarction
size was not performed, and we relied on electrocardiography and biomarkers, both imperfect surrogate measures.49
This may play a role in the lack of association of CRP with
angiographic coronary disease or biomarkers. CRP changes
dynamically after myocardial infarction, and in most studies, such as the present one, it was measured at only 1 time
point;34,42,50 this may account for discrepant results observed in other studies.
The strengths of our study include its prospective community-based design, whereby all consecutive patients in a
geographically defined population were included and
among whom CRP was measured, as recommended,50
within 24 hours of admission using a high-sensitivity assay.
Additional important strengths include rigorous ascertainment approaches that rely on standardized criteria to define
myocardial infarction and heart failure, and the comprehensive nature of the follow-up, which includes all inpatient
and outpatient events. These important methodologic
strengths optimize the robustness of our findings.
CONCLUSION
These prospective data indicate that in the community, heart
failure and death remain frequent after myocardial infarction. CRP is associated with a large increase in the risk of
heart failure and death independently of other risk predictors. These data suggest that inflammatory processes play an
independent role in the development of heart failure and
death after myocardial infarction. Thus, CRP may assist in
risk stratification after myocardial infarction.
621
ACKNOWLEDGMENTS
We thank the following individuals for their support with
data collection, data entry and analysis, and article preparation: Kay A. Traverse, RN, Susan Stotz, RN, and Kristie
K. Shorter. We are grateful to Ellen Koepsell, RN, study
manager.
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