Elevated plasma levels of osteoglycin in cardiovascular patients: a systematic review and meta-analysis
Original Article

Elevated plasma levels of osteoglycin in cardiovascular patients: a systematic review and meta-analysis

Zhi Zuo1#, Meng-Huan Li2#, Xu-Hui Zheng2, Wen-Ming Yao1, Hui Wang1, Xin-Li Li1

1Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China; 2Nanjing Medical University, Nanjing, China

Contributions: (I) Conception and design: XL Li; (II) Administrative support: H Wang; (III) Provision of study materials or patients: WM Yao; (IV) Collection and assembly of data: XH Zheng; (V) Data analysis and interpretation: Z Zuo, MH Li; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.

#These authors contributed equally to this work and should be considered as co-first authors.

Correspondence to: Hui Wang; Xin-Li Li. Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China. Email: Wangnuo@188.com; Xinli3267@njmu.edu.cn.

Background: To evaluate the levels of osteoglycin (OGN) in patients with cardiovascular disease.

Methods: A meta-analysis was conducted on retrospective studies that compared patients with and without cardiovascular disease. Data including the levels of OGN, low density lipoprotein (LDL), and high density lipoprotein (HDL) were analyzed and expressed as mean differences (MD) with a 95% confidence interval (CI).

Results: This meta-analysis included 6 studies with a total of 1,443 patients. The results showed that the concentration of OGN in the blood of patients with cardiovascular disease was significantly elevated compared to that observed in control patients. There were no significant differences in LDL and HDL expression between cardiovascular patients and control patients. Sensitivity analysis and funnel plots showed that this investigation was robust and had low publication bias.

Discussion: This report demonstrated that the blood concentration of OGN in patients with cardiovascular disease is significantly elevated compared to that in control patients. Furthermore, the elevated levels of OGN suggests that OGN may be a biomarker/or therapeutic target for patients with cardiovascular disease. Although the structure of OGN is simple, it is indispensable in many important life processes. It plays a protective role in the occurrence of cardiovascular and cerebrovascular diseases through antioxidant, anti-inflammatory, anti-apoptosis and increasing tolerance to hypoxia.

Keywords: Osteoglycin (OGN); mimecan; cardiovascular disease; meta

Submitted Sep 30, 2021. Accepted for publication Feb 22, 2022.

doi: 10.21037/apm-22-104

Introduction

The incidence of cardiovascular disease continues to escalate with an aging population, as well as changes in lifestyle and social and economic status. In fact, cardiovascular disease is the leading cause of death worldwide (1,2) and causes significant health and financial burden (3,4). Smoking, hypertension, and hypercholesterolemia are the main risk factors of cardiovascular disease (5-7).

Osteoglycin (OGN) has been noted for its implication in cardiovascular disease in recent studies. OGN is a member of proteoglycans (PGs) and belongs to the family of small leucine-rich proteoglycans (SLRP). The SLRPs share a central structure composed of 6–12 leucine-rich repeats in series and the core protein that is composed of N-terminal and C-terminal-specific cysteine clusters has been shown to play a vital role in cardiovascular function and tumor cell growth, adhesion, and migration (8,9). OGN has vital roles in many biological processes. It exists in the extracellular matrix (ECM) of connective tissues and participates in matrix synthesis and the regulation of collagen fiber formation (10,11). OGN is thought to be expressed in normal, differentiated, and non-proliferating vascular smooth muscle cells (VSMCs), with increased expression during proliferation, which then decreases at the end of proliferation (12,13). Furthermore, OGN may be involved in the repair and reconstruction of arterial injury and contribute to vascular reconstruction. Studies have shown that OGN is related to cardiovascular function, especially the proliferation of coronary artery smooth muscle cells, which is related with cardiovascular disease (14,15). This is particularly important as the growth of collateral arteries can make up for the impact of central artery stenosis. We present the following article in accordance with the PRISMA reporting checklist (available at https://apm.amegroups.com/article/view/10.21037/apm-22-104/rc).

Methods

Literature search strategy

The whole searching process is based on Population, Intervention, Comparison, Outcomes and Study (PICOS) criteria. A systematic literature search was conducted using the PubMed, Embase, Web of Science, Wangfang and China National Knowledge Infrastructure databases from establishment to July 2019 with no restrictions on year or language of publication. The following keywords were used: osteoglycin; mimecan; OGN; cardiovascular disease; and meta. Boolean operators AND/OR were included in the search strategy for the key terms. To identify additional eligible studies, the reference lists from the literature identified in the database searches were reviewed.

Study selection

The following inclusion criteria were applied to original research articles: (I) the observation group consisted of patients with cardiovascular disease; (II) the control group consisted of healthy patients; and (III) the study related to cardiovascular disease. Literature relating to other diseases or autoimmune diseases, as well as studies with insufficient available data were excluded.

Data extraction and quality assessment

The titles and abstracts of all publications identified from the database search using PubMed, Embase, Web of Science, and China National Knowledge Infrastructure were independently screened for inclusion by two reviewers. Relevant data were extracted from the included literature, including first author, publication year, research design, and baseline demographic features. In addition, patient parameters including OGN, low density lipoprotein (LDL), and high density lipoprotein (HDL) levels were collated. The validity of eligible retrospective trials was assessed using the Cochrane risk of bias tool in Review Manager 5.2. Egger’s tests and funnel plots were used to evaluate the risk of bias across studies. The quality of each included study was assessed by Cochrane bias risk tool.

Statistical analysis

The Review Manager (Version 5.2, Cochrane Collaboration, 2011) was used to estimate the impact of the results in the selected report. Random-effects meta-analysis was performed to produce unadjusted and adjusted summary effect estimates [odds ratios (OR) with 95% confidence intervals (CI)]. Heterogeneity across studies was measured using I2 statistic and Cochran’s Q test. When P<0.05 or I2>50%, there is a certain degree of heterogeneity in the study, which is analyzed by random effect model. When P≥0.05 and I2≤50%, there is no or small heterogeneity between studies, and the fixed effect model is used for analysis. A fixed-effects model was used for calculations without evidence of heterogeneity, otherwise, a random-effects model was applied. Publication bias was represented graphically by funnel plots of the standard difference in means versus the standard error. The asymmetry of the funnel chart was assessed to resolve possible minor effects. A scenario sensitivity analysis was used to evaluate the robustness of the results.

Results

Search process

A total of 1,125 related articles were identified through the main literature search. Among them, 254 were excluded due to duplication, leaving 871 unique articles. After applying the inclusion and exclusion criteria in the title screening process, a further 736 citations were excluded, and 135 eligible articles were selected for full text review. A further 129 articles were excluded due to different research designs or insufficient data. Finally, a total of 6 publications were included for this meta-analysis. Figure 1 shows a flowchart summarizing the literature selection process.

Figure 1 A flowchart of the literature search and study selection process.

Characteristics of the included studies

Table 1 lists the main characteristics of the included literature (16-21). There were 6 trials involving 1,443 patients aged in their 60s, including 1,017 (70.5%) males and 426 (29.5%) females. Of the 1,443 patients, 808 patients were healthy controls and the experimental group consisted of 635 cardiovascular disease patients (16-21). All 6 studies were published in English, 4 were from China, and the other 2 were from the United States and the Netherlands.

Table 1

The characteristics of the studies included in this systematic review and meta-analysis

Study Year Language Country Groups Gender (male/female) Age (years) Numbers Duration of study
Cheng 2014 English Netherlands Healthy participants 136/40 64.5±10.3 176 December 2008 to February 2011
Cardiovascular disease 68/20 65.8±11.2 88
Gu 2015 English China Healthy participants 30/24 60.3±11.7 54 December 2011 to December 2013
Cardiovascular disease 60/56 63.6±11.5 116
Hu 2015 English China Healthy participants 42/38 58.75±6.51 80 July 2010 to March 2013
Cardiovascular disease 40/38 56.38±3.31 78
Motiwala 2014 English America Healthy participants 64/13 59.0±13.8 77 February 2000 to July 2012
Cardiovascular disease 34/5 71.5±9.6 39
Shen 2016 English China Healthy participants 297/53 63.3±11.0 350 February 2011 and August 2015
Cardiovascular disease 146/63 69.5±10.0 209
Yang 2018 English China Healthy participants 39/32 59.4±8.6 71 May 2010 to December 2010
Cardiovascular disease 61/44 64.0±9.5 105

Quality assessment

A qualitative assessment was performed using the Cochrane tool for risk of bias. A high risk of performance bias and reporting bias was detected in two different studies (Figure 2). A summary of the risk of bias assessment for each study is shown in Figure 3. In general, 2 trials showed bias risk and 4 trials did not show any risk bias.

Figure 2 Risk of bias of the included studies. Low bias is represented by green, unclear bias is represented by yellow, and high bias is represented by red.
Figure 3 Summary of the risk of bias included in the study. Red shading indicates high risk of deviation, yellow shading indicates some concerns, and green indicates low risk of deviation.

Heterogeneity tests

Heterogeneity of OGN levels between normal patients and cardiovascular patients was reported in two studies. Meta-analysis showed that there were significant differences between the two groups (MD =−6.76; 95% CI: −11.69 to −1.83; P<0.00001; random effects model) and the heterogeneity was significant (I2=100%; Figure 4).

Figure 4 A forest map showing the comparison of osteoglycin concentrations in the blood between normal patients and cardiovascular patients.

A meta-analysis of the heterogeneity of LDL levels between normal patients and cardiovascular patients showed no significant difference between the two groups (MD =−0.10; 95% CI: −0.18 to −0.03; P=0.41; fixed effects model) and the heterogeneity of the included studies was low (I2=0%; Figure 5).

Figure 5 A forest map showing the comparison of low density lipoprotein cholesterol levels in the blood between normal patients and cardiovascular patients.

Meta-analysis of the heterogeneity of HDL between normal patients and cardiovascular patients showed no significant difference between the two groups (MD =0.05; 95% CI: 0.01 to 0.09; P=0.17; fixed effects model) and the heterogeneity of the included study was low (I2=48%; Figure 6).

Figure 6 A forest map showing the comparison of high density lipoprotein cholesterol levels in the blood between normal patients and cardiovascular patients.

Sensitivity analysis and publication bias

A total of 6 studies analyzed the plasma concentration of OGN in patients. The forest plot showed that the concentration of bone glycine in cardiovascular patients is higher than that in the control group. A sensitivity analysis was conducted by removing the study by Hu et al. 2015 (17). There was little change in the results (I2 changed from 100% to 98%; Figure 7), suggesting that the results of the included articles are robust.

Figure 7 A forest plot showing the pooled sensitivity for the studies.

A funnel chart was used to assess the publication bias of thrombosis. The shape of the funnel chart was symmetrical, indicating no significant publication bias in this meta-analysis (Figure 8).

Figure 8 A funnel plot showing publication bias in this meta-analysis. MD, mean difference; SE, standard error.

Discussion

Cardiovascular and cerebrovascular diseases refer to ischemic or hemorrhagic diseases of the heart, brain, and systemic tissues caused by hyperlipidemia, blood viscosity, atherosclerosis, and hypertension (22,23). It is highly prevalent and is characterized by significant disability, morbidity, and mortality. Despite treatment, more than 50% of survivors of cerebrovascular accidents cannot take care of themselves (24,25). Cardiovascular and cerebrovascular disease is the leading cause of mortality worldwide, contributing to as many as 15 million deaths every year.

OGN, also known as mimecan, is encoded by a single gene located on human chromosome 9q22. It is an ECM protein and belongs to the third family of small leucine rich proteoglycans (SLRPs) (26-28). It has important physiological functions and its main precursor form is secreted in the ECM. Mimecan not only participates in the regulation of collagen fiber formation but also plays an important role in cell migration and proliferation, and tumor growth, adhesion, and migration, as well as the regulation of growth factors.

González-Salvatierra et al. (29) demonstrated that bone glycine is closely related to cardiovascular disease and plays a vital role in vascular formation, pathophysiological changes, atherosclerosis, myocardial disease, and heart function. The conclusions in our current report agree with this latter study. Further in-depth investigation relating to the roles and mechanisms of OGN may provide novel insights into the treatment and prevention of cardiovascular diseases (30,31).

This meta-analysis revealed that the blood concentration of OGN in patients with cardiovascular disease is significantly elevated compared to that in control patients, suggesting that OGN may be a novel therapeutic target for the treatment and prevention of cardiovascular disease (32,33). However, there were some limitations to this study. First, this study did not document the medications used by the patients nor the details of any co-existing morbidities (34,35). Second, the report is limited by the number and quality of included studies. The conclusion should be further verified by using a larger cohort in multicenter follow-up controlled trials.

Acknowledgments

Funding: Scientific and technological Innovation Project for Overseas-educated Scholars in Nanjing in 2021.

Footnote

Reporting Checklist: The authors have completed the PRISMA reporting checklist. Available at https://apm.amegroups.com/article/view/10.21037/apm-22-104/rc

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://apm.amegroups.com/article/view/10.21037/apm-22-104/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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(English Language Editor: J. Teoh)

Cite this article as: Zuo Z, Li MH, Zheng XH, Yao WM, Wang H, Li XL. Elevated plasma levels of osteoglycin in cardiovascular patients: a systematic review and meta-analysis. Ann Palliat Med 2022;11(2):498-505. doi: 10.21037/apm-22-104

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