Alfieri et al. (1995) assessed the total fiber intake by means of 3-day food records in 3 population groups (one normal, one moderately and one severely obese group). These authors showed that fiber intake was significantly higher in the normal weight group and was inversely associated with BMI after adjusting for several potential confounders. Recently, new research conducted as part of the PREDIMED study has also shown a significant inverse relationship between TDF consumption and body mass index or

In an observational study looking at the effect of overall diet on body composition in obese and lean subjects it was demonstrated that lean men and women had significantly higher fiber intake versus obese males and females (27.0 g/d and 22.7 g/d vs. 22.0 g/d and 15.0 g/d respectively) (Miller et al., 1994). These results were supported in another study with a cohort of over 5000 subjects, which showed that higher fiber intake is associated with a lower body mass index (BMI) in both men and women (Appleby et al.,

In a prospective cohort with 252 premenopausal, non-smoker women free from serious disease, Tucker & Thomas (2009) conducted a study to determine whether changes in fiber intake (total, soluble, and insoluble) influence the risk of gaining weight and body fat over time (20 months). Increasing DF significantly reduces the risk of women gaining weight and fat. For each 1 g increase in total fiber consumed, weight decreased by 0.25 kg (*P* = 0.0061) and fat decreased by 0.25 percentage point (*P* = 0.0052). Controlling for potential confounders did not affect the relationships, except for changes in energy intake, which weakened the associations by 24-32%. Soluble and insoluble fibers were borderline

Banerjee et al., 2004).

weight gain than women in the lowest quintile.

abdominal circumference (Estruch et al., 2009).

predictors of changes in weight and fat.

1998).

subscapular skinfold thickness and body mass index.

DF has a potentially important effect on lipids and lipoproteins when consumed in plant foods or as supplements. Viscous subgroups of DF, including pectins, b-glucans, glucomannans, guar and psyllium, which are generally water soluble, all lower total and LDL cholesterol between 5 and 10 g/day, lowering LDL by about 5% (Truswell, 2002)**.**

A cross-sectional epidemiological data, based on the EURODIAB Complications Study, which included over 2000 patients in 31 European centers, showed an inverse association between DF intake and HbA1c and LDL cholesterol (in men only) and a positive association with HDL cholesterol in men and women (Toeller et al., 1999)**.**

In an analysis of dietary factors and cardiovascular risk performed in a sample of 3,452 Swiss adults, it was observed that a healthy diet characterized by high consumption of DF was associated with lower rates of serum triglycerides and higher HDL-c (Berg et al., 2008). A 10-year study of a cohort of 2,909 healthy adults aged between 18 and 30 showed a strong negative association between fiber intake and blood pressure and levels of triglyceride, HDL cholesterol, LDL cholesterol, and fibrinogen even after adjusting for confounding factors (Ludwig et al., 1999)**.** In a cohort of 316 Japanese-Brazilian subjects, a decrease of 12.5 mg/dl was observed in the serum total cholesterol levels (*P* < 0.05) for each increase of 10 g in the consumption of DF intake in a 7- year follow up (de Castro et al., 2006)**.** Wu et al. ( 2003) studied a cohort of 573 adults aged between 40 and 60 and found and inverse relationship between the ratio of TC/HDL-c and the total intake of DF (*P* = 0.01); the ratio of TC/HDL-c has been proposed as a good indicator of cardiovascular risk.

Van Dam RM, et al. (2003) performed a cross-sectional study of 19,750 randomly selected men and women aged 20-65 y from 3 Dutch municipalities. Three dietary factors were identified: Cosmopolitan pattern (rich in fried vegetables, salad); traditional pattern (rich red meat) and refined pattern (rich sugar-beverages and white bread). A higher adherence to the Cosmopolitan pattern was significantly associated with lower blood pressure and higher HDL-c concentrations; the traditional dietary pattern was associated with higher blood pressure and higher concentrations of HDL cholesterol, total cholesterol, and glucose; and the refined dietary pattern was associated with higher total cholesterol concentrations.

Whole grain was also inversely associated with total cholesterol (*P* for trend = 0.02), LDL cholesterol (*P* for trend = 0.04), and 2-h glucose (*P* for trend = 0.0006) in a cross-sectional analysis of 1516 community-dwelling participants in the Baltimore Longitudinal Study of Aging. Associations between cereal fiber and anthropometrics and plasma lipids were similar (Newby et al., 2007)**.**

Effects of Dietary Fiber Intake on Cardiovascular Risk Factors 473

(95% CI, 1.16-3.16) for GI (*P* =0.12) and 0.41 (95% CI, 0.24-0.72) for cereal fiber intake (*P*=

In conclusion, increasing intakes of foods rich in DF are associated with a reduced risk of developing T2DM. DF intakes associated with favorable effects are about 25 to 30 g per day,

Increased DF has been associated with a lower risk of hypertension, and a meta-analysis of clinical studies of fiber supplementation also supports an inverse association between fiber

In a cross-sectional study, Lairon D et al. (2007) determined the quintiles of fiber intake from dietary record, separately for 2532 men and 3429 women. The highest total DF and insoluble DF intakes were associated with a significantly (*P* < 0.05) lower risk of overweight and elevated waist-to-hip ratio, BP, plasma apolipoprotein (apo) B, apo B:apo A-I, cholesterol, triacylglycerols, and homocysteine. Fiber from cereals was associated with a lower body mass index, BP, and homocysteine concentration; fiber from vegetables with a lower BP and homocysteine concentration; and fiber from fruit with a lower waist-to-hip ratio and BP. Fiber from dried fruit or nuts and seeds was associated with a lower body mass index,

Estruch et al. (2009) analyzed 772 cardiovascular high-risk subjects (age 69±5 years). On randomization they were assigned to a low-fat diet or two recommendations for increasing vegetable, fruit and legume intake. Body weight, waist circumference and mean systolic and

In a meta-analysis of randomized placebo-controlled trials to estimate the effect of fiber supplementation on BP overall and in population subgroups, fiber supplementation (average dose, 11.5 g/d) changed systolic BP by –1.13 mm Hg (95% CI: –2.49 to 0.23) and diastolic BP by –1.26 mm Hg (–2.04 to –0.48). Reductions in BP tended to be greater in older (>40 years) and in hypertensive populations than in younger and in normotensive subjects

Many epidemiological studies have evaluated the effects of DF on the risk of coronary heart disease (CHD) (Rimm et al., 1996; Todd et al., 1999; Liu et al., 2002; Mozaffarian et al., 2003). Most likely, as assessed in prospective studies, DF intake with the usual diet is a marker of healthy food choices with an overall cardiovascular benefit, while changing the diet to increase DF at late stages, when clinical consequences of atherosclerosis have developed,

A meta-analysis, involving four of the largest studies published, suggested a 28% reduction in the risk of CHD on comparing individuals in the highest and lowest quintiles of intake of whole grains (relative risk 0.72, 95% confidence intervals: 0.48, 0.94) (Anderson, 2003)**.**

After adjustment for cardiovascular risk factors, in the Iowa Women's Health Study the relative risks for cardiovascular disease were 1.0, 0.96, 0.71, 0.64 and 0.70 in ascending

diastolic BP significantly decreased across the quintiles of fiber intake (*P*<0.005).

although the contribution of DF per se to this effect remains to be established.

waist-to-hip ratio, and fasting apo B and glucose concentrations.

0.05).

**4.4 Blood pressure**

and blood pressure.

(Streppel et al., 2005)**.**

may not be protective.

**4.5 Cardiovascular disease**

In conclusion, viscous types of DF mainly from fruits, vegetables and whole grains may contribute to reducing total and LDL-cholesterol concentrations. The effects are limited to amounts usually consumed from foods.

#### **4.3 Glycemic index and Type 2 diabetes mellitus**

Glycemic control is of crucial importance in the management of T2DM. Few intervention studies have investigated the effects of fiber intake on measures of glucose tolerance or insulin sensitivity, but recent observations have shown the favourable effects of a diet with abundant fiber-rich foods, particularly whole grain, bran and germ intake, on the risk of T2DM (Murakami et al., 2005**;** Krishnan et al., 2007**;** Schulze et al., 2007**;** de Munter et al., 2007)**.**

In the Nurses' Health Study, wholegrain consumption appeared to be protective for T2DM. When comparing the highest and lowest quintiles of intake, the age and energy adjusted relative risk was 0.62 (95% CI: 0.53, 0.71). Further adjustment for other risk factors did not appreciably alter this risk estimate (Liu et al., 2000**;** Salmeron, et al., 1997) virtually identical risk reduction was observed among men participating in the Health Professionals Study (Fung et al., 2002)**.** A relative risk of 0.63 was reported in association with three or more servings/day of wholegrain. In the Iowa Women's Health Study, postmenopausal women in the upper quintile of wholegrain consumption (more than 33 servings per week) were 20% less likely to develop T2DM than those in the lowest quintile (fewer than 13 servings per week) (Meyer et al., 2000)**.** Cereal fiber appears to be associated with a protective dose– response effect that is present after controlling for a range of potentially confounding factors. The role of whole grains and DF in diabetes has been reviewed in detail by Venn and Mann (Venn & Mann, 2004)**.**

Two large cross-sectional studies, using validated food frequency questionnaires to assess nutrient intake and either the frequently sampled intravenous glucose tolerance test or homoeostasis model assessment for insulin resistance, found that intake of DF was inversely associated with the probability of having insulin resistance (Lau et al., 2005**;** Liese et al., 2005) and it was possible to demonstrate that fiber was associated with increased insulin sensitivity even after adjustment for body mass index.

During 8 years of follow-up (1995-2003) 1964 incident cases of T2DM were reported in a prospective cohort study including 41,186 participants of the Black Women's Health Study without a history of diabetes or CVD. Daily consumption of whole grain was associated with a lower risk of T2DM compared with consumption less than once a week. After mutual adjustment, the hazard ratio was 0.73 (0.63-0.85; *P* for trend = 0.0001) for whole grains (van Dam et al., 2006)**.**

Krishnan S et al. (2007)examined the association of glycemic load, GI, and cereal fiber with risk of T2DM in 59000 black women with T2DM, CVD or cancer from the Black Women's Health Study. During 8 years of follow-up, there were 1,938 incident cases of diabetes. GI was positively associated with the risk of diabetes: the incidence rate ratios (IRR) for the highest quintile relative to the lowest was 1.23 (95% CI, 1.05-1.44). Cereal fiber intake was inversely associated with the risk of T2DM with an IRR of 0.82 (95% CI, 0.70-0.96) for the highest *vs*. the lowest quintiles of intake. Stronger associations were seen among women with a body mass index lower than 25: IRRs for the highest *vs.* the lowest quintile were 1.91 (95% CI, 1.16-3.16) for GI (*P* =0.12) and 0.41 (95% CI, 0.24-0.72) for cereal fiber intake (*P*= 0.05).

In conclusion, increasing intakes of foods rich in DF are associated with a reduced risk of developing T2DM. DF intakes associated with favorable effects are about 25 to 30 g per day, although the contribution of DF per se to this effect remains to be established.

#### **4.4 Blood pressure**

472 Recent Advances in Cardiovascular Risk Factors

In conclusion, viscous types of DF mainly from fruits, vegetables and whole grains may contribute to reducing total and LDL-cholesterol concentrations. The effects are limited to

Glycemic control is of crucial importance in the management of T2DM. Few intervention studies have investigated the effects of fiber intake on measures of glucose tolerance or insulin sensitivity, but recent observations have shown the favourable effects of a diet with abundant fiber-rich foods, particularly whole grain, bran and germ intake, on the risk of T2DM (Murakami et al., 2005**;** Krishnan et al., 2007**;** Schulze et al., 2007**;** de Munter et al.,

In the Nurses' Health Study, wholegrain consumption appeared to be protective for T2DM. When comparing the highest and lowest quintiles of intake, the age and energy adjusted relative risk was 0.62 (95% CI: 0.53, 0.71). Further adjustment for other risk factors did not appreciably alter this risk estimate (Liu et al., 2000**;** Salmeron, et al., 1997) virtually identical risk reduction was observed among men participating in the Health Professionals Study (Fung et al., 2002)**.** A relative risk of 0.63 was reported in association with three or more servings/day of wholegrain. In the Iowa Women's Health Study, postmenopausal women in the upper quintile of wholegrain consumption (more than 33 servings per week) were 20% less likely to develop T2DM than those in the lowest quintile (fewer than 13 servings per week) (Meyer et al., 2000)**.** Cereal fiber appears to be associated with a protective dose– response effect that is present after controlling for a range of potentially confounding factors. The role of whole grains and DF in diabetes has been reviewed in detail by Venn

Two large cross-sectional studies, using validated food frequency questionnaires to assess nutrient intake and either the frequently sampled intravenous glucose tolerance test or homoeostasis model assessment for insulin resistance, found that intake of DF was inversely associated with the probability of having insulin resistance (Lau et al., 2005**;** Liese et al., 2005) and it was possible to demonstrate that fiber was associated with increased insulin

During 8 years of follow-up (1995-2003) 1964 incident cases of T2DM were reported in a prospective cohort study including 41,186 participants of the Black Women's Health Study without a history of diabetes or CVD. Daily consumption of whole grain was associated with a lower risk of T2DM compared with consumption less than once a week. After mutual adjustment, the hazard ratio was 0.73 (0.63-0.85; *P* for trend = 0.0001) for whole grains (van

Krishnan S et al. (2007)examined the association of glycemic load, GI, and cereal fiber with risk of T2DM in 59000 black women with T2DM, CVD or cancer from the Black Women's Health Study. During 8 years of follow-up, there were 1,938 incident cases of diabetes. GI was positively associated with the risk of diabetes: the incidence rate ratios (IRR) for the highest quintile relative to the lowest was 1.23 (95% CI, 1.05-1.44). Cereal fiber intake was inversely associated with the risk of T2DM with an IRR of 0.82 (95% CI, 0.70-0.96) for the highest *vs*. the lowest quintiles of intake. Stronger associations were seen among women with a body mass index lower than 25: IRRs for the highest *vs.* the lowest quintile were 1.91

amounts usually consumed from foods.

and Mann (Venn & Mann, 2004)**.**

Dam et al., 2006)**.**

sensitivity even after adjustment for body mass index.

2007)**.**

**4.3 Glycemic index and Type 2 diabetes mellitus**

Increased DF has been associated with a lower risk of hypertension, and a meta-analysis of clinical studies of fiber supplementation also supports an inverse association between fiber and blood pressure.

In a cross-sectional study, Lairon D et al. (2007) determined the quintiles of fiber intake from dietary record, separately for 2532 men and 3429 women. The highest total DF and insoluble DF intakes were associated with a significantly (*P* < 0.05) lower risk of overweight and elevated waist-to-hip ratio, BP, plasma apolipoprotein (apo) B, apo B:apo A-I, cholesterol, triacylglycerols, and homocysteine. Fiber from cereals was associated with a lower body mass index, BP, and homocysteine concentration; fiber from vegetables with a lower BP and homocysteine concentration; and fiber from fruit with a lower waist-to-hip ratio and BP. Fiber from dried fruit or nuts and seeds was associated with a lower body mass index, waist-to-hip ratio, and fasting apo B and glucose concentrations.

Estruch et al. (2009) analyzed 772 cardiovascular high-risk subjects (age 69±5 years). On randomization they were assigned to a low-fat diet or two recommendations for increasing vegetable, fruit and legume intake. Body weight, waist circumference and mean systolic and diastolic BP significantly decreased across the quintiles of fiber intake (*P*<0.005).

In a meta-analysis of randomized placebo-controlled trials to estimate the effect of fiber supplementation on BP overall and in population subgroups, fiber supplementation (average dose, 11.5 g/d) changed systolic BP by –1.13 mm Hg (95% CI: –2.49 to 0.23) and diastolic BP by –1.26 mm Hg (–2.04 to –0.48). Reductions in BP tended to be greater in older (>40 years) and in hypertensive populations than in younger and in normotensive subjects (Streppel et al., 2005)**.**

#### **4.5 Cardiovascular disease**

Many epidemiological studies have evaluated the effects of DF on the risk of coronary heart disease (CHD) (Rimm et al., 1996; Todd et al., 1999; Liu et al., 2002; Mozaffarian et al., 2003). Most likely, as assessed in prospective studies, DF intake with the usual diet is a marker of healthy food choices with an overall cardiovascular benefit, while changing the diet to increase DF at late stages, when clinical consequences of atherosclerosis have developed, may not be protective.

A meta-analysis, involving four of the largest studies published, suggested a 28% reduction in the risk of CHD on comparing individuals in the highest and lowest quintiles of intake of whole grains (relative risk 0.72, 95% confidence intervals: 0.48, 0.94) (Anderson, 2003)**.**

After adjustment for cardiovascular risk factors, in the Iowa Women's Health Study the relative risks for cardiovascular disease were 1.0, 0.96, 0.71, 0.64 and 0.70 in ascending

Effects of Dietary Fiber Intake on Cardiovascular Risk Factors 475

Jenkins et al. (2003) reported reduced CRP levels in hyperlipidaemic patients consuming a high carbohydrate diet rich in viscous fiber-containing foods. However, the diets were also high in nuts (almonds), plant sterols and soy proteins, and it is therefore impossible to disentangle separate effects. A recent study (Kasim-Karakas et al., 2006) found that when carbohydrate replaced a substantial proportion of dietary fat under eucaloric conditions, the levels of several inflammatory markers increased along with an increase in triglycerides.

Data from the Massachusetts Hispanic Elders Study (Gao et al., 2004) obtained from 445 Hispanic and 154 non-Hispanic white elders showed that greater frequency of fruit and vegetable intake, which are reach in fiber, was associated with lower CRP and homocysteine concentrations. With each additional serving of fruit and vegetable intake, the risk of having high CRP (>10 mg/l) and homocysteine concentrations decreased by 21% and 17%,

The relation between DF and CRP was examined from 1999 to 2000 in 3,920 participants in the National Health and Nutrition Examination Survey (Ajani, Ford, & Mokdad, 2004). DF intake was inversely associated with serum CRP concentrations: The adjusted odds ratio for increased CRP levels (>3 mg/l) was 0.59 (*P* = 0.006) for the highest quintile of fiber intake compared with the lowest. The results were not affected after exclusion of persons with diabetes, cancer, CVD, or CRP levels >10 mg/l. The results of Ajani et al. confirmed the

Most of the data available on disease prevalence and events are from epidemiological studies. However, it is necessary to also resort to clinical trials to test effects of different types and sources of DF on cardiovascular risk factors taking into account a specific

Although epidemiological data and mechanistic studies support the contention that fiber has beneficial effects on body weight regulation; there has been inconsistent data from randomized controlled clinical trials that have evaluated how body weight is affected by supplementing fiber in the diet (Rodriguez-Moran et al., 1998; Birketvedt et al., 2000; Pittler

In a systematic review, Howarth et al. (2001) analyzed several clinical trials conducted in small and heterogeneous population samples over relatively short periods of time (from 1 to 12 months). The findings were that the intake of 12 g fiber/day resulted in a decrease of 10% in energy intake and a body weight loss of 1.9 kg over 3.8 months, with this effect on body

Esposito et al. (2004) explored the possible mechanisms underlying a dietary intervention and randomized 180 patients (99 men, 81 women) with the metabolic syndrome to a Mediterranean-style diet (instructions about increasing daily consumption of whole grains, vegetables, fruits, nuts, and olive oil) versus a cardiac prudent diet with fat intake less than 30%. After 2 years, body weight decreased more in the intervention group than in the control group, even after controlling for weight loss, inflammatory markers, such as IL-6, IL-

respectively.

**5. Clinical trials**

population.

**5.1 Body weight**

& Ernst, 2001).

7, IL-18, and CRP.

previous findings (King et al., 2003).

weight loss being greater in obese subjects.

quintiles of whole grain intake, *P* <0.02 (Jacobs et al., 1998)**.** The Nurses' Health Study (Liu et al., 2000) observed risk reductions of magnitude similar to those observed for CHD (relative risk 0.69, 95% CI: 0.50, 0.98 when comparing the highest relative to the lowest quintile of intake of whole grains).

The suggestion that reduced cardiovascular risk principally results from consumption of wholegrain rather than DF was supported by findings from the Iowa Women's Health Study. CHD rates were compared in women consuming similar amounts of cereal fiber from either predominantly refined grain sources or predominantly wholegrains. After adjustments, all-cause mortality was significantly lower, and CHD appreciably (though not statistically significantly) reduced among the latter group (Jacobs et al., 2000)**.**

In the Nurses' Health Study and the Health Professionals' Study (Hu et al., 2000; Fung et al., 2001), factor analysis was used to examine the association between CHD and the two major dietary patterns identified: "western" characterized by higher intakes of red and processed meats, sweets and desserts, French fries and refined grains and 'prudent' characterized by higher intakes of fruit, vegetables, legumes, fish, poultry and wholegrains. After adjustment for cardiovascular risk factors, the prudent diet score was associated with relative risks of 1.0, 0.87, 0.79, 0.75 and 0.70 from the lowest to the highest quintiles. Conversely, the relative risks across increasing quintiles of the western pattern score were 1.0, 1.21, 1.35, 1.40 and 1.64. The patterns were also related to biochemical markers of CHD.

The effect of DF may be largely explained by fiber derived from wholewheat, rye or pumpernickel breads, in a multicenter study among 3588 men and women aged 65 years or older and free of known CVD at baseline (Mozaffarian et al., 2003). During a mean followup of 8.6 years, there were 811 incident CVD events. After adjustment for different confounder factors, cereal fiber consumption was inversely associated with incident CVD (*P* for trend=0.02), with 21% lower risk (HR: 0.79; 95% CI: 0.62-0.99) in the highest quintile of intake, compared with the lowest quintile. In similar analyses, neither fruit fiber intake (*P* for trend=0.98) nor vegetable fiber intake (*P* for trend=0.95) were associated with incident CVD.

Furthermore, in a combined analysis of 10 prospective cohort studies conducted in the USA and Europe Pereira et al. (2004) showed a 25% decrease in the risk of CHD for each 10 g increase in fiber intake, after adjusting for several dietary and cardiovascular confounding factors. A relative risk of 0.90 (95% CI: 0.77, 1.07 that is not statistically significant) was reported for total CHD events for each 10 g/day increase in cereal fiber. When considering CHD deaths, the relative risk, 0.75 (95% CI: 0.63, 0.91) was statistically significant, the association being independent of a number of dietary factors and other cardiovascular risk factors.

Recently, Streppel et al. (2008) also observed that CHD mortality and all-cause mortality were reduced by 17% and 9%, respectively for every additional 10 g of DF per day, with no clear associations for different types of DF.

#### **4.6 Inflammatory markers**

CRP is an inflammatory marker useful in the prediction of coronary events. Results from recent epidemiologic studies have consistently shown an inverse association between DF intake and plasma CRP levels. In a recent study, both increasing fiber intake by about 30 g/day from a diet rich in fiber or from a supplement reduced the levels of CRP.

Jenkins et al. (2003) reported reduced CRP levels in hyperlipidaemic patients consuming a high carbohydrate diet rich in viscous fiber-containing foods. However, the diets were also high in nuts (almonds), plant sterols and soy proteins, and it is therefore impossible to disentangle separate effects. A recent study (Kasim-Karakas et al., 2006) found that when carbohydrate replaced a substantial proportion of dietary fat under eucaloric conditions, the levels of several inflammatory markers increased along with an increase in triglycerides.

Data from the Massachusetts Hispanic Elders Study (Gao et al., 2004) obtained from 445 Hispanic and 154 non-Hispanic white elders showed that greater frequency of fruit and vegetable intake, which are reach in fiber, was associated with lower CRP and homocysteine concentrations. With each additional serving of fruit and vegetable intake, the risk of having high CRP (>10 mg/l) and homocysteine concentrations decreased by 21% and 17%, respectively.

The relation between DF and CRP was examined from 1999 to 2000 in 3,920 participants in the National Health and Nutrition Examination Survey (Ajani, Ford, & Mokdad, 2004). DF intake was inversely associated with serum CRP concentrations: The adjusted odds ratio for increased CRP levels (>3 mg/l) was 0.59 (*P* = 0.006) for the highest quintile of fiber intake compared with the lowest. The results were not affected after exclusion of persons with diabetes, cancer, CVD, or CRP levels >10 mg/l. The results of Ajani et al. confirmed the previous findings (King et al., 2003).

#### **5. Clinical trials**

474 Recent Advances in Cardiovascular Risk Factors

quintiles of whole grain intake, *P* <0.02 (Jacobs et al., 1998)**.** The Nurses' Health Study (Liu et al., 2000) observed risk reductions of magnitude similar to those observed for CHD (relative risk 0.69, 95% CI: 0.50, 0.98 when comparing the highest relative to the lowest quintile of

The suggestion that reduced cardiovascular risk principally results from consumption of wholegrain rather than DF was supported by findings from the Iowa Women's Health Study. CHD rates were compared in women consuming similar amounts of cereal fiber from either predominantly refined grain sources or predominantly wholegrains. After adjustments, all-cause mortality was significantly lower, and CHD appreciably (though not

In the Nurses' Health Study and the Health Professionals' Study (Hu et al., 2000; Fung et al., 2001), factor analysis was used to examine the association between CHD and the two major dietary patterns identified: "western" characterized by higher intakes of red and processed meats, sweets and desserts, French fries and refined grains and 'prudent' characterized by higher intakes of fruit, vegetables, legumes, fish, poultry and wholegrains. After adjustment for cardiovascular risk factors, the prudent diet score was associated with relative risks of 1.0, 0.87, 0.79, 0.75 and 0.70 from the lowest to the highest quintiles. Conversely, the relative risks across increasing quintiles of the western pattern score were 1.0, 1.21, 1.35, 1.40 and

The effect of DF may be largely explained by fiber derived from wholewheat, rye or pumpernickel breads, in a multicenter study among 3588 men and women aged 65 years or older and free of known CVD at baseline (Mozaffarian et al., 2003). During a mean followup of 8.6 years, there were 811 incident CVD events. After adjustment for different confounder factors, cereal fiber consumption was inversely associated with incident CVD (*P* for trend=0.02), with 21% lower risk (HR: 0.79; 95% CI: 0.62-0.99) in the highest quintile of intake, compared with the lowest quintile. In similar analyses, neither fruit fiber intake (*P* for trend=0.98) nor vegetable fiber intake (*P* for trend=0.95) were associated with incident CVD. Furthermore, in a combined analysis of 10 prospective cohort studies conducted in the USA and Europe Pereira et al. (2004) showed a 25% decrease in the risk of CHD for each 10 g increase in fiber intake, after adjusting for several dietary and cardiovascular confounding factors. A relative risk of 0.90 (95% CI: 0.77, 1.07 that is not statistically significant) was reported for total CHD events for each 10 g/day increase in cereal fiber. When considering CHD deaths, the relative risk, 0.75 (95% CI: 0.63, 0.91) was statistically significant, the association being independent of a number of dietary factors and other cardiovascular risk

Recently, Streppel et al. (2008) also observed that CHD mortality and all-cause mortality were reduced by 17% and 9%, respectively for every additional 10 g of DF per day, with no

CRP is an inflammatory marker useful in the prediction of coronary events. Results from recent epidemiologic studies have consistently shown an inverse association between DF intake and plasma CRP levels. In a recent study, both increasing fiber intake by about 30

g/day from a diet rich in fiber or from a supplement reduced the levels of CRP.

statistically significantly) reduced among the latter group (Jacobs et al., 2000)**.**

1.64. The patterns were also related to biochemical markers of CHD.

intake of whole grains).

factors.

clear associations for different types of DF.

**4.6 Inflammatory markers**

Most of the data available on disease prevalence and events are from epidemiological studies. However, it is necessary to also resort to clinical trials to test effects of different types and sources of DF on cardiovascular risk factors taking into account a specific population.

#### **5.1 Body weight**

Although epidemiological data and mechanistic studies support the contention that fiber has beneficial effects on body weight regulation; there has been inconsistent data from randomized controlled clinical trials that have evaluated how body weight is affected by supplementing fiber in the diet (Rodriguez-Moran et al., 1998; Birketvedt et al., 2000; Pittler & Ernst, 2001).

In a systematic review, Howarth et al. (2001) analyzed several clinical trials conducted in small and heterogeneous population samples over relatively short periods of time (from 1 to 12 months). The findings were that the intake of 12 g fiber/day resulted in a decrease of 10% in energy intake and a body weight loss of 1.9 kg over 3.8 months, with this effect on body weight loss being greater in obese subjects.

Esposito et al. (2004) explored the possible mechanisms underlying a dietary intervention and randomized 180 patients (99 men, 81 women) with the metabolic syndrome to a Mediterranean-style diet (instructions about increasing daily consumption of whole grains, vegetables, fruits, nuts, and olive oil) versus a cardiac prudent diet with fat intake less than 30%. After 2 years, body weight decreased more in the intervention group than in the control group, even after controlling for weight loss, inflammatory markers, such as IL-6, IL-7, IL-18, and CRP.

Effects of Dietary Fiber Intake on Cardiovascular Risk Factors 477

In a meta-analysis of 8 controlled trials, it was observed that the hypolipidemic effects of physillium in hypocholesterolemic individuals already consuming a low-fat diet achieved reductions with diet only. Results confirm that *Psyllium* significantly lowers an additional 4% of serum total and cholesterol and an additional 7% relative of LDL-c concentrations in

In a randomized, crossover study Maki KC et al. (2007) compared the effects of consuming high-fiber oat and wheat cereals on postprandial metabolic profiles in healthy men. Twentyseven subjects received oat (providing 5.7 g/day beta-glucan) or wheat (control) cereal products, in random order, incorporated into their usual diets for two weeks. Peak triglyceride concentration was lower after oat vs. wheat cereal consumption. Mean area

In a recent parallel, double-blind, placebo-controlled clinical trial, 200 overweight or obese patients were randomized to receive a mixed dose of soluble fiber (3 g *Plantago ovata husk* and 1 g glucomannan) or a placebo twice or three times daily in the context of an energyrestricted diet for a period of 16 weeks. Differences in plasma LDL-c changes between the groups were significant, with greater reductions in the two fiber supplemented groups in

Insoluble fiber, such as that from wheat or cellulose, has not been reported to have any significant effect on blood cholesterol (Jenkins et al., 2000**;** Sola et al., 2007)**,** possibly because of the presence, along with DF, of several bioactive and antioxidant phytochemical substances in foodstuffs (Salas-Salvado et al., 2006) or because of the effect that fiber has on

On glycemic control, several randomized controlled trials have been performed to determine the effect of DF on insulin sensitivity, blood glucose control and hypoglycemic episodes. However, all were short-term studies. A whole grain diet led to a postprandial improvement in insulin sensitivity when compared to a refined grain diet. Plasma glucose concentrations were significantly lower for the high fiber diet than for the low-fiber diet. In clinical studies using fiber supplements, it appears that only soluble fiber plays a significant role in reducing postprandial glycemia. However, prospective epidemiological studies have shown that insoluble fiber, but not soluble fiber, from natural food sources was inversely

Giacco and co-workers (Giacco et al., 2000) carried out a 6-month randomized parallel study comparing a diet containing 50 g/d of soluble fiber with a diet containing only 15 g/d of fiber. Thirty-two patients (intervention group) and 31 patients (control group) were randomized to follow a high-fiber or low-fiber diet for a 24-week period. This study confirmed the potential for around 40 g/d DF (half of the soluble type from legumes, fruits and vegetables) to improve glycemic control. They found an improvement in the daily blood glucose profile and the HbA1c levels, as well as a marked reduction in the number of

Chandalia et al. (2000) also demonstrated that high-fiber diets contributed to better metabolic control in 13 T2DM diabetic patients. In a cross-over study, patients were

comparison to a placebo group consuming a low fat diet (Anderson, 2000)**.**

blood pressure, body weight and postprandial glycemia or insulin levels.

under the triglyceride curve also tended to be lower.

comparison to the placebo (Salas-Salvado et al., 2008)**.**

**5.3 Glycemic index and type 2 diabetes mellitus**

related to the risk of diabetes.

hypoglycemic events.

In randomized placebo-controlled studies, 176 overweight or obese men and women were included to receive either active fiber substance or placebo during a five-week observation period. The fiber supplements consisted of the viscous fibers glucomannan (Chrombalance), glucomannan and guar gum (Appe-Trim) and glucomannan, guar gum and alginat (Glucosahl). All fiber supplements plus a balanced 1200 kcal diet induced a significant weight reduction more than placebo and diet alone, during the observation period (Birketvedt et al., 2005)**.**

Salas-Salvador et al. (2008) evaluated the effect of a mixed fiber supplement on body-weight loss, in 200 overweight or obese patients in a parallel, double-blind, placebo-controlled clinical trial. Weight loss tended to be higher after both doses of fiber (-4.52 ± 0.56 and -4.60 ± 0.55 kg) than placebo (-0.79 ± 0.58 kg); the differences in changes between groups were not statistically significant. Postprandial satiety increased in both fiber groups compared to the placebo. Estruch et al. (2009) analyzed 772 cardiovascular high-risk subjects that were assigned to a low-fat diet or two recommendations for increasing the intake of vegetables, fruit and legumes. Body weight, waist circumference and BP significantly decreased across the quintiles of fiber intake (*P*=0.04).

In a dietary intervention involving 107 overweight and obese children it was shown that low GI diets are more effective in reducing weight than low-fat diets (Spieth et al., 2000). The BMI of subjects assigned to the low GI diet reduced significantly in comparison to those on the low-fat diet across all three tertiles (<28.3 kg/m2, 28.3–34.9 kg/m2 and >34.9 kg/m2). The mean overall reduction was 1.53 kg/m2 vs. 0.06 kg/m2 (*P* < 0.001). Another study showed that low GI diets result in the greatest reduction in fat mass, especially in women (McMillan-Price et al., 2006).

#### **5.2 Serum lipids**

Several studies have shown that a high consumption of DF, particularly soluble fiber (pectin, guar gumm, -glucans, glucomannan, and psyllium), significantly decreases serum levels of total and LDL cholesterol (Anderson, 2000; Brighenti, 2007). Other clinical trials support the hypocholesterolemic effects of soluble fiber derived both from supplements or fiber derived from foods in patients at high risk of cardiovascular disease.

In a double-blind placebo-controlled study, Rodríguez-Morán M et al., (1998) determined the plasma-lowering effects of *Plantago psyllium*, as an adjunct to dietary therapy, on lipid and glucose levels, in patients with T2DM. The study included 125 subjects undergoing a 6 week period of diet counseling followed by a 6-week treatment period in which *Plantago psyllium* or placebo was given in combination with a low fat diet. No significant changes were observed in the patient's in either group. Fasting plasma glucose, total cholesterol, LDL-c, and triglyceride levels, showed a significant reduction (*P* < 0.05), whereas HDL-c increased significantly (*P* < 0.01) following *Psyllium* treatment.

A meta-analysis carried out by Brown et al. (1999) indicates that the effects of different types of viscous fibers on TC concentrations are modest. These results were obtained from 67 experimental metabolic studies carried out on 2,990 subjects showing that for each gram of soluble fiber added to the diet, the TC and the LDL-c concentration decreased by 1.7 mg/dL and 2.2 mg/dL, respectively.

In randomized placebo-controlled studies, 176 overweight or obese men and women were included to receive either active fiber substance or placebo during a five-week observation period. The fiber supplements consisted of the viscous fibers glucomannan (Chrombalance), glucomannan and guar gum (Appe-Trim) and glucomannan, guar gum and alginat (Glucosahl). All fiber supplements plus a balanced 1200 kcal diet induced a significant weight reduction more than placebo and diet alone, during the observation period

Salas-Salvador et al. (2008) evaluated the effect of a mixed fiber supplement on body-weight loss, in 200 overweight or obese patients in a parallel, double-blind, placebo-controlled clinical trial. Weight loss tended to be higher after both doses of fiber (-4.52 ± 0.56 and -4.60 ± 0.55 kg) than placebo (-0.79 ± 0.58 kg); the differences in changes between groups were not statistically significant. Postprandial satiety increased in both fiber groups compared to the placebo. Estruch et al. (2009) analyzed 772 cardiovascular high-risk subjects that were assigned to a low-fat diet or two recommendations for increasing the intake of vegetables, fruit and legumes. Body weight, waist circumference and BP significantly decreased across

In a dietary intervention involving 107 overweight and obese children it was shown that low GI diets are more effective in reducing weight than low-fat diets (Spieth et al., 2000). The BMI of subjects assigned to the low GI diet reduced significantly in comparison to those on the low-fat diet across all three tertiles (<28.3 kg/m2, 28.3–34.9 kg/m2 and >34.9 kg/m2). The mean overall reduction was 1.53 kg/m2 vs. 0.06 kg/m2 (*P* < 0.001). Another study showed that low GI diets result in the greatest reduction in fat mass, especially in women (McMillan-

Several studies have shown that a high consumption of DF, particularly soluble fiber (pectin, guar gumm, -glucans, glucomannan, and psyllium), significantly decreases serum levels of total and LDL cholesterol (Anderson, 2000; Brighenti, 2007). Other clinical trials support the hypocholesterolemic effects of soluble fiber derived both from supplements or

In a double-blind placebo-controlled study, Rodríguez-Morán M et al., (1998) determined the plasma-lowering effects of *Plantago psyllium*, as an adjunct to dietary therapy, on lipid and glucose levels, in patients with T2DM. The study included 125 subjects undergoing a 6 week period of diet counseling followed by a 6-week treatment period in which *Plantago psyllium* or placebo was given in combination with a low fat diet. No significant changes were observed in the patient's in either group. Fasting plasma glucose, total cholesterol, LDL-c, and triglyceride levels, showed a significant reduction (*P* < 0.05), whereas HDL-c

A meta-analysis carried out by Brown et al. (1999) indicates that the effects of different types of viscous fibers on TC concentrations are modest. These results were obtained from 67 experimental metabolic studies carried out on 2,990 subjects showing that for each gram of soluble fiber added to the diet, the TC and the LDL-c concentration decreased by 1.7 mg/dL

fiber derived from foods in patients at high risk of cardiovascular disease.

increased significantly (*P* < 0.01) following *Psyllium* treatment.

(Birketvedt et al., 2005)**.**

Price et al., 2006).

**5.2 Serum lipids**

and 2.2 mg/dL, respectively.

the quintiles of fiber intake (*P*=0.04).

In a meta-analysis of 8 controlled trials, it was observed that the hypolipidemic effects of physillium in hypocholesterolemic individuals already consuming a low-fat diet achieved reductions with diet only. Results confirm that *Psyllium* significantly lowers an additional 4% of serum total and cholesterol and an additional 7% relative of LDL-c concentrations in comparison to a placebo group consuming a low fat diet (Anderson, 2000)**.**

In a randomized, crossover study Maki KC et al. (2007) compared the effects of consuming high-fiber oat and wheat cereals on postprandial metabolic profiles in healthy men. Twentyseven subjects received oat (providing 5.7 g/day beta-glucan) or wheat (control) cereal products, in random order, incorporated into their usual diets for two weeks. Peak triglyceride concentration was lower after oat vs. wheat cereal consumption. Mean area under the triglyceride curve also tended to be lower.

In a recent parallel, double-blind, placebo-controlled clinical trial, 200 overweight or obese patients were randomized to receive a mixed dose of soluble fiber (3 g *Plantago ovata husk* and 1 g glucomannan) or a placebo twice or three times daily in the context of an energyrestricted diet for a period of 16 weeks. Differences in plasma LDL-c changes between the groups were significant, with greater reductions in the two fiber supplemented groups in comparison to the placebo (Salas-Salvado et al., 2008)**.**

Insoluble fiber, such as that from wheat or cellulose, has not been reported to have any significant effect on blood cholesterol (Jenkins et al., 2000**;** Sola et al., 2007)**,** possibly because of the presence, along with DF, of several bioactive and antioxidant phytochemical substances in foodstuffs (Salas-Salvado et al., 2006) or because of the effect that fiber has on blood pressure, body weight and postprandial glycemia or insulin levels.

#### **5.3 Glycemic index and type 2 diabetes mellitus**

On glycemic control, several randomized controlled trials have been performed to determine the effect of DF on insulin sensitivity, blood glucose control and hypoglycemic episodes. However, all were short-term studies. A whole grain diet led to a postprandial improvement in insulin sensitivity when compared to a refined grain diet. Plasma glucose concentrations were significantly lower for the high fiber diet than for the low-fiber diet. In clinical studies using fiber supplements, it appears that only soluble fiber plays a significant role in reducing postprandial glycemia. However, prospective epidemiological studies have shown that insoluble fiber, but not soluble fiber, from natural food sources was inversely related to the risk of diabetes.

Giacco and co-workers (Giacco et al., 2000) carried out a 6-month randomized parallel study comparing a diet containing 50 g/d of soluble fiber with a diet containing only 15 g/d of fiber. Thirty-two patients (intervention group) and 31 patients (control group) were randomized to follow a high-fiber or low-fiber diet for a 24-week period. This study confirmed the potential for around 40 g/d DF (half of the soluble type from legumes, fruits and vegetables) to improve glycemic control. They found an improvement in the daily blood glucose profile and the HbA1c levels, as well as a marked reduction in the number of hypoglycemic events.

Chandalia et al. (2000) also demonstrated that high-fiber diets contributed to better metabolic control in 13 T2DM diabetic patients. In a cross-over study, patients were

Effects of Dietary Fiber Intake on Cardiovascular Risk Factors 479

concluding that plasma concentrations of CRP decreased in parallel with increasing DF

A review of seven clinical trials of at least 2 weeks in duration, with an increased and measurable consumption of DF, reported significantly lower CRP concentrations of 25-54% with increased DF consumption with dosages ranging between 3.3-7.8 g/MJ. The seventh trial with *Psyllium* fiber supplementation failed to lower CRP levels significantly in overweight/obese individuals. Weight loss and altered fatty acid intakes were present in most of the studies (North et al., 2009). The mechanisms are inconclusive but may involve the effect of DF on weight loss, and/or changes in the secretion, turnover or metabolism of

Based on epidemiological and clinical studies that have attributed important health effects to fiber, several organizations such as the American Dietetic Association and the Institute of Medicine recommend an intake of 14 g of DF per 1,000 kcal, or 25 g/day for adult women and 38 g/day for adult men, to protect against the risk of CHD and T2DM and improved weight maintenance. However, in most Western countries, the current intakes of DF are below those recommended with, for instance, an average consumption of 19 and 16 g per day for men and women, respectively. In order to improve the DF intake of the population,

national dietary guidelines usually recommend the consumption of high-fiber foods.

Since no biomarker of DF intake is available, food frequency questionnaire (FFQ) data is the only source of information on food consumption, including DF. FFQs are known to contain measurement errors, a reason why energy intake should be included as a covariate in the models to achieve the equivalent of an isoenergetic diet and thereby

The evidence available shows that the intake of foods that are high in fiber has clear benefits regarding lipid profile and other cardiovascular risk factors. Although some studies of fiber supplements have shown positive effects on the lipid profile, the number of adults who adhere to the use of fiber supplements tends to be low. Likewise, these effects are modest when compared with a whole foods approach that encourages the consumption of fiber-rich

Epidemiologic studies show that intact fruit, vegetables, whole grains, nuts and legumes, all of which are rich in potentially cardioprotective components, protect the body from cardiovascular diseases and mortality. There is debate in relation to cereals that are especially rich in insoluble fiber, but some studies have shown an inverse association between their intake and blood pressure. However, in clinical studies, only soluble viscous fiber has been demonstrated to have metabolic advantages. This paradox can be explained by the fact that food rich in fiber contains other phytochemical compounds that have been demonstrated to modulate inflammation, oxidation, insulin resistance and cholesterol

Consequently, a Mediterranean-style diet rich in fiber-rich foods should be recommended to

insulin, glucose, adiponectin, interleukin-6, free fatty acids and triglycerides.

(*P*=0.04).

**6. Conclusions**

overcome this problem.

foods.

metabolism.

reduce the risk of cardiovascular disease.

randomized to a diet containing a moderate amount of fiber (8 g of soluble fiber and 16 g insoluble fiber) or to a diet containing a high amount of fiber (25 g of soluble fiber and 25 g insoluble fiber). Plasma glucose concentrations were significantly lower for the high fiber than for the low-fiber diet.

In a controlled 6-week study, overweight hyperinsulinaemic adults consumed diets providing 55% energy from carbohydrate and 30% from fat, Pereira et al. (Pereira et al., 2002) observed that insulin sensitivity measured by a euglycemic hyperinsulinaemic clamp was appreciably improved in the wholegrain compared with the refined grain diet. Fasting insulins and area under the 2-h insulin curve were lower, despite body weight not being significantly different in the two diets. In this intervention, carbohydrates were derived from predominantly wholegrain or refined grain cereals, with DF content of the wholegrain diet 28 g compared with 17 g on the refined grain diet. DF was predominantly from cereal sources.  Rye bread has also been shown to improve insulin sensitivity in overweight and obese women too (Juntunen et al., 2003).

Likewise, Weicker and co-workers (Weickert et al., 2006) used the same method to measure insulin sensitivity in overweight and obese women and found that this increased after 3 days of a diet containing bread enriched with insoluble fiber compared to another diet containing white bread

In a recent 6-month parallel, randomized clinical trial composed of 210 patients with T2DM the patients were randomized to either a high cereal fiber diet (GI = 80.8) or a low GI diet (GI = 69.6). The low GI diet resulted in statistically significant reductions in fasting plasma glucose and HbA1c (Jenkins et al., 2008). The results of this study confirm the notion that high fiber diets in a low GI setting are more effective in managing and preventing T2DM in comparison with high fiber diets that have medium or high GI.

A recent meta-analysis of randomized controlled trials looking at the effect of legumes on glycemic markers concluded that legumes as part of a high fiber diet significantly reduce fasting blood glucose and glycated proteins (Sievenpiper et al., 2009)**.**

#### **5.4 Inflammatory markers**

In hyperlipidemic patients a reduction was founded in CRP levels (28% vs. baseline) following a whole diet approach, which was low in saturated fat and included viscous fibers, almonds, soy protein, and plant sterols being comparable to statin therapy (33% reduction of CRP levels) and independent of changes in body weight. The diet also induced a reduction in lipids that was comparable to lovastatin therapy (Jenkins et al., 2003)**.** They reported reduced CRP levels in hyperlipidemic patients consuming a high carbohydrate diet rich in viscous fiber-containing foods. However, the diets were also high in nuts (almonds), plant sterols and soy proteins, and it was therefore impossible to disentangle separate effects.

Kasim-Karakas et al. (2006) found that when carbohydrates replaced a substantial proportion of dietary fat under eucaloric conditions in post-menopausal women, the levels of several inflammatory markers increased along with an increase in triglycerides. However, when the participants consumed the 15% fat diet *ad libitum* under free living conditions, they lost weight and triglyceride and the levels of inflammatory markers decreased. In another study, Estruch et al. (2009) analyzed 772 cardiovascular high-risk subjects concluding that plasma concentrations of CRP decreased in parallel with increasing DF (*P*=0.04).

A review of seven clinical trials of at least 2 weeks in duration, with an increased and measurable consumption of DF, reported significantly lower CRP concentrations of 25-54% with increased DF consumption with dosages ranging between 3.3-7.8 g/MJ. The seventh trial with *Psyllium* fiber supplementation failed to lower CRP levels significantly in overweight/obese individuals. Weight loss and altered fatty acid intakes were present in most of the studies (North et al., 2009). The mechanisms are inconclusive but may involve the effect of DF on weight loss, and/or changes in the secretion, turnover or metabolism of insulin, glucose, adiponectin, interleukin-6, free fatty acids and triglycerides.

#### **6. Conclusions**

478 Recent Advances in Cardiovascular Risk Factors

randomized to a diet containing a moderate amount of fiber (8 g of soluble fiber and 16 g insoluble fiber) or to a diet containing a high amount of fiber (25 g of soluble fiber and 25 g insoluble fiber). Plasma glucose concentrations were significantly lower for the high fiber

In a controlled 6-week study, overweight hyperinsulinaemic adults consumed diets providing 55% energy from carbohydrate and 30% from fat, Pereira et al. (Pereira et al., 2002) observed that insulin sensitivity measured by a euglycemic hyperinsulinaemic clamp was appreciably improved in the wholegrain compared with the refined grain diet. Fasting insulins and area under the 2-h insulin curve were lower, despite body weight not being significantly different in the two diets. In this intervention, carbohydrates were derived from predominantly wholegrain or refined grain cereals, with DF content of the wholegrain diet 28 g compared with 17 g on the refined grain diet. DF was predominantly from cereal sources.  Rye bread has also been shown to improve insulin sensitivity in overweight and obese

Likewise, Weicker and co-workers (Weickert et al., 2006) used the same method to measure insulin sensitivity in overweight and obese women and found that this increased after 3 days of a diet containing bread enriched with insoluble fiber compared to another diet

In a recent 6-month parallel, randomized clinical trial composed of 210 patients with T2DM the patients were randomized to either a high cereal fiber diet (GI = 80.8) or a low GI diet (GI = 69.6). The low GI diet resulted in statistically significant reductions in fasting plasma glucose and HbA1c (Jenkins et al., 2008). The results of this study confirm the notion that high fiber diets in a low GI setting are more effective in managing and preventing T2DM in

A recent meta-analysis of randomized controlled trials looking at the effect of legumes on glycemic markers concluded that legumes as part of a high fiber diet significantly reduce

In hyperlipidemic patients a reduction was founded in CRP levels (28% vs. baseline) following a whole diet approach, which was low in saturated fat and included viscous fibers, almonds, soy protein, and plant sterols being comparable to statin therapy (33% reduction of CRP levels) and independent of changes in body weight. The diet also induced a reduction in lipids that was comparable to lovastatin therapy (Jenkins et al., 2003)**.** They reported reduced CRP levels in hyperlipidemic patients consuming a high carbohydrate diet rich in viscous fiber-containing foods. However, the diets were also high in nuts (almonds), plant sterols and soy proteins, and it was therefore impossible to disentangle separate effects. Kasim-Karakas et al. (2006) found that when carbohydrates replaced a substantial proportion of dietary fat under eucaloric conditions in post-menopausal women, the levels of several inflammatory markers increased along with an increase in triglycerides. However, when the participants consumed the 15% fat diet *ad libitum* under free living conditions, they lost weight and triglyceride and the levels of inflammatory markers decreased. In another study, Estruch et al. (2009) analyzed 772 cardiovascular high-risk subjects

comparison with high fiber diets that have medium or high GI.

fasting blood glucose and glycated proteins (Sievenpiper et al., 2009)**.**

than for the low-fiber diet.

women too (Juntunen et al., 2003).

containing white bread

**5.4 Inflammatory markers**

Based on epidemiological and clinical studies that have attributed important health effects to fiber, several organizations such as the American Dietetic Association and the Institute of Medicine recommend an intake of 14 g of DF per 1,000 kcal, or 25 g/day for adult women and 38 g/day for adult men, to protect against the risk of CHD and T2DM and improved weight maintenance. However, in most Western countries, the current intakes of DF are below those recommended with, for instance, an average consumption of 19 and 16 g per day for men and women, respectively. In order to improve the DF intake of the population, national dietary guidelines usually recommend the consumption of high-fiber foods.

Since no biomarker of DF intake is available, food frequency questionnaire (FFQ) data is the only source of information on food consumption, including DF. FFQs are known to contain measurement errors, a reason why energy intake should be included as a covariate in the models to achieve the equivalent of an isoenergetic diet and thereby overcome this problem.

The evidence available shows that the intake of foods that are high in fiber has clear benefits regarding lipid profile and other cardiovascular risk factors. Although some studies of fiber supplements have shown positive effects on the lipid profile, the number of adults who adhere to the use of fiber supplements tends to be low. Likewise, these effects are modest when compared with a whole foods approach that encourages the consumption of fiber-rich foods.

Epidemiologic studies show that intact fruit, vegetables, whole grains, nuts and legumes, all of which are rich in potentially cardioprotective components, protect the body from cardiovascular diseases and mortality. There is debate in relation to cereals that are especially rich in insoluble fiber, but some studies have shown an inverse association between their intake and blood pressure. However, in clinical studies, only soluble viscous fiber has been demonstrated to have metabolic advantages. This paradox can be explained by the fact that food rich in fiber contains other phytochemical compounds that have been demonstrated to modulate inflammation, oxidation, insulin resistance and cholesterol metabolism.

Consequently, a Mediterranean-style diet rich in fiber-rich foods should be recommended to reduce the risk of cardiovascular disease.

Effects of Dietary Fiber Intake on Cardiovascular Risk Factors 481

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#### **7. Acknowledgments**

The authors are grateful for the support granted by the Spanish Minister of Health (RETIC G03/140 and RD06/0045), the Spanish Minister of Science and Innovation (AGL2010-22319- C03-02), the FIS 070473, Centro Nacional de Investigaciones Cardiovasculares (CNIC06) and CIBEROBN that is an initiative of Instituto de Salud Carlos III, Spain. Sara Arranz received support from the Sara Borrell postdoctoral program with reference CD10/00151 supported by the Instituto de Salud Carlos III, Spain.

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**25**

*Spain*

Mercedes Sotos Prieto

**Mediterranean Diet and Gene-Mediterranean**

**Diet Interactions in Determining Intermediate**

*University of Valencia, Department of Preventive Medicine and Public Health and*

Currently, cardiovascular diseases (CVD) are one of the most important problems in the world. In fact, CVD are the first cause of death all over the world and, according to the World Health Organization (WHO), it is expected to remain so over coming years due to aging population and the increase of prevalence of CVD in countries with fewer resources. According to European statistics, 2008 for CVD, the leading causes of death in Europe are coronary heart disease and stroke. In Europe, deaths from these diseases are 4.3 million each year. Nearly half (48%) of all deaths are due to CVD (54% of deaths in women and 43% of deaths in men). Regional variations in cardiovascular mortality have been observed both between and within countries in Europe (Sans et al., 1997; Müller et al., 2004). Coronary heart disease mortality patterns showed a clear north–east to south–west gradient in CVD mortality (1990–1992; 45–74 years age-adjusted) with the lowest rates for both men and women in France, Spain, Switzerland, and Italy (Sans et al., 1997). Many factors could be

related to the different distribution (eating behaviours, life style, and genetics).

determinants to better understand and focus the aim of this chapter.

To begin with the development of this chapter it is necessary to consider firstly the health

The model of health fields proposed by Laframboise in 1973 and developed in Lalonde Report in 1974 (Lalonde 1974) has revolutionized contemporary public health due to the approaching and explaining of the health levels in the populations and therefore, the way of formulating health policies. Marc Lalonde proposed a new "health field" concept that can be broken up into four broad elements: Human biology, Environment, Lifestyle, and Health

Of the four determinants of health, the one which is most susceptible to be modified is lifestyle. Apart from not smoking, the most important lifestyle determinants of good health are what we eat and how active we are. A healthy diet helps to maintain or improve our health. However, as we said before, the CVD are increasing all over the word, and authorities view it as one of the most serious Public Health problems in the 21st century.

**1. Introduction**

Care Organization".

**Cardiovascular Disease Phenotypes**

*CIBER Fisiopatología de la Obesidad y Nutrición,*

### **Mediterranean Diet and Gene-Mediterranean Diet Interactions in Determining Intermediate Cardiovascular Disease Phenotypes**

Mercedes Sotos Prieto

*University of Valencia, Department of Preventive Medicine and Public Health and CIBER Fisiopatología de la Obesidad y Nutrición, Spain*

#### **1. Introduction**

488 Recent Advances in Cardiovascular Risk Factors

Wong, J. M., de Souza, R., Kendall, C. W., Emam, A., & Jenkins, D. J. (2006). Colonic health:

Wu, H., Dwyer, K. M., Fan, Z., Shircore, A., Fan, J., & Dwyer, J. H. (2003). Dietary fiber and

*Journal of Clinical Nutrition, 78*(6), 1085-1091.

235-243.

fermentation and short chain fatty acids. *Journal of clinical gastroenterology, 40*(3),

progression of atherosclerosis: the Los Angeles Atherosclerosis Study. *The American*

Currently, cardiovascular diseases (CVD) are one of the most important problems in the world. In fact, CVD are the first cause of death all over the world and, according to the World Health Organization (WHO), it is expected to remain so over coming years due to aging population and the increase of prevalence of CVD in countries with fewer resources.

According to European statistics, 2008 for CVD, the leading causes of death in Europe are coronary heart disease and stroke. In Europe, deaths from these diseases are 4.3 million each year. Nearly half (48%) of all deaths are due to CVD (54% of deaths in women and 43% of deaths in men). Regional variations in cardiovascular mortality have been observed both between and within countries in Europe (Sans et al., 1997; Müller et al., 2004). Coronary heart disease mortality patterns showed a clear north–east to south–west gradient in CVD mortality (1990–1992; 45–74 years age-adjusted) with the lowest rates for both men and women in France, Spain, Switzerland, and Italy (Sans et al., 1997). Many factors could be related to the different distribution (eating behaviours, life style, and genetics).

To begin with the development of this chapter it is necessary to consider firstly the health determinants to better understand and focus the aim of this chapter.

The model of health fields proposed by Laframboise in 1973 and developed in Lalonde Report in 1974 (Lalonde 1974) has revolutionized contemporary public health due to the approaching and explaining of the health levels in the populations and therefore, the way of formulating health policies. Marc Lalonde proposed a new "health field" concept that can be broken up into four broad elements: Human biology, Environment, Lifestyle, and Health Care Organization".

Of the four determinants of health, the one which is most susceptible to be modified is lifestyle. Apart from not smoking, the most important lifestyle determinants of good health are what we eat and how active we are. A healthy diet helps to maintain or improve our health. However, as we said before, the CVD are increasing all over the word, and authorities view it as one of the most serious Public Health problems in the 21st century.

Mediterranean Diet and Gene-Mediterranean Diet

consumption of poultry instead of other meats.

are being lost and should be restored.

al., 1986) (Figure 1).

2006).

**2.1 Definition of the Mediterranean diet**

Interactions in Determining Intermediate Cardiovascular Disease Phenotypes 491

countries bordering the Mediterranean Sea. Food habits have been consolidated over the centuries and are the result of geographical and climatic factors, as well as cultural, political and religious factors of Mediterranean people. Mediterranean area is identified by characteristics based on agriculture (natural grain, olives, wine and vegetables), fishing and

Furthermore, Mediterranean diet includes food and cooking techniques typical of Mediterranean countries which have been gradually abandoned by western patterns.

The Mediterranean diet has been described as a model from a nutritional point of view due to the good balance that provides its food items (micronutrients, vitamins, antioxidants). Nevertheless, as well as the cooking techniques have been abandoned, in the last few years changes in lifestyle have triggered a move away from the recommended intakes in relation to several nutrients. All these changes make it even more difficult to ensure adequate intakes of vitamins and minerals. This problem could affect more to certain risk groups such us women, the elderly, children, gestating and lactating women and ill people. Knowing the extent of this reality it seems worthy to inform people and society in general about the necessary changes in the diet and about the characteristics of the Mediterranean diet which

The concept of the Mediterranean diet originated from several observational studies in the 1950s, being the most known the Seven Countries Study initiated by Ancel Keys (Ancel Keys 1970). Subsequently, several studies have associated increased longevity, lower mortality and morbidity to Mediterranean diet (Keys et al., 1986; de Lorgeril et al., 1999; Singh et al., 2002; Trichopoulou et al., 2003; Knoops et al., 2004). Taken as a whole, these studies showed that, despite a high fat intake, these populations had low rates of coronary heart disease and other vascular diseases, cancer, inflammatory and degenerative diseases, resulting in a long life expectancy. The Mediterranean dietary pattern was considered to be largely responsible for the good health observed in these regions (Keys et al., 1986). Currently, there is a great number of clinical and epidemiological studies that have shown the benefits of the Mediterranean diet. However, these effects are attributed to the traditional Mediterranean diet and not to the Westernized patterns that nowadays

Although there are several variations of the Mediterranean diet, the main characteristics include high consumption (daily consumption) of vegetables, fruit, whole grain cereals and low fat dairy products; weekly consumption of fish, poultry, tree nuts and legumes; relatively low consumption of red meat (approximately twice a month) as well as moderate daily consumption of alcohol (preferably in the form of wine) normally with meals (keys et

Most of the articles published so far on Mediterranean diet are observational studies. However, there is a lack of intervention studies that demonstrate causal relationship. Although there are few randomized controlled trials of dietary intervention with Mediterranean Diet, we have recently strong data from one large randomize control trial supporting the beneficial effects of Mediterranean diet on CVD prevention (Estruch et al.,

characterize the South European countries (Serra-Majem et al., 2004).

CVD are complex and the risk factors that contribute to the development of CVD can be classified into different categories depending on whether they are modified or not (Posner et al., 1991, Haskell et al., 2003) and how they contribute to the development of CVD (Linton et al., 2003). Thus, on the one hand, we have not modifiable factors such as age, sex, family history and genetics. With regard to genetics, we inherit the genetic risk to develop CVD, but this risk can be modulated by other modifiable factors. In this chapter we will deeply discuss the relation between genes and environmental factors (especially diet) in the prevention of CVD (Figure 1).

On the other hand, we also have factors that are susceptible to be modified such as cholesterol concentrations, hypertension, smoking, diabetes, type of diet, obesity, sedentary lifestyle, stress and consumption of oral contraceptives. The more risk factors a person has, the higher risk of developing CVD. Some risk factors can be changed, treated or modified, and some others not. But controlling the largest possible number of risk factors through changes in lifestyle and/or drugs can reduce cardiovascular risk. Among the environmental factors associated with CVD, and as a part of one of the health determinants proposed by Lalonde, diet has a great impact on lipid metabolism, oxidative stress and the development of the atherosclerotic process (Ordovas et al., 2004) (Figure 1). Changes in eating behaviours have contributed to the growing epidemic of chronic diseases. These changes are characterized by an unbalanced diet consisting of food with a high density of energy rich in saturated fatty acids (SAF) as well as a decrease in physical activity. This process is called nutritional transition. Given these facts, researchers are trying to elucidate the best diet to prevent CVD. However, there is a widespread of controversy. Different proposals have been considered such as low-fat diet, diet low in carbohydrates and high in proteins, among others, all promoted by the acquisition of knowledge, fashion or business interests (Ordovas et al., 2004).

Traditionally, the American Heart Association (AHA) has based dietary recommendations for primary care of cardiovascular risk in a low-fat diet (Krauss MR et al, 2000).  This type of diet causes a decrease in total cholesterol (TC) and LDL-C, and a decrease or not variation in HDL-C and increases or unchanged triglycerides (TG) concentrations (Obarzanek et al., 2001; Lichtensein et al., 2002, Howard et al., 2006). Later on, in 2005, a new version of USDA pyramid in which food groups are presented in vertical and which incorporates the concept that the diet should be tailored to individual needs came up (USDA, 2005).

After the AHA recommendations, other types of diets have been proposed such as diets rich in protein, low carb, Mediterranean diet, etc. Mediterranean diet has attracted the most interest by its great relevance regarding the protective role in primary and secondary care of CVD.

The aim of this chapter is to analyse the role of the Mediterranean diet in determining intermediate CVD phenotypes. We also review one of the most emerging topics currently: the role of gene-Mediterranean diet interactions on CVD.

#### **2. Mediterranean diet**

Due to the great incidence of CVD, Mediterranean diet has gained a considerable popularity during the last decades. The Mediterranean area is a sociocultural construction built on the countries bordering the Mediterranean Sea. Food habits have been consolidated over the centuries and are the result of geographical and climatic factors, as well as cultural, political and religious factors of Mediterranean people. Mediterranean area is identified by characteristics based on agriculture (natural grain, olives, wine and vegetables), fishing and consumption of poultry instead of other meats.

Furthermore, Mediterranean diet includes food and cooking techniques typical of Mediterranean countries which have been gradually abandoned by western patterns.

The Mediterranean diet has been described as a model from a nutritional point of view due to the good balance that provides its food items (micronutrients, vitamins, antioxidants). Nevertheless, as well as the cooking techniques have been abandoned, in the last few years changes in lifestyle have triggered a move away from the recommended intakes in relation to several nutrients. All these changes make it even more difficult to ensure adequate intakes of vitamins and minerals. This problem could affect more to certain risk groups such us women, the elderly, children, gestating and lactating women and ill people. Knowing the extent of this reality it seems worthy to inform people and society in general about the necessary changes in the diet and about the characteristics of the Mediterranean diet which are being lost and should be restored.

#### **2.1 Definition of the Mediterranean diet**

490 Recent Advances in Cardiovascular Risk Factors

CVD are complex and the risk factors that contribute to the development of CVD can be classified into different categories depending on whether they are modified or not (Posner et al., 1991, Haskell et al., 2003) and how they contribute to the development of CVD (Linton et al., 2003). Thus, on the one hand, we have not modifiable factors such as age, sex, family history and genetics. With regard to genetics, we inherit the genetic risk to develop CVD, but this risk can be modulated by other modifiable factors. In this chapter we will deeply discuss the relation between genes and environmental factors (especially diet) in the

On the other hand, we also have factors that are susceptible to be modified such as cholesterol concentrations, hypertension, smoking, diabetes, type of diet, obesity, sedentary lifestyle, stress and consumption of oral contraceptives. The more risk factors a person has, the higher risk of developing CVD. Some risk factors can be changed, treated or modified, and some others not. But controlling the largest possible number of risk factors through changes in lifestyle and/or drugs can reduce cardiovascular risk. Among the environmental factors associated with CVD, and as a part of one of the health determinants proposed by Lalonde, diet has a great impact on lipid metabolism, oxidative stress and the development of the atherosclerotic process (Ordovas et al., 2004) (Figure 1). Changes in eating behaviours have contributed to the growing epidemic of chronic diseases. These changes are characterized by an unbalanced diet consisting of food with a high density of energy rich in saturated fatty acids (SAF) as well as a decrease in physical activity. This process is called nutritional transition. Given these facts, researchers are trying to elucidate the best diet to prevent CVD. However, there is a widespread of controversy. Different proposals have been considered such as low-fat diet, diet low in carbohydrates and high in proteins, among others, all promoted by

the acquisition of knowledge, fashion or business interests (Ordovas et al., 2004).

concept that the diet should be tailored to individual needs came up (USDA, 2005).

the role of gene-Mediterranean diet interactions on CVD.

Traditionally, the American Heart Association (AHA) has based dietary recommendations for primary care of cardiovascular risk in a low-fat diet (Krauss MR et al, 2000).  This type of diet causes a decrease in total cholesterol (TC) and LDL-C, and a decrease or not variation in HDL-C and increases or unchanged triglycerides (TG) concentrations (Obarzanek et al., 2001; Lichtensein et al., 2002, Howard et al., 2006). Later on, in 2005, a new version of USDA pyramid in which food groups are presented in vertical and which incorporates the

After the AHA recommendations, other types of diets have been proposed such as diets rich in protein, low carb, Mediterranean diet, etc. Mediterranean diet has attracted the most interest by its great relevance regarding the protective role in primary and secondary care of

The aim of this chapter is to analyse the role of the Mediterranean diet in determining intermediate CVD phenotypes. We also review one of the most emerging topics currently:

Due to the great incidence of CVD, Mediterranean diet has gained a considerable popularity during the last decades. The Mediterranean area is a sociocultural construction built on the

prevention of CVD (Figure 1).

CVD.

**2. Mediterranean diet**

The concept of the Mediterranean diet originated from several observational studies in the 1950s, being the most known the Seven Countries Study initiated by Ancel Keys (Ancel Keys 1970). Subsequently, several studies have associated increased longevity, lower mortality and morbidity to Mediterranean diet (Keys et al., 1986; de Lorgeril et al., 1999; Singh et al., 2002; Trichopoulou et al., 2003; Knoops et al., 2004). Taken as a whole, these studies showed that, despite a high fat intake, these populations had low rates of coronary heart disease and other vascular diseases, cancer, inflammatory and degenerative diseases, resulting in a long life expectancy. The Mediterranean dietary pattern was considered to be largely responsible for the good health observed in these regions (Keys et al., 1986). Currently, there is a great number of clinical and epidemiological studies that have shown the benefits of the Mediterranean diet. However, these effects are attributed to the traditional Mediterranean diet and not to the Westernized patterns that nowadays characterize the South European countries (Serra-Majem et al., 2004).

Although there are several variations of the Mediterranean diet, the main characteristics include high consumption (daily consumption) of vegetables, fruit, whole grain cereals and low fat dairy products; weekly consumption of fish, poultry, tree nuts and legumes; relatively low consumption of red meat (approximately twice a month) as well as moderate daily consumption of alcohol (preferably in the form of wine) normally with meals (keys et al., 1986) (Figure 1).

Most of the articles published so far on Mediterranean diet are observational studies. However, there is a lack of intervention studies that demonstrate causal relationship. Although there are few randomized controlled trials of dietary intervention with Mediterranean Diet, we have recently strong data from one large randomize control trial supporting the beneficial effects of Mediterranean diet on CVD prevention (Estruch et al., 2006).

Mediterranean Diet and Gene-Mediterranean Diet

2002).

countries.

**phenotypes**

Mediterranean diet.

diet on the aforementioned phenotypes.

**3.1 Mediterranean diet and obesity**

Interactions in Determining Intermediate Cardiovascular Disease Phenotypes 493

The *Lyon Diet Heart Study* (de Lorgeril et al., 1999), a randomized, controlled trial with freeliving subjects (half of 600 men and women in France), tested the effectiveness of a Mediterranean-type diet (consistent with the new AHA Dietary Guidelines) on composite measures of the coronary recurrence rate after a first myocardial infarction during 46 months. Subjects in the experimental group were instructed by cardiologists and dietitians to adopt a Mediterranean-type diet. They demonstrated the effectiveness of Mediterranean diet in the secondary care of CVD. However, the intervention group with Mediterranean diet received margarine rich in alpha-linolenic fatty acid, fact that distorted the interpretation of results, as margarine is not a component of traditional Mediterranean diet. Something similar happens with the Indo-Mediterranean Diet Heart Study (Singh et al.,

The *Indo Mediterranean Diet Heart* study is a randomized, single-blind trial in 1000 patients with angina pectoris, myocardial infarction, or surrogate risk factors for CVD. 499 patients were allocated to a diet rich in whole grains, fruits, vegetables, walnuts, and almonds. 501 controls consumed a local diet similar to the step I National Cholesterol Education Program (NCEP) prudent diet. They showed that an Indo-Mediterranean diet, that is rich in alinolenic acid, might be more effective in primary and secondary prevention of CVD than the conventional step I NCEP prudent diet. However, as in the Lyon Diet Heart Study, the intervention group with Mediterranean diet increased the consumption of alpha-linolenic fatty acid from soybean and mustard oil, which are not typical from Mediterranean

**3. Mediterranean diet in determining intermediate cardiovascular disease**

There is a great number of studies analysing the effect of the consumption or adherence to Mediterranean diet and intermediate CVD phenotypes. In the following sections we review the studies analysing Mediterranean diet and obesity, lipid metabolism, glucose concentrations, blood pressure and inflammation. Table 1 shows the effect of Mediterranean

Currently, it is not known which is the best diet is to lose weight (low-carb, high protein, low fat diet, etc.). Consumption of nuts, and high fat diets (rich in MUFA), characteristics of the Mediterranean diet, have been traditionally associated with an increased body weight by its high contain in fats. However, recent scientific evidence does not support these data. Adherence to Mediterranean diet was inversely associated with BMI and obesity in a crosssectional survey carried out in the northeast of Spain (Schröder et al., 2004). Obesity risk decreased in both men and women with increasing adherence to the traditional

Results from epidemiological studies on large populations indicate that subjects who usually consume nuts have lower BMI than those who do not consume (Bes-Rastrollo et al, 2009, Garcia-Lorda et al, 2003; Schroder et al, 2004). In addition, the SUN cohort (Seguimiento Universidad de Navarra) (follow-up University of Navarra) evaluated 11,895 participants and found an inverse association between consumption of nuts and weight gain

#### **2.2 Principal studies that focus on Mediterranean diet and cardiovascular diseases**

In general, there is a predominance of observational studies related to Mediterranean Diet compared to clinical trials in the study of CVD. Thus, most of the studies are cross-sectional studies with a level III of evidence (based on the quality of evidence according to the 2nd edition of the U.S. Task Force (Harris et al., 2001)). The *ATTICA* study is the most remarkable (Pitsavos et al., 2003) and it was conducted on a representative sample of Greek men and women recruited from May 2001 to December 2002 in order to analyze cardiovascular risk factors, establish associations with lifestyle, socioeconomic factors, psychological characteristics, and assess their impact on CVD over a year, five and ten years. Several studies found a positive association between Mediterranean Diet and CVD (Tzima et al., 2007; Panagiotakos et al., 2006; Pitsavos et al., 2007).

Two other large European cohort studies (evidence level II-2) include the Greek cohort within *EPIC* (European Prospective Investigation into Cancer) (Trichopoulou et al., 2003, Slimani et al., 2002). They study the relationship between nutrition and cancer in 519,978 participants from 23 centers located in 20 European countries.

Another cohort study is the *HALE* (Knoops et al., 2004) (Healthy Ageing: Longitudinal Study in Europe). This project analyzed age-related changes and the determinants of healthy aging in terms of mortality and morbidity, and physical, mental, cognitive and social functionality in 13 European countries. Results from this study suggest that a high adherence to Mediterranean diet is associated with a reduction in both overall mortality and cardiovascular mortality.

Regarding intervention studies (level I of scientific evidence), two of the most known studies analyzing Mediterranean Diet are *PREDIMED* study (Prevention with Mediterranean diet) (Estruch et al., 2006) and *Medi-RIVAGE* study (Mediterranean Diet, Cardiovascular Risks and Gene Polymorphism) (Vincent-Baudry et al., 2005).

*PREDIMED* study is a multicenter, prospective, randomized, controlled trial whose goals are to assess the efficacy and safety of a Mediterranean diet in primary care of CVD. It was designed in 2002 and it is the first long-term clinical trial that recruits high-risk patients (around 7,000 participants from different regions in Spain) to follow a Mediterranean diet supplemented with virgin olive oil (VOO) (1 liter a week) or nuts (30 g per day of which 15 g almonds and 15 g walnuts).

*Medi-RIVAGE* study is a randomized clinical trial conducted in France on 212 women and men with at least one cardiovascular risk factor. The aims of the study are to evaluate the effect of two types of diet in the prevention of CVD and to investigate biological mechanisms and genetic polymorphisms related to metabolism. On the one hand, they study the traditional Mediterranean diet (35-38% of total energy from fat: 50% monounsaturated fatty acids (MUFA), 25% polyunsaturated fatty acids (PUFA), 25% SFA) and on the other hand, a low fat diet based on the AHA (30% of total energy from fat: 33% MUFA, 33% PUFA, 33% SFA).

With regard to studies that analyze final cardiovascular risk phenotypes, two of the most outstanding studies (level I of scientific evidence) are the Lyon Diet Heart Study and the Indio-Mediterranean Diet Heart study.

Two other large European cohort studies (evidence level II-2) include the Greek cohort within *EPIC* (European Prospective Investigation into Cancer) (Trichopoulou et al., 2003, Slimani et al., 2002). They study the relationship between nutrition and cancer in 519,978

Another cohort study is the *HALE* (Knoops et al., 2004) (Healthy Ageing: Longitudinal Study in Europe). This project analyzed age-related changes and the determinants of healthy aging in terms of mortality and morbidity, and physical, mental, cognitive and social functionality in 13 European countries. Results from this study suggest that a high adherence to Mediterranean diet is associated with a reduction in both overall mortality and

Regarding intervention studies (level I of scientific evidence), two of the most known studies analyzing Mediterranean Diet are *PREDIMED* study (Prevention with Mediterranean diet) (Estruch et al., 2006) and *Medi-RIVAGE* study (Mediterranean Diet,

*PREDIMED* study is a multicenter, prospective, randomized, controlled trial whose goals are to assess the efficacy and safety of a Mediterranean diet in primary care of CVD. It was designed in 2002 and it is the first long-term clinical trial that recruits high-risk patients (around 7,000 participants from different regions in Spain) to follow a Mediterranean diet supplemented with virgin olive oil (VOO) (1 liter a week) or nuts (30 g per day of which 15

*Medi-RIVAGE* study is a randomized clinical trial conducted in France on 212 women and men with at least one cardiovascular risk factor. The aims of the study are to evaluate the effect of two types of diet in the prevention of CVD and to investigate biological mechanisms and genetic polymorphisms related to metabolism. On the one hand, they study the traditional Mediterranean diet (35-38% of total energy from fat: 50% monounsaturated fatty acids (MUFA), 25% polyunsaturated fatty acids (PUFA), 25% SFA) and on the other hand, a low fat diet based on the AHA (30% of total energy from fat: 33%

With regard to studies that analyze final cardiovascular risk phenotypes, two of the most outstanding studies (level I of scientific evidence) are the Lyon Diet Heart Study and the

Cardiovascular Risks and Gene Polymorphism) (Vincent-Baudry et al., 2005).

**2.2 Principal studies that focus on Mediterranean diet and cardiovascular diseases** In general, there is a predominance of observational studies related to Mediterranean Diet compared to clinical trials in the study of CVD. Thus, most of the studies are cross-sectional studies with a level III of evidence (based on the quality of evidence according to the 2nd edition of the U.S. Task Force (Harris et al., 2001)). The *ATTICA* study is the most remarkable (Pitsavos et al., 2003) and it was conducted on a representative sample of Greek men and women recruited from May 2001 to December 2002 in order to analyze cardiovascular risk factors, establish associations with lifestyle, socioeconomic factors, psychological characteristics, and assess their impact on CVD over a year, five and ten years. Several studies found a positive association between Mediterranean Diet and CVD (Tzima

et al., 2007; Panagiotakos et al., 2006; Pitsavos et al., 2007).

participants from 23 centers located in 20 European countries.

cardiovascular mortality.

g almonds and 15 g walnuts).

MUFA, 33% PUFA, 33% SFA).

Indio-Mediterranean Diet Heart study.

The *Lyon Diet Heart Study* (de Lorgeril et al., 1999), a randomized, controlled trial with freeliving subjects (half of 600 men and women in France), tested the effectiveness of a Mediterranean-type diet (consistent with the new AHA Dietary Guidelines) on composite measures of the coronary recurrence rate after a first myocardial infarction during 46 months. Subjects in the experimental group were instructed by cardiologists and dietitians to adopt a Mediterranean-type diet. They demonstrated the effectiveness of Mediterranean diet in the secondary care of CVD. However, the intervention group with Mediterranean diet received margarine rich in alpha-linolenic fatty acid, fact that distorted the interpretation of results, as margarine is not a component of traditional Mediterranean diet. Something similar happens with the Indo-Mediterranean Diet Heart Study (Singh et al., 2002).

The *Indo Mediterranean Diet Heart* study is a randomized, single-blind trial in 1000 patients with angina pectoris, myocardial infarction, or surrogate risk factors for CVD. 499 patients were allocated to a diet rich in whole grains, fruits, vegetables, walnuts, and almonds. 501 controls consumed a local diet similar to the step I National Cholesterol Education Program (NCEP) prudent diet. They showed that an Indo-Mediterranean diet, that is rich in alinolenic acid, might be more effective in primary and secondary prevention of CVD than the conventional step I NCEP prudent diet. However, as in the Lyon Diet Heart Study, the intervention group with Mediterranean diet increased the consumption of alpha-linolenic fatty acid from soybean and mustard oil, which are not typical from Mediterranean countries.

#### **3. Mediterranean diet in determining intermediate cardiovascular disease phenotypes**

There is a great number of studies analysing the effect of the consumption or adherence to Mediterranean diet and intermediate CVD phenotypes. In the following sections we review the studies analysing Mediterranean diet and obesity, lipid metabolism, glucose concentrations, blood pressure and inflammation. Table 1 shows the effect of Mediterranean diet on the aforementioned phenotypes.

#### **3.1 Mediterranean diet and obesity**

Currently, it is not known which is the best diet is to lose weight (low-carb, high protein, low fat diet, etc.). Consumption of nuts, and high fat diets (rich in MUFA), characteristics of the Mediterranean diet, have been traditionally associated with an increased body weight by its high contain in fats. However, recent scientific evidence does not support these data. Adherence to Mediterranean diet was inversely associated with BMI and obesity in a crosssectional survey carried out in the northeast of Spain (Schröder et al., 2004). Obesity risk decreased in both men and women with increasing adherence to the traditional Mediterranean diet.

Results from epidemiological studies on large populations indicate that subjects who usually consume nuts have lower BMI than those who do not consume (Bes-Rastrollo et al, 2009, Garcia-Lorda et al, 2003; Schroder et al, 2004). In addition, the SUN cohort (Seguimiento Universidad de Navarra) (follow-up University of Navarra) evaluated 11,895 participants and found an inverse association between consumption of nuts and weight gain

Mediterranean Diet and Gene-Mediterranean Diet

Interactions in Determining Intermediate Cardiovascular Disease Phenotypes 495

Moreover, seven studies of 29 clinical trials with 3,822 subjects (2,202 assigned to Mediterranean diet and 1,903 assigned to a control diet) reported beneficial effects of adherence to Mediterranean diet on HDL-C (Papadaki & Scott, 2008; Esposito et al., 2004; Estruch et al., 2006; Esposito et al., 2003; Esposito et al., 2009; Athryros et al., 2011). A recent meta-analysis (Kastorini et al., 2011) showed that, overall, adherence to Mediterranean diet

Benefits in TC have also been shown in some randomized controlled trials (Estruch et al., 2006; Vincent-Baudry et al., 2005; Ambring et al., 2004). In this sense, Estruch et al., (2006) carried out a study of 3 months with individuals who had diabetes mellitus or one or more cardiovascular risk factors, which were assigned to three intervention groups (n = 257-8 / group) (2 Mediterranean diet (one supplemented with VOO and another one with 15g of almonds+15g walnuts/day) and one control diet low in fats). Regarding the lipid profile, both Mediterranean diets showed significant increase in HDL-C levels (p = <0.001 and p = 0.006, respectively) and a significant reduction (p <0.001 and p = 0.002, respectively) in the atherogenic index (TC/HDL-C) in contrast to the control group. However, only Mediterranean diet supplemented with nuts showed a significantly reduction in TC (p = 0.040) and TG (p = 0.022), compared to control. Neither of the Mediterranean diets

Concerning TG, three observational studies reported a beneficial effect of Mediterranean diet (Chrysohoou et al., 2004; Tzima et al., 2007; Barzi et al., 2003) as compared with low adherence to Mediterrenean diet. Five interventional studies showed beneficial effects of Mediterranean diet on TG concentrations (Shai et al., 2008; Esposito et al., 2004; Estruch et al., 2006; Esposito et al., 2009; Elhayany et al., 2011), whereas other studies did not find significant differences (de Lorgeril et al., 1994; Castro et al., 2000; Michalsen et al., 2006).

Moreover, results from a crossover study during 4 weeks for each intervention (22 healthy people (12H/10M)) found an improvement in lipid profile to compare a Mediterranean diet (rich in omega 3) with a Swedish standard diet (Ambring et al., 2004). The results showed a significant decrease in TC, LDL-C, TG (17%, 22%, and 17%) in the group with Mediterranean diet. On the other hand, one non-randomize control trial carried out in Italy (47 obese women) during 4-month with an hypoenergetic Mediterranean diet together with a program of physical exercise showed a significant decrease in total cholesterol and TG concentrations. Levels of LDL-C decreased (p <0.001) after 4 months of intervention, whereas HDL-C increased (Andreoli et al., 2008). However, another study carried out in 71 healthy Canadian found a significant decrease in TC at 6 weeks of intervention (p <0.05), whereas no significant changes were observed after 12 weeks. Levels of HDL-C, LDL-C and TG were not affected after 6 or 12 weeks of intervention (Goulet et al., 2003). Different characteristics of the recruitment of individuals can influence the final results of the studies. The relationship between nut consumption and reduced risk of CVD has been established in numerous epidemiological studies. Thus, Ros et al (2004), in a crossover study carried out in hypercholesterolemia subjects in Spain, determined whether a diet containing nuts (18% of energy) could improve markers related to endothelial function against another typical Mediterranean diet with similar energy intake, fat, protein, carbohydrates, but not MUFA intake, after 4 weeks. Estruch et al (2006) also found a significant decrease in TC (p = 0.017) and LDL-C (p = 0.010). However, no differences were found in TG concentrations and HDL-

was associated with higher HDL-C levels as compared with a control diet.

significantly reduced LDL-C compared to the control diet (low fat diet).

per year (Martinez-Gonzalez & Bes-Ballostro, 2011). Similarly, a recent study carried out in EPIC-PANACEA project showed that individuals with high adherence to Mediterranean diet, according to the score based on a questionnaire of adherence to Mediterranean diet (11- 18 points), showed in a weight change of 20.16 kg (95% CI :20,2-20, 7 kg) 5 years and they were also 10% less likely to become overweight and obese compared with individuals with lower adherence (0-6 points) (Romaguera et al., 2010). Furthermore, a study that evaluated 497,308 individuals aged between 25-70 years in 10 European countries found that high adherence to the Mediterranean diet is associated with lower abdominal adiposity, using waist circumference as a measure (Romaguera et al., 2009).

With respect to intervention studies, it has been shown that subjects that consume daily tree nuts in their diet are less likely to gain weight (Li et al., 2010). A study evaluating the intake of almonds (42-72 g daily) in 81 patients over 6 months found that there was no significant weight gain (Fraser et al., 2002). Similarly, García-Londa et al, (2003) found that in the short term, the addition of tree nuts to diet, in amounts up to 50 g daily, does not increase weight. After one year of intervention in the PREDIMED study, beneficial effects on waist circumference were shown (Martinez-Gonzalez & Bes-Ballostro, 2011).

Finally, a meta-analysis regarding Mediterranean diet and weight loss analyzing randomize controlled trials has been recently published (Esposito et al., 2011), and it concludes that Mediterranean diet does not cause weight gain, which removes the objection to its relatively high fat content. Mediterranean diet could be a strategy to help people lose weight.

Some of the proposed mechanisms that might explain these facts are that the absorption of nuts may be incomplete, thus some of its fat content may not be absorbed by the body and would be excreted in the feces. Moreover, the consumption of nuts may have a satiating effect, producing a decrease in consumption of other foods and helping to control total energy intake. Although it still has not been proved, there may be an adaptation of the metabolism, so that energy consumption could be more efficient and get the body burn more energy, thus avoiding an accumulation of body fat (Brennan et al., 2010; Garcia-Lorda et al., 2003; Rajaram & Sabaté, 2006).

#### **3.2 Mediterranean diet and lipid metabolism**