C-reactive Protein is a Predictor of Mortality in ST-segment Elevation Acute Myocardial Infarction

Results: Of the 118 patients analyzed, 20 died during hospitalization. Higher levels of hs-CRP (p = 0.001) and older ages (p = 0.003) were observed among those patients who died. Logistic regression showed that a one unit increase in hs-CRP increased the risk of death by 15% (p = 0.0017), after adjustment for established risk factors. Similarly, each one-year increase in age increases the risk of death by 6.6% (p = 0.003).


Introduction
Cardiovascular diseases are the leading cause of mortality and morbidity in the world. 1 Inflammation is thought to be the key mechanism in the pathogenesis of atherosclerosis and the value of assessing the levels of inflammatory biomarkers has risen. 2 Many prospective cohort studies have demonstrated that baseline levels of high-sensitivity C-reactive protein (hs-CRP) in apparently healthy men and women are highly predictive of future risk of heart attack. 3wever, inflammation is important in all phases of heart disease, including in the short-term prognosis after acute myocardial infarction (AMI). 3In recent years, many inflammatory biomarkers have been studied to determine whether increased levels of these molecules are related to a poor prognosis in patients who have had myocardial infarction.Several studies have shown an association between C-reactive protein (CRP) and recurrent coronary events in patients with acute coronary syndrome. 3,4P is a plasma protein of the pentraxin family, widely used as a general inflammatory marker, since it is an acute phase protein synthesized by hepatocytes in response to proinflammatory cytokines, particularly interleukin-6.Currently, among systemic markers of inflammation, hs-CRP has been the most studied risk predictor in the clinical practice. 1,5

Original Article
One of the main components of the response to tissue injury caused by myocardial infarction is a robust inflammatory reaction. 6,7In the early phase of myocardial infarction, hs-CRP may be a simple marker of the magnitude of the inflammatory response to myocardial ischemia, potentially providing prognostic information regarding the risk of death. 6,8,9 aimed to evaluate the association of hs-CRP levels on admission, and other clinical characteristics with occurrence of in-hospital death of patients with acute ST-segment elevation myocardial infarction (STEMI).

Study design
A retrospective cohort study of 136 patients admitted with acute STEMI to the emergency department or the coronary care unit during a one-year period was conducted.Eighteen patients were excluded from the study because of insufficient data, and thus 118 patients were analyzed.The following variables were evaluated -sex, age, diabetes mellitus, smoking habit, drinking habit, reperfusion therapy, arterial hypertension, hs-CRP on admission, and body mass index (BMI).
We identified a cohort of patients with a median age of 60 years old (interquartile range of 19.75 years), 69% of males.Table 1 shows clinical characteristics of the cohort.ST-segment elevation was identified at first admission to the emergency department or the coronary care unit and myocardial infarction was diagnosed according to the Joint European Society of Cardiology/American College of Cardiology 10 criteria.
Diabetes mellitus was defined as fasting plasma glucose ≥ 126 mg/dL, glycated hemoglobin ≥ 6.5%, or treatment with insulin or hypoglycemic agents.Patients with systolic/ diastolic blood pressure > 140/90 mmHg or using any antihypertensive medication were defined as hypertensive.Drinking habit was defined as ingestion of alcoholic beverage in the last year, whereas cigarette smoking was defined as active smoking in the last six months.

Blood sampling and hs-CRP assay
Venous blood samples were obtained on admission and serum hs-CRP was determined by the turbidimetric method.This method assesses agglutination of latex particles coated with antibody against CRP by quantifying the absorbed light.The assay has a detection limit of 0.4 mg/dL

Statistical analysis
Data were analyzed by the computer software program R (R CORE TEAM, 2017), version 3.4.0.Descriptive characteristics were calculated for continuous variables (median and interquartile range, IQR) and for categorical variables (frequency/percentage).Our data followed a non-normal distribution.Continuous variables were analyzed by non-parametric Mann-Whitney U test, whereas categorical variables were analyzed using the chi-square test.Also, predictive factors were identified using binary logistic regression analysis after adjusting for age and hs-CRP.Multivariate analysis was performed expressing odds ratio per one unit increase in independent continuous variables.
A p-value of < 0.05 was considered statistically significant.
The institutional review committee on human research approved the study protocol.

Results
We Clinical characteristics, hs-CRP levels at admission and use of reperfusion therapy of patients categorized by group, according to occurrence of in-hospital death, are shown in table 2. There were no significant differences regarding reperfusion therapy between patients who died and those who survived.Body mass index did not significantly differ between the two groups.The prevalence of diabetes was higher in patients who died (40%) comparing with those who survived (32.65%), but the difference was not significant between the groups (p = 0.7089).
Smoking and drinking habits were not statistically associated with in-hospital death.Regarding sex distribution, the proportion of females was 40% among those who died and 29.6% among survivors.This difference was not statistically significant (p = 0.51).
Systemic arterial hypertension had no influence on inhospital mortality in this group of patients with infarction even on univariate analysis.
In univariate analyses, we observed (Figure 1) significantly higher levels (p = 0.001) of hs-CRP in patients who died (median 10.47 [IQR 23.99]) compared to those who survived (median 2.13 [IQR 5.66]).Therefore, in patients with STEMI, an increase in the hs-CRP level at admission is associated with a poorer short-term prognosis and may represent an independent factor for death in the hospital.
A clear association between age and in-hospital death was also observed.Median age was significantly higher (p = 0.003) in patients who died (median 73 [IQR 22.75]) than in those who survived (median 59 [IQR 17]).
Multiple logistic regression analysis was performed to evaluate the independent contribution of hs-CRP levels to the risk of death.By binary logistic regression analysis (Figure 2), in-hospital death was associated with higher concentration of hs-CRP (odds ratio = 1.15 per unit increase; p = 0.0017) and older age (odds ratio = 1.066 per one year increment; p = 0.003).Therefore, a one unit increase in hs-CRP increased the risk of death by 15%, after adjustment for established risk factors.Similarly, a one year increase in age increased the risk of death by around 6.6% in patients with same hs-CRP levels.

Discussion
Our results demonstrated an important relationship between hs-CRP level on admission and in-hospital mortality after STEMI.
The present study showed a mortality rate after AMI of 16.9%, which is similar with those reported in previous studies (3.2-20.6%). 11,12

Original Article
Our results also demonstrated that in-hospital mortality after STEMI was strongly associated with elderly patients.Previous studies have investigated the relationship between age and death in patients with AMI and showed that age is an important predictor of mortality in these cases. 13 England, one third to half of the patients admitted to a hospital with acute myocardial infarction are older than 70 years, 14 whereas 74.4% of the deaths attributed to this condition occur in patients older than 70 years. 15There are many possible reasons for this.Elderly population has more severe coronary artery disease, receive less adequate treatment than younger individuals, and presents later at the hospital after the onset of infarction symptoms. 16garding sex distribution, our results demonstrate a higher proportion of females among those who died (40%) comparing to survivors (29.6%, p = 0.51).Several studies have already shown that female sex is independently associated with early mortality after STEMI. 13e present study also demonstrates a strong, positive association between hs-CRP obtained on admission and in-hospital mortality.
8][19][20] It allows CRP levels to be a simple marker of the magnitude of the inflammatory response to myocardial ischemia, potentially providing prognostic information regarding the risk of death. 8,9[23] Besides myocardial necrosis and ischemia, other kinds of tissue damage could cause CRP elevation in patients with AMI, such as atherosclerotic mass, underlying inflammatory process and circulating proinflammatory cytokines. 24ere have been several studies on the prognostic value of hs-CRP in AMI.High sensitivity CRP has been shown to be associated with hospital outcomes, such as death, myocardial infarction and angina, 4,[25][26][27][28][29][30][31] suggesting it to be a useful biomarker in risk assessment of patients with acute coronary syndrome.
Raposeiras-Roubín et al., 32 also evaluated the prognostic value of hs-CRP, showing that a higher level of hs-CRP is a predictor of in-hospital cardiac events in acute MI, independently of the GRACE (Global Registry of Acute Coronary Events) risk score.Tanveer et al., 33 analyzed 190 patients with STEMI to investigate the relationship between hs-CRP level and complications of myocardial infarction.However, there were no significant differences in hs-CRP values between patients who died and who survived during hospitalization.Suleiman et al., 7 reported that patients with AMI with higher CRP levels on admission were older, had higher baseline creatinine levels and were at increased risk of long-term development of heart failure.Schiele et al., 34 showed an independent predictive role of CRP in patients with acute coronary syndrome; those in the highest quartile of CRP showed increased mortality rates at 30 days of follow-up.
In recent years, there has been an attempt to predict the risk of early adverse events in patients with STEMI.In order to stratify STEMI patients according to this risk, risk scores have been created with a strong prognostic capacity, such as the GRACE risk score.Inflammatory markers can add prognostic information to these scoring systems even in the current era of high-sensitivity cardiac troponin assays. 35I is associated with an extensive myocardial inflammation, which leads to a systemic inflammatory response. 6,36Our results demonstrate that hs-CRP can measure inflammatory response to tissue injury after a STEMI, providing a means for assessing short-term prognosis and the risk of death.
The present study also has some limitations, because it is a retrospective study and it could not establish a cut-off point for CRP level in relation to mortality.This study can help us better understand the prognostic significance of hs-CRP levels over the AMI spectrum, however further studies are needed to elucidate the inflammatory process due to myocardial ischemia.

Conclusions
Our results demonstrate a strong, positive association between high-sensitivity C-reactive protein obtained on admission and in-hospital mortality after STEMI.Moreover, in-hospital mortality is tightly associated with elderly patients.These findings suggest that hs-CRP levels can measure inflammatory response to myocardial ischemia after STEMI, providing prognostic information regarding the risk of death.Therefore, CRP on admission of patients with STEMI is a strong univariate predictor of mortality.
Milano et al.C-reactive protein as a predictor of mortality Int J Cardiovasc Sci.2018; [online].aheadprint, PP.0-0 Original Article

Table 1 -General characteristics of the cohort
*Thrombolytic therapy or primary angioplasty; hs-CRP: highsensitivity C-reactive protein; BMI: body mass index.Milano et al.C-reactive protein as a predictor of mortality Int J Cardiovasc Sci.2018; [online].aheadprint, PP.0-0

Table 2 -Statistical association of risk variables with in-hospital mortality Variable Median (IQR) or n (%) p value Survived (n = 98) Died (n = 20)
1. Data analyzed by non-parametric Mann-Whitney U test. 2. Data analyzed using the chi-square test.* Thrombolytic therapy or primary angioplasty.IQR: Interquartile range; hs-CRP: high-sensitivity C-reactive protein; BMI: body mass index.