Invest Clin 61(1): 39 - 49, 2020 https://doi.org/10.22209/IC.v61n1a04

A comparison of macrophage migration inhibitory factor with C reactive protein in diabetic hypertensive patients with myocardial infarction that underwent

primary percutaneous coronary intervention.

Feyan Mirdan Abdullah and Ruqaya Mohammed Ghareeb Taher Al-Barzinji

Unit of Medical Microbiology, Department of Basic Sciences, College of Medicine, Hawler Medical University, Erbil, Iraq.

Key words: diabetes mellitus; hypertension; macrophage migration inhibitory factor; high sensitivity C-reactive protein; myocardial infarction.

Abstract. The inflammatory response is one of the complications of dia- betic hypertensive patients with myocardial infarction (MI). The purpose of this study was to determine the diagnostic value of macrophage migration inhibi- tory factor (MIF) compared with high sensitivity C reactive protein (hs-CRP) in diabetic hypertensive patients presented with MI; and to determine the con- comitant association between these factors in MI patients. For this purpose, 100 patients with MI were categorized into four groups, according to the exis- tence of diabetes mellitus (DM) and/or hypertension (HTN), with 38 subjects with normal angiography considered as the control group. The levels of MIF and hs-CRP were estimated quantitatively using a sandwich enzyme-linked immu- nosorbent assay and a particle-enhanced immune turbidimetric assay, respec- tively. In addition, lipid profiles, hematological indicators, and certain clinical features were compared among the studied groups. The levels of MIF and hs- CRP increased significantly in MI patients compared to the controls (p<0.05). Additionally, the levels of MIF differed significantly between all MI groups and the control group (p<0.05). Although the group DM-HTN showed the highest MIF level within the MI groups, the difference was not significant (p>0.05). However, the hs-CRP level showed a significant difference (p<0.05). In addi- tion, the MIF level correlated positively with hs-CRP, leukocytes, and neutro- phils (p<0.05). Both MIF and hs-CRP levels correlated positively with age, body mass index (BMI), total cholesterol, triglyceride, low-density lipoprotein-cho- lesterol (LDL -C) and non-high density lipoprotein (HDL), but they correlated negatively with HDL -C. According to the results, although MIF was a valuable diagnostic marker for MI, the hs-CRP showed to be a better prognostic indica- tor than MIF in diabetic hypertensive patients that presented MI.

Corresponding Author: Feyan Mirdan Abdullah, Unit of Medical Microbiology, Department of Basic Sciences, College of Medicine, Hawler Medical University, Erbil, Iraq. Phone: +964- 750-432-5540. E-mail: awa198011@gmail.com

Comparación entre el factor inhibitorio de la migración de macrófagos con la proteína C reactiva en pacientes diabéticos hipertensos con infarto del miocardio, sometidos a una intervención coronaria percutánea primaria.

Invest Clin 2020; 61 (1): 39-49

Palabras clave: diabetes mellitus; hipertensión; factor inhibidor de la migración de ma- crófagos; proteína C- reactiva de alta sensibilidad; infarto de miocardio.

Resumen. La respuesta inflamatoria es una complicación del infarto de miocardio (IM) en pacientes diabéticos hipertensos. Este estudio se realizó para determinar el valor diagnóstico del factor inhibitorio de la migración de macrófagos (MIF) en comparación con la proteína C reactiva de alta sensibi- lidad (hs-PCR), en pacientes diabéticos hipertensos con IM; y también para precisar la asociación concomitante entre estos factores en pacientes con IM. Con este propósito, 100 pacientes con IM se clasificaron en cuatro grupos, de acuerdo con la existencia de diabetes mellitus (DM) y/o hipertensión (HTN) y 38 sujetos con angiografía normal se consideraron como el grupo control. Los niveles de hs-PCR y MIF se estimaron cuantitativamente utilizando un ensayo inmunoabsorbente ligado a enzimas y un ensayo inmunoturbidimétrico mejo- rado con partículas, respectivamente. Además, se compararon entre los grupos del estudio, los perfiles lipídicos, parámetros hematológicos y algunas caracte- rísticas clínicas específicas. Los niveles de MIF y hs-PCR aumentaron significa- tivamente en pacientes con IM en comparación con los controles (p<0,05). Así mismo, los niveles de MIF fueron significativamente diferentes entre todos los grupos con IM y el grupo control (p<0,05). Aunque el grupo DM-HTN mostró el nivel más alto de MIF dentro de los grupos IM, la diferencia no fue estadística- mente significativa (p>0,05). Sin embargo, los niveles de hs-PCR sí mostraron una diferencia significativa (p<0,05). Adicionalmente, los niveles de MIF se co- rrelacionaron positivamente con la hs-PCR, leucocitos y neutrófilos (p<0,05). Tanto los niveles de hs-PCR como los de MIF se correlacionaron positivamente con la edad, índice de masa corporal, colesterol total, triglicéridos, LDL -C, y no HDL, pero mostraron una correlación negativa con HDL -C. Según los resul- tados, aunque el MIF representó un valioso marcador de diagnóstico para el infarto de miocardio, la hs-PCR mostró ser un mejor indicador pronóstico que el MIF para pacientes diabéticos hipertensos con IM.

Received: 22-08-2019 Accepted: 23-01-2020

INTRODUCTION

Evidence shows that inflammation oc- curs at every stage of coronary atherosclero- sis, which starts from fatty streaks as well as plaque development and ends in its rupture, causing acute coronary syndrome (ACS) (1),

including myocardial infarction (MI) (2). The coexistence of both, diabetes mellitus (DM) and hypertension (HTN), appears to be relat- ed to mortality more frequently in patients with ACS than in those with either DM or HTN (3). Macrophage migration inhibitory factor (MIF) is a proinflammatory and pro-

atherosclerotic factor involved in the induc- tion of foam cell production, atheroprogres- sion, and plaque vulnerability (4). Reports indicate that deficiencies in MIF prevent the heart from suffering ischemia reperfusion damage in mice by overcoming the inflam- matory response (5). In addition, reports indicate that MI results in the fast release of MIF from myocardium to the circulatory system. As a result, MIF makes peripheral blood mononuclear cells produce proinflam- matory mediators and facilitates myocardial inflammatory responses. The weakening of these events and the post-MI cardiac rupture by the anti MIF anti-body suggests that MIF could be a possible therapeutic target after MI (6).

It has been reported that high sensi- tivity C-reactive protein (hs-CRP) levels are elevated in patients with coronary artery atherosclerosis, which is associated with its severity and complications (7); howev- er, the principal mechanisms of hs-CRP as a catalyst of ACS, for instance MI, are not fully known. Research has revealed that hs- CRP presumably activates complements and leads to the persistence of the inflammatory process of plaque or causes plaque rupture and its bleeding, yet it has not been deter- mined whether the level of hs-CRP is asso- ciated with the severity of the damage (8). This study aims to compare the diagnostic significance of MIF with that of hs-CRP in MI diabetic hypertensive patients and to deter- mine the correlation between both factors in MI patients.

MATERIALS AND METHODS

A total of 100 patients with MI was en- rolled consecutively in this case control study, who attended the emergency department of the surgical specialty hospital-cardiac center in Erbil City, Iraq, for primary percutaneous coronary intervention (PCI) during the pe- riod from January 2017 to December 2017. MI was diagnosed based on the World Health Organization (WHO) criteria, including clin-

ical history, abnormal electrocardiogram (ECG) findings, and raised cardiac markers (troponin and creatine kinase-MB) (9). An angiography was performed for all patients with positive troponin, and patients with no arterial occlusion were excluded from the study.

In addition, stroke and post-MI pa- tients, those with heart failure, congenital heart disease, cardiomyopathy, myocarditis, pericarditis, severe valvular heart disease, the ones with the history of recent surger- ies or traumas, malignancies, active inflam- matory or autoimmune diseases, as well as those with bleeding and clotting disorders were excluded from the study. Patients were categorized into the following groups, based on the patients’ history of DM and/or HTN:

1. Those with neither DM nor HTN

2. Those with only DM but no HTN

3. Those with only HTN but no DM

4. Those with both DM and HTN

The study excluded certain groups such as DM without MI or HTN, as the main point of the study was focusing on MI and the men- tioned group was not engaged within the study aim.

The control group included 38 sub- jects who were confirmed angiographically to have normal coronary arteries and found out to have chest pain not related to cardiac source and showed no any apparent mean- ingful manifestations of lung alteration. The serum concentrations of high-sensitive car- diac troponin T and CKMB were within the allowed ranges. Subjects in this group did not suffer from DM and obesity.

The study protocol was approved by the medical ethics committee at the Col- lege of Medicine, Hawler Medical University. Information on the medical history was ob- tained during personal interviews using es- pecially formatted questionnaires. Diabetic patients were diagnosed on the basis of the past history of DM in case they were treated with or without anti-diabetic therapies and

were confirmed to have haemoglobin A1c (HbA1c) level >6.5% (10). In the same vein, hypertension (≥140/90 mmHg) was con- firmed based on one of the factors of past diagnosis, the receiving of antihypertensive drugs at present, and repetitive blood pres- sure measurements minimally 2-3 times un- der stable conditions. Weight (kg)/height m2 was the standard method for calculating the body mass index (BMI).

Coronary angiography (COA) was per- formed for all study groups, i.e. patients and controls, on the right femoral artery as a standard method for the decision of hav- ing either normal or diseased artery, which achieved only to those who admitted for dif- ferent reasons (for example atherosclerotic coronary artery disease, MI, and chest pain. The control group comprised individuals who complained from chest pain but were confirmed by angiography to have normal coronary arteries (no lesions). Many other reasons could be the source for the chest pain, for example psychological causes like severe depression and severe stress, but ac- tually we were just concerned if the patient was free from chest pain related with cardiac origin but no other causes. All patients re- ceived the loading doses of aspirin (300 mg) and clopidogrel 300-600 mg; or were reload- ed with ticagrelor 180 mg before the angi- ography procedure and with heparin prior to PCI for patients confirmed to have had a new arterial occlusion. Diagnostic and guiding catheters were used through a 6 French fem- oral sheath to engage the coronary sinuses. All patients with new arterial occlusion un- derwent PCI for culprit lesions. The location of the culprit lesions and the number (one, two, or three) of the affected vessel(s) were determined using COA findings.

Blood samples were drawn from all par- ticipants immediately after admission and prior to COA using the venipuncture tech- nique. Serum and plasma were obtained from the collected blood and stored at -80°C for further analysis. Baseline laboratory inves- tigations of biochemical and hematological

tests were carried out for all participants. The plasma MIF level was measured quanti- tatively using the human MIF ELISA kit (My- biosource, USA). Cobas c111 was used to de- termine hs-CRP (Roche Diagnostics GmbH) concentrations based on the particle en- hanced immunoturbidimetric assay. HbA1c and lipid profiles were analyzed using cobas c111 (Roche Diagnostics GmbH), and the to- tal blood count was determined using Swelab Alpha Coulter Analyzer (Swelab, Sweden).

Data were analyzed statistically using SPSS Statistics 23.0. The continuous vari- ables of the studied groups were determined as mean ± SE. The one-way analysis of vari- ance (ANOVA) was used for multiple com-

parisons. Student’s 𝑡-test was performed to

compare the two continuous parameters. In

addition, categorical variables were evaluated using a chi-squared test or Fisher’s exact test. The correlation between MIF and hs-CRP as well as the correlation between the two mark- ers and other study parameters were deter- mined using Pearson’s correlation coefficient. P-value was considered significant at P<0.05.

RESULTS

As Table I shows, the levels of MIF and hs-CRP increased significantly in MI patients compared to the controls (P<0.05). In ad- dition, the increased levels of leukocytes, neutrophils, platelets, low density lipopro- tein–cholesterol (LDL -C), non-high density lipoprotein-cholesterol (HDL -C), total cho- lesterol/HDL, LDL/HDL, BMI, and HbA1c differed significantly between the two groups (P<0.05). No statistically significant differ- ences were observed between the patients and the controls in systolic blood pressure (SBP), diastolic blood pressure (DBP), cho- lesterols, and triglycerides (P>0.05). Ac- cording to the COA results, the majority of MI patients had three diseased vessels, and the most frequently affected artery was the left anterior descending artery (LAD), fol- lowed by the right coronary artery (RCA) and the left circumflex (LCX).

TABLE I

BASELINE CHARACTERISTICS OF MYOCARDIAL INFARCTION PATIENTS AND CONTROLS

Values are presented as mean± SE and n (%) for continuous variables (t-test) and categorical variables, respectively. MI: myocardial infarction.

Non-DM, Non-HTN represented 30% of the MI groups, followed by DM-HTN, HTN only, and DM only (28%, 24%, and 18% re- spectively). The mean values of age, BMI, total cholesterol, triglycerides, LDL -C, non- HDL, total cholesterol/HDL, and LDL /HDL were higher in the group DM-HTN. Increased levels of inflammatory markers were ob- served in all MI groups compared to the con- trol group. Although the group of diabetic hypertensive patients showed an increase in MIF, hs-CRP, and platelet count, a significant difference was observed only in hs-CRP com- pared with other MI groups (p<0.05). The details are illustrated in Table II.

Patients aged ≥55 were found more in the DM-HTN group (78.57%) than in other groups. A higher rate of smokers was found in the group HTN only (83.33%), followed by group DM-HTN (82.14%). The mean duration of DM and HTN was higher in the group DM- HTN than in the groups DM only and HTN only, respectively (p>0.05). A lower percent- age of patients with the ≥6-hour duration of MI onset and a higher percentage of those treated by statin were found in the group DM only (55.56% and 88.89%, respectively). LCX was the least frequently affected artery among all MI groups, while among all MI groups, the group non-DM-non-HTH was the least affect- ed by three diseased vessels (Table III).

The results of the Pearson’s correlation coefficient proved the significant positive correlation of MIF and hs-CRP (r=0.356, p=0.011) with leukocytes (r=0.493, p=0.001) and neutrophils (r=0.411, p=0.003). Both MIF and hs-CRP showed an

no significant positive correlation with age, BMI, total cholesterol, triglyceride, LDL -C, non-HDL, and platelets. However, HDL -C correlated negatively with MIF, hs-CRP (r=- 0.043, P=0.769), and (r=-0.038, P=0.791)

respectively (Table IV).

DISCUSSION

According to the findings of this study, the levels of MIF, and hs-CRP increased sig-

nificantly in all MI patients compared to the control group, with this finding being in agreement with past research (11–13). Al- though the MIF is formed by numerous cell types in the human atherosclerotic plaque (14), myocardium is the main source of cir- culating MIF because of its high MIF content (15). Unlike many cytokines, MIF could be released rapidly with no need for de novo synthesis due to the constitutive expression of MIF and its storage in intracellular pools (16). In addition, hs-CRP increases rapidly following tissue damage, including MI. High cytokine production and inflammatory cell distribution occur in the ischemic and ne- crotic areas, with the elevated levels of hs- CRP being in part associated with the infarct size (17,18).

This study showed a non-significant in- crease in MIF but a significant increase in hs- CRP in the DM-HTN group, when compared to other MI groups. To the best of our knowl- edge, few studies have been done on compar- ing MIF with hs-CRP in diabetic hypertensive patients with MI. MIF and hs-CRP levels were found out to increase more in hypertensive hyperlipidemic patients than in the healthy controls (19). Recent studies show an insig- nificant increase in MIF levels in coronary artery disease (CAD) patients with DM com- pared to those with non-DM (20). Similar re- sults were obtained concerning hs-CRP (21). In addition, MIF increased significantly in diabetic ACS patients compared to diabetic stable CAD and stable angina pectoris (20). The aforementioned findings elucidate the impact of both DM and HTN on MIF levels and verify the significance of MIF as a diag- nostic inflammatory marker for ACS. This is indicative of the fact that the major rea-son for the increase in MIF in the present study could be the severity of the MI itself, and the minor reason could be the effects of DM and HTN. According to past research, a high per- centage of MI patients showed an increase in MIF in the first samples obtained, with this predicting the final infarct intensity and the degree of cardiac remodeling (22).

MIF and C-reactive protein in MI diabetic hypertensive patients

TABLE II

MEAN CONCENTRATION OF INFLAMMATORY MARKERS AND OTHER VARIABLES IN MYOCARDIAL INFARCTION GROUPS COMPARED WITH CONTROLS

Variables

Age (yr)

SBP (mmHg) DBP (mmHg) BMI (kg/m²) HbA1c%

Lipid profile and lipid ratios

P value 0.258

0.257

0.334

0.292

0.000

Vol. 61(1): 39 - 49, 2020

Total cholesterol (mg/dL) 176.82±11.45a 172.63±9.48a 191.97±11.78a 194.16±12.08a 169.47±15.49a 0.526

Triglyceride (mg/dL) 125.06±18.17a 137.63±19.38a 161.52±40.52ab 214.50±41.39b 118.02±13.57a 0.131

HDL -C (mg/dL) 34.94±1.97a 34.69±1.52a 42.80±4.03bc 36.50±2.50ac 49.01±2.83b 0.001

LDL -C (mg/dL) 121.20±8.42a 117.04±8.61ab 124.99±9.14a 128.88±7.99a 94.93±11.14b 0.084

Non-HDL (mg/dL) 141.87±10.56ac 137.94±9.29abc 149.17±11.21ac 157.65±11.27a 120.46±15.58bc 0.251

Total cholesterol /HDL ratio 5.16±0.31a 5.03±0.32a 4.80±0.45a 5.61±0.52a 3.59±0.34b 0.011

LDL /HDL ratio 3.56±0.27a 3.42±0.29a 3.09±0.26a 3.76±0.39a 2.01±0.23b 0.001

Inflammatory biomarkers

MIF(ng/mL) 41.81±5.21a 35.61±6.22a 43.41±7.21a 43.69±6.50a 19.01±3.05b 0.015

hs-CRP(mg/L) 7.94±2.22a 7.02±2.45a 7.61±3.23a 17.79±4.71b 1.92±0.37a 0.009

Heamatological indices

Leucocyte count (103/µL) 12.49±0.67a 11.58±1.15a 13.53±1.10a 12.00±0.66a 6.22±0.40b 0.000

Neutrophil count (103/µL) 9.68±0.63a 9.18±1.42a 10.27±1.23a 9.36±0.65a 3.75±0.56b 0.019

Platelet (103/µL) 239.66±14.16a 239.22±22.83a 239.41±13.73a 241.64±10.63a 184.38±14.37b 0.027

Values are presented as mean ± SE, tests between groups (ANOVA), different letters mean significant differences between the groups (p<0.05), and similar letters mean insignificant differences (p>0.05).

45

MI, myocardial infarction; Non-DM- Non-HTN, non-diabetic non-hypertensive; DM only, diabetes only; HTN only, hypertensive only; DM-HTN, diabetic hyper- tensive.

TABLE III

COMPARISION OF SOME RISK FACTORS AND OTHER VARIABLES IN MYOCARDIAL INFARCTION AND CONTROL GROUPS

MI Control

Age (years)

Non-HTN n: 30 (30%)

n: 18(18%)

n: 24 (24%)

No (%)

n: 28 (28%)

HTN

n: 26 (68.42%)

≥55 14(46.67) 8(44.44) 14(58.33) 22(78.57) 12(46.15) 0.064

Male 28(93.33 ) 12( 66.67) 20(83.33) 16(57.14) 16(61.54 ) 0.006

Smoker 21(70) 8( 44.44) 20(83.33) 23(82.14) 10(38.46) 0.001

Duration of diabetes

mellitus (years)* - 6.79 ±2.00 - 7.74±2.28 - 0.758

Duration of hypertension

(years)* - - 8.88 ±2.4 9.25±2.32 - 0.910

Duration of MI onset:

≥6 hours 19(63.33) 10(55.56) 18(75) 17(60.71) - 0.582

Numbers of affected

vessels

1. vessel

2. vessels

3. vessels

Location of culprit lesion

LAD RCA LCX

Medications

4(13.33)

8(26.67)

18(60)

12(40)

11(36.67)

7(23.33)

3(16.67)

3(16.67)

12(66.66)

16(88.89)

2(11.11)

0(0)

4(16.67)

4(16.67)

16(66.66)

9(37.5)

14(58.33)

1(4.17)

4(14.29)

5(17.85)

19(67.86)

12(42.86)

12(42.86)

4(14.28)

- 0.978

- 0.003

Statin 24(80) 16(88.89) 20(83.33) 22(78.57) - 0.874

Tests of significance between groups (chi-square test, Fisher exact test), * mean+- SE, t-test analysis.

MI, myocardial infarction; Non-DM-Non-HTN, non-diabetic-non-hypertensive; DM only, diabetic only; HTN only, hypertensive only; DM-HTN, diabetic hypertensive.

In the present study, although the DM group experienced an increase in MIF, hs- CRP, leukocytes, and neutrophils compared to the controls, it had the lowest values com- pared to other MI groups. Several consider- ations may explain this finding; the DM only group was comprised of the lowest percent- age of smokers and had the lowest duration of MI onset (≤6 hours), but it had the high- est percentage of receiving statin among the other groups (23–26). Although all pa- rameters were high in the DM-HTN group, levels of SBP, DBP, HbA1c, leukocytes, and

neutrophils were found out to be slightly lower than those of a particular MI group. In addition, all risk factors and other disease severity indicators were higher in DM-HTN, but they showed non-significant variations compared to other MI groups, with this indi- cating that MI patients associated with both DM and HTN experienced more complicated states.

Past research shows that MIF is posite- vely correlated with BMI, total cholesterol, triglycerides, hs-CRP, and leukocytes, but it is correlated negatively with HDL -C (27).

TABLE IV

CORRELATION BETWEEN MIF AND DIFFERENT RISK FACTORS IN MYOCARDIAL INFARCTION PATIENTS

Similar results were obtained in the present study; moreover, a significant positive cor- relation was found between MIF and hs-CRP with leukocytes and neutrophils in MI pa- tients, indicating acute systemic inflamma- tion.

The current study had some limitations, namely the level of MIF was measured only within 24 hours in a relatively small sample size in MI patients; thus, repeated measure- ments for longer times in larger sample sizes could be required to estimate MIF levels at different intervals starting from time of ad- mission and is recommended. In addition, the estimation of MIF in recurrent MI and heart failure with higher MIF levels, com- pared to those with lower MIF levels could be useful in determining the predictive value of this parameter.

In conclusion, the MIF could be used as a new valuable diagnostic inflammatory biomarker for MI, but the hs-CRP proved to be significantly a better prognostic inflam- matory parameter than MIF for MI intensity associated with DM and HTN.

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