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Effects of pistachios on cardiovascular disease risk factors and potential mechanisms of action: a dose-response study^1,2,3

¹ From Integrative Biosciences (SKG and PMK-E) and the Departments of Nutritional Sciences (CDK, DB, and PMK-E) and Biobehavioral Health (SGW and CDK), Pennsylvania State University; Oklahoma Medical Research Foundation, (PA)

² Supported by the California Pistachio Commission, the Lester and Audrey Peters ('46) Hogan Scholarship Fund, and the GCRC, Pennsylvania State University (NIH grant M01RR10732).

³ Address reprint requests and correspondence to PM Kris-Etherton, Department of Nutritional Sciences, S-126 Henderson Building, Pennsylvania State University, University Park, PA 16802. E-mail: pmk3{at}psu.edu.

	ABSTRACT

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Background:Nut consumption lowers cardiovascular disease (CVD) risk. Studies are lacking about the effects of pistachios, a nutrient-dense nut, on CVD risk factors, dose-response relations, and lipid-lowering mechanisms.

Objective:We evaluated the effects of 2 doses of pistachios, added to a lower-fat diet, on lipids and lipoproteins, apolipoprotein (apo)-defined lipoprotein subclasses, and plasma fatty acids. To investigate the mechanisms of action, we measured cholesteryl ester transfer protein and indexes of plasma stearoyl-CoA desaturase activity (SCD).

Design:In a randomized crossover controlled-feeding study, 28 individuals with LDL cholesterol 2.86 mmol/L consumed 3 isoenergetic diets for 4 wk each. Baseline measures were assessed after 2 wk of a typical Western diet. The experimental diets included a lower-fat control diet with no pistachios [25% total fat; 8% saturated fatty acids (SFAs), 9% monounsaturated fatty acids (MUFAs), and 5% polyunsaturated fatty acids (PUFAs)], 1 serving/d of a pistachio diet (1 PD; 10% of energy from pistachios; 30% total fat; 8% SFAs, 12% MUFAs, and 6% PUFAs), and 2 servings/d of a pistachio diet (2 PD; 20% of energy from pistachios; 34% total fat; 8% SFAs, 15% MUFAs, and 8% PUFAs).

Results:The 2 PD decreased (P < 0.05 compared with the control diet) total cholesterol (–8%), LDL cholesterol (–11.6%), non-HDL cholesterol (–11%), apo B (–4%), apo B/apo A-I (–4%), and plasma SCD activity (–1%). The 1 PD and 2 PD, respectively, elicited a dose-dependent lowering (P < 0.05) of total cholesterol/HDL cholesterol (–1% and –8%), LDL cholesterol/HDL cholesterol (–3% and –11%), and non-HDL cholesterol/HDL cholesterol (–2% and –10%).

Conclusions:Inclusion of pistachios in a healthy diet beneficially affects CVD risk factors in a dose-dependent manner, which may reflect effects on SCD.

	INTRODUCTION

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Epidemiologic and clinical studies have established cardioprotective effects of tree nuts and the legume peanuts (1–4). Almonds and walnuts have been studied most extensively; less is known about the effects of other nuts, including pistachios. Pistachios have a unique nutrient and fatty acid profile. They are a good source of unsaturated fatty acids and numerous antioxidants, including -tocopherol, β-carotene, lutein, selenium, flavonoids, and phytoestrogens (5, 6). Compared with other commonly consumed nuts, pistachios are the richest source of phytosterols (279 mg total phytosterols/100 g; 210 mg β-sitosterol/100 g, as the predominant phytosterol) (7), potassium (1042 mg/100 g), vitamin B-6 (1.3 mg/100 g), β-carotene (157 µg/100 g), and lutein + zeaxanthin (1205 µg/100 g) and are one of the richest sources of protein (21.4 g/100 g), fiber (10.3 g/100 g), selenium (9.3 mcg/100 g), and -tocopherol (22.5 mg/100 g) (5). Previous studies have shown beneficial effects of pistachios (15–20% of energy) on lipids and lipoproteins; however, significant reductions in LDL cholesterol, VLDL cholesterol, apolipoprotein (apo) A-I, and apo B have not been reported (8–10). Although the fatty acid composition of pistachios has been proposed as the primary mechanism for lipid lowering (9), previous studies have not reported plasma fatty acid profiles or evaluated other potential mechanisms of action.

Many studies have assessed the effects of nutrients and foods on concentrations of apo A-I and apo B, which have been shown to have antiatherogenic and proatherogenic effects, respectively. However, individual lipid particles include several apolipoproteins. Recent work suggests that these unique apolipoprotein-defined lipoprotein profiles may determine their relative atherogenicity and clearance rate (11) and that unsaturated fatty acids affect apolipoprotein-defined lipoprotein profiles (11, 12).

The present study comprehensively evaluated the effects of heart-healthy diets that included 2 doses of pistachios on cardiovascular disease (CVD) risk using multiple risk factors, including lipids, lipoproteins, apolipoproteins, and plasma fatty acids. We also assessed whether the experimental diets affected 2 metabolic pathways that are essential for lipid metabolism. Cholesteryl ester transfer protein (CETP) is a plasma protein that plays a key role in reverse cholesterol transport by transferring cholesteryl esters (CEs) from HDL particles to LDL and VLDL particles in exchange for triacylglycerols. Stearoyl-CoA desaturase (SCD) is the rate-limiting enzyme that catalyzes the synthesis of monounsaturated fatty acids (MUFAs; 18:1 and 16:1) from saturated fatty acids (SFAs; 18:0 and 16:0) and plays an important role in cholesterol, triacylglycerol, and lipoprotein metabolism. Both CETP and SCD have been shown to be regulated by fatty acids (13, 14) and are important potential mechanisms to explain how pistachios affect lipids and lipoproteins. To our knowledge, this is the first randomized controlled feeding study to assess potential mechanisms that may account for the lipid and lipoprotein responses to a cholesterol-lowering diet with varying doses of pistachios.

	SUBJECTS AND METHODS

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Subjects and study design
Twenty-eight men (n = 10) and women (n = 18) with elevated LDL cholesterol (2.86 mmol/L) completed the study. Nine women were not menstruating (4 because of natural menopause and 5 because of hysterectomies, 4 of whom had their ovaries removed). One subject dropped out because of an inability to comply with the study protocol. Inclusion criteria were as follows: triacylglycerols < 3.94 mmol/L, blood pressure < 160/90 mm Hg, body mass index (BMI; in kg/m²) between 21 and 35, and fasting blood glucose 6.93 mmol/L. All participants were otherwise in good health and nonsmokers. Exclusion criteria included the inability to comply with the study protocol, the use of blood pressure–or cholesterol/lipid-lowering medication or substances (psyllium, fish oil, soy lecithin, and phytoestrogens), being pregnant or wishing to become pregnant 6 mo before or during the study, lactating 6 wk before or during the study, having a weight loss 10% body weight within the 6 mo before the study, following vegetarian or weight-loss diets, or having any of the following conditions: stroke, diabetes, liver disease, kidney disease, or autoimmune diseases. The Institutional Review Board at the Pennsylvania State University approved the experimental protocol, and all subjects provided written informed consent. Body weight was assessed by using a digital scale at the General Clinical Research Center (GCRC) at the Pennsylvania State University.

The study used a 3-period randomized crossover controlled-feeding design. A 2-wk run-in period preceded the first test diet to establish a baseline for a typical American diet. Subjects were then randomly assigned to 3 treatment diets for 4 wk each. Short compliance breaks (average of 2 wk) separated the diet periods. Study personnel who measured outcome variables were blinded to the diet assignments.

Diets
The nutrient composition of the diets is shown in Table 1. Total energy was held constant throughout the 3 feeding periods. An average intake of 2500 kcal/d was required to maintain weight. The run-in diet was a typical American diet, and the control diet was designed as a Step I diet, both with no pistachios. The typical American diet contained full-fat cheese and dairy products and more oil and butter, whereas the Step I diet contained low-fat or nonfat versions of these foods and less oil and butter. All diets were rich in fruit, vegetables, lean meats, and whole grains, consistent with current food-based dietary recommendations. For the pistachio diets, pistachio intake was calculated as 10% and 20% of total energy, and the doses ranged from 32 to 63 g/d and from 63 to 126 g/d, respectively, depending on calorie level assignment. The pistachio diets (PD) are referred to by the number of servings of pistachios consumed per day (1 PD and 2 PD), according to the Food and Drug Administration definition of a serving for the nuts and heart disease health claim. As expected, the pistachio diets were higher in protein and unsaturated fats and lower in carbohydrate. The control and pistachio diets were matched for SFAs and cholesterol. The pistachio diets were lower in sodium than was the control diet because of the substitution of pistachios (roasted and salted) as a snack for pretzels and baked potato chips, which are higher in sodium. All meals and snacks were prepared at the Metabolic Diet Study Center at the Pennsylvania State University. Blood was drawn on 2 consecutive days at the end of each diet period. Participants ate one meal per day, Monday through Friday, in the center and had their other meals prepared and packed for off-site consumption. Adherence with the experimental diets was very good, as indicated by daily compliance questionnaires. In addition, linoleic acid (LA) in plasma dose-dependently increased with the pistachio diets and was consistent with dietary approximations. Also, the subjects were weighed daily. Pistachios were consumed as a snack (50% of dose; roasted and salted) and were incorporated into various recipes (50% of dose; roasted and unsalted).

Lipids, lipoproteins, apolipoproteins, and CETP
Total cholesterol and triacylglycerols were measured by using enzymatic procedures with commercially available kits (total cholesterol: CHOP/PAP, Boeringer, Mannheim, Mannheim, Germany; triacylglycerols and free glycerol: Abbott Laboratories, Diagnostic Division, Irving, TX). HDL cholesterol was estimated according to the modified heparin-manganese precipitation procedure of Warnick and Albers (15). LDL cholesterol was calculated by using Friedewald's equation: LDL cholesterol = total cholesterol –(HDL cholesterol + triacylglycerols/5) (16). Apolipoprotein analyses were carried out in the laboratory of one of the authors (PA), as previously described (12). Serum CETP concentrations were measured by using an enzyme-linked immunosorbent assay kit (Wako Diagnostics, Richmond, VA) and carried out in the Pennsylvania State University GCRC Cytokine Core Laboratory. The intraassay CVs ranged from 1.5% to 1.6% for lipids and lipoproteins, 1.0% to 6.5% for apolipoproteins, and 5.0% to 5.4% for CETP.

Insulin and glucose
Insulin was measured by radioimmunoassay by using ¹²⁵I-labeled human insulin and a human insulin antiserum (cross-reactivity with proinsulin < 0.2%; Linco Research, St Charles, MO) (17). Glucose was determined with an immobilized enzyme biosensor using the YSI 2300 STAT Plus Glucose & Lactate Analyzer (Yellow Springs Instruments, Yellow Springs, OH) (18). Insulin and glucose were measured at Hershey Medical Center (in Laurence Demers' laboratory).

Plasma fatty acids
Plasma fatty acids were measured at the University of Guelph (in Bruce Holub's laboratory). Fatty acids were extracted according to the method described by Folch et al (19) in the presence of the internal standard. Fatty acid methyl esters were prepared by using boron trichloride in methanol and heating the methylation tubes in a boiling water bath. Fatty acid methyl ester profiles were measured on a Varian 3400 chromatograph (Varian, Palo Alto, CA) with an autosampler (model 8200) equipped with a flame ionization detector and a J&W DB-23 fused silica capillary column (60 m x 0.32 mm, 0.2-µm film thickness). The column parameters were as follows: an initial column temperature of 50 °C was maintained for 0.8 min; the temperature was then programmed at 15 °C/min to 158 °C and remained at this temperature for 0 min and then at 1.5 °C/min to 186 °C with a hold time of 0 min. The final temperature was programmed at 50 °C/min to 220 °C for 1 min. Injector and detector temperatures were 250 and 260 °C, respectively. The carrier gas was hydrogen at 40 cm/min. Hydrogen flow to the detector was 30 mL/min, airflow was 350 mL/min, and the flow of nitrogen make-up gas was 20 mL/min. Fatty acid peaks were identified by using pure methyl ester standards (GLC-617; Nu-Chek Prep, Inc, Elysian, MN) and Varian Star software (version 5.51; Varian, Palo Alto, CA). All chemicals and solvents were analytic grade. The ratios of plasma 16:1 to 16:0 and of 18:1 to 18:0 were used as markers of SCD activity.

Statistical analyses
All statistical analyses were performed by using SAS (version 9.1; Statistical Analyses System, Cary, NC). The natural logarithmic transformation was used on the variable BMI, and the analysis was performed using transformed values. The results are reported as least-squares means ± SEMs. The mixed-models procedure (PROC MIXED) in SAS was used to test the effects of diet, order, period, and their interactive effects on each outcome variable. Tukey-Kramer–adjusted P values were used to determine whether the differences in the outcome variables were significant (20, 21). Change scores for each variable were calculated by subtracting the value at the end of the run-in period (the pretreatment baseline) from the end of the treatment value. Percentage change was calculated from baseline. Within-subject correlations were used to test associations between clinical variables (lipids, lipoproteins, and apolipoproteins) and mechanistic variables (CETP and SCD activity). PROC GLM was used to test whether the slopes of the regression lines were equal across the 3 diets. When that requirement was met, correlations were reported as pooled values, collapsing across the treatments and taking into account the fact that repeated measurements from each subject were not independent.

	RESULTS

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Subject characteristics at baseline
The baseline characteristics of the participants are presented in Table 2. Women were significantly older than men (50.9 ± 1.7 y compared with 43.6 ± 2.2 y; P < 0.05). No other baseline characteristics were significantly different between men and women. Diets were designed to be isocaloric, and there was no significant difference in pre- and posttreatment means for body weight (76.6 ± 2.5 compared with 76.1 ± 2.5 kg; P > 0.05) and BMI (26.7 ± 0.7 compared with 26.6 ± 0.7; P > 0.05). In addition, there were no significant differences in body weight or BMI when the control diet was compared with the pistachio diets (P > 0.05).

Table 3

Figure 1

View larger version (10K): [in this window] [in a new window]   FIGURE 1. Percentage change (± SEM) in lipids and lipoproteins from baseline (n = 28). The MIXED procedure (version 9.1; SAS Institute Inc, Cary, NC) was used to test the effects of diet. *Significantly different from the control diet (P < 0.05). Significantly different from 1 PD (P < 0.05).

Table 4

Table 5

In the group as a whole, CETP concentrations were not significantly different between the experimental diets (Table 3). We also examined the relations between CETP and lipids and lipoproteins irrespective of diet. Individuals with lower baseline triacylglycerols (median: <1.08 mmol/L; n = 17) had significantly higher concentrations of CETP (Figure 2). Furthermore, individuals with a higher baseline CETP concentration (median: 1.3 mg/L; n = 15) had significantly lower VLDL-cholesterol and triacylglycerol concentrations (Figure 3) and apo C-III (not shown).

View larger version (5K): [in this window] [in a new window]   FIGURE 2. Comparison of cholesteryl ester transfer protein (CETP) in individuals with relatively low (<2.5 mmol/L) or high (2.5 mmol/L) triacylglycerol (TG) concentrations. The MIXED procedure (version 9.1; SAS Institute Inc, Cary, NC) was used to test the effects of diet and group and the diet x group interaction. Individuals with lower TG concentrations had significantly higher concentrations of CETP (significant effect of group: P < 0.05). The diet x TG group interaction was not significant.

View larger version (8K): [in this window] [in a new window]   FIGURE 3. Comparison of triacylglycerol (TG) and VLDL-cholesterol concentrations in individuals with relatively low (<1.3 mg/L) or high (1.3 mg/L) cholesteryl ester transfer protein (CETP) concentrations. The MIXED procedure (version 9.1; SAS Institute Inc, Cary, NC) was used to test the effects of diet and group and the diet x group interaction. Individuals with a higher CETP concentration had a significantly lower TG and VLDL-cholesterol concentration (significant effect of group: P < 0.05). The diet x CETP group interaction was not significant for the TG or VLDL-cholesterol concentration.

	DISCUSSION

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Previous studies using similar doses of pistachios (15–20% of total energy) found no significant changes in LDL cholesterol, VLDL cholesterol, triacylglycerols, apo A-I, or apo B (8–10), perhaps because they relied on participants to consume pistachios (and replace other foods) under free-living conditions and assessed intake by diet records. Controlled-feeding studies are very important for studying energy-dense foods, such as nuts, because total calorie intake can be held constant while the fatty acid profile of the diets is varied systematically. Our approach was to exchange a fixed percentage of total energy (10% and 20% of total energy) for pistachios, while keeping SFAs, cholesterol, energy, and body weight constant.

In several clinical studies of nuts, including this one, LDL cholesterol lowering was greater than predicted on the basis of the fatty acid profile of the test diets (1, 26). The LDL cholesterol reduction that we observed was 7 times that expected on the basis of fatty acid composition alone (27). This suggests that the lipid-lowering effects in this study not only reflect the fatty acid profile of the diet, but also are the result of other bioactive components in pistachios, such as phytosterols and fiber. The 1 PD and 2 PD provided 103 mg and 321 mg of phytosterols/d, respectively, whereas the Step I control diet provided 37.5 mg/d (5). A meta-analysis of the effects of stanols and sterols on cholesterol showed that intake of 2 g/d of stanols or sterols reduced LDL cholesterol by 10% with additive effects with other diet interventions; trials testing lower doses suggest that half of the effect may be achieved at doses of 0.7 to 1.5 g/d (28). Irrespective of the mechanisms, it is apparent that pistachios, and specifically the "package" of nutrients and bioactive factors that they bring to the diet, account for the marked beneficial effects on lipids and lipoproteins.

It was surprising that the lower-fat control diet did not decrease total cholesterol or LDL cholesterol as designed. The control diet was lower in PUFAs and higher in carbohydrates than were the run-in and pistachio diets, and this may partially explain the lack of LDL cholesterol response. As was reported in several previous clinical studies reviewed in references 29 and 30, triacylglycerols increased during a Step I diet. Increasing the total fat intake by adding pistachios to the diet prevented this potentially adverse response. The finding of a lower triacylglycerol concentration with the 2 PD than with the control diet is consistent with the significant reduction observed in non-HDL cholesterol after the 2 PD.

The reduction in apo B with the 2 PD reflects the significant decrease in the atherogenic cholesterol-rich LpB subclass. Recent evidence suggests that apo B concentrations and the ratio of apo B/apo A-I may be a better predictor than LDL cholesterol as an index of CVD risk (25, 31, 32). A recent study of the acute effects of individual fatty acids on apo B–containing lipoproteins indicates that unsaturated fatty acids differentially affect apo B–containing lipoprotein subclasses (12). Our study is one of the first to test the chronic effects of diet on apolipoprotein-defined lipoprotein subclasses and indicates that pistachio consumption in the context of a heart-healthy diet may reduce concentrations of atherogenic apo B, LpB, and LpB:E+LpB:C:E.

We also examined potential underlying mechanisms that might explain the cholesterol-lowering effects of pistachios. SCD plays an important role in lipid metabolism by catalyzing the synthesis of MUFAs, mainly 18:1 and 16:1, from SFAs. The ratio of SFAs to MUFAs in plasma reflects the membrane phospholipid composition, and increases in this ratio have been implicated in diseases such as CVD, obesity, and diabetes (14). Hepatic SCD1 gene expression has been shown to be up-regulated by numerous dietary factors, including high-carbohydrate diets, glucose, and cholesterol and it is down-regulated by PUFAs (14). In this study, consuming a nut that contains high levels of unsaturated fats resulted in a significantly lower ratio of 16:1/16:0. The direct correlations between change in SCD activity and lipids and lipoproteins suggest that SCD activity may contribute to the lipid-lowering effects of pistachios.

CETP mediates the transfer of CEs from HDL to VLDL and LDL in exchange for triacylglycerols. Although CETP has been studied in great detail in in vitro studies, the clinical significance of CETP is controversial. CETP may be antiatherogenic in that it increases the rate of reverse cholesterol transport, but it may be proatherogenic in that it transports CE from HDL, which is protective, to VLDL and LDL, which are atherogenic (33). Studies in humans have shown that the intakes of SFAs (34–36) and trans fatty acids (37, 38) increase CETP, whereas the intake of MUFAs decreases (39) and the intake of PUFAs decreases (40) or has no effect on CETP (13, 35, 41). The lack of a significant effect of diet on CETP in the present study may have been due to the similar plasma MUFA composition of the 3 experimental diets and also to the relatively small sample size of the study. After the 2 PD, triacylglycerols, LDL cholesterol, and VLDL cholesterol decreased significantly, all of which are substrates for CETP; thus, CETP activity may have decreased after the pistachio diets, even though CETP mass was unchanged.

Individuals with lower baseline triacylglycerols (less than the median value) had significantly higher concentrations of CETP throughout the study than did those with higher baseline triacylglycerols (greater than or equal to the median value). In keeping with 2 recent studies (42, 43), we found that higher CETP in this subpopulation may be beneficial. Individuals with higher baseline CETP concentrations had significantly lower triacylglycerol and VLDL-cholesterol concentrations (Figure 3). Our results suggest that the triacylglycerol concentration modifies CETP, even in a population with relatively low baseline triacylglycerols, and that the CETP concentration affects lipid and apolipoprotein risk factors (triacylglycerols, VLDL cholesterol, and apo C-III). Further research is needed to determine how CETP affects CVD risk status in different population groups.

Our results extend those of previous nut studies, which have shown LDL cholesterol lowering effects of nuts incorporated into various dietary patterns, by clarifying mechanisms to explain the lipid- and lipoprotein-lowering effects of pistachios. We present evidence that SCD activity may modulate the lipid-lowering effect of the pistachio diets. In summary, our study showed a dose-response effect of pistachio consumption within the context of a healthy dietary pattern on CVD risk factors. Importantly, these effects were observed with a low dose of pistachios (1 serving/d), which can be easily incorporated into a healthy dietary pattern.

	ACKNOWLEDGMENTS

 
We thank Bruce Holub for measuring the plasma fatty acids.

The authors' responsibilities were as follows—SKG, SGW, CDK, DB, and PMK-E: designed the study; SKG and DB: recruited the subjects; SKG and CDK: collected the data; SKG and SGW: analyzed the data; SKG, SGW, CDK, PA, DB, and PMK-E: interpreted the data; SKG, SGW, and PMK-E: wrote the manuscript; SKG, SGW, CDK, PA, DB, and PMK-E: critically reviewed the manuscript and provided scientific and editorial input; and PA developed the methodology for measuring apolipoprotein-defined lipoprotein subclasses. None of the authors had a conflict of interest.

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