Abstract
Background: As elevation of serum C-reactive protein (CRP) is
occurred following left ventricular dysfunction (LVD), relationship
between increasing serum CRP level and abnormal changes in
electrocardiography(ECG) pattern. The present study aimed to examine
association between increase level of high-sensitive CRP (hs-CRP) and
non-arrhythmic ECG changes and echocardiographic abnormalities in
patients with acute coronary syndrome (ACS).
Methods: This cross-sectional study was conducted on 120
consecutive patients finally diagnosed as ACS and hospitalized at
cardiac care units (CCU). The participants were classified as the two
groups with increased level or normal of hs-CRP level.
Results: The patients with the increased level of hs-CRP had
significantly higher level of cardiac enzymes. The group with increased
level of hs-CRP experienced more ST-segment elevation myocardial
infarction (STEMI) than those with normal serum hs-CRP level, but other
diagnoses including unstable angina, non-STEMI, heart failure, and
emergency hypertension were similarly observed in both groups. The two
groups were comparable in terms of mean left ventricular ejection
fraction (LVEF), left ventricular end diastolic diameter (LVeDD),
prevalence of valvular heart diseases as well as in wall motion
abnormality assessed by echocardiography. ST-segment elevation in
different leads was more frequent in those with elevated hs-CRP level
than in the group with normal hs-CRP condition (19.6% versus 1.4%, p =
0.001); but ST-segment depression and T wave inversion were similarly
revealed in the two groups.
Conclusion: Elevated level of hs-CRP can predict occurrence of
STEMI, but may not be valuable to predict echocardiographic
abnormalities including LVD or hypertrophy.
Key words: CRP, acute coronary syndrome, ECG, myocardial
infarction
Running title: CRP changes in patients with acute coronary
syndrome
INTRODUCTION
CRP as an acute-phase reactant protein normally circulates at non-sensed
low level in the serum, however in some conditions including acute
inflammatory processes, tissue injuries, or acute infections, its
producing in hepatic cells and rising in circulation can be markedly
induced [1,2]. In this regard, it has been a growing interest in the
use of this marker as a sensitive marker for predicting and following
progression of each clinical conditions underlined by inflammatory or
infectious processes [3-5]. As recently revealed, different abnormal
cardiac conditions such as coronary atherosclerosis, ventricular
hypertrophy and other ventricular filling abnormalities, heart failure,
and even valvular heart diseases has an underlying inflammatory
etiologies accompanied by increased level of inflammatory responses and
thus CRP may have a major role to predict various types of
cardiovascular diseases even in apparently healthy subjects [6,7].
This hypothesis has been strengthened by recent histological studies
discovering activated circulating leucocytes, evidence of systemic
release of thromboxanes, and other inflammatory mediators besides
elevated level of CRP in these abnormal cardiovascular conditions
[8,9].
Furthermore, the significant association between elevation level of CRP
with reduced left ventricular systolic and diastolic dysfunction as well
as abnormality in long-term left ventricular remodeling has been well
recognized [10,11]. Because of the presence of close association
between ventricular systolic and diastolic dysfunction and abnormal
changes in electrocardiographic and echocardiographic patterns, it has
been recently hypothesized that as elevation of serum CRP is occurred
following LVD, relationship between increasing serum CRP level and
abnormal changes in electrocardiography pattern can be expected. Hence,
the present study aimed to assess association between increase level of
hs-CRP and non-arrhythmic ECG changes and echocardiographic
abnormalities in patients with acute coronary syndrome.
METHODS
This cross-sectional study was conducted on 120 consecutive patients
finally diagnosed as acute coronary syndrome and hospitalized at CCU
wards of Mostafa Khomeini hospital in Ilam(Iran) in 2018-2019. The
diagnosis of acute coronary syndrome based on clinical manifestation,
rising cardiac enzymes, and electrocardiographic ischemic changes so
acute was defined by a positive troponin blood test in the setting of
symptoms of angina or an anginal equivalent and/or electrocardiographic
changes consistent with an MI (evolutionary ST-T changes or a new Q
wave) [12]. Also, patients were diagnosed with unstable angina if
they had a negative troponin blood test and any one of the following:
new onset angina of at least Canadian Cardiovascular Society
Classification class III, rest angina, recent worsening of angina, or
angina that occurred within myocardial infarction 2 weeks of an
myocardial infarction [13].
Baseline characteristics of the participants including demographics,
medical history, history of medications, and the level of cardiac
enzymes were collected by interviewing on admission or reviewing
hospital recorded charts. On admission, the level of HS-CRP was measured
using a commercial kit in all participants. The participants were
classified as the two groups with increased level of HS-CRP
(> 1 mg/dl) as the case group and with normal HS-CRP level
(≤ 1 mg/dl) as the control group. The patients in both groups were
monitored during CCU hospitalization and any abnormal non-arrhythmic
changes in ECGs were recorded at study checklist. Also, the levels of
lipid profile were also measured in all subjects.
Results were presented as mean ± standard deviation (SD) for
quantitative variables and were summarized by frequency (percentage) for
categorical variables. Continuous variables were compared using t test
or Mann-Whitney U test whenever the data did not appear to have normal
distribution or when the assumption of equal variances was violated
across the study groups. Categorical variables were, on the other hand,
compared using chi-square test. For the statistical analysis, the
statistical software SPSS version 20.0 for windows (SPSS Inc., Chicago,
IL) was used. P values of 0.05 or less were considered statistically
significant.
RESULTS
Among 120 patients suffered acute coronary syndrome, 46 (38.3%) faced
with increased level of hs-CRP. Table 1 compares baseline
characteristics between the two groups with normal and elevated level of
hs-CRP. The two groups were similar in gender and age distribution,
prevalence of cardiovascular risk factors including obesity, diabetes
mellitus, hyperlipidemia, and hypertension, clinical manifestations,
vital signs, as well as oral medications. Regarding laboratory
parameters, increased level of hs-CRP was accompanied with raised levels
of fasting blood sugar, triglyceride, and liver enzymes in serum. With
respect to the difference in cardiac condition, those with the increased
level of hs-CRP had significantly higher level of cardiac enzymes
including lactate dehydrogenase (LDH), creatine kinase MB (CKMB),
troponin I, and also N-acetyl cysteine (NAC) when compared with normal
serum hs-CRP status (table 2). Regarding underlying cardiovascular
abnormalities, the group with increased level of hs-CRP experienced more
ST-segment elevation myocardial infarction (STEMI) than those with
normal serum hs-CRP level, but other diagnoses including unstable
angina, non-STEMI, heart failure, and emergency hypertension were
similarly observed in both groups. With regard to the difference in
echocardiographic parameters, the two groups with increased and normal
serum hs-CRP level were comparable in terms of mean left ventricular
ejection fraction (LVEF), left ventricular end diastolic diameter
(LVeDD), prevalence of valvular heart diseases such as aortic
insufficiency, mitral regurgitation, and tricuspid regurgitation, as
well as in left ventricular hypertrophy. Also, there was no difference
in regional wall motion abnormality between the two groups (table 2).
With regard to common non-arrhythmic ECG abnormalities (table 3),
ST-segment elevation in different leads was more frequent in those with
elevated hs-CRP level than in the group with normal hs-CRP condition
(19.6% versus 1.4%, p = 0.001); but ST-segment depression was
similarly revealed in the two groups (36.5% versus 41.3%, p = 0.598).
In group with increased level of hs-CRP, ST changes was occurred in
precordial leads in 37.0%, in limbs leads in 13.0%, and in both types
of leads in 8.7%; while these frequencies in another group were 18.9%,
8.1%, and 10.8%, respectively with no difference (table 3). The
frequency of inverted T wave in the two groups was 37.0% and 29.7%,
respectively with no difference (p = 0.411).
DISCUSSION
Our study demonstrated a similar abnormal changed in echocardiography
parameters between the groups with and without serum hs-CRP elevation
regarding left ventricular dysfunction, left ventricular hypertrophy and
wall motion abnormality, however with respect to non-arrhythmic ECG
changes, ST segment elevation indicating STEMI was more frequent in
those with increased level of hs-CRP. On the other hand, elevation level
of hs-CRP could effectively predict occurrence of STEMI and thus
elevated level of hs-CRP may have a major role in pathophysiological
basis of STEMI. However, elevation of this biomarker may not have
central role in occurring other non-arrhythmic ECG changes. Similar
finding was found in a study by Adler et al. that showed a significant
association between high CRP levels on the second and third day
following first AMI and ST elevation in ECG pattern [14]. In
contrast, Okin et al. demonstrated only a weak correlation between CRP
and ECG ST depression pattern [15]. In a population-based study of
8,076 subjects, Asselbergs et al. showed that although ST-segment and
T-wave abnormalities were modest univariate correlates of an increased
CRP, only Q-wave myocardial infarction remained associated with
increased CRP levels after adjusting for standard cardiovascular risk
factors [16]. In fact, in our study, although increased level of
hs-CRP could effectively predict STEMI, however we could not reveal
association between elevated level of this marker and left ventricular
dysfunction assessed by echocardiography. On the other hand, early
increased level of hs-CRP may predict early ischemic events such as
STEMI; however occurrence of left ventricular dysfunction or other
echocardiographic events may need to more time. So, it has been shown
that even a mild elevation of the CRP level in STEMI patients may be
associated with worsening of diastolic function and elevated left
ventricular filling pressure, independent of left ventricular systolic
function or cardiac out-put. Previous studies have demonstrated the
relation of early CRP elevation with left ventricular systolic function,
future heart failure, and mortality in MI patients [17–21].
Besides, our study finding on insignificant association between elevated
level of hs-CRP and echocardiographic indices such as left ventricular
dysfunction and hypertrophy may be affected by considering a narrow
range of hs-CRP measurements in our study population ranged less than
10, so considering a wide range of CRP may reveal positive association
between elevation of hs-CRP level and left ventricular dysfunction and
hypertrophy in echocardiography.
For explaining pathophysiological fundaments of inducing STEMI following
elevation of hs-CRP, it has been shown that myocardial infarction size
following acute coronary occlusion can be determined by complement
mediated inflammation, and that human CRP, indicated in both human and
animal studies, can be responsible for some of this complement
activation [22]. Some other mechanisms revealed for this event
include increasing phosphatidylinositol3-kinase activity, upregulating
inducible nitric oxide synthase, certain cell signal transduction
pathways including the mitogen-activated protein kinase pathway, and
nuclear factor κ-B, upregulating angiotensin II type 1 receptor in
vascular smooth muscle cells, and directly quenching the production of
nitric oxide by endothelial cells, resulting in increased production of
endothelin-1, and elevation of von Willebrand factor, which is known to
be associated with endothelial dysfunction [23-27].
In conclusion, elevated level of serum hs-CRP can effectively predict
occurrence of STEMI in patients with acute coronary syndrome. The
present study could not demonstrate predictive role of this biomarker
for abnormal echocardiographic changes including left ventricular
hypertrophy or dysfunction as well as abnormal regional wall motion
abnormality probably due to considering a narrow range of hs-CRP (less
than 10) or employing a small sample size.
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Table 1: Comparing baseline characteristics between the study groups