Tor-Arne Hagve

Prevention of cardiac dysfunction during adjuvant breast cancer therapy (PRADA): a 2 × 2 factorial, randomized, placebo-controlled, double-blind clinical trial of candesartan and metoprolol

Abstract Aims Contemporary adjuvant treatment for early breast cancer is associated with improved survival but at the cost of increased risk of cardiotoxicity and cardiac dysfunction. We tested the hypothesis that concomitant therapy with the angiotensin receptor blocker candesartan or the β-blocker metoprolol will alleviate the decline in left ventricular ejection fraction (LVEF) associated with adjuvant, anthracycline-containing regimens with or without trastuzumab and radiation. Methods and results In a 2 × 2 factorial, randomized, placebo-controlled, double-blind trial, we assigned 130 adult women with early breast cancer and no serious co-morbidity to the angiotensin receptor blocker candesartan cilexetil, the β-blocker metoprolol succinate, or matching placebos in parallel with adjuvant anticancer therapy. The primary outcome measure was change in LVEF by cardiac magnetic resonance imaging. A priori, a change of 5 percentage points was considered clinically important. There was no interaction between candesartan and metoprolol treatments (P = 0.530). The overall decline in LVEF was 2.6 (95% CI 1.5, 3.8) percentage points in the placebo group and 0.8 (95% CI −0.4, 1.9) in the candesartan group in the intention-to-treat analysis (P-value for between-group difference: 0.026). No effect of metoprolol on the overall decline in LVEF was observed. Conclusion In patients treated for early breast cancer with adjuvant anthracycline-containing regimens with or without trastuzumab and radiation, concomitant treatment with candesartan provides protection against early decline in global left ventricular function.

Effect of dietary fats on arachidonic acid and eicosapentaenoic acid biosynthesis and conversion to C22 fatty acids in isolated rat liver cells.

The desaturation, chain elongation and esterification of [1-14C]eicosapentaenoic acid, [1-14C]arachidonic acid, [1-14C]eicosatrienoic acid, [1-14C]linolenic acid and [1-14C]linoleic acid were studied in isolated liver cells. Rats fed diets with either 15% hydrogenated coconut oil or 15% partially hydrogenated marine oil, both deficient in essential fatty acids, 15% soybean oil or standard pellet diet with 6% fat, were used. The delta 4-desaturation of 22:5(n - 3) and 22:4(n - 6) as well as the delta 6-desaturase activity was distinctly higher in cells from animals fed coconut or marine oil than with soybean oil or standard pellet. The rate of delta 5-desaturation of 20:3(n - 6) and 20:4(n - 3) was nearly the same in cells from rats fed coconut, marine and soybean oils and higher than with standard pellet. The chain elongation of 20:5(n - 3) to 22:5(n - 3) was distinctly more pronounced than the elongation of 20:4(n - 6) with all four diets. 20:5(n - 3) was mainly esterified in the phospholipids with marine and coconut oils, and mainly in triacylglycerol with standard pellet and soybean oils. The proportion of [1-14C]20:4(n - 6) in the phospholipids to that in triacylglycerol decreased in the order marine oil greater than coconut oil greater than standard pellet greater than soybean oil. The different endogenous arachidonic acid content in the phospholipids induced by the different diets increased in the same order. 20:5(n - 3) was rapidly esterified in triacylglycerol and phospholipids, then liberated especially from the triacylglycerol fraction, chain elongated to 22:5(n - 3) and reesterified.

Peroxisomal retroconversion of docosahexaenoic acid (22:6(n-3)) to eicosapentaenoic acid (20:5(n-3)) studied in isolated rat liver cells

Retroconversion of docosahexaenoic acid (DHA, 22:6(n-3)) to eicosapentaenoic acid (EPA, 20:5(n-3)) was studied in isolated rat liver cells. 20% of the substrate was retroconverted to EPA in control cells by one cycle of beta-oxidation probably with delta 4 enoyl CoA reductase and delta 3, delta 2 enoyl CoA isomerase as auxiliary enzymes. This conversion was not stimulated by (-)-carnitine and was not inhibited by the addition of (+)-decanoylcarnitine. In hepatocytes from fasted rats little EPA was formed from DHA. These results strongly suggest that the retroconversion of DHA to EPA is a peroxisomal function. Retroconverted EPA, produced from DHA was rapidly incorporated in triacylglycerol, the phosphatidylcholine and phosphatidyletanolamine fractions. During longer incubation time EPA was partly removed from the phospholipid fractions, chain-elongated to 22:5(n-3) and incorporated in the triacylglycerol fraction.

Evidence for peroxisomal retroconversion of adrenic acid (22:4(n-6)) and docosahexaenoic acids (22:6(n-3)) in isolated liver cells

The intracellular localization of the oxidation of [2-14C]adrenic acid (22:4(n-6)) and [1-14C]docosahexaenoic acid (22:6(n-3)) was studied in isolated liver cells. The oxidation of 22:4(n-6) was 2-3-times more rapid than the oxidation of 22:6(n-3), [1-14C]arachidonic acid (20:4(n-6)) or [1-14C]oleic acid (18:1). (+)-Decanoylcarnitine and lactate, both known to inhibit mitochondrial beta-oxidation, reduced the oxidation of 18:1 distinctly more efficiently than with 22:4(n-6) and 22:6(n-3). In liver cells from rats fed a diet containing partially hydrogenated fish oil, the oxidation of 22:6(n-6) and 22:6(n-3) was increased by 30-40% compared with cells from rats fed a standard pellet diet. With 18:1 as substrate, the amount of fatty acid oxidized was very similar in cells from animals fed standard pellets or partially hydrogenated fish oil. Shortened fatty acids were not produced from [5,6,8,9,11,12,14,15-3H]arachidonic acid. In hepatocytes from rats starved and refed 20% fructose, a large fraction of 14C from 22:4 was recovered in 14C-labelled C14-C18 fatty acids. Oxidation of 22:4 thus caused a high specific activity of the extramitochondrial pool of acetyl-CoA. The results suggest that 22:4(n-6) and to some extent 22:6(n-3) are oxidized by peroxisomal beta-oxidation and by this are retroconverted to arachidonic acid and eicosapentaenoic acid.

Effects of dietary purified eicosapentaenoic acid (20:5(n − 3)) and docosahexaenoic acid (22:6(n − 3)) on fatty acid desaturation and oxidation in isolated rat liver cells

The effects of dietary supplementation of eicosapentaenoic acid (20:5(n-3), EPA) and docosahexaenoic acid (22:6(n-3), DHA) on the metabolism of polyunsaturated fatty acids were studied in isolated rat liver cells. Both pure EPA and pure DHA and a mixture of the two n-3 fatty acids in different doses were used. The supplementation of moderate amounts of n-3 fatty acids suppressed the activity of delta 6-desaturase (50%) and to a smaller extent of the delta 5-desaturase (60-70%) compared to controls. When higher doses of dietary purified EPA and DHA were used, this inhibitory effect on the delta 6- and delta 5-desaturase activities disappeared. The delta 4-desaturase activity seemed to be unaffected by the feeding conditions used. The supplementation of the n-3 fatty acids in the diet at all dose levels used increased the beta-oxidation of all the polyunsaturated fatty acids, especially of linoleic acid, linolenic acid and eicosapentaenoic acid. The results suggest an increase both in peroxisomal and mitochondrial beta-oxidation. The peroxisomal beta-oxidation of n-3 fatty acids seemed to be particularly increased.

Effects of unsaturated fatty acids on cell membrane functions

Biological membranes consist of lipid bilayers composed primarily of phospholipids and cholesterol. Proteins with important membrane functions, such as enzymes, receptors and transporters are enclosed in the lipid bilayer. A basic question is whether interactions with lipids in the bilayer can modulate the activity of membrane proteins. From the standpoint of cellular physiology and metabolic regulation, a critical point has been whether changes in membrane lipid composition actually occur in living cells as a response to changes in the lipid availability, and if so, whether the changes are of sufficient magnitude to influence membrane functions. During the last decade an extensive amount of information regarding these issues has been obtained, especially from studies with liposomes and mammalian cells in culture. The purpose of this review is briefly to describe how changes in membrane lipids, especially fatty acid composition, may modulate physiological properties of membranes, such as fluidity, and cel...

Self-Reported Dietary Supplement Use Is Confirmed by Biological Markers in the Norwegian Mother and Child Cohort Study (MoBa)

Background/Aims: A food frequency questionnaire (FFQ) and a database for dietary supplements were developed for use in the Norwegian Mother and Child Cohort Study (MoBa). The aim of the present study was to investigate the relation between reported use and biomarkers in supplement and nonsupplement users and to validate self-reported intake of dietary supplements in mid pregnancy. Method: 120 women were recruited from MoBa, and 119 subjects completed the MoBa FFQ and a 4-day weighed food diary. Information on supplement use was collected by both methods. Venous blood specimens and 24-hour urine samples were obtained for measurement of dietary biomarkers. Results: Biomarker concentration/excretion and intake differed significantly between supplement and nonsupplement users for vitamin D, carotenoids, folate, the n–6/n–3 fatty acid ratio and iodine (p < 0.05 for all variables). Flavonoid excretion was higher in flavonoid-supplement users (p < 0.05). Significant correlations between total dietary intake (food and supplements) and biomarker concentration/excretion were found for vitamin D (r = 0.45, p < 0.001), folate (r = 0.26, p = 0.005), the n–6/n–3 fatty acid ratio (r = 0.36, p < 0.001) and iodine (r = 0.42, p < 0.001). Conclusion: The biochemical indicators examined in this study confirmed differences in self-reported micronutrient intake between supplement and nonsupplement users for vitamin D, beta-carotene, folate, n–3 fatty acids, flavonoids and iodine.

Exploration of biomarkers for total fish intake in pregnant Norwegian women

OBJECTIVE Few biomarkers for dietary intake of various food groups have been established. The aim of the present study was to explore whether selenium (Se), iodine, mercury (Hg) or arsenic may serve as a biomarker for total fish and seafood intake in addition to the traditionally used n-3 fatty acids EPA and DHA. DESIGN Intake of fish and seafood estimated by an FFQ was compared with intake assessed by a 4 d weighed food diary and with biomarkers in blood and urine. SETTING Validation study in the Norwegian Mother and Child Cohort Study (MoBa). SUBJECTS One hundred and nineteen women. RESULTS Total fish/seafood intake (median 39 g/d) calculated with the MoBa FFQ was comparable to intake calculated by the food diary (median 30 g/d, rS = 0.37, P < 0.001). Erythrocyte DHA and blood Hg, Se and arsenic concentrations were positively correlated with intake of fish and seafood, but the association for DHA was weakened by the widespread use of supplements. The main finding was the consistent positive association between the intake of fish/seafood and blood arsenic concentration. In multivariate analyses, blood arsenic was associated with blood Hg and fish and seafood intake. In these models, arsenic turned out to be the best indicator of intake of fish and seafood, both totally and in subgroups of fish/seafood intake. CONCLUSIONS While DHA reflected the intake of fatty fish and n-3 PUFA supplements, blood arsenic concentration also reflected the intake of lean fish and seafood. Blood arsenic appears to be a useful biomarker for total fish and seafood intake.

Natriuretic Peptides: Physiologic and Analytic Considerations

Natriuretic peptides play a central role in cardiovascular, endocrine, and renal homeostasis and can be considered physiologic antagonists to the renin-angiotensin-aldosterone system. ANP and BNP in the circulation are derived primarily from the myocardium, whereas CNP is mainly derived from endothelial cells and the central nervous system. Increased ventricular and atrial diastolic wall stretch augment synthesis and release of BNP and NT-proBNP from cardiomyocytes, and is the principal stimulus controlling BNP production. Circulating BNP and NT-proBNP levels are increased in heart failure in proportion to disease severity, but elevated levels may also be observed in other cardiac and noncardiac disease states, including cardiac arrhythmias, ventricular hypertrophy, myocardial ischemia, pulmonary embolism, acute and chronic cor pulmonale, renal failure, anemia, hyperthyroidism, and sepsis. Fully automated analyses of both BNP and NT-proBNP can be rapidly performed on large hospital-based platforms as well as on small point-of-care devices.

linolenic acid desaturation and chain elongation and rapid turnover of phospholipid n − 3 fatty acids in isolated rat liver cells

The desaturation and chain elongation of [1-14C]linolenic acid was studied in isolated liver cells from rats fed a diet deficient in essential fatty acids. 14C-labelled 18:4, 20:3, 20:4, 20:5, 22:5 and 22:6, all n - 3 fatty acids, were formed. In the presence of lactate relatively large amounts of 20:5, 22:5 and 22:6 were formed. 20:5 was mainly present in phospholipids, 22:5 and 22:6 were present in both phospholipids and triacylglycerols. (+)-Decanoylcarnitine and (-)-hydroxycitrate decreased the formation of 20:5, 22:5 and 22:6 and increased the recovery of 18:4. The unchanged 18:3 substrate was also initially rapidly incorporated both in the phospholipids and in the triacylglycerol fraction. During long incubation periods, continued after nearly all the [14C]linolenic acid substrate had been metabolized either by esterification or by oxidation, the phospholipid content of labelled 18:3 and 18:4 decreased while the content of 20:5, 22:5 and 22:6 increased markedly, suggesting a remodeling of the phospholipid n - 3 fatty acid content by a series of deacylations-reacylations. The n - 3 fatty acid pattern in the triacylglycerol fraction changed little. 22:5 and 22:6 appeared in the VLDL fraction secreted by the isolated liver cells.