Healthy Middle-aged Men Research Articles

Short Report: Association of IL-15 with Peripheral and Hepatic Insulin Sensitivity in Healthy Middle-Aged Men

Rodent study suggests that interleukin (IL)-15 administration enhances insulin sensitivity. Although it is well known that circulating levels of typical inflammatory markers (C-reactive protein [CRP] and IL-6) are positively associated with homeostasis model assessment-insulin resistance (HOMA-IR), there are no studies investigating the associations of other inflammatory markers including IL-15 with peripheral/hepatic insulin sensitivity in humans. The current study aimed to examine the relationship between the levels of adiopokines or inflammatory cytokines and insulin sensitivity in 8 healthy middle-aged men. Circulating levels of 10 insulin sensitizing adipokines or inflammatory cytokines (total adiponectin [APN], high molecular weight adiponectin [HMW-APN], IL-4, IL-5, IL-6, IL-8, IL-15, interferon [IFN]-γ, tumor necrosis factor [TNF]-α, and TNF-β) were measured. A stable-labeled frequently sampled intravenous glucose tolerance test was performed to assess peripheral () and hepatic () insulin sensitivity estimated by 2-compartment minimal model. The levels of 3 inflammatory cytokines (IL-4, IL-6, and IL-15) were significantly and inversely correlated with either and . The association between IL-15 and either or was significant even after adjusting for age and percent body fat (p

The Effects of Marathon Running on Retinol Binding Protein 4 and C-reactive Protein Levels in Healthy Middle-aged Korean Men

Background: The purpose of this study was to investigate the effects of marathon running (42.195 km) on retinol binding protein4 (RBP4) and C-reactive protein (CRP) in healthy middle aged Korean men. Methods: Fourteen men aged from 40 to 50 participated in the current study. Eight participants completed marathon running while six participants in the control group took a rest. Blood samples were collected 90 minutes before running the marathon and right after it. Blood samples from the control group were drawn approximately at the same time. Results: Marathon running (average marathon finishing time: 256.75 ± 11.52 min) did not influence plasma levels of RBP4 (pre: 86.63 ± 28.87 vs post: 92.22 ± 42.20 μg/mL) or CRP (pre: 0.04 ± 0.04 vs post: 0.04 ± 0.04 mg/dL). After running the marathon, white blood cells increased by 235% (pre: 5.80 ± 1.64 th/mm 3 vs post: 13.62 ± 3.62 th/mm 3 ). Total cholesterol level also increased significantly after marathon running (P < 0.05). Conclusion: Marathon running did not affect RBP4 or CRP levels, but it increased WBC level significantly. Further studies are needed to elucidate the exact physiological indicators associated with marathon running, as in WBC, RBP4, and CRP.

Letter by Morris et al Regarding Article, “Low Heart Rates Predict Incident Atrial Fibrillation in Healthy Middle-Aged Men” by Grundvold et al

We read with great interest the article by Grundvold et al1 describing low heart rate on exercise as a predictor of atrial fibrillation (AF) in healthy middle-aged men. The article makes an important contribution to the emerging body of evidence that exercise can lead to cardiovascular remodeling, increasing the risk of AF in later life. Although the authors concede that conclusions regarding the pathophysiological mechanisms underlying these observations are difficult, they argue that a predominance of parasympathetic tone may account for both low heart rate and …

Response to Letter by Morris et al Regarding Article, “Low Heart Rates Predict Incident Atrial Fibrillation in Healthy Middle-Aged Men” by Grundvold et al

We appreciate the comments of Morris et al and share their curiosity about the pathophysiological mechanisms that lead to atrial fibrillation (AF). Our cohort of initially healthy middle-aged men demonstrated that those with high fitness and low heart rates at a modest workload (<100 beats per minute at 100 W bicycling for 6 minutes) had an increased incidence of AF, especially if their blood pressure was elevated.1 We speculated that vagal dominance might be involved, causing relative bradycardia and larger stroke volumes both at rest and during moderate exercise, as well as more atrial stretch resulting in remodeling, which may be electric …

Apolipoprotein B/Apolipoprotein A-I Ratio and Apolipoprotein B

We investigated whether serum concentrations of apolipoprotein (apo) B and apoA-I and the apoB/apoA-I ratio provided predictive information on myocardial infarction (MI) and ischemic stroke during 13 years of follow-up in a group of initially clinically healthy 58-year-old men, free from previous cardiovascular disease, diabetes, other established disease, or treatment with cardiovascular drugs. Multivariate logistic regression analysis showed that the apoB/apoA-I ratio and apoB were significant and independent determinants of MI (exponentiation of the B coefficient [Exp(β)] 3.1, 95% confidence interval [CI] 1.6-6.3, P=.001, Exp(β) 2.8, 95% CI 1.1-7.7, P=.045, respectively). The area under the receiver-operating characteristics curve as a relative measure of test efficiency was highest and significant for both apoB/apoA-I ratio and apoB (area under the curve=0.75, P<.001). In conclusion, the apoB/apoA-I ratio and apoB are independent risk factors for MI and has the highest efficiencies for predicting MI in initially healthy middle-aged men.

Self-reported faster eating is positively associated with accumulation of visceral fat in middle-aged apparently healthy Japanese men

Faster eating is positively associated with body mass index in apparently healthy Japanese populations. In the present study, we examined the associations between self-reported rate of eating and visceral and subcutaneous fat areas in apparently healthy middle-aged Japanese men. We conducted a cross-sectional study of men who participated in health checkups in Japan. We removed participants who were diagnosed with metabolic diseases by the time of their health checkups. A total of 320 subjects aged 30-64 years (mean ± standard deviation, 47.4 ± 8.6 years) were selected. We compared the associations between rate of eating and various clinical parameters including visceral and subcutaneous fat areas, using analysis of covariance (ANCOVA), which was adjusted by age and lifestyle factors such as alcohol intake, energy intake, smoking, and physical activity. Multivariate logistic regression analyses (MLRA) were performed with visceral fat area (cm(2)) as the dependent variable and independent variables that included self-reported rate of eating. Tukey's multiple test following ANCOVA showed that self-reported rate of eating was positively associated with visceral fat area (cm(2)), but not with subcutaneous fat area (cm(2)). MLRA showed that the odds ratio of rate of eating for visceral fat area in tertile (T) 3 (>100 cm(2)) compared with T1 (≤70 cm(2)) was 1.99 (95% CI 1.40-2.90, P < 0.01), and the association remained after adjustment for the subcutaneous fat area. The present results show that self-reported faster eating is positively associated with visceral fat accumulation, independently of subcutaneous fat accumulation, in apparently healthy Japanese men.

Triiodothyronine and Free Thyroxine Levels are Differentially Associated with Metabolic Profile and Adiposity-Related Cardiovascular Risk Markers in Euthyroid Middle-Aged Subjects

We have previously shown that in healthy young men, a less favorable body composition is associated with higher free triiodothyronine (fT3) levels within the euthyroid range. Besides, a higher free-triiodothyronine-to-free-thyroxin (fT3-to-fT4) ratio has been related to a less favorable metabolic phenotype and more placental growth in pregnant women. In the present study, we therefore investigated whether serum thyrotropin (TSH), thyroid hormone levels, and the fT3-to-fT4 ratio are associated with metabolic and adiposity-related cardiovascular risk markers in a healthy population of middle-aged euthyroid men and women. Thyroid parameters were measured in 2524 generally healthy subjects from the Asklepios Study (35-55 years, mean age 46 years). Analyses were restricted to 2315 subjects (1138 women and 1177 men), not using thyroid medication, not having anti-TPO levels above clinical cutoff values or TSH levels outside the reference range (0.27-4.2 mU/L). Twenty-seven percent of the women and 47.5% of the men were overweight, while 13% of women and 17% of men were obese. Twenty percent of the subjects were active smokers. Serum thyroid function parameters were determined by electrochemiluminescence. fT3 and the fT3-to-fT4 ratio were positively related to body mass index (BMI), waist circumference, and components of metabolic syndrome, that is, triglycerides, systolic and diastolic blood pressure, and fasting plasma glucose, and negatively with HDL-cholesterol levels, whereas fT4 was negatively associated with BMI, waist circumference, and triglycerides (p<0.001). TSH related positively with total cholesterol levels (p<0.01), triglycerides, and systolic and diastolic blood pressure (p<0.001). The fT3-to-fT4 ratio was further positively associated with the adiposity-related inflammation markers interleukin-6 and high-sensitivity C-reactive protein and to pulse wave velocity. All associations were adjusted for sex, age, height, and smoking, and most associations persisted after additional adjustment for weight or waist circumference. In healthy euthyroid middle-aged men and women, higher fT3 levels, lower fT4 levels, and thus a higher fT3-to-fT4 ratio are consistently associated with various markers of unfavorable metabolic profile and cardiovascular risk.

Effects of body position and sex group on tongue pressure generation

Fine control of orofacial musculature is necessary to precisely accelerate and decelerate the articulators across exact distances for functional speech and coordinated swallows (Amerman &amp; Parnell, 1990; Benjamin, 1997; Kent, Duffy, Slama, Kent, &amp; Clift, 2001). Enhanced understanding of neural control for such movements could clarify the nature of and potential remediation for some dysarthrias and other orofacial myofunctional impairments. Numerous studies have measured orolingual force and accuracy during speech and nonspeech tasks, but have focused on young adults, maximum linguapalatal pressures, and upright positioning (O’Day, Frank, Montgomery, Nichols, &amp; McDade, 2005; Solomon &amp; Munson, 2004; Somodi, Robin, &amp; Luschei, 1995; Youmans, Youmans, &amp; Stierwalt, 2009). Patients’ medical conditions or testing procedures such as concurrent neuroimaging may preclude fully upright positioning during oral motor assessments in some cases. Since judgments about lingual strength and coordination can influence clinical decisions regarding the functionality of swallowing and speech, it is imperative to understand any effects of body positioning differences. In addition, sex differences in the control of such tasks are not well defined. Therefore, this study evaluated whether pressures exerted during tongue movements differ in upright vs. supine body position in healthy middle-aged men and women. Twenty healthy middle-aged adults compressed small air-filled plastic bulbs in the oral cavity at predetermined fractions of task-specific peak pressure in a randomized block design. Tasks including phoneme repetitions and nonspeech isometric contractions were executed in upright and supine positions. Participants received continuous visual feedback regarding targets and actual exerted pressures. Analyses compared average pressure values for each subject, task, position, and effort level. Speech-like and nonspeech tongue pressures did not differ significantly across body position or sex groups. Pressure matching was significantly less accurate at higher percentages of maximum pressure for both tasks. These results provide preliminary comparative data for the clinical assessment of individuals with orofacial myofunctional and neurological disorders.

Is Low Testosterone Concentration a Risk Factor for Metabolic Syndrome in Healthy Middle-aged Men?

To clarify the probability of low serum testosterone level as a risk factor for metabolic syndrome (MS) in middle-aged men, we measured serum total testosterone (TT) and assessed several metabolic factors because the direct risk for MS has not been investigated fully in men. This study comprised 1150 men aged≥30 years. Physical and laboratory variables were assessed. Analyses were conducted to determine the association between serum TT level and incidence risk of MS and MS factors by a separate logistic regression model. Mean (± standard deviation [SD]) serum TT level was 5.4 ± 1.7 ng/mL in the 1150 men, and only 92 men (8.0%) were classified as having MS by the Japanese criteria. In age-adjusted analyses, higher levels of serum TT were independently associated with a lower risk of MS (odds ratio, per SD decrement of TT, 2.3; 95% confidence interval [CI], 1.7-2.9). MS risk increased by lower quintile of TT: ORs were 15.1 (95% CI, 4.6-50.0) for first quintile, 8.8 (95% CI, 2.6-29.9) for second quintile, 5.8 (95% CI, 1.7-20.5) for third quintile, and 5.0 (95% CI, 1.4-17.9) for fourth quintile compared with highest quintile of TT. Age-adjusted ORs for the incidence of dichotomous components of MS per SD decrement of TT were 1.8 (95% CI, 1.5-2.3) for waist circumference, 1.6 (95% CI, 1.1-2.2) for dyslipidemia, and 1.5 (95% CI, 1.2-1.8) for hypertension. We found that higher probability of MS was associated with lower levels of serum TT level in relatively healthy middle-aged Japanese men.

Life style and longevity among initially healthy middle-aged men: prospective cohort study.

BackgroundFew studies have examined how various lifestyle factors in midlife predict longevity, and none of these studies have examined the impact of physical fitness. The present study aimed to examine longevity in relation to smoking, overweight and physical fitness.MethodsWe prospectively studied longevity (defined as reaching at least 85 years of age) in relation to smoking status, body mass index and physical fitness in 821 healthy men between 51 and 59 years of age. Of these, 369 were smokers, 320 were overweight, and 31 were obese. The associations were adjusted for age, systolic blood pressure and cholesterol level, using multivariate logistic regression analysis. Deaths were registered until the 31st of December, 2006. Physical fitness was measured as the total work performed in a maximal exercise tolerance bicycle test.Results252 men survived to the age of 85 years (30.7%). Smoking status was significantly and independently related to longevity; 37.2% of the non-smokers survived to the age of 85, and 22.8% of the smokers. Among non-smokers, overweight and physical fitness were significantly and independently related to longevity after adjustment for age, blood pressure and cholesterol level, but not among smokers. Among non-smokers with high physical fitness, 48.8% reached the age of 85 years, compared to 27.9% among non-smokers with low physical fitness.ConclusionLifestyle variables appear to be strong and independent predictors of longevity in initially healthy middle-aged men. The probability of longevity may be a useful concept when informing the general public about the benefits of a healthy lifestyle.

Differences in Adiponectin Gene Expression: Adiponectin Gene Expression is Higher in Gluteal than in Abdominal Adipose Tissue

Objective: Obesity down regulated the adiponectin gene expression, but differences in adiponectin gene expression in gluteal adipose tissue (GAT) and in abdominal adipose tissue (AAT) are not well known. Therefore, the purpose of this study was to examine the differences in adiponectin gene expression in GAT and in AAT. Material &amp; Methods: Nineteen healthy obese middle aged men (aged 41.4±6.1 years; mean ± SD) Adipose tissue (AT) biopsies from the subcutaneous abdominal and subcutaneous gluteal depots were obtained. Results: Adiponectin gene expression was 22.7% higher in subcutaneous GAT than in subcutaneous AAT. Conclusion: Adiponectin gene expression is higher in GAT than in AAT, suggesting GAT to be more important for circulating adiponectin levels. DOI: http://dx.doi.org/10.3126/ajms.v5i1.4412 Asian Journal of Medical Science Vol.5(1) 2014 pp.34-38

Low Heart Rates Predict Incident Atrial Fibrillation in Healthy Middle-Aged Men

Low resting heart rate (HR) has been associated with atrial fibrillation (AF) in athletes. We aimed to study whether low HR at rest or during exercise testing was a predictor of AF in initially healthy middle-aged men. A total of 2014 healthy Norwegian men participated in a prospective cardiovascular survey, including a standardized bicycle exercise test in 1972 to 1975. During ≤35 years of follow-up (53,000 person-years of observation), 270 men developed incident AF, documented by scrutiny of health charts in all Norwegian hospitals. Risk estimation was analyzed with Cox proportional hazard models. Low exercise HR after 6 minutes exercise on the moderate workload of 100 W (HR100W) was a predictor of incident AF. Men with HR100W <100 beats per minute (n=260) were characterized by high physical fitness, low resting and low maximum HR, and they had 1.60-fold AF risk (95% confidence interval, 1.11-2.26) compared with men with HR100W ≥100 beats per minute when adjusted for age, systolic blood pressure, and physical fitness. Additional adjustment for relative heart volume slightly reduced the association. The subgroup of men (n=860) with hypertensive blood pressure measurements at baseline had the highest risk difference between low and high HR100W with hazard ratio 2.08 (1.19-3.45). Our data indicate that low exercise HR on a moderate workload is a long-term predictor of incident AF in healthy middle-aged men. Elevated baseline blood pressure substantially amplifies this risk. The present results suggest a relationship between increased vagal tone, high stroke volumes and incident AF, and particularly so in physically fit men.

Particle numbers of lipoprotein subclasses and arterial stiffness among middle-aged men from the ERA JUMP study

We examined the association between serum lipoprotein subclasses and the three measures of arterial stiffness i.e. (i) carotid-femoral pulse wave velocity (cfPWV) which is a gold standard measure of central arterial stiffness, (ii) brachial-ankle PWV (baPWV) which is emerging as a combined measure of central and peripheral arterial stiffness, and (iii) femoral-ankle PWV (faPWV) which is a measure of peripheral arterial stiffness. Among a population-based sample of 701 apparently healthy Caucasian, Japanese American and Korean men aged 40–49 years, concentrations of lipoprotein particles were assessed by nuclear magnetic resonance (NMR) spectroscopy, and PWV was assessed with an automated waveform analyzer (VP2000, Omron, Japan). Multiple linear regressions were performed to analyze the association between each NMR lipoprotein subclasses and PWV measures, after adjusting for cardiovascular risk factors and other confounders. A cut-off of p<0.01 was used for determining significance. All PWV measures had significant correlations with total and small low-density lipoprotein particle number (LDL-P) (all p<0.0001) but not LDL-cholesterol (LDL-C) (all p>0.1), independent of race and age. In multivariate regression analysis, no NMR lipoprotein subclass was significantly associated with cfPWV (all p>0.01). However, most NMR lipoprotein subclasses had significant associations with both baPWV and faPWV (p<0.01). In this study of healthy middle-aged men, as compared to cfPWV, both baPWV and faPWV had stronger associations with particle numbers of lipoprotein subclasses. Our results may suggest that both baPWV and faPWV are related to arterial stiffness and atherosclerosis, whereas cfPWV may represent arterial stiffness alone.

Triglycerides-diabetes association in healthy middle-aged men: Modified by physical fitness?: A long term follow-up of 1962 Norwegian men in the Oslo Ischemia Study

AimsTo examine the impact of physical fitness (PF) on the association between fasting serum triglycerides (FTG) and diabetes risk and whether temporal changes in FTG predict diabetes risk in healthy middle-aged men. MethodsFTG and PF (bicycle exercise test) were measured in 1962 men aged 40–59 years in 1972–1975 (Survey 1) and repeated in 1387 still healthy men on average 7.3 years later (Survey 2). Diabetes was diagnosed according to WHO 1985-criteria. ResultsDuring 35 years follow-up 202/1962 (10.3%) men developed diabetes. Compared with the lowest, the upper FTG tertile had a 2.58-fold (95% CI: 1.81–3.74) diabetes risk adjusted for age, fasting blood glucose and maternal diabetes, and a 2.29-fold (95%CI: 1.60–3.33) when also adjusting for PF. Compared with unchanged (±25%) FTG levels (n=664), FTG reduction of more than 25% (n=261) was associated with 56% lower (0.44; 95% CI: 0.24–0.75) diabetes risk, while FTG increase of more than 25% (n=462) was associated with similar risk. These associations were unchanged when adjusted for PF and PF change. ConclusionsHigh FTG-levels predicted long-term diabetes risk in healthy middle-aged men, and the association was only modestly weakened when adjusted for PF. A reduction in FTG was associated with decreased diabetes risk.

Comparison of normal fasting and one-hour glucose levels as predictors of future diabetes during a 34-year follow-up

Introduction. Early identification of those at risk of developing type 2 diabetes (T2DM) is essential. We examined how normoglycemic levels of fasting blood glucose (FBG) and 1-hour glucose predict the development of diabetes among men initially at low risk.Methods. In the Helsinki Businessmen Study (men born in 1919– 1934), 1,145 men had normal FBG (< 5.0 mmol/L) in 1974, and 1-hour glucose values available. Multivariate, adjusted models were used to investigate how fasting and 1-hour glucose at baseline related to new-onset diabetes during a follow-up of 34 years.Results. The median FBG and 1-hour glucose values at baseline were 4.4 and 6.6 mmol/L, respectively. During follow-up, 108 men developed diabetes. The risk of incident diabetes was doubled for the highest quintile of FBG (fully adjusted relative risk (RR) 2.22, 95% confidence interval (CI) 1.10–4.50), and quadrupled for that of 1-hour glucose (RR 4.23, 95% CI 2.49–7.17). FBG could not separate the risk for those with higher levels of glucose in the range < 5.0 mmol/L, whereas 1-hour glucose discriminated the risk better at higher values.Conclusions. Higher values in the normoglycemic range for both fasting and 1-hour glucose predicted long-term incidence of diabetes in healthy middle-aged men.

External validation of the 2008 Framingham cardiovascular risk equation for CHD and stroke events in a European population of middle-aged men. The PRIME study

ObjectiveTo test the applicability of the sex-specific 2008 Framingham general cardiovascular risk equation for coronary heart disease (CHD) and stroke in European middle-aged men from Ireland and France. MethodsIn the PRIME study, 9638 healthy middle-aged men recruited in France and Ireland were surveyed for 10years for the occurrence of first CHD and stroke events. The original Framingham equation, the partially calibrated Framingham equation (using the PRIME baseline survival at 10years), and the completely calibrated Framingham equation (additionally using risk factor means calculated in PRIME) were assessed. Model fit (expected versus observed events) and discrimination ability were assessed using a modified Hosmer–Lemeshow Chi-square statistic and Harrell's c-index respectively. ResultsThe original (uncalibrated) Framingham equation overestimated by 1.94-fold the risk of CHD and stroke combined in PRIME, and by 2.23 and 1.42-fold in PRIME-France and PRIME-Ireland respectively. Adequate fit was found after complete calibration. However, discrimination ability of the Framingham equation was poor as shown by Harrell's c-index lower than 0.70. ConclusionThe (completely) calibrated 2008 Framingham equation predicted accurate number of CHD and stroke events but discriminated poorly individuals at higher from those at lower event risk in a European population of middle-aged men.

Associations of (F)T3and the ratio FT3:FT4with a cluster of obesity-related cardiovascular risk markers in healthy euthyroid middle-aged men and women

Associations of (F)T₃and the ratio FT₃:FT₄with a cluster of obesity-related cardiovascular risk markers in healthy euthyroid middle-aged men and women

Lycopene Concentrate Supplementation Decreases Plasma Values for C‐Reactive Protein and Oxidized LDL

Various lines of indirect evidence suggest that lycopene can exert anti‐inflammatory effects relevant to problems such as cardiovascular disease (CVD). However, a beneficial influence for lycopene supplementation on measures relevant to inflammation remain largely lacking. In the present study, a lycopene rich extract from tomato (20 mg lycopene/day in Lyc‐O‐Mato® tomato lycopene complex), or placebo, was given to healthy middle aged men for 6 weeks (N = 10 per group). Subjects did not have to follow a low lycopene diet, but a preliminary screening eliminated people with a history of frequent tomato product intake. In the lycopene group, plasma c‐reactive protein concentrations, which rise with CVD‐relevant inflammation, showed a mean decrease of almost 30% (p &lt; 0.05, 2‐tailed paired t‐test). Placebo gave no statistically significant effect. Lycopene also produced a mean decrease of 5.1% in plasma oxidized LDL values, an atherosclerosis‐related measure that can be increased by inflammation (p &lt; 0.05, 2‐tailed paired t‐test). Although this percent decrease was not tremendously large, longer intervention periods and/or combination with other natural products may heighten the effect. Again, placebo was ineffective. Neither of the lycopene effects was boosted by adding supplementation with zinc arginate (15 mg zinc/day) + selenium (200 μg selenium/day) in another group of subjects. These mineral supplements did improve zinc and selenium functional status based on two measures for each mineral. In summary, in a small study, supplementation with a tomato extract‐lycopene by itself produced changes in two cardiovascular disease‐relevant measures related to inflammation.

Seven-Year Increase in Exercise Systolic Blood Pressure at Moderate Workload Predicts Long-Term Risk of Coronary Heart Disease and Mortality in Healthy Middle-Aged Men

Exercise systolic blood pressure (SBP) predicts coronary heart disease (CHD) in the general population. We tested whether changes in exercise SBP during 7 years predict CHD (including angina pectoris, nonfatal myocardial infarction, and fatal CHD) and mortality over the following 28 years. Peak SBP at 100 W workload (=5.5 METS [metabolic equivalents]; completed by all participants) was measured among 1392 apparently healthy men in 1972-75 and repeated in 1979-82. The men were divided into quartiles (Q1-Q4) of exercise SBP change. Relative risks were calculated using Cox proportional hazard regression adjusting for family history of CHD, age, smoking status, resting SBP, peak SBP at 100 W, total cholesterol at first examination (model 1), and further for physical fitness and change in physical fitness (model 2). The highest quartile, Q4, was associated with a 1.55-fold (95% confidence interval, 1.17-2.03) adjusted (model 1) risk of CHD and a 1.93-fold (1.24-3.02) risk of coronary heart death compared with the lowest, Q1. Q4 had a 1.40-fold (1.06-1.85) risk of CHD and a 1.70-fold (1.08-2.68) risk of coronary heart death using model 2. Q4 was associated with increased risk of cardiovascular death and all-cause death compared with Q1 in model 1, but not in model 2. Our results indicate that an increase in exercise SBP at 100 W over 7 years is independently associated with increased long-term risk of CHD and substantiate our previous finding that high exercise SBP is an important risk factor for CHD in healthy men.

Sildenafil Increases Sympathetically Mediated Vascular Tone in Humans

Sildenafil, a selective phosphodiesterase-type-5 (PDE-5) inhibitor, produces vasodilation that improves erectile dysfunction and pulmonary hypertension. Sildenafil could also cause baroreflex sympathetic activation that would enhance vascular tone and oppose direct vasodilation. We tested the hypothesis that sildenafil administration increases sympathetically mediated vascular tone in healthy middle-aged men. We randomized 9 healthy, middle-aged, male volunteers (mean age 45±2 years) in a double-blind, crossover fashion to receive a single oral dose of sildenafil 100mg or placebo on 2 separate study days. Hemodynamics and forearm blood flow responses were measured at baseline, at 30 and 45 minutes after study drug administration, and then during intra-arterial infusions of vasoactive drugs. After sildenafil and placebo administration, intrabrachial medications were infused to test forearm alpha receptor sensitivity (norepinephrine), cyclic-AMP-mediated vasodilation (isoproterenol), and sympathetically mediated vascular tone (phentolamine) (adenosine was a control vasodilator). Blood samples were taken before and 60 minutes after study drug administration and at the end of the intrabrachial infusions for measurement of plasma norepinephrine concentrations. Forearm vascular responses to norepinephrine, isoproterenol, and adenosine were not different after placebo and sildenafil administration. Percentage reduction in forearm vascular resistance during phentolamine was significantly lower after sildenafil than placebo (-73% ± 3% vs -63% ± 3%; P = 0.0002). Sildenafil significantly increased plasma norepinephrine compared with placebo 60 minutes after study drug administration and at the end of the study session (P = 0.02). Sildenafil increased sympathetically mediated vascular tone in middle-aged healthy men. Alpha-adrenergic-mediated vasoconstriction may offset vasodilation during PDE-5 inhibition and may explain the significant hypotension observed in patients taking alpha-blockers with sildenafil.