Abstract

Background: Cytokines can be key factors in the pathogenesis of coronary artery disease (CAD). This systematic review and meta-analysis aimed to assess the levels of interleukin-10 (IL-10), an anti-inflammatory cytokine, in the serum/plasma of patients with CAD.

Methods: An exhaustive search was conducted across the Web of Science, PubMed/Medline, Scopus, and Cochrane Library databases up to March 25, 2022. Review Manager 5.3 software was used to calculate the effect sizes, presenting the standardized mean difference (SMD) along with a 95% confidence interval (CI). STRING software, which maps protein-protein interactions (PPI), was utilized to explore the functional interactions among the genes under study.

Results: From the 1130 records retrieved from the databases, 26 articles were included in the meta-analysis. The pooled SMD for CAD cases compared to controls was 0.33 (p = 0.15). The sample size was adequate for comparing blood IL-10 levels in CAD patients versus controls.

Conclusion: The findings suggest there was no significant difference in the serum/plasma levels of IL-10 between CAD patients and controls. Hence, the pathogenesis of CAD can be multifactorial and complex.

Introduction

Heart diseases (HDs) are the leading cause of death worldwide, with the majority of fatalities, approximately 80%, occurring in low- to middle-income countries. If current trends continue, it is projected that by 2030, cardiovascular diseases will claim the lives of about 23.6 million individuals, predominantly through heart attacks and strokes1, 2. Ischemic HD is recognized as a significant threat in the 21st century3, also known as coronary artery disease (CAD) or coronary HD. A large number of individuals with CAD live with chronic disabilities and impaired quality of life4.

One of the most significant risk factors associated with HD is a family history of HD5. The increase in HD risk due to family history can be attributed to shared genetic, environmental, and lifestyle factors. The importance of genetics becomes more apparent with the early onset of HD in the family and the number of family members affected6. It is believed that an imbalance between pro- and anti-inflammatory activities plays a crucial role in the development of atherosclerosis7. Inflammation contributes to the early stages of HD, and therefore, may drive the progression of this disease8, 9.

CAD is the primary cause of deaths related to cardiovascular issues10, and atherosclerosis is the most common reason for CAD, which is a longstanding inflammatory condition of the arterial walls that arises from an inappropriate inflammatory response and an imbalance in lipid metabolism11. A multitude of evidence, including both clinical trials and experimental studies, collectively indicates that inflammation is integral to all phases of atherosclerosis development9, 12, 13.

Several signaling pathways have been reported and linked to CAD pathogenesis14, 15, 16, 17. Cytokines, which are part of the extracellular signaling proteins, are secreted by both immune and non-immune cells, including cells of the vascular endothelium18. Increased levels of inflammatory cytokines in the plasma have been documented in patients with CAD, especially in those with unstable disease conditions10. Conversely, the presence of anti-inflammatory mediators is less well documented. Interleukin-10 (IL-10) is a potent anti-inflammatory cytokine that plays a vital and often indispensable role in warding off inflammatory and autoimmune conditions19, 20, 21, 22. The gene for human IL-10 is located on chromosome 1, specifically at the juncture of regions 1q31 and 1q3223. IL-10 can reduce the likelihood of atherosclerosis development and improve the progression of atherosclerosis and vascular complications24. Studies have documented the role of plasma/serum IL-10 levels in CAD patients but with varying and contradictory results25, 26, 27. The interactions of IL-10 are complex and can vary depending on the specific context and conditions28, 29, 30.

To our knowledge, this topic has not been the subject of a meta-analysis. Therefore, the goal of this meta-analysis was to assess the levels of IL-10 in the blood of patients with CAD to obtain better and more accurate results and to identify the possible reasons for these discrepancies between the results of individual studies. Another aim was to understand the pathogenesis, protein-protein interactions (PPI), and patient-specific factors as research gaps.

Methods Design and Registration

This study adhered to the guidelines set forth by PRISMA31. Additionally, the protocol for this meta-analysis was registered in the PROSPERO database under the registration number CRD42022335594. The question posed in terms of PECO was: Is there an association between serum/plasma levels of IL-10 and the risk of CAD in studies with a case-control design?

Article Discovery

An author of the study, M.S., carried out a comprehensive search in databases such as PubMed/MEDLINE, Web of Science, Scopus, and Cochrane Library up until March 25, 2022, without imposing any restrictions, to collect relevant articles. M.S. also reviewed the titles and abstracts of these articles. Subsequently, the full texts of the articles that met the selection criteria were obtained. The search strategy included keywords/title/abstract: ("coronary atherosclerotic heart disease" or "coronary heart disease" or "coronary artery disease" or "ischemic heart disease" or "myocardial infarction" or "acute coronary syndrome" or "angina pectoris") and ("interleukin-10" or "IL-10" or "IL10" or "interleukin 10") and ("plasma" or "serum" or "blood") and ("control" or "normal" or "healthy"). The bibliographies of the retrieved articles were scrutinized to ensure no significant studies were missed. Another author, R.H.M., verified the search and selection procedures. In the event of any discrepancies between the two authors, a third author, N.S., intervened in the resolution.

Criteria for Selection and Rejection

The inclusion criteria were as follows: 1) Any study that reported the levels of IL-10 in the serum or plasma of CAD patients and control subjects. 2) Studies that included more than 10 cases in both the case and control groups. 3) CAD was defined based on the criteria reported in Alshammary's study32, and Table 1 shows the criteria for each study. 4) CAD patients without any other systemic diseases and control subjects who were in good health. 5) CAD patients with or without medical treatment, such as statins. Conversely, review articles, meta-analyses, articles with missing data, studies conducted on animals, articles lacking a control group, commentary papers, conference papers, book chapters, duplicate studies, studies that included disease-afflicted controls, and studies involving cases under treatment were excluded.

Table 1.

Definition of CAD used in each study included in the analysis

First author, publication year CAD definition Mazzone, 1999 33 Standard progressive changes in electrocardiography linked with a rise in CK values exceeding twice the upper normal limit and alterations in the ST-segment Mizia-Stec, 2002 34 Coronangiography Mizia-Stec, 2003 35 Coronangiography was performed if there was a constriction of the diameter by 75% or more in at least one of the three primary epicardial coronary arteries Lee, 2006 36 Cardiac catheterization Nilsson, 2006 37 Angiography Szodoray, 2006 38 Angiography Paulsson, 2008 39 Angiography Cheng, 2009 40 Scanning with radioactive thallium or coronary angiogram Jha, 2009 41 Angiography Jha, 2010 42 Angiography Khan, 2011 43 Angiography revealing a stenosis of more than 70% in at least one coronary vessel Tapp, 2012 44 European Society of Cardiology definition Karu, 2013 45 NR Li, 2015 46 Clinical symptoms, ECG alterations, coronary angiography, and cardiac troponin tests Mirhafez, 2015 47 Angiography Cheng, 2016 48 Coronary stenosis with at least one main coronary vessel with 50% luminal narrowing Liang, 2016 49 A narrowing of the lumen by 50% or more was observed in at least one primary coronary artery or its main branches Bergström, 2017 25 Non-segment elevation myocardial infarction identified through characteristic ECG alterations and increased levels of troponins Tajfard, 2017 50 An occlusion of 50% or more in at least one coronary artery Xu, 2017 51 Stenosis exceeding 50% in at least one primary vessel Boles, 2018 26 Angiography Kharaeva, 2018 27 Angiography Kumari, 2018 18 NR Ansari, 2019