Archives of Academic Emergency Medicine. 2022; 10(1): e51 REV I EW ART I C L E Premature Coronary Artery Disease and Plasma Levels of Interleukins; a Systematic Scoping Review and Meta- Analysis Mohammad Haji Aghajani1,2, Amirmohammad Toloui3, Koohyar Ahmadzadeh3, Arian Madani Neishaboori3∗, Mahmoud Yousefifard4,3 † 1. Prevention of Cardiovascular Disease Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran. 2. Department of Cardiology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran. 3. Physiology Research Center, Iran University of Medical Sciences, Tehran, Iran. 4. Pediatric Chronic Kidney Disease Research Center, Tehran University of Medical Sciences, Tehran, Iran. Received: March 2022; Accepted: May 2022; Published online: 27 June 2022 Abstract: Introduction: Interleukins (ILs) can act as a predictive indicator of Premature Coronary Artery Disease (pCAD) and may be useful in screening of high-risk patients. However, there is no consensus on the relationship of serum levels of ILs and pCAD, yet. As a result, this study has been conducted in order to review the literature on the relationship between serum levels of different ILs and pCAD. Methods: Medline, Scopus, Embase, and Web of Science databases were searched until December 7th 2020. Two reviewers independently screened and summarized eligible articles. A meta-analysis was performed to assess the relationship of ILs and pCAD. Results: 12 case-control articles were included. IL-6 plasma changes do happen in pCAD patients with a standardized mean difference (SMD) of 0.51 (95% CI: 0.12-0.90; p=0.010) compared with the control group. This difference was also observed when evaluating the plasma levels of IL-1 and IL-17, with an SMD of 1.42 (95% CI: 1.11- 1.73; p<0.001) and 0.59 (95% CI: 0.14-1.04; p=0.011), respectively. Meanwhile, no significant difference existed in plasma levels of IL-10 (SMD=0.26; 95% CI: -0.17-0.70; p=0.236), and IL-18 (SMD=1.44; 95% CI: -0.19-3.07; p=0.083) between pCAD patients and those in the control group. Conclusion: Low level of evidence showed that there may be a significant relationship between increased plasma levels of ILs and the occurrence of pCAD. As a result, prospective cohort studies with serial assessments of serum ILs during follow up period, focusing on controlling classical risk factors of pCAD and increase in level of ILs, should be conducted. Keywords: Coronary artery disease; cardiovascular disease; interleukins; Prognosis; Biomarkers Cite this article as: Haji Aghajani M, Toloui A, Ahmadzadeh K, Madani Neishaboori A, Yousefifard M. Premature Coronary Artery Dis- ease and Plasma Levels of Interleukins; a Systematic Scoping Review and Meta-Analysis. Arch Acad Emerg Med. 2022; 10(1): e51. https://doi.org/10.22037/aaem.v10i1.1605. 1. Introduction Coronary artery disease (CAD) is a condition in which buildup of atherosclerotic plaques leads to narrowing of the coronary arteries. This disease manifests in various clinical ∗Corresponding Author: Arian Madani Neishaboori, Physiology Research Center, School of Medicine, Iran University of Medical Sciences, Shahid Hem- mat Highway, Tehran 14496-14535, Iran. Tel: +98 (21) 86704771; Email: ar- ian.md7@gmail.com, ORCID: http://orcid.org/0000-0002-1920-9299. † Corresponding Author: Mahmoud Yousefifard; Pediatric Chronic Kidney Disease Research Center, Tehran University of Medical Sciences, Children’s Medical Center, Gharib St., Tehran, Iran. Tel: +98 (21) 86704771; Email: youse- fifard.m@iums.ac.ir, ORCID: http://orcid.org/0000-0001-5181-4985. forms, including angina and myocardial infarction (MI). CAD is the leading cause of death worldwide (1, 2), having a preva- lence of 6.7% (18.2 million individuals) amongst people aged 20 years or older, with one individual having an MI every 40 seconds in US (3). Given its importance and profound bur- den on the society, identifying its risk factors and managing them could play a key role in helping affected patients. Furthermore, coronary artery disease can occur in younger ages, which is named Premature Coronary Artery Disease (pCAD). In particular, it has a cut off age, mostly suggested to be less than 55 and 65 years for men and women, respec- tively (4). Although most studies suggest a low incidence rate for pCAD, it is possible that with the rise in cardiovascular risk This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem M. Haji Aghajani et al. 2 factors, such as smoking and obesity, among younger popu- lation, the number of young individuals with underlying con- ditions that may lead to pCAD is much higher than currently estimated (5). In addition, because of the devastating effects of this disease on the more active lifestyle of young patients, and also the importance of early detection and treatment of young individuals, prompt and accurate identification of young individuals who are at the greatest risk is necessary (6). pCAD is defined as an inflammatory disease (7), and cardio- vascular events are more common in patients with high cir- culating levels of several inflammatory markers. In this re- gard, treating patients based on inflammatory parameters, such as hs-C reactive protein (hs-CRP), has been proved to improve outcomes (8). On the other hand, interleukins (ILs) are a group of cytokines with important roles in the reg- ulation of immune and inflammatory responses. Several ILs (such as IL-1 and IL-6) are major players at the down- stream of vascular inflammatory cascades (9). As it has been shown in several studies, there might be a relationship be- tween serum level of different types of ILs (IL-1, IL-6, etc.) and coronary artery diseases (10-12). Since other inflamma- tory cytokines such as hs-C reactive protein have been classi- cally linked to coronary events, it is also reasonable to study the possible relationship between ILs and coronary events. Therefore, ILs can serve as a predictive indicator of pCAD and may be useful in screening of high-risk patients. However, there is no consensus on the relationship of serum levels of ILs and pCAD, yet. As a result, this study has been conducted in order to review the literature on the relationship between serum levels of different ILs and pCAD. 2. Methods 2.1. Study design and search strategy The current systematic review and meta-analysis is designed for the aim of investigating the changes in the plasma level of different types of ILs following a coronary artery disease in the younger population, or pCAD as previously defined. Accordingly, PICO was defined as follows: patients (P): male patients younger than 55 and female patients younger than 65 years of age, with angiographically confirmed coronary artery stenosis more than 50% in coronary vessels. Index test (I): measuring plasma level of ILs in patients. Comparison (C): comparing results of the case group (with the defined coronary artery stenosis) with those of the control group (pa- tients without the defined coronary artery stenosis). Out- come (O): occurrence of pCAD. For this purpose, Medline (via PubMed), Scopus, Embase, and Web of Science databases were thoroughly searched us- ing carefully selected keywords. These keywords were se- lected using MeSH and Emtree vocabularies, reviewing sim- ilar articles’ relevant keywords, and with the help of experts in the field. Then, a systematic search strategy was designed based on the defined P and I and using the selected key- words. This search was initially performed for articles pub- lished until November 6th, 2020, and then updated until De- cember 7th 2020. The search strategy in Medline database is presented in Appendix 1. In addition, a manual search was also performed in Google and Google scholar to obtain any preprints and possibly missing papers. 2.2. Selection criteria The inclusion criteria in the present systematic review were reporting plasma levels of ILs, independently in case and control groups, and conducting the research on a popula- tion of pCAD patients, regardless of their underlying condi- tion. The exclusion criteria consisted of not having a control group, case report studies, and review articles. 2.3. Data collection Two reviewers independently screened titles and abstracts of the retrieved articles, for inclusion based on the inclusion cri- teria. Then, eligible articles were obtained and exclusion cri- teria were applied to select the included articles. Finally, a summary of the included articles’ data was recorded using a checklist, consisting of the following variables: first author’s name, publication year, country in which the study was con- ducted, study design, definition of the pCAD patients, num- ber of patients in case group, number of patients in the con- trol group, mean age of the patients in the case group, mean age of the patients in the control group, type of the mea- sured ILs, plasma level of the ILs in the case group, plasma level of the ILs in the control group, and the time interval between angiography and measurement of ILs levels in pa- tients’ plasma sample. Any disagreement between the re- viewers was resolved via discussion with a third reviewer. 2.4. Quality assessment Two independent reviewers performed the quality assess- ments using National Heart, Lung, and Blood Institute (NHLBI) quality assessment tools for case-control studies (13). Any disagreement was resolved through discussion with a third reviewer. 2.5. Statistical analysis All analyses were performed using STATA 14.0 statistical pro- gram. Data were recorded as mean and standard devia- tion (SD) in case and control groups, separately. Then using “metan” command in STATA program a standardized mean difference (SMD) was calculated for each individual study. Finally, a pooled SMD and 95% confidence interval (95% CI) was reported. Heterogeneity among studies was assessed, using I2 test. Egger’s test and funnel plot were used to assess publication bias. This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem 3 Archives of Academic Emergency Medicine. 2022; 10(1): e51 3. Results 3.1. Study characteristics The systematic search in the electronic databases yielded 622 records. 269 duplicates were eliminated and 353 arti- cles remained. Afterwards, reviewers performed the initial screening according to the inclusion criteria, gathering 44 ar- ticles were found to be potentially eligible to enter the current study. Then, applying the exclusion criteria, the next screen- ing process was performed, resulting in the inclusion of 12 articles (all of them had case-control design) in the present systematic review and meta-analysis (Figure 1) (14-25), three of which measured more than one type of ILs in the studied patients (14, 15, 19). IL-6 was measured in seven studies (14- 17, 20, 21, 24), IL-10 was measured in four studies (14, 19, 22, 25), IL-18 was measured in three studies (14, 19, 23) and IL-1 (15) and IL-17 (18) were each measured in one study. Overall, 3098 patients with pCAD and 3711 control subjects were studied in the included articles. Among them, 2696 of the pCAD patients and 2271 of control patients were male. These studies had taken place in various countries: Pakistan (14, 19), Greece (15), India (16), South Korea (17), Turkey (18), South Africa (21), Sweden (20), Mexico (22), Australia (23), Poland (24), and China (25). Regarding the design of the in- cluded studies, seven studies were conducted prospectively (14, 15, 18, 19, 21, 24, 25) and the other five were conducted retrospectively (16, 17, 20, 22, 23). All of the included studies confirmed pCAD performing a coronary angiography. De- tailed characteristics of the articles is summarized in Table 1. 3.2. Risk of bias assessment Sample size justification, blinding of the assessors, adjust- ment of the results based on key confounding variables, and the use of concurrent controls were not recorded in any of the studies. Also, none of the study samples were randomly taken from their target population. Table 2 presents details of risk of bias assessment among the included studies. 3.3. Publication bias Publication bias was assessed regarding the report of the case and control groups’ plasma levels of IL-6, IL-10 and IL- 18, while IL-17 and IL-1 were separately measured in only one article each. As depicted on Figure 2, no publication bias exists regarding the assessment of IL-6 (p=0.440), IL-10 (p=0.960), and IL-18 (p=0.181) in the pCAD patients. 3.4. Meta-analysis The differences in the plasma levels of ILs between pCAD pa- tients and control patients were evaluated, and the results are depicted in Figure 3. It was shown that IL-6 plasma changes do happen in pCAD patients with a standardized mean dif- ference (SMD) of 0.51 (95% CI: 0.12 to 0.90; p = 0.010) com- pared with the control group. This difference was also ob- served when evaluating the plasma levels of IL-1 and IL-17, with an SMD of 1.42 (95% CI: 1.11 to 1.73; p < 0.001) and 0.59 (95% CI: 0.14 to 1.04; p = 0.011), respectively. Mean- while, no significant difference existed in plasma levels of IL-10 (SMD=0.26; 95% CI: -0.17 to 0.70; p =0.236), and IL-18 (SMD=1.44; 95% CI: -0.19 to 3.07; p = 0.083) between pCAD patients and the control group. However, the I2 test revealed a considerable amount of heterogeneity among the studies. 4. Discussion The present systematic review and meta-analysis evaluated the changes of the plasma levels of different types of ILs fol- lowing pCAD. For this purpose, IL plasma levels were com- pared between the pCAD patients and the participants in the control groups in the included studies. As mentioned above, an explicit correlation exists between the occurrence of pCAD and the plasma levels of IL-6, IL-1 and IL-17. As a re- sult, it can be concluded that in pCAD patients, a rise in the plasma levels of the three ILs will possibly be observed. How- ever, the heterogeneity among the studies was considerably high, making it tough to firmly conclude on the exact corre- lation between IL plasma levels and the occurrence of pCAD. Moreover, the existing literature regarding this subject is also controversial. For instance, Satti et al. reports that increased plasma levels of IL-6 is associated with higher risk of CAD (26), while Ghazouani et. al reports no correlation between CAD and IL-6 (27), while in both studies, pCAD patients were present among the study population. Overall, these hetero- geneities in the studies can be attributed to many factors. Firstly, none of the studies included in our group of eligible articles reported their results with respect to coronary risk factors, for example diabetes, lipid profile, smoking status, existence of hypertension and etc., which were present in their study populations. These risk factors could result in dif- ferent amounts of change in IL plasma levels. Thus, we do recommend that in future studies, these risk factors be care- fully evaluated and matched between the case and the con- trol groups. Secondly, the time interval between IL measurement and the occurrence of pCAD was somewhat vague in the studies. As a result, IL plasma levels could change in time following a coronary event in patients. With respect to the definitions of pCAD patient not being exactly the same between the in- cluded studies, this limitation could be overturned by adopt- ing exactly similar definitions regarding the occurrence of pCAD and, accordingly calculating the time interval between the coronary event and the measurement of IL’s plasma level. In addition, all included studies had case-control design and there were no prospective cohort studies. Therefore, the This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem M. Haji Aghajani et al. 4 overall level of evidence in the present meta-analysis is low. 5. Conclusion Low level of evidence showed that there may be a significant relationship between plasma levels of ILs and the occurrence of pCAD. Since, there were no prospective cohort studies, in- cluded in the present meta-analysis, the screening value of ILs in prediction of pCAD is not clear. As a result, prospective cohort studies with serial assessments of serum ILs during follow up period, focusing on controlling classical risk factors of pCAD and increase in level of ILs, should be conducted, with respect to the mentioned limitations, to resolve this un- certainty. 6. Declarations 6.1. Acknowledgments None. 6.2. Availability of data and materials All data generated or analyzed during this study are included in this published article. 6.3. Authors’ contributions Study design: MY, MHA Performing search and designing search strategy: All authors. Data gathering and quality assessment of included studies: KA, AMN, AT, MHA Analysis: MY Drafting: AMN, AT, KA, MY Critically revised: MY and MHA 6.4. Funding and supports Prevention of Cardiovascular Disease Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran. 6.5. Conflict of interest There is no conflict of interest. 6.6. Role of the Sponsor The Prevention of Cardiovascular Disease Research Center, Shahid Beheshti University of Medical Sciences had no role in the design and conduct of the study; collection, manage- ment, and analysis of the data. References 1. Anthony D, George P, Eaton CB. Cardiac risk factors: en- vironmental, sociodemographic, and behavioral cardio- vascular risk factors. FP Essent. 2014;421:16-20. 2. Williams RA. Cardiovascular disease in African American women: a health care disparities issue. J Natl Med Assoc. 2009;101(6):536-40. 3. Virani SS, Alonso A, Benjamin EJ, Bittencourt MS, Call- away CW, Carson AP, et al. Heart disease and stroke statis- tics—2020 update: a report from the American Heart As- sociation. Circulation. 2020:E139-E596. 4. 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This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem M. Haji Aghajani et al. 6 Figure 1: Flow diagram of the present meta-analysis. This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem 7 Archives of Academic Emergency Medicine. 2022; 10(1): e51 Figure 2: Funnel plot for the analysis of publication bias regarding the correlation between the occurrence of premature coronary artery disease and the changes in the plasma level of interleukins (ILs). No publication bias was observed for IL-6 (p=0.440), IL-10 (p=0.960) and IL-18 (p=0.181). This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem M. Haji Aghajani et al. 8 Figure 3: Forest plot for the assessment of the changes in the plasma levels of interleukins (ILs) in premature coronary artery disease (pCAD) patients compared with that of the control group. SMD: Standardized mean difference; CI: Confidence interval. This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem 9 Archives of Academic Emergency Medicine. 2022; 10(1): e51 Table 1: Summary and characteristics of the included studies Author; Year; Coun- try Study design Definition of pCAD in the study No. of pa- tients in the case group No. of pa- tients in the con- trol group Mean age of pa- tients in the case group Mean age of pa- tients in the con- trol group No. of males in the case group No. of males in the con- trol group Type of IL Time interval be- tween angiog- raphy and IL mea- sure- ment (hours) IL plasma level in the case group IL plasma level in the control group Unit IL-18 0 236.6± 42.5 175.6±21.8 pg/ml Ansari; 2017; Pak- istan Prospective >70% stenosis in at least one coronary vessel & age<45 329 310 42 39 329 298 IL-6 3.8± 1.5 2.9±1.9 ng/dl IL-10 0.83± 0.53 0.87±0.36 pg/ml Antoniades; 2005; Greek Prospective ST Segment Elevation MI & age<49 58 205 48.6 49.7 58 180 IL-1b 24 1.37± 1.41 0.31±0.37 pg/ml IL-6 7.7±4.3 2.16±2.15 pg/m Ghatge; 2016; India Retrospective >70% stenosis in at least one coronary vessel & age<45 in males or age<50 in females 93 120 41.79 41.78 93 93 IL-6 12 3.66± 0.19 2.98±0.15 pg/ml Cho; 2015; Korea Retrospective >50% stenosis in at least two coronary vessels & age<55 in males or age<60 in females 414 503 49.3 48.6 414 414 IL-6 NR 9.6±44.1 3.6±8.9 pg/ml Demir; 2015; Turkey Prospective angiography confirmed coronary artery disease & age<45 45 35 39.6 40.1 35 19 IL-17A 12 2 ± 1.88 0.9±1.86 pg/ml IL-18 0 302.25±114.81 145±88.89 pg/ml Khan; 2011; Pakistan Prospective >70% stenosis in at least one coronary vessel & age<45 98 74 40 35 89 65 IL-10 2.03±1.7 1.63±1.85 pg/ml Ludman; 2007; Swe- den Retrospective Myocardial infarction and age between 45-55 41 26 51 51 41 26 IL-6 NR 3.7± 2.28 3.81±3.49 ng/dl Phulukdare; 2013; South Africa Prospective angiography confirmed coronary artery disease & age<45 41 61 NR NR 41 61 IL-6 NR 0.91±0.01 0.86±0.13 pg/ml This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem M. Haji Aghajani et al. 10 Table 1: Summary and characteristics of the included studies Author; Year; Coun- try Study design Definition of pCAD in the study No. of pa- tients in the case group No. of pa- tients in the con- trol group Mean age of pa- tients in the case group Mean age of pa- tients in the con- trol group No. of males in the case group No. of males in the con- trol group Type of IL Time interval be- tween angiog- raphy and IL mea- sure- ment (hours) IL plasma level in the case group IL plasma level in the control group Unit Posadas- Sanchez; 2018; Mex- ico Retrospective infarction or >50% stenosis in coronary vessel & age<55 in males and age<65 in females 1160 1106 54 51 940 455 IL-10 NR 1.01±0.83 0.53±0.55 pg/ml Thompson; 2007; Aus- tralia Retrospective >50% stenosis in at least one coronary vessel & age<60 556 1109 50 53 487 558 IL-18 NR 366.2±156 327.8±146.6 pg/ml Pauli; 2019; Poland Prospective angiography confirmed coronary artery disease & age<55 in males and age<60 in females 100 50 49.9 48 75 37 IL-6 12 1.69±2.77 1.47±0.33 pg/ml Wang; 2005; China Prospective infarction or >50% stenosis in coronary vessel & age<55 in males and age<65 in females 163 112 51 49 94 65 IL-10 NR 33.28±11.26 30.83±10.07 pg/ml pCAD: Premature Coronary Artery Disease; IL: interleukin. This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem 11 Archives of Academic Emergency Medicine. 2022; 10(1): e51 Table 2: Risk of bias assessment of the included studies Author; Year Items 1 2 3 4 5 6 7 8 9 10 11 12 Ansari; 2017 YES YES NO YES YES YES NA NR YES YES NR NO Antoniades; 2005 YES YES NO YES YES YES NA NR YES YES NR NO Ghatge; 2016 YES YES NO YES NR YES NA NR YES YES NR NO Cho; 2015 YES YES NO YES YES YES NA NR YES YES NR NO Demir; 2015 YES YES NO YES YES YES NA NR YES YES NR NO Khan; 2011 YES YES NO YES YES YES NA NR YES YES NR NO Ludman; 2007 YES YES NO YES YES YES NA NR YES YES NR NO Phulukdaree; 2013 NR NO NO YES YES YES NA NR YES YES NR NO Posadas-Sanchez; 2018 YES YES NO YES YES YES NA NR YES YES NR NO Thompson; 2007 YES YES NO NO YES YES NA NR YES YES NR NO Pauli; 2019 YES YES NO YES YES YES YES NR YES YES NR NO Wang; 2005 YES YES NO YES YES YES NA NR YES YES NR NO NA: Not applicable; NR: Not reported. Items: 1. Was the research question or objective in this paper clearly stated and appropriate? 2. Was the study population clearly specified and defined? 3. Did the authors include a sample size justification? 4. Were controls selected or recruited from the same or similar population that gave rise to the cases (including the same timeframe)? 5. Were the definitions, inclusion and exclusion criteria, algorithms or processes used to identify or select cases and controls valid, reliable, and implemented consistently across all study participants? 6. Were the cases clearly defined and differentiated from controls? 7. If less than 100 percent of eligible cases and/or controls were selected for the study, were the cases and/or controls randomly selected from those eligible? 8. Was there use of concurrent controls? 9. Were the investigators able to confirm that the exposure/risk occurred prior to the development of the condition or event that defined a participant as a case? 10. Were the measures of exposure/risk clearly defined, valid, reliable, and implemented consistently (including the same time period) across all study participants 11. Were the assessors of exposure/risk blinded to the case or control status of participants? 12. Were key potential confounding variables measured and adjusted statistically in the analyses? If matching was used, did the investigators account for matching during study analysis This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem M. Haji Aghajani et al. 12 Appendix 1: Medline search query Search terms 1. “Coronary Artery Disease” [mh] OR “Myocardial Infarction” [mh] OR “Myocardial Ischemia” [mh] OR “Acute Coronary Syndrome” [mh] OR “Coronary Stenosis” [mh] OR “ST Elevation Myocardial Infarction” [mh] OR “Non-ST Elevated Myocardial Infarction” [mh] OR Premature CAD[tiab] OR Premature coronary artery disease[tiab] OR Coronary Artery Disease[tiab] OR Artery Dis- ease, Coronary[tiab] OR Artery Diseases, Coronary[tiab] OR Coronary Artery Diseases[tiab] OR Disease, Coronary Artery[tiab] OR Diseases, Coronary Artery[tiab] OR Coronary Arteriosclerosis[tiab] OR Arterioscleroses, Coronary[tiab] OR Coronary Arte- rioscleroses[tiab] OR Atherosclerosis, Coronary[tiab] OR Atheroscleroses, Coronary[tiab] OR Coronary Atheroscleroses[tiab] OR Coronary Atherosclerosis[tiab] OR Arteriosclerosis, Coronary[tiab] OR Myocardial Infarction[tiab] OR Infarction, Myocardial[tiab] OR Infarctions, Myocardial[tiab] OR Myocardial Infarctions[tiab] OR Cardiovascular Stroke[tiab] OR Cardiovascular Strokes[tiab] OR Stroke, Cardiovascular[tiab] OR Strokes, Cardiovascular[tiab] OR Myocardial Infarct[tiab] OR Infarct, Myocardial[tiab] OR In- farcts, Myocardial[tiab] OR Myocardial Infarcts[tiab] OR Heart Attack[tiab] OR Heart Attacks[tiab] OR Myocardial Ischemia[tiab] OR Ischemia, Myocardial[tiab] OR Ischemias, Myocardial[tiab] OR Myocardial Ischemias[tiab] OR Ischemic Heart Disease[tiab] OR Heart Disease, Ischemic[tiab] OR Disease, Ischemic Heart[tiab] OR Diseases, Ischemic Heart[tiab] OR Heart Diseases, Is- chemic[tiab] OR Ischemic Heart Diseases[tiab] OR Acute Coronary Syndrome[tiab] OR Acute Coronary Syndromes[tiab] OR Coro- nary Syndrome, Acute[tiab] OR Coronary Syndromes, Acute[tiab] OR Syndrome, Acute Coronary[tiab] OR Syndromes, Acute Coronary[tiab] OR Premature heart attack[tiab] OR Coronary Stenosis[tiab] OR Stenoses, Coronary[tiab] OR Stenosis, Coro- nary[tiab] OR Coronary Artery Stenosis[tiab] OR Artery Stenoses, Coronary[tiab] OR Artery Stenosis, Coronary[tiab] OR Coro- nary Artery Stenoses[tiab] OR Stenoses, Coronary Artery[tiab] OR Stenosis, Coronary Artery[tiab] OR Coronary Stenoses[tiab] OR ST Elevation Myocardial Infarction[tiab] OR ST Segment Elevation Myocardial Infarction[tiab] OR ST Elevated Myocardial In- farction[tiab] OR STEMI[tiab] OR Non-ST Elevated Myocardial Infarction[tiab] OR Non ST Elevated Myocardial Infarction[tiab] OR NSTEMI[tiab] OR Non-ST-Elevation Myocardial Infarction[tiab] OR Infarction, Non-ST-Elevation Myocardial[tiab] OR Infarc- tions, Non-ST-Elevation Myocardial[tiab] OR Myocardial Infarction, Non-ST-Elevation[tiab] OR Myocardial Infarctions, Non-ST- Elevation[tiab] OR Non ST Elevation Myocardial Infarction[tiab] OR Non-ST-Elevation Myocardial Infarctions[tiab] 2. Premature[tiab] OR early onset[tiab] 3. “Interleukin-1”[mh] OR “Interleukin-1alpha”[mh] OR “Interleukin-1beta”[mh] OR “Interleukin-10”[mh] OR “Interleukin-11”[mh] OR “Interleukin-12”[mh] OR “Interleukin-12 Subunit p35”[mh] OR “Interleukin-12 Subunit p40”[mh] OR “Interleukin-13”[mh] OR “Interleukin-15”[mh] OR “Interleukin-16”[mh] OR “Interleukin-17”[mh] OR “Interleukin-18”[mh] OR “Interleukin-2”[mh] OR “Interleukin-23”[mh] OR “Interleukin-12 Subunit p40”[mh] OR “Interleukin-23 Subunit p19”[mh] OR “Interleukin-27”[mh] OR “Interleukin-3”[mh] OR “Interleukin-33”[mh] OR “Interleukin-4”[mh] OR “Interleukin-5”[mh] OR “Interleukin-6”[mh] OR “Interleukin-7”[mh] OR “Interleukin-8”[mh] OR “Interleukin-9”[mh] OR Interleukins[tiab] OR Interleukin[tiab] OR Interleukin- 1[tiab] OR Interleukin 1[tiab] OR IL-1[tiab] OR T Helper Factor[tiab] OR Lymphocyte-Activating Factor[tiab] OR Lymphocyte Acti- vating Factor[tiab] OR Macrophage Cell Factor[tiab] OR Epidermal Cell Derived Thymocyte-Activating Factor[tiab] OR Epidermal Cell Derived Thymocyte Activating Factor[tiab] OR Interleukin I[tiab] OR Interleukin-1alpha[tiab] OR Interleukin 1alpha[tiab] OR IL-1 alpha[tiab] OR Interleukin-1 alpha[tiab] OR Interleukin 1 alpha[tiab] OR Hematopoietin-1[tiab] OR Hematopoietin 1[tiab] OR Interleukin-1beta[tiab] OR Interleukin 1beta[tiab] OR IL-1 beta[tiab] OR Interleukin-1 beta[tiab] OR Interleukin 1 beta[tiab] OR Catabolin[tiab] OR Interleukin-10[tiab] OR Interleukin 10[tiab] OR IL10[tiab] OR IL-10[tiab] OR CSIF-10[tiab] OR Cytokine Synthe- sis Inhibitory Factor[tiab] OR Interleukin-11[tiab] OR Interleukin 11[tiab] OR IL-11[tiab] OR IL11[tiab] OR Adipogenesis Inhibitory Factor[tiab] OR Factor, Adipogenesis Inhibitory[tiab] OR Inhibitory Factor, Adipogenesis[tiab] OR Interleukin-12[tiab] OR Natu- ral Killer Cell Stimulatory Factor[tiab] OR IL-12[tiab] OR Cytotoxic Lymphocyte Maturation Factor[tiab] OR IL 12[tiab] OR IL-12 p70[tiab] OR Interleukin-12 p70[tiab] OR Interleukin 12 p70[tiab] OR Interleukin 12[tiab] OR IL12[tiab] OR Edodekin Alfa[tiab] OR Interleukin-13[tiab] OR IL-13[tiab] OR Interleukin 13[tiab] OR IL 13[tiab] OR IL13[tiab] OR Interleukin-15[tiab] OR IL15[tiab] OR Interleukin 15[tiab] OR IL-15[tiab] OR Interleukin-16[tiab] OR Interleukin 16[tiab] OR IL16[tiab] OR Lymphocyte Chemoattractant Factor[tiab] OR Chemoattractant Factor, Lymphocyte[tiab] OR IL-16[tiab] OR LCF Factor[tiab] OR Interleukin-17[tiab] OR Inter- leukin 17[tiab] OR CTLA-8[tiab] OR IL-17[tiab] OR Interleukin-17F[tiab] OR Interleukin 17F[tiab] OR IL-17F[tiab] OR Cytokine ML-1[tiab] OR Cytokine ML 1[tiab] OR Interleukin-17C[tiab] OR Interleukin 17C[tiab] OR IL-17C[tiab] OR Cytokine CX2[tiab] OR CX2, Cytokine[tiab] OR Interleukin-17E[tiab] OR Interleukin 17E[tiab] OR Interleukin-25[tiab] OR Interleukin 25[tiab] OR IL-17E[tiab] OR IL 17E[tiab] OR Interleukin-17A[tiab] OR Interleukin 17A[tiab] OR Cytotoxic T lymphocyte-Associated Antigen 8[tiab] OR Cytotoxic T lymphocyte Associated Antigen 8[tiab] OR IL-17A[tiab] OR CTLA8[tiab] OR Interleukin-17B[tiab] OR In- terleukin 17B[tiab] OR IL-17B[tiab] OR Interleukin-18[tiab] OR Interleukin 18[tiab] OR IFN-gamma-Inducing Factor[tiab] OR IL-18[tiab] OR Interferon-gamma Inducing Factor[tiab] OR Inducing Factor, Interferon-gamma[tiab] OR Interferon gamma In- ducing Factor[tiab] OR Interferon-gamma-Inducing Factor[tiab] OR IFN-gamma Inducing Factor[tiab] OR IFN gamma Inducing Factor[tiab] OR Inducing Factor, IFN-gamma[tiab] OR IL18[tiab] OR Interleukin-2[tiab] OR Interleukin 2[tiab] OR IL-2[tiab] OR IL2[tiab] OR TCGF[tiab] OR Interleukine 2[tiab] OR Lymphocyte Mitogenic Factor[tiab] OR Mitogenic Factor, Lymphocyte[tiab] OR T-Cell Growth Factor[tiab] OR T Cell Growth Factor[tiab] OR T-Cell Stimulating Factor[tiab] OR T Cell Stimulating Factor[tiab] OR Thymocyte Stimulating Factor[tiab] OR Interleukin II[tiab] OR Ro-23-6019[tiab] OR Ro 23 6019[tiab] OR Ro236019[tiab] OR Ro-236019[tiab] OR Ro 236019[tiab] OR RU 49637[tiab] OR RU-49637[tiab] OR RU49637[tiab] OR Interleukin-23[tiab] OR Inter- leukin 23[tiab] OR IL-23[tiab] OR Interleukin-27[tiab] OR Interleukin 27[tiab] OR IL-17D[tiab] OR IL27[tiab] OR IL-27[tiab] OR Interleukin-17D[tiab] OR Interleukin 17D[tiab] OR Interleukin-3[tiab] OR Interleukin 3[tiab] OR IL-3[tiab] OR Mast-Cell Colony- Stimulating Factor[tiab] OR Multipotential Colony-Stimulating Factor[tiab] OR Multipotential Colony Stimulating Factor[tiab] OR Erythrocyte Burst-Promoting This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem 13 Archives of Academic Emergency Medicine. 2022; 10(1): e51 Appendix 1: Medline search query Search terms Factor[tiab] OR Erythrocyte Burst Promoting Factor[tiab] OR Burst-Promoting Factor, Erythrocyte[tiab] OR Burst Promoting Fac- tor, Erythrocyte[tiab] OR Colony-Stimulating Factor 2 Alpha[tiab] OR Colony-Stimulating Factor, Mast-Cell[tiab] OR Colony Stim- ulating Factor, Mast Cell[tiab] OR Colony-Stimulating Factor, Multipotential[tiab] OR Colony Stimulating Factor, Multipoten- tial[tiab] OR Eosinophil-Mast Cell Growth-Factor[tiab] OR Eosinophil Mast Cell Growth Factor[tiab] OR Hematopoietin-2[tiab] OR Hematopoietin 2[tiab] OR P-Cell Stimulating Factor[tiab] OR P Cell Stimulating Factor[tiab] OR Interleukin-33[tiab] OR Inter- leukin 33[tiab] OR IL33[tiab] OR IL-33[tiab] OR Interleukin-4[tiab] OR Interleukin 4[tiab] OR B-Cell Growth Factor-1[tiab] OR B Cell Growth Factor 1[tiab] OR B-Cell Growth Factor-I[tiab] OR B Cell Growth Factor I[tiab] OR B-Cell Proliferating Factor[tiab] OR B Cell Proliferating Factor[tiab] OR B-Cell Stimulating Factor-1[tiab] OR B Cell Stimulating Factor 1[tiab] OR B-Cell Stim- ulatory Factor 1[tiab] OR B-Cell Stimulatory Factor-1[tiab] OR BCGF-1[tiab] OR Binetrakin[tiab] OR BSF-1[tiab] OR IL-4[tiab] OR IL4[tiab] OR Mast Cell Growth Factor-2[tiab] OR Mast Cell Growth Factor 2[tiab] OR MCGF-2[tiab] OR B Cell Stimulatory Factor-1[tiab] OR B Cell Stimulatory Factor 1[tiab] OR Interleukin-5[tiab] OR Interleukin 5[tiab] OR BCGF-II[tiab] OR Differ- entiation Factor, Eosinophil[tiab] OR T-Cell- Replacing Factor[tiab] OR T Cell Replacing Factor[tiab] OR IL-5[tiab] OR IL5[tiab] OR T-Cell Replacing Factor[tiab] OR Replacing Factor, T-Cell[tiab] OR B-Cell Growth Factor-II[tiab] OR B Cell Growth Factor II[tiab] OR Eosinophil Differentiation Factor[tiab] OR Interleukin-6[tiab] OR Interleukin 6[tiab] OR IL6[tiab] OR B-Cell Stimula- tory Factor 2[tiab] OR B-Cell Stimulatory Factor-2[tiab] OR Differentiation Factor-2, B-Cell[tiab] OR Differentiation Factor 2, B Cell[tiab] OR B-Cell Differentiation Factor-2[tiab] OR B Cell Differentiation Factor 2[tiab] OR BSF-2[tiab] OR Hybridoma Growth Factor[tiab] OR Growth Factor, Hybridoma[tiab] OR IFN-beta 2[tiab] OR Plasmacytoma Growth Factor[tiab] OR Growth Factor, Plasmacytoma[tiab] OR Hepatocyte-Stimulating Factor[tiab] OR Hepatocyte Stimulating Factor[tiab] OR MGI-2[tiab] OR Myeloid Differentiation-Inducing Protein[tiab] OR Differentiation-Inducing Protein, Myeloid[tiab] OR Myeloid Differentiation Inducing Protein[tiab] OR B-Cell Differentiation Factor[tiab] OR B Cell Differentiation Factor[tiab] OR Differentiation Factor, B-Cell[tiab] OR Differentiation Factor, B Cell[tiab] OR IL-6[tiab] OR Interferon beta-2[tiab] OR Interferon beta 2[tiab] OR beta-2, Inter- feron[tiab] OR B Cell Stimulatory Factor-2[tiab] OR B Cell Stimulatory Factor 2[tiab] OR Interleukin-7[tiab] OR Interleukin 7[tiab] OR IL7[tiab] OR Lymphopoietin-1[tiab] OR Lymphopoietin 1[tiab] OR IL-7[tiab] OR Interleukin-8[tiab] OR Interleukin 8[tiab] OR IL8[tiab] OR Monocyte-Derived Neutrophil Chemotactic Factor[tiab] OR Neutrophil Activation Factor[tiab] OR Neutrophil- Activating Peptide, Lymphocyte-Derived[tiab] OR Lymphocyte-Derived Neutrophil-Activating Peptide[tiab] OR Neutrophil Ac- tivating Peptide, Lymphocyte Derived[tiab] OR Neutrophil-Activating Peptide, Monocyte-Derived[tiab] OR Monocyte-Derived Neutrophil-Activating Peptide[tiab] OR Neutrophil Activating Peptide, Monocyte Derived[tiab] OR Alveolar Macrophage Chemo- tactic Factor-I[tiab] OR Alveolar Macrophage Chemotactic Factor I[tiab] OR AMCF-I[tiab] OR Anionic Neutrophil-Activating Peptide[tiab] OR Anionic Neutrophil Activating Peptide[tiab] OR Neutrophil-Activating Peptide, Anionic[tiab] OR Peptide, An- ionic Neutrophil-Activating[tiab] OR Chemokine CXCL8[tiab] OR CXCL8, Chemokine[tiab] OR Chemokines, CXCL8[tiab] OR CXCL8 Chemokines[tiab] OR Chemotactic Factor, Macrophage-Derived[tiab] OR Chemotactic Factor, Macrophage Derived[tiab] OR Macrophage-Derived Chemotactic Factor[tiab] OR Chemotactic Factor, Neutrophil[tiab] OR Neutrophil Chemotactic Fac- tor[tiab] OR Chemotactic Factor, Neutrophil, Monocyte-Derived[tiab] OR CXCL8 Chemokine[tiab] OR Chemokine, CXCL8[tiab] OR Granulocyte Chemotactic Peptide-Interleukin-8[tiab] OR Chemotactic Peptide-Interleukin-8, Granulocyte[tiab] OR Granulo- cyte Chemotactic Peptide Interleukin 8[tiab] OR IL-8[tiab] OR Interleukin-9[tiab] OR Interleukin 9[tiab] OR T-Cell Growth Factor P40[tiab] OR T Cell Growth Factor P40[tiab] OR P40 T-Cell Growth Factor[tiab] OR P40 T Cell Growth Factor[tiab] OR IL-9[tiab] OR IL9[tiab] 4. #1 AND #2 AND #3 This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem Introduction Methods Results Discussion Conclusion Declarations References