Previous radiotherapy improves treatment responses and causes a trend toward longer time to progression among patients with immune checkpoint inhibitor-related adverse events.

BACKGROUND: Immune-related adverse events (irAEs) are frequently encountered by patients during immune checkpoint inhibitor (ICI) treatment and are associated with better treatment outcomes. The sequencing of radiotherapy (RT) and ICIs is widely used in current clinical practice, but its effect on survival has remained unclear. METHODS: In a real-world multicenter study including 521 patients who received ICI treatment for metastatic or locally advanced cancer, RT schedules and timing, irAEs, time to progression, overall survival, and treatment responses were retrospectively reviewed. RESULTS: Patients who received previous RT and developed irAE (RT +/AE +) had the best overall response rate (ORR 44.0%). The ORR was 40.1% in the RT -/AE + group, 26.7% in the RT -/AE - group and 18.3% in the RT + /AE - group (p < 0.001). There was a significantly longer time to progression (TTP) in the RT + /AE + group compared to the RT -/AE - and RT + /AE - groups (log rank p = 0.001 and p < 0.001, respectively), but the trend toward longer TTP in the RT + /AE + group did not reach statistical significance in pairwise comparison to that in the RT -/AE + group. Preceding RT timing and intent had no statistically significant effect on TTP. In a multivariate model, ECOG = 0 and occurrence of irAEs remained independent positive prognostic factors for TTP (HR 0.737; 95% CI 0.582-0.935; p = 0.012, and HR 0.620; 95% CI 0.499-0.769; p < 0.001, respectively). CONCLUSIONS: Better ORR and a trend toward longer TTP were demonstrated for patients with RT preceding ICI treatment and development of irAEs, which suggests that RT may boost the therapeutic effect of immunotherapy in patients with metastatic cancers.

Associations of Serum Fatty Acid Proportions with Obesity, Insulin Resistance, Blood Pressure, and Fatty Liver: The Cardiovascular Risk in Young Finns Study.

BACKGROUND: The links between fatty acids (FAs) and cardiometabolic outcomes are topics of debate. OBJECTIVE: Our aim was to investigate the associations between serum standardized FA percentages and cardiometabolic outcomes. METHODS: We used cross-sectional (n = 2187-2200 subjects, age 24-39 y, women 54%) and 10-year prospective data (n = 975-1414 subjects) from the Young Finns Study. Outcomes included prevalent and incident obesity, insulin resistance (HOMA-IR index in the upper quintile), elevated blood pressure (BP; taking medication, or diastolic or systolic BP in the upper quintile), and incident nonalcoholic fatty liver. Logistic regression models were used to calculate ORs per SD increase in fatty acids (FAs). The models were adjusted for age and sex, and additionally for other potential confounders. RESULTS: Several cross-sectional findings were also statistically significant in prospective models (Bonferroni corrected P < 0.003). In fully-adjusted models for obesity, these consisted of SFAs (OR: 1.28) and MUFAs (OR: 1.38), including palmitoleic (OR: 1.39) and oleic acids (OR: 1.37). Furthermore, PUFAs (OR: 0.70), including linoleic (OR: 0.67) and docosahexaenoic acids (OR: 0.75), were inversely related with obesity, whereas γ-linolenic acid (OR: 1.32) was positively associated with obesity. In age- and sex-adjusted models for insulin resistance, MUFAs (OR: 1.26) and oleic acid (OR: 1.25) were positively, and PUFAs (OR: 0.81), particularly linoleic acid (OR: 0.78), were inversely associated with HOMA-IR. Similarly with elevated BP, palmitic acid (OR: 1.22), MUFAs (OR: 1.28), and oleic acid (OR: 1.28) were positively associated with elevated BP, whereas PUFAs (OR: 0.77), n-6 (omega-6) PUFAs (OR: 0.79), and linoleic acid (OR: 0.77) were inversely associated. In fully-adjusted models for incident fatty liver, the most consistent predictors were high palmitic (OR: 1.61) and low linoleic acid (OR: 0.63) percentages. The n-6/n-3 (omega-3) PUFA ratio was not linked with any adverse outcomes. CONCLUSIONS: High serum percentages of total SFAs and MUFAs and low PUFAs, but also several specific FAs, predict future unfavorable cardiometabolic outcomes in Finnish adults.

Metabolic profiling of fatty liver in young and middle-aged adults: Cross-sectional and prospective analyses of the Young Finns Study.

Nonalcoholic fatty liver is associated with obesity-related metabolic disturbances, but little is known about the metabolic perturbations preceding fatty liver disease. We performed comprehensive metabolic profiling to assess how circulating metabolites, such as lipoprotein lipids, fatty acids, amino acids, and glycolysis-related metabolites, reflect the presence of and future risk for fatty liver in young adults. Sixty-eight lipids and metabolites were quantified by nuclear magnetic resonance metabolomics in the population-based Young Finns Study from serum collected in 2001 (n = 1,575), 2007 (n = 1,509), and 2011 (n = 2,002). Fatty liver was diagnosed by ultrasound in 2011 when participants were aged 34-49 years (19% prevalence). Cross-sectional associations as well as 4-year and 10-year risks for fatty liver were assessed by logistic regression. Metabolites across multiple pathways were strongly associated with the presence of fatty liver (P < 0.0007 for 60 measures in age-adjusted and sex-adjusted cross-sectional analyses). The strongest direct associations were observed for extremely large very-low-density lipoprotein triglycerides (odds ratio [OR] = 4.86 per 1 standard deviation, 95% confidence interval 3.48-6.78), other very-low-density lipoprotein measures, and branched-chain amino acids (e.g., leucine OR = 2.94, 2.51-3.44). Strong inverse associations were observed for high-density lipoprotein measures, e.g., high-density lipoprotein size (OR = 0.36, 0.30-0.42) and several fatty acids including omega-6 (OR = 0.37, 0.32-0.42). The metabolic associations were attenuated but remained significant after adjusting for waist, physical activity, alcohol consumption, and smoking (P < 0.0007). Similar aberrations in the metabolic profile were observed already 10 years before fatty liver diagnosis. CONCLUSION: Circulating lipids, fatty acids, and amino acids reflect fatty liver independently of routine metabolic risk factors; these metabolic aberrations appear to precede the development of fatty liver in young adults. (Hepatology 2017;65:491-500).

Metabolite profiling and cardiovascular event risk: a prospective study of 3 population-based cohorts.

BACKGROUND: High-throughput profiling of circulating metabolites may improve cardiovascular risk prediction over established risk factors. METHODS AND RESULTS: We applied quantitative nuclear magnetic resonance metabolomics to identify the biomarkers for incident cardiovascular disease during long-term follow-up. Biomarker discovery was conducted in the National Finnish FINRISK study (n=7256; 800 events). Replication and incremental risk prediction was assessed in the Southall and Brent Revisited (SABRE) study (n=2622; 573 events) and British Women's Health and Heart Study (n=3563; 368 events). In targeted analyses of 68 lipids and metabolites, 33 measures were associated with incident cardiovascular events at P<0.0007 after adjusting for age, sex, blood pressure, smoking, diabetes mellitus, and medication. When further adjusting for routine lipids, 4 metabolites were associated with future cardiovascular events in meta-analyses: higher serum phenylalanine (hazard ratio per standard deviation, 1.18; 95% confidence interval, 1.12-1.24; P=4×10(-10)) and monounsaturated fatty acid levels (1.17; 1.11-1.24; P=1×10(-8)) were associated with increased cardiovascular risk, while higher omega-6 fatty acids (0.89; 0.84-0.94; P=6×10(-5)) and docosahexaenoic acid levels (0.90; 0.86-0.95; P=5×10(-5)) were associated with lower risk. A risk score incorporating these 4 biomarkers was derived in FINRISK. Risk prediction estimates were more accurate in the 2 validation cohorts (relative integrated discrimination improvement, 8.8% and 4.3%), albeit discrimination was not enhanced. Risk classification was particularly improved for persons in the 5% to 10% risk range (net reclassification, 27.1% and 15.5%). Biomarker associations were further corroborated with mass spectrometry in FINRISK (n=671) and the Framingham Offspring Study (n=2289). CONCLUSIONS: Metabolite profiling in large prospective cohorts identified phenylalanine, monounsaturated fatty acids, and polyunsaturated fatty acids as biomarkers for cardiovascular risk. This study substantiates the value of high-throughput metabolomics for biomarker discovery and improved risk assessment.

Factors associated with six-year weight change in young and middle-aged adults in the Young Finns Study.

OBJECTIVE: To examine factors associated with weight change and obesity risk in young and middle-aged adults. SUBJECTS/METHODS: The Young Finns Study with its 923 women and 792 men aged 24-39 years at baseline were followed for six years. Variables associated with the weight change were investigated with regression models. RESULTS: The average weight change was 0.45 kg/year in women and 0.58 kg/year in men. In women, weight change was steady across all ages. In men, weight changes were more pronounced in younger age groups. In women (weight gain > 2 kg, n = 490), medication for anxiety, low occupational status, high baseline BMI (body mass index), high intake of sweet beverages, high childhood BMI, high salt (NaCl and/or KCl) use, low number of children, low childhood family income, high stature and low level of dependence (a temperament subscale) were associated with increased weight gain (in the order of importance). In men (weight gain > 2 kg, n = 455), high stature, high intake of french fries, low intake of sweet cookies, young age, recent divorce, low intake of cereals, high intake of milk, depressive symptoms, rural childhood origin, high baseline BMI and unemployment were associated with more pronounced weight gain. Sedentarity (screen-time) was associated with weight gain only in young men. Physical activity and genetic risk for high BMI (score of 31 known variants) were not consistently associated with weight change. CONCLUSIONS: Socio-economic factors, temperamental and physical characteristics, and some dietary factors are related with weight change in young/middle-aged adults. The weight change occurring in adulthood is also determined by childhood factors, such as high BMI and low family income.

Role of childhood food patterns on adult cardiovascular disease risk.

Accumulating evidence indicates that childhood nutrition plays a role in the adulthood cardiovascular health. A lifelong tracking of dietary habits, following a long-term exposure to unhealthy dietary patterns or independent effects, is a potential effect-mediating mechanism. Dietary patterns have been studied by data-driven and hypothesis-based approaches. Typically, either data-driven healthy or prudent childhood dietary patterns have been characterized and found to be associated with lower adulthood cardiovascular disease (CVD) risk in the published cohort studies. With regard to the individual food groups or food quality indices, intakes particularly of vegetables and fruits (or fiber indicating plant food intake) and polyunsaturated fatty acids have shown protective effects. The evidence which could confirm the long-term healthiness of a hypothesis-based Mediterranean diet is limited, requiring further investigation. Overall, the recent literature strengthens the view that a healthy childhood diet is associated with lowered adulthood CVD risk.

Childhood serum fatty acid quality is associated with adult carotid artery intima media thickness in women but not in men.

Childhood nutrition may play a role in the development of cardiovascular disease risk in adulthood. We examined the links between childhood dietary fatty acid quality and adult subclinical atherosclerosis in a cohort of 374 males and 449 females, aged 3-18 y at baseline in 1980, followed for 27 y. Serum cholesterol ester fatty acid (CEFA) percentages were analyzed as markers of dietary fatty acid intake. Adulthood carotid artery intima media thickness (cIMT, µm), adjusted for childhood and adulthood lipid and nonlipid risk markers, was used as the outcome. In women, after adjustment for age and childhood nonlipid risk markers, the childhood saturated CEFA (B = 11.3; P = 0.011), monounsaturated CEFA (B = 2.5; P = 0.025), and n3 (ω3) polyunsaturated CEFA (B = 16.2; P = 0.035) percentages were directly associated with adult cIMT. In contrast, the n6 (ω6) polyunsaturated CEFA percentage was negatively associated with cIMT (B = -2.3; P = 0.008). Similar relationships were observed between childhood dietary intake data and adult cIMT. In men, these associations were generally weak and nonsignificant (P > 0.05) after controlling for confounders. These longitudinal data suggest that fat quality as reflected in the serum cholesterol ester fraction in childhood is associated with adult cIMT in women.

The associations of oxidized lipoprotein lipids with lipoprotein subclass particle concentrations and their lipid compositions. The Cardiovascular Risk in Young Finns Study.

OBJECTIVE: Oxidation of low-density lipoprotein (LDL) may promote atherosclerosis, whereas the reverse transport of oxidized lipids by high-density lipoprotein (HDL) may contribute to atheroprotection. To provide insights into the associations of lipoprotein lipid oxidation markers with lipoprotein subclasses at the population level, we investigated the associations of oxidized HDL lipids (oxHDLlipids) and oxidized LDL lipids (oxLDLlipids) with lipoprotein subclasses in a population-based cross-sectional study of 1395 Finnish adults ages 24-39 years. METHODS: The analysis of oxidized lipids was based on the determination of the baseline level of conjugated dienes in lipoprotein lipids. A high-throughput nuclear magnetic resonance (NMR) platform was used to quantify circulating lipoprotein subclass concentrations and analyze their lipid compositions. RESULTS: OxHDLlipids were mainly not associated with lipoprotein subclass lipid concentrations and lipid composition after adjustment for Apolipoprotein-A1 (Apo-A1), waist circumference and age. OxLDLlipids were associated with several markers of lipoprotein subclass lipid concentrations and composition after adjustment for Apolipoprotein-B (Apo-B), age and waist circumference. Several measures of HDL and LDL subclasses, including phospholipid and triglyceride composition, associated directly with oxLDLlipids. Cholesterol ester and free cholesterol composition in HDL and LDL associated inversely with oxLDLlipids. CONCLUSION: We conclude that these results do not support the idea that HDL's particle size or composition would reflect its functional capacity in the reverse transport of oxidized lipids. On the contrary, oxLDLlipids were associated with the entire lipoprotein subclass profile, including numerous associations with the compositional descriptors of the particles. This is in line with the suggested role of LDL oxidation in atherogenesis.

Elevated circulating LDL phenol levels in men who consumed virgin rather than refined olive oil are associated with less oxidation of plasma LDL.

In human LDL, the bioactivity of olive oil phenols is determined by the in vivo disposition of the biological metabolites of these compounds. Here, we examined how the ingestion of 2 similar olive oils affected the content of the metabolic forms of olive oil phenols in LDL in men. The oils differed in phenol concentrations as follows: high (629 mg/L) for virgin olive oil (VOO) and null (0 mg/L) for refined olive oil (ROO). The study population consisted of a subsample from the EUROLIVE study and a randomized controlled, crossover design was used. Intervention periods lasted 3 wk and were preceded by a 2-wk washout period. The levels of LDL hydroxytyrosol monosulfate and homovanillic acid sulfate, but not of tyrosol sulfate, increased after VOO ingestion (P < 0.05), whereas the concentrations of circulating oxidation markers, including oxidized LDL (oxLDL), conjugated dienes, and hydroxy fatty acids, decreased (P < 0.05). The levels of LDL phenols and oxidation markers were not affected by ROO consumption. The relative increase in the 3 LDL phenols was greater when men consumed VOO than when they consumed ROO (P < 0.05), as was the relative decrease in plasma oxLDL (P = 0.001) and hydroxy fatty acids (P < 0.001). Plasma oxLDL concentrations were negatively correlated with the LDL phenol levels (r = -0.296; P = 0.013). Phenols in LDL were not associated with other oxidation markers. In summary, the phenol concentration of olive oil modulates the phenolic metabolite content in LDL after sustained, daily consumption. The inverse relationship of these metabolites with the degree of LDL oxidation supports the in vivo antioxidant role of olive oil phenolics compounds.

Effect of olive oils on biomarkers of oxidative DNA stress in Northern and Southern Europeans.

High consumption of olive oil in the Mediterranean diet has been suggested to protect DNA against oxidative damage and to reduce cancer incidence. We investigated the impact of the phenolic compounds in olive oil, and the oil proper, on DNA and RNA oxidation in North, Central, and South European populations. In a multicenter, double-blind, randomized, controlled crossover intervention trial, the effect of olive oil phenolic content on urinary oxidation products of guanine (8-oxo-guanine, 8-oxo-guanosine and 8-oxo-deoxyguanosine) was investigated. Twenty-five milliliters of three olive oils with low, medium, and high phenolic content were administered to healthy males (n=182) daily for 3 wk. At study baseline the urinary excretion of 8-oxo-guanosine (RNA oxidation) and 8-oxo-deoxyguanosine (DNA oxidation) was higher in the Northern regions of Europe compared with Central and Southern European regions (P=0.035). Urinary excretion of the 8 hydroxylated forms of guanine, guanosine, deoxyguanosine and their nonoxidized forms were not different when comparing olive oils with low, medium, and high phenolic content given for 2 wk. Testing the effect of oil from urinary 8-oxo-deoxyguanosine changes from baseline to post-treatment showed a reduction of DNA oxidation by 13% (P=0.008). These findings support the idea that ingestion of olive oil is beneficial and can reduce the rate of oxidation of DNA. This effect is not due to the phenolic content in the olive oil. The higher DNA and RNA oxidation in Northern European regions compared with that in Central and Southern regions supports the contention that olive oil consumption may explain some of the North-South differences in cancer incidences in Europe.

Changes in LDL fatty acid composition as a response to olive oil treatment are inversely related to lipid oxidative damage: The EUROLIVE study.

OBJECTIVE: The aim of our study was to assess the changes in the fatty acid composition of low density lipoproteins (LDL) after sustained consumption of olive oil at real-life doses (25 mL/day) and their relationship with lipid oxidative damage. METHODS: A multi-center randomized, cross-over, clinical trial with 3 similar types of olive oils, but with differences in the phenolic content, was conducted on 200 healthy European subjects. Intervention periods were of 3 weeks separated by 2-week washout periods. The LDL fatty acid content was measured in samples drawn at baseline and after the last intervention period. RESULTS: After olive oil ingestion oleic acid concentration in LDL increased (1.9%; p < 0.001) and those of linoleic (1.1%; p < 0.002) and arachidonic acid (0.5%; p < 0.001) decreased. Monounsaturated/polyunsaturated fatty acid and oleic/linoleic acid ratios in LDL increased after olive oil consumption. An inverse relationship between the oleic/linoleic acid ratio and biomarkers of oxidative stress was observed. One unit increase in the oleic/linoleic acid ratio was associated with a decrease of 4.2 microg/L in plasma isoprostanes. CONCLUSION: Consumption of olive oil at real-life doses improved the fatty acid profile in LDL, the changes being associated with a reduction of the oxidative damage to lipids.

The effect of polyphenols in olive oil on heart disease risk factors: a randomized trial.

BACKGROUND: Virgin olive oils are richer in phenolic content than refined olive oil. Small, randomized, crossover, controlled trials on the antioxidant effect of phenolic compounds from real-life daily doses of olive oil in humans have yielded conflicting results. Little information is available on the effect of the phenolic compounds of olive oil on plasma lipid levels. No international study with a large sample size has been done. OBJECTIVE: To evaluate whether the phenolic content of olive oil further benefits plasma lipid levels and lipid oxidative damage compared with monounsaturated acid content. DESIGN: Randomized, crossover, controlled trial. SETTING: 6 research centers from 5 European countries. PARTICIPANTS: 200 healthy male volunteers. MEASUREMENTS: Glucose levels, plasma lipid levels, oxidative damage to lipid levels, and endogenous and exogenous antioxidants at baseline and before and after each intervention. INTERVENTION: In a crossover study, participants were randomly assigned to 3 sequences of daily administration of 25 mL of 3 olive oils. Olive oils had low (2.7 mg/kg of olive oil), medium (164 mg/kg), or high (366 mg/kg) phenolic content but were otherwise similar. Intervention periods were 3 weeks preceded by 2-week washout periods. RESULTS: A linear increase in high-density lipoprotein (HDL) cholesterol levels was observed for low-, medium-, and high-polyphenol olive oil: mean change, 0.025 mmol/L (95% CI, 0.003 to 0.05 mmol/L), 0.032 mmol/L (CI, 0.005 to 0.05 mmol/L), and 0.045 mmol/L (CI, 0.02 to 0.06 mmol/L), respectively. Total cholesterol-HDL cholesterol ratio decreased linearly with the phenolic content of the olive oil. Triglyceride levels decreased by an average of 0.05 mmol/L for all olive oils. Oxidative stress markers decreased linearly with increasing phenolic content. Mean changes for oxidized low-density lipoprotein levels were 1.21 U/L (CI, -0.8 to 3.6 U/L), -1.48 U/L (-3.6 to 0.6 U/L), and -3.21 U/L (-5.1 to -0.8 U/L) for the low-, medium-, and high-polyphenol olive oil, respectively. LIMITATIONS: The olive oil may have interacted with other dietary components, participants' dietary intake was self-reported, and the intervention periods were short. CONCLUSIONS: Olive oil is more than a monounsaturated fat. Its phenolic content can also provide benefits for plasma lipid levels and oxidative damage. International Standard Randomised Controlled Trial number: ISRCTN09220811.

Effects of astaxanthin supplementation on lipid peroxidation.

Astaxanthin, the main carotenoid pigment in aquatic animals, has greater antioxidant activity in vitro (protecting against lipid peroxidation) and a more polar configuration than other carotenoids. We investigated the effect of three-month astaxanthin supplementation on lipid peroxidation in healthy non-smoking Finnish men, aged 19-33 years by using a randomized double-blind study design. Also absorption of astaxanthin from capsules into bloodstream and its safety were evaluated. The intervention group received two 4-mg astaxanthin (Astaxin) capsules daily, and the control group two identical-looking placebo capsules. Astaxanthin supplementation elevated plasma astaxanthin levels to 0.032 pmol/L (p < 0.001 for the change compared with the placebo group). We observed that levels of plasma 12- and 15-hydroxy fatty acids were reduced statistically significantly in the astaxanthin group (p = 0.048 and p = 0.047 respectively) during supplementation, but not in the placebo group and the change of 15-hydroxy fatty acid was almost significantly greater (p = 0.056) in the astaxanthin group, as compared with the placebo group. The present study suggests that intestinal absorption of astaxanthin delivered as capsules is adequate, and well tolerated. Supplementation with astaxanthin may decrease in vivo oxidation of fatty acids in healthy men.

Postprandial LDL phenolic content and LDL oxidation are modulated by olive oil phenolic compounds in humans.

Olive oil phenolic compounds are potent antioxidants in vitro, but evidence for antioxidant action in vivo is controversial. We examined the role of the phenolic compounds from olive oil on postprandial oxidative stress and LDL antioxidant content. Oral fat loads of 40 mL of similar olive oils, but with high (366 mg/kg), moderate (164 mg/kg), and low (2.7 mg/kg) phenolic content, were administered to 12 healthy male volunteers in a cross-over study design after a washout period in which a strict antioxidant diet was followed. Tyrosol and hydroxytyrosol, phenolic compounds of olive oil, were dose-dependently absorbed (p<0.001). Total phenolic compounds in LDL increased at postprandial state in a direct relationship with the phenolic compounds content of the olive oil ingested (p<0.05). Plasma concentrations of tyrosol, hydroxytyrosol, and 3-O-methyl-hydroxytyrosol directly correlated with changes in the total phenolic compounds content of the LDL after the high phenolic compounds content olive oil ingestion. A 40 mL dose of olive oil promoted a postprandial oxidative stress, the degree of LDL oxidation being lower as the phenolic content of the olive oil administered increases. In conclusion, olive oil phenolic content seems to modulate the LDL phenolic content and the postprandial oxidative stress promoted by 40 mL olive oil ingestion in humans.

Consumption of juice fortified with oregano extract markedly increases excretion of phenolic acids but lacks short- and long-term effects on lipid peroxidation in healthy nonsmoking men.

Oregano has been shown to possess antioxidant capacity in various in vitro models and has thus been suggested to be potentially beneficial to human health, but studies in humans are lacking. The aim of this study was to investigate the bioavailability and the effects of Origanum vulgare extract supplementation on serum lipids and lipid peroxidation in healthy nonsmoking men. A four-week double-blinded supplementation trial was concluded in which volunteers (n = 45) were randomized to consume daily mango-orange juice (placebo), mango-orange juice enriched with 300 mg/d total phenolic compounds from oregano extract, or mango-orange juice enriched with 600 mg/d total phenolic compounds from oregano extract. The excretion of phenolic compounds was markedly increased in the higher phenolic group as compared to the placebo group, but no significant changes were observed in the safety parameters, serum lipids, or biomarkers of lipid peroxidation.

Longitudinal study of circulating oxidized LDL and HDL and fatty liver: the Cardiovascular Risk in Young Finns Study.

Oxidative reactions are thought to play a role in the inflammatory condition called fatty liver. It is unclear whether oxidized lipoprotein lipids or proteins are associated with future fatty liver. In the Cardiovascular Risk in Young Finns Study, we determined the circulating levels of LDL and HDL oxidized lipids and studied their associations with fatty liver assessed by ultrasonography. There were 1286 middle-aged subjects with normal liver and 288 subjects with fatty liver. Analysis of oxidized lipids consisted of conjugated dienes in isolated HDL (oxHDLlipids) and LDL (oxLDLlipids). Oxidized LDL was also measured with a method based on antibodies against oxidized apolipoprotein B (oxLDLprot). After adjustment for age, sex, leisure-time physical activity, body mass index, alcohol intake, smoking, serum LDL and HDL cholesterol as well as particle concentrations, participants with elevated oxLDLlipids (odds ratio for 1-SD change in oxLDLlipids = 1.27, p =0.011) had an increased risk for fatty liver. Similarly, a high oxidation score (oxLDLlipids + oxLDLprot) was directly associated with fatty liver (odds ratio=1.34, p = 0.012). The strongest direct association was seen with a high oxLDLlipids/oxHDLlipids ratio (odds ratio=1.49, p = 0.001). These data suggest that oxidized lipoprotein lipids are linked with the risk of fatty liver in middle-aged adults.

Six-year effect of combined vitamin C and E supplementation on atherosclerotic progression: the Antioxidant Supplementation in Atherosclerosis Prevention (ASAP) Study.

BACKGROUND: Self-selected supplementation of vitamin E has been associated with reduced coronary events and atherosclerotic progression, but the evidence from clinical trials is controversial. In the first 3 years of the ASAP trial, the supplementation with 136 IU of vitamin E plus 250 mg of slow-release vitamin C twice daily slowed down the progression of carotid atherosclerosis in men but not women. This article examines the 6-year effect of supplementation on common carotid artery (CCA) intima-media thickness (IMT). METHODS AND RESULTS: The subjects were 520 smoking and nonsmoking men and postmenopausal women aged 45 to 69 years with serum cholesterol > or =5.0 mmol/L (193 mg/dL), 440 (84.6%) of whom completed the study. Atherosclerotic progression was assessed ultrasonographically. In covariance analysis in both sexes, supplementation reduced the main study outcome, the slope of mean CCA-IMT, by 26% (95% CI, 5 to 46, P=0.014), in men by 33% (95% CI, 4 to 62, P=0.024) and in women by 14% (not significant). In both sexes combined, the average annual increase of the mean CCA-IMT was 0.014 mm in the unsupplemented and 0.010 mm in the supplemented group (25% treatment effect, 95% CI, 2 to 49, P=0.034). In men, this treatment effect was 37% (95 CI, 4 to 69, P=0.028). The effect was larger in subjects with either low baseline plasma vitamin C levels or CCA plaques. Vitamin E had no effect on HDL cholesterol. CONCLUSIONS: These data replicate our 3-year findings confirming that the supplementation with combination of vitamin E and slow-release vitamin C slows down atherosclerotic progression in hypercholesterolemic persons.

The effects of coffee consumption on lipid peroxidation and plasma total homocysteine concentrations: a clinical trial.

Despite extensive research, the cardiovascular effects of coffee consumption in humans remain controversial. Our aim was to investigate the excretion of coffee phenols and the effects of filtered coffee consumption on oxidative stress and plasma homocysteine (tHcy) concentration in humans. The study consisted of a multiple-dose clinical supplementation trial and a single-dose study. In the long-term trial, 43 healthy nonsmoking men optionally consumed daily either no coffee, 3 cups (450 mL), or 6 cups (900 mL) of filtered coffee for 3 weeks, while in the short-term study 35 subjects consumed a single dose of 0, 1 (150 mL), or 2 cups (300 mL) of coffee. Long-term consumption of coffee increased the urinary excretion of caffeic and ferulic acid. The change in the total excretion of phenolic acids in 3 and 6 cups groups represented 3.8 and 2.5% of the amount ingested daily. Plasma tHcy concentrations increased nonsignificantly, but the consumption of coffee had neither short-nor long-term effects on lipid peroxidation or the activity of measured antioxidant enzymes. In conclusion, the consumption of filtered coffee does not have any detectable effects on lipid peroxidation in healthy nonsmoking men. The effect of coffee consumption on tHcy concentrations needs further investigation.

Polyphenol-rich phloem enhances the resistance of total serum lipids to oxidation in men.

In humans, polyphenol supplementation studies have resulted in inconsistent findings in lipid peroxidation. Our aim was to investigate the effects of a 4-week consumption of polyphenol-rich phloem on serum lipids and lipid peroxidation in the hydrophilic fraction of serum and on isolated lipoproteins. We conducted a randomized double-blind supplementation study consisting of 75 nonsmoking hypercholesterolemic men. Participants consumed 70 g daily of either rye bread (placebo) or phloem-fortified rye bread containing 31 mg (low polyphenol, LP) or 62 mg (high polyphenol, HP) of catechins. The ex vivo susceptibility of total serum lipids and VLDL and LDL to oxidation after copper induction was measured as a lag time to the maximal oxidation rate at the baseline and after the supplementation. In the HP group, an increase in the oxidation resistance of total serum lipids was observed (11.4%), while no effect was seen in the LP group (-0.8%) or in the placebo group (-1.0%) (p = 0.007). No differences were observed in the oxidation resistance of VLDL and LDL between the study groups. The phloem also increased in vitro oxidation resistance of serum lipids and radical scavenging activity (DPPH.) in a dose-dependent manner. Our results suggest that polyphenols may inhibit lipid peroxidation in the hydrophilic fraction of serum.

Paraoxonase-1 and oxidized lipoprotein lipids. The Cardiovascular Risk in Young Finns Study.

OBJECTIVE: Paraoxonase-1 (PON1) is suggested to have a role in the antioxidant activity of high-density lipoprotein (HDL). PON1 activity levels are strongly genetically determined by the rs662 polymorphism (PON1 Q192R). To clarify the role of PON1 in lipoprotein oxidation at the population level, we examined the relations between PON1 activity, the rs662 polymorphism and oxidized lipoprotein lipids in young adults. METHODS: A population-based cross-sectional study of 1895 Finnish adults ages 24-39 years (872 males and 1023 females). PON1 activity was determined with paraoxon as the substrate. Analysis of oxidized lipids in isolated HDL (oxHDLlipids) and low-density lipoprotein (oxLDLlipids) was based on the determination of conjugated dienes. Oxidized LDL was also measured with a method based on antibodies against oxidized Apo-B (oxLDLprot). Serum lipids and apolipoproteins were measured. Genotyping was performed with the Illumina Bead Chip (Human 670 K). RESULTS: In multivariable models, PON1 activity associated inversely with oxLDLlipids (p = 0.0001, semi-partial R(2) = 0.09%), but it was not associated with oxHDLlipids (p = 0.93). There was a borderline significant association between PON1 activity and oxLDLprot (p = 0.08). PON1 rs662 polymorphism was strongly associated with PON1 activity (P-value<0.0001), but not with oxidized lipoprotein lipids and oxLDLprot. CONCLUSION: Higher PON1 activity is associated with decreased oxLDLlipids levels, but not with oxHDLlipids in a population of young Finnish adults. These findings support the suggestion that PON1 activity may have a role in the oxidation of LDL lipids. There is a strong association between PON1 rs662 polymorphism and PON1 activity, but PON1 rs662 polymorphism is not associated with oxidized lipoprotein lipids and oxLDLprot.