Heart failure could be described as a modern plague, as it is the leading cause of hospital admissions in the United States [
The assessment of the risk for developing left ventricular systolic dysfunction and eventually systolic heart failure in ACS patients is of considerable clinical and public health importance; while the comparative role of CRP and WBC count in occurence of left ventricular systolic dysfunction in the setting of ACS is still unclear.
The aim of this study is to investigate the implication of inflammation, characteristically expressed by the levels of CRP, and white blood cell count, on the occurrence of LVSD in the acute coronary syndrome (ACS) process, thus providing insights in the contribution of inflammation to the deterioration of the systolic function of the heart in the setting of ACS. Moreover, we aim to estimate the comparative predictive value of the two markers assessed.
During 2006–2008, we enrolled 798 consecutive patients who developed an ACS event. From the above we finally included in the study 283 males (
At entry a 12-lead electrocardiogram was performed, and clinical symptoms were evaluated in all patients, by a cardiologist of the study. Based on the electrocardiographic findings patients were classified as having ST-segment elevations, non-ST segment elevations, or other electrocardiographic abnormalities. Moreover, troponin I measurements were performed to detect evidence of myocardial cell death. We included only cases with diagnosis of ACS (acute myocardial infarction (MI) or unstable angina (UA)). In particular, acute myocardial infarction was defined according to the latest guidelines [
Using a Hewlett Packard 5500 Sonos with a multifrequency transducer (2, 5-4 MHz) we evaluated the systolic function of the left ventricle during the first 48 hours and at the discharge day. Systolic heart failure was defined as left ventricular ejection fraction at the discharge day below 40%, according to the recent European Society of Cardiology guidelines for the diagnosis and treatment of acute heart failure [
The study was approved by the Medical Research Ethics Committee of our Institution and was carried out in accordance with the Declaration of Helsinki (1989) of the World Medical Association, while each patient gave written consent for participating.
In all patients a detailed medical history was recorded, including previous hospitalization for cardiovascular disease (i.e., coronary heart disease, stroke, or other cardiovascular disease), presence and management of hypertension, hypercholesterolemia, renal failure, and diabetes mellitus. Moreover, we recorded patients’ medical family history. In addition to troponin I, we also measured the MB fraction of creatine phosphokinase (CPK), urea, and uric acid. The biochemical evaluation was carried out in the same laboratory that followed the criteria of the World Health Organization Reference Laboratories. Total-, high-density lipoprotein, cholesterols, blood glucose, and triglycerides were also measured in all participants, using colorimetric enzymic method in a Technicon automatic analyzer RA-1000 (
White blood cell count was measured at the initial blood test at entry, and C-reactive protein levels were measured during the first 12 hours of hospitalization, specifically at 9:00 a.m. of the next morning. CRP levels were measured by nephelometry.
Renal insufficiency was initially quantified by the baseline estimated creatinine clearance rate (CrCl). Based on baseline serum creatinine (Cr), the CrCl was calculated using the Cockcroft-Gault formula (14): CrCl = [[(140
Sociodemographic characteristics included age, sex, marital status, number of children, years of school, type of occupation. Height and weight were measured and to the nearest 0.5 cm and 100 g, respectively. Body mass index (BMI) was then calculated as weight (in kilograms) divided by height (in meters) squared. Physical activity was defined as any type of exercise (occupational or leisure) at least once per week during the past year. Other participants were defined as physically inactive. Current smokers were defined as those who smoked at least one cigarette per day or have stopped cigarette smoking during the past 12 months. Former smokers were defined as those who had stopped smoking more than one year previously. The rest of them were defined as never smokers or rare smokers.
In this work continuous variables are presented as mean values
Table
Clinical characteristics of the patients according to systolic heart function.
With LVSD | Without LVSD | ||
---|---|---|---|
356 | 404 | ||
Age (yrs) | .17 | ||
Male sex (%) | 80 | 78 | .58 |
BMI (Kg/ | .14 | ||
Systolic blood pressure at entry | .013 | ||
Diastolic blood pressure at entry | .05 | ||
Heart rate at entry | .71 | ||
Diagnosis MI (%) | 84 | 71 | |
Number of Vessel disease | |||
Previous CHD (%) | 49 | 47 | .62 |
Time delay (min) | .65 | ||
Troponin I at entry | |||
Uric acid (mg/dL) | |||
Blood glucose at entry (mg/dL) | .01 | ||
CRP (mg/L) | |||
WBC count | .05 | ||
Creat clear (mL/min) | .01 | ||
Ht (%) | .93 | ||
LDL (mg/dL) | .59 | ||
Prior statin therapy (% hyperlipidemics) | 44 | 42 | .21 |
Current smoking % | 49 | 47 | .49 |
Physical activity (%) | 58 | 66 | .30 |
Hypertension (%) | 59 | 62 | .36 |
Receiving medication for hypertension (%) | 41 | 49 | .32 |
Diabetes mellitus (%) | 36 | 30 | .13 |
Receiving oral medication for diabetes mellitus (%) | 31 | 36 | .08 |
Insulin therapy (%) | 30 | 33 | .18 |
LVSD indicates left ventricular systolic dysfunction; BMI indicates body mass index; Ht indicates hematocrit; Time delay = time in minutes from symptoms onset till hospitalization; Previous CHD: previous known coronary heart disease.
Then, we divided WBC count in tertiles (lower tertile
Results from ANOVA that presents the distribution of clinical and biochemical characteristics among WBC tertile.
1st tertile | 2nd tertile | 3rd tertile | ||
WBC | WBC | |||
225 | 235 | 237 | ||
Age (yrs) | ||||
Male sex % | 76 | 80 | 82 | .287 |
Body mass index (Kg/m2) | .132 | |||
Time delay (min) | .251 | |||
Presence of MI, % | 63 | 77 | 90 | |
History of CHD, % | 45 | 35 | 24 | |
Troponin I at entry (ng/mL) | .004 | |||
Smoking, % | 34 | 54 | 56 | |
Hypertension, % | 63 | 63 | 58 | .480 |
Diabetes % | 35 | 28 | 33 | .303 |
Hypercholesterolemia, % | 55 | 60 | 58 | .754 |
Creatinine clearance | ||||
Systolic blood pressure at entry (mm Hg) | .26 | |||
Diastolic blood pressure at entry (mm Hg) | .55 | |||
Heart rate at entry (beats/min) | .05 |
Time delay: time in minutes from symptoms onset till hospitalization; MI: myocardial infarction; History CHD: previous known coronary heart disease.
Results from ANOVA that presents the distribution of clinical and biochemical characteristics among CRP tertile.
1st tertile | 2nd tertile | 3rd tertile | ||
CRP | CRP | |||
207 | 209 | 204 | ||
Age (yrs) | .014 | |||
Male sex % | 80 | 77 | 81 | .549 |
Body mass index (Kg/ | .709 | |||
Time delay (min) | .721 | |||
Presence of MI, % | 75 | 85 | 90 | |
History of CHD, % | 31 | 28 | 26 | .625 |
Troponin I at entry (ng/mL) | .006 | |||
Smoking, % | 45 | 53 | 51 | .221 |
Hypertension, % | 63 | 56 | 59 | .310 |
Diabetes % | 27 | 30 | 35 | .180 |
Hypercholesterolemia, % | 62 | 59 | 51 | .299 |
Creatinine clearance | .007 | |||
Systolic blood pressure at entry (mm Hg) | .97 | |||
Diastolic blood pressure at entry (mm Hg) | .68 | |||
Heart rate at entry (beats/min) | .28 |
Time delay: time in minutes from symptoms onset till hospitalization; MI: myocardial infarction; History CHD: previous known coronary heart disease.
Logistic regression analysis, after controlling for sex, age, diagnosis of myocardial infarction, troponin I levels at entry, systolic and diastolic blood pressure levels at entry, and creatinine clearance, revealed that an increase per 10 mg/L of serum CRP levels independently increases by 6% the likelihood of developing LVSD after an acute coronary event (OR =
Results from logistic regression model that evaluated the role of CRP and WBC (independent covariates) on the occurrence of LVSD in patients who had had an acute coronary event, after adjustment for several common confounders*.
Odds ratio | 95% confidence interval | |
---|---|---|
Model 1: CRP (per mg/L) | 1.06 | 1.02–1.10 |
Model 2: WBC (per 1000 count) | 1.07 | 1.02–1.12 |
*Covariates also used in both models were age, sex, diagnosis of myocardial infarction, creatinine and troponin I levels at entry, systolic, and diastolic blood pressure levels at entry.
We used two logistic regression models using the same confounders each time and entering CRP the first time and WBC count afterwards. Comparing the
In this study we revealed that higher values of white blood cell count are associated with higher probability of developing left ventricular systolic dysfunction after an acute coronary syndrome, independently of diagnosis of myocardial infarction or other common conditions that might contribute to this. We also demonstrated that CRP is an independent predictor of development of left ventricular systolic dysfunction after an ACS, as well, after controlling for common confounders (including myocardial infarction diagnosis). Although WBC count seems to be a slightly more powerful predictor for the development of systolic dysfunction than CRP, this difference was not statistically significant.
In the setting of acute coronary syndromes, inflammation is known to have a key role in disease progression and development of complications. We assessed left ventricular dysfunction occurrence using two widely used and easily measured markers: CRP is a proven marker of inflammation, yet the WBC count seem to hold its role in predicting poor prognosis in a manner that exceeds just inflammation.
It is well known that the leucocyte count is elevated in the setting of myocardial infarction. Leukocytes are the first cells drawn to an infarct area of necrosis trying to repair the tissue damage. As we revealed in our study that the initial WBC count seems to be higher in younger patients, who more frequently suffer from myocardial infarction rather than unstable angina, have higher heart rate at entry, have higher troponin I levels, have less frequently prior history of coronary heart disease, and are more often current smokers (Table
The leukocytes seem to mediate left ventricular systolic dysfunction in the setting of an acute coronary syndrome in many ways; elevated white blood cell count is associated with more extensive coronary artery disease, as assessed by coronary angiography [
It appears that leykocytes may have an important role in tissue repair, but seem to enhance a portion of further tissue damage, thus explaining their contribution to the development of systolic dysfunction, regardless of the infarct itself.
It is previously shown that CRP is elevated in cases of myocardial infarction, as CRP rises in response to various inflammatory stimuli, including tissue necrosis and myocardial infarction [
CRP may be linked to left ventricular systolic dysfunction progression through three different mechanisms: its relation to the extent of coronary artery disease, its relation to thrombus burden, and the proinflammatory effect that may mediate further tissue damage in cases of myocardial infarction. CRP is reported to be associated to CAD extent in myocardial infarction patients [
It is known that CRP concentration demonstrates diurnal variation that is statistically significant and may bias epidemiological studies [
Among the two inflammatory markers assessed in this work, the WBC count seems to have a slightly better predictive power for the development of left ventricular systolic dysfuncton after an ACS, when compared to CRP. CRP is related to systolic dysfunction after an ACS through three different mechanisms: that of total atherosclerotic burden which means that it is related to more extensive coronary vascular disease, that of thrombus burden which means that having procoagulant effects, may account for a portion of thrombus formation, and that of inflammatory escalation. On the other hand, leukocytes are implicated more actively and in more pathophysiologic steps than CRP; they are related to more extensive coronary vascular disease and they contribute to inflammatory escalation, oxidative stress, proteolytic enzymes release; microvascular plugging, lytic action of macrophages. This can partly explain the findings of another study that associates high neutrophil count (among all leucocyte subtypes) with higher mortality rates following an ACS, independently of CRP levels [
In retrospective case-control studies, two main sources of systematic errors may exist, the selection and the recall bias. In order to eliminate selection bias we tried to set objective criteria, both for patients and controls having the same echocardiographic evaluation of left ventricular function obtained by two independent physicians at the discharge day, in order to eliminate the impact of stunning myocardium of the first days after the event. Also, in case-control studies, it is usually observed that patients who had a recent adverse event are more likely to place greater emphasis (overestimate) on several factors related to the disease than the control group (recall bias). In order to reduce this type of bias, we made an effort to obtain accurate information from the patients as well as from their relatives or their accompanying persons. Besides, the two groups were patients with different disease severity. Another limitation is that we have also included patients with previous history of coronary heart disease. These patients may have had impaired left ventricular function before the index event. In order to eliminate this bias we have included the information of previous known history of coronary heart disease in the multivariate analysis; the percentage of patients with previous CHD history had no significant difference between the two groups of patients.
The CRP assay was not a high sensitivity one, but this fact is not expected to influence our results, as all patients are suffering from an acute coronary syndrome and are, therefore, expected to exhibit elevated values of CRP.
Concerning the medical information, we tried to avoid recall bias by obtaining accurate and detailed data from subjects’ medical records. However, over/under estimation may still exist, especially in the measurement of smoking habits and the onset of the investigated cardiovascular risk factors. Moreover, the coronary patients who died at entry or the day after were not included in the study. This bias could influence our results, but, since the proportion of deaths during the first two days was estimated between 2–4%, we believe that the inability to include the fatal events did not alter significantly our findings. Furthermore, regarding the potential effect of uncontrolled—unknown confounders, we tried to reduce it by using the same study base, both for patients and controls, but their influence on the outcome may still exist.
Elevated WBC and CRP levels are independent predictors of development of left ventricular systolic dysfunction after an ACS, regardless of several confounders including diagnosis of myocardial infarction. The WBC count seems to be slightly more predictive than CRP in this direction. Hopefully clinicians may consider the initial WBC count and CRP as almost equally powerful measures of possible left ventricular systolic dysfunction occurence, that may lead to heart failure. The inflammatory process may also be targeted for therapy, as this may provide some protection against heart failure occurrence.