Role of the fractalkine receptor CX3CR1 polymorphisms V249I and T280M as risk factors for early-onset coronary artery disease in patients with no classic risk factors.

OBJECTIVES: CX3CR1 is a monocyte chemokine receptor and adhesion molecule. Two CX3CR1 mutations, V249I and T280M, reportedly decrease coronary artery disease (CAD) risk independent of established risk factors. An I249 protective effect is attributed to reducing CX3CR1 binding to fractalkine, its ligand. MATERIAL AND METHODS: We examined the frequencies of V249I and T280M among early-onset CAD patients (G1; n = 149; <50 years), late-onset CAD patients (G2; n = 150; >65 years) and healthy controls (HC; n = 149, 47-93 years) without known CAD risk factors. We compared plasma total cholesterol (TC)/high density lipoprotein-C (HDL-C) and apolipoprotein B (APOB)/apolipoprotein AI (APOAI) ratios among the groups and mutation carriers and non-carriers, and the prevalence of the mutations in G1 and G2 patients with multiple coronary vessel disease (MVD) and myocardial infarction (MI). RESULTS: G1 patients had non-significantly lower frequencies of I249 versus (vs.) G2 or controls (G1; 51 %, G2: 61 %, controls: 58 %, p = 0.19), with no difference in T280M (p = 0.8). TC/HDL-C and APOB/APOAI ratios were significantly higher in G1 patients vs. G2 and controls (p<0.0001) independently of either mutation. More G2 patients had MVD than younger ones (p<0.0001); however, more G1 patients were homozygous for V249 compared to G2 patients, who more often had the I249 allele (p<0.02). There was no such association with T280M (p = 0.38). Although more G1 patients had MI, this was not mutation related. CONCLUSIONS: There were significantly higher lipid ratios in G1 compared to G2 and HC (G1>G2>HC), but not in mutation prevalence. I249 mutation was associated with MVD in older patients, while V249 homozygosity was associated with the early-onset CAD. Neither allele affected MI or lipid levels.

Effect of a very-high-fiber vegetable, fruit, and nut diet on serum lipids and colonic function.

We tested the effects of feeding a diet very high in fiber from fruit and vegetables. The levels fed were those, which had originally inspired the dietary fiber hypothesis related to colon cancer and heart disease prevention and also may have been eaten early in human evolution. Ten healthy volunteers each took 3 metabolic diets of 2 weeks duration. The diets were: high-vegetable, fruit, and nut (very-high-fiber, 55 g/1,000 kcal); starch-based containing cereals and legumes (early agricultural diet); or low-fat (contemporary therapeutic diet). All diets were intended to be weight-maintaining (mean intake, 2,577 kcal/d). Compared with the starch-based and low-fat diets, the high-fiber vegetable diet resulted in the largest reduction in low-density lipoprotein (LDL) cholesterol (33% +/- 4%, P <.001) and the greatest fecal bile acid output (1.13 +/- 0.30 g/d, P =.002), fecal bulk (906 +/- 130 g/d, P <.001), and fecal short-chain fatty acid outputs (78 +/- 13 mmol/d, P <.001). Nevertheless, due to the increase in fecal bulk, the actual concentrations of fecal bile acids were lowest on the vegetable diet (1.2 mg/g wet weight, P =.002). Maximum lipid reductions occurred within 1 week. Urinary mevalonic acid excretion increased (P =.036) on the high-vegetable diet reflecting large fecal steroid losses. We conclude that very high-vegetable fiber intakes reduce risk factors for cardiovascular disease and possibly colon cancer. Vegetable and fruit fibers therefore warrant further detailed investigation.

A novel source of wheat fiber and protein: effects on fecal bulk and serum lipids.

BACKGROUND: Wheat fiber is a laxative and wheat protein may affect blood lipids. OBJECTIVE: We therefore tested the effects on laxation and serum lipid metabolism of a novel source of wheat fiber and protein produced by the amylolytic digestion of starch from wheat. DESIGN: Twenty-four healthy men and women consumed 3 different test cereals in random order, each for 2 wk. The test supplement and the positive control, American Association of Cereal Chemists wheat bran supplement, both provided the same amount of fiber (21 g/d) and the negative control supplement provided 1.7 g fiber/d. RESULTS: The test supplement and the positive control supplement increased fecal bulk similarly (239.5+/-19 and 216.7+/-19 g/d, respectively) and significantly more than did the negative control supplement (165.6+/-16 g/d, P < 0.010). Compared with the negative and positive control supplements, the week 2 value of the test supplement for the ratio of total to HDL cholesterol was significantly reduced (P = 0.046). CONCLUSION: We conclude that the product of amylolytic digestion of starch from wheat flakes, which is high in wheat fiber and protein, has a fecal bulking effect similar to that of wheat bran and may have a beneficial effect on serum lipids.

Long-term effect of soluble-fiber foods on postprandial fat metabolism in dyslipidemic subjects with apo E3 and apo E4 genotypes.

To determine the long-term effect of soluble fiber on postprandial fat metabolism, we studied 33 dyslipidemic subjects, 16 with apolipoprotein (apo) E3/3 (E3) and 17 with E3/4 or E4/4 (E4) genotypes. They ate preweighed low-fat (20% of energy), high-fiber (> 5.7 g/MJ) diets for two 4-mo periods separated by a 2-mo washout period according to a randomized, crossover design. One diet contained foods rich in insoluble fiber and the other foods rich in soluble fiber. On 1 d during the last 2 wk of each diet, subjects ingested a standard, fiber-free, fatty liquid meal containing retinyl palmitate as a marker of intestinally derived lipoproteins. Plasma samples were obtained at hourly intervals for 10 h. Compared with the insoluble-fiber diet, soluble fiber reduced fasting plasma total cholesterol in both E3 (6.6 +/- 2.1%, P = 0.007)and E4 subjects (5.6 +/- 2.1%, P = 0.017). Soluble fiber increased fecal total bile acid output in both E3 (76 +/- 18%, P < 0.001) and E4 subjects (85 +/- 19%, P < 0.001). The incremental area under the chylomicron triacylglycerol response curve was significantly greater after soluble fiber than after insoluble fiber in E3 (3.56 +/- 0.56 compared with 2.87 +/- 0.38 mmol x h/L, respectively, P = 0.046) but not in E4 subjects (5.19 +/- 0.78 compared with 4.92 +/- 0.81 mmol x h/L). Kinetic analysis suggested an increase in retinyl palmitate absorption in E3 subjects after soluble fiber, but no difference in E4 subjects. These results suggest that a long-term increase in dietary soluble fiber has no effect on postprandial fat metabolism in subjects with an apo E3/4 or E4/4 genotype. However, soluble fiber enhances apparent fat absorption in E3 subjects, which could be due to an increased bile acid pool and increased micelle formation.

Effect of a diet high in vegetables, fruit, and nuts on serum lipids.

We assessed the effect of a diet high in leafy and green vegetables, fruit, and nuts on serum lipid risk factors for cardiovascular disease. Ten healthy volunteers (seven men and three women aged 33 +/- 4 years [mean +/- SEM]; body mass index, 23 +/- 1 kg/m2) consumed their habitual diet (control diet, 29% +/- 2% fat calories) and a diet consisting largely of leafy and other low-calorie vegetables, fruit, and nuts (vegetable diet, 25% +/- 3% fat calories) for two 2-week periods in a randomized crossover design. After 2 weeks on the vegetable diet, lipid risk factors for cardiovascular disease were significantly reduced by comparison with the control diet (low-density lipoprotein [LDL] cholesterol, 33% +/- 4%, P < .001; ratio of total to high-density lipoprotein [HDL] cholesterol, 21% +/- 4%, P < .001; apolipoprotein [apo] B:A-I, 23% +/- 2%, P < .001; and lipoprotein (a) [Lp(a)], 24% +/- 9%, P = .031). The reduction in apo B was related to increased intakes of soluble fiber (r = .84, P = .003) and vegetable protein (r = -.65, P = .041). On the vegetable compared with the control diet, the reduction in total serum cholesterol was 34% to 49% greater than would be predicted by differences in dietary fat and cholesterol. A diet consisting largely of low-calorie vegetables and fruit and nuts markedly reduced lipid risk factors for cardiovascular disease. Several aspects of such diets, which may have been consumed early in human evolution, have implications for cardiovascular disease prevention.

Effect of psyllium in hypercholesterolemia at two monounsaturated fatty acid intakes.

We performed two studies to determine whether the lipid-lowering effect of viscous soluble fiber was modified by monounsaturated fatty acid (MUFA). First, psyllium (1.4 g/MJ) was compared with wheat bran (control) in 1-mo metabolic diets by using a randomized crossover design (n = 32 hyperlipidemic subjects). The background diet contained approximately 6% of energy as MUFA (20% of total fat). The second study (n = 27 hyperlipidemic subjects) was similar to the first but the background diet contained approximately 12% MUFA (29% of total fat) because of the addition of canola oil. At both fat intakes, psyllium resulted in significant reductions in total, low-density-lipoprotein (LDL), and high-density-lipoprotein (HDL) cholesterol compared with the wheat bran control. For the psyllium diet at 6% compared with 12% MUFA, the decreases in LDL cholesterol were 12.3 +/- 1.5% (P < 0.001) and 15.3 +/- 2.4% (P < 0.001), respectively. With the higher-MUFA diet triacylglycerol fell significantly over the control phase (16.6 +/- 5.5%, P = 0.006) and the ratio of LDL to HDL cholesterol fell significantly over the psyllium phase (7.3 +/- 2.8%, P = 0.015). Psyllium and MUFA intakes were negatively related to the percentage change in the ratio of LDL to HDL cholesterol (r = -0.34, P = 0.019 and r = -0.44, P = 0.002, respectively). Chenodeoxycholate synthesis rate increased (30 +/- 13%, P = 0.038) with the psyllium diet in the 12 subjects in whom this was assessed. We conclude that psyllium lowered LDL- and HDL-cholesterol concentrations similarly at both MUFA intakes. However, there may be some advantage in combining soluble fiber and MUFA to reduce the ratio of LDL to HDL cholesterol.

Method of administration influences the serum cholesterol-lowering effect of psyllium.

To determine whether psyllium must be mixed with food to lower serum cholesterol, 18 modestly hypercholesterolemic subjects were studied for three 2-wk periods, in random order, separated by a 2-wk return to a National Cholesterol Education Program Step 2 diet. Compared with values for subjects consuming control wheat-bran cereal (63 g/d), after 2 wk of 54 g psyllium-enriched cereal/d containing 7.3 g psyllium, serum total, LDL, and HDL cholesterol, respectively, were reduced by 8% (6.15 +/- 0.15 vs 6.71 +/- 0.19 mmol/L, P < 0.01), 11% (4.24 +/- 0.15 vs 4.78 +/- 0.19 mmol/L, P < 0.02), and 7% (0.99 +/- 0.05 vs 1.07 +/- 0.05 mmol/L, P < 0.01). When 7.6 g of the same type of psyllium as in the test cereal was taken between meals, serum total (6.50 +/- 0.19 mmol/L), LDL (4.50 +/- 0.21 mmol/L), and HDL (1.06 +/- 0.06 mmol/L) cholesterol were no different from control values, and total cholesterol was greater than after psyllium cereal (P < 0.05). We conclude that psyllium must be mixed with foods to have the maximum effect on serum cholesterol.

Psyllium reduces blood lipids in men and women with hyperlipidemia.

To see if a modest amount of soluble fiber reduced blood lipids in subjects with hyperlipidemia who were on a low-fat diet, 42 subjects (21 men, 21 women) consuming an American Heart Association step 2 diet took two servings of breakfast cereal daily for two 2-week periods in a randomized crossover trial. There were two types of test cereals, each providing 6.7 g psyllium fiber daily, and two types of wheat bran control cereals, matched for available carbohydrate and total fiber. Half the subjects tested each type of cereal, and the results were pooled because the psyllium cereals had similar effects on serum cholesterol levels. Comparing values at the end of 2 weeks, psyllium reduced serum total (6.33 +/- 0.12 mmol/L versus 6.76 +/- 0.12 mmol/L, p < 0.001), low-density lipoprotein (LDL; 4.36 +/- 0.11 mmol/L versus 4.73 +/- 0.12 mmol/L, p < 0.001) and high-density lipoprotein cholesterol levels (HDL; 1.10 +/- 0.05 mmol/L versus 1.14 +/- 0.05 mmol/L, p < 0.05) and the LDL/HDL cholesterol ratio (4.27 +/- 0.20 versus 4.48 +/- 0.22, p < 0.02) with no effect on triglycerides. There was no significant interaction between the effects of treatment and sex for any of the blood lipid variables. Women tended to have greater decreases in total, LDL, and HDL cholesterol levels than men, but the percent decrease in LDL/HDL ratio on psyllium was similar in men, 4.9%, and women, 4.7%. It is concluded that 6.7 g of psyllium fiber daily, with a low-fat diet, reduces serum cholesterol levels in both men and women with hyperlipidemia.

Effect on blood lipids of very high intakes of fiber in diets low in saturated fat and cholesterol.

BACKGROUND: It is known that soluble fiber in the diet can lower blood lipid levels. It is less certain, however, that eating foods with soluble fiber will further lower blood lipids when the intake of saturated fat and cholesterol has already been reduced to very low levels. Furthermore, the mechanism of the lipid-lowering effect of fiber has not been elucidated. METHODS: To address these questions, we studied 43 volunteers with hyperlipidemia in a crossover study involving two four-month dietary periods. The two metabolic diets contained foods high in either soluble or insoluble fiber and were separated by a two-month National Cholesterol Education Program Step 2 diet. The metabolic diets were low in saturated fat (< 4 percent of total calories) and cholesterol (< 25 mg per 1000 kcal), high in carbohydrate (> or = 60 percent of total calories), and very high in fiber (> 24 g per 1000 kcal). RESULTS: Blood lipids fell to their lowest levels by week 4 of both study diets. When the soluble-fiber period was compared with the insoluble-fiber period, the subjects' total, low-density lipoprotein (LDL), and high-density lipoprotein (HDL) cholesterol levels were found to be lower by a mean (+/- SE) of 4.9 +/- 0.9 percent (P < 0.001), 4.8 +/- 1.3 percent (P < 0.001), and 3.4 +/- 1.3 percent (P = 0.014), respectively. In contrast, the ratio of total to HDL cholesterol was not significantly different during the two dietary periods. The loss of fecal bile acids was 83 +/- 14 percent greater during the soluble-fiber period than during the insoluble-fiber period (P < 0.001) and was related to the differences in total and LDL cholesterol and apolipoprotein B levels (r = 0.42, P = 0.005; r = 0.49, P < 0.001; and r = 0.33, P = 0.035, respectively). The difference in serum cholesterol levels between the two dietary periods was greater among the men (7.5 +/- 1.2 percent, P < 0.001) than among the women (3.4 +/- 1.2 percent, P = 0.008). CONCLUSIONS: Very high intakes of foods rich in soluble fiber lower blood cholesterol levels even when the main dietary modifiers of blood lipids--namely, saturated fat and cholesterol--are greatly reduced.