Sys Rev Pharm 2021;12(1):869-877 A mTultihfaceeted rBevieiwojoumrnal ian trhekfieled orf psharmAacyssociated With

1 2 3 4 1S,2uUanaidveArbsiataysoLfaBftaasra,hA-wcaotlliefgHeaomfesecdienIscsea/I*ra,qMazin Abed Hazza , Alaa Hussein Abed 3University of Basrah- college of medicine/Iraq 4 Basrah for science and technology private university college /Iraq Corresponding Author: [email protected]

ABSTRACT Introduction: Myocardial infarction (MI) is a major cause of morbidity and Keywords: Associated, Myocardial Infarction mortality worldwide. It is caused by a blockage of a coronary artery due to the Correspondence: accumulation of fat within its inner surface (atherosclerosis). Early diagnosis of MI Awatif Hameed Issa has an important role in assisting clinicians in prompt planning for its treatment University of Basrah- college of science/Iraq and thus reducing the number of its deaths. There are many biomarkers that used in the diagnosis of MI, especially in the first hours of chest pain attack. Cardiac *Corresponding author: Awatif Hameed Issa email-address: enzymes, as cTnI, H-FABP, MYO, and CK-MB are released after heart muscle injury [email protected] due to insufficient blood supply. In the past, it was based solely on the theory of lipids role in the etiology of atherosclerosis. Currently, has been stated to play an essential role in developing atherosclerosis. Monocytes, macrophages, lymphocytes and smooth muscle cells accumulates release many cytokines or inflammatory biomarkers. Therefore, many studies have emerged seeking to investigate the use of anti-inflammatory drugs to reduce the progression of the atherosclerosis process. The aim of the present study was to investigate the association of cardiac and inflammatory biomarkers to myocardial infarction and the correlation between inflammatory markers (CRP, Hs-CRP, IL-6 and PCT) and cardiac markers in MI patients. Patients and Method: The present study included 20 MI patients and 20 healthy individuals (controls). In all the cases and controls, levels of cardiac and inflammatory biomarkers were measured by special kits from Hotgen company via phosphorous technology using UPT-3A converting phosphor immunological analyzer. Results: The levels of both cardiac and inflammatory biomarkers were significantly increased in MI cases as compared to controls. Also, there was significant positive correlation between cardiac and inflammatory biomarkers in MI cases. Conclusions: The positive correlation between cardiac and inflammatory biomarkers in MI indicates that inflammation occurs in myocardial infarction. Hence it is concluded that inflammatory biomarkers (CRP, Hs-CRP, IL-6 and PCT) can be markers of MI and can be used for diagnostic purposes in patients.

INTRODUCTION smoking, and alcohol consumption) and non-modifiable is the leading cause of death factors (age, gender, race, and family history). It has been worldwide. The number of cardiovascular deaths is stated that chronic inflammation has a roleeitn ainl.c, reasing higher than cancer deaths and more than any other causeet the risk of cardiovascular disease, especially psoriatic aolf.,death (AHA, 2019). The deaths reach up to 17.9million arthritis and (Groh 2018). annually, which is equal to 31% of all deathest (aWl.,ierer Moreover, the statement of bacterial and viral 2018). In Iraq, the mortality rate due to cardiovascular participation in the process of atherosclerosis diseases is about 33% of all deaths (Turk 2018). development, justifies mentioning that targeting Myocardial infarction is a type of coronary heart disease infectionest awl.i,th antibiotics can be promising as being a (CHD), that results from rupture of an arterial sclerosis part of a protocol option to reduce atherosclerosis plaque and a thrombus that works toebt laolc. k the coronary (Ridker 2020; Moriya, 2019). eatrtaelr.y, , which supply the heart, causing necrosis and Measuring biomarkers levelestianl.,the patient's serum is a death of part of the heart muscle (Shi , 2016; Rathore method for decision-making and can predict the severity 2017). Internationally, it was reported that at least of atherosclerosis (Martinez 2020). one American develops myocardial infarction Cardiac troponin I (cTnI) is an extremely sensitive approximately every 40 minutes (AHA, 2019). In the past, in diagnosing and determining the severity of it was based solely on the theory of lipids role in the coronary heart diesetaasle, and highly septeaclific in excluding etiology of atherosclerosis. Currently, inflammation has the disease. It gives more predictive values than the been stated to play an essential role in developing stress ECG (Aydin ., 2019; Anwar ., 2016). atherosclerosis. Monocytes, macrophages, lymphocytes Creatine kinase –Myocardial Band (CK-MB) is an enzyme and smooth muscle cells accumulates release many found in the heart muscle, which is an important cytokines or inflammatory biomarkers (Beverly and biomarker for the diagnosis of myocardial infarction. It is Budoff, 2019) The underlying cause of a heart attack due more specific than other heart eentzaylm., es and consideetraeld., to MI is atherosclerotic, which is caused by the the golden standard for diagnosing myocardial infarction. development of layers of fatty deposits on the inner walls (Mytili and Malathi, 2015; Aydin 2019; Anwar of the arteries (Amirfakhryan, 2019). The development of 2016). these deposits leads to entaarrl.o, wing and gradual blockage D-dime is a promising and important vital indicatoert faolr., of blood flow in the artery. It is a long-term disease that identifying blood clots, which molecules result from the progresses slowly (Lacy 2019). breakdown of fibrin in the blood vessels (Zhang Atherosclerosis is a chronic pathology of multiple 2019). modifiable risk factors (diabetes, hypertension, obesity, sedentary life, emotional stress, unhealthy food habit, 869 Systematic Reviews in Pharmacy

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N-terminal pro-B-type natriuretic peptide (NT-proBNP) by Rotofix 32 A at a speed of 3000 cycles per minute for is a diagnostic marker for detecting 10 minutes. Then cardiac and inflammatory biomarker (Eriksson et al., 2019; Pan et al., 2017). testes were done numbers and averages, and quantitative C-reactive protein (CRP) is a biomarker secreted by the variables are expressed as a mean± SD. A comparison by liver after being stimulated by cytokines in cases of special kits from Hotgen company via phosphorous infections, and can be used to assess the risk of technology using UPT-3A converting phosphor cardiovascular disease; however, it has a low specificity immunological analyzer. (Zhu et al., 2018). All statistical analyzes were performed using Statistical High sensitivity-CRP (Hs-CRP) is a technique developed Package of Social Sciences (SPSS) version 23. Categorical to detect very low levels of CRP to more accurately variables are expressed as percentages, was made determine the existence of the inflammation process between patients and the control groups using chi-square compared to CRP (Pelusoet al., 2019). test or Fisher's exact test qualitative variables, and Mann- Procalcitonin (PCT) ehtoraml.,one is a peptideet caoln.,sists of 116 Whitney test for quantitative nonparametric variables. amino acids with low molecular weight, approximately Spearman's test was used to find the correlation between 13 kDa (Ichihara 2016) (Jiao 2015). The the nonparametric quantitative variables. The level of proportion of the hormone is 0.033 ng/ml and rises to significance was set at (P < 0.05). 5000 ng/ml in cases of bacterial only, but it does not rise in viral infections (Bradford, 2019). RESULTS Interlukine-6 (IL-6) is a type of cytokines, which has A total of 40 individuals were included in this study. Of hormone-like properties. It has anti-inflammatory those, 20 were cases of MI and 20 were controls. Table (1) properties, has a role in innate and adaptive immunity, shows the levels of cardiac and inflammatory markers in causes fever during infection, and is secreted by cases and controls. The levels of these markers were monocytes, macrophage devoured in response to other statistically significantly (p<0.05) increased in MI cases cytokines such as IL-11, TNF. Its function is to regulate as compared to controls. acute phase proteinest anl d chronic infectieotnasl, and its levels Table (2) and figure (1) show the correlation between increase in patients with vascular diseases compared to cardiac and inflammatory markers in MI cases. Positive healthy people (Yu ., 2017; Nassem ., 2016). correlations were found between cardiac and inflammatory markers in MI cases. PATIENTS AND METHOD Serum CRP levels were found to be strongly positively Out of a total of 20 patients, 5 (25%) were females and 15 correlated with CK-MB, H-FABP, MYO and cTnI (r=0.682, (75%) males, with a mean age of 55.25± 12.53 (range of 0.653, 0.613 and 0.566, respectively, in a significance 35-80) years, participated in this study. All patients were level of p<0.01). diagnosed as having MI. A total of 20 healthy individuals A strong positive correlation was found between serum enrolled in this study as a control group; their age and PCT levels with NT-proBNP, MYO and H-FABP (r= 0.644, gender were matched with the patients group. Cancer 0.567 and 0.501 respectively, in a significance level of and hepatitis patients were excluded from this study. p<0.01) in MI patients. Data were collected from the cardiac center in Al-Sadr On the other hand, we found medium significant Teaching Hospital via specially structured questionnaire. correlations of Serum CRP levels with D-dimer and NT- This included sociodemographic and health data. The proBNP (r= 0.478, 0.41 respectively, both p<0.013); Hs- study took place during the period from 13 October 2019 CRP with NT-proBNP (r=0.455); PCT with (cTnI, CK-MB to 27 October 2020. and D-dimer), and IL-6 with (cTnI, H-FABP, NT-proBNP, Venous blood was collected from patients and controls in CK-MB and D-dimer). TEDabTlAe, (1s)o:dTiuhme dicfifterraetenceasnidn thgeelletvuebles.ofCceanrtdrifaucgantidoninflammaFtionrayllby,ioamsmarakllecrosrrinelaMtiIocnaosef sILa-n6dwcitohnMtrYoOls(. r=0.284). processes were being done to obtain serum and plasma MI Control Biomarker P-Value N (%) N (%)

IL-6 ( pg/ml ) <7 6 (30%) 16 (80%) 0.001 ≥7 14 (70%) 4 (20%) CRP (mg/L) <8 6 (30%) 19 (95%) 0.0001 ≥8 14 (70%) 1 (5%) hs-CRP (mg/L) <1 0 (0%) 12 (60%) 0.0001 ≥1 20 (100%) 8 (40%) PCT( ng/ml ) <0.5 9 (45%) 20 (100%) 0.0001 ≥0.5 11 (55%) 0 (0%) H-FABP ( ng/ml ) 0.0001 <7 5 (25%) 20 (100%) 870 Systematic Reviews in Pharmacy

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≥ 7 15 (75%) 0 (0%) MYO ( ng/ml ) <48 11 (55%) 20 (100%) 0.001 ≥ 48 9 (45%) 0 (0%) cTnI ( ng/ml ) <0.5 4 (20%) 20 (100%) 0.0001 ≥ 0.5 16 (80%) 0 (0%) CK-MB ( ng/ml ) <4.99 0 (0%) 20 (100%) 0.0001 ≥4.99 20 (100%) 0 (0%) NT-proBNP ( pg/ml ) <450 (age≤750) <900 (age≥75) 7 (35%) 20 (100%) 0.0001 ≥ 450 ( age≤75) ≥900 (age≥75) 13 (65%) 0 (0%) D-dimer ( ng/ml ) <500 8 (40%) 19 (95%) 0.0001 Table (2): The correlatio≥n5c0o0efficient, r-values, between cardi1a2c a(6n0d%in)flammatory bi1om(5a%rk) ers in patients of MI 6 Inflammatory Cardiac biomarkers biomarkers H-FABP MYO cTnI CK-MB NT-proBNP D-dimer

IL-6

0.384* 0.248 0.379* 0.331* 0.402* 0.404*

CRP

0.653** 0.613** 0.566** 0.682** 0.413** 0.478**

HS-CRP

0.662** 0.596** 0.593** 0.767** 0.455** 0.548**

PCT

0.501** 0.567** 0.452** 0.418** 0.644** 0.431**

* significant (p<0.05) ** highly significant (p<0.01)

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Figure (1): The correlation between CRP and cardiac biomarkers in MI cases and control groups.

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Figure (2): The correlation between Hs-CRP and cardiac biomarkers in MI cases and control groups.

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Figure (3): The correlation between PCT and cardiac biomarkers in MI cases and control groups.

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Figure (4): The correlation between IL-6 and cardiac biomarkers in MI cases and control groups.

et al., DISCUSSION (p2r0e0vi2o)usly, the total CK was used to assess myocardial In the present study, the association of cardiac markers infarction. Mytili and Malathi, (2015) and Singh (cTnI, H-FABP, MYO, CK-MB, NT-proBNP and D-dimer) concluded that a CK-MB activity can be sufficient and inflammatory markers (CRP, Hs-CRP, IL-6 and PCT) for the eaertlyald.,iagnosis of acute myocardial infarction with MI was assessed and the correlation between the (AMI). two types of markers was tested. Eriksson (2019) stated that NT-proBNP has a We found significantly increased levels of all cardiac and prognostic value in patients with heart failure. Although, inflammatory biomarkers in MI cases compared to NT-proBNP was found to be significantly associated with controls (p<0.05), which is mostly consistent with the MI, and previous research has shown that its elevation results of several previous studies that documented a role can be a predictive marker of death and heart failure, it for inflammation in the development of atherosclerosis. was stated that it cannot be used for the diagnosis of AMI CMaorrdeioavceMr, awrekeforsu:nd significant correlations between the (Mytili and Malathi, 2015). markers from the two groups. D-dimer was shown to be associated with the extent of coronary heart disease, which agrees the results of this H-FABP is mainly found in the heart muscle; and in case study, but it has a low specificity; theetraelf.,ore, all. other of heart muscle cells, it is released early to the blood. An IfinbfrlianmolmysaistocroynMdiatiroknesrsshould be excluded when used as a elevated level of H-FABP can be tested in 30 minutes after risk marker for atherosclerosis (Tibaut 2019) the injury, reaches its peak in up to 8 hours and decreases to its original level after 24 hours (Mytili and Malathi, IL-6 has a major role in theertecarl.u, itment and activation of 2015). This goes with the finding of the current study, inflammatory cells in response to ischemia (Mytilietaanld which fouetndal.t,hat it is extremely significantly statistically Malathi, 2015). Wennberg (2012) documented an associated with MI when compared to control individuals. association between IL-6 and MI risks; and Filardo ., Rathore (2017) in their study observed significant (2015) reported that seropositivity of IL-6 may be higher mean levels of cardiac markers MYO activity in predictive of atherosclerotic cardiovascular risk. AMI cases when compared to that of controls, which Furthermore, it is considered as one of the impoerttaanlt agrees the results of this study. Again it is one of the early tools for assessing the risk of coronary atherosclerosis, elevated markers in the blood after the onset of injury to which sueptpaolr.,ts the results of this steutdyal (Ridker , the heart muscle, reaches its peak in up to 12 hours and 2020). declines to its original level very shortly. However, it (Sesani 2016) and (Rathore ., 2017), who lacks specificity to the heart tissue. That is why its level is mention that CRP is the most frequent marker of recomemteanld., ed to be tested in conjunction with the cTnI inflammation, which its relation to MI haest beael.n, s(t2u0d1ie2d) or CK-MB (Mytili and Malathi, 2015). extensively in recent years. In agreement with the Singh (2016) concluded that a combination of cTnI present study findings, Wennberg activity was sufficient for the early diagnosis of acute documented an association of inflammatory markers, myocardial infarction (AMI). It is specific for the such as CRP, with MI risks. Moreover, it was state(d20t1h7at myocardium, which has made it an excellent cardiac these markers are of considerable importance in the marker of injury. pathophysiology of the disease. Ahmed et al., ) It starts to increase in up to 8 hours post heart muscle mentioned in their study that it is of benefit. to measure injury, (Mytili and Malathi, 2015). It is a highly sensitive serum levels of PCT and CRP in diagneotsainl.g c2a0r1d2iovascular test for diagnosing and etprael.dicting .coronary artery complications in type 2 diabetic patients Our study disease and plays a considerable role in the process of results agree the results of Baruah , ( ) in their risk stratification (Tibaut , 2019) These facts can study showed that the role and importance of the CRP, explain tehtearle.,sults of our study, when it was found to be contributes to provide a predictive value in the diagnosis extremely associated to MI. of AMI. Also, it sensitivity and specificity (Mytili and Rathore (2017) documented higher levels of CK-MB Malathi, 2015). in AMI patients when compared to controls, which agrees When Hs-CRP is considered, it has been documented that the results of this study. It is not measured as a single screening techniquesethaalve been developed, to detect it, diagnostic indicator, but in conjunction with the are used to assess heart disease risk associated with troponins or MYO (Mytili and Malathi, 2015). Although, infections (Limijadi, ., 2020). Recent studies have also 875 Systematic Reviews in Pharmacy

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demonstrated the ability of HS-CRP to predict the associated with plaque progression and instability presence of atherosclerotic peltaaqlues and it is an impoerttaanlt in patients with carotid atherosclerosis. Mediators tool that can help physicians in putting immediate of Inflammation, 2015. treatment plans (Ammirati ., 2015; Macfadyenet al., 4. Amirfakhryan, H. (2019). Vaccination against 2017), as it was found that it has a major role in atherosclerosis: An overview. Hellenic Journal of improving the risk stratification of CAD (Chong Cardiology. 2020; Fonseca and Izar, 2016; Koenig, 2013). The 5. Anwar, A. W. A. I. S., Khan, H. A., Hafeez, S. A. M. R. A., mechanism has been stated to link high serum Hs-CRP and Firdous, K. (2016). A comparative study of levels to the process of inflammation of the myocardium creatine kinase-MB and Troponin levels among and higheretleavlels of Hs-CRP are correlatetdalwith the diabetic and non-diabetic patients with acute MI. severity of the inflammation of the injured myocardium Pak J Med Health Sci, 10, 296-298. (Yao, H. C. , 2013). In addition, Filardo ., (2015) 6. Aydin, S., Ugur, K., Aydin, S., Sahin, İ., and Yardim, M. reported that seropositivity of HS-CRP may be predictive (2019). Biomarkers in acute myocardial infarction: of atherosclerotic cardiovascular risk. current perspectives. Vascular health and risk All the above support the results of our study, when we management, 15, 1. found that Hs-CRP is associated with MI and is posietitveally. 7. Baruah, M., Nath, C. K., Chaudhury, B., Devi, R., & correlated to the cardiac biomarkers. Ivvala, A. S. (2012). A study of serum uric acid and This study results agreed the results oeft (aKl.afkas , C-reactive protein in acute myocardial infarction. 2008) weht oaldocumented that PCT was significantly International Journal of Basic Medical Sciences and associated with MI. Moreover, (ENTürk , 2007) and Pharmacy (IJBMSP), 2(1). (Özbay ., 2020) who recommended its use in 8. Beverly, J. K., and Budoff, M. J. (2019). assessing the prognosis and severity of coronary artery Atherosclerosis: Pathophysiology of insulin disease. resistance, hyperglycemia, hyperlipidemia, and inflammation. LIMITATIONS 9. Bradford, D. J. (2019). The Development of a Researchers find it is crucial to point out the following Medical Biomarker Test to Aid in Rapid Screening limitations of the study, without which, the results would for the Presence of Infectious Diseases. be better conclusive: 10. Chong, Y., Ren, Q., Li, Y., Li, C., Feng, F., & Zhou, Y. 1. The time of taking blood samples to be tested was (2020). Biomarkers for Prediction of variable among patients and lied between 5 -12 Cardiovascular Events in Community-Dwelling hours after being admitted to the coronary care unit Adults Aged 40 or Older. International Heart in the hospital. This was a bit wide range for the Journal, 19-240. levels of markers tested. That is to say, the levels 11. ENTürk, T., Cordan, J., Baran, I., Özdemir, B., Güllülü, among patients do not represent close/similar time S., Aydinlar, A., & GÖral, G. (2007). Procalcitonin in period after the MI attack. However, in spite of this, patients with acute coronary syndrome: correlation the differences among markers levels were with high-sensitive C-reactive protein, prognosis statistically extremely significant, and the wide and severity of coronary artery disease. Acta variability in post attack period could no mask the cardiologica, 62(2), 135-141. significance. 12. Filardo, S., Di Pietro, M., Farcomeni, A., Schiavoni, G., 2. The results based on a single center only, which & Sessa, R. (2015). Chlamydia pneumonia-mediated could lead to selection bias. inflammation in atherosclerosis: a meta-analysis. 3. The sample size was too small to produce Mediators of inflammation, 2015. conclusive results. That was because of the 13. Eriksson, B., Wändell, P., Dahlström, U., Näsman, P., restriction imposed due to the outbreak of COVID- Lund, L. H., and Edner, M. (2019). Limited value of 19. However, the result was not different from other NT-proBNP as a prognostic marker of all-cause studies worldwide. mortality in patients with heart failure with preserved and mid-range ejection fraction in CONCLUSIONS primary care: A report from the swedish heart The current results found increased levels of failure register. Scandinavian journal of primary inflammatory markers (CRP, HS-CRP, IL-6 and PCT) along health care, 37 (4), 434-443. with cardiac markers (cTnI, H-FABP, MYO, CK-MB, NT- 14. Fonseca, F. A. H., & Izar, M. C. D. 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