SOY AND HEART HEALTH
Coronary artery disease and stroke account for over 20% of deaths worldwide  but there are striking variations in age-adjusted cardiovascular disease (CVD) mortality rates among countries. These international variations are not due to genetic differences among populations. This is evident from trends in rates within countries and changes in rates among migrants moving from low-risk to high-risk countries.
The United States has one of the highest rates of CVD in the world  . In the most recent year for which data are available, an estimated 15.4 million Americans were affected by coronary heart disease (CHD) alone, which includes myocardial infarction and angina pectoris.
- One in six deaths in the United States is from CHD which makes it the number one killer of Americans  .
- 620,000 Americans have a new coronary attack (defined as first hospitalized myocardial infarction or coronary heart disease death) each year.
- 295,000 have a recurrent coronary attack.
- 150,000 people experience silent first myocardial infarctions each year.
The number of coronary deaths divides approximately evenly between men and women, although the average age of a first heart attack is 64.5 for men and 70.3 for women.
In 2013, the American Heart Association (AHA) issued new guidelines for the assessment of CVD risk . According to the AHA, in addition to age and gender, risk is primarily determined by total cholesterol level, HDL-cholesterol, systolic blood pressure, and whether one smokes and has diabetes.
Evidence indicates that adjusted population attributable fractions for CHD mortality are as follows:
- 34.7% for high blood pressure
- 16.7% for smoking
- 20.6% for poor diet
- 7.8% for insufficient physical activity
- 7.5% for abnormal glucose levels
From the information above, it is clear that dietary choices can significantly impact the risk of developing CHD. While markedly reducing CHD risk via dietary modification requires a comprehensive approach, there is no doubt that soyfoods can play an important role in heart-healthy diets.
Effects of Soyfoods on Circulating Lipid Levels
Soyfoods have been recognized by nutritionists for decades as rich sources of high-quality protein. But over the past 20 years, the effect of soy protein on blood cholesterol levels has attracted attention from the nutrition and medical communities. The first rodent studies [6, 7] showing that soy protein lowered cholesterol levels were published more than 60 years ago, and the first clinical trial demonstrating this effect was published in 1967 . Throughout the 1970s and 1980s, Italian researchers were instrumental in showing that soy protein directly lowered blood cholesterol levels in very hypercholesterolemic patients [9-11] . Nevertheless, it was not until 1995 that the cholesterol-lowering effects of soy protein received widespread recognition.
In that year, a meta-analysis of the clinical data, which included 38 different comparisons, found that soy protein reduced low-density-lipoprotein cholesterol (LDLC) by approximately 13 percent . This reduction was independent of the fatty acid content of soyfoods and was larger than that reported for any other single non-pharmacological treatment. Because statins were not yet widely used in clinical practice, the effect of soy protein was essentially equal to that of the available cholesterol-lowering medications.
The results of the 1995 meta-analysis prompted much investigation into the cholesterol-lowering effects of soy protein. Some of this research has been directed at identifying the specific soybean components and mechanisms responsible for cholesterol reduction, whereas other research explored the responses to soy protein in different subpopulations such as hypercholesterolemic individuals and pre- and postmenopausal women. In regard to mechanism, some data suggest that cholesterol reduction is a result of the upregulation of hepatic LDL receptors by the peptides formed upon digestion of soy protein [13, 14] . Researchers also continue to explore whether isoflavones in soybeans impact the cholesterol-lowering effects of soy protein . Soybeans are essentially the only nutritionally-relevant source of these diphenolic compounds .
In 1999, the U.S. Food and Drug Administration (FDA) approved a health claim for soy protein and CHD based on its cholesterol-lowering effects . Similar claims have been approved in a number of other countries since then including the Canadian Cardiovascular Society’s 2013 recommendation to consume soy as a means of lowering cholesterol levels  . However, despite the large amount of research upon which the FDA-health claim was based, the cholesterol-lowering ability of soy protein has come under challenge in recent years. The FDA announced in December 2007 their intention to re-evaluate the evidence in support of the claim, although they have stated publically that the reason for doing so is not because the evidence is no longer supportive, but rather, because of the large number of relevant clinical trials published since the claim was first approved.
In 2008, the American Heart Association (AHA) formally expressed their opposition to the health claim. In their 2006 position paper, the AHA acknowledged the important role soyfoods can have in heart-healthful diets because they are low in saturated and high in polyunsaturated fat . However, the decrease in LDLC in response to soy protein, which they estimated as approximately 3%, based on the results of 22 studies, was insufficient in their view to warrant a health claim . The AHA endorsed the health claim in 2000 shortly after it was first issued .
Importantly, however, the AHA did not conduct a formal statistical meta-analysis of the 22 studies upon which they based their estimate of the potency of soy protein. When such an analysis was conducted, Jenkins et al.  found that the AHA had considerably underestimated the hypocholesterolemic effects of soy protein since the analysis showed that soy protein lowered LDL by 4.3 percent. Further, when the analysis was limited to the 11 studies that provided evidence that the control and soy diets were matched, soy protein was found to lower LDL by 5.2 percent. This estimate is in line with the results of other recently published meta-analyses [22-24] and is similar to the effects of soluble fiber, which also has a health claim . Research also suggests that soy protein decreases postprandial triglyceride levels, which is increasingly viewed as important for reducing CHD risk .
In addition to the direct effect of soy protein, Jenkins et al. , using National Health and Nutrition Examination Survey III population data, estimated that as a result of differences in fatty acid intake, when soyfoods replace more traditional sources of protein in the Western diet, LDLC is reduced by 3 to 6 percent. There was a 4% reduction in LDL when 24 g soy protein – an amount similar to the 25 g/day established by FDA as the threshold intake for cholesterol reduction – replaced a comparable amount of the more commonly consumed protein sources. Thus, as a result of the displacement of traditional sources of protein in Western diets (which tend to be high in saturated fat) by soyfoods, in combination with the direct effects of soy protein, soyfoods can be expected to decrease LDLC by approximately 8 percent. Although the current estimates of the cholesterol-lowering effects of soy protein are lower than initially reported, the effect of soy protein is still clinically relevant. Since each 1% decrease in LDLC lowers CHD risk by 1 to 3 percent, incorporating soyfoods into the diet can substantially reduce CHD morbidity and mortality [27, 28] .
It is important to note that 25 g/day soy protein was established as the threshold intake for cholesterol reduction because most trials used at least this much protein, not because less than this amount is ineffective. In fact, there is evidence suggesting that lower amounts are indeed efficacious [23, 29] . Not surprisingly, comprehensive dietary approaches that have resulted in reductions in LDLC ranging from 20 to 30 percent have relied heavily on soyfoods; the high quality of soy protein and its hypocholesterolemic effects combined with the favorable fatty acid profile of soyfoods make these foods especially attractive in such diets  .
Recent guidelines from the AHA call for consuming a diet that is no more than 5 to 6% saturated fat . Recommendations to reduce saturated fat intake are not new. However, views on the relationship between dietary fatty acid intake and risk of CHD have changed considerably in recent years. For decades, it was thought that simply reducing saturated fat intake would lower CHD risk. This no longer appears to be the case. Comprehensive analyses indicate that, replacing saturated fat with carbohydrate, at least the high-glycemic index kind so prominent in Western diets, is not protective. It is not even clear that replacing saturated fat with monounsaturated fat is beneficial. To lower CHD risk, saturated fat should be replaced with polyunsaturated fatty acids (PUFA) [32, 33] . In fact, a recent analysis of the observational and clinical data concluded that the “current evidence does not clearly support cardiovascular guidelines that encourage high consumption of polyunsaturated fatty acids and low consumption of total saturated fats” although when restricting the analysis to the trial data, substitution of oils with a mix of omega-6 and omega-3 PUFA for saturated fat did lower risk .
Approximately 84% of the lipids in soybeans are unsaturated. The predominant fatty acid in conventional soybeans is the essential omega-6 PUFA linoleic acid, which comprises about 55% of the total fat in soybeans and which reduces blood cholesterol levels when replacing saturated fat . Nevertheless, some concerns have arisen that too much of this fatty acid could increase CHD risk by increasing inflammation and possibly oxidation. However, the AHA has rejected concerns about the pro-inflammatory and oxidative properties of linoleic acid and concluded that omega-6 PUFA play a critically important role in heart-healthy diets . This position is supported by a comprehensive review by Johnson and Fritsche , published in 2012, which concluded that “virtually no evidence is available from randomized, controlled intervention studies among healthy, non-infant human beings to show that addition of LA [linoleic acid] to the diet increases the concentration of inflammatory markers.” One reason for this lack of effect may be because linoleic acid is converted to arachidonic acid (AA), from which a number of pro-inflammatory eicosanoids are produced, tissue levels of AA don’t substantially increase because they are tightly regulated .
Those who oppose the AHA’s position on omega-6 PUFA cite trials showing that interventions with oils containing only omega-6 PUFA don’t reduce the risk of CHD whereas trials intervening with oils comprised of a mix of linoleic acid and omega-3 PUFAs do reduce risk . Regardless of which position (omega-6 vs a mix of omega-6 and omega-3) is shown by future research to be correct, soy oil and full-fat soyfoods will be considered heart-healthful. This is because the soybean is one of few foods that provide both omega-6 and omega-3 fatty acids. Approximately 6% of the fat in soybeans is comprised of the essential omega-3 fatty acid alpha-linolenic acid (ALA)  . Although ALA does not possess the same properties as the long-chain omega-3 fatty acids found in cold-water fish, evidence suggests that ALA has direct coronary benefits; the degree is a matter of some debate [41-43] .
Finally, in response to the ingestion of soy protein, meta-analyses have found very modest increases (1 to 3%) in high-density-lipoprotein (HDLC) cholesterol and modest decreases (5 to 10%) in triglyceride levels. Each 1% or 1 mg increase in HDLC lowers CHD risk by 2 to 3 percent [44-46] . Although there is debate about whether an elevated triglyceride level is an independent predictor of CHD risk , recent evidence suggests that the role of fasting triglyceride levels in the etiology of CHD has been underestimated [48, 49] . Furthermore, new research suggests that soy protein decreases postprandial triglyceride levels, elevated levels of which are increasingly viewed as an important CHD risk .
Beyond Effects on Lipid Levels
There is epidemiologic evidence that soyfoods exert coronary benefits independent of their effect on blood cholesterol levels. For example,
- In Shanghai, a prospective study involving nearly 65,000 postmenopausal women found soy protein intake was associated with an 86% reduction in the risk of non-fatal myocardial infarction . This analysis controlled for a wide variety of CHD risk factors.
- A cross-sectional study involving 406 Chinese adults, ages 40 to 65 years old (134 males, 272 females) without confirmed relevant diseases, found that soyfood intake was inversely related to bifurcation intima-media thickness, although the association was more apparent in men than women .
- In Japan, a prospective study involving 40,462 participants, ages 40 to 59 years old without cardiovascular disease or cancer at baseline, found that when comparing women with frequent (≥5x/week) versus infrequent (≤2x/week) soy consumption, the multivariable hazard ratios were 0.64, 0.55 and 0.31 for risk of the incidence of cerebral infarction, myocardial infarction and CHD mortality, respectively .
In contrast to these three studies, a large prospective study from Shanghai found that over the 5.4 year follow-up period, soy intake was associated with an increased risk of CHD among men  . Although this finding is inconsistent with a considerable amount of data and contrasts with the effects in women, this result warrants additional investigation.
For two reasons, it is highly unlikely that the cholesterol-lowering effects of soyfoods were primarily responsible for the protective effects observed in three of the four epidemiologic studies cited above. First, soy protein consumption in the upper intake categories was between 8 and 16 g/day, which, based on the results from the clinical studies, is likely too little to lower cholesterol. Second, the protective effects were far greater than could be expected from the cholesterol reduction typically associated with soy protein. Perhaps the explanation is a “healthy user effect,” i.e., that soyfood consumption is associated with an overall healthier lifestyle. This explanation is unlikely, however, because most of the studies controlled for a wide range of potentially confounding variables. Also, soy consumption in Asia is much less reflective of an overall lifestyle than it is in countries where soyfoods have not been part of the traditional diet.
In support of the epidemiologic studies are various clinical studies that show soyfoods, soy protein or soybean isoflavones favorably affect a number of biological measures that impact heart disease risk. For example, four recently published meta-analyses concluded that soy modestly lowers blood pressure [54-57] . In the largest of these, which included 27 studies, soy lowered systolic and diastolic blood pressure by 2.21 and 1.44 mgHg, respectively . In various studies soy has also been shown to improve endothelial function and systematic arterial compliance and to reduce LDL oxidation and LDL particle size . However, because of the inconsistent and/or limited data, no conclusions can be made about the effects of soy on these CHD markers except for endothelial function.
Endothelial cells line the blood vessels and their functioning can impact CHD risk. A recent meta-analysis found that soybean isoflavones favorably improved endothelial function in postmenopausal women  . When the data from this meta-analysis were sub-analyzed, the improvement was only found in those women who had impaired endothelial function at baseline. Of course, these women are at greater risk of having or developing CHD. This finding provides an explanation for the inconsistent literature in that some studies included women with both impaired endothelial function and others with normal endothelial function. It may also be that some of the observed anti-inflammatory effects of isoflavones occur only in people at risk of CHD who have elevated levels of inflammatory markers .
One of the more important clinical trials to evaluate the impact of soy intake on CHD risk is the Women’s Isoflavone Soy Health (WISH) study, a 3-year study involving 350 healthy postmenopausal women ages 45 to 92, which found that isoflavone-rich soy protein inhibited the progression of subclinical atherosclerosis . Subclinical atherosclerosis can be assessed using ultrasound to measure the thickness of the carotid arteries—which are located on both sides of the neck beneath the jawline and provide the main blood supply to the brain. The thickness of the carotid artery is referred to as carotid intima-media thickness or CIMT. Typically, CIMT increases or progresses over time; the extent of progression reflects risk of future coronary events. Participants in the WISH study were randomly assigned to groups consuming either 25 g of isolated soy protein per day or 25 g of milk protein. The soy protein provided 99 mg of isoflavones (expressed in aglycone equivalent weight).
At study termination, progression among the women consuming soy was 16% lower than in the milk group. The difference was not statistically significant, however. Nevertheless, the results are intriguing. If a 16% decrease in the progression of CIMT translates into a 16% decrease in the risk of future coronary events, the public health implications would be rather dramatic. Furthermore, the difference between groups increased steadily over the 3-year study period. This suggests that after a longer period of soy exposure, progression would have been reduced to an even greater extent, and with it, risk of coronary events.
Additionally, subanalysis of the results revealed that among women who were fewer than 5 years, 5 to 10 years, and more than 10 years post-menopause, CIMT progression was reduced by 68 (p=0.05), 17 (p=0.51) and 9% (p=0.77), respectively. That progression was reduced so significantly in early postmenopausal women is notable for two reasons. First, it adds substantially to the biologically plausibility of the findings and second, it provides clear insight into the soy component responsible for the beneficial effects. The pronounced effect in early menopausal women suggests isoflavones were primarily responsible for the reduced CIMT progression because over the past 10 years a hypothesis has emerged, referred to as the “estrogen timing hypothesis,” which maintains that exposure to estrogen-like compounds leads to dramatic coronary and cognitive benefits when begun soon after menopause, but has less effect in later years 
Finally, it is worth noting there is some, although inconsistent clinical evidence, indicating that isoflavone exposure reduces levels of C-reactive protein (CRP) . CRP is a general indicator of inflammation; the measurement of this marker was recently designated by the AHA as an optional screening test when risk-based decisions regarding initiation of pharmacological therapy are uncertain following quantitative risk assessment .
Summary and Conclusions
In summary, soyfoods may make important contributions to heart-healthy diets through several different mechanisms. They provide high-quality protein but minimal amounts of saturated fat. They provide ample amounts of omega-6 and omega-3 essential fatty acids. Importantly, soy protein directly lowers blood LDLC levels, modestly elevates HDLC and decreases triglyceride levels. Finally, soyfoods appear to favorably affect CHD risk factors independent of lipid levels including endothelial function, systematic arterial compliance, LDL oxidation, LDL particle size and blood pressure.
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