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

Sara Hazim, Peter J Curtis, Manuel Y Schär, Luisa M Ostertag, Colin D Kay, Anne-Marie Minihane, Aedín Cassidy, Sara Hazim, Peter J Curtis, Manuel Y Schär, Luisa M Ostertag, Colin D Kay, Anne-Marie Minihane, Aedín Cassidy

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.

Figures

FIGURE 1
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
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.

References

    1. Setchell KD, Cole SJ. Method of defining equol-producer status and its frequency among vegetarians. J Nutr 2006;136(8):2188–93.
    1. Setchell KD, Clerici C. Equol: history, chemistry, and formation. J Nutr 2010;140(7, Suppl):1355S–62S.
    1. Liu ZM, Ho SC, Chen YM, Liu J, Woo J. Cardiovascular risks in relation to daidzein metabolizing phenotypes among Chinese postmenopausal women. PLoS One 2014;9:e87861.
    1. Tormala R, Appt S, Clarkson TB, Groop PH, Ronnback M, Ylikorkala O, Mikkola TS. Equol production capability is associated with favorable vascular function in postmenopausal women using tibolone; no effect with soy supplementation. Atherosclerosis 2008;198(1):174–8.
    1. Guo K, Zhang B, Chen C, Uchiyama S, Ueno T, Chen Y, Su Y. Daidzein-metabolising phenotypes in relation to serum lipids and uric acid in adults in Guangzhou, China. Br J Nutr 2010;104:118–24.
    1. Sakane N, Kotani K, Tsuzaki K, Takahashi K, Usui T, Uchiyama S, Fujiwara S. Equol producers can have low leptin levels among prediabetic and diabetic females. Ann Endocrinol (Paris) 2014;75:25–8.
    1. Curtis PJ, Potter J, Kroon PA, Wilson P, Dhatariya K, Sampson M, Cassidy A. Vascular function and atherosclerosis progression after 1 y of flavonoid intake in statin-treated postmenopausal women with type 2 diabetes: a double-blind randomized controlled trial. Am J Clin Nutr 2013;97:936–42.
    1. Setchell KD, Zhao X, Shoaf SE, Ragland K. The pharmacokinetics of S-(–)equol administered as SE5-OH tablets to healthy postmenopausal women. J Nutr 2009;139(11):2037–43.
    1. Setchell KD, Zhao X, Jha P, Heubi JE, Brown NM. The pharmacokinetic behavior of the soy isoflavone metabolite S-(-)equol and its diastereoisomer R-(+)equol in healthy adults determined by using stable-isotope-labeled tracers. Am J Clin Nutr 2009;90:1029–37.
    1. Choi EJ, Kim GH. The antioxidant activity of daidzein metabolites, odesmethylangolensin and equol, in HepG2 cells. Mol Med Rep 2014;9:328–32.
    1. Hwang J, Wang J, Morazzoni P, Hodis HN, Sevanian A. The phytoestrogen equol increases nitric oxide availability by inhibiting superoxide production: an antioxidant mechanism for cell-mediated LDL modification. Free Radic Biol Med 2003;34:1271–82.
    1. Jackman KA, Woodman OL, Chrissobolis S, Sobey CG. Vasorelaxant and antioxidant activity of the isoflavone metabolite equol in carotid and cerebral arteries. Brain Res 2007;1141:99–107.
    1. Muñoz Y, Garrido A, Valladares L. Equol is more active than soy isoflavone itself to compete for binding to thromboxane A(2) receptor in human platelets. Thromb Res 2009;123:740–4.
    1. Clerici C, Setchell KD, Battezzati PM, Pirro M, Giuliano V, Asciutti S, Castellani D, Nardi E, Sabatino G, Orlandi S, et al. . Pasta naturally enriched with isoflavone aglycons from soy germ reduces serum lipids and improves markers of cardiovascular risk. J Nutr 2007;137(10):2270–8.
    1. Kreijkamp-Kaspers S, Kok L, Bots ML, Grobbee DE, Lampe JW, van der Schouw YT. Randomized controlled trial of the effects of soy protein containing isoflavones on vascular function in postmenopausal women. Am J Clin Nutr 2005;81(1):189–95.
    1. Hippisley-Cox J, Coupland C, Robson J, Brindle P. Derivation, validation, and evaluation of a new QRISK model to estimate lifetime risk of cardiovascular disease: cohort study using QResearch database. BMJ 2010;341:c6624.
    1. Liu ZM, Ho SC, Chen YM, Tomlinson B, Ho S, To K, Woo J. Effect of whole soy and purified daidzein on ambulatory blood pressure and endothelial function-a 6-month double-blind, randomized controlled trial among Chinese postmenopausal women with prehypertension. Eur J Clin Nutr 2015;69(10):1161–8.
    1. Carranza-Lira S, Cirigo-Hernandez B, Sandoval-Barragan MP, Ramos-Leon JC. Comparison of brachial artery vascular responses among postmenopausal women receiving different doses of tibolone. Int J Gynaecol Obstet 2013;122:75–7.
    1. Carranza-Lira S, Cuan-Martinez JR, Rosales-Ortiz S. Brachial artery responses in menopausal women using tibolone. Int J Gynaecol Obstet 2008;101:43–6.
    1. Yee S, Burdock GA, Kurata Y, Enomoto Y, Narumi K, Hamada S, Itoh T, Shimomura Y, Ueno T. Acute and subchronic toxicity and genotoxicity of SE5-OH, an equol-rich product produced by Lactococcus garvieae. Food Chem Toxicol 2008;46(8):2713–20.
    1. Usui T, Tochiya M, Sasaki Y, Muranaka K, Yamakage H, Himeno A, Shimatsu A, Inaguma A, Ueno T, Uchiyama S, et al. . Effects of natural S-equol supplements on overweight or obesity and metabolic syndrome in the Japanese, based on sex and equol status. Clin Endocrinol (Oxf) 2013;78:365–72.
    1. British Cardiac Society BHS, Diabetes UK, HEART UK, Primary Care Cardiovascular Society, The Stroke Association. JBS 2: Joint British Societies' guidelines on prevention of cardiovascular disease in clinical practice. Heart 2005;91(Suppl 5):v1–52.
    1. Grace PB, Mistry NS, Carter MH, Leathem AJ, Teale P. High throughput quantification of phytoestrogens in human urine and serum using liquid chromatography/tandem mass spectrometry (LC-MS/MS). J Chromatogr B Analyt Technol Biomed Life Sci 2007;853:138–46.
    1. Bryan NS, Calvert JW, Gundewar S, Lefer DJ. Dietary nitrite restores NO homeostasis and is cardioprotective in endothelial nitric oxide synthase-deficient mice. Free Radic Biol Med 2008;45:468–74.
    1. Franke AA, Lai JF, Halm BM. Absorption, distribution, metabolism, and excretion of isoflavonoids after soy intake. Arch Biochem Biophys 2014;559:24–8.
    1. Hall WL, Formanuik NL, Harnpanich D, Cheung M, Talbot D, Chowienczyk PJ, Sanders TA. A meal enriched with soy isoflavones increases nitric oxide-mediated vasodilation in healthy postmenopausal women. J Nutr 2008;138(7):1288–92.
    1. Zubik L, Meydani M. Bioavailability of soybean isoflavones from aglycone and glucoside forms in American women. Am J Clin Nutr 2003;77:1459–65.
    1. Hickson SS, Butlin M, Broad J, Avolio AP, Wilkinson IB, McEniery CM. Validity and repeatability of the Vicorder apparatus: a comparison with the SphygmoCor device. Hypertens Res 2009;32:1079–85.
    1. Pucci G, Cheriyan J, Hubsch A, Hickson SS, Gajendragadkar PR, Watson T, O’Sullivan M, Woodcock-Smith J, Schillaci G, Wilkinson IB, et al. . Evaluation of the Vicorder, a novel cuff-based device for the noninvasive estimation of central blood pressure. J Hypertens 2013;31:77–85.
    1. Bonetti PO, Barsness GW, Keelan PC, Schnell TI, Pumper GM, Kuvin JT, Schnall RP, Holmes DR, Higano ST, Lerman A. Enhanced external counterpulsation improves endothelial function in patients with symptomatic coronary artery disease. J Am Coll Cardiol 2003;41:1761–8.
    1. Watanabe S, Otaki N, Uehara M, Suzuki K, Ueno T, Uchiyama S, Mizuno S. Pharmacokinetics of an equol supplement in humans. Antiaging Medicine 2007;4:57–62.
    1. Messina M. Insights gained from 20 years of soy research. J Nutr 2010;140(12, Suppl):2289S–95S.
    1. Jenks BH, Iwashita S, Nakagawa Y, Ragland K, Lee J, Carson WH, Ueno T, Uchiyama S. A pilot study on the effects of S-equol compared to soy isoflavones on menopausal hot flash frequency. J Womens Health (Larchmt) 2012;21:674–82.
    1. Joy S, Siow RC, Rowlands DJ, Becker M, Wyatt AW, Aaronson PI, Coen CW, Kallo I, Jacob R, Mann GE. The isoflavone equol mediates rapid vascular relaxation: Ca2+-independent activation of endothelial nitric-oxide synthase/Hsp90 involving ERK1/2 and Akt phosphorylation in human endothelial cells. J Biol Chem 2006;281(37):27335–45.
    1. Chin-Dusting JP, Boak L, Husband A, Nestel PJ. The isoflavone metabolite dehydroequol produces vasodilatation in human resistance arteries via a nitric oxide-dependent mechanism. Atherosclerosis 2004;176:45–8.
    1. Taylor JI, Grace PB, Bingham SA. Optimization of conditions for the enzymatic hydrolysis of phytoestrogen conjugates in urine and plasma. Anal Biochem 2005;341:220–9.
    1. Rubinshtein R, Kuvin JT, Soffler M, Lennon RJ, Lavi S, Nelson RE, Pumper GM, Lerman LO, Lerman A. Assessment of endothelial function by non-invasive peripheral arterial tonometry predicts late cardiovascular adverse events. Eur Heart J 2010;31(9):1142–8.
    1. Vlachopoulos C, Xaplanteris P, Aboyans V, Brodmann M, Cifkova R, Cosentino F, De Carlo M, Gallino A, Landmesser U, Laurent S, et al. . The role of vascular biomarkers for primary and secondary prevention. A position paper from the European Society of Cardiology Working Group on peripheral circulation: endorsed by the Association for Research into Arterial Structure and Physiology (ARTERY) Society. Atherosclerosis 2015;241:507–32.
    1. Mitchell GF, Hwang SJ, Vasan RS, Larson MG, Pencina MJ, Hamburg NM, Vita JA, Levy D, Benjamin EJ. Arterial stiffness and cardiovascular events: the Framingham Heart Study. Circulation 2010;121:505–11.
    1. Vlachopoulos C, Aznaouridis K, Stefanadis C. Prediction of cardiovascular events and all-cause mortality with arterial stiffness: a systematic review and meta-analysis. J Am Coll Cardiol 2010;55(13):1318–27.
    1. Rowlands DJ, Chapple S, Siow RC, Mann GE. Equol-stimulated mitochondrial reactive oxygen species activate endothelial nitric oxide synthase and redox signaling in endothelial cells: roles for F-actin and GPR30. Hypertension 2011;57(4):833–40.
    1. Fitch RM, Vergona R, Sullivan ME, Wang YX. Nitric oxide synthase inhibition increases aortic stiffness measured by pulse wave velocity in rats. Cardiovasc Res 2001;51:351–8.
    1. Townsend RR, Wilkinson IB, Schiffrin EL, Avolio AP, Chirinos JA, Cockcroft JR, Heffernan KS, Lakatta EG, McEniery CM, Mitchell GF, et al. . Recommendations for improving and standardizing vascular research on arterial stiffness: a scientific statement from the American Heart Association. Hypertension 2015;66:698–722.
    1. Kim JY, Lee MY, Park HM. The effect of eqoul, a metabolite of isoflavone, on endothelial cell-independent vasodilatation of human uterine artery in vitro. J Bone Metab 2015;22:57–69.
    1. Törmälä RM, Appt S, Clarkson TB, Tikkanen MJ, Ylikorkala O, Mikkola TS. Individual differences in equol production capability modulate blood pressure in tibolone-treated postmenopausal women: lack of effect of soy supplementation. Climacteric 2007;10:471–9.
    1. Bolca S, Possemiers S, Herregat A, Huybrechts I, Heyerick A, De Vriese S, Verbruggen M, Depypere H, De Keukeleire D, Bracke M, et al. . Microbial and dietary factors are associated with the equol producer phenotype in healthy postmenopausal women. J Nutr 2007;137:2242–6.

Source: PubMed

Szponzorok és közreműködők

Egészségi állapot

Kábítószer-beavatkozások

3
Iratkozz fel