Significant association between serum resistin and hypersensitive troponin I levels in patients with a first ST-segment elevation myocardial infarction

Background Resistin, a proinflammatory adipocytokine secreted predominately by macrophages in humans, plays an important role in the pathogenesis and development of atherosclerosis. The present research mainly investigated the association between serum resistin level and peak hypersensitive cardiac troponin I (hs-cTnI) in patients with ST-segment elevation myocardial infarction (STEMI).Methods We consecutively enrolled 92 patients with a first STEMI in this cross-sectional and observational study. Resistin concentrations upon admission and 24 h and 72 h after primary percutaneous coronary intervention (PCI) were all measured. The change in resistin (δ Resistin) was defined as (serum resistin concentration at admission)-(serum resistin concentration 24 h after intervention).Results Serum resistin concentration decreased rapidly after primary PCI. Resistin at admission correlated positively with tumour necrosis factor-α (r = 0.522, p<0.001) and macrophage migration inhibitory factor (r = 0.471, p<0.001). Additionally, resistin at admission correlated negatively with the reactive oxygen species scavengers superoxide dismutase (r = -0.261, p = 0.012) and glutathione peroxidase (r = -0.235, p = 0.024). Most importantly, serum resistin concentrations upon admission (r = 0.381, p<0.001) and 24 h (r = 0.372, p<0.001) and 72 h (r = 0.347, p = 0.001) after primary PCI all correlated with peak hs-cTnI, while δ Resistin was not associated with peak hs-cTnI. After multiple linear regression analysis, serum resistin (beta = 13.593, 95% CI 5.951 to 21.235, p < 0.001) at admission and 24 h (beta = 13.972, 95% CI 5.662 to 22.282, p = 0.001) and 72 h (beta = 14.455, 95% CI 5.178 to 23.733, p = 0.003) after intervention remained associated with peak hs-cTnI.Conclusions In our present research, serum resistin concentrations at different time points all correlated positively with peak hs-cTnI, which may suggest that serum resistin concentrations during the acute phase of STEMI for forecasting myocardial infarction size and prognosis in

PCI. Additionally, our research also indicated that resistin may regulate myocardial IRI partly by promoting the inflammatory process and oxidative stress.

Background
Various adipocytokines and proinflammatory cytokines, including resistin, can deteriorate in obesity-related disorders, including insulin resistance, type 2 diabetes, atherosclerosis, and coronary artery disease (CAD) [1,2]. Resistin is primarily known as a hormone secreted by adipocytes primarily in rodents, while it is mainly expressed by macrophages in humans [3,4]. Given the correlation between murine resistin and insulin resistance, numerous experimental and clinical studies have found that elevated human resistin may play a critical role in the pathophysiology of insulin resistance via various potential mechanisms [5,6]. Additionally, growing evidence supports the idea that resistin promotes atherogenic dyslipidaemia and contributes to the development of hypertension [7][8][9][10].
Elevated resistin contributes to the formation of atherosclerosis through not only its indirect influences on the exacerbation of risk factors, such as insulin resistance, atherogenic dyslipidaemia, and hypertension, but also its direct effects on key steps of atherosclerosis [5]. Some experimental studies have indicated that resistin regulates the progression of atherosclerosis via inducing endothelial dysfunction, the artery inflammatory response, and the formation of foam cells in human macrophages [1,2,5].
Additionally, clinical research with a large sample size also indicated that serum resistin may act as a risk factor for coronary disease in the general population, especially in women [11]. Furthermore, serum resistin concentration is also associated with the severity of CAD and in-stent restenosis, as some studies have shown [12,13].
Although the serum resistin level increased markedly in patients with CAD, especially STsegment elevation myocardial infarction (STEMI) patients [12,[14][15][16], there are no studies investigating the kinetics of serum resistin during the acute phase of STEMI and the correlation between serum resistin level and myocardial injury in STEMI patients.
Therefore, the present research demonstrated the serial change in serum resistin concentration and the association between serum resistin and peak hypersensitive cardiac troponin I (hs-cTnI) level in STEMI patients who underwent primary percutaneous coronary intervention (PCI).

Study population
We consecutively enrolled 92 first STEMI patients from Beijing Anzhen Hospital from August 2017 to July 2018. To be recruited in the present study, each patient had to meet the following inclusion criteria: age range from 18 to 80 years, admitted to the emergency department for typical symptoms and subsequently confirmed STEMI according to the fourth universal definition of myocardial infarction, primary PCI performed successfully within 12 h from the onset of symptoms. All participants who had acute and chronic inflammation diseases, hepatic and renal dysfunction, active infection, a previous history of acute myocardial infarction (AMI) or a previous history of PCI and coronary artery bypass grafting (CABG) were excluded from enrolment.
The present research had ethics approval from the local Ethics Committee and was also performed according to the Declaration of Helsinki. Additionally, we secured written informed consent from the patients included in this study.

Primary PCI and medication
All participants who met the inclusion criteria were treated with a loading dose of 600 mg clopidogrel and 300 mg aspirin. Additionally, routine use of unfractionated heparin (70-100 U/kg) was recommended for all the patients recruited during the periprocedure. Then, the primary PCI was conducted in compliance with the newest guidelines on myocardial revascularization by the interventional cardiologist. The selection of new-generation drug-eluting stents, thrombus aspiration and intracoronary injection with glycoprotein IIb/IIIa inhibitors and vasodilators were all at the discretion of the operator. In addition to lifestyle intervention and risk factor control, dual antiplatelet therapy, beta-blockers, angiotensin-converting enzyme inhibitors (ACEI)/angiotensin receptor blocker (ARB) and statins were also recommended to the patients after primary PCI.

Baseline clinical data collection
Baseline data such as age, sex, body mass index (BMI), history of disease, and medication use at discharge were all gathered through the medical records. We also gathered data concerning primary PCI, including total ischaemic time, the culprit vessel, the number of diseased vessels, thrombolysis in myocardial infarction (TIMI )flow grade pre-PCI or post-PCI, and the number of stents implanted. Additionally, medication use at discharge was recorded.

Sample collection and assays
We obtained 5 ml fasting venous blood from the participants upon admission and 24 h and at 72 h after intervention. Samples upon admission and at 24 h and 72 h after intervention were centrifuged at 2500 rpm for 15 min. Then, we collected the serum and kept it at -80℃. Enzyme linked immunosorbent assay (ELISA) kits were applied to measure resistin levels upon admission and 24 h and 72 h after primary PCI. Tumour necrosis factor-α (TNFα) and macrophage migration inhibitory factor (MIF) levels upon admission were also determined by ELISA (Shanghai BlueGene Biotech Co., Ltd., Shanghai, China). Additionally, we measured serum superoxide dismutase (SOD) and glutathione peroxidase (GSH-PX) levels at admission by a colorimetric method (Nanjing JianCheng Biotech Co., Ltd., Nanjing, China). δ Resistin was defined as (Serum resistin concentration at admission)-(serum resistin concentration 24 h after intervention).
Both the intra-assay and inter-assay coefficient of variation were < 5%. The samples included in the present research were all measured in duplicate.
We determined the serum Hs-cTnI level on admission and every 12 h for the following 3 days at the clinical biochemistry laboratory of Beijing Anzhen Hospital to identify peak Hs-cTnI. Additionally, the other routine biochemical parameters were also measured at the clinical biochemistry laboratory of Beijing Anzhen Hospital.

Statistical analysis
Normally distributed continuous parameters were summarized as the mean ± SD, and continuous parameters with skewed distributions were summarized as medians (25th, 75th percentiles). Additionally, categorical variables were summarized as percentages. The association between resistin and other parameters was evaluated by Pearson correlation analysis. Furthermore, we applied univariate and multivariate linear models to assess the correlation between resistin and peak hs-cTnI after adjustment for other variables. SPSS software (version 20.0; SPSS, Inc., Chicago, IL) was used to conduct the statistical analysis. Additionally, p-values < 0.05 were considered significant.

Baseline characteristics
The baseline clinical characteristics are indicated in table 1. In the present study, 92 patients (25.0% female) aged 55.82 ± 12.04 years were recruited. Atherosclerosis risk factors, hypertension, diabetes mellitus, and current smoking status were documented in 47 (51.1%), 17 (18.5%), and 63 (68.5%) patients, respectively. Regarding angiographic data, the culprit vessel was the left anterior descending artery in 57.6% of the patients, and TIMI flow grade 0 was seen in 84.8% of the patients. The patients enrolled in the present research all received timely reperfusion therapy with a median time of 286.50 mins, ranging from 197.00 mins to 412.75 mins. After the primary PCI, TIMI flow grade 3 was observed in 76.1% of the participants. Additionally, the percentages of patients receiving dual antiplatelet therapy, statin, ACEI/ARB, and beta-blockers were 100.0%, 100.0%, 69.6%, and 88.0%, respectively, at discharge.

Change in serum resistin concentration
The mean levels of serum resistin on admission and 24 h and 72 h after intervention were 1.85±0.42 ng/ml, 1.62±0.40 ng/ml, and 1.64±0.36 ng/ml, respectively (p < 0.001). As

Serum resistin was correlated with the inflammatory response and oxidative stress
We first examined the correlation between serum resistin concentration and inflammation.

Serum resistin was associated with myocardial injury
We next analysed the association between serum resistin concentration at each time point with peak hs-cTnI. As revealed in Figure 3, serum resistin level at admission (r = 0.381, p < 0.001; Figure 3A), serum resistin concentration at 24 h (r = 0.372, p < 0.001; Figure 3B) and serum resistin concentration at 72 h (r = 0.347, p = 0.001; Figure 3C) after intervention were all correlated positively with peak hs-cTnI. However, as shown in Figure   3D, serum peak hs-cTnI had no association with δ Resistin (r = 0.046, p = 0.667).
Furthermore, as shown in

Discussion
This is the first prospective study investigating the kinetics of serum resistin in patients with a first STEMI after primary PCI, and several relationships were observed. First, our present research revealed that serum resistin concentration was highest at admission in patients with STEMI and declined after intervention, reaching the lowest level 24 h after primary PCI. Second, we revealed that admission serum resistin has an association with inflammatory parameters (TNF-α and MIF) and markers of oxidative stress (SOD and GSH-PX). Last, our present study indicated that serum resistin at admission and serum resistin 24 h and 72 h after primary PCI were all predictive of later changes in the necrotic marker peak hs-cTnI after multiple linear regression analysis.
Resistin, a 12.5 kDa peptide, is secreted predominately by white adipose tissue in mice [5,6]. However, human resistin is expressed mainly by peripheral blood mononuclear cells (PBMCs), macrophages, and bone marrow cells, which suggests that resistin may be linked to inflammation [5,6]. There is much evidence indicating that serum resistin concentration is markedly increased in CAD patients, especially in patients with acute coronary syndrome (ACS) [15][16][17]. Additionally, both resistin protein and resistin mRNA increase significantly in epicardial adipose tissue in patients with ACS [18]. Our present paper extends these prior investigations by showing that the increased serum resistin admission decreased significantly 72 h after intervention. Furthermore, clinical research with 6636 adults from the general population indicated that the mean resistin level in men was lower than that in women [11]. In contrast, our present research indicates that there are no significant differences in resistin concentration at admission between women and men in STEMI patients. We speculated that the dramatically elevated serum resistin level at the onset of STEMI may contribute partly to this controversy. Additionally, there were no significant associations between resistin at admission and BMI, fasting blood glucose, triglycerides, low density lipoprotein, high density lipoprotein, and creatinine in our present research, which is in accordance with the studies by Tarek E Korah et al and Qiao et al [15,16].
It is well known that inflammation plays a critical role in the process of myocardial ischaemia-reperfusion injury (IRI) [19][20][21]. Prior clinical and experimental studies have shown that resistin may promote the inflammatory process via upregulating the expression of proinflammatory cytokines, including TNF-α, interleukin-6, and monocyte chemoattractant protein-1 [5,22]. TNF-α and MIF levels upon admission all participate in the process of IRI [19,23,24], and our present research indicated for the first time that resistin at admission correlated positively with them in STEMI patients. In addition to inflammation, previous studies revealed that oxidative stress also contributed to IRI via reactive oxygen species (ROS) [20,21,25]. SOD and GSH-PX may produce cardioprotective effects by eliminating ROS [26]. Our present study revealed that serum resistin has a negative association with SOD and GSH-PX in STEMI patients. Additionally, previous research by D.V. Godin also suggested that nitric oxide (NO) can prevent myocardium damage due to ischaemic/reperfusion by balancing the homeostasis of mitochondrial Ca 2+ [26,27]. However, resistin may reduce the NO concentration significantly in human endothelial cells, as previous studies indicated [28]. Furthermore, research by Laurikka and colleagues revealed that resistin levels also correlate with the oxidative stress marker myeloperoxidase [29].
Subsequently, we investigated the association between serum resistin and myocardial injury. Previous studies revealed that serum resistin levels correlated positively with peak creatine kinase (CK), peak MB isoenzyme of CK (CK-MB), and peak cardiac troponin I (cTnI) [15][16][17] Furthermore, Laurikka and colleagues showed that the maximal change in resistin concentration has a positive association with myocardial injury in patients who underwent cardiac surgery [29]. However, the change in resistin level (δ Resistin) has no association with myocardial injury in STEMI patients, as indicated by our data. Various factors, such as the type of patient recruited and the time points of sample extraction, may all contribute to discrepancies. From the evidence above, we speculated that resistin may promote myocardium IRI, and promoting the inflammatory process and oxidative stress may be part of the potential mechanisms.
Several limitations in the present research should be noted. First, this is a cross-sectional and observational study with a small sample size. Second, the patients recruited in the present study were all the first STEMI patients who underwent primary PCI successfully, which may affect the results and make the results of our study unsuitable for the general population. Third, we only used peak hs-cTnI as a marker of myocardial necrosis. Future studies should use cardiac magnetic resonance imaging or single-photon emission computed tomography imaging to quantify myocardial infarction size. Finally, our present research mainly focuses on the association between resistin and peak hs-cTnI. Future studies are required to evaluate the mechanism and causality between resistin and myocardial IRI.

Conclusions
The present study established that serum resistin concentration was associated with peak hs-cTnI in STEMI patients. Additionally, from our research, we speculated that resistin may regulate myocardial IRI partly through promoting inflammatory processes and oxidative stress. Future studies are warranted to elucidate the causality and underlying mechanisms between serum resistin expression and myocardial IRI.   Total ischaemic time, from symptom onset to recanalization of culprit vessel. Age, gender, culprit vessel, total ischaemic time, fasting blood glucose and other variables with p < 0.05 in the univariable analysis were all included in the multivariable linear regression analysis mode.