Effect of cardamom consumption on inflammation and blood pressure in adults: A systematic review and meta‐analysis of randomized clinical trials

Abstract Cardamom has the potential to offer anti‐inflammatory and antihypertensive advantages, but the findings from clinical trials have been inconsistent. To address this knowledge gap, the present systematic review and meta‐analysis were conducted to evaluate the anti‐inflammatory and antihypertensive effects of cardamom in adults. We systematically searched databases including PubMed, Scopus, and ISI Web of Sciences, for papers published up to October 2022 to identify clinical studies. Eight eligible studies were included in the meta‐analysis. A fixed model was used to estimate weighted mean difference (WMD), standardized mean difference (SMD), and 95% confidence interval (95% CI). The results showed that cardamom significantly reduced the levels of inflammatory factors, including hs‐CRP (SMD: −0.60 mg/dL; 95% CI: −0.78 to 0.42), IL‐6 (WMD: −1.25 mg/dL; 95% CI: −1.48 to −1.03), TNF‐α (WMD: −2.10 kg; 95% CI: −2.36 to −1.84, p < .001), and measures of systolic (WMD: −0.54 mmHg, 95% CI: −0.88, −0.19, p = .002) and diastolic (WMD: −0.90 mmHg; 95% CI: −1.07 to −0.73) blood pressure. The current meta‐analysis showed that cardamom can help reduce inflammation and improve blood pressure. However, due to the limited number of studies, caution must be exercised when interpreting the current results.

1,8-cineol, the dominant compound in cardamom, has been shown to have antibacterial, antioxidant, and anti-inflammatory effects.
It also prevents the release of inflammatory factors and reactive oxygen species (ROS).The reduction in blood pressure by 1,8-cineol might be achieved through the regulation of nitric oxide (NO) production and the improvement of cardiac systolic function (Cai et al., 2021;Farhanghi et al., 2022).Moreover, it has also been reported in animal models that cardamom reduces blood pressure through vasorelaxation effects (Kanthlal et al., 2020).Verma et al. (2009) showed that a daily intake of 3 g cardamom in subjects with stage 1 hypertension led to a significant reduction in blood pressure after 12 weeks of intervention.A clinical trial among patients with nonalcoholic fatty liver disease showed that consuming 3 g of cardamom over a period of 3 months reduced the levels of inflammatory factors, including TNF-α, IL-6, and hs-CRP (Daneshi-Maskooni et al., 2018).In contrast, a trial involving 204 patients with type 2 diabetes mellitus found that cardamom did not have a significant impact on sICAM-1, as well as systolic and diastolic blood pressures (SBP and DBP) (Azimi et al., 2016).
Another study conducted in patients with type 2 diabetes showed that consuming cardamom for 8 weeks did not result in significant changes in hs-CRP levels (Azimi et al., 2014).
Due to conflicting findings, the impact of cardamom on inflammation and blood pressure remains uncertain.Therefore, we conducted a comprehensive systematic review and meta-analysis of clinical trials on adults to summarize the potential antihypertensive and anti-inflammatory effects of cardamom.

| ME THODS
The systematic review and meta-analysis protocol have been registered with the International Prospective Register of Systematic Reviews (PROSPERO), with the assigned number CRD42022365939.A systematic literature search was conducted following the guidelines of the Reporting Items for Systematic Reviews and Meta-analysis (PRISMA-2020) (Page et al., 2021).

| Search strategy
Two authors (AH & NT) independently conducted systematic searches of databases, including PubMed, Scopus, and ISI Web of Science, up to October 2022, to identify and select studies.Related search terms were used to identify studies published in the English language (Data S1).Furthermore, we conducted a comprehensive manual search and cross-checked the references of the included studies to ensure that we did not overlook any relevant articles.

| Data extraction
After the study selection process, two independent reviewers conducted data extraction.The following information was systematically extracted from each included randomized trial: study design, the surname of the first author, study location, publication year, sample size, participants' gender, mean age, intervention details (including dose, type, and duration), health status of participants, changes in mean and SD of BMI, inflammatory biomarkers, and SBPs and DBPs from pre-to postintervention (Table 1).

| Quality assessment of studies
The Revised Cochrane Risk-Of-Bias tool for randomized trials (RoB 2) was used to evaluate the quality of studies.Several methodological aspects were considered for the assessment.These include random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessments, incomplete outcome data, selective reporting, and other potential threats to validity.Studies were stratified into low, high, or unclear risk of bias for each domain (Table 2).Disagreements were resolved through arbitration or consensus.

| Quantitative data synthesis and statistical analysis
Mean and SD of the baseline and postintervention measures were used in both the intervention and control groups to assess the effects of cardamom on inflammatory markers, including TNF-α, IL-6, and hs-CRP, as well as on blood pressure measures (i.e., SBPs and DBPs).
In the studies that did not report mean and SD, available statistics were converted into mean and SD using a proper formula: conservative correlation coefficient (R) estimate (0.9) was used (Borenstein et al., 2021).The following formula was employed to convert standard error of the mean (SEM) to SD: SD = SEM × √n, being "n" the number of subjects in each group.Medians and interquartile ranges were converted to mean and SD using the following formula: SD = IQR/1.35(symmetrical data distribution) (Hozo et al., 2005).To ascertain the relationship with forest plots, we used a fixed-effects model.The I-squared (I 2 ) statistic was used to estimate heterogeneity.Evidence of heterogeneity was confirmed when I 2 was greater than 50% with a p-value <.1 (Cochran, 1954).
To discern the potential sources of heterogeneity, we performed a subgroup analysis based on the duration of intervention and sex.To estimate the pooled effect size, a sensitivity analysis was performed.Eggers' regression symmetry test and visual funnel plots were used to investigate potential publication biases (Egger et al., 1997;Peters et al., 2008).Quantitative analysis of homogeneity and heterogeneity was performed using the I 2 statistic and χ 2 test (Higgins et al., 2019).STATA software version 16.1 was used to perform the statistical analyses.A p-value of <.05 was considered to be statistically significant.studies was assessed, and 8 articles were eventually included in the current study (Azimi et al., 2014(Azimi et al., , 2016;;Cheshmeh et al., 2022;Daneshi-Maskooni et al., 2018;Fatemeh et al., 2017;Ghazi Zahedi et al., 2021;Kazemi et al., 2017;Zahedi et al., 2022) (Figure 1).
Moreover, studies conducted predominantly among females might be the source of heterogeneity (Table 3).
Moreover, a significant heterogeneity (I 2 = 98.0%, p < 0.001) was observed.The effect of cardamom on TNF-α is presented in Figure 2e.

| Publication bias and sensitivity analysis
To determine the impact of each trial on the pooled effect size, we conducted a sensitivity analysis.The sensitivity analysis for hs-CRP and IL-6 showed that the overall estimates were not affected by the elimination of any of the included studies.We also examined publication bias by visually inspecting the funnel plot and conducting Egger's weighted regression tests.The results of the funnel plot (Figure 3) and Egger's test showed no publication bias for hs-CRP (p = .459)and IL-6 (p = .627).

| DISCUSS ION
For centuries, cardamom has been used in traditional medicine to treat a variety of conditions such as tooth and gum infections, asthma, kidney and digestive disorders, diarrhea, nausea, cataracts, and cardiac disorders (Ashokkumar et al., 2020).According to a recent narrative review, Elettaria Cardamomum (green cardamom) may have lipid-modifying, antihypertensive, antiinflammatory, antioxidant, and antithrombotic properties and these are thought to be attributed to the presence of polyphenol compounds (Yahyazadeh et al., 2021).In this systematic review and meta-analysis, we summarized the results of clinical trials assessing the effect of Elettaria Cardamomum (green cardamom) on inflammatory indices and blood pressure measures.The current study showed that supplementation with green cardamom reduces the levels of inflammatory factors, including TNF-α, hs-CRP, and IL-6, as well as blood pressure measures, including SBP and DBP.
Subgroup analyses showed a significant reduction in IL-6 for both study duration (≤10 vs. >10 weeks) and sex (male vs. female).Additionally, subgroup analyses showed that although hs-CRP did not change significantly in studies that lasted less than 10 weeks, a significant reduction was observed in studies conducted for greater or equal to 10 weeks.Moreover, subgroup analysis based on sex (male vs. female) showed a significant reduction in the level of hs-CRP.In line with the current results, a clinical trial reported that 3 g of cardamom combined with a low-calorie diet over 16 weeks reduced serum levels of inflammatory factors including TNF-α, IL-6, and hs-CRP (Cheshmeh et al., 2022).In another RCT, Winarsi and Susilowati (2018) found that consuming a drink rich in antioxidant rhizome cardamom (Fd-Carrhi) for 2 months reduced IL-6 and CRP levels in women with atherosclerosis.Green cardamom potentially reduces inflammation by downregulating the expression of COX-2 and iNOS and decreasing inflammatory cytokines such as IL-6 and TNF-α.Furthermore, cardamom improves oxidative stress through the regeneration of antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT), and reduced glutathione (GSH) (Kandikattu et al., 2017;Sengupta et al., 2005).One of the major compounds in cardamom is 1,8-Cineole, which possesses anti-inflammatory and antioxidant properties, as well as protective effects against cardiovascular disease.Also, 1,8-cineole inhibits NF-κB phosphorylation and its transfer into the nucleus, regulating the expression of important transcription factors such as NF-κB and Nrf2, which can potentially regulate the inflammatory response (Cai et al., 2021).In line with the current findings on blood pressure plasma nitrite levels (Moon et al., 2014).In this meta-analysis, although we conducted a comprehensive search and covered most of the main databases, there is still a possible risk of publication bias.There are some limitations to consider.All included studies were conducted in Iran.Therefore, the current results may not be generalizable to other communities.Furthermore, the results of this study should be interpreted with caution due to significant heterogeneity among the included studies.However, subgroup analyses were used to reduce heterogeneity.

| CON CLUS ION
In conclusion, the current systematic review and meta-analysis provide convincing evidence in favor of the effectiveness of green F I G U R E 3 Funnel plots for the effect of cardamom consumption on (a) hs-CRP; (b) IL-6.
, and one study included overweight or obese individuals with nonalcoholic fatty liver disease (Daneshi-Maskooni et al., 2018).[corrections added on 26 October 2023, after the first online publication: Yaghooblou et al. (2015) was replaced by Fatemeh et al. (2017).] General Low Risk < 2 high risk, General moderate risk = 2 high risk, General high risk > 2 high risk.

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I G U R E 2 (Continued)measures, a single-arm study conducted byMohammed and Mohammed (2020) showed that daily consumption of 3 g of cardamom for 3 months led to a decrease in SBP and DBP among patients with stage 1 hypertension.Another single-arm study investigated the impact of cardamom on blood pressure in patients with stage 1 hypertension and found that supplementing with 3 g of cardamom powder for 3 months significantly reduced SBP and DBP as well as the mean blood pressure(Verma et al., 2009).In contrast,Azimi et al. (2014) reported that consumption of cardamom, cinnamon, ginger, and saffron along with tea for 8 weeks did not result in significant changes in blood pressure measures in people with type 2 diabetes.Various mechanisms have been suggested to explain how cardamom can help regulate blood pressure.These mechanisms include acting as a calcium channel antagonist, promoting vasodilation through cholinergic activity, stimulating the release of nitric oxide from the endothelium, and having a diuretic effect(Gilani et al., 2008).Moreover, based on previous studies, angiotensin II contributes to the development of cardiovascular diseases and blood pressure regulation.Another potential mechanism is the role of 1,8-cineole in suppressing angiotensin.In animal models of hypertension, cineole has been shown to decrease SBP and increase Characteristics of the included studies.
TA B L E 3 Subgroup analyses of cardamom consumption on inflammatory factors in adults.
a Standardized mean difference.