Abstract
Epidemiologic studies have suggested an inverse association between flavonoids and cardiovascular disease (CVD). However, the results might have been influenced by the use of dietary assessment methods, which are error prone. The aim of this paper was to systematically review and analyse the literature for evidence of associations between polyphenol biomarkers and CVD and mortality risk in observational studies. Eligible studies were identified through PubMed, Web of Science, and reference lists. Multivariable adjusted associations were extracted. Data were log-transformed and pooled using the random effects model. In total, eight studies were included, investigating 16 different polyphenol biomarkers in association with CVD and mortality. Blood and urine were used as biospecimens, and enterolactone, a lignan metabolite, was most often investigated. Three meta-analyses were conducted investigating the association between enterolactone, and all-cause and CVD mortality, and non-fatal myocardial infarction. A 30% and 45% reduced all-cause and CVD mortality risk were revealed at higher enterolactone concentrations. Furthermore, inverse associations were observed between polyphenol biomarkers and all-cause mortality, kaempferol, and acute coronary syndrome. There is evidence to suggest that enterolactone is associated with a lower CVD mortality risk. This emphasises the importance of the role of the microbiota in disease prevention. To strengthen the evidence, more studies are warranted.
Generated Summary
This systematic review and meta-analysis investigated the association between polyphenol biomarkers and cardiovascular disease (CVD) and mortality risk in observational studies. The study identified eligible studies through PubMed and Web of Science, including those investigating various polyphenol biomarkers, such as flavonoids, lignans, and phenolic acids, and their associations with CVD and mortality outcomes. The research employed a random-effects model for meta-analyses, extracting multivariable adjusted associations and pooling data. Eight studies were included, exploring 16 different polyphenol biomarkers in relation to CVD and mortality. The primary aim was to analyze the literature for evidence of associations between polyphenol biomarkers and CVD and mortality risk in observational studies, with a focus on identifying the relationship between biomarkers and health outcomes. Additionally, the research sought to conduct meta-analyses of individual biomarkers and outcomes to assess the strength and consistency of the observed associations.
Key Findings & Statistics
- The review included a total of eight observational studies [20–27] that investigated polyphenol biomarkers in association with mortality or CVD.
- The study investigated 16 polyphenolic compounds (Table 1).
- Five studies investigated ENL [21–25], two END [22,23], and one total polyphenols [26], resveratrol [27], lignans [23], flavonoids [20], flavonols [20], flavanones [20], flavones [20], and phloretin [20].
- Two studies solely investigated all-cause mortality [26,27], two studied all-cause and CVD mortality [23,25], two studied CVD incidence and mortality [20,21], and three CVD incidence [21,22,24].
- Meta-analyses were conducted when at least two studies were available with a common exposure and outcome. This resulted in a total of three meta-analyses investigating the association between ENL, and all-cause and CVD mortality, and non-fatal myocardial infarction.
- A 30% and 45% reduced all-cause and CVD mortality risk were revealed at higher enterolactone concentrations (Figure 2A).
- Furthermore, decreased mortality risks of 30%, 35%, and 35% were observed at higher total urinary polyphenol (TUP) [26], enterolignans [23], and ENL [23] concentrations, respectively.
- Inverse associations were also found between ENL and CHD mortality [25], and kaempferol excretion and acute coronary syndrome (ACS) [20].
- In a subgroup analysis of men, a 47% reduced non-fatal MI risk was observed (RR (95% CI): 0.53 (0.29, 0.98)).
- The meta-analysis of two studies [23,25] revealed a 30% lower all-cause mortality risk at higher ENL concentrations (Figure 2A).
- Pooling data for CVD mortality, a 45% reduced risk was revealed when the highest and the lowest quantile of ENL concentration were compared (Figure 2B).
Other Important Findings
- In line with the inverse association that was revealed in the present meta-analysis of all- cause mortality, is the 40% reduced risk observed for dietary lignans in Spanish community-dwelling elderly [28] and the 31% reduced risk for matairesinol found in elderly Dutch men [29].
- The statistically significant reduced ACS risk of the kaempferol biomarker [20] is in line with the results of a meta-analysis [31] and a prospective Italian study [32].
- The null associations found for flavonoid biomarkers and ACS [20] are consistent with a meta-analysis of total dietary flavonoids and their subgroups [31], dietary flavonols and flavanones, in two prospective studies [33,34], and flavones in three prospective studies [32–34].
- In contrast, a statistically significant decreased CVD risk trend was observed for dietary dihydrochalcone intake [34] (class of phloretin [20]).
Limitations Noted in the Document
- The studies included in the meta-analysis did not consider antibiotic use, a known factor influencing lignan metabolites, potentially leading to underestimated risks.
- The included studies used single samples of blood and urine, which may not reliably reflect the total bioavailable concentration of polyphenolic compounds.
- The heterogeneity observed in the meta-analysis of MI could be attributed to sex differences or the lower ENL concentrations in one study [22], or due to the differences in biospecimens.
- The search in gray literature was not conducted.
- The review focused on specific biomarkers of polyphenols, limiting the scope of the overall dietary impact of polyphenols.
Conclusion
The meta-analyses revealed significant inverse associations between enterolactone (ENL) and all-cause and CVD mortality, highlighting the potential of ENL as a protective factor. The study underscores the importance of considering individual polyphenolic compounds and their metabolites rather than total polyphenols for more precise insights. The identification of inverse associations between ENL and CVD mortality, along with the observation of reduced risks at higher ENL levels, emphasizes the role of the microbiota in disease prevention. The current review suggests that the polyphenol biomarkers strongly reflect internal doses, which are not necessarily strongly associated with long-term intake due to the many factors influencing bioavailability [3,36]. The authors emphasize that future research should focus on comparability across studies and consider collecting multiple biospecimen samples or 24 h urine samples to accurately capture circadian polyphenol exposure. Moreover, the authors highlight the need for further investigation into specific polyphenolic compounds and metabolites to enhance understanding of their role in cardiovascular health. This approach could offer more detailed insights compared to total polyphenols. Furthermore, they note that evidence from biomarker studies is limited, and more research is warranted. In conclusion, the study provides a complete overview of published evidence of associations between polyphenol biomarkers and CVD risk and mortality in human population-based studies, offering valuable insights into the potential of these biomarkers for understanding and preventing cardiovascular diseases.