Conditioned nutritional deficiencies in the cardiomyopathic hamster heart.

BACKGROUND: Evidence indicates that nutritional factors may be important in the maintenance of myocyte structure and energetics. The failing myocardium has been reported to exhibit a depletion of several nutrients that are important for the maintenance of intracellular calcium homeostasis and cellular energetics, and levels of oxidative stress. This nutrient depletion may contribute to the progressive deterioration in myocardial structure and function observed in heart failure. OBJECTIVE: To examine the extent to which advanced cardiomyopathy results in a depletion of nutrients and/or metabolites and antioxidants, and whether supplementation with these nutrients may influence cellular structure or function. SUBJECTS AND METHODS: Cardiomyopathic hamsters were randomly placed to one of the three following diet groups: chow; control gelled diet; or a supplemented gelled diet that provided taurine, carnitine, coenzyme Q10, selenium, vitamins E and C, creatine, thiamine and L-cysteine. After approximately three months of supplementation, one group of hamsters underwent functional testing using a modified Langendorff technique with biopsy samples taken for electron microscopy. Myocardial nutrient concentrations were determined in a second group of diseased and nondiseased hamsters of the same age. RESULTS: Cardiomyopathy resulted in a depletion of vitamin E, creatine, carnitine, taurine and coenzyme Q10. Supplementation resulted in improved cardiac ultrastructure, function and contractility compared with nonsupplemented hamsters. CONCLUSIONS: These studies suggest that heart failure results in 'condition-related nutrient deficiencies' that, once corrected, can significantly impact on heart function and structure.

A controlled clinical trial of vitamin E supplementation in patients with congestive heart failure.

BACKGROUND: Oxidative stress is increased in patients with congestive heart failure and can contribute to the progressive deterioration observed in these patients. Increased oxidative stress is the result of either an increased production of free radicals or a depletion of endogenous antioxidants, such as vitamin E. OBJECTIVE: We aimed to determine whether vitamin E supplementation of patients with advanced heart failure would modify levels of oxidative stress, thereby preventing or delaying the deterioration associated with free radical injury. DESIGN: Fifty-six outpatients with advanced heart failure (New York Heart Association functional class III or IV) were enrolled in a double-blind randomized controlled trial for 12 wk. At a baseline visit and at 2 follow-up visits, blood and breath samples were collected for the measurement of indexes of heart function and disease state, including malondialdehyde, isoprostanes, and breath pentane and ethane. Quality of life was also assessed at baseline and after 12 wk of treatment. RESULTS: Vitamin E treatment significantly increased plasma concentrations of alpha-tocopherol in the treatment group but failed to significantly affect any other marker of oxidative stress or quality of life. In addition, concentrations of atrial natriuretic peptide (a humoral marker of ventricular dysfunction), neurohormonal-cytokine markers of prognosis, tumor necrosis factor, epinephrine, and norepinephrine were unchanged with treatment and were not significantly different from those in the control group. CONCLUSION: Supplementation with vitamin E did not result in any significant improvements in prognostic or functional indexes of heart failure or in the quality of life of patients with advanced heart failure.

Increased oxidative stress in patients with congestive heart failure.

OBJECTIVES: We sought to study the markers of lipid peroxidation and defenses against oxidative stress in patients with varying degrees of heart failure. BACKGROUND: Despite advances in other areas of cardiovascular disease, the morbidity and mortality from congestive heart failure (CHF) are increasing. Data mainly from animal models suggest that free radical injury may promote myocardial decompensation. However, there are no studies in humans correlating the severity of heart failure with increased free radical injury and antioxidants. METHODS: Fifty-eight patients with CHF and 19 control subjects were studied. In addition to complete clinical and echocardiographic evaluations, the prognosis of these patients was established by measuring the levels of soluble tumor necrosis factor-alpha receptors 1 and 2 (sTNF-R1 and sTNF-R2). Oxidative stress was evaluated by measuring plasma lipid peroxides (LPO), malondialdehyde (MDA), glutathione peroxidase (GSHPx) and vitamin E and C levels. RESULTS: The patients' age range, cause of heart failure and drug intake were comparable across the different classes of heart failure. Heart failure resulted in a significant increase in LPO (p < 0.005), MDA (p < 0.005), sTNF-R1 (p < 0.005) and sTNF-R2 (p < 0.005). There was a significant positive correlation between the clinical class of heart failure and LPO, MDA, sTNF-R1 and sTNF-R2 levels. There was an inverse correlation between GSHPx and LPO. With increased lipid peroxidation in patients with CHF, the levels of vitamin C decreased, but vitamin E levels were maintained. CONCLUSIONS: These data demonstrate a progressive increase in free radical injury and encroachment on antioxidant reserves with the evolution of heart failure; they also suggest that oxidative stress may be an important determinant of prognosis. The therapeutic benefit of administering antioxidant supplements to patients with CHF should be evaluated.

Lipid peroxidation during n-3 fatty acid and vitamin E supplementation in humans.

The purpose of this study was to investigate in healthy humans the effect of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) intake, alone or in combination with dL-alpha-tocopherol acetate (vitamin E) supplements on lipid peroxidation. Eighty men were randomly assigned in a double-blind fashion to take daily for 6 wk either menhaden oil (6.26 g, n-3 fatty acids) or olive oil supplements with either vitamin E (900 IU) or its placebo. Antioxidant vitamins, phospholipid composition, malondialdehyde (MDA), and lipid peroxides were measured in the plasma at baseline and week 6. At the same time, breath alkane output was measured. Plasma alpha-tocopherol concentration increased in those receiving vitamin E (P < 0.0001). In those supplemented with n-3 fatty acids, EPA and DHA increased in plasma phospholipids (P < 0.0001) and plasma MDA and lipid peroxides increased (P < 0.001 and P < 0.05, respectively). Breath alkane output did not change significantly and vitamin E intake did not prevent the increase in lipid peroxidation during menhaden oil supplementation. The results demonstrate that supplementing the diet with n-3 fatty acids resulted in an increase in lipid peroxidation, as measured by plasma MDA release and lipid peroxide products, which was not suppressed by vitamin E supplementation.

Effects of beta-carotene supplementation on lipid peroxidation in humans.

The ability of beta-carotene (BC) to reduce lipid peroxidation in humans was investigated. In this randomized double-blind controlled trial, 42 nonsmokers and 28 smokers received either 20 mg BC or placebo daily for 4 wk. Twenty-five smokers and 38 nonsmokers completed the trial. Changes in plasma BC concentrations increased significantly (P < 0.0005) and to the same extent in both groups supplemented with BC. There were no significant changes among the placebo groups. At baseline, lipid peroxidation measured by breath-pentane output (BPO) was significantly higher in the two smoking groups (BC: 8.8 +/- 1.1, placebo: 9.4 +/- 1.4 pmol.kg-1.min-1) than in the two nonsmoking groups (BC: 5.7 +/- 0.5, placebo: 5.9 +/- 0.6 pmol.kg-1.min-1) (P < 0.005). BPO decreased significantly only in smokers receiving BC (6.5 +/- 0.7 pmol.kg-1.min-1) (P < 0.04). Changes in breath-ethane output were not significant. Therefore, lipid peroxidation measured by BPO is significantly higher in smokers than in nonsmokers and is reduced by BC supplementation in smokers. There was no significant change (95% CI - 1.26, 1.12) in BPO when nonsmokers received BC.

Vitamin E suppresses increased lipid peroxidation in cigarette smokers.

Cigarette smoke contains many xenobiotics, including oxidants and free radicals, which can increase lipid peroxidation. Recently, breath pentane output (BPO) has been recognized as a good indicator of lipid peroxidation. Vitamin E is known to be a potent free radical scavenger which can protect biological membranes against oxidative damage. We investigated the effect of vitamin E (dl-alpha-tocopherol) on lipid peroxidation in 13 healthy smokers. The results showed (1) smokers had increased BPO as compared with 19 healthy non-smokers (16.3 +/- 1.9 vs 5.8 +/- 0.5, pmol/kg body weight/min, p less than 0.001) although both groups had comparable plasma vitamin E and selenium concentrations, (2) supplementation with vitamin E (800 mg/day for 2 weeks) decreased BPO in smokers, and (3) the concentration of plasma selenium-dependent glutathione peroxidase was restored to normal in those smokers (five out of 13) in whom this was low initially. We conclude that a normal plasma concentration of vitamin E does not prevent this increase of lipid peroxidation in smokers but that substantial doses of vitamin E will significantly reduce this increased lipid peroxidation. If a major function of vitamin E is to protect lipids from peroxidation, then smokers have a conditioned insufficiency of vitamin E on a normal diet.

Increased lipid peroxidation after lipid infusion as measured by breath pentane output.

We studied the effect of intravenous lipid infusion on lipid peroxidation as measured by breath pentane. Pentane, plasma alpha-tocopherol (alpha-tox) and plasma gamma-tocopherol (gamma-toc), selenium, and Se-dependent glutathione peroxidase (Se-GSHPx) were measured in 10 normal control subjects and in 10 home parenteral nutrition (HPN) patients before and after infusion of 100 mL Nutralipid 10% over 30 min. Before infusion, breath pentane was significantly higher and alpha-toc was significantly lower in the HPN group than in the control subjects. These two measurements were significantly negatively correlated (r = -0.54, p less than 0.05). Pentane, alpha-toc, and Se-GSHPx were significantly increased in both groups after lipid was infused but were still significantly higher in HPN patients than in control subjects. Thus, infusion of a small amount of lipid rich in linoleic acid induced a significant increase in breath pentane, reflective of increased lipid peroxidation.

Plasma vitamin E and selenium and breath pentane in home parenteral nutrition patients.

Because both vitamin E and selenium protect against lipid peroxidation, we evaluated the relationship between breath pentane, evolved from the peroxidation of linoleic acid, and plasma levels of alpha-tocopherol (vitamin E), Se, and Se-dependent glutathione peroxidase (Se-GSHPx). Nine home parenteral-nutrition (HPN) patients received added Se in intravenous solutions and were compared with 10 normal control subjects. The excretion of pentane (pmol.kg-1.min-1, means +/- SEM) in control subjects (6.34 +/- 0.96) was significantly lower than in HPN patients (15.02 +/- 1.12, p less than 0.001). alpha-Tocopherol (mumol/L), Se (mumol/L), and Se-GSHPx (U) values were, respectively, 18.13 +/- 1.70, 1.70 +/- 0.05, and 5.34 +/- 0.27 in control subjects and 10.21 +/- 1.66, 1.35 +/- 0.14, and 7.01 +/- 0.31 in HPN patients. All differences were statistically significant. Significant negative correlations were observed between plasma alpha-tocopherol levels and HPN duration and between pentane output and plasma alpha-tocopherol levels (r = -0.58, p less than 0.01). In HPN patients with reduced plasma alpha-tocopherol levels associated with increased pentane output, there is, inferentially, increased lipid peroxidation despite normal plasma Se and Se-GSHPx levels.

Breath pentane analysis as an index of lipid peroxidation: a functional test of vitamin E status.

Pentane, which evolves from the reaction involving omega-6 fatty acids, is a good index of lipid peroxidation. We describe a method for measuring breath pentane excretion in adult humans. After a 4-minute washout period, expired air was analyzed by gas chromatography. Breath was passed through a cooled loop of alumina to adsorb, concentrate, and release, on heating, pentane. Pentane was analyzed by a Porasil-D column with a derived calibration curve. The mean excretion of pentane in 10 normal adults was 6.34 +/- 0.96 pmol X kg-1 X min-1 (mean +/- SEM) and was significantly higher in five patients with plasma vitamin E deficiency (15.39 +/- 1.84 pmol X kg-1 X min-1). There was a significant negative correlation between pentane output and plasma vitamin E levels (r = -0.66, p less than 0.01). Moreover, breath pentane excretion was significantly decreased after a 10-d supplementation with vitamin E in five normal subjects. We conclude that breath pentane output is a sensitive, noninvasive, functional test for assessing vitamin E status.

Nutritional absorption in short bowel syndrome. Evaluation of fluid, calorie, and divalent cation requirements.

Eight patients with a short bowel resulting from intestinal resection and clinically stable for at least one year were studied for 10 days. The diet chosen was lactose-free with a low fiber content and contained 22% of total calories as protein, 32% as carbohydrate, and 46% as fat. Total fluid volume was kept constant, and all patients were in positive nitrogen balance. During the 10-day period, blood chemical concentrations, stool, and/or ostomy volume, urine volume, electrolyte excretion, and calorie and divalent cation absorption were measured. In addition it was determined that fluid restriction during meals did not affect these parameters. In these patients the absorptions of fat, carbohydrate, protein, and total calories were 54%, 61%, 81%, and 62%, respectively. Similarly the absorption of the divalent cations, calcium, magnesium, and zinc, were 32%, 34%, and 15%, respectively. We suggest that patients with short bowel syndrome, who have been stable for at least one year and who can tolerate oral diets, do not need to restrict fat or to separate fluids from solids during their meals. Furthermore, they should increase their oral intake to 35-40 kcal/kg ideal body weight in order to counteract their increased losses. The diet should contain 80-100 g protein/day in order to maintain a positive nitrogen balance and a large margin of safety. In addition, these patients may take oral supplementation of calcium, magnesium, and zinc to maintain divalent cation balance.

Vitamin E and selenium status of patients receiving short-term total parenteral nutrition.

In a prospective protocol, plasma tocopherols, selenium (Se), Se-dependent glutathione peroxidase, platelet aggregation and erythrocyte hemolysis were measured in 23 control subjects, and 15 patients receiving total parenteral nutrition (TPN), before and after 2 wk of TPN unsupplemented with vitamin E and Se. The results indicate that short-term TPN did not alter status of these nutrients. However, TPN patients had significantly lower plasma levels of Se (p less than 0.01) and alpha-tocopherol (p less than 0.01) relative to control subjects. Low plasma levels, with no attendant decrease in function, suggest a marginal depletion. In view of this, and considering the low amount of vitamin E and Se supplied by the TPN solutions, supplementation with these nutrients is recommended.

Copper metabolism and requirements in total parenteral nutrition.

Copper metabolism and requirements in patients receiving total parenteral nutrition were studied in 28 patients with gastrointestinal diseases. During each of the 3 wk of the study period, each of 24 patients received in their total parenteral nutrition solutions, a daily dose of copper amounting to 0.25 mg, 1.05 mg, or 1.85 mg, in a random order. The other 4 patients received a fixed daily dose of 1 mg throughout the 3 wk. Increased losses of copper through the gastrointestinal tract occurred in patients with diarrhea or high-output stomas or fistulas. Patients with abnormalities of liver excretory functions had decreases in gastrointestinal copper losses. Urinary copper excretion was twice that of normal subjects. Copper infused in excess of the requirements was retained and not excreted. Plasma copper did not reflect the copper balance and cannot be used as a guide for copper supplementation. Copper requirements were found to be 0.3 mg/day in patients with normal amounts of gastrointestinal excretion. In the presence of diarrhea or increased fluid loss through gastrointestinal stomas or fistulas, the copper requirements for total parenteral nutrition are 0.4--0.5 mg/day.