Download C-Reactive Protein Levels in Chronic Congestive Heart Failure

Original Article
Acta Cardiol Sin 2004;20:7-14
Congestive Heart Failure
C-Reactive Protein Levels in Chronic
Congestive Heart Failure
Wen-Pin Huang, Wei-Hsian Yin, Hsu-Lung Jen, Meng-Cheng Chiang, An-Ning Feng and Mason Shing Young1
Background: Serum concentrations of C-reactive protein (CRP) are elevated in patients with congestive heart
failure (CHF). However, clinical data about the prognostic value of CRP levels in patients with chronic stable
CHF are sparse. We hypothesized that measurement of CRP might provide prognostic information in these
patients.
Methods: We measured serum levels of CRP in 72 patients with chronic CHF and left ventricular ejection fraction
(LVEF) < 50%. Major adverse cardiac events (death or hospitalization with worsening CHF) during a median
follow-up period of 449 days were determined. Multivariate Cox regression analysis was performed to identify
independent predictors of major adverse cardiac events.
Results: The concentrations of CRP in the sample population were significantly increased with the severity of CHF.
The 25 patients who had adverse events had significantly higher CRP levels (p = 0.0065) than the 47 patients who
were event-free. We further divided the 72 CHF patients into tertiles on the basis of this sample, with the cutoff
points for each tertile being £ 2.69, > 2.69 to £ 5.38, and > 5.38 mg per liter, respectively. The differences between
event-free curves were insignificant between tertiles 1 and 2 but were significant between tertiles 1 and 3 and
between tertiles 2 and 3 (p = 0.0048, p = 0.0103, respectively). In a multivariate analysis (n = 58), left ventricular
end-diastolic pressure (LVEDP) and serum levels of CRP > 5.38 mg per liter were found to be independently
significant predictors for major adverse cardiac events in patients with chronic CHF. The CRP levels were
significantly correlated with LVEDP (r = 0.26, p = 0.048; n = 58).
Conclusions: These findings suggest that the levels of CRP are related to clinical outcomes and that measurement
of CRP has the potential to play an important role as an adjunct for risk assessment in patients with chronic CHF.
Key Words:
C-reactive protein · Congestive heart failure · Prognosis
INTRODUCTION
these cytokines may be negatively associated with
prognosis.2,3
C-reactive protein (CRP), as a marker of inflammation, has been shown to be associated with an increased
risk of various cardiovascular diseases. 4-7 The serum
concentration of CRP is also elevated in patients with
congestive heart failure (CHF),8-10 and Gottdiener et al.
reported that increased CRP was an independent predictor
of incident CHF in a community-based elderly population.11
However, clinical data about the prognostic value of CRP
in patients with chronic CHF are sparse and inconsistent.9,10 The likely reason for this is that the mildly elevated CRP concentrations in these patients fall well
within the range found in healthy subjects, and the standard clinical assays for CRP lack sensitivity within the
Activation of the immune system has been implicated
in the pathogenesis of congestive heart failure (CHF).1,2
Cytokines such as tumor necrosis factor alpha (TNF-a)
and interleukin-6 are significantly elevated, producing
negative inotropic effects on the heart, and the levels of
Received: April 29, 2003
Accepted: October 7, 2003
Division of Cardiology, 1Department of Internal Medicine,
Cheng-Hsin General Hospital, Taipei, Taiwan.
Address correspondence and reprint requests to: Dr. Mason Shing
Young, Department of Internal Medicine, Cheng-Hsin General Hospital,
No. 45, Cheng-Hsin Street, Taipei 112, Taiwan. Tel: 886-2-28261242; Fax: 886-2-2826-1242; E-mail: [email protected]
7
Acta Cardiol Sin 2004;20:7-14
Wen-Pin Huang et al.
low-normal range: thus they cannot be used effectively
for cardiovascular risk prediction. Since high-sensitivity
commercial assays for CRP are now available,12 we hypothesized that measurement of CRP might provide
prognostic information in these patients.
This study was designed to evaluate the level of CRP
using high-sensitivity kits in patients with chronic CHF
and to examine the relation between the degree of CRP elevation and clinical outcome.
monary capillary wedge pressure, was measured with a
7Fr Swan-Ganz catheter, and cardiac output was measured by the thermodilution technique.
The LVEF was determined by left ventriculography
with standard radionuclide or contrast medium.
Blood sampling and measurement of circulating
levels of CRP
For those 54 patients who underwent right heart
catheterization for clinical (noninvestigational) evaluation,
venous blood was drawn during right heart catheterization
(central vein). For other patients, blood samples were collected into vacuum tubes at bedside (peripheral vein). All
samples were then frozen to –20 °C and were stored at
that temperature until analysis. The time interval between
blood sampling and LVEF studies for every patient was
less than one week.
Samples were assayed for CRP with a validated,
high-sensitivity assay (DRG Instruments, Germany). The
intra-assay and inter-assay coefficients for each factor
were about 5% and about 10%, respectively.
METHODS
Patient population
Seventy-two patients (48 men and 24 women, aged
46 to 76 years [mean 61 ± 15] with chronic CHF were
enrolled. Patients were included if, at the time of enrollment, they had New York Heart Association (NYHA)
class II to IV symptoms of heart failure and a left ventricular ejection fraction (LVEF) of < 50% by left
ventriculography with radionuclide or contrast medium.
Although all patients had low LVEFs, they had all been
clinically stable without signs or symptoms of pulmonary congestion for at least two weeks before their entry
into this study. Patients were excluded if there was severe comorbidity, renal failure, myocardial infarction or
unstable angina in the 6 weeks leading up to enrollment,
leukocytosis (WBC count > 10000 per deciliter), infection or an inflammatory illness such as sepsis,
malignancy, arthritis or connective tissue disease.
An age-matched group of 16 volunteers provided blood
samples for use as a control. All of these subjects were free
of heart disease and other major medical problems.
Clinical follow-up
All patients were followed either in-hospital or
through regular outpatient visits. Clinical information regarding major adverse cardiac events (cardiac death or
hospitalization with a primary diagnosis of worsening
CHF) during a median follow-up period of 449 days was
provided by the treating cardiologist without knowledge
of the CRP levels.
Data analysis
All values, except for the CRP level, were expressed
as mean ± SD. Because the distribution of the CRP levels
in these patients did not follow a normal distribution, they
were expressed by a median (25th to 75th percentiles).
The patients with CHF were divided into two groups:
mild CHF (NYHA class II) and severe CHF (NYHA class
III or IV) groups. Comparisons of the levels of CRP
among these 2 groups and the controls were determined
by means of a Kruskal-Wallis one-way analysis of variance on ranks test.
The CHF patients were then divided into those who
had major adverse cardiac events during follow-up and
those who were event-free. Univariate comparisons of
clinical and hemodynamic characteristics between these
two groups were made with the Student’s t test for quanti-
Baseline clinical evaluation and hemodynamic
measurements
Baseline clinical evaluation was performed on the 72
patients with CHF. Sixty-nine patients underwent cardiac
catheterization or coronary arteriography for clinically indicated purposes. Informed consent was obtained from all
patients according to a protocol approved by the committee on human investigation at our institution. Left-sided
cardiac catheterization, including left ventriculography
and coronary arteriography, was performed in 58 patients.
Right-sided cardiac catheterization, both with and without
endomyocardial biopsy, was performed in 13 and in 41
patients, respectively. Right heart pressure, such as pulActa Cardiol Sin 2004;20:7-14
8
CRP in Chronic Heart Failure
tative data and with the Fisher exact test for qualitative
data. Levels of CRP were compared between these two
groups by the Wilcoxon rank-sum test. Cox proportional
hazards analysis was performed to determine the significance of LVEF, left ventricular end-diastolic pressure
(LVEDP) and circulating levels of CRP as independent
predictors of CHF.
We also divided the population data into three
groups of equal numbers of patients (24 in each) with
respect to increasing CRP levels, and constructed
Kaplan-Meier curves for event-free survival analysis.
The differences between event-free curves were tested
by a log rank test.
Linear regression analysis was used to determine the
correlation between the levels of CRP, LVEF, LVEDP and
various hemodynamic parameters derived from cardiac
catheterization.
A p value < 0.05 was considered statistically significant.
cause of heart failure was ischemic heart disease in 21
(29%) patients, dilated cardiomyopathy in 21, and valvular heart disease in 30. The mean LVEF was 36%; 32
patients were in NYHA class II (mild CHF group), 40
were in class III or IV (severe CHF group). All patients
were clinically stable on blood sampling while receiving
continuous therapy for heart failure. Thirty-nine patients
used digoxin and fifty-four used diuretics; 45 patients
were also treated with angiotensin-converting enzyme inhibitors, 30 with beta-blockers, and 31 with vasodilators
Table 1. Baseline clinical characteristics of 72 patients with
congestive heart failure
61 ± 15
36 ± 14
48 (67%)
21 (29%)
32 (44%)
24 (33%)
16 (22%)
54 (75%)
45 (63%)
30 (42%)
39 (54%)
31 (43%)
Age (y)
LVEF (%)
Men
Ischemic heart failure
NYHA class II
NYHA class III
NYHA class IV
Diuretics
ACEI/ARB
Âeta-blocker
Digoxin
Vasodilator
RESULTS
Patient characteristics and hemodynamic data
A sample of 72 patients meeting the study criteria was
chosen; their baseline characteristics are shown in Table 1.
There were more men than women in this sample. The
LVEF = left ventricular ejection fraction; NYHA= New York
Heart Association; ACEI/ARB = angiotensin-converting enzyme
inhibitors or angiotensin receptor blockers.
Table 2. Patient characteristics and hemodynamic data in patients with congestive heart failure who had major adverse cardiac events
during follow-up and those who were event-free
Age (yrs)
Male, n (%)
LVEF (%)
Ischemic heart failure
Diuretics
Digitalis
ACEI/ARB therapy
Vasodilator therapy
Beta-blockers
Cardiac index (L/min/M2)
Left ventricular end-diastolic pressure (mmHg)
Systemic vascular resistance (dynes-sec-cm-5)
Pulmonary vascular resistance (dynes-sec-cm-5)
Total pulmonary resistance (dynes-sec-cm-5)
C-reactive protein (mg/L)
MACE(-) (n = 47)
MACE(+) (n = 25)
p value
60 ± 15
30 (64%)
41 ± 11
10
34
23
28
17
19
2.0 ± 0.6 (n = 28)
21 ± 8 (n = 39)
2600 ± 939 (n = 29)
294 ± 192 (n = 24)
846 ± 468 (n = 24)
3.12 (2.24 - 4.95)
63 ± 14
18 (72%)
27 ± 13
11
20
16
17
14
11
2.1 ± 0.7 (n = 16)
28 ± 10 (n = 19)
2301 ± 888 (n = 16)
273 ± 195 (n = 16)
1039 ± 615 (n = 16)
5.76 (2.89 - 25.22)
NS
NS
< 0.0001
NS
NS
NS
NS
NS
NS
NS
0.007
NS
NS
NS
0.0065
MACE = major adverse cardiac event; LVEF = left ventricular ejection fraction; ACEI/ARB = angiotensin-converting enzyme inhibitors
or angiotensin receptor blockers.
9
Acta Cardiol Sin 2004;20:7-14
Wen-Pin Huang et al.
on blood sampling.
The CHF patients were then divided into those who
had major adverse cardiac events during follow-up and
those who were event-free (Table 2). No significant differences in age, sex or cause of CHF were detected
between the two groups. However, by univariate analysis,
the mean LVEF was significantly lower (p < 0.0001) and
the LVEDP was significantly higher (p = 0.007) in the
group with major adverse cardiac events than in the
event-free group.
pared in Figure 2. The 25 patients who had adverse events
had significantly higher CRP levels (p = 0.0065) than the
Circulating levels of CRP in patients with CHF
Not all of the 72 patients with CHF had elevated CRP.
However, the concentrations of CRP were significantly
higher in the CHF patients than in the 16 healthy controls
and increased with the severity of CHF, especially in the
severe (NYHA class III or IV) group (Figure 1).
Prognosis
The median follow-up period was 449 days (246 to
497 days, 25th to 75th percentiles). There was a 35% (25
of 72) overall event rate in the CHF population. Seven of
the seventy-two patients died of cardiac causes (4 died of
sudden death without premonition of the progression of
symptoms, presumed to be due to arrhythmia, and 3 of intractable end-stage CHF) during the follow-up period.
Eighteen patients were readmitted for worsening heart
failure.
The exact CRP levels of the patients of both adverse-event and event-free groups are shown and com-
Figure 2. The circulating levels of C-reactive protein (CRP) in
patients with congestive heart failure who had no major adverse
cardiac events [MACE (-)] versus those who did have adverse events
[MACE (+)] during follow-up.
Figure 1. Circulating levels of C-reactive protein (CRP) in patients with chronic congestive heart failure (CHF). Control = age-matched control
subjects (n = 16); Mild CHF = New York Heart Association (NYHA) class II (n = 32); Severe CHF = NYHA class III or IV (n = 40). Values are
expressed by a median (25th to 75th percentiles). * p < 0.0001.
Acta Cardiol Sin 2004;20:7-14
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CRP in Chronic Heart Failure
47 patients who were event-free.
This is further illustrated by a Kaplan-Meier analysis
of event-free survival, dividing the 72 CHF patients into 3
equal groups (tertiles) of 24 each based on their levels of
CRP (shown in Figure 3). On the basis of this sample, the
cutoff points for each tertile were £ 2.69, >2.69 to £ 5.38,
and > 5.38 mg per liter, respectively. The differences between event-free curves were insignificant between
tertiles 1 and 2 but were significant between tertiles 1 and
3 and between tertiles 2 and 3 (p = 0.0048, p = 0.0103, respectively).
levels were minimally correlated with LVEF (r = -0.22, p
= 0.063) (Figure 4).
DISCUSSION
Comparison with previous studies
Chronic CHF is the final common pathway of a variety
of cardiac disorders, and it is usually progressive. Recent
studies suggest that CHF may, in part, be an inflammatory
disease, and it is well known that proinflammatory
cytokines such as TNF-a and interleukin-6 are significantly elevated in such patients and that their levels are
negatively associated with clinical outcomes.1-3 C-reactive
protein, an inflammatory marker synthesized in the liver,
has been shown to predict myocardial infarction, stroke
and vascular death in a variety of settings, and it has been
proven to be one of the strongest independent predictors of
future cardiovascular events in apparently healthy men and
women.4-7 Increased CRP has also been reported to be an
independent predictor of incident CHF in a community-based elderly population.11
Although the serum concentration of CRP is elevated
in patients with CHF,8-10 clinical data about the prognostic
value of CRP in patients with chronic CHF are lacking
and inconsistent.9,10 This is because the mildly elevated
CRP concentrations in these patients fall well within the
range found in healthy subjects. Traditionally, clinical assays for CRP typically have a lower detection limit of 3 to
8 mg/L, and it has been suggested that CRP values of less
Correlation between concentrations of CRP,
LVEDP and LVEF
According to the Cox proportional hazards analysis (n
= 58), CRP > 5.38 mg per liter and LVEDP were found to
be independently significant predictors for major adverse
cardiac events in these CHF patients (Table 3). The circulating levels of CRP were significantly correlated with
LVEDP (r = 0.26, p = 0.048; n = 58), however, the CRP
Table 3. Predictors of events during follow-up: multivariate Cox
proportional hazard analysis (n = 58)
Variable
LVEF
LVEDP
CRP > 5.38
Coefficient Hazard ratio
0.942
1.222
1.07
2.564
3.394
2.915
95% C.I. for
hazard ratio
p value
0.759 - 8.66
1.076 - 10.707
1.099 - 7.732
0.129
0.037
0.032
LVEF = left ventricular ejection fraction; LVEDP = left ventricular
end-diastolic pressure; CRP = C-reactive protein (mg/L).
Figure 3. Kaplan-Meier event probability for patients with chronic congestive heart failure, stratified into increasing tertiles on the basis of
circulating levels of C-reactive protein (CRP).
11
Acta Cardiol Sin 2004;20:7-14
Wen-Pin Huang et al.
n = 72
r = -0.22
p = 0.063
140
n = 58
r = 0.26
p = 0.048
120
120
C-reactive protein (mg/L)
C-reactive protein (mg/L)
100
100
80
60
40
20
0
80
60
40
20
0
0
10
20
30
40
50
60
0
LVEF (%)
10
20
30
40
50
60
LVEDP (mmHg)
Figure 4. Correlation between circulating levels of C-reactive protein (CRP), left ventricular end-diastolic pressure (LVEDP) and left
ventricular ejection fraction (LVEF) in patients with chronic congestive heart failure.
than 10 mg/L should be regarded as clinically unimportant. 13 These assays thus lack sensitivity within the
low-normal range and cannot be used effectively for risk
prediction. Since inexpensive high-sensitivity commercial
assays for CRP are now available,12 we hypothesized that
measurement of CRP using these assays might provide
prognostic information in patients with chronic CHF.
Our data showed that circulating levels of CRP were
significantly correlated with LVEDP, were elevated in patients with chronic stable CHF, and increased with the
severity of CHF. Using Cox proportional hazards analysis, both LVEDP and CRP > 5.38 mg/L were both
independently predicting risk factors. The patients in our
study who had CRP concentrations above 5.38 mg/L,
which fall within the normal ranges in healthy subjects,12
were more likely to succumb to adverse cardiac events. It
is surprising that LVEF was not an independent predictor
for future adverse events. However, the limited sample
size and the inclusion of 30 patients with valvular heart
disease (all of them had significant aortic or mitral regurgitation) in this study, which might show better LVEF and
mask the severity of LV dysfunction, may be the underlying causes.
Interleukin-6 is a major inducer of CRP, and it is produced in monocytes/macrophages, endothelial cells,
vascular smooth muscle cells, fibroblasts and also cardiac
myocytes under hypoxic stress.10,14 In the setting of CHF,
cardiac decompensation itself and injuries to other organs
like the liver, kidney, brain or skeletal muscle, induced by
low cardiac output, hypoperfusion, hypoxia and venous
congestion, may each be sources of interleukin-6, which,
in turn, may induce the production of CRP.
CRP not only may be a marker of low-grade chronic
systemic inflammation but also may be directly involved in
CHF. CRP has many pathophysiologic roles in the inflammatory process.15 It can amplify the inflammatory response
through complement activation, which may cause myocardial cell apoptosis and thus ventricular damage or
dysfunction.16 Also, at concentrations known to predict adverse vascular events, it directly quenches the production
of nitric oxide, which, in turn, inhibits angiogenesis, an important compensatory mechanism in chronic ischemia. In
doing so, CRP may facilitate the development and worsening of CHF.17 Other proin- flammatory effects of CRP
include the induction of inflammatory cytokines and tissue
factor in monocytes15 and a direct proinflammatory effect
on human endothelial cells.18
Potential role of CRP in the pathogenesis and
progression of CHF
Recent studies suggest that, in addition to the activation of the sympathetic nervous and the renin-angiotensinaldosterone systems, immune activation and inflammation
also play roles in the pathogenesis and progression of
CHF.1,2
Acta Cardiol Sin 2004;20:7-14
Clinical implications
Since treatment of CHF can decrease the plasma levels
of TNF-a and CRP in patients with CHF,10,19,20 risk reduction strategies designed to lower plasma CRP may be
effective by improving nitric oxide bioavailability and endothelial function.21,22 These factors may become potential
12
CRP in Chronic Heart Failure
targets for the treatment of CHF.23 However, future trials
with refined hypotheses and approaches will be needed.
Clinical application of CRP testing should depend not
only on the demonstration of independent predictive
value, but also on the demonstration that the addition of
CRP testing to traditional screening methods improves
risk prediction. Our data suggests that CRP is an independent predictor for future adverse cardiac events in
patients with chronic CHF and that assessment of CRP
level provides additional prognostic information.
6.
7.
8.
9.
Study limitations
This study is limited by its small sample size. However, because of its observational design, the findings are
hypothesis-generating rather than conclusive. Further and
larger studies will be required to confirm and refine these
findings in order to address the issue regarding the relative contributions of CRP as marker, causative agent or
consequence of CHF.
10.
11.
12.
13.
CONCLUSIONS
14.
This study assessed the predictive ability of concentrations of CRP for adverse cardiac events in patients with
chronic stable CHF. Our findings indicate that levels of
CRP increase with the severity of CHF and are related to
clinical outcomes. Measurement of CRP thus has the potential to play an important role as an adjunct for risk
assessment in patients with chronic stable CHF.
15.
16.
17.
18.
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