Red wine alleviates atherosclerosis-related inflammatory markers in healthy subjects rather than in high cardiovascular risk subjects: A systematic review and meta-analysis

Abstract

Background:

Moderate red wine (RW) consumption is associated with a low risk of cardiovascular disease (CVD). However, few studies have evaluated the effects of RW and white wine (WW) on inflammatory markers related to atherosclerosis in healthy individuals and high-risk subjects for CVD. This study aimed to assess the effect of RW on inflammatory markers in healthy individuals and high-risk subjects for CVD compared with moderate alcohol consumption.

Methods:

The Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 (PRISMA) was followed in this study. The PubMed, Embase, Cochrane, Web of Science, SinoMed, EbscoHost, and ScienceDirect databases were searched. The risk of bias and quality of the included trials were assessed using the Cochrane Handbook. The main results are summarized in Stata 12.

Results:

Twelve studies were included in the meta-analysis. The results demonstrated that RW significantly decreased circulating intercellular cell adhesion molecule-1, vascular cell adhesion molecule-1 (VCAM-1), tumor necrosis factor-alpha (TNF-α), lymphocyte function-associated antigen-1, and Sialyl-Lewis X expression on the surface of monocytes in healthy subjects, but not in patients with CVD. Additionally, RW significantly decreased Sialyl-Lewis X but increased clusters of differentiation 40 (CD40) expressed on the surface of T lymphocytes and significantly decreased C-C chemokine receptor type 2 (CCR2) and very late activation antigen 4 (VLA-4) expressed on the surface of monocytes. Interestingly, subgroup analysis also found that RW significantly decreased circulating interleukin-6 (IL-6) in Spain but not in other countries, and significantly increased αMβ2 (Mac-1) in the group that had an intervention duration of less than 3 weeks.

Conclusions:

Moderate consumption of RW is more effective than WW in alleviating atherosclerosis-related inflammatory markers in healthy people rather than high-risk subjects for CVD, but this needs to be further confirmed by studies with larger sample sizes.

1. Introduction

Atherosclerosis (AS) is the leading cause of death from cardiovascular diseases (CVD) worldwide and is characterized by inflammation of larger arteries.^[1] Endothelial injury is a sign of the onset and progression of AS and can be caused by the release of cell adhesion molecules, such as lymphocyte function-associated antigen-1 (LFA-1), very late activation antigen 4 (VLA-4), C-C chemokine receptor type 2 (CCR2), vascular cell adhesion molecule-1 (VCAM-1), intercellular cell adhesion molecule-1 (ICAM-1), and monocyte chemotactic protein-1 (MCP-1).^[2-4] Mature and differentiated monocytes then produce high levels of inflammatory factors, such as interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), c-response protein (CRP), and interleukin-10 (IL-10), leading to the development of AS.^[5] Thus, preventing cell adhesion and decreasing inflammatory biomarkers are considered effective methods for preventing AS.

It is unclear whether the health benefits of red wine (RW) are due to ethanol or non-ethanol active substances. Recent studies have suggested that the health benefits of RW can be attributed to ethanol rather than reactive molecules.^[6] Moderate alcohol consumption has been found to impede the permeability of monolayers caused by serum amyloid A1 (SAA1), as well as the expression of ICAM-1, VCAM-1, and monocyte adhesion.^[7] Several studies also revealed that moderate and stable alcohol consumption is associated with a lower risk of coronary heart disease.^[8,9] Imhof suggested that moderate ethanol intake for a short duration was more effective at inhibiting MCP-1 expression in monocytes than dealcoholized RW.^[10] On the other hand, research has indicated that the benefits of moderate consumption of RW are due to the presence of a variety of polyphenolic compounds in the beverage.^[6] Janega et al^[11] found that the cardioprotective effect of alcohol-free RW extract was related to its anti-inflammatory properties. Additionally, Lombardo et al^[12] evaluated the correlations between acute and chronic RW consumption and health to uncover the benefits of moderate RW consumption in patients with type 2 diabetes mellitus and indicated that RW has a potential effect on antioxidant stress, thrombosis and inflammation markers, lipid profile, and gut microbiota. Serio et al^[13] found that RW polyphenols have beneficial effects on lipid, oxidative stress, and glucose metabolism. It is not difficult to discover that moderate RW and alcohol consumption are benefit for human health.^[14,15] However, it is uncertain whether RW is more effective for human health than moderate alcohol consumption. Therefore, this meta-analysis is the first to evaluate the effects of RW on inflammatory markers related to atherosclerosis.

It is important to note that many studies have focused on the effects of moderate consumption of RW and alcohol on CVD while ignoring the benefits of moderate consumption of RW in healthy people. As far as we know, moderate RW may reduce the expression of inflammation-and oxidative stress-related genes^[16] and adiponectin^[17] and inhibit DNA oxidative damage,^[18] but significantly increase plasma total homocysteine (tHcy),^[19] acutely slow cardiac conduction, and prolonged repolarization in healthy individuals.^[20] These studies indicate that the anti-inflammatory and antioxidant effects of moderate RW consumption in healthy subjects are controversial. It remains unclear whether moderate RW consumption is beneficial for healthy people or high-risk subjects for CVD when compared to moderate ethanol intake.

Therefore, it is necessary to comprehensively evaluate the effects of RW and white wine (WW) on inflammatory markers in healthy people and patients with CVD compared with moderate ethanol consumption, with the aim of providing a clinical basis for different RW consumers in their daily lives.

2. Methods

2.1. Registry of systematic review protocol

The protocol was prospectively registered in the International Prospective Register of Systematic Reviews (registration number: CRD42021269378).^[21]

2.2. Research strategy

This review was conducted in accordance with the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 and Cochrane Handbook for Systematic Reviews of Interventions, Version 5.1.0. A comprehensive search of the PubMed, Embase, Cochrane, Web of Science, SinoMed, EbscoHost, and ScienceDirect databases was conducted to identify relevant articles. The medical terms (MeSH) were used: “coronary disease” OR “atherosclerosis” OR “carotid atherosclerosis” OR “coronary artery atherosclerosis” AND “red wine” OR “wine grape” OR “red wine consumption” OR “red wine polyphenols” AND “clinical trial.” The deadline for the literature search was August 1, 2023.

2.3. Eligibility criteria

2.3.1. Inclusion criteria

1. Study design: The study must be a randomized controlled trial (RCT) of human subjects in the English language.

2. Subjects: healthy subjects or high-risk subjects for CVD.

3. Intervention: The treatment group was polyphenol-rich RW and the control group was polyphenol-free or low-polyphenol WW. The ethanol consumed in the 2 groups was equal (<30 g every day).

4. The ending indicator must include at least one of the following outcomes: LFA-1, VLA-4, Mac-, CD40, VCAM-1, ICAM-1, CD36, CCR2, IL-6, IL-10, TNF-α, and MCP-1.

2.3.2. Exclusion criteria

1. The treatment group consisted of polyphenol-rich alcoholic beverages, and the control group consisted of polyphenol-free WW.

2. Reviews, editorials, case reports, letters, and commentaries.

3. The outcomes could not be extracted or obtained.

4. Non-RCT studies.

2.4. Data synthesis and analysis

Differences in the mean and standard difference (SD) changes were calculated according to the method reported by Asgary S for each study.^[22] Heterogeneity was assessed based on formal statistical testing using I² and P values. In this study, inverse variance estimates were conducted with a fixed-effects model to calculate the standard mean difference (SMD) and their 95% CIs when I² values were less than 50% or P values were more than .05, using the STATA 12 software. Subgroup analysis was performed to explore heterogeneity or between-subgroup effects.^[23] The Cochrane risk-bias assessment tool was used to assess the methodological quality of the included studies.

3. Results

3.1. Study selection and characteristics

A total of 154 articles were searched from the PubMed, Embase, Cochrane, Web of Science, SinoMed, EbscoHost, and ScienceDirect databases. After eliminating 62 duplicate articles, 92 records were identified and considered to be potentially relevant. Following a review of titles and abstracts, 71 articles were excluded and 21 records were selected for full-text review based on the population-intervention-comparison-outcomes-study design (PICOS) model.^[24,25] One study^[10] was discarded due to a lack of SD of the outcomes, and 4 studies were excluded because of the irrelevance of the outcomes.^[26-29] Moreover, 4 records were eliminated owing to inappropriate interventions.^[30-33] Ultimately, 12 studies^[34-45] were included in the review, which were conducted between 2004 and 2022, as shown in Flow Diagram (Fig. 1). A total of 426 participants (aged 21–80 years) completed the study, with both the RW and WW groups consuming moderate amounts of ethanol daily. The duration of the RCTs ranged from 4 to 4 weeks (Table 1).

Figure 1.

PRISMA flow diagram. PRISMA = the preferred reporting items for systematic reviews and meta-analyses.

Table 1.

Study characteristics.

Study ID	Country	Ages (yr)	Population	Concentrations of phenolicsubstances	Ethanol consumption(g/d)	Main measurement outcome	Duration
Gemma Chiva-Blanch 2012[35]	Spain	55–75	67 men with CVD, accept RW or gin	RW W 2933.35 mg/L, gin 930	30	LFA-1, VLA-4, Mac-1, CD40, CD40, CD36, CCR2, IL-6, IL-10, TNF-α, ICAM-1, VCAM-1	4 wk
G. Chiva-Blanch 2015[39]	Spain	61 ± 6	33 men with CVD, accept beer and gin	Beer ee1290 mg, gin 290	30	LFA-1, VLA-4, Mac-1, CD40, CD36, CCR2, IL-10, TNF-α, MCP-1, ICAM-1, VCAM-1	4 wk
Irene Roth 2018[36,37]	Spain	55–80	38 men with CVD, accept AWW and gin	RW W 927.8 mg/L, gin 270	30	LFA-1, VLA-4, Mac-1, CD40, CD36, CCR2, IL-6, IL-10, TNF-α, MCP-1, ICAM-1, VCAM-1	3 wk
Irene Roth 2018[36,37]	Spain	55–80	39 men with CVD, accept AWW and gin	RW W 927.8 mg/L, gin g/0	30	LFA-1, VLA-4, Mac-1, CD40, CD36, CCR2	4 h
Elizabeth Fragopoulou 2021[38]	Greece	49–74	men with CVD, 21 accept RW, 16 accept tsipouro	NOT mentioned	27	IL-6, VCAM-1	4 wk
Emilio Sacanella 2007[40]	Spain	20–50	35 Healthy females, accept RW and WW	RW Wa1945 mg/mL, WW 94308 mg/mL	20	LFA-1, VLA-4, Mac-1, CD40, SLeX, MCP-1, IL-6, TNF-α, CRP, ICAM-1, VCAM-1, E-selectin	4 wk
Michael 2004[34]	New Zealand	48–70	13 men with CVD, accept RW and WW	RW W 1170 mg/mL, WW 17210 mg/mL	44.2	IL-6, ICAM-1, VCAM-1	6 h
Ramon Estruch. 2004[41]	Spain	30–50	20 healthy men, accept RW and WW	RW Wa636.5 mg/mL, WW 360	30	LFA-1, VLA-4, Mac-1, MCP-1, TNF-α, CRP, ICAM-1, VCAM-1, E-selectin	4 wk
Eva Badía 2004[42]	Spain	30–50	8 healthy men accept RW and WW	RW Wh636.5 mg/mL, WW 360	30	LFA-1, VLA-4, Mac-1, MCP-1	4 wk
Monica Vazquez-Agell 2007[43]	Spain	25–50	20 healthy men accept Cava and gin	RW W 242 mg/mL, WW 420	30	LFA-1, VLA-4, Mac-1, CD40, SLeX, ICAM-1, VCAM-1, TNF-α, CRP, E-selectin, IL-6	4 wk
Wotherspoon A 2020[44]	UK	21–70	77 healthy men accept RW and gin	NOT mentioned	24	CRP, IL-6, ICAM-1, VCAM-1	2 wk
Henrique 2022[45]	Brazil	44.3 4.10.3	39 healthy men or female accept RW and cachaça	NOT mentioned	24	CRP, IL-6, IL-10, TNF-α	4 wk

CVD = cardiovascular disease, ICAM-1 = intercellular cell adhesion molecule-1, IL-6 = interleukin-6, LFA-1 = lymphocyte function-associated antigen-1, Mac-1 = αMβ2, MCP-1 = monocyte chemotactic protein-1, RW = red wine, TNF-α = tumor necrosis factor-alpha, VCAM-1 = vascular cell adhesion molecule-1, VLA-4 = very late activation antigen 4.

3.2. Risk of bias

The selection bias of 9 studies was judged to have a low risk of bias. Nine studies were deemed to have a high risk of performance bias owing to single blinding. The outcome assessors were blinded to the 4 studies, resulting in a low detection bias. Four studies judged to be at a high risk of attrition bias showed unequal withdrawal of participants between groups. Eleven studies were judged to have a low risk of bias owing to complete outcome measures. The condition of the remaining patients was unclear because of missing information. Figure 2 displays the evaluation of the risk of bias in the 12 studies.

Figure 2.

Risk of bias of 12 studies.

3.3. Circulating inflammatory markers

The subgroup analysis of 8 studies based on fixed effect model revealed that RW significantly decreased the level of circulating ICAM-1 (SMD: −0.27, 95% CI: −0.49 to −0.04, heterogeneity I² = 31.8%), VCAM-1 (SMD: −0.68, 95% CI: −1.01 to −0.34, heterogeneity I² = 35.8%), and TNF-α (SMD: −0.52, 95% CI: −0.78 to −0.25, heterogeneity I² = 21.3%) in healthy subjects but not in high-risk subjects for CVD compare with moderate alcohol consumption. Interestingly, this study found that RW significantly decreased the level of circulating IL-6 in subjects from Spain (SMD: −0.69, 95% CI: −0.92 to −0.46, heterogeneity I² = 56.6%) but was not significant in non-Spanish subjects (SMD: 0.06, 95% CI: −0.17 to 0.28, heterogeneity I² = 0.0%), as shown in Figure 3. Additionally, no significant differences were observed in circulating CRP (SMD: −0.06, 95% CI: −0.21 to 0.10, heterogeneity I² = 0.0%), E-selectin (SMD: −0.14, 95% CI: −0.35 to 0.07, heterogeneity I² = 34.8%), IL-10 (SMD: 0.06, 95% CI: −0.15 to 0.27, heterogeneity I² = 52.8%), and MCP-1 (SMD: 0.09, 95% CI: −0.13 to 0.31, heterogeneity I² = 0.0%) after pooling the standardized mean difference of 3 or 4 studies following moderate RW consumption (Figure S1, Supplemental Digital Content, http://links.lww.com/MD/M674). No heterogeneity was found in circulating inflammatory markers (P > .05), and the fixed-effects model was adopted.

Figure 3.

Forest plot of pooled standardized mean difference of circulating ICAM-1, VCAM-1, IL-6, and TNF-α after moderate RW and WW consumption. ICAM-1 = intercellular cell adhesion molecule-1, IL-6 = interleukin-6, RW = red wine, TNF-α = tumor necrosis factor-alpha, VCAM-1 = vascular cell adhesion molecule-1, WW = white wine.

3.4. Cell adhesion molecules on T lymphocytes

As shown in Figure 4, 4 to 7 studies reported cell adhesion molecules expressed on the surface of T lymphocytes, including LFA-1, VLA-4, CD40, Sialyl-Lewis X (SLeX), and Mac-1, which were pooled to evaluate the effect of RW consumption. The results showed that moderate RW consumption significantly increased the SMD of CD40 (SMD:0.22, 95% CI: 0.03–0.40, heterogeneity I² = 36.1%) and significantly decreased SLeX (SMD: −0.30, 95% CI: −0.53 to −0.08, heterogeneity I² = 0.0%) but did not significantly change the standardized mean difference of LAF-1 (SMD: −0.09, 95% CI: −0.31 to 0.13, heterogeneity I² = 0.0%), VLA-4 (SMD: −0.12, 95% CI: −0.29 to 0.06, heterogeneity I² = 49.9%), and Mac-1 (SMD: −0.12, 95% CI: −0.33 to −0.09, heterogeneity I² = 0.0%). I² < 50% suggested that the heterogeneity among the studies was insignificant, and the fixed-effect model was adopted.

Figure 4.

Forest plot for cell adhesion molecules expressed on the surface of T lymphocytes.

3.5. Cell adhesion molecules on monocytes

Subgroup analysis of LFA-1 expressed on the surface of monocytes suggested that RW consumption significantly inhibited the expression of LFA-1 (SMD: −0.97, 95% CI: −1.30 to −0.65, heterogeneity I² = 35.3%) in healthy subjects, but had no significant difference in high-risk subjects for CVD (SMD: 0.21, 95% CI: 0.00–0.42, heterogeneity I² = 0.0%). RW also decreased the level of SLeX (SMD: −0.61, 95% CI: −0.99 to −0.22, heterogeneity I² = 0.0%) expressed on the surface of monocytes in healthy subjects, but not in subjects at high risk of CVD (SMD: −0.04, 95% CI: −0.32 to 0.24, I² = 0.0%). The pooled result demonstrated that RW had no significant difference on Mac-1 after 4 weeks (SMD: −0.20, 95% CI: −0.41 to 0.00, heterogeneity I² = 0.0%), moderate RW consumption compared to WW consumption, but had a significant difference when treated for less than 3 weeks (SMD:0.62, 95% CI: 0.29–0.94, heterogeneity I² = 42.0%). I² < 50% suggested that the heterogeneity among the studies was insignificant, and the fixed-effect model was adopted (Fig. 5).

Figure 5.

Forest plot of pooled standardized mean difference of LFA-1, SLeX, and Mac-1 expressed on the surface of monocytes. LFA-1 = lymphocyte function-associated antigen-1, Mac-1 = αMβ2, SLeX = Sialyl-Lewis X.

Additionally, as shown in Figure 6, RW significantly decreased the expression levels of VLA-4 (SMD: −0.46, 95% CI: −0.90 to −0.02, heterogeneity I² = 82.2%) and CCR2 (WMD: −49.68, 95% CI: −58.70 to −40.65, heterogeneity I² = 0.0%) on the surface of monocytes. There was no change in the CD40 level (SMD: −0.08, 95% CI: −0.40 to 0.24, heterogeneity I² = 66.0%). There was significant heterogeneity among studies in VLA-4 and CD40 (P < .05), and the random-effects model was adopted.

Figure 6.

Forest plot of pooled standardized mean difference of CCR2 and VLA-4 expressed on the surface of monocytes. CCR-2 = C-C chemokine receptor type 2, VLA-4 = very late activation antigen 4.

4. Discussion

This meta-analysis found that RW significantly decreased circulating ICAM-1, VCAM-1, TNF-α, and LFA-1, SLeX expressed on the surface of monocytes in healthy subjects but not in CVD patients compared to moderate alcohol consumption. Additionally, RW significantly decreased the expression of CCR2 and VLA-4 on the surface of monocytes and decreased SLeX but increased CD40 expression on the surface of T lymphocytes. Interestingly, RW significantly decreased circulating IL-6 in Spanish subjects but not in other counties, and significantly increased Mac-1 in the group in which the duration of intervention was less than 3 weeks. In addition, there were no significant differences in circulating CRP, E-selectin, IL-10, MCP-1, and CD40 expressed on the surface of monocytes and VLA-4, Mac-1, and LFA-1 expressed on the surface of T lymphocytes compared to moderate alcohol consumption.

The heterogeneity of this meta-analysis was mainly due to whether the subjects were healthy. In addition, the heterogeneity of circulating IL-6 did not come from the health of the subjects but from their ethnic differences. The heterogeneity of MAC -1 expression on monocytes was due to the duration of the trials. Subgroup analysis of subjects, region, and duration showed that heterogeneity was reduced to an acceptable level (I² < 50%, P > .05), especially for ICAM-1, VCAM-1, TNF-α, IL-6, LFA-1, and Mac-1. However, subgroup analysis did not reduce the heterogeneity of VLA-4 and CD40 expressed on the surface of monocytes. Furthermore, the heterogeneity of VLA-4 was mainly derived from 2 studies reported by Monica Vazquez-Agell and Gemma Chiva-Blanch using the Stata 12.0 software. A careful review of both studies found that the units of VLA-4 reported by Monica Vazquez-Agell were not consistent with the other 11 included RCTs, and the results reported by Gemma Chiva-Blanch showed that the baseline values of RW and WW were the same. Therefore, it is speculated that the heterogeneity of VLA-4 may be related to the units and the baseline. In conclusion, the pooled results were convincing after the subgroup analysis.

Currently, RW has the potential to improve vascular health in at-risk human populations, particularly with respect to lowering systolic blood pressure.^[46] However, few studies have evaluated the effects of RW on inflammatory markers in healthy individuals or in high-risk subjects for CVD. The key finding of this meta-analysis was that moderate consumption of RW reduced most inflammatory markers in healthy subjects. The pooled results showed that RW significantly reduced AS markers of inflammation, including ICAM-1, VCAM-1, TNF-α, LFA-1, and SLeX in healthy subjects, but did not reduce markers of inflammation in high-risk subjects for CVD. A prospective randomized controlled trial of 108 patients with carotid atherosclerosis demonstrated that RW did not affect middle cerebral and internal carotid blood flow velocities in patients with carotid atherosclerosis.^[29] Moreover, high doses of resveratrol increase the levels of sVCAM-1 and sICAM-1 in older adults, thereby increasing the risk of CVD.^[47] A clinical trial in a healthy population revealed that moderate RW consumption significantly decreased low-grade inflammation biomarker scores and increased adiponectin, and was better than moderate consumption of alcohol and beer.^[17,48] This evidence supports our pooled results and suggests that moderate consumption of RW, such as moderate consumption of alcohol, does not reduce markers of inflammation in high-risk subjects for CVD. However, moderate daily consumption of RW is associated with lower levels of inflammatory markers related to AS and better health than alcohol consumption in healthy individuals, while ensuring moderate consumption and non-addiction. Additionally, the reduction of RW in inflammatory markers related to AS may also be related to the duration of RW intervention and the region of the subjects. This pooled analysis found that RW significantly reduced circulating IL-6 levels in Spanish subjects compared with moderate alcohol consumption but did not reduce IL-6 levels in non-Spanish subjects. A clinical trial of 16 healthy Spanish volunteers demonstrated that moderate RW intake decreased the mean concentrations of hsCRP, TNF-α, and IL-6 induced by a fat-enriched diet.^[49] In addition, this meta-analysis suggests that acute consumption of RW may be more beneficial in reducing MAC-1 levels on monocyte surfaces. However, this is thought to be accidental, and further research is needed to corroborate and explain this finding.

However, this meta-analysis also has some shortcomings. First, this meta-analysis included a limited number of studies, and more studies are needed to explore the health effects of RW on the subjects. Second, this meta-analysis only examined the effect of moderate consumption of RW on AS inflammatory markers and not the overall effect on CVD. Finally, the meta-analysis did not clearly reveal the effect of race and duration of intervention on the reduction of inflammatory markers in RW, and we look forward to more clinical studies that focus on the population, ethnicity, and timing of intervention to reduce inflammatory markers in RW.

In conclusion, moderate RW consumption positively reduced inflammatory markers related to atherosclerosis in healthy populations, but not in high-risk subjects for CVD, compared to moderate consumption of WW.

5. Conclusion

This meta-analysis demonstrated that RW significantly decreased circulating ICAM-1, VCAM-1, TNF-α, and LFA-1, SLeX expressed on the surface of monocytes in healthy subjects but not in high-risk subjects for CVD compared to moderate alcohol consumption. Additionally, RW significantly decreased the expression of CCR2 and VLA-4 on the surface of monocytes and decreased SLeX but increased CD40 expression on the surface of T lymphocytes. However, no benefit was found for circulating CRP, E-selectin, IL-10, MCP-1, or CD40.

Acknowledgments

We thank all participants for their kind help during the formation and finalization of the manuscript. The authors declare that they have no affiliations with or involvement in any organization or entity with any financial interest in the subject matter or materials discussed in this manuscript.

Author contributions

Conceptualization: Yingkun Sheng.

Data curation: Guibing Meng.

Formal analysis: Guibing Meng.

Funding acquisition: Yingkun Sheng.

Investigation: Guibing Meng.

Methodology: Guibing Meng.

Supervision: Guidong Li, Jianfeng Wang.

Validation: Guidong Li.

Visualization: Yingkun Sheng.

Writing – original draft: Yingkun Sheng.