Effects of dark chocolate consumption on the prothrombotic response to acute psychosocial stress in healthy men

Flavanoid-rich dark chocolate consumption benefits cardiovascular health, but underlying mechanisms are elusive. We investigated the acute effect of dark chocolate on the reactivity of prothrombotic measures to psychosocial stress. Healthy men aged 20-50 years (mean ± SD: 35.7 ± 8.8) were assigned to a single serving of either 50 g of flavonoid-rich dark chocolate (n=31) or 50 g of optically identical flavonoid-free placebo chocolate (n=34). Two hours after chocolate consumption, both groups underwent an acute standardised psychosocial stress task combining public speaking and mental arithmetic. We determined plasma levels of four stress-responsive prothrombotic measures (i. e., fibrinogen, clotting factor VIII activity, von Willebrand Factor antigen, fibrin D-dimer) prior to chocolate consumption, immediately before and after stress, and at 10 minutes and 20 minutes after stress cessation. We also measured the flavonoid epicatechin, and the catecholamines epinephrine and norepinephrine in plasma. The dark chocolate group showed a significantly attenuated stress reactivity of the hypercoagulability marker D-dimer (F=3.87, p=0.017) relative to the placebo chocolate group. Moreover, the blunted D-dimer stress reactivity related to higher plasma levels of the flavonoid epicatechin assessed before stress (F=3.32, p = 0.031) but not to stress-induced changes in catecholamines (p's=0.35). There were no significant group differences in the other coagulation measures (p's≥0.87). Adjustments for covariates did not alter these findings. In conclusion, our findings indicate that a single consumption of flavonoid-rich dark chocolate blunted the acute prothrombotic response to psychosocial stress, thereby perhaps mitigating the risk of acute coronary syndromes triggered by emotional stress.

Stress-induced modulation of NF-κB activation, inflammation-associated gene expression, and cytokine levels in blood of healthy men

Acute psychosocial stress stimulates transient increases in circulating pro-inflammatory plasma cytokines, but little is known about stress effects on anti-inflammatory cytokines or underlying mechanisms. We investigated the stress kinetics and interrelations of pro- and anti-inflammatory measures on the transcriptional and protein level. Forty-five healthy men were randomly assigned to either a stress or control group. While the stress group underwent an acute psychosocial stress task, the second group participated in a non-stress control condition. We repeatedly measured before and up to 120min after stress DNA binding activity of the pro-inflammatory transcription factor NF-κB (NF-κB-BA) in peripheral blood mononuclear cells, whole-blood mRNA levels of NF-κB, its inhibitor IκBα, and of the pro-inflammatory cytokines interleukin (IL)-1ß and IL-6, and the anti-inflammatory cytokine IL-10. We also repeatedly measured plasma levels of IL-1ß, IL-6, and IL-10. Compared to non-stress, acute stress induced significant and rapid increases in NF-κB-BA and delayed increases in plasma IL-6 and mRNA of IL-1ß, IL-6, and IκBα (p's<.045). In the stress group, significant increases over time were also observed for NF-κB mRNA and plasma IL-1ß and IL-10 (p's<.055). NF-κB-BA correlated significantly with mRNA of IL-1β (r=.52, p=.002), NF-κB (r=.48, p=.004), and IκBα (r=.42, p=.013), and marginally with IL-6 mRNA (r=.31, p=.11). Plasma cytokines did not relate to NF-κB-BA or mRNA levels of the respective cytokines. Our data suggest that stress induces increases in NF-κB-BA that relate to subsequent mRNA expression of pro-inflammatory, but not anti-inflammatory cytokines, and of regulatory-cytoplasmic-proteins. The stress-induced increases in plasma cytokines do not seem to derive from de novo synthesis in circulating blood cells.

Enhanced emotional empathy after psychosocial stress in young healthy men

Empathy is a core prerequisite for human social behavior. Relatively, little is known about how empathy is influenced by social stress and its associated neuroendocrine alterations. The current study was designed to test the impact of acute stress on emotional and cognitive empathy. Healthy male participants were exposed to a psychosocial laboratory stressor (trier social stress test, (TSST)) or a well-matched control condition (Placebo-TSST). Afterwards they participated in an empathy test measuring emotional and cognitive empathy (multifaceted empathy test, (MET)). Stress exposure caused an increase in negative affect, a rise in salivary alpha amylase and a rise in cortisol. Participants exposed to stress reported more emotional empathy in response to pictures displaying both positive and negative emotional social scenes. Cognitive empathy (emotion recognition) in contrast did not differ between the stress and the control group. The current findings provide initial evidence for enhanced emotional empathy after acute psychosocial stress.

Maximal exercise hemodynamics and risk of mortality in apparently healthy men and women

The use of exercise electrocardiography (ECG) to detect latent coronary heart disease (CHD) is discouraged in apparently healthy populations because of low sensitivity. These recommendations however, are based on the efficacy of evaluation of ischemia (ST segment changes) with little regard for other measures of cardiac function that are available during exertion. The purpose of this investigation was to determine the association of maximal exercise hemodynamic responses with risk of mortality due to all-causes, cardiovascular disease (CVD), and coronary heart disease (CHD) in apparently healthy individuals. Study participants were 20,387 men (mean age = 42.2 years) and 6,234 women (mean age = 41.9 years) patients of a preventive medicine center in Dallas, TX examined between 1971 and 1989. During an average of 8.1 years of follow-up, there were 348 deaths in men and 66 deaths in women. In men, age-adjusted all-cause death rates (per 10,000 person years) across quartiles of maximal systolic blood pressure (SBP) (low to high) were: 18.2, 16.2, 23.8, and 24.6 (p for trend $<$0.001). Corresponding rates for maximal heart rate were: 28.9, 15.9, 18.4, and 15.1 (p trend $<$0.001). After adjustment for confounding variables including age, resting systolic pressure, serum cholesterol and glucose, body mass index, smoking status, physical fitness and family history of CVD, risks (and 95% confidence interval (CI)) of all-cause mortality for quartiles of maximal SBP, relative to the lowest quartile, were: 0.96 (0.70-1.33), 1.36 (1.01-1.85), and 1.37 (0.98-1.92) for quartiles 2-4 respectively. Similar risks for maximal heart rate were: 0.61 (0.44-0.85), 0.69 (0.51-0.93), and 0.60 (0.41-0.87). No associations were noted between maximal exercise rate-pressure product mortality. Similar results were seen for risk of CVD and CHD death. In women, similar trends in age-adjusted all-cause and CVD death rates across maximal SBP and heart rate categories were observed. Sensitivity of the exercise test in predicting mortality was enhanced when ECG results were evaluated together with maximal exercise SBP or heart rate with a concomitant decrease in specificity. Positive predictive values were not improved. The efficacy of the exercise test in predicting mortality in apparently healthy men and women was not enhanced by using maximal exercise hemodynamic responses. These results suggest that an exaggerated systolic blood pressure or an attenuated heart rate response to maximal exercise are risk factors for mortality in apparently healthy individuals. ^

Organization of the human myostatin gene and expression in healthy men and HIV-infected men with muscle wasting

Myostatin, a member of the transforming growth factor-β superfamily, is a genetic determinant of skeletal muscle growth. Mice and cattle with inactivating mutations of myostatin have marked muscle hypertrophy. However, it is not known whether myostatin regulates skeletal muscle growth in adult men and whether increased myostatin expression contributes to wasting in chronic illness. We examined the hypothesis that myostatin expression correlates inversely with fat-free mass in humans and that increased expression of the myostatin gene is associated with weight loss in men with AIDS wasting syndrome. We therefore cloned the human myostatin gene and cDNA and examined the gene’s expression in the skeletal muscle and serum of healthy and HIV-infected men. The myostatin gene comprises three exons and two introns, maps to chromosomal region 2q33.2, has three putative transcription initiation sites, and is transcribed as a 3.1-kb mRNA species that encodes a 375-aa precursor protein. Myostatin is expressed uniquely in the human skeletal muscle as a 26-kDa mature glycoprotein (myostatin-immunoreactive protein) and secreted into the plasma. Myostatin immunoreactivity is detectable in human skeletal muscle in both type 1 and 2 fibers. The serum and intramuscular concentrations of myostatin-immunoreactive protein are increased in HIV-infected men with weight loss compared with healthy men and correlate inversely with fat-free mass index. These data support the hypothesis that myostatin is an attenuator of skeletal muscle growth in adult men and contributes to muscle wasting in HIV-infected men.

Whole body nitric oxide synthesis in healthy men determined from [15N] arginine-to-[15N]citrulline labeling.

The rates of whole body nitric oxide (NO) synthesis, plasma arginine flux, and de novo arginine synthesis and their relationships to urea production, were examined in a total of seven healthy adults receiving an L-amino acid diet for 6 days. NO synthesis was estimated by the rate of conversion of the [15N] guanidino nitrogen of arginine to plasma [15N] ureido citrulline and compared with that based on urinary nitrite (NO2-)/nitrate (NO3-) excretion. Six subjects received on dietary day 7, a 24-hr (12-hr fed/12-hr fasted) primed, constant, intravenous infusion of L-[guanidino-15N2]arginine and [13C]urea. A similar investigation was repeated with three of these subjects, plus an additional subject, in which they received L-[ureido-13C]citrulline, to determine plasma citrulline fluxes. The estimated rates (mean +/- SD) of NO synthesis over a period of 24 hr averaged 0.96 +/- 0.1 mumol .kg-1.hr-1 and 0.95 +/- 0.1 mumol.kg-1.hr-1, for the [15N]citrulline and the nitrite/nitrate methods, respectively. About 15% of the plasma arginine turnover was associated with urea formation and 1.2% with NO formation. De novo arginine synthesis averaged 9.2 +/- 1.4 mumol. kg-1.hr-1, indicating that approximately 11% of the plasma arginine flux originates via conversion of plasma citrulline to arginine. Thus, the fraction of the plasma arginine flux associated with NO and also urea synthesis in healthy humans is small, although the plasma arginine compartment serves as a significant precursor pool (54%) for whole body NO formation. This tracer model should be useful for exploring these metabolic relationships in vivo, under specific pathophysiologic states where the L-arginine-NO pathway might be altered.

Alpha-lipoic acid does not acutely affect resistance and conduit artery function or oxidative stress in healthy men

Aims Alpha-lipoic acid (ALA) is a thiol compound with antioxidant properties used in the treatment of diabetic polyneuropathy. ALA may also improve arterial function, but there have been scant human trials examining this notion. This project aimed to investigate the effects of oral and intra-arterial ALA on changes in systemic and regional haemodynamics, respectively. Methods In study 1, 16 healthy older men aged 58 +/- 7 years (mean +/- SD) received 600 mg of ALA or placebo, on two occasions 1 week apart, in a randomized cross-over design. Repeated measures of peripheral and central haemodynamics were then obtained for 90 min. Central blood pressure and indices of arterial stiffness [augmentation index (AIx) and estimated aortic pulse wave velocity] were recorded non-invasively using pulse wave analysis. Blood samples obtained pre- and post-treatments were analysed for erythrocyte antioxidant enzyme activity, plasma nitrite and malondialdehyde. In study 2 the effects of incremental cumulative doses (0.5, 1.0, 1.5 and 2.0 mg ml(-1) min(-1)) of intra-arterial ALA on forearm blood flow (FBF) were assessed in eight healthy subjects (aged 31 +/- 5 years) by conventional venous occlusion plethysmography. Results There were no significant changes on any of the central or peripheral haemodynamic measures after either oral or direct arterial administration of ALA. Plasma ALA was detected after oral supplementation (95% confidence intervals 463, 761 ng ml(-1)), but did not alter cellular or plasma measures of oxidative stress. Conclusions Neither oral nor intra-arterial ALA had any effect on regional and systemic haemodynamics or measures of oxidative stress in healthy men.

Habitual chocolate consumption and risk of cardiovascular disease among healthy men and women

Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Habitual chocolate consumption and risk of cardiovascular disease among healthy men and women

Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Habitual chocolate consumption and the risk of incident heart failure among healthy men and women

Acknowledgments The authors would like to thank the participants of the EPIC-Norfolk cohort. We thank the nutritionist team and data management team of the EPIC-Norfolk cohort. The EPIC-Norfolk study was supported by grants from the Medical Research Council and Cancer Research UK. Funders had no role in study design or interpretation of the findings.

Habitual chocolate consumption and the risk of incident heart failure among healthy men and women

Acknowledgments The authors would like to thank the participants of the EPIC-Norfolk cohort. We thank the nutritionist team and data management team of the EPIC-Norfolk cohort. The EPIC-Norfolk study was supported by grants from the Medical Research Council and Cancer Research UK. Funders had no role in study design or interpretation of the findings.

Oral melatonin reduces blood coagulation activity: a placebo-controlled study in healthy young men

Melatonin has previously been suggested to affect hemostatic function but studies on the issue are scant. We hypothesized that, in humans, oral administration of melatonin is associated with decreased plasma levels of procoagulant hemostatic measures compared with placebo medication and that plasma melatonin concentration shows an inverse association with procoagulant measures. Forty-six healthy men (mean age 25 +/- 4 yr) were randomized, single-blinded, to either 3 mg of oral melatonin (n = 25) or placebo medication (n = 21). One hour thereafter, levels of melatonin, fibrinogen, and D-dimer as well as activities of coagulation factor VII (FVII:C) and VIII (FVIII:C) were measured in plasma. Multivariate analysis of covariance and regression analysis controlled for age, body mass index, mean arterial blood pressure, heart rate, and norepinephrine plasma level. Subjects on melatonin had significantly lower mean levels of FVIII:C (81%, 95% CI 71-92 versus 103%, 95% CI 90-119; P = 0.018) and of fibrinogen (1.92 g/L, 95% CI 1.76-2.08 versus 2.26 g/L, 95% CI 2.09-2.43; P = 0.007) than those on placebo explaining 14 and 17% of the respective variance. In all subjects, increased plasma melatonin concentration independently predicted lower levels of FVIII:C (P = 0.037) and fibrinogen (P = 0.022) explaining 9 and 11% of the respective variance. Melatonin medication and plasma concentration were not significantly associated with FVII:C and D-dimer levels. A single dose of oral melatonin was associated with lower plasma levels of procoagulant factors 60 min later. There might be a dose-response relationship between the plasma concentration of melatonin and coagulation activity.

The effect of exercise on large artery haemodynamics in healthy young men

Background Brachial blood pressure predicts cardiovascular outcome at rest and during exercise. However, because of pulse pressure amplification, there is a marked difference between brachial pressure and central (aortic) pressure. Although central pressure is likely to have greater clinical importance, very little data exist regarding the central haemodynamic response to exercise. The aim of the present study was to determine the central and peripheral haemodynamic response to incremental aerobic exercise. Materials and methods Twelve healthy men aged 31 +/- 1 years (mean +/- SEM) exercised at 50%, 60%, 70% and 80% of their maximal heart rate (HRmax) on a bicycle ergometer. Central blood pressure and estimated aortic pulse wave velocity, assessed by timing of the reflected wave (T-R), were obtained noninvasively using pulse wave analysis. Pulse pressure amplification was defined as the ratio of peripheral to central pulse pressure and, to assess the influence of wave reflection on amplification, the ratio of peripheral pulse pressure to nonaugmented central pulse pressure (PPP : CDBP-P-1) was also calculated. Results During exercise, there was a significant, intensity-related, increase in mean arterial pressure and heart rate (P < 0.001). There was also a significant increase in pulse pressure amplification and in PPP : CDBP-P-1 (P < 0.001), but both were independent of exercise intensity. Estimated aortic pulse wave velocity increased during exercise (P < 0.001), indicating increased aortic stiffness. There was also a positive association between aortic pulse wave velocity and mean arterial pressure (r = 0.54; P < 0.001). Conclusions Exercise significantly increases pulse pressure amplification and estimated aortic stiffness.

Inflammatory cytokine responses to progressive resistance training and supplementation with fortified milk in men aged 50+ years : an 18-month randomized controlled trial

We examined the effects of progressive resistance training (PRT) and supplementation with calcium-vitamin D(3) fortified milk on markers of systemic inflammation, and the relationship between inflammation and changes in muscle mass, size and strength. Healthy men aged 50-79 years (n = 180) participated in this 18-month randomized controlled trial that comprised a factorial 2 x 2 design. Participants were randomized to (1) PRT + fortified milk supplement, (2) PRT, (3) fortified milk supplement, or (4) a control group. Participants assigned to PRT trained 3 days per week, while those in the supplement groups consumed 400 ml day(-1) of milk containing 1,000 mg calcium plus 800 IU vitamin D(3). We collected venous blood samples at baseline, 12 and 18 months to measure the serum concentrations of IL-6, TNF-alpha and hs-CRP. There were no exercise x supplement interactions, but serum IL-6 was 29% lower (95% CI, -62, 0) in the PRT group compared with the control group after 12 months. Conversely, IL-6 was 31% higher (95% CI, -2, 65) in the supplement group compared with the non-supplemented groups after 12 and 18 months. These between-group differences did not persist after adjusting for changes in fat mass. In the PRT group, mid-tibia muscle cross-sectional area increased less in men with higher pre-training inflammation compared with those men with lower inflammation (net difference similar to 2.5%, p < 0.05). In conclusion, serum IL-6 concentration decreased following PRT, whereas it increased after supplementation with fortified milk concomitant with changes in fat mass. Furthermore, low-grade inflammation at baseline restricted muscle hypertrophy following PRT.