Isoflavones, equol producing status, and atherosclerosis in Japanese men in Japan

Public Health/Epidemiology

Committee: 
Akira Sekikawa (chair, epidemiology)
Thomas Songer (epidemiology)
Emma Barinas-Mitchell (epidemiology)
Robert Boundreau (epidemiology)
Jared Magnani (medicine)

Abstract: Coronary heart disease (CHD) is the leading cause of morbidity and mortality worldwide. Soy is a potential nutritional source for preventing CHD and is a standard part of the traditional Asian diet. The main components of soy that may exert cardioprotective effects are soy isoflavones (ISFs). The predominant ISFs, daidzein and genistein, are structurally similar to estradiol and mimic some effects of estrogen. Estradiol exerts its biological action by binding both estrogen receptor α (ERα) expressed in reproductive, central nervous, cardiovascular and other systems and estrogen receptor β (ERβ) expressed in cardiovascular, central nervous and others systems. ISFs, however, preferentially bind to ERβ. ISFs may reduce the risk of CHD by reducing inflammation and oxidation; the latter may prevent the oxidative damage to low-density lipoprotein (LDL) that contributes to atherogenesis.

Although there are clear cardiovascular benefits of ISFs in preclinical studies, evidence in humans is conflicting. A recent meta-analysis of 23 prospective cohort studies showed that dietary intake of ISFs was significantly and inversely associated with all-cause and cancer mortality yet not cardiovascular disease (CVD) mortality. Furthermore, ISFs have very small or no effects on traditional CVD risk factors.

A growing hypothesis is that the ability of humans to metabolize daidzein to equol may contribute to the cardioprotective effects of ISFs. A case-control study of myocardial infarction (MI) nested within a prospective cohort study in women in China reported a significant inverse association of incident MI with urinary equol rather than ISFs and their other metabolites. Cell culture and preclinical studies show that equol has a greater affinity for ERβ than its precursor daidzein, a longer half-life, greater bioavailability than daidzein and genistein, and more potent antioxidant activity than any other ISFs. Therefore, equol may be more cardioprotective than ISFs.

The mechanistic model of action of equol on atherosclerosis is not completely understood. Investigation of the effects of equol has mostly been conducted in the in vitro assays and preclinical studies and lacks a sturdy conclusion. In addition, very few studies have explored the association between equol-producing status and atherosclerosis in humans. Therefore, I first conducted a systematic review summarizing the current knowledge about the mechanisms underlying the potential cardioprotective effect of equol on inflammation, oxidation, and endothelial function. I then conducted two cross-sectional analyses to delineate the link between equol producing status and aortic calcification in Japanese, a population being widely acknowledged to have a high prevalence of equol-producers.