Inflammatory cytokines affecting cardiovascular function: a scoping review [version 1; peer review: awaiting peer review]

1Faculty of Dental Medicine, Universitas Airlangga, Surabaya, Indonesia 2Department of Dental Public Health, Faculty of Dental Medicine, Universitas Airlangga, Surabaya, Indonesia 3Department of Oral Biology, Faculty of Dental Medicine, Universitas Airlangga, Surabaya, Indonesia 4Faculty of Medicine and Health Science, Universitas Islam Negeri Maulana Malik Ibrahim Malang, Malang, Indonesia 5Department of Physiology, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia 6Department of Orthodontics, Faculty of Dental Medicine, Universitas Airlangga, Surabaya, Indonesia 7Faculty of Dental Surgery, Royal College of Surgery, Edinburgh University, Edinburgh, UK


Introduction
One of the diseases that currently can cause health and socio-economic losses, both in developing and developed countries is cardiovascular disease. 1 This is due to the increase in the number of cardiovascular diseases. Cardiovascular diseases that cause mortality and disability in the world include heart disease, vascular disease, and atherosclerosis. 2,3 The major risk factor for the development of cardiovascular disease is inflammation. 4,5 The occurrence of the inflammatory response is regulated by cytokines. 6 Several studies have shown that cardiovascular disease can be triggered by some inflammatory cytokines and their receptors at a time when the inflammatory process occurs on an ongoing basis. 7,8 Cardiovascular diseases such as atherosclerotic heart disease, coronary heart disease, and congestive heart failure are associated with an increase in inflammatory cytokines such as Interleukin 1 Beta (IL-1β), Interferon-γ (IFN-γ), and Tumor Necrosis Factor -Alpha (TNF-α), these cytokines are known to induce atherosclerotic plaque formation. 9 Additionally, higher quantities of the cytokines TNF-α, IL-1, and IL-6 have been demonstrated to induce the expression of proatherogenic genes in new findings. 10 Infection, nutritional imbalance, genetic factors, hypoxia, UV, allergic irritant, drugs, and physical stress can cause inflammation resulting in increased level of inflammatory cytokines. Enhancement of inflammatory cytokines induce cardiovascular diseases by triggering the expression of proatherogenic gen, induce the formation of atherosclerotic lesion, causing myocardial disfunction and cardiac hypertrophy. 11 This scoping review will map cytokines that have elevated in some inflammatory conditions and their effects on cardiovascular function. Exposure factor mapping will show various inflammatory conditions that can increase cytokines. The results of the outcome mapping will provide an overview of the effect of increasing cytokines on cardiovascular function while from the results of each study that we present will inform cytokine levels that can interfere with cardiovascular function.

Methods
Scoping review was chosen because the review does not attempt to answer very specific study questions, but rather discusses a broader topic so that it is possible to apply more various study designs. We used guidance from Hilary Arksey & Lisa O'Malley framework in implementing the scoping review protocol which consisted of the following stages.

Stage 1: Identifying the research question
Discussions are carried out with the team to determine research questions by considering several key aspects such as study population, exposure, and outcomes. The research questions we will try to answer are : (1) What cytokines can affect cardiovascular function? (2) What inflammatory conditions can increase cytokine levels and interfere with cardiovascular function? (3) What types of disorders in cardiovascular function can appear due to increased cytokine levels? (4) What are the levels of cytokines that can cause impaired cardiovascular function?

Stage 2 : Identifying relevant studies
The articles were taken from two database namely Pubmed (https://pubmed.ncbi.nlm.nih.gov) and SpringerLink(https:// link.springer.com). Articles were searched using the terms related to cytokine, interleukin, inflammation, infection, cardiovascular. The search keywords for each database presented below: Search keywords for PUBMED: (

(cytokine OR interleukin[MeSH Terms] AND ((fft[Filter]) AND (english[Filter]))) AND (inflammation OR infection[MeSH Terms] AND ((fft[Filter]) AND (english[Filter])))) AND (cardiovascular AND coronary artery[MeSH Terms] AND ((fft[Filter]) AND (english[Filter]
))) Search keywords for SPRINGER LINK:(cytokine OR interleukin) AND inflammation AND cardiovascular AND "coronary artery" AND human NOT extract NOT "a review" NOT "systematic review" Selected articles are restricted to English language and research articles only without using the publication year limit. The most recent search was executed on September 15, 2021 and duplicate articles will be filtered immediately.

Stage 3: Study selection
Two reviewers selected articles that were free from duplication. The selection of articles that suitable with the inclusion criteria is carried out based on reading the tittle and abstract. Studies that included in this step are: (1) Research articles both observational and experimental with human subjects that analyze changes in cytokines concentrations due to inflammatory condition and their effects on heart function, (2) The outcome of the research is the type of the cytokine that has increased and the type of disturbance in cardiovascular system, (3) no review articles. Furthermore, selection is carried out according to the eligibility criteria through full text reading to reselect articles that will be included in the scoping review process. The selected articles were articles that used the parameters of increasing cytokines in the population experiencing inflammatory conditions in their studies. Inflammatory conditions in the cardiovascular system that can elevate cytokines systemically and weaken cardiovascular function will be included. Any disagreement resolved through a third reviewer.
Stage 4: Charting the data Two reviewer indenpendently charted the data from final articles used MS Word 2019 form. The key data entered are: tittle, author, study design, subject, types of inflammatory conditions that cause an increase in cytokine levels and types of cytokines that have increased (cytokines exposure), outcomes on cardiovascular function, study results including cytokine levels that can interfere cardiovascular function, and research conclusion.

Results
Firstly, the researcherr collected the articles from two databases and found 3,926 articles, 295 of those were taken from PubMed and 3,631 articles were taken from Springerlink. Those articles were selected first to find the duplicated articles from both databases. 24 duplicated articles were found and removed, so there were 3901 remaining articles. Then, from the remaining articles, there were 75 selected articles that met the criteria based on abstract readings. Furthermore, the researcher selected articles by reading the entire content and obtained as many as 21 articles for review ( Figure 1). More information about the final selected articles has been listed in Table 1.

Characteristics of the articles
The articles reviewed based on research from eight countries, include: five articles from China, five from Italy, three from America, two each from Poland and Germany, and one each from Korea, Johannesburg and Australia. One of the studies took the samples from 31 health centers in Europe. The number of the sample from each study varied from the smallest amount 55 to the largest amount 6783with the sample classification consisting of two articles using samples from children and 19 articles using sampes from adults. A total of 16 studies used cross sectional research design, three studies used cohort design, one study used case control, and one study used a combination of cross sectional and cohort research designs. Article selection was conducted without limitation of the year of publication.
Cytokines that affect cardiovascular function There are 6 cytokines that can affect cardiovascular function, namely:

IL-6
A total of 14 studies reported that an increased in IL-6 can lead the cardiovascular function disorders, in which two studies used samples of children suffering from Kawasaki Disease. A research found that IL-6 concentration were higher in patient with Kawasaki Disease with coronary artery lesion compared to people Kawasaki Disease without coronary artery lesion (p=0.016). 12 The study Si, et al., 2017, showed serum IL-6 concentration, higher in the group of Kawasaki Disease patients accompanied by coroner artery lesions than the Kawasaki Disease patient group without coroner artery lesions (p<0.05). 13  • Inflammatory responses were also associated with impaired coronary circulation. • The levels of EC-SOD in the control and CAD groups were the same.
• There was a significant difference in levels of radical peroxide (p<0.01), hs-CRP (p<0.01), and hs-IL-6 (p<0.001) between subjects with CAD and control groups.
• There was an increase in hs-IL-6 levels in subjects with more impaired coroner's arteries (p<0.05).
• hs-IL-6 can be used as a marker in efforts to prevent and characterize artery coronary disease. Two studies confirmed the presence of impaired cardiovascular function in rheumatoid arthritis patients. One study found that rheumatoid arthritis sufferers had an increase in IL-6 (p=0.024) levels as well as a 29% 14 decrease in myocardial flow reserve. This study was supported by other studies that showed an increased in IL-6 in people with rheumatoid arthritis can lead to impaired function in the endothelial (p≤0.03). 15 According to a study, greater IL-6 levels were linked to a higher calcium level (p<0.05) and the development of calcification of the coroner's arteries in individuals with chronic kidney disease (p<0.05). 16 There were 2 other studies with samples of people with diabetes mellitus that showed an increased association of IL-6 and the risk of cardiovascular disease. The first researcher proved that the elevated risk of cardiovascular disease was caused by an increase in IL-6 in patients with type 1 diabetes mellitus (Z score=-0.28, 0.06 with CI=95% and a value of p<0.001). 17 Another study found that the volume of epicardial fat in young early-adult-onset diabetes mellitus patients is linked to the presence of coronary artery calcification and IL-6 levels (β=0.05AE0.02 pg/ml/cm 3 , p=0.03; β= 005 AE 0.01 pg/ml/cm 3 , p=0.002). 18 There was one study that reported an increase in IL-6 in obesity conditions at risk of cardiovascular disease, where coronary flow reserve in obese people was lower than that of people without obesity (p=0.02) and a multivariate analysis revealed that IL-6 was a determinant of coronary flow reserve (p<0.02). 19 In addition, one study showed that if a person has a high level of IL-6, he will have a higher atherosclerotic load (p<0.001) and increase the risk to develop a major adverse cardiac events (MACE) (p<0.0001). 20 Three studies reported that cardiovascular patients may experience an increased in IL-6 which ultimately increases the risk of developing the disease. Research Lubrano et al. (2006), found that subjects with coronary artery disease who had higher levels of IL-6 had more impaired coronary arteries than those who had lower levels of IL-6 (p<0.05). 21 The study was supported by other studies proving that people suffering from coronary artery disease with higher levels of IL-6 are at risk of developing impaired diastole function in the left ventricle (β=-0.28AE0.13; p=0.03) for the initial diastole velocity and (β=-0.34AE0.13; p=0.014) for the ratio of blood flow speed at the peak of the initial diastole versus the speed of blood flow at the end of diastole. 22 One study reported that people with acute myocardial infarction infected with influenza virus had markers of atherosclerosis and higher levels of IL-6 than the control group (p=0.01). 23 Other studies also confirmed that IL-6 can be an independent predictor for acute myocardial infarction for someone who has suffered from cardiovascular disease (p=0.03). 24 Anoher study proving that an increased cytokine IL-6 can also increase the risk of cardiovascular disease was also conducted by Jenny et al. (2010), against a multiethnic sample in America. According to the findings, increased levels of IL-6 had a relative risk of 1.22 based on gender and ethnicity for causing coronary artery calcification. 25

TNF-α
Six studies found a link between an increase in TNF-α, which occurs in an elevated risk of cardiovascular disease and inflammatory diseases. One study in people with chronic kidney failure showed that elevated concentrations of TNF-α (p<0.01) were associated with vascular cellular adhesion molecule-1 (VCAM-1) (p<0.05) where an increased in VCAM-1 will increase the risk of calcification of the coroner's arteries. 16 This study is also supported by other studies where the increased risk of cardiovascular disease is caused by an increase in TNF-α in patients with type 1 diabetes mellitus (Z score=-0.28, 0.06 with CI=95% and a value of p<0.001. 17 The study Si F et al. (2017), showed serum TNF-α levels, higher in the Kawasaki Disease patient group accompanied by coroner's artery lesions than the Kawasaki Disease patient group without coroner artery lesions (p<0.05). 13 Two studies showed that increased levels of TNF-α in someone suffering from cardiovascular disease will aggravate the progression of the disease. One study proved an increase in TNF-α in people with coronary artery ectasia which resulted in an increase in flow in the coroner's arteries (r=0.92, p<0.05). 26 One study reported that people with acute myocardial infarction infected with influenza virus had higher levels of TNF-α and markers of atherosclerosis than the control group (p=0.01). 23 Another condition that can increase TNF-α levels is obesity. The study showed that, from the results of multivariate analysis in a sample of people with obesity, TNF-α levels are a determinant of coronary flow reserve (p<0.02) where with increasing levels of TNF-α there will be a decrease in coronary flow reserve. 19

IL-1β
Three studies reported a level that increases the risk of cardiovascular disease is IL-1β, whereas one study showed an increased association of IL-1β and cardiovascular disease risk in inflammatory diseases. The study Si F et al. (2017), showed serum IL-1β levels is higher in Kawasaki Disease patient group accompanied by coroner artery lesions than the Kawasaki Disease patient group without coroner artery lesions (p<0.05). 13 Another study confirmed that people with cardiovascular disease itself were at risk of increased levels of IL-1β which worsened the disease. An increase in IL-1β in coronary artery ectasia compared to atherosclerosis and control (p<0.05) can result in increased flow in right coronary artery and left anterior descending coronary artery (p<0.01). 26 Other studies reported an increased in IL-1β (p<001) as a risk factor for increased levels of ABCA1 promoter methylation (r=0.385, p<0.01) where the higher the level of ABCA1 promote methylation, the higher the risk of premature coroner artery disease. 27

IL-17
Research in the obese group showed that at higher eotaxin levels there was an increase in carotid intima thickening (p=0.0059), an increase in IL-17 was related with an increase in serum eotaxin levels (95%CI: p<0.0001), which is a risk factor for atherosclerosis. 28 This study was supported by another study found an increase in the cytokine IL-17 (p<0.05) in unstable angina patients and acute myocardial infarction compared to the control group. 24

IL-18
One study showed that people with acute myocardial infarction infected with influenza virus had higher levels of IL-18 and atherosclerosis marker markers (p=0.01) than the control group. 23

IL-2
The study from Guan et al. (2012), proved that there was an increased in IL-2 and marker markers of atherosclerosis in acute myocardial infarction sufferers infected with influenza virus (p=0.01). 23 Cytokine levels that affect cardiovascular function The summary for cytokines that have increased in inflammatory conditions and their effect on the cardiovascular system can be seen in Table 2. One study showed that compared to type 1 diabetes mellitus without cardiovascular disease, type 1 diabetes mellitus patients with cardiovascular disease had higher levels of inflammatory cytokines (IL-6: 2 pg/ml and 1.5 pg/ml; TNF-α: 3 pg/ml and 2 pg/ml for). 17 In the Kawasaki Disease with coronary artery lesions group, IL-6 levels were 228. 26  One study in the obese group showed that the group with decreased coronary flow reserve, the average levels of IL-6 and TNF-α were 4.6 (3.6 -6.1) ng/l and 12 (10.5 -15.0) ng/l, higher than the group without a normal coronary flow reserve rates where IL-6 ang TNF-α levels were three (2 -3.8) ng/l and ten (8.8 -11.5) ng/l. 19 Another study using samples of patients with cardiovascular disease proved that the group with simple lesions on the coronary arteries, the IL-6 levels were 46.62 AE 16.33 pg/ml and the group with complex lesions, the levels of IL-6 were 53.24 AE 33.30 pg/ml. 24 One study showed that the average IL-6 concentration in the group with narrowed lumen diameter in 1 coronary artery was 2.7 AE 0.7 pg/ml, 2 arteries was 2.6 AE 1.7 pg/ml, 3 arteries was 3.3 AE 1.0 pg/ml, and four arteries was 3.5 AE 0.6 pg/ml and also the average concentration of TNF-α in the group with narrowed lumen diameter in one coronary artery was 1.05 AE 0.3 pg/ml, two arteries was 1.34 AE 0.2 pg/ml, three arteries was 0.98 AE 0.14 pg/ml, and four arteries was 3.9 AE 1.5 pg/ml. 21 The group with premature coronary artery disease also showed a higher average IL-1β level of 57.74 AE 12.55 pg/ml compared to the healthy group of 47.66 AE 14.77 pg/ml. 27

Discussion
In this present study, the investigation of inflammatory cytokines that associated to cardiovascular system disease was done. According to the review that has been conducted, it was found that the increased in some cytokines can cause impaired function in cardiovascular system, especially in the coroner's arteries. There were three most widely reported inflammatory cytokines: IL-1β, IL-6 and TNF-α. Elevated IL-6 may be at risk of causing lesions of artery coronaria. 12,13,16,18,20,24,25 IL-6 increased the angiotensin II receptors activity and expression of adhesion molecules in endothelial cells, triggering inflammation of blood vessels. 29 The development of atherosclerosis and vascular diseases is complicated by blood vessel inflammation. 30,31 Pro-inflammatory cytokine may enhance the risk factor of cardiovascular system through narrowing blood vessel resulted to high blood pressure. The increased level of pro-inflammatory cytokines can be a trigger for decreased function and cause the disease in the cardiovascular system.
Cell adhesion molecules (VCAM1 and ICAM-1) promote leukocyte adhesion and migration to the subendothelial space. 32 In addition, increased levels of IL-6 can also cause disruptions in the flow in the coronary arteries. 8,19,22 The complex interaction between TF and Von Willebrand Factor (vWF), vascular dysfunction and endothelial damage is triggered by inflammation of various cells in the walls of blood vessels. 33,34 IL-6 can trigger the expression of tissue factor (TF) (index for coagulation), chemokines, and adhesion molecules on endothelial cell surfaces. 33,35,36 Increased damage to endothelial cells can lead to a decrease in nitric oxide levels released into blood vessels resulting in impaired vascular function and decreased blood flow. 37,38 In addition, the decreased in coronary flow reserve (CFR) can be caused by narrowing of the coroner's arteries or it could be due to endothelial dysfunction that occurs before the narrowing of the arteries. Multivariate analysis shows that microvascular dysfunction is not a risk factor for the early phase of atherosclerosis in asymptomatic obese individuals, but rather the role of inflammation. 39 The increased in IL-6 not only occurs in infectious disease conditions, but there are also other conditions that can cause an increased in IL-6, namely obesity and increased volume of epicardial fat. 18,19 Cytokines such as TNF-α and IL-6 can be produced by fat cells which are mediators in the occurrence of inflammatory responses in subjects with obesity. 40 An increased level of TNF-α can trigger the formation of lesions on the coroner's arteries that can lead to atherosclerosis and acute myocardial infarction. 13,16,23 TNF-α can accelerate the occurrence of aphrgenesis by triggering increased expression of Monocyte Chemotactic Protein-1 (MCP-1), E-selectin, VCAM-1, and ICAM-1. 41 In addition, TNF-α can increase the expression of NF-κβ, so that Fractalkine expression can also increase which triggers the formation of atherosclerosis lesions. 42 TNF-α can cause impaired function in endothelial and microvascular cells and potentially decrease flow in the coronary artery. 19,26 Decreased in artery coronaria due to the increased of TNF-α caused by TNF-α can decrease the availability of nitric oxide in endothelial cells so that the ability of vasodilation of blood vessels is also impaired. In addition, TNF-α causes an increased in apoptosis of endothelial cells that result in injury to blood vessels. 41 IL-1β triggers inflammation in endothelial cells. 43 IL-1 induces the attachment of molecules such as VCAM-1, ICAM-1 which can lead to recruitment of leucocytes. IL-1 also stimulates chemokines such as monocyte chemoattractant protein (MCP)-1 (C-C motif chemokine ligand [CCL]-2) which is a chemoattractant for mononuclear phagocytes, implying a role for IL-1 in cardiovascular disease. When exposed to inflammatory stimuli, atheroma cells secrete IL-1. 44,45 Moreover, IL-1β may increase the risk of lesions in the coroner's arteries 13 because IL-1 β induces IL-6 production. The increased of IL-6 production will trigger the liver to produce fibrinogen and plasminogen activator inhibitors that stimulate in the formation of thrombus accumulation as a precursor to atherosclerosis. 46 In addition, increased levels of IL-6 triggered by IL-1 β also cause impaired vascular function and decreased blood flow. 37,38 Elevated levels of inflammatory cytokines can also be caused by cardiovascular disease itself and lead to increased progression of more severe disease, such as calcified coronary artery lesions, increased coronary artery luminal narrowing, and coronary artery flow disturbances. 21,22,23,24,26 There are several inflammatory cytokine that associated with cardiovascular disease, high risk patient should modify their lifestyle such as healthy diet and light continuous exercise to minimize the cardiovascular disease risk. Health general checkup frequently also play important role to control the risk of cardiovascular disease.
However, in the process, the scoping review that has been carried out has several limitations, the articles included do not all have the determination of cytokine levels that can cause impaired cardiovascular function and the determination of the type of disorders in cardiovascular function is not done specifically. Further study is urgently needed such as systematic review with meta-analysis to provide the higher evidence level about this topic.

Future research
Research that has been done shows that levels of inflammatory cytokines that can trigger disorders of the cardiovascular system vary widely, this seems to be strongly influenced by many factors. Further research is needed to determine the levels of inflammatory cytokines that can trigger disorders of the cardiovascular system by considering confounding factors such as type of inflammatory disease, age, BMI, and lifestyle so that more appropriate data is obtained for determining inflammatory cytokine levels.

Conclusion
Based on the results of this review, it is known that inflammatory cytokines can cause impaired function in cardiovascular system. This means that cardiovascular disease prevention approaches can be taken through controlling factors that can trigger an increase in inflammatory cytokines, especially inflammatory diseases and infections.

Data availability
All data underlying the results are available as part of the article and no additional source data are required.