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Whole Grain Foods and Heart Disease Risk

Metabolic Research Group, Nutritional Sciences, Division of Biostatistics, VA Medical Center and University of Kentucky, Lexington, Kentucky

Address reprint requests to: James W. Anderson, MD, Medical Service, 111C, 2250 Leestown Road, Lexington, Kentucky 40511

	ABSTRACT

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Coronary heart disease (CHD) is the leading cause of death in most developed nations and is rapidly increasing in prevalence in developing countries. Death rates from cardiovascular disease exceed 1 million annually in the United States and account for the largest disease-related cost to health with total costs estimated to exceed $120 billion per annum. Many dietary factors, including total and saturated fat consumption, fruit and vegetable intake and dietary fiber, have been shown to contribute to risk for CHD. We have systematically reviewed literature from the past 20 years evaluating an association between dietary fiber and CHD. Foods that are rich in dietary fiber, including fruits, vegetables, legumes and whole grain cereals, also tend to be a rich source of vitamins, minerals, phytochemicals, antioxidants and other micronutrients. Each of these factors may be independently contributing to the cardiovascular protective effects of fiber-rich foods.

Key words: whole grains, fiber, coronary heart disease

Key teaching points:

• Whole grain consumption has consistently been linked with protection from coronary heart disease (CHD).

• Meta-analysis of 12 studies providing appropriate risk ratios for CHD showed that regular intake of whole grain foods was associated with a 26% reduction in risk for CHD.

• Whole grain foods decrease serum LDL-cholesterol and triglycerides, thus contributing to their protective role against CHD.

• In addition to favorable effects on fasting and postprandial serum lipoproteins, whole grain foods affect a number of other CHD risk factors such as hypertension, diabetes and obesity.

• Foods rich in dietary fiber, including fruits, vegetables, legumes and whole grain cereals, tend to be a rich source of vitamins, minerals, phytochemicals, antioxidants and other micronutrients. These factors can independently contribute to the cardiovascular protective effects of fiber-rich foods.

• In 1999 the US Food and Drug Administration approved the health claim: "Diets rich in whole-grain foods and other plant foods and low in total fat, saturated fat and cholesterol may reduce the risk for heart disease and certain cancers."

	INTRODUCTION

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The protective effect of whole grain cereals for coronary heart disease has been suggested for almost 40 years. [1] Burkitt [2], Cleave [3], Trowell [4], and Walker [5] pioneered the concept that highly refined foods are major contributors to Western diseases including coronary artery disease. Over 25 years ago Trowell [4] formulated the fiber hypothesis related to CHD. He stated that "Data has been produced to support a hypothesis that high consumption of natural starchy carbohydrates, taken with their full complement of fiber, is protective against hyperlipidemia and IHD (ischemic heart disease)" [4]. The first scientific study to support the Trowell hypothesis was the report of Morris et al. [6] that higher cereal fiber intake was associated with lower rates of heart attacks among British working men. Since this report, a large number of epidemiologic studies [7–16] have supported the hypothesis that those individuals with higher intake of whole grains have a lower risk of CHD than individuals with a low intake of whole grains. The studies led to the approval by the US Food and Drug Administration of the health claim: "Diets rich in whole-grain foods and other plant foods and low in total fat, saturated fat and cholesterol may reduce the risk for heart disease and certain cancers." (FDA Docket #99P-2209).

Whole grain foods, in addition to being rich in fiber, usually provide complex carbohydrates, minerals, vitamins and phytochemicals. Some whole grain foods also deliver n-3 fatty acids, oligosaccharides and resistant starch. When considering epidemiologic associations, it is important to consider the effects of specific foods (some soy foods, for example, are rich in fiber but also deliver soy protein and isoflavones) [17] and specific components of foods (fruits, for example, are rich in potassium, which could have major effects on blood pressure) [18]. Clinical studies with whole grain foods are difficult to perform because it is almost impossible to provide control foods that are similar in characteristics to ensure blinding of investigators and volunteers. Studies using fiber supplements can be blinded, but may not mimic "real-world" situations using whole foods because the fiber supplements may not contain the mineral, phytochemical and other components of whole foods. Thus epidemiologic studies lack specificity, and clinical trial studies are handicapped by the inability to provide blinded control products.

This review will examine the strength of the evidence that links intake of whole grains to protection from CHD. We will review the epidemiologic data and the clinical trials related to this issue. We performed a meta-analysis of the population-based cohort studies to ascertain the strength and consistency of these studies. We compared the effects of intake of whole grains with the effects of intake of total dietary fiber, vegetables and fruits. Finally, we discuss mechanisms by which whole grain foods and their components may exert their protective effects.

	MATERIALS AND METHODS

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Identification of Studies
To evaluate the literature related to whole grain intake and CHD risk the following criteria were implemented. First, the study provided some dietary measure related to whole grain intake or dietary fiber intake. Second, the study provided some outcome data related to CHD events. Third, the study provided some estimate of the variance that allowed us to make variance-adjusted calculations.

Searching MEDLINE for the period 1966 to 1999 identified candidate studies. MEDLINE returned 3188 articles with the key terms fiber and CHD, CVD and/or IHD. Additional studies published during this period and prior to 1966 were identified using the "ancestry approach" [19] by consulting reference lists from single studies or literature reviews.

Studies were identified as assessing whole grain, total fiber, cereal, fruit or vegetable intake. Whole grains are defined as being a rich source of dietary fiber, resistant starch, vitamins, minerals, phytoestrogens, antioxidants and other important nutrients. Whole grains are composed of the endosperm (approximately 80%), the germ and the bran of the grain. The authors use the term cereal to describe those studies evaluating either breakfast cereal or cereal fiber intake. Breakfast cereal is defined as hot or ready-to-eat cereal. The major cereal grains include wheat, rice and grain. Minor cereal grains include oats, rye, barley, triticale, sorghum and millet. Total fiber includeswhole grains, cereal grains and a variety of other fiber sources.

Twenty-nine separate published reports [6,8–11,13–16,20–39] met the initial criteria. Six reports [14,34,36,38–40] were excluded because they did not provide sufficient data to calculate effect estimates. Three studies [8,9,11] specifically reported whole grain intake allowing comparisons for this criterion. A fourth study reporting whole wheat bread intake [15] was aggregated with those reporting whole grains as whole wheat bread is a surrogate marker for whole grain consumption. Additional studies provided information on total dietary fiber [10,13,14,20,23–26,29,31–33,35–37], cereal fiber intake [6,10,13,14,16,23,30], vegetable intake [10,13,16,22,23,25,28,33,34,38] and fruit intake [10,13–16,23,25,28]. These data were analyzed and appear in summary tables to compare the consistency of results across different fiber sources. However, only twelve of the reports met the criterion, and had sufficient data, for inclusion in the meta-analysis statistical computations.

We assessed CHD events and CHD deaths as primary outcome measures. Stroke events were also included where these data were provided. Most studies made initial adjustments for demographic data such as age; these adjustments are termed "primary adjustments." These primary adjustments were generally followed with adjustments for additional CHD risk factors such as body mass index (BMI), total energy intake, smoking and blood pressure; these adjustments are termed "secondary adjustments."

Meta-analysis
Population-based cohort studies provided the data for analysis of CHD risk relative to dietary fiber and whole grain intake. Twelve studies [8–11,13,15,23,25,28,30,32,33] provided sufficient data and were appropriate for inclusion in the meta-analysis computations. Meta-analysis of population-based cohort studies is appropriate, but careful attention must be paid to pooling of data [42–44].

In our study, estimates of average effect of whole grain intake on CHD event rates and 95% confidence intervals were calculated using fixed-effects model assumptions [45]. Fixed-effects models assume that each study estimates the same true population value for the effect of interest and, thus, that differences between observed results of studies can be fully accounted for by sampling variation. Appropriateness of this assumption can be formally evaluated by tests of homogeneity of results between studies [43].

All analyses were performed on SAS-PC Version 6.12 (SAS Institute, Inc., Cary, NC), using formulae and adapting template code provided by Wang and Bushman [46]. For each study, summary results of all outcome variables were tabulated and the variance calculated or verified.

	RESULTS

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Attributes of Studies
The summary characteristics of the twenty-nine studies meeting initial criteria for inclusion on their basis of ascertaining whole grain or dietary fiber intake and outcome data related to CHD events or mortality are presented in Table 1. In some cases data from the same parent sample were used in two or more reports. For example, Jacobs et al. [9,11] evaluated the same participant population, the Iowa Women’s Health Study, in both their 1998 and 1999 whole grains publications. The majority of the CHD events or CHD mortality studies were conducted in the United States (14 reports) followed by Europe (10 reports), China (2 reports), South Africa (1 report), Puerto Rico (1 report) and one international collaboration. The majority of the studies were prospective population-based cohorts, with a few case-control trials included as well. The number of subjects included in each study was highly variable, ranging from 119 to 75,521. The vast majority of the studies included in this evaluation were of middle-age subjects. Of these studies, 13 included solely males while five included exclusively females and 11 were mixed gender. Diet was assessed using a variety of techniques. These include food frequency questionnaires (13 reports), three-day dietary records (1 report), dietary history questionnaires (4 reports), 24-hour dietary recalls (7 reports), 7-day dietary records (3 reports) and food balance sheets (1 report). The foods assessed in these 29 studies included whole grains, cereal fiber, whole wheat bread, total fiber, fruits and vegetables. Most of the studies included data on several of these parameters. Outcome data included in this analysis was slightly variable, but the majority of the trials included information on either CHD risk or CHD mortality. CHD, coronary artery disease (CAD) and ischemic heart disease (IHD) have been aggregated under the category CHD. We chose CHD because it refers to atherosclerotic disease of the coronary arteries.

Six of the seven studies evaluating whole grains and similar CHD endpoints found a negative association between whole grain intake and CHD risk or CHD mortality (Table 2). This trend was statistically significant in five of the seven studies. Of note, Gramenzi et al. [28] did report a slightly positive correlation between wholemeal bread intake and risk of myocardial infarction. However, as discussed by Jacobs [11], this result was later negated by additional follow-up. Therefore, it is not included in the meta-analysis computation.

Variance Weighted Primary and Secondary Risk Factor Adjusted Relative Risks
Twelve reports were included in the meta-analysis computations. Adjustment for similar confounding factors was fairly consistent for the trials included in the meta-analysis, in particular those population-based observational studies published in the last three years [8–10,13,20,23] (Table 3). Age was the most frequent primary adjusted factor (7 reports). Total energy intake (2 reports), other dietary factors (1 report) and smoking (1 report) were also considered as primary adjustments. Dietary factors include protein intake and various micronutrients such as Vitamin B₆. Gender (3 reports), smoking (9 reports), body mass index (9 reports), alcohol intake (7 reports), family history of heart disease (3 reports), blood pressure or hypertension (11 reports), cholesterol or personal history of heart disease (7 reports), physical activity (7 reports), hormone replacement therapy or menopausal status (4 studies), dietary factors (5 reports), supplement use (4 studies), education level (5 studies) and use of aspirin (2 reports) were considered as secondary adjustment factors.

Beneficial associations between fiber intake and CHD have been found in both men and women. However, available information is insufficient to compare the magnitude of these associations between men and women.

	DISCUSSION

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Whole grain consumption is consistently linked with protection from CHD [8,9,11,15]. Our tabulated summary of 29 published reports provided a qualitative overview of the effects of different foods and fiber sources on risk for CHD. Consumption of whole grains and total dietary fiber had the strongest and most consistent association with protection from CHD. The effect of fruit or vegetable fiber intake was intermediate while cereal fiber intake had a lower frequency of significant negative correlations with CHD.

Our meta-analysis of 12 studies providing appropriate risk ratios for CHD showed that the regular intake of whole grain foods was associated with a risk ratio for CHD of 0.74 indicating a significant reduction of risk of 26%. Total dietary fiber intake was accompanied by a similar reduction in risk. Cereal fiber, which includes whole grain as well as refined grain products, had the least impressive association with reduced risk for CHD—with a reduction of 10%. Refined grains provide only the cell wall structures surrounding the starch granules, while bran contains the seed coat containing fatty acids and phytochemicals in addition to the fiber [47]. Lignans, potent phytoestrogens, are concentrated in wheat bran [48]. The presence of antioxidants, phytoestrogens and other phytochemicals, and polyunsaturated fatty acids in whole grain products may contribute importantly to their protective effect. Jacobs and colleagues [9] document that high levels of whole grain intake have much greater protective effects than high levels of refined grain product use.

The highest level of total fiber intake was also associated with reductions in CHD risk that were 27%. These reductions were not as consistently reported across studies, suggesting that vegetable or fruit intake, at levels achieved in these populations, has a modest protective effect. Fruits and vegetables are botanically much more diverse than grains, and each variety is eaten in much smaller quantities than is grain. Since many fruits and vegetables are important sources of soluble or viscous fiber, reductions in serum LDL-cholesterol levels could contribute to this protective effect [7].

Assuming that whole grain foods have a significant protective effect with respect to CHD, what are the mechanisms? We recently reviewed this question [49]. Dietary fiber remains the leading candidate to explain the significant reduction in CHD risk associated with whole grain consumption. As recently catalogued [49], dietary fiber and associated substances have favorable effects on a number of CHD risk factors. We will review the issues that seem most relevant to whole grain intake.

Dyslipidemia, or alterations in serum lipoprotein concentrations, has received major attention in relationship to CHD risk [50]. Whole grain products provide from 20% to 50% of their fiber in the soluble or viscous forms [51]. Bakery products [52], oat products [53] and soluble fiber-rich foods lower serum cholesterol, LDL-cholesterol and apolipoprotein B concentrations [54]. The wheat bran component of whole grain products has important serum triglyceride-lowering effects [49]. These effects may be mediated by the anti-estrogen characteristics of the phytoestrogens [55]. Little is known about the effects of whole grain intake on LDL-particle size or the type of HDL particles in the circulation. Theoretically, whole grain intake could decrease concentrations of the more atherogenic small, dense LDL particles and increase concentrations of the less atherogenic larger, less dense LDL particles. Theoretically, also, high fiber diets could increase concentrations of the protective apolipoprotein A-1 ("A-1 only") HDL particles and decrease concentrations of the non-protective, apolipoprotein A-1/A-2 HDL particles [56]. Our meta-analysis of psyllium studies [57] suggests that psyllium supplements increase apolipoprotein A-1 concentrations but this question requires further study. Thus, much additional research is required to understand the protective effects of whole grain intake on the functions of lipoprotein particles.

Whole grain intake also appears to reduce insulin resistance, a major problem in Western countries [58]. Cereal fiber intake significantly reduces risk for developing diabetes [59,60]. More than 20 years ago Brodribb and Humphries [61] reported the puzzling observation that long-term wheat bran administration improves glucose tolerance better than pectin administration. Others confirmed the beneficial effects of wheat bran consumption on glucose tolerance in contrast to the effects of soluble fibers [62]. These observations suggested that wheat bran might have properties to decrease insulin resistance. Our subsequent research using high fiber, high carbohydrate diets rich in wheat bran have documented the favorable effects of whole grain intake for healthy younger and older non-diabetic individuals [63] and for persons with Type 1 diabetes [64]. Phytochemicals, phytoestrogens, or fatty acids present in whole grain cereals and bran may provide these insulin-sensitizing effects.

The potential effects of whole grains and other fiber-rich foods on hypertension and obesity are reviewed elsewhere [49,58]. Whole grain products are rich in vitamins and are often fortified in such a way to reduce serum homocysteine levels, a recently identified risk factor for CHD [65]. Interestingly, many refined foods are also folate-fortified and improve serum homocysteine levels as well. Our animal research [66] suggests that small increases in levels of antioxidants such as soy isoflavones can significantly reduce oxidation of LDL, a central event in the atherosclerotic process. Furthermore, population-based cohort studies [67,68] suggest that small increases in vitamin E intake are associated with significant reductions in risk for CHD. Thus, the vitamins and antioxidants provided by whole grain foods may contribute to their cardioprotective effects. High fiber diets and presumably the generous intake of whole grains foods appear to reduce the thrombogenic potential of blood thus reducing CHD risk [58].

Abnormal vascular reactivity is emerging as an important contributor to heart attacks and strokes. Hormone replacement therapy significantly decreases risk for CHD in postmenopausal women [69]. Estrogen therapy acts at the blood vessel level to increase vasodilatation and decrease the vessel response to injury and the resultant development of atherosclerosis [69]. Recent studies in monkeys indicate that soy isoflavones, like estrogens, reduce abnormal vasoconstriction in atherosclerotic arteries [70,71]. Thus, whole grain foods may offer major protection from heart and brain attacks by providing vasoprotective phytoestrogens.

Thus, the "Trowell hypothesis" related to CHD has been strengthened in recent years [4]. Dr. Hugh Trowell was disappointed that his "whole grain" hypothesis was supplanted by "dietary fiber" hypotheses linking protection to intake of dietary fiber (personal communication, 1976). He championed the intake of whole grains as a major protective mechanism for a whole host of diseases. Dr. Denis Burkitt also focused on wheat bran as a major protective food and encouraged intake of whole meal bread and bran cereals (personal communication, 1980). These visionaries were not entrapped by the "simple-minded" focus on dietary fiber and insisted that whole foods should receive the emphasis. Recent emergence of the "whole grain story" validates their foresight.

Whole grain foods commonly consumed in the US include these: dark bread, whole-grain or bran breakfast cereals, bran, popcorn, oatmeal, wheat germ and brown rice [8]. The highest level of whole grain intake, median value for the highest quintile, was 2.7 [8] or 3.0 [9] servings per day including 1.7 servings of dark bread daily. Thus, these protective effects could be achieved with intake of one serving of bran cereal or oatmeal and two slices of dark bread daily. Brown rice or popcorn, preferably without oil, could be substituted for the dark bread for variety.

In conclusion, this meta-analysis of 12 population-based cohort studies indicated that those individuals with the highest intake of whole grains had an adjusted risk for CHD of 0.74 (95% CI, 0.67 to 0.80) compared to individuals with the lowest intake of whole grains. Whole grain intake had a stronger association with protection from CHD than intake of cereal fiber, vegetables or fruits. These studies suggest that the intake of three servings of whole grains per day may have an important cardioprotective effect.

Received February 1, 2000.

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