Mediators of Inflammation

Mediators of Inflammation / 2020 / Article

Research Article | Open Access

Volume 2020 |Article ID 1719279 | https://doi.org/10.1155/2020/1719279

Xia Li, Dianxuan Guo, Ying Chen, Youdong Hu, Fenglin Zhang, "Effects of Altered Levels of Pro- and Anti-Inflammatory Mediators on Locations of In-Stent Reocclusions in Elderly Patients", Mediators of Inflammation, vol. 2020, Article ID 1719279, 12 pages, 2020. https://doi.org/10.1155/2020/1719279

Effects of Altered Levels of Pro- and Anti-Inflammatory Mediators on Locations of In-Stent Reocclusions in Elderly Patients

Academic Editor: Daniela Novick
Received31 May 2020
Revised19 Aug 2020
Accepted27 Aug 2020
Published23 Sep 2020

Abstract

Imbalances of proatherogenic inflammatory and antiatherogenic inflammatory mediators were involved in the pathogenesis of atherosclerosis. This study sought to investigate the effects of proatherogenic inflammatory and antiatherogenic inflammatory mediators on the proximal, middle, and distal coronary artery reocclusions in elderly patients after coronary stent implantations. We measured the expression levels of proatherogenic inflammatory/antiatherogenic inflammatory cytokines. This included interleukin-1 β (IL-1 β), interleukin-6 (IL-6), interleukin-8 (IL-8), tumor necrosis factor-α (TNF-α), high-sensitivity C-reactive protein (hs-CRP), interleukin-10 (IL-10), interleukin-17 (IL-17), interleukin-13 (IL-13), and interleukin-37 (IL-37) in the elderly patients with the proximal, middle, and distal coronary artery reocclusions after coronary stent implantations. Levels of IL-1 β, IL-6, IL-8, TNF-α, and hs-CRP were remarkably increased (), and levels of IL-10, IL-17, IL-13, and IL-37 were remarkably lowered () in the elderly patients with the proximal, middle, and distal coronary artery reocclusions. Imbalances of proatherogenic inflammatory and antiatherogenic inflammatory mediators may be involved in the formation and progression of proximal, middle, and distal coronary artery reocclusions in elderly patients after coronary stent implantations.

1. Introduction

The cytokines were related to the complex proinflammatory responses in the atherosclerotic lesions, and the cytokines were involved in the formation and disruption of atherosclerotic plaques. The cytokines were divided into proatherogenic inflammatory and antiatherogenic inflammatory cytokines depending on whether they led to the development and progression of atherosclerosis [1].

Atherosclerosis was a chronic inflammatory disease, and the proatherogenic inflammatory cytokine interleukin-1 β (IL-1 β) was related to the progression of atherosclerosis and the lack of IL-1 β reduced the development of atherosclerosis [2, 3]. The proatherogenic inflammatory cytokine interleukin-6 (IL-6) was a biomarker of the blood vascular inflammation that was an important risk factor for cardiovascular diseases. The IL-6 played a key role in inflammatory response and atherosclerosis [4]. The interleukin-8 (IL-8) expression was in human atherosclerotic lesions, and increased levels of proatherogenic inflammatory cytokine IL-8 were related to the development of atherosclerosis, and IL-8 was involved in the unstable coronary heart disease [5, 6]. Proatherogenic inflammatory cytokine tumor necrosis factor-α (TNF-α) was elevated in patients with unstable atherosclerotic lesions and acute myocardial infarction. Increased levels of TNF-α were the predictions of sudden coronary death and cardiovascular events after acute myocardial infarction. The TNF-α was related to severe atherosclerotic plaques and played a key role in the development of coronary heart disease [7, 8]. High-sensitivity C-reactive protein (hs-CRP) was the inflammatory biomarker, synthesizing through the liver under stress, and was involved in the inflammatory response. The levels of hs-CRP were elevated in patients with acute coronary syndrome undergoing percutaneous coronary intervention [9].

Interleukin-10 (IL-10) was an antiatherogenic inflammatory cytokine that played the protective role in coronary atherosclerosis, and IL-10 deletion accelerated the progression of atherosclerosis. IL-10 decreased atherogenesis and enhanced the stability of coronary plaques [10]. The administration of inhibitors of the interleukin-17 (IL-17) signaling pathway and decreased IL-17 as antiatherogenic inflammatory cytokine was related to the high risk of major adverse cardiac events in the patients with an acute heart attack. High levels of IL-17 were related to the decreased atherosclerotic plaque size and artery plaque stability. The specific deletion of the IL-17 signaling pathway inhibited the atheroprotective effect and led to vascular inflammatory response and promoted the development of atherosclerosis [11]. The antiatherogenic inflammatory cytokine interleukin-13 (IL-13) had an anti-inflammatory response and the antiatherogenic role by inhibiting atherosclerotic plaque compositions and modulating the morphology of atherosclerotic plaques, and the deletion of IL-13 accelerated the formation of atherosclerosis. IL-13 also inhibited proatherogenic inflammatory cytokines (TNF-α and IL-1 β) [12, 13]. The overexpression of interleukin-37 (IL-37) as antiatherogenic inflammatory cytokine is protected against the inflammatory response by inhibiting proinflammatory cytokines [14, 15], and IL-37 inhibited atherosclerosis and was a novel cytokine for the prevention and treatment of atherosclerotic diseases [16]. In the present study, we tried to measure the levels of proatherogenic inflammatory and antiatherogenic inflammatory mediators in the elderly patients with proximal, middle, and distal coronary artery reocclusions after coronary stent implantations and to clarify whether imbalances of proatherogenic inflammatory and antiatherogenic inflammatory mediators were involved in the formation and progression of proximal, middle, and distal coronary artery reocclusions after coronary stent implantations in the elderly patients.

2. Materials and Methods

2.1. Patient Population

From 3rd of April 2013 to 8th of March 2017, this study included consecutive patients with distal coronary artery (Dist CA) reocclusion (), middle coronary artery (Mid CA) reocclusion (), proximal coronary artery (Prox CA) reocclusion (), and proximal+middle coronary artery (Prox Mid CA) reocclusion (). The inclusion criteria in this research project were (1) the patients aged 65 to 88 years old, (2) the patients with proximal, middle, and distal coronary artery reocclusions after coronary stent implantations. The research protocols were approved by the Xuzhou Medical University and the Research Ethics Committee of University Affiliated Huaian Hospital and the Medical Review Board in accordance with relevant laws and regulations of Chinese Government, and all patients gave their written informed consent prior to inclusion into the research protocols in accordance with the Declaration of Helsinki. The following conditions were excluded from the research participation: (1) the uses of proatherogenic inflammatory cytokine antagonists (Beta-adrenoceptor antagonists and Canakinumab), (2) the uses of anti-inflammatory and antiatherogenic agents (Hydrocortisone, Dexamethasone, 1,25 Dihydroxyvitamin D3 and Tanderil), (3) rheumatic diseases, (4) inflammatory bowel diseases, (5) neurodegenerative diseases, (6) infectious diseases, (7) multiple sclerosis, (8) arthritis, (9) asthma, (10) acute respiratory distress syndrome, (11) bronchiectasis, (12) Behçet’s disease, (13) periodontal disease, (14) peripheral arterial and veno-occlusive diseases, (15) autoimmune diseases, and (16) acute coronary reocclusion.

2.2. Study Design

Health individuals were divided into a control (CON) group (). The patients with right coronary artery reocclusion were divided into distal right coronary artery (Dist RCA) reocclusion group (), middle right coronary artery (Mid RCA) reocclusion group (), proximal right coronary artery (Prox RCA) reocclusion group (), and proximal+middle right coronary artery (Prox Mid RCA) reocclusion group (). The patients with left circumflex artery reocclusion were divided into distal left circumflex artery (Dist LCX) reocclusion group (), middle left circumflex artery (Mid LCX) reocclusion group (), proximal left circumflex artery (Prox LCX) reocclusion group (), and proximal+middle left circumflex artery (Prox Mid LCX) reocclusion group (). The patients with left anterior descending artery reocclusion were divided into distal left anterior descending artery (Dist LAD) reocclusion group (), middle left anterior descending artery (Mid LAD) reocclusion group (), proximal left anterior descending artery (Prox LAD) reocclusion group (), and proximal+middle left anterior descending artery (Prox Mid LAD) reocclusion group ().

2.3. Quantitative Evaluations of the Cardiac Angiographies and Echocardiograms

The proximal, middle, and distal coronary artery reocclusions were performed using the cardiovascular angiographic analysis system (QAngio XA). The coronary artery angiograms were confirmed independently by two prominent cardiologists blinded the patient’s clinical data. The Doppler echocardiograms were performed with synchronized electrocardiography recordings by independent cardiac medicine experts blinded to the clinical data in accordance with the standards committee of the American Society of Echocardiography.

2.4. Determinations of the Levels of IL-1 β, IL-6, IL-8, TNF-α, and hs-CRP

For analyses of IL-1 β, IL-6, IL-8, and TNF-α, the blood samples were collected from the patients at 8 am after an overnight fast. The serum samples were immediately centrifuged and were stored at -80°C until further determination. IL-1β, IL-6, and IL-8 were determined with the commercial enzyme-linked immunosorbent assay kits (human IL-1β: R&D Systems INC., Minnesota, USA; human IL-6: high sensitivity enzyme-linked immunosorbent assay, Immunotech S. A, Marseille, France; human IL-8: enzyme-linked immunosorbent assay; BD Bioscience, La Jolla, CA) as previously described [17, 18]. The serum samples were stored in -80°C until further determination, and the serum levels of TNF-α were determined by a high sensitivity enzyme-linked immunosorbent assay kit (Biosource, International, Inc.) according to the manufacturer’s instructions [19]. The serum levels of high sensitive C reaction protein (hs-CRP) were analyzed with a commercially available assay kit (hs-CRP test kits, Millipore Corp, Billerica, MA, USA), and the levels of hs-CRP were expressed as mg/L.

2.5. Determinations of the Levels of IL-10, IL-17, IL-13, and IL-37

Blood samples from patients were collected at 8 am after 12 hours fast for the determinations of IL-10, IL-17, IL-13, and IL-37. The blood serum samples were stored at -80°C for this study until further determination. Serum levels of IL-10, IL-17, IL-13, and IL-37 were tested with the enzyme-linked immunosorbent assays (IL-10: R&D Systems INC., Minnesota, USA; IL-17: R&D Systems, Minneapolis, MN, USA; IL-13: Calbiochem, San Diego, CA, U.S.A.; IL-37: R&D Systems INC, Minnesota, USA) according to the manufacturer’s instructions [11, 13, 16, 20].

2.6. The Related Data in Type, Length, and Diameter of Stents

The patients underwent percutaneous coronary intervention for coronary reocclusions with drug-eluting stent implantations before this study. In our research center, the sirolimus-eluting stents (Cordis, Warren, New Jersey, USA) were available in diameters of 2.50 mm, 3.00 mm, 3.50 mm, and 4.00 mm. The stent length was 8 mm for stents with a diameter of 2.50 mm, 15 mm for stents with a diameter of 3.00 mm, 18 mm for stents with a diameter of 3.50 mm, and 23 mm for stents with a diameter of 4.00 mm.

2.7. Myocardial Ischemia Flow Grades and Angina Pectoris Grades

This study included the patients with coronary in-stent chronic total reocclusion defined as total coronary artery reocclusion of ≥3-month duration with coronary artery 100% diameter restenosis and thrombolysis in myocardial ischemia (TIMI) flow grade 0 in the target artery after successful coronary stenting. Angiographic TIMI flow grade is used for the assessment of myocardial ischemia degree in the patients according to grade 0 defined as no flow, grade 1 defined as penetration without perfusion, grade 2 defined as partial perfusion, and grade 3 defined as complete perfusion of flow.

Angina pectoris, the pain of myocardial ischemia, is the main clinical symptom of coronary in-stent chronic total reocclusion. In this study, the stable angina pectoris (SAP) is classified into class I defined as no limitation in ordinary physical activities, class II defined as slight limitation of ordinary activities, and class III defined as marked limitation of ordinary activities according to the Canadian Cardiovascular Society Classification. The unstable angina pectoris (UAP) is classified into grade-I defined as accelerated angina pectoris, grade-II defined as subacute angina at rest, and grade-III defined as acute angina at rest according to Braunwald Classification.

2.8. Determinations of TC, TG, HDL-C, LDL-C, and VLDL-C

All patients received continuative treatment with atorvastatin 20 mg/d after coronary stent implantation. Fasting blood samples were taken from all patients in the morning. The serum levels of total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein-cholesterol (LDL-C), and very low-density lipoprotein-cholesterol (VLDL-C) were measured by HLC-729LPII (Tosoh Corporation).

2.9. Statistical Analysis

For all these experiments, all quantitative research data on the proatherogenic inflammatory/antiatherogenic inflammatory cytokine levels were expressed as the (). The paired two-sample Student’s -tests were used for assessing every pair of the matching observed data, and the one-way analysis of variance was performed to compare the variance among the means of different groups. Multivariate regression analysis was used for evaluating the significance of variables for the proximal, middle, and distal coronary artery reocclusions. The observed values smaller than 0.05 () were considered to indicate a statistically significant difference. All statistical analyses were conducted using the SPSS statistical package version 20.0 software (IBM Corp., Armonk, NY, USA) for all statistical tests of differential expression of proatherogenic inflammatory and antiatherogenic inflammatory mediators.

3. Results

3.1. Basic Clinical Features of the Elderly Patients with the Proximal, Middle, and Distal Coronary Artery Reocclusions

The baseline clinical characteristics were very similar among the different study groups of the elderly patients with the proximal, middle, and distal coronary artery reocclusions (Table 1). The patients in each group were well matched without statistically differences in gender (), age (), familial coronary artery disease defined as asymptomatic persons with a parent or sibling with coronary artery disease (), chest pain defined as pain located in the chest region (), alcohol consumption defined as 1-2 drinks/day about 3 times weekly (), smoking defined as a person who smokes tobacco regularly (), dyslipidaemia defined as a condition marked by abnormal concentrations of lipids or lipoproteins in the blood (), diabetes mellitus defined as the fasting plasma (7.0 mmol/L); or 2-h plasma (11.1 mmol/L) during oral glucose tolerance test; or hemoglobin (48 mmol/mol) (), and hypertension defined as systolic blood , or diastolic blood ().


CON Dist CA reocclusions Mid CA reocclusions Prox CA reocclusions Prox+Mid CA reocclusions

Gender (male/female)39/3085/8077/7063/6050/51
65-70-year-old age13/1020/1619/2120/1812/15
71-76-year-old age11/823/1415/2017/1510/17
77-82-year-old age9/720/2625/1214/1211/9
83-88-year-old age6/522/2418/1712/1517/10
Familial coronary artery disease0/041/3764/5754/5051/48
Dyslipidaemia0/074/6359/4754/5149/42
Chest pain0/062/5463/5951/4951/45
Diabetes mellitus0/059/6157/5048/4547/41
Hypertension0/070/6949/5239/4141/46
Alcohol consumption0/054/4335/3040/3440/49
Smoker0/067/5861/5763/5052/45

Data were expressed as the number of male and female subjects.
3.2. Cytokine and hs-CRP Levels in the Elderly Patients with the Proximal, Middle, and Distal CA Reocclusions

The levels of IL-1 β, IL-6, IL-8, TNF-α, and hs-CRP were increased significantly in Prox CA reocclusion group compared to Mid CA reocclusion and Dist CA reocclusion groups, respectively () and were further increased significantly in Prox+Mid CA reocclusion group compared to Prox CA reocclusion and Mid CA reocclusion groups, respectively (). The levels of IL-10, IL-17, IL-13, and IL-37 were decreased significantly in Prox CA reocclusion group compared to Mid CA reocclusion and Dist CA reocclusion groups, respectively () and were further decreased significantly in Prox+Mid CA reocclusion group compared to Prox CA reocclusion and Mid CA reocclusion groups, respectively (). These data suggested that increased levels of IL-1 β, IL-6, IL-8, TNF-α, and hs-CRP and decreased levels of IL-10, IL-17, IL-13, and IL-37 promoted the proximal, middle, and distal CA reocclusions in the elderly patients after coronary artery implantations. Imbalances of proatherogenic inflammatory and antiatherogenic inflammatory cytokines were involved in the proximal, middle, and distal CA reocclusions in the elderly patients after coronary artery implantations (Table 2).


CON Dist CA reocclusions Mid CA reocclusions Prox CA reocclusions Prox+Mid CA reocclusions

IL-1 β (pg/mL)
IL-6 (pg/mL)
IL-8 (pg/mL)
TNF-α (ng/L)
IL-10 (pg/mL)
IL-17 (pg/mL)
IL-13 (pg/mL)
IL-37 (pg/mL)
hs-CRP (mg/L)

Student’s -test: (CON group/Dist CA reocclusion group). (Dist CA reocclusion group/Mid CA reocclusion group). (Mid CA reocclusion group/Prox CA reocclusion group). (Prox CA reocclusion group/Prox+Mid CA reocclusion group). Group comparisons (CON/Dist CA reocclusion group/Mid CA reocclusion group/Prox CA reocclusion group/Prox+Mid CA reocclusion group) were made using ANOVA, .
3.3. Levels of IL-1 β, IL-6, IL-8, TNF-α, IL-10, hs-CRP, IL-17, IL-13, and IL-37 in the Elderly Patients with the Proximal, Middle, and Distal RCA Reocclusions

The levels of IL-1 β, IL-6, IL-8, TNF-α, and hs-CRP were increased significantly in Prox RCA reocclusion group compared to Mid RCA reocclusion and Dist RCA reocclusion groups, respectively () and were further increased significantly in Prox+Mid RCA reocclusion group compared to Prox RCA reocclusion and Mid RCA reocclusion groups, respectively (). The levels of IL-10, IL-17, IL-13, and IL-37 were decreased significantly in Prox RCA reocclusion group compared to Mid RCA reocclusion and Dist RCA reocclusion groups, respectively (), and were further decreased significantly in Prox+Mid RCA reocclusion group compared to Prox RCA reocclusion and Mid RCA reocclusion groups, respectively (). These data suggested that increased levels of IL-1 β, IL-6, IL-8, TNF-α, and hs-CRP and decreased levels of IL-10, IL-17, IL-13, and IL-37 were related to the proximal, middle, and distal RCA reocclusions in the elderly patients after coronary artery implantations. Imbalances of proatherogenic inflammatory and antiatherogenic inflammatory mediators promoted the proximal, middle, and distal RCA reocclusions in the elderly patients after coronary artery implantations (Table 3).


CON Dist RCA reocclusions Mid RCA reocclusions Prox RCA reocclusions Prox+Mid RCA reocclusions

IL-1 β (pg/mL)
IL-6 (pg/mL)
IL-8 (pg/mL)
TNF-α (ng/L)
IL-10 (pg/mL)
IL-17 (pg/mL)
IL-13 (pg/mL)
IL-37 (pg/mL)
hs-CRP (mg/L)

Student’s -test: (CON group/Dist RCA reocclusion group). (Dist RCA reocclusion group/Mid RCA reocclusion group). (Mid RCA reocclusion group/Prox RCA reocclusion group). (Prox RCA reocclusion group/Prox+Mid RCA reocclusion group). Group comparisons (CON/Dist RCA reocclusion group/Mid RCA reocclusion group/Prox RCA reocclusion group/Prox+Mid RCA reocclusion group) were made using ANOVA, .
3.4. Expressions of IL-1 β, IL-6, IL-8, TNF-α, hs-CRP, IL-10, IL-17, IL-13, and IL-37 in the Elderly Patients with the Proximal, Middle, and Distal LCX Reocclusions

The levels of IL-1 β, IL-6, IL-8, TNF-α, and hs-CRP were increased significantly in Prox LCX reocclusion group compared to Mid LCX reocclusion and Dist LCX reocclusion groups, respectively (), and were further increased significantly in Prox+Mid LCX reocclusion group compared to Prox LCX reocclusion and Mid LCX reocclusion groups, respectively (). The levels of IL-10, IL-17, IL-13, and IL-37 were decreased significantly in Prox LCX reocclusion group compared to Mid LCX reocclusion and Dist LCX reocclusion groups, respectively (), and were further decreased significantly in Prox+Mid LCX reocclusion group compared to Prox LCX reocclusion and Mid LCX reocclusion groups, respectively (). Imbalances of proatherogenic inflammatory and antiatherogenic inflammatory mediators had a significantly higher risk of developing proximal, middle, and distal LCX reocclusions after coronary artery implantations (Table 4).


CON Dist LCX reocclusions Mid LCX reocclusions Prox LCX reocclusions Prox+Mid LCX reocclusions

IL-1 β (pg/mL)
IL-6 (pg/mL)
IL-8 (pg/mL)
TNF-α (ng/L)
IL-10 (pg/mL)
IL-17 (pg/mL)
IL-13 (pg/mL)
IL-37 (pg/mL)
hs-CRP (mg/L)

Student’s -test: (CON group/Dist LCX reocclusion group). (Dist LCX reocclusion group/Mid LCX reocclusion group). (Mid LCX reocclusion group/Prox LCX reocclusion group). (Prox LCX reocclusion group/Prox+Mid LCX reocclusion group). Group comparisons (CON/Dist LCX reocclusion group/Mid LCX reocclusion group/Prox LCX reocclusion group/Prox+Mid LCX reocclusion group) were made using ANOVA, .
3.5. Expression Levels of IL-1 β, IL-6, IL-8, TNF-α, hs-CRP, IL-10, IL-17, IL-13, and IL-37 in the Elderly Patients with the Proximal, Middle, and Distal LAD Reocclusions

The levels of IL-1 β, IL-6, IL-8, TNF-α, and hs-CRP were increased significantly in Prox LAD reocclusion group compared to Mid LAD reocclusion and Dist LAD reocclusion groups, respectively (), and were further increased significantly in Prox+Mid LAD reocclusion group compared to Prox LAD reocclusion and Mid LAD reocclusion groups, respectively (). The levels of IL-10, IL-17, IL-13, and IL-37 were decreased significantly in Prox LAD reocclusion group compared to Mid LAD reocclusion and Dist LAD reocclusion groups, respectively (), and were further decreased significantly in Prox+Mid LAD reocclusion group compared to Prox LAD reocclusion and Mid LAD reocclusion groups, respectively (). The results showed that the imbalances of proatherogenic inflammatory and antiatherogenic inflammatory mediators may accelerate the formation of the proximal, middle, and distal LAD reocclusions after coronary stenting (Table 5).


CON Dist LAD reocclusions Mid LAD reocclusions Prox LAD reocclusions Prox+Mid LAD reocclusions

IL-1 β (pg/mL)
IL-6 (pg/mL)
IL-8 (pg/mL)
TNF-α (ng/L)
IL-10 (pg/mL)
IL-17 (pg/mL)
IL-13 (pg/mL)
IL-37 (pg/mL)
hs-CRP (mg/L)

Student’s -test: (CON group/Dist LAD reocclusion group). (Dist LAD reocclusion group/Mid LAD reocclusion group). (Mid LAD reocclusion group/Prox LAD reocclusion group). (Prox LAD reocclusion group/Prox+Mid LAD reocclusion group). Group comparisons (CON/Dist LAD reocclusion group/Mid LAD reocclusion group/Prox LAD reocclusion group/Prox+Mid LAD reocclusion group) were made using ANOVA, .
3.6. Stents Features of the Elderly Patients with Distal, Middle, and Proximal Coronary Artery Reocclusions

The type, length, and diameter of stents were very similar among the different study groups of elderly patients with the proximal, middle, and distal coronary artery reocclusions without statistical differences (Table 6).


Dist CA reocclusions Mid CA reocclusions Prox CA reocclusions Prox+Mid CA reocclusions

Stent lengths
 8.0 mm ( (%))48 (29)30 (20)32 (26)21 (21)
 15.0 mm ( (%))46 (28)41 (28)31 (25)25 (25)
 18.0 mm ( (%))45 (27)42 (29)35 (28)23 (23)
 23.0 mm ( (%))26 (16)33 (22)25 (20)32 (31)
0.140.850.430.16

Stent diameters
 2.50 mm ( (%))48 (29)30 (20)32 (26)21 (21)
 3.00 mm ( (%))46 (28)41 (28)31 (25)25 (25)
 3.50 mm ( (%))45 (27)42 (29)35 (28)23 (23)
 4.00 mm ( (%))26 (16)33 (22)25 (20)32 (31)
0.140.850.430.16

3.7. Data of TIMI Flow Grades and Ischemic A