Vitamin K1 intake is associated with lower risk for all-cause and cardiovascular disease mortality in community-dwelling older Australian women.

BACKGROUND AND AIMS: Assessing the relationship between vitamin K1 intakes, using region-specific food databases, with both all-cause, and cardiovascular disease (CVD) mortality warrants further investigation to inform future preventative strategies. Consequently, we examined the aforementioned associations in the Perth Longitudinal Study of Ageing Women (PLSAW). METHODS AND RESULTS: 1436 community-dwelling older Australian women (mean ± SD age 75.2 ± 2.7 years) completed a validated food frequency questionnaire at baseline (1998). Vitamin K1 intake was calculated based on an Australian vitamin K food database, supplemented with published data. All-cause and CVD mortality data was obtained from linked health records. Associations were examined using restricted cubic splines within Cox-proportional hazard models, adjusted for a range of cardiovascular and lifestyle related risk factors. Over 15 years of follow-up, 601 (41.9%) women died, with 236 deaths (16.4%) due to CVD. Compared to women with the lowest vitamin K1 intakes (Quartile 1, median 49.1 µg/day), those with the highest intakes (Quartile 4, median 119.3 µg/day) had lower relative hazards for all-cause mortality (HR 0.66 95%CI 0.51-0.86) and CVD mortality (HR 0.61 95%CI 0.41-0.92). A plateau in the inverse association was observed from vitamin K1 intakes of approximately ≥80 µg/day. CONCLUSION: Higher vitamin K1 intakes were associated with lower risk for both all-cause and CVD mortality in community-dwelling older women, independent of CVD related risk factors. A higher intake of vitamin K1 rich foods, such as leafy green vegetables, may support cardiovascular health.

Performance of Urinary Phenyl-γ-Valerolactones as Biomarkers of Dietary Flavan-3-ol Exposure.

BACKGROUND: Phenyl-γ-valerolactones (PVLs) have been identified as biomarkers of dietary flavan-3-ol exposure, although their utility requires further characterization. OBJECTIVES: We investigated the performance of a range of PVLs as biomarkers indicative of flavan-3-ol intake. METHODS: We report the results of 2 companion studies: a 5-way randomized crossover trial (RCT) and an observational cross-sectional study. In the RCT (World Health Organization, Universal Trial Number: U1111-1236-7988), 16 healthy participants consumed flavan-3-ol-rich interventions (of apple, cocoa, black tea, green tea, or water [control]) for 1 d each. First morning void samples and 24-h urine samples were collected with diet standardized throughout. For each participant, 1 intervention period was extended (to 2 d) to monitor PVL kinetics after repeat exposure. In the cross-sectional study, 86 healthy participants collected 24-h urine samples, and concurrent weighed food diaries from which flavan-3-ol consumption was estimated using Phenol-Explorer. A panel of 10 urinary PVLs was quantified using liquid chromatography tandem mass spectrometry. RESULTS: In both studies, 2 urinary PVLs [5-(3'-hydroxyphenyl)-γ-valerolactone-4'-sulfate and putatively identified 5-(4'-hydroxyphenyl)-γ-valerolactone-3'-glucuronide] were the principal compounds excreted (>75%). In the RCT, the sum of these PVLs was significantly higher than the water (control) after each intervention; individually, there was a shift from sulfation toward glucuronidation as the total excretion of PVLs increased across the different interventions. In the extended RCT intervention period, no accumulation of these PVLs was observed after consecutive days of treatment, and after withdrawal of treatment on the third day, there was a return toward negligible PVL excretion. All results were consistent, whether compounds were measured in 24-h urine or first morning void samples. In the observational study, the sum of the principal PVLs correlated dose dependently (Rs = 0.37; P = 0.0004) with dietary flavan-3-ol intake, with similar associations for each individually. CONCLUSIONS: Urinary 5-(3'-hydroxyphenyl)-γ-valerolactone-4'-sulfate and putatively identified 5-(4'-hydroxyphenyl)-γ-valerolactone-3'-glucuronide are recommended biomarkers for dietary flavan-3-ol exposure.

Change in habitual intakes of flavonoid-rich foods and mortality in US males and females.

BACKGROUND: Higher baseline intakes of flavonoid-rich foods and beverages are associated with a lower risk of chronic disease and mortality in observational studies. However, associations between changes in intakes and mortality remain unclear. We aimed to evaluate associations between 8-year changes in intakes of (1) individual flavonoid-rich foods and (2) a composite measure (termed the 'flavodiet') of foods and beverages that are known to be main contributors to flavonoid intake and subsequent total and cause-specific mortality. METHODS: We evaluated associations between 8-year changes in intakes of (1) individual flavonoid-rich foods and (2) a novel 'flavodiet' score and total and cause-specific mortality. We included 55,786 females from the Nurses' Health Study (NHS) and 29,800 males from the Health Professionals Follow-up Study (HPFS), without chronic disease at baseline in our analyses. Using multivariable-adjusted Cox proportional hazard models, we examined associations of 8-year changes in intakes of (1) flavonoid-rich foods and (2) the flavodiet score with subsequent 2-year lagged 6-year risk of mortality adjusting for baseline intakes. Data were pooled using fixed-effects meta-analyses. RESULTS: We documented 15,293 deaths in the NHS and 8988 deaths in HPFS between 1986 and 2018. For blueberries, red wine and peppers, a 5%, 4% and 9% lower risk of mortality, respectively, was seen for each 3.5 servings/week increase in intakes while for tea, a 3% lower risk was seen for each 7 servings/week increase [Pooled HR (95% CI) for blueberries; 0.95 (0.91, 0.99); red wine: 0.96 (0.93, 0.99); peppers: 0.91 (0.88, 0.95); and tea: 0.97 (0.95, 0.98)]. Conversely, a 3.5 servings/week increase in intakes of onions and grapefruit plus grapefruit juice was associated with a 5% and 6% higher risk of total mortality, respectively. An increase of 3 servings per day in the flavodiet score was associated with an 8% lower risk of total mortality [Pooled HR: 0.92 (0.89, 0.96)], and a 13% lower risk of neurological mortality [Pooled HR: 0.87 (0.79, 0.97)], after multivariable adjustments. CONCLUSIONS: Encouraging an increased intake of specific flavonoid-rich foods and beverages, namely tea, blueberries, red wine, and peppers, even in middle age, may lower early mortality risk.

Vegetable, but Not Potato, Intake Is Associated With a Lower Risk of Type 2 Diabetes in the Danish Diet, Cancer and Health Cohort.

OBJECTIVE: To examine the relationship between intake of vegetables/potatoes and incident type 2 diabetes (T2D) and explore whether the relationship between vegetable intake and incident T2D is mediated by baseline BMI. RESEARCH DESIGN AND METHODS: Cross-sectional associations between exposure (baseline intake of total vegetables, vegetable subgroups, and potatoes) and baseline BMI were assessed by multivariable-adjusted linear regression models. Associations between exposure and incident T2D were examined by multivariable-adjusted Cox proportional hazards models. Mediation by BMI was quantified through exploration of natural direct and indirect effects. RESULTS: Among 54,793 participants in the Danish Diet, Cancer and Health cohort, 7,695 cases of T2D were recorded during a median follow-up of 16.3 years. Participants in the highest total vegetable intake quintile (median 319 g/day) had a 0.35 kg/m2 (95% CI -0.46, -0.24) lower BMI and a 21% (95% CI 16, 26%) lower risk of incident T2D after multivariable adjustment compared with those in the lowest quintile (median 67 g/day). Baseline BMI mediated ∼21% of the association between vegetable intake and incident T2D. Participants in the highest compared with the lowest (median 256 vs. 52 g/day) potato intake quintile had a 9% (95% CI 2, 16%) higher risk of T2D after multivariable adjustment, with no association found after accounting for underlying dietary pattern. Of the vegetable subclasses, higher intake of green leafy and cruciferous vegetables was associated with a statistically significantly lower risk of T2D. CONCLUSIONS: The findings provide evidence that a higher vegetable, but not potato, intake might help mitigate T2D risk, partly by reducing BMI.

Higher Habitual Dietary Flavonoid Intake Associates With Less Extensive Abdominal Aortic Calcification in a Cohort of Older Women.

BACKGROUND: The extent of abdominal aortic calcification (AAC) is a major predictor of vascular disease events. We have previously found regular apple intake, a major source of dietary flavonoids, associates with lower AAC. Whether total dietary flavonoid intake impacts AAC remains unknown. Here, we extend our observations to habitual intakes of total flavonoids, flavonoid subclasses, and specific flavonoid-containing foods, with the odds of extensive AAC. METHODS: We conducted cross-sectional analyses on 881 females (median [interquartile range] age, 80 [78-82] years; body mass index, 27 [24-30] kg/m2) from the PLSAW (Perth Longitudinal Study of Ageing Women). Flavonoid intake was calculated from food-frequency questionnaires. Calcifications of the abdominal aorta were assessed on lateral lumbar spine images and categorized as less extensive or extensive. Logistic regression was used to investigate associations. RESULTS: After adjusting for demographic, lifestyle and dietary confounders, participants with higher (Q4), compared with lower (Q1) intakes, of total flavonoids, flavan-3-ols, and flavonols had 36% (odds ratio [95% CI], 0.64 [0.43-0.95]), 39% (0.61 [0.40-0.93]) and 38% (0.62 [0.42-0.92]) lower odds of extensive AAC, respectively. In food-based analyses, higher black tea intake, the main source of total flavonoids (75.9%), associated with significantly lower odds of extensive AAC (2-6 cups/d had 16%-42% lower odds compared with 0 daily intake). In a subset of nonconsumers of black tea, the association of total flavonoid intake with AAC remained (Q4 versus Q1 odds ratio [95% CI], 0.11 [0.02-0.54]). CONCLUSIONS: In older women, greater habitual dietary flavonoid intake associates with less extensive AAC.

Increased nitrate intake from beetroot juice does not alter soluble cellular adhesion molecules and circulating inflammatory cytokines in individuals with treated hypertension: a randomised, controlled trial.

Dietary nitrate, found predominantly in green leafy vegetables and other vegetables such as radish, celery, and beetroot, has been shown to beneficially modulate inflammatory processes and immune cell function in animals and healthy individuals. The impact of increased nitrate intake on soluble inflammatory mediators in individuals with hypertension is unclear. We assessed whether the daily consumption of dietary nitrate via beetroot juice for 1-week lowered levels of circulating inflammatory markers in men and women with treated hypertension. Twenty-seven male and female participants were recruited to a randomized, placebo-controlled, double-blind crossover trial. The effects of 1-week intake of nitrate-rich beetroot juice versus 1-week intake of nitrate-depleted beetroot juice (placebo) were investigated. Plasma concentrations of circulating soluble adhesion molecules (ICAM-1, VCAM-1, CD62E, CD62P), inflammatory cytokines (IL-1ß, IL-6, IL-10, IL-12p70, TNF-α) and chemokines (IL-8, MCP-1) were measured by multiplex flow cytometric bead array in samples collected on day 7 of each intervention period. Other outcomes included alterations in nitrate metabolism assessed by measuring nitrate and nitrite concentrations in plasma, saliva, and urine. One week of beetroot juice did not alter levels of the soluble adhesion markers or cytokines assessed. A 7-fold increase in salivary nitrite, an 8-fold increase in salivary nitrate, a 3-fold increase in plasma nitrate and nitrite, and a 4-fold increase in urinary nitrate and nitrite compared to the placebo was observed (p < 0.001 for all comparisons). Increasing dietary nitrate consumption over 7 days is not effective in reducing soluble inflammatory mediators in individuals with treated hypertension. This trial was registered at anzctr.org.au as ACTRN 12613000116729.

Dietary Vitamin K1 intake is associated with lower long-term fracture-related hospitalization risk: the Perth longitudinal study of ageing women.

This study examined the association between dietary Vitamin K1 intake with fracture-related hospitalizations over 14.5 years in community-dwelling older Australian women (n = 1373, ≥70 years). Dietary Vitamin K1 intake at baseline (1998) was estimated using a validated food frequency questionnaire and a new Australian Vitamin K nutrient database, which was supplemented with published data. Over 14.5 years, any fracture (n = 404, 28.3%) and hip fracture (n = 153, 10.7%) related hospitalizations were captured using linked health data. Plasma Vitamin D status (25OHD) and the ratio of undercarboxylated osteocalcin (ucOC) to total osteocalcin (tOC) from serum was assessed at baseline. Estimates of dietary Vitamin K1 intake were supported by a significant inverse association with ucOC : tOC; a marker of Vitamin K status (r = -0.12, p < 0.001). Compared to women with the lowest Vitamin K1 intake (Quartile 1, <61 µg d-1), women with the highest Vitamin K1 intake (Quartile 4, ≥99 µg d-1) had lower hazards for any fracture- (HR 0.69 95%CI 0.52-0.91, p < 0.001) and hip fracture-related hospitalization (HR 0.51 95%CI 0.32-0.79, p < 0.001), independent of 25OHD levels, as part of multivariable-adjusted analysis. Spline analysis suggested a nadir in the relative hazard for any fracture-related hospitalizations at a Vitamin K1 intake of approximately 100 µg day-1. For hip fractures, a similar relationship was apparent. Higher dietary Vitamin K1 is associated with lower long-term risk for any fracture- and hip fracture-related hospitalizations in community-dwelling older women.

The effect of vitamin K1 on arterial calcification activity in subjects with diabetes mellitus: a post hoc analysis of a double-blind, randomized, placebo-controlled trial.

BACKGROUND: Coronary and aortic artery calcifications are generally slow to develop, and their burden predicts cardiovascular disease events. In patients with diabetes mellitus, arterial calcification is accelerated and calcification activity can be detected using 18F-sodium fluoride positron emission tomography (18F-NaF PET). OBJECTIVES: We aimed to determine whether vitamin K1 supplementation inhibits arterial calcification activity in individuals with diabetes mellitus. METHODS: This was a post hoc analysis of the ViKCoVaC (effect of Vitamin-K1 and Colchicine on Vascular Calcification activity in subjects with Diabetes Mellitus) double-blind randomized controlled trial conducted in Perth, Western Australia. Individuals with diabetes mellitus and established coronary calcification (coronary calcium score > 10), but without clinical coronary artery disease, underwent baseline 18F-NaF PET imaging, followed by oral vitamin K1 supplementation (10 mg/d) or placebo for 3 mo, after which 18F-NaF PET imaging was repeated. We tested whether individuals randomly assigned to vitamin K1 supplementation had reduced development of new 18F-NaF PET positive lesions within the coronary arteries and aorta. RESULTS: In total, 149 individuals completed baseline and follow-up imaging studies. Vitamin K1 supplementation independently decreased the odds of developing new 18F-NaF PET positive lesions in the coronary arteries (OR: 0.35; 95% CI: 0.16, 0.78; P = 0.010), aorta (OR: 0.27; 95% CI: 0.08, 0.94; P = 0.040), and in both aortic and coronary arteries (OR: 0.28; 95% CI: 0.13, 0.63; P = 0.002). CONCLUSIONS: In individuals with diabetes mellitus, supplementation with 10 mg vitamin K1/d may prevent the development of newly calcifying lesions within the aorta and the coronary arteries as detected using 18F-NaF PET. Further long-term studies are needed to test this hypothesis.This trial was registered at anzctr.org.au as ACTRN12616000024448.

Dietary Nitrate Intake Is Positively Associated with Muscle Function in Men and Women Independent of Physical Activity Levels.

BACKGROUND: Nitrate supplements can improve vascular and muscle function. Whether higher habitual dietary nitrate is associated with better muscle function remains underexplored. OBJECTIVE: The aim was to examine whether habitual dietary nitrate intake is associated with better muscle function in a prospective cohort of men and women, and whether the relation was dependent on levels of physical activity. METHODS: The sample (n = 3759) was drawn from the Australian Diabetes, Obesity, and Lifestyle Study (AusDiab) (56% female; mean ± SD baseline age: 48.6 ± 11.1 y). Habitual dietary intake was assessed over 12 y by obtaining an average [of at least 2 time points, e.g., baseline (2000/2001) and 2004/2005 and/or 2011/2012] from a food-frequency questionnaire. Nitrate intake was calculated from a validated nitrate database and other published literature. Muscle function was quantified by knee extension strength (KES) and the 8-ft-timed-up-and-go (8ft-TUG) test performed in 2011/2012. Physical activity was assessed by questionnaire. Generalized linear models and logistic regression were used to analyze the data. RESULTS: Median (IQR) total nitrate intake was 65 (52-83) mg/d, with ∼81% derived from vegetables. Individuals in the highest tertile of nitrate intake (median intake: 91 mg/d) had 2.6 kg stronger KES (11%) and 0.24 s faster 8ft-TUG (4%) compared with individuals in the lowest tertile of nitrate intake (median intake: 47 mg/d; both P < 0.05). Similarly, individuals in the highest tertile of nitrate intake had lower odds for weak KES (adjusted OR: 0.69; 95% CI: 0.47, 0.73) and slow 8ft-TUG (adjusted OR: 0.63; 95% CI: 0.50, 0.78) compared with those in the lowest tertile. Physical activity did not influence the relationship between nitrate intake and muscle function (KES; P-interaction = 0.86; 8ft-TUG; P-interaction = 0.99). CONCLUSIONS: Higher habitual dietary nitrate intake, predominantly from vegetables, could be an effective way to promote lower-limb muscle strength and physical function in men and women.

Phenolic composition of 91 Australian apple varieties: towards understanding their health attributes.

INTRODUCTION: Apples, an important contributor to total dietary phenolic intake, are associated with cardiovascular health benefits. Determining the phenolic composition of apples, their individual variation across varieties, and the phenolic compounds present in plasma after apple consumption is integral to understanding the effects of apple phenolics on cardiovascular health. METHODS: Using liquid chromatography we quantified five important polyphenols and one phenolic acid with potential health benefits: quercetin glycosides, (-)-epicatechin, procyanidin B2, phloridzin, anthocyanins, and chlorogenic acid, in the skin and flesh of 19 apple varieties and 72 breeding selections from the Australian National Apple Breeding program. Furthermore, we measured the phenolic compounds in the plasma of 30 individuals post-consumption of an identified phenolic-rich apple, Cripp's Pink. RESULTS: Considerable variation in concentration of phenolic compounds was found between genotypes: quercetin (mean ± SD: 16.1 ± 5.9, range: 5.8-30.1 mg per 100 g); (-)-epicatechin (mean ± SD: 8.6 ± 5.8, range: 0.2-19.8 mg per 100 g); procyanidin B2 (mean ± SD: 11.5 ± 6.6, range: 0.5-26.5 mg per 100 g); phloridzin (mean ± SD: 1.1 ± 0.6, range: 0.3-4.3 mg per 100 g); anthocyanins (mean ± SD: 1.8 ± 4.4, range: 0-40.8 mg per 100 g); and chlorogenic acid (mean ± SD: 11.3 ± 9.9, range: 0.4-56.0 mg per 100 g). All phenolic compounds except chlorogenic acid were more concentrated in the skin compared with flesh. We observed a significant increase, with wide variation, in 14 phenolic compounds in plasma post-consumption of a phenolic-rich apple. CONCLUSION: This information makes an important contribution to understanding the potential health benefits of apples.

Flavonoid intake is associated with lower mortality in the Danish Diet Cancer and Health Cohort.

Flavonoids, plant-derived polyphenolic compounds, have been linked with health benefits. However, evidence from observational studies is incomplete; studies on cancer mortality are scarce and moderating effects of lifestyle risk factors for early mortality are unknown. In this prospective cohort study including 56,048 participants of the Danish Diet, Cancer, and Health cohort crosslinked with Danish nationwide registries and followed for 23 years, there are 14,083 deaths. A moderate habitual intake of flavonoids is inversely associated with all-cause, cardiovascular- and cancer-related mortality. This strong association plateaus at intakes of approximately 500 mg/day. Furthermore, the inverse associations between total flavonoid intake and mortality outcomes are stronger and more linear in smokers than in non-smokers, as well as in heavy (>20 g/d) vs. low-moderate (<20 g/d) alcohol consumers. These findings highlight the potential to reduce mortality through recommendations to increase intakes of flavonoid-rich foods, particularly in smokers and high alcohol consumers.

Acute effects of quercetin-3-O-glucoside on endothelial function and blood pressure: a randomized dose-response study.

BACKGROUND: Epidemiologic studies have suggested that a flavonoid-rich diet can reduce the risk of developing cardiovascular disease. Certain flavonoids, in particular quercetin, have been shown to ameliorate endothelial dysfunction and reduce blood pressure (BP), possibly by increasing the bioavailability of the potent vasodilator nitric oxide (NO). Several studies have indicated that improvements in measures of cardiovascular health do not occur linearly, but rather, plateau or decrease with an increasing dose of flavonoids. OBJECTIVES: We determined whether the acute administration of increasing doses of a common quercetin glycoside (quercetin-3-O-glucoside) improves endothelial function and reduces BP in a dose-dependent manner. We also explored whether any effects were correlated with changes in plasma NO production. DESIGN: A randomized, controlled, crossover study was performed in 15 healthy volunteers who each completed 5 visits with a minimum washout period of 1 wk between testing days. Participants received each of the following 5 interventions in a random order: 1) 0, 2) 50, 3) 100, 4) 200, or 5) 400 mg quercetin-3-O-glucoside. Endothelial function and BP were assessed before and 60 min after intervention. A blood sample was taken before and 90 min after intervention for the analysis of plasma nitrate and nitrite as markers of NO production as well as of plasma quercetin metabolites. RESULTS: Although we observed a significant correlation between the dose of quercetin-3-O-glucoside and plasma concentrations of total quercetin (R(2) = 0.52, P < 0.001) and isorhamnetin (R(2) = 0.12, P = 0.005), we showed no improvements in endothelial function or BP and no changes in NO production after any dose. CONCLUSION: From these results, we conclude that there are no acute changes in BP or the NO-mediated endothelium-dependent relaxation of the brachial artery with doses of quercetin ranging from 50 to 400 mg in healthy men and women. This trial was registered at www.anzctr.org.au as ACTRN12615001338550.