In the present study we investigate three interleukins (IL-1β – IL-8 and IL-11) as probable and practical biomarkers along with cardiac biomarkers (troponin and CK-MB) in order to have efficient and timely diagnosis of MI. Since the sensitivity and specificity of biomarkers for diagnosing myocardial injuries is of high importance, we could take the advantage of inflammatory biomarkers assessments as a complementary way of diagnosis as well as follow-up procedure, together with the routine biomarkers. These would be beneficial to follow-up patients in terms of treatment steps and anticipating eventual reinfarction.
In the current research, blood sugar and lipid profiles of each patient (both sexes) were measured at the beginning of the experiment. A higher amounts of blood sugar and HDL have been reported in males, while TG, cholesterol and LDL were higher in females. Haseeb A. Khan et al noticed that total cholesterol (TC), LDL and HDL decreased significantly in acute myocardial infarction patients (AMI). They mentioned that although TC reduction did not prevent the AMI risk, a decrement in HDL would make these patients vulnerable to AMI incidence(18). Also, Amit Kumar Shrivastava and his colleagues, who evaluated 400 AMI patients, illustrated a significant decrease in TC, LDL and HDL and a remarkable elevation in TG and inflammatory markers such as : IL-6 and IL-10 within the first 2 days of sampling. They represented the serum level’s correction of mentioned factors at 7 days of AMI onset. Thus, the assessments of serum lipid profiles are highly recommended after the MI diagnosis in order to reduce the risks(19). There are also more researches which highlights the importance of lipids and lipoprotein measurements in cardiovascular diseases like Bahattin Balci who underlined An increase in TG and low density lipoproteins and decrease in LDL, HDL and TC in patients with Acute Coronary Syndrome (ACS). He suggested that fasting lipid profile assessment and statin therapy for these patients, as long as they admit to the hospital, would probably reduce morbidity and mortality(20).
Studies have claimed that both gender and age differences have influenced the amounts of serum lipid profiles in patients with MI. In 2017 Zhixiong Zhong et al showed the higher TC, LDL, HDL and TG levels in females than males in elderly Hakka patients with acute myocardial infarction in southern China. They also mentioned a higher chance of dyslipidemia in non-elderly male patients than elderly one. Therefore, they had a great suggestion of lipid-lowering therapy for their elderly patients in order to decrease the cardiovascular difficulties’ risks(21). Our study confirms that the amount of serum lipid profile is sex-dependent and any contradiction between these studies would stem from a population differences.
In some recent studies many researches have introduced how serum lipid profile evaluation could be essential within the 24 hours of admission with acute coronary syndrome symptoms. In 2018 William T. Wang et al depicted that post-MI follow-up of patients in terms of their serum lipid profiles were taken for granted throughout the clinical processes, although the American College of Cardiology/American Heart Association guidelines emphasized on the positive influence of lipid-lowering therapy immediately after the patient’s admission and discharge. In spite of a periodically decreasing pattern for TC, LDL, and HDL to reach their plateau in MI patients, lipid-lowering therapy should be begun in the first days of diagnosis. In addition, in 2019 Naresh Kumar et al reported the serum lipid profile changes in the first 24 hours of and after 48 hours of MI incident. The decrement of TC, LDL and HDL and the increment of TG showed over a period in question. All in all, the phasic evaluation of lipid profiles would probably make it easier to follow their trend, making a wise decision toward the application of lipid-lowering therapy for MI patients in no time(22, 23).
In the current study the amount of Troponin and CK-MB were changed with the same pattern similar to the finding of other researches. TnC blood levels increased within the first hours of patient’s admission, continuing its rise to reach its peak and stay high for the next 2–3 weeks. Although CK-MB demonstrated the same increasing trend as TnC, it has decreased to reach its normal levels with the next 48–72 hours. Various researches depicted that CK-MB is no longer evaluated as an emergency biomarker and could be used to estimate infarct size and prognosis processes(24, 25).
Due to the importance of having biomarkers with high sensitivity and specificity for MI diagnosis along with patient’s follow-up, we decided to investigate some inflammatory cytokines (1L-1β, IL-8 & IL-11) and compare them with the routine biomarkers.
Regarding the IL-1β blood levels, the increasing pattern has been depicted not only in the first sampling but after 72 hours. This showed a marked similarity with the troponin changes throughout the experimental period. In a recent study Johanne Silvain et al. found that high IL-1β levels were closely associated with cardiovascular mortality, major cardiovascular events (MACE) and as a whole all-cause mortality. These findings were represented as a result of 90-days and one-year follow up of patients with acute MI. They have also support the necessity of using IL-1β inhibitors in the acute MI patients as a treatment and risk reductions(26). Paul M Ridker et al. reported that the anti-inflammatory therapy approach toward IL-1β with Canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, without any changes of LDL cholesterol levels could substantially reduce the cardiovascular diseases’ incidents in the patients with the MI history(27). According to the results of another study, it has been demonstrated that IL-1β levels were in connection with repairing process of patients with the MI history(STEMI). They indeed mentioned the importance of this inflammatory cytokine and dysfunctional myocardial remodeling after the reperfused MI that would bring about myocardial function impairment and heart failure(28).
In the recent letter published in 2019 Hirotaka Mor et al. illustrated that that nolotinib, prescribing for chronic myeloid leukemia (CML) patients, could increase the IL-1β serum levels and cardiovascular events. Despite the effectiveness of nilotinib for CML, it should not be prescribed for patients with the cardiovascular history and risk factors. They have also showed that IL-1β might contribute to apoptosis through releasing from injured cardio myocytes in the AMI patients. Apoptosis was induced by IL-1β in cardio myocytes of murine MI models. Taken together, IL-1β would elevate the risk of apoptosis and should be controlled specifically in high risk patients(29). Recently Mona Panahi et al. were represent the adverse effects of post-MI inflammation which led to heart failure (HF). A timely decision like blockade of inflammatory cytokines (IL-1) could prevent the incidence of post-MI excessive inflammation which curb the repairing processes by immune system(30).
Moreover, myriad of researches have demonstrated the plausible association between IL-1β + 3954C/T polymorphism (rs1143634) and MI incidence. This has been proved via a meta-analysis by Yizhen Fang et al., specifically amongst Caucasian populations(31). We have to take into account that although the circulation levels of IL-1β is very low to investigate, this inflammatory biomarkers’ assessment would be beneficial in order to eliminate its probable adverse impact on cardiovascular remodeling in reperfused MI patients.
We also studied IL-8 and IL-11 in MI cases. Both inflammatory biomarkers followed the same falling pattern in an experimental period. IL-8 has decreased dramatically after the 2nd time point, while IL-11 changes was not statistically significant. Kathrin Schömig et al. showed the association between IL-8 levels and progenitor cells in circulation of AMI patients. Progenitor cells are released during inflammation, giving rise to neovascularization. This would clarify the possibility of beneficial impacts induced by inflammatory biomarkers instead of their mere adverse effects(32). On the contrary Christian Shetelig et al. ( 2018) reported the link between IL-8 high levels and some cardiovascular difficulties in STEMI patients such as: microvascular obstruction, large infarct size, LV remodeling and further clinical post-MI incidences. They have supposed the possible IL-8’s therapeutic approach toward identifying high risk STEMI patients as well as post- infarct inflammation reduction(14). Our result confirms the increase in the IL-8 serum levels with the onset of MI. Owing to the probable effects of this inflammatory biomarker to deteriorate the post-MI conditions, it could have been used as an inflammatory regulation target in post-infarct patients in order to curb new events.
In another recent review in 2018 researches have provided the results related to the benefits of cytokines’ (IL-1, -6, -8, MCP-1, CC chemokines, CXC chemokines and TNF-α) inhibition on cardiac function. However, adverse or even neutral results was indeed represented for some of these cytokines (IL-1, IL-6, IL-8, and MCP-1). There were still some conflicting animal model results. They have showed the use of monoclonal antibody against IL-8 for ischemic reperfusion rabbit model and its association with infarct size reduction, while in another study the IL-8 receptor overexpression in a chronic MI rat model caused a decrease in infarct size and inflammatory cells and finally LEVF improvement(33). In a case-control study by S Zarrouk-Mahjoub et al., 30 MI patients have been compared with 30 healthy individuals (controls) in terms of their serum concentrations of interleukin-8 (IL8), tumor-necrosis factor-alpha (TNFα) and interleukin-10 (IL10), pro- and anti-inflammatory cytokines, on days 2 and 30 of post-MI. They illustrated the rise in pro-inflammatory cytokines (IL-8 and TNF-α) along with the fall in anti-inflammatory one, IL-10. This inequality between pro and anti-inflammatory cytokines would lead to heart failure(34). Our results reconcile with the previous studies regarding the increased IL-8 levels just after MI onset.
Since there was a belief about the link between inflammation and coronary heart disease (CHD), Zhengxia Liu et al. have evaluated the inflammatory cytokines levels (CD121a, interleukin [IL]-1β, IL-8, and IL-11) in CHD and CHD-free patients. Although the CD121a levels were high in MI patients, IL-1β levels were unchanged throughout the experiment. Like CD121a, IL-8 levels were also high in AMI patients. Meanwhile they have mentioned the highest levels of IL-11 in CHD patients rather than non-CHD ones(35). In a case report in 2016, 4 different cases have been treated with IL-11, known as a cardio protective cytokine, in ST elevation myocardial infarction (STEMI) patients. There was not any adverse drug reaction throughout the treatment with recombinant human IL-11 (rhIL-1) and ultimately all cases left the hospital without any HF symptoms(36).
According to the IL-11 treatment, Masanori Obana et al. have illustrated that IL-11 treatment for coronary artery ligation animal model could alleviate post MI cardiac fibrosis via STAT3. They have proved a notable upregulation of IL-11 mRNA in cardiac myocytes of MI cases. Therefore, intravenous administration of IL-11, almost after ligation, could decrease the fibrosis area. These all gave a new perspective for IL-11 treatment against post-MI complications(37). In a recent study in 2019 researchers have investigated the association between IL-11 levels and cardiac prognosis of chronic HF patients. Although the specific mechanisms of IL-11 remained unknown, higher levels of IL-11 have been reported throughout the cardiac events which might have severe outcomes(38). Our result confirmed the IL-11 increment that has been reported throughout the cardiac evets in mentioned studies. Moreover, due to the conflicting evidences from different researches we suggest a thorough evaluation of pro and anti-inflammatory cytokines as well as a long term follow-up till the patients’ stable conditions.
Some limitations can be enumerated for present study. The sample size was relatively small owing to the lack of enough volunteers to join the research study. Furthermore, we recommend the evaluation of various related pro and anti-inflammatory cytokines simultaneously along with in depth clinical MI and HF investigations in the hospital to conduct a concrete conclusion.