Acute benefits of the microbial-derived isoflavone metabolite equol on arterial stiffness in men prospectively recruited according to equol producer phenotype: a double-blind randomized controlled trial

Abstract

Background: There is much speculation with regard to the potential cardioprotective benefits of equol, a microbial-derived metabolite of the isoflavone daidzein, which is produced in the large intestine after soy intake in 30% of Western populations. Although cross-sectional and retrospective data support favorable associations between the equol producer (EP) phenotype and cardiometabolic health, few studies have prospectively recruited EPs to confirm this association.

Objective: The aim was to determine whether the acute vascular benefits of isoflavones differ according to EP phenotype and subsequently investigate the effect of providing commercially produced S-(-)equol to non-EPs.

Design: We prospectively recruited male EPs and non-EPs (n = 14/group) at moderate cardiovascular risk into a double-blind, placebo-controlled crossover study to examine the acute effects of soy isoflavones (80-mg aglycone equivalents) on arterial stiffness [carotid-femoral pulse-wave velocity (cfPWV)], blood pressure, endothelial function (measured by using the EndoPAT 2000; Itamar Medical), and nitric oxide at baseline (0 h) and 6 and 24 h after intake. In a separate assessment, non-EPs consumed 40 mg S-(-)equol with identical vascular measurements performed 2 h after intake.

Results: After soy intake, cfPWV significantly improved in EPs at 24 h (cfPWV change from 0 h: isoflavone, -0.2 ± 0.2 m/s; placebo, 0.6 ± 0.2 m/s; P < 0.01), which was significantly associated with plasma equol concentrations (R = -0.36, P = 0.01). No vascular effects were observed in EPs at 6 h or in non-EPs at any time point. Similarly, no benefit of commercially produced S-(-)equol was observed in non-EPs despite mean plasma equol concentrations reaching 3.2 μmol/L.

Conclusions: Acute soy intake improved cfPWV in EPs, equating to an 11-12% reduced risk of cardiovascular disease if sustained. However, a single dose of commercially produced equol had no cardiovascular benefits in non-EPs. These data suggest that the EP phenotype is critical in unlocking the vascular benefits of equol in men, and long-term trials should focus on confirming the implications of EP phenotype on cardiovascular health. This trial was registered at clinicaltrials.gov as NCT01530893.

Keywords: CVD risk; arterial stiffness; equol producer phenotype; flavonoids; isoflavone; vascular function.

FIGURE 1

Enrollment, randomization, and trial design. *Ten-year absolute percentage of cardiovascular disease risk calculated at screening by using the British Hypertension Society risk calculator (22), incorporating plasma lipids, BMI, and SBP. CMC, carboxy-methyl cellulose; CV, cardiovascular; EP, equol producer; SBP, systolic blood pressure.

FIGURE 2

Acute effect of isoflavone consumption after 24 h on cfPWV in EPs and non-EPs. Values are means ± SEMs. Differences in study endpoints between interventions were analyzed by using ANOVA, with changes from baseline assessed by using a mixed general linear model including interaction between 1 within-subject factor (repeated-measures ANOVA for treatment) and 1 between-subject factor (EP phenotype). Bonferroni post hoc corrections were conducted where significant between-group differences were identified. Further analysis with the use of repeated-measures ANOVA for intervention effect (isoflavone compared with placebo in EPs for change from 0 to 24 h) was performed. ****P = 0.002 for cfPWV and P = 0.007 for S-equol. cfPWV, carotid-femoral pulse-wave velocity; EP, equol producer; N.D., not detectable.